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Terlipressin Improves Renal Function and Reverses Hepatorenal Syndrome in Patients With Systemic Inflammatory Response Syndrome
Accepted Manuscript Terlipressin Improves Renal Function and Reverses Hepatorenal Syndrome in Patients with Systemic Inflammatory Response Syndrome Florence Wong, Stephen Chris Pappas, Thomas D. Boyer, Arun J. Sanyal, Jasmohan S. Bajaj, Shannon Escalante, Khurram Jamil
PII: DOI: Reference:
S1542-3565(16)30437-2 10.1016/j.cgh.2016.07.016 YJCGH 54837
To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 15 July 2016 Please cite this article as: Wong F, Pappas SC, Boyer TD, Sanyal AJ, Bajaj JS, Escalante S, Jamil K, on behalf of the REVERSE Investigators, Terlipressin Improves Renal Function and Reverses Hepatorenal Syndrome in Patients with Systemic Inflammatory Response Syndrome, Clinical Gastroenterology and Hepatology (2016), doi: 10.1016/j.cgh.2016.07.016. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Terlipressin Improves Renal Function and Reverses Hepatorenal Syndrome in Patients with Systemic Inflammatory Response Syndrome
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Short title: SIRS and Response to Terlipressin in HRS
Florence Wong,* Stephen Chris Pappas,‡ Thomas D. Boyer,§ Arun J. Sanyal,║ Jasmohan S. Bajaj,║ Shannon Escalante,¶ Khurram Jamil,¶ on behalf of the
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REVERSE Investigators
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*Department of Medicine, University of Toronto, Toronto, Ontario, Canada; ‡Orphan Therapeutics, Lebanon, New Jersey; §Department of Medicine, University of Arizona, Tucson, Arizona; ║Department of Medicine, Virginia Commonwealth University, Richmond, Virginia; ¶Ikaria Therapeutics LLC/a Mallinckrodt Company, Hampton,
Funding
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New Jersey
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This study was sponsored by Ikaria Therapeutics LLC/a Mallinckrodt Company. The
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sponsor participated in the design and conduct of the study, interpretation of study data, and writing of this report.
Abbreviations used in this paper: CHRSR, complete hepatorenal syndrome reversal; HRS-1, hepatorenal syndrome type 1; SCr, serum creatinine; SIRS, systemic inflammatory response syndrome.
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ACCEPTED MANUSCRIPT Address correspondence to: Florence Wong, 9EB/222 Toronto General Hospital, 200 Elizabeth Street, Toronto M5G2C4, ON, Canada. Telephone: 1-416-3403834; fax: 1-416-3405019; e-mail: [email protected].
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Conflicts of Interest
Florence Wong is a consultant for Ikaria Therapeutics LLC/a Mallinckrodt Company, has served on the advisory board for Grifols Inc., and has received grant support
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from Gilead Sciences. Stephen Chris Pappas is a consultant for Orphan
Therapeutics and Ikaria Therapeutics LLC/a Mallinckrodt Company. Thomas D.
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Boyer is a consultant for Ikaria Therapeutics LLC/a Mallinckrodt Company. Arun J. Sanyal has stock options in Genfit; has served as a consultant for AbbVie Inc., AstraZeneca, Exalenz Bioscience Ltd., FibroGen Inc., Genfit, Immuron Ltd, Ikaria Therapeutics LLC/a Mallinckrodt Company, Nimbus Therapeutics, Nitto Denko
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Corporation, Salix Pharmaceuticals, Takeda Pharmaceutical Company, and Tobira Therapeutics; and has been an unpaid consultant for Echosens and Intercept Pharmaceuticals. Jasmohan S. Bajaj has served as a consultant for Grifols Inc.,
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Norgine, and Salix Pharmaceuticals; his institution has received grants from Grifols
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Inc. and Salix Pharmaceuticals. Shannon Escalante and Khurram Jamil are employees of Ikaria Therapeutics LLC/a Mallinckrodt Company.
Acknowledgments
The authors would like to thank the REVERSE study investigators and study participants, as well as Peter Teuber, PhD, of Orphan Therapeutics for assistance with analysis and interpretation of the study data, and Michael Morren, MBA, RPh, of Peloton Advantage, LLC, for administrative and publishing support.
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Author Contributions Florence Wong, Stephen Chris Pappas, Thomas D. Boyer, Arun J. Sanyal, Jasmohan S. Bajaj, and Khurram Jamil collected data. Florence Wong, Stephen C.
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Pappas, Thomas D. Boyer, Arun J. Sanyal, Jasmohan S. Bajaj, and Khurram Jamil analyzed and interpreted the data. Shannon Escalante provided statistical analysis and support. Florence Wong, Stephen C. Pappas, Thomas D. Boyer, Arun J. Sanyal,
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Jasmohan S. Bajaj, and Khurram Jamil drafted the manuscript. All authors have read
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and approved the final version submitted and accept responsibility for its content.
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ACCEPTED MANUSCRIPT ABSTRACT BACKGROUND & AIMS: Patients with systemic inflammatory response syndrome (SIRS) along with decompensated cirrhosis and renal dysfunction have a poor prognosis and a lower response to treatment. We evaluated the effect of SIRS on
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the response of hepatorenal syndrome type 1 (HRS1) to terlipressin.
METHODS: We performed a retrospective study of data from a trial of the effects of
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terlipressin (1 mg every 6 hours or placebo with concomitant albumin) in 198 patients with HRS1, performed at 50 investigational sites in the United States and 2 in
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Canada from October 2010 through February 2013. We identified patients with 2 or more criteria for SIRS, without untreated infections (28 received terlipressin and 30 received placebo), as well as patients with less than 2 criteria for SIRS (controls). Primary endpoints included HRS reversal (a decrease in serum level of creatinine to
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≤1.5 mg/dL), confirmed HRS reversal (defined as 2 serum creatinine levels ≤1.5 mg/dL, ≥ 48 hours apart), and survival for 90 days after treatment.
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RESULTS: Baseline characteristics were similar between groups, apart from slightly
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higher white blood cell counts and heart rates, and slightly lower serum levels of bicarbonate in patients with SIRS vs without SIRS. HRS was reversed in 42.9% of patients who received terlipressin with SIRS (12/28) vs 6.7% of patients who received placebo (2/30) (P=.0018); confirmed HRS reversal occurred in 32.1% of patients who received terlipressin with SIRS (9/28) vs 3.3% who received placebo (1/30) (P=.0048). A larger proportion of patients with SIRS who received terlipressin survived for 90 days without a transplant (13/28, 46.4%) than patients with SIRS who received placebo (7/30, 23.3%) (P=.076).
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Conclusion: In an analysis of data from a placebo-controlled study, we found that terlipressin improved renal function and reversed HRS in a higher proportion of
ClincialTrials.gov, number NCT01143246.
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patients with HRS1 and SIRS than patients who received albumin plus placebo.
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Keywords: HRS-1; renal dysfunction; REVERSE trial; cirrhosis
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ACCEPTED MANUSCRIPT The systemic inflammatory response syndrome (SIRS) is a non-specific inflammatory response to various insults such as trauma, ischemia, or infection.1 SIRS occurs frequently in patients with decompensated cirrhosis,2,3 possibly related to increased translocation of bacteria and their breakdown products across the gut
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wall,4 independent of an obvious infection.5 Many of these bacterial products can stimulate the production of various inflammatory cytokines from immune cells.6.
Pathophysiologically, many of these cytokines can initiate an inflammatory cascade,
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resulting in a pro-coagulant response, especially in the microcirculation. This
ultimately leads to the development of micro-thrombi and loss of circulatory integrity,7
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contributing to the development of multi-organ failure in patients with SIRS.8 Indeed, the severity of the systemic inflammation and the magnitude of the immune response have been identified as predictors of poor patient outcome.2,9
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Hepatorenal syndrome type 1 (HRS-1) is a unique form of acute kidney injury observed in advanced cirrhosis and ascites10 with a high mortality risk if left untreated.11 Traditionally, the pathogenesis of HRS-1 is attributed to abnormal
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hemodynamics of decompensated cirrhosis,12 which ultimately lead to decreased
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renal blood flow and reduced glomerular filtration. The fact that treatments aimed at correcting the hemodynamic abnormalities do not reverse the majority of cases of HRS-113,14 suggests that other pathogenetic factors may also be involved. It has been proposed that inflammation with various inflammatory cytokines can induce changes in the renal microcirculation and bring about an increase in oxidative stress, thereby causing renal tubular damage, especially in the presence of infection.16 Bacterial infections, the most common precipitant of HRS-1 in cirrhosis,17 are associated with an intense inflammatory response. Therefore, it is plausible that the
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ACCEPTED MANUSCRIPT presence of SIRS in patients with cirrhosis and HRS-1 may adversely affect the response to vasoconstrictor therapy, although this has never been reported.
The REVERSE study was a phase 3, randomized, placebo-controlled study of
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patients with decompensated cirrhosis and HRS-1 treated with terlipressin or
placebo, both with concomitant albumin. Since patients with ≥2 SIRS criteria without a current uncontrolled infection were included, an evaluation of this subgroup was
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considered important, particularly because of concern for the inadvertent enrollment of patients with covert sepsis and the reported poorer prognosis of patients with ≥2
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SIRS criteria.3. Thus, the aims of this post-hoc study were 1) to evaluate the effects of SIRS on the response to terlipressin in patients with decompensated cirrhosis and HRS-1, and 2) to determine the effects of SIRS on the 90-day survival of these
Methods
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patients.
This study employs the data collected in the REVERSE study (clinical trial
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registration identifier NCT01143246; ClinicalTrials.gov), which was conducted at 50
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investigational sites in the United States and 2 in Canada from October 2010 to February 2013. The REVERSE study design, protocol, and ethical oversight have previously been described.18 Briefly, patients with HRS-1, as defined by the International Club of Ascites,12 without uncontrolled infection, were included and randomized to receive terlipressin, 1 mg every 6 hours or placebo via slow intravenous bolus injections for up to 16 days, together with albumin 20 to 40 g/d for both treatment groups. The terlipressin dose was doubled after a minimum of 10 doses on Day 4 if the serum creatinine (SCr) had not decreased by at least 30%
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ACCEPTED MANUSCRIPT from the baseline value. The study endpoints included HRS-1 reversal, defined as a decrease in SCr to ≤1.5 mg/dL while on treatment, confirmed HRS-1 reversal (CHRSR), defined as 2 SCr levels of ≤1.5 mg/dL at least 48 hours apart while on treatment, and 90-day survival. Patients were then followed for 90 days to evaluate
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the rates of liver transplantation and renal replacement therapy, as well as survival. The study also collected 3 of the 4 SIRS parameters1 at enrollment, namely, a heart rate of >90 beats/min, a white blood cell count of <4 or >12 x 109/L, and a serum
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bicarbonate of <21 mmol/L, which was used as a surrogate for partial arterial
pressure of CO2 of <32 mm Hg.19 The fourth parameter, body temperature, was
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subsequently requested and available for 129 patients. Patients were separated into those meeting ≥2 SIRS criteria and those meeting <2 SIRS criteria at enrollment; they were evaluated with respect to response to terlipressin treatment and 90-day
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survival.
All authors had access to the study data and reviewed and approved the final
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manuscript.
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Statistical Analysis
All efficacy analyses were based on the intent-to-treat population, defined as all randomized patients who had ≥1 baseline assessment. The safety population was defined as all randomized patients who received ≥1 dose of study medication (terlipressin or placebo). The incidence rates for patients with HRS reversal and CHRSR were analyzed using the Cochran-Mantel-Haenszel chi-square test. An analysis of variance with main effect treatment for continuous variables and a Cochran-Mantel-Haenszel test for general association for discrete variables were
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ACCEPTED MANUSCRIPT used for comparisons of the SIRS group versus the non-SIRS group and terlipressin versus placebo within groups (see Tables 1 and 2). Transplant-free and overall survival at 90 days were analyzed using a 2-sample log rank test stratified by qualifying SCr level. SCr changes from baseline to the end of treatment were
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evaluated using a repeated measures analysis of covariance, with treatment as a main effect and qualifying SCr level and day as covariates. The frequency of adverse
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events and other safety events were summarized descriptively.
Results
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196 patients who fulfilled all inclusion criteria were enrolled. Of these, 97 patients were randomized to receive terlipressin and 99 to receive placebo. In all, 58 patients (30%) met ≥2 SIRS criteria and were termed “the SIRS group” (terlipressin: n=28, placebo: n=30). The remaining 138 patients were termed “the non-SIRS group,” 69
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(50%) were randomized to receive terlipressin and 69 (50%) to receive placebo.
Baseline demographic and laboratory data for all the patients are shown in Table 1.
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All patients who had infections in the 14 days prior to enrollment had received
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appropriate antibiotics and did not have sepsis at the time of enrollment. There was no significant difference in the acute-on-chronic liver failure grade or the proportion of patients on antibiotics between the SIRS and Non-SIRS subgroups at baseline (Supplementary Table 1). Significantly more patients in the SIRS subgroup (19/58 [32.8%]) had alcoholic hepatitis versus the non-SIRS group (26/138 [18.8%]; P = .035). A significantly higher mean [±SD] heart rate (85 [±13] vs. 77 [±12] beats/min; P = .0001), significantly higher mean [±SD] white blood cell count (9.9 [±7.6] vs. 6.8 [±2.8] x 109/L; P = .0001), and significantly lower mean [±SD] serum bicarbonate (17
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ACCEPTED MANUSCRIPT [±3] vs. 20 [±4] mmol/L; P = .0001) were observed in the SIRS group versus the nonSIRS group. However, no difference in the baseline mean [±SD] temperature (36.5°C [± .4] vs. 36.6°C [± .6]; P = NS) was observed between the two groups of
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patients.
HRS-1 Treatment Response
Terlipressin was administered for a mean (±SD) duration of 6.0 (±4.9) days (SIRS
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group: 7.8 [±6.8] days; non-SIRS group: 5.3 [±3.9] days), and placebo was
administered for a mean (±SD) duration of 5.9 (±4.1) days (SIRS group: 7.2 [±4.5]
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days; non-SIRS group: 5.8 [±3.8] days). Overall, 22.4% (13/58) of patients in the SIRS group and 32.6% (45/138) in the non-SIRS group received their assigned treatment for ≤3 days (P = .17) because of liver transplant, initiation of renal replacement therapy, adverse events, or lack of response. The total terlipressin or
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placebo doses administered in the SIRS group were higher than those administered in the non-SIRS group (Table 2), but there was no significant difference in mean doses of albumin used. This appeared to be related to more patients in the non-SIRS
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group discontinuing the study drug either at Day 4 because of a lack of response
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(SCr at or above baseline after 3 days of treatment) or because of adverse events (Supplementary Table 2).
Amongst the SIRS patients, despite the fact that both SIRS subgroups received similar doses of terlipressin or placebo and albumin, there was a significantly higher rate of HRS-1 reversal in response to terlipressin compared to placebo (Figure 1A). Such a difference was not observed between the terlipressin versus the placebo subgroups in the non-SIRS patients (Figure 1A). The same improved renal
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ACCEPTED MANUSCRIPT response with terlipressin compared with placebo was also noted among the SIRS group with respect to confirmed HRS reversal (Figure 1B). Furthermore, only the SIRS group but not the non-SIRS group showed a significantly greater mean reduction in SCr with terlipressin between end-of-treatment and baseline (Figure
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1C).
Other Clinical Outcomes
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Many complications were recorded during the study period. However, the overall frequency of adverse events and serious adverse events was similar between the
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SIRS group and the non-SIRS group. During the study, 6 patients in the SIRS group (terlipressin: n=3 [10.7%]; placebo: n=3 [10%]) and 18 (13%) patients in the nonSIRS group (terlipressin: n=15 (21.7%); placebo: n=3 (4.6%) discontinued treatment because of adverse events (Supplementary Table 2). Table 3 shows the important
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severe adverse events that occurred during the treatment period. No significant difference was observed between the SIR and non-SIRS groups with respect to the
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Survival
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frequency of clinically important adverse events.
In the SIRS group, 2 patients who received terlipressin underwent a liver transplant up to Day 90 compared with 8 patients who received placebo. In the non-SIRS group, 27 patients receiving terlipressin and 24 receiving placebo underwent a liver transplant up to Day 90. The overall 90-day survival was not significantly different between the SIRS and non-SIRS groups, irrespective of whether patients received terlipressin or placebo. However, there was a trend toward an improved 90-day transplant-free survival in the SIRS group who received terlipressin (46.4% [13/28]
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ACCEPTED MANUSCRIPT versus those who received placebo (23.3% [7/30]; P = .076). No such trend was observed in the non-SIRS group between patients receiving terlipressin versus placebo (Figure 2). Causes of death included multi-organ failure, end-stage liver
between the SIRS versus the non-SIRS groups.
DISCUSSION
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disease, infection, respiratory failure, and renal failure, with no differences observed
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SIRS is known to occur in a significant number of patients with decompensated cirrhosis,2,3 and is associated with a negative impact on patient outcome,2,20
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especially in patients with renal dysfunction.3 The REVERSE study,21 a treatment study for HRS-1, did not show a greater efficacy for terlipressin plus albumin versus placebo plus albumin in reversing HRS-1, contrary to expectations. The question is then raised as to whether the presence of SIRS could have contributed to the
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negative outcome in the REVERSE study.21 Therefore, it was necessary to compare the response to terlipressin plus albumin in patients with HRS-1 and SIRS versus those without SIRS. The results demonstrate that patients with HRS-1 and SIRS had
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an improved response to terlipressin plus albumin compared with placebo plus
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albumin, whereas no such difference was observed in the non-SIRS group. Furthermore, the presence of SIRS also had a positive impact on renal function in patients who received terlipressin plus albumin, with significantly more patients achieving CHRSR. There was also a trend toward increased 90-day transplant-free survival in the same patients, compared with those who received placebo plus albumin as well as those in the non-SIRS group.
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ACCEPTED MANUSCRIPT These unexpected findings seem to contradict previously published reports of SIRS conferring a negative impact on patient outcomes.2,3 However, a recent small study demonstrating the effectiveness of terlipressin in improving renal function and reversing HRS-1 in patients with cirrhosis and sepsis22 seems to support our
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findings, as these patients by definition had to have significant inflammation.
Although SIRS has been withdrawn from the latest SEPSIS 3 definition,23 we feel that these findings related to SIRS are important in this population of patients, as the
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presence of SIRS represents a subgroup with inflammation and therefore may behave differently. The mechanisms whereby SIRS could improve the renal
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response to terlipressin plus albumin are not obvious. The SIRS and non-SIRS groups had similar severity of renal dysfunction at enrollment. Their infection history and antibiotic use in the immediate pre-enrollment period were also similar. It is possible that the longer treatment duration in the SIRS group, and therefore a higher
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total terlipressin dose together with a higher albumin dose, could have contributed to the improved renal function in the SIRS group. However, the reported elimination half-life for terlipressin is 50 minutes and the effective half-life of terlipressin is 6
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hours.24 There are no published data to support a hypothesis that a higher
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cumulative dose of terlipressin will yield an improved renal response. The lack of increased effects on regional hemodynamics with higher doses of terlipressin has been reported in an animal model of sepsis.25 The fact that terlipressin 2 mg, administered as a bolus intravenously in cirrhotic patients, provides the same portal hypotensive effect as a terlipressin 1 mg bolus dose26 also suggests that there are minimal additional effects with higher doses in humans. However, this will need to be formally studied.
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ACCEPTED MANUSCRIPT The fact that the presence of SIRS improved the renal response to terlipressin in patients with HRS-1 is an intriguing observation. Terlipressin improves renal function in HRS-1 by virtue of its vasoconstrictive effects on the systemic and the splanchnic circulations. In the systemic circulation, terlipressin induces arterial vasoconstriction
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and increases the systemic vascular resistance.24 The improvement in mean arterial pressure and hence renal perfusion pressure can improve the renal circulation and glomerular filtration. Indeed, an increase in mean arterial pressure has been
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identified as a predictor of renal response to terlipressin in patients with HRS-127,28 Terlipressin also induces vasoconstriction in the mesenteric arterioles, thereby
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reducing portal inflow and hence portal pressure29 However, in the presence of SIRS, terlipressin appears to produce and enhance renal response that may not be entirely explained by a possible reduction in portal pressure or an increase in renal
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perfusion pressure alone.
The presence of SIRS is associated with increased levels of various inflammatory cytokines.30 Patients with cirrhosis have higher levels of circulating endotoxins,
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possibly related to increased bacterial translocation across the gut wall as a result of
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portal hypertension,31 and increased intestinal permeability. The bacterial stimulus promotes the production of many pro-inflammatory cytokines, especially tumornecrosis factor-α and interleukin 632 and substances that cause vasodilatation such as nitric oxide. The bacterial translocation tends to worsen with progression of cirrhosis, occurring in at least 30% of patients with decompensated cirrhosis.4 Therefore, it is feasible that with the likely reduction of portal pressure with terlipressin, there may a reduction of bacterial translocation, with consequent reduction in endotoxemia and in production of pro-inflammatory cytokines. It is
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ACCEPTED MANUSCRIPT possible that the reduction in pro-inflammatory cytokines with terlipressin is amplified in the presence of SIRS. Alternatively, it has been suggested that terlipressin may have a direct anti-inflammatory action independent of it portal hypotensive effect.33
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It has been suggested that the effects of terlipressin are enhanced in the presence of infection and increased inflammation, independent of changes in pro-inflammatory cytokine levels.34 Using isolated aortic rings from animals with cirrhosis induced by
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bile duct ligation, terlipressin abolished the hyporesponsive reaction to
vasoconstrictors to a much greater degree in the presence of lipopolysaccharide, a
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product of gram-negative bacteria, compared with those without a lipopolysaccharide challenge.34 This exaggerated response with terlipressin in the presence of infection or inflammation mimics the enhanced renal response to terlipressin that we have observed with our patients with HRS-1. This may have been sufficient to lead to an
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improved 90-day transplant-free survival in the SIRS group who received terlipressin.
It appears that a subset of cirrhotic patients with HRS-1 and SIRS but without
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uncontrolled infection may benefit from receiving terlipressin. A limitation of the study
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is that it was not designed to evaluate the mechanisms involved in this improved renal response in the presence of SIRS. Thus, we can only propose the possible explanations for the results. SIRS, in the absence of infection, may prove to be an additional predictive factor that identifies a subgroup of patients with HRS-1 who would benefit from treatment with terlipressin.
In conclusion, SIRS is common in patients with advanced cirrhosis, ascites, and HRS-1. Despite being more ill, the proportion of patients with HRS-1 and SIRS in this
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ACCEPTED MANUSCRIPT study who responded to treatment with terlipressin was significantly greater than that for patients with SIRS who received placebo, and also for patients without SIRS.
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Future studies should explore the possible mechanisms involved.
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ACCEPTED MANUSCRIPT Figure Legends
Figure 1. Renal outcomes in response to treatment between the SIRS and nonSIRS groups: (A) percentage of patients with HRS-1 reversal, defined as 1 SCr
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reading of ≤1.5 mg/dL while on treatment, (B) percentage of patients with confirmed HRS-1 reversal, defined as 2 SCr readings of ≤1.5 mg/dL at least 48 hours apart while on treatment, and (C) the mean decrease in SCr in mg/dL. HRS-1, hepatorenal
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syndrome type 1; SCr, serum creatinine; SIRS, systemic inflammatory response
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syndrome.
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ACCEPTED MANUSCRIPT Figure 2. Transplant-free survival up to 90 days in the SIRS and non-SIRS groups,
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further separated by treatment assignment.
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24. Kam PC, Williams S, Yoong FF. Vasopressin and terlipressin: pharmacology and its clinical relevance. Anaesthesia 2004;59:993-1001. 25. Ishikawa K, Wan L, Calzavacca P, et al. The effects of terlipressin on regional hemodynamics and kidney function in experimental hyperdynamic sepsis. PLoS One 2012;7:e29693. 26. Escorsell A, Bandi JC, Moitinho E, et al. Time profile of the haemodynamic effects of terlipressin in portal hypertension. J Hepatol 1997;26:621-627.
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ACCEPTED MANUSCRIPT 27. Boyer TD, Sanyal AJ, Garcia-Tsao G, et al. Predictors of response to terlipressin plus albumin in hepatorenal syndrome (HRS) type 1: relationship of serum creatinine to hemodynamics. J Hepatol 2011;55:315-321. 28. Nazar A, Pereira GH, Guevara M, et al. Predictors of response to therapy with
syndrome. Hepatology 2010;51:219-226.
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terlipressin and albumin in patients with cirrhosis and type 1 hepatorenal
29. Narahara Y, Kanazawa H, Taki Y, et al. Effects of terlipressin on systemic,
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hepatic and renal hemodynamics in patients with cirrhosis. J Gastroenterol Hepatol 2009;24:1791-1797.
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30. Jaffer U, Wade RG, Gourlay T. Cytokines in the systemic inflammatory response syndrome: a review. HSR Proc Intensive Care Cardiovasc Anesth 2010;2:161175.
31. Giannelli V, Di Gregorio V, Iebba V, et al. Microbiota and the gut-liver axis:
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bacterial translocation, inflammation and infection in cirrhosis. World J Gastroenterol 2014;20:16795-16810.
32. Albillos A, Lario M, Alvarez-Mon M. Cirrhosis-associated immune dysfunction:
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distinctive features and clinical relevance. J Hepatol 2014;61:1385-1396.
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33. Zhao L, Brinton RD. Suppression of proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha in astrocytes by a V1 vasopressin receptor agonist: a cAMP response element-binding protein-dependent mechanism. J Neurosci 2004;24:2226-2235. 34. Moreau R, Barriere E, Tazi KA, et al. Terlipressin inhibits in vivo aortic iNOS expression induced by lipopolysaccharide in rats with biliary cirrhosis. Hepatology 2002;36:1070-1078.
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ACCEPTED MANUSCRIPT Table 1. Baseline Patient Demographics and Blood Levels a
SIRS group
b
Terlipressin
Placebo
Terlipressin
Placebo
28
30
69
69
56.3 (± 8.0)
54.1 (± 7.9)
55.6 (± 8.6)
55.2 (± 8.8)
Sex, male : female
13:15
22:8
39:30
45:24
Alcoholic hepatitis
7 (25)
12 (40)
13 (18.8)
13 (18.8)
MAP, mm Hg (± SD)
74.6 (± 11.5)
76.4 (± 10.8)
76.1 (± 12.0)
75.0 (± 10.5)
Heart rate, beats/min
83 (± 15)
86 (± 10)
78 (± 12)
76 (± 12)
n
13
20
45
51
o
C (± SD)
36.7 (± .4)
36.5 (± .4)
SCr, mg/dL (± SD)
3.7 (± 1.2)
3.7 (± 1.1)
Patients with SCr
16 (57.1)
14 (46.7)
n Age, y (± SD)
(± SD)
3.7 (± 1.1)
27 (39.1)
37 (46.4)
132 (± 5)
132 (± 6)
132 (± 6)
12.6 (± 11.7)
10.8 (± 11.2)
10.7 (± 10.3)
12.6 (± 13.4)
10.3 (± 7.4)
9.5 (± 7.9)
7.1 (± 2.9)
6.5 (± 2.7)
< .0001
< .0001
132 (± 7)
(± SD) -
Serum HCO3 , mmol/L
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9
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3.5 (± 1.0)
(± SD) WBC count x 10 /L
17 (± 3)
17 (± 3)
21 (± 4)
19 (± 4)
10.4 (± 1.83)
10.5 (± 1.88)
10.5 (± 1.80)
10.3 (± 1.67)
19 (67.9)
20 (66.7)
47 (68.1)
43 (62.3)
33.2 (± 7.4)
32.3 (± 5.7)
33.6 (± 5.8)
32.8 (± 5.4)
Pneumonia
0 (0)
1 (3.3)
6 (8.7)
2 (2.9)
Urinary tract
5 (17.9)
6 (20.0)
20 (29)
13 (18.8)
6 (21.4)
4 (13.3)
8 (11.6)
13 (18.8)
24
27
62
63
9.8±3.06
9.4±2.02
9.8±2.07
9.7±2.07
(± SD) Child-Pugh score
Child-Pugh class C, n (%)
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MELD score (± SD)
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(± SD)
Infection in the
previous 14 days, n (%)
infection Spontaneous bacterial peritonitis CLIF-SOFA Score (n) (±SD)
c
.0001
36.6 (± .6)
(± SD) Serum bilirubin, mg/dL
c
.0349
36.5 (± .5)
≥3.6 mg/dL, n (%) Serum sodium, mEq/L
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Temperature
P value
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Parameter
Non-SIRS group
23
c
c
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HCO3 , bicarbonate; MAP, mean arterial pressure; MELD, model for end-stage liver disease; SCr, serum creatinine; SIRS, systemic inflammatory response syndrome. a
Patients who met ≥2 SIRS criteria.
b
Patients who met <2 SIRS criteria.
c
SIRS versus non-SIRS, analysis of variance, with main effect treatment for continuous variables and
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a Cochran-Mantel-Haenszel test for general association for discrete variables.
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Table 2. Treatment Information and Medication Doses Used in the Study SIRS group Placebo
28
30
7.8 (± 6.8)
7.2 (± 4.5)
.73
34.7 (± 43.2)
36.1 (± 33.5)
.900
Total albumin dose, g (± SD)
197.8 (± 162.79)
293.1 (± 232.05)
.101
Mean daily albumin dose, g
48.9 (± 31.14)
48.0 (± 17.06)
83.1 (± 13.77)
74.2 (± 12.06)
7.6 (± 16.56)
2.5 (± 1.63)
N Treatment duration, days
value
69
5.3 (± 3.9)
5.8 (± 3.8)
.4918
.0068
23.3 (± 22.8)
.8076
.0067
181.5 (± 145.66)
222.3 (± 162.98)
.1513
.0836
.892
50.2 (± 23.62)
51.3 (± 27.82)
.8120
.5859
.014
80.7 (± 12.20)
75.3 (± 11.10)
.0095
.9395
−2.2 (± 11.08)
.012
4.6 (± 13.33)
.2 (± 10.53)
.0394
.9308
3.4 (± 1.80)
.090
3.2 (± 1.99)
3.6 (± 2.04)
.1930
.2370
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placebo) dose, mg (± SD)
mm Hg (± SD) ∆ MAP from baseline to end of SCr at end of treatment, mg/dL (± SD)
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treatment, mm Hg (± SD)
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(± SD) MAP at end of treatment,
valueb
69
22.2 (± 25.9)
value
P a
Placebo
(± SD) Total treatment (terlipressin/
P
Terlipressin
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Terlipressin
a
SC
Parameter
Non-SIRS group
P
a
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association for discrete variables. b
SIRS versus non-SIRS, analysis of variance, with main effect treatment for continuous variables and a Cochran-Mantel-Haenszel test for general association
for discrete variables.
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ACCEPTED MANUSCRIPT Table 3. Serious Adverse Events Reported Up to 30 Days Post-treatment SIRS group
Non-SIRS group
Placebo
Terlipressin
Placebo
25
30
68
65
4 (16.0)
1 (3.3)
8 (11.8)
4 (6.2)
Infection, n (%)
7 (28)
3 (10.0)
6 (8.8)
8 (12.3)
Respiratory events, n (%)c
4 (16)
6 (20.0)
Hypotension n (%)b
0 (0)
4 (13.0)
N Multi-organ failure, n (%)
SIRS, systemic inflammatory response syndrome. a
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Terlipressin
9 (13.2)
6 (9.2)
2 (2.9)
1 (1.5)
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Included pulmonary edema, respiratory failure, pleural effusion, pulmonary hypertension, acute
respiratory distress syndrome, obstructive airway disorder, aspiration pneumonia. b
As reported by the investigator; a general guidance was provided to define hypotension as mean
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arterial pressure <70 mm Hg or decrease >40 mm Hg in systolic blood pressure from baseline.
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Supplementary Table 1. ACLF Grade and Antibiotic Use at Baseline by SIRS and Non-SIRS and Treatment Groups SIRS groupa
n
Terlipressin Placebo
Total
28
30
58
0
1 (3.6)
0
1 (1.7)
1
9 (32.1)
15 (50.0) 24 (41.4)
2
12 (42.9)
12 (40.0) 24 (41.4)
3
6 (21.4)
3 (10.0)
17 (60.7)
17 (56.7) 34 (58.6)
P valuec
Terlipressin
Placebo
Total
69
69
138
0
1 (0.7)
ACLF grade,
n (%)
1 (1.4)
33 (47.8)
35 (50.7) 68 (49.3)
23 (33.3)
18 (26.1) 41 (29.7)
12 (17.4)
16 (23.2) 28 (20.3)
.7949
40 (58.0)
43 (62.3) 83 (60.1)
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Antibiotic use
.3096
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9 (15.5)
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n (%)
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Parameter
Non-SIRS groupb
a
Patients who met ≥2 SIRS criteria. Patients who met <2 SIRS criteria.
b
Comparing terlipressin versus placebo using Fisher's exact test.
d
Comparing SIRS total versus non-SIRS total using Fisher’s exact test.
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c
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ACLF, acute-on-chronic liver failure; SIRS, systemic inflammatory response syndrome.
1
P valuec P valued
.5455
.3136
.7282
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Supplementary Table 2. Reasons for Discontinuation of Study Treatment by the SIRS Group (Intent-to-Treat Population) SIRS groupa
n
Terlipressin
Placebo
Terlipressin
Placebo
28
30
69
69
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Reason for discontinuation, n (%)
Non-SIRS groupb
3 (10.7)
3 (10.0)
15 (21.7)
3 (4.3)
Confirmed HRS reversal
9 (32.1)
2 (6.7)
11 (15.9)
12 (17.4)
1 (3.3)
0 (0)
0 (0)
0 (0)
4 (5.8)
11 (15.9)
SC
Adverse event
0 (0)
Other
4 (14.3)
Physician decision
2 (7.1)
4 (13.3)
3 (4.3)
7 (10.1)
Protocol violation
0 (0)
0 (0)
0 (0)
1 (1.4)
1 (3.6)
4 (13.3)
3 (4.3)
3 (4.3)
4 (14.3)
3 (10.0)
7 (10.1)
7 (10.1)
1 (3.6)
2 (6.7)
1 (1.4)
3 (4.3)
4 (14.3)
8 (26.7)
14 (20.3)
16 (23.2)
0 (0)
3 (10.0)
11 (15.9)
6 (8.7)
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Death
Received maximum duration of randomized study
Renal replacement therapy
SCr at or above baseline value Transplant
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Request of patient or legally authorized representative
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medication treatment per protocol
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HRS, hepatorenal syndrome; SCr, serum creatinine; SIRS, systemic inflammatory response syndrome. a Patients who met ≥2 SIRS criteria. b Patients who met <2 SIRS criteria.
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol
1.
TITLE PAGE
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TERLIPRESSIN, LUCASSIN® IK-4001-HRS-301 A MULTI-CENTER, RANDOMIZED, PLACEBOCONTROLLED, DOUBLE-BLIND STUDY TO CONFIRM THE REVERSAL OF HEPATORENAL SYNDROME TYPE I WITH LUCASSIN® (TERLIPRESSIN) (REVERSE TRIAL)
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FORMERLY ORPHAN THERAPEUTICS PROTOCOL NUMBER OT-1001
Document type:
Clinical Study Protocol
Development phase:
Phase 3
IND number:
Ikaria Therapeutics LLC
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Company/Sponsor:
07 June 2010
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Release date:
68,582
6 Route 173 Clinton, NJ 08809 Telephone: 908-238-6600
This confidential document is the property of Ikaria Therapeutics LLC. No unpublished information contained herein may be disclosed without prior written approval from Ikaria Therapeutics LLC. Access to this document must be restricted to relevant parties.
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EMERGENCY CONTACT INFORMATION Name
Address and Telephone number
Study Lead
Diane Stebbins
6 State Route 173 Clinton, NJ 08809 Office: 908-238-6647
Medical Lead
Khurram Jamil, MD
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Role in Study
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6 State Route 173 Clinton, NJ 08809 Office: 908-238-6416
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INVESTIGATOR’S AGREEMENT
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I have read the attached protocol entitled “A Multi-Center, Randomized, Placebo-Controlled, Double-Blind Study To Confirm The Reversal Of Hepatorenal Syndrome Type 1 with Lucassin® (Terlipressin) (REVERSE Trial)” and agree to abide by all provisions set forth therein. I agree to comply with the International Conference on Harmonization (ICH) Tripartite Guideline on Good Clinical Practice (GCP), the ethical principles stated in the latest version of the Declaration of Helsinki, and the applicable local and international regulations, whichever provide the greater protection of the individual.
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I agree to ensure that the confidential information contained in this document will not be used for any purpose other than the evaluation or conduct of the clinical investigation without the prior written consent of Sponsor, Ikaria Therapeutics LLC.
Signature
Sponsor Statement
Date
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Principal Investigator
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Signature
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This study protocol was subject to critical review and has been approved by the following Sponsor representative.
Khurram Jamil, MD 6 Route 173 Clinton, NJ 08809
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2.
SYNOPSIS
Name of Sponsor/Company: Ikaria Therapeutics LLC
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Name of Investigational Product: Lucassin® Name of Active Ingredient: Terlipressin
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Title of Study: A Multi-Center Randomized, Placebo-Controlled, Double-Blind Study to Confirm the Reversal of Hepatorenal Syndrome Type 1 with Lucassin® (Terlipressin) (REVERSE Trial) (Formerly Orphan Therapeutics Protocol Number OT-1001)
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Study center(s): 40 - 55 sites in the United States and 0 - 10 in Canada
Phase of development: Phase 3
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Studied period (years): Estimated date first subject enrolled: October 2010 Estimated date last subject enrolled: February 2012 Duration of Treatment: up to14 days (maximum of 15/16 days if HRS reversal first achieved on Day 13/14) Duration of Study: (including all follow-up assessments): 90 days Estimated Study Completion Date: May 2012
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Objectives: Primary: To confirm the efficacy and safety of intravenous terlipressin versus placebo in the treatment of subjects with hepatorenal syndrome (HRS) type 1 receiving standard of care albumin therapy. Secondary: To demonstrate that terlipressin improves renal function and reverses HRS type 1 compared to placebo.
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Methodology: Placebo-controlled, double-blind, randomized, multicenter study. 1:1 randomization to terlipressin (Lucassin®) 1 mg IV q6h versus placebo. Number of subjects (planned): Approximately 150 subjects Diagnosis and main criteria for inclusion: Adult subjects with cirrhosis, ascites, and a diagnosis of HRS type 1 based on the 2007 International Ascites Club (IAC) diagnostic criteria. Main Inclusion Criteria: Subjects ≥ 18 years of age with cirrhosis, ascites, and rapidly progressive reduction in renal function (e.g., doubling of serum creatinine within 2 weeks) to a serum creatinine (SCr) ≥ 2.5 mg/dL without sustained improvement in renal function (< 20% decrease in SCr and SCr ≥ 2.25 mg/dL) 48 hours after both diuretic withdrawal and the beginning of plasma volume expansion with albumin.
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Exclusion Criteria: SCr level > 7 mg/dL; shock; sepsis or systemic inflammatory response syndrome (SIRS); < 2 days antiinfective therapy for documented/suspected infection; proteinuria > 500 mg/day; hematuria or microhematuria (> 50 red blood cells per high power field); clinically significant casts on urinalysis, including granular casts; evidence of intrinsic or parenchymal renal disease (including acute tubular necrosis); obstructive uropathy or other renal pathology on ultrasound or other medical imaging; current or recent treatment (within 4 weeks) with nephrotoxic drugs; current or recent (within 4 weeks) renal replacement therapy (RRT); superimposed acute liver injury due to factors other than acute alcoholic hepatitis including acute viral hepatitis, drugs, medications, or other toxins; current or recent treatment (within 48 hours) with octreotide, midodrine, vasopressin, dopamine or other vasopressors; severe cardiovascular disease as judged by investigator; estimated life expectancy of less than 3 days; confirmed pregnancy; known allergy or sensitivity to terlipressin or any component of study medication; participation in other clinical research involving investigational drugs or devices within 30 days
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Investigational product, dosage and mode of administration: Single-use, sterile 6-mL vials containing a lyophilized solid of 1 mg terlipressin acetate (equivalent to 0.85 mg terlipressin free base) with 10 mg mannitol as a bulking agent/stabilizer. Each vial will be reconstituted with 5 mL of sterile 0.9% sodium chloride solution. The following dosing scheme will be utilized for both terlipressin and matching placebo: Initial Dosing: Blinded Lucassin® (terlipressin for injection) or placebo will be administered intravenously as a slow bolus injection over 2 minutes at a dose of 1 mg (1 vial) every 6 hours (4 mg/day). Dose Modifications: • If on Day 4 of therapy (after a minimum of 10 doses), serum creatinine has decreased, but by less than 30% from the baseline value, the dose will be increased to 2 mg every 6 hours (8 mg/d). • The dose will not be increased if the subject has coronary artery disease; or in the clinical setting of circulatory overload, pulmonary edema, or treatment-refractory bronchospasm. • If dosing is interrupted due to a non-ischemic adverse event, study medication may be restarted, at the discretion of the investigator, at the same or lower dose (i.e., 0.5-1 mg q6h). Treatment Discontinuation: • Treatment will continue until at least two SCr values ≤ 1.5 mg/dL have been obtained at least 48 hours apart, or up to a maximum of 14 days (maximum of 15/16 days if SCr first reaches 1.5 mg/dL on Day 13/14, respectively). • If on Day 4 (after a minimum of 10 doses) SCr is at or above baseline value, study medication will be discontinued. • Treatment must be discontinued when the subject is to undergo RRT or transplantation. • Dosing must be permanently discontinued if an ischemic event occurs. Retreatment: If judged by the investigator to be potentially beneficial, subjects who demonstrated at least a 30% reduction in SCr during initial treatment who develop recurrence of HRS type 1 may be retreated once with the initially assigned study medication. To qualify for retreatment the subject must again meet the study inclusion/exclusion criteria. Duration of treatment: The active treatment period is 14 days (exception: 15 or 16 days as described above), with one
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol retreatment cycle allowed. Subjects will be contacted for follow-up assessments on Days 30, 60 and 90. Reference therapy, dosage and mode of administration: Matching placebo vials (containing 11 mg mannitol) that are identical in appearance to terlipressin for injection vials. Each vial will be reconstituted with 5 mL of sterile 0.9% sodium chloride solution.
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Criteria for evaluation: Primary Efficacy Endpoint: Confirmed HRS Reversal - the percentage of subjects with two serum creatinine (SCr) values ≤ 1.5 mg/dL, at least 48 hours apart, on treatment Secondary Efficacy Endpoints:
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•
Renal function: change from baseline through end of treatment in SCr values HRS Reversal: the percentage of subjects with at least one SCr value ≤ 1.5 mg/dL on treatment Transplant-free Survival up to 90 days, defined as the time (in days) that each subject survives without liver transplantation from the day of randomization. Overall Survival up to 90 days, defined as the time (in days) that each subject survives from the day of randomization
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• • •
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Other Efficacy Endpoints: • Glomerular filtration rate (GFR): change from baseline through end of treatment in GFR using both MDRD and Cockcroft-Gault equations • Fractional excretion of sodium (FENa): change from baseline through end of treatment in FENa • HRS type 1 recurrence until transplantation, hospital discharge, or Day 14, whichever occurs first. • Dialysis free survival up to 90 days: defined as the time (in days) that each subject survives without dialysis from the day of randomization Safety: • Non-serious adverse events up to 7 days post end of treatment • Serious adverse events up to 30 days post end of treatment • General safety profile, including vital signs and laboratory tests • Mortality up to 90 days Pharmacokinetics: • Population PK using sparse sampling approach. One baseline sample and additional three sparse samples during the 1st dose period on Day 1 will be collected. The time points for sample collection will be randomly assigned at the time of randomization. A previously developed population PK model will be used to characterize the pharmacokinetics of terlipressin and lysine-vasopressin in HRS subjects. • The relationship between drug exposure (AUC or Cmax) and response (SCr, MAP, and HR) during the treatment with terlipressin will also be explored. Exploratory Biomarker (optional): Exploratory analysis of gene expression for receptor polymorphism (DNA) as a biomarker for terlipressin treatment effects.
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Statistical methods: The primary efficacy endpoint for this study is the incidence of confirmed HRS Reversal defined as the percentage of subjects with two SCr values of ≤ 1.5 mg/dL, at least 48 hrs apart, on treatment (see Section 13.5.1). The intent-to-treat (ITT) population, excluding any SCr values obtained posttransplantation or post-renal replacement therapy, will be used for analysis; Subjects will be stratified by qualifying SCr (< 3.6 mg/dL or ≥ 3.6 mg/dL) and alcoholic hepatitis (present or not). The primary efficacy endpoint will be analyzed in the ITT population using a Cochran-Mantel-Haenszel (CMH) chisquare test stratified for SCr and alcoholic hepatitis (present or not). Secondary efficacy variables that are similar to the primary endpoint will be analyzed similarly using the CMH test. The pre-specified secondary endpoints will be analyzed in a sequential fashion. Change from baseline in variables (such as SCr) through end of treatment will be analyzed using repeated measures analysis of covariance. Subgroup analysis by pre-specified criteria and other exploratory analyses are planned. In the OT-0401 study, for subjects with baseline SCr ≤ 7 mg/dL, the confirmed HRS reversal rate in the placebo group was 12.5% (7/56). The rate for terlipressin was 36% (18/50). One-hundred-and-fifty subjects (75 subjects per group) will provide 90% power to detect a statistically significant (p ≤ 0.05 two-sided test) difference between the two treatment groups. A Data Safety Monitoring Board (DSMB) will review safety and mortality data as per DSMB charter.
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TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES
1.
TITLE PAGE ..............................................................................................................1
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3.
EMERGENCY CONTACT INFORMATION ................................................................................2 INVESTIGATOR’S AGREEMENT ...............................................................................................3 SYNOPSIS ...................................................................................................................4
3.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .................8
4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................15
5.
INTRODUCTION ......................................................................................................18
5.1.
Hepatorenal Syndrome ...............................................................................................18
5.2.
Terlipressin Background .............................................................................................19
5.3.
Nonclinical Studies .....................................................................................................19
5.4.
Clinical Studies ...........................................................................................................20
5.4.1.
Pharmacokinetics and Pharmacodynamics .................................................................20
5.4.2.
Healthy Volunteers .....................................................................................................20
5.4.3.
Patients with HRS Type 1...........................................................................................20
5.4.4.
Clinical Efficacy in Hepatorenal Syndrome Type 1 (Study OT-0401) ......................21
5.4.5.
Clinical Safety in Study OT-0401 ..............................................................................22
5.4.6.
Other Parameters in Study OT-0401 ..........................................................................23
5.4.6.1.
Antigenicity ................................................................................................................23
5.4.6.2.
QT Effects ...................................................................................................................23
5.4.6.3.
Known and Potential Risks .........................................................................................23
5.5.1. 5.5.2. 6.
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Study Rationale ...........................................................................................................24 Primary Endpoint Rationale .......................................................................................24
Dosing Regimen and Recommended Co-treatment with Albumin ............................25 OBJECTIVES .............................................................................................................26
6.1.
Primary Objective .......................................................................................................26
6.2.
Secondary Objective(s) ...............................................................................................26
6.3.
Efficacy Variables ......................................................................................................26
6.3.1.
Primary Efficacy Variables.........................................................................................26
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6.3.3.
Other Efficacy Variables ............................................................................................26
7.
INVESTIGATIONAL PLAN .....................................................................................28
7.1.
Overall Study Design and Plan: Description ..............................................................28
8.
STUDY POPULATION .............................................................................................29
8.1.
Population Rationale ...................................................................................................29
8.2.
Number of subjects to be studied................................................................................29
8.3.
Inclusion criteria .........................................................................................................29
8.4.
Exclusion criteria ........................................................................................................30
8.5.
Subject Withdrawal criteria ........................................................................................32
9.
PROTOCOL DEVIATIONS ......................................................................................33
10.
TREATMENT OF SUBJECTS ..................................................................................34
10.1.
Terlipressin .................................................................................................................34
10.1.1.
Initial Dosing ..............................................................................................................34
10.1.2.
Dose Modifications .....................................................................................................34
10.2.
Placebo ........................................................................................................................34
10.3.
Blinding ......................................................................................................................34
10.4.
Randomization ............................................................................................................34
10.5.
Retreatment .................................................................................................................35
10.6.
Discontinuation of Treatment .....................................................................................35
10.7.
Concomitant Medication ............................................................................................35
10.7.1.
Recommended Concomitant Medication ...................................................................35
10.7.1.1.
Albumin ......................................................................................................................35
10.7.1.2.
Prohibited or Discouraged Concomitant Medications ................................................35
10.8.
Treatment Compliance................................................................................................36
11. 11.1.
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6.3.2.
Medical Hotline ..........................................................................................................36
STUDY DRUG MATERIAL AND MANAGEMENT .............................................37 Description of Terlipressin for Injection ....................................................................37
11.2.
Packaging and Labeling..............................................................................................38
11.3.
Study Drug Storage and Preparation ..........................................................................38
11.3.1.
Reconstitution .............................................................................................................38
11.3.2.
Administration ............................................................................................................38
11.4.
Study Drug Accountability .........................................................................................38
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol RANDOMIZATION, BREAKING OF BLINDED CODES .....................................39
12.1.
Randomization and blinding .......................................................................................39
12.1.1.
Randomization ............................................................................................................39
12.1.2.
Blinding of Study Medications ...................................................................................39
12.1.3.
Unblinding of Treatment Assignment ........................................................................39
13.
ASSESSMENTS AND PROCEDURES ....................................................................40
13.1.
Schedule of Assessments and Procedures ..................................................................40
13.2.
Study Assessment Phases ...........................................................................................44
13.2.1.
Subject Screening Phase .............................................................................................44
13.2.2.
Pre-Treatment Phase ...................................................................................................44
13.2.3.
Active Study Phase (14 Days) ....................................................................................44
13.2.4.
Follow-up Phase .........................................................................................................44
13.3.
Detail of Safety Assessments and Procedures ............................................................45
13.3.1.
Vital Sign Measurements ............................................................................................45
13.3.2.
Encephalopathy Score ................................................................................................45
13.3.3.
Model for End-Stage Liver Disease (MELD) Score ..................................................45
13.3.4.
Adverse Events ...........................................................................................................45
13.4.
Detail of Laboratory Assessments and Procedures ....................................................46
13.4.1.
Local Laboratory at Investigational Site.....................................................................46
13.4.1.1.
Serum Electrolytes & Biochemistry ...........................................................................46
13.4.1.2.
Hematology.................................................................................................................47
13.4.1.3.
Urine ...........................................................................................................................47
13.5.
Detail of Efficacy Assessments and Procedures .........................................................47
13.5.1.
Primary Efficacy Variables.........................................................................................47
13.5.2.
Secondary Efficacy Variables.....................................................................................48
13.5.3.
Other Efficacy Variables ............................................................................................48
13.5.4.
Other Exploratory Analyses .......................................................................................49
13.5.5.
Pharmacokinetics ........................................................................................................49
13.6.
Optional Sub-Study for Biomarker Genetic Assessments ..........................................50
13.6.1.
Genetic Assessments ..................................................................................................50
14.
ADVERSE EVENTS..................................................................................................51
14.1.
Definitions ..................................................................................................................51
14.1.1.
Adverse Event .............................................................................................................51
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14.2.
Severity And Causality Assessments For Adverse Events ........................................51
14.2.1.
Severity Assessment ...................................................................................................51
14.2.2.
Study Medication Causality........................................................................................52
14.3.
Collection, Recording and Reporting of Adverse Events ...........................................52
14.3.1.
Adverse Event Recording ...........................................................................................52
14.3.2.
Procedure for Serious Adverse Event Reporting ........................................................53
15.
STATISTICAL PLAN................................................................................................54
15.1.
Safety Variables ..........................................................................................................54
15.2.
Subject Accounting and Baseline Characteristics ......................................................54
15.3.
Statistical Methodology ..............................................................................................55
15.3.1.
Sample Size Calculation .............................................................................................55
15.3.2.
Patient Populations .....................................................................................................55
15.3.2.1.
Intention to Treat (ITT) Population ............................................................................55
15.3.2.2.
Safety Population ........................................................................................................55
15.3.2.3.
Per Protocol (PP) Population ......................................................................................55
15.3.3.
Statistical Analyses .....................................................................................................55
15.3.4.
Demographic and Baseline Characteristics ................................................................55
15.3.5.
Efficacy Analyses .......................................................................................................56
15.3.5.1.
Other Efficacy Variables ............................................................................................57
15.3.5.2.
Safety Analysis ...........................................................................................................57
15.3.6.
Pharmacokinetics ........................................................................................................58
15.3.7.
Definition of Time Points ...........................................................................................58
15.3.8.
Missing Data ...............................................................................................................58
15.3.9.
Procedure for Amendments to Statistical Plan ...........................................................58
16.
DATA MANAGEMENT ...........................................................................................59
16.2.
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14.1.2.
Data Collection ...........................................................................................................59 Records Retention .......................................................................................................59
16.3.
Inspection of Records .................................................................................................59
16.4.
Retention of Records/Critical Documents ..................................................................60
17.
QUALITY CONTROL AND QUALITY ASSURANCE .........................................61
17.1.
Study Monitoring ........................................................................................................61
17.2.
Auditing ......................................................................................................................61
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol Ethics and Responsibility ...........................................................................................61
17.4.
Informed Consent .......................................................................................................61
17.5.
Institutional Review Board/Independent Ethics Committee ......................................62
17.6.
Confidentiality ............................................................................................................62
18.
REGISTRATION OF STUDY AND PUBLICATION OF DATA ...........................63
19.
REFERENCES ...........................................................................................................64
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APPENDIX A. STUDY IK-4001-HRS-301: NOMOGRAM TO DETERMINE CRITERION FOR SCr DOUBLING OVER TWO WEEKS ....................................68
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol
LIST OF TABLES Abbreviations and Specialist Terms ...........................................................................15
Table 2:
Overview of Safety Data – Study OT-0401 ...............................................................23
Table 3:
Prohibited/Discouraged Concomitant Medications ....................................................36
Table 4:
Schedule of Assessments ............................................................................................41
Table 5:
West Haven Criteria for Semiquantitative Grading of Mental State15 .......................45
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Table 1:
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol
LIST OF FIGURES Forest Plots Of Random Effects Meta-Analyses On Terlipressin Plus Albumin Versus Albumin For Patients With HRS.20 .................................................22
Figure 2:
Schematic Diagram of Trial Design ...........................................................................28
Figure 3:
Lucassin® (Terlipressin for Injection) ........................................................................37
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Figure 1:
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol
4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
The following abbreviations and specialist terms are used in this study protocol. Table 1:
Abbreviations and Specialist Terms Explanation
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine amino transferase, also known as SGPT
ANCOVA
analysis of covariance
AST
aspartate amino transferase, also known as SGOT
AUC
area under the curve
BP
blood pressure
BUN
blood urine nitrogen
CBC
complete blood count
CFR
Code of Federal Regulations
Cmax
maximum concentration
CMH
Cochran-Mantel-Haenszel
CO2
carbon dioxide
chronic obstructive pulmonary disease
CRF
case report form
d
day
EC ECG Emax EVH
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DSMB
data clarification form
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DCF
DNA
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COPD
dL
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Abbreviation or specialist term
deciliter deoxyribonucleic acid Data Safety Monitoring Board Ethics Committee electrocardiogram maximum effect esophageal variceal hemorrhage
FENa
fractional excretion of sodium
FDA
Food and Drug Administration
FU
follow-up
GCP
Good Clinical Practice
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol Explanation
GFR
glomerular filtration rate
h
hour
HR
heart rate
HRS
hepatorenal syndrome
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IND
Investigational New Drug
INR
International Normalized Ratio
IRB
Institutional Review Board
ITT
intent-to-treat
IV
intravenous
IVRS
Interactive Voice Response System
MAP
mean arterial pressure
MedRA
Medical Dictionary for Regulatory Activities
MELD
model for end-stage liver disease
MDRD
modification of diet in renal disease
NSAIDs
nonsteroidal anti-inflammatory drugs polymerase chain reaction
PK
pharmacokinetic
PD
pharmacodynamic
RRT SAE SAER SBP
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RNA
per protocol
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RBC
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PCR
q6h
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Abbreviation or specialist term
once every six hours red blood cell ribonucleic acid renal replacement therapy serious adverse event serious adverse event report systolic blood pressure
SCr
serum creatinine
SGOT
serum glutamic-oxaloacetic transaminase, also known as AST
SGPT
serum glutamic-pyruvic transaminase, also known as ALT
SmPC
summary of product characteristics
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol Explanation
SNPs
single nucleotide polymorphisms
TBD
to be determined
TIPS
transjugular intrahepatic portosystemic shunt
US
United States
UTI
urinary tract infection
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Abbreviation or specialist term
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol
5.
INTRODUCTION
5.1.
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This protocol describes the procedures and instructions for this randomized, double-blind, placebo-controlled phase 3 study. This study is designed to evaluate the efficacy and safety of intravenous Lucassin® (terlipressin) versus placebo for the treatment of type 1 hepatorenal syndrome (HRS) in subjects receiving standard of care albumin therapy. This study will be conducted in compliance with International Conference of Harmonization (ICH) / Good Clinical Practices (GCP) including the Declaration of Helsinki and all applicable regulatory requirements.
Hepatorenal Syndrome
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Hepatorenal syndrome is a rare syndrome of marked renal dysfunction in patients with cirrhosis, decompensated liver disease, and portal hypertension.4, 5, 9, 10, 19 Hepatorenal syndrome is characterized by functional renal failure (very low renal perfusion and glomerular filtration rates) in the absence of underlying kidney pathology. Hepatorenal syndrome is at one end of a spectrum of functional renal abnormalities caused by severe vasoconstriction of the renal circulation leading to a pronounced reduction in glomerular filtration rate (GFR). Hepatorenal syndrome type 1 is characterized by a rapid progressive renal impairment and has a very poor prognosis with > 80% mortality within 3 months.1, 18, 25, 31
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Patients with HRS have a hyperdynamic circulation characterized by arterial hypotension and very low systemic vascular resistance; in the splanchnic circulation, there is marked arterial vasodilation, which is responsible for impairment in circulatory function and homeostatic activation of the endogenous vasoconstrictor systems. In the early stages of decompensated cirrhosis, renal blood flow is maintained within normal limits due to an increased production of systemic and renal vasodilators (mainly prostaglandins). As cirrhosis progresses, the effect of circulating vasoconstrictors overcomes the effect of renal vasodilators, resulting in severe renal vasoconstriction and a reduction in GFR. In some patients, precipitating factors (including bacterial infections) worsen circulatory dysfunction and aggravate renal vasoconstriction. Once renal vasoconstriction occurs, intra-renal mechanisms perpetuate HRS since hypoperfusion leads to an imbalance in local vasoactive systems that, in turn, cause more vasoconstriction.10
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The diagnostic criteria for HRS were originally described by a consensus workshop of the International Ascites Club in 1996 and were updated in 2007.4, 41 Hepatorenal syndrome is a diagnosis of exclusion; other causes of renal failure, e.g., shock, parenchymal kidney disease, nephrotoxic drugs, and volume depletion must be ruled out. Hepatorenal syndrome type 1 is characterized by rapidly progressive renal failure, e.g., a doubling of the serum creatinine (SCr) concentration to ≥ 2.5 mg/dL in less than 2 weeks. At present, there is no approved pharmacological therapy for the treatment of HRS type 1 in the USA, Canada or Australia. The only curative treatment for HRS type 1 and the underlying endstage cirrhosis is liver transplantation.8, 19, 30 However, not all patients are candidates for liver transplantation and liver transplantation is not universally available. For those who are transplant candidates, a suitable organ may not be found quickly enough. Furthermore, even when an organ is available, the presence of uncorrected HRS type 1 worsens the outcome of liver transplantation.21, 39 One retrospective case-control study suggests that HRS patients treated with vasopressin analogues before liver transplant have a post-transplant outcome similar to that of Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol patients with no HRS pre-transplant.38 Thus, even in the best possible clinical scenario, there is a high need for effective medical therapy to reverse HRS type 1; in the absence of access to transplant, medical therapy is the only alternative.
5.2.
Terlipressin Background
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Substantial data available from many published clinical investigations in the literature provide compelling evidence suggesting that administration of terlipressin improves renal function in patients with HRS.14, 20, 29, 42 In HRS patients with hyperdynamic circulation, the strong V1 receptor-mediated vasoconstrictor activity of terlipressin, particularly in the splanchnic area, results in an increase in effective arterial volume, an increase in mean arterial pressure (MAP), normalization of endogenous vasoconstrictor systems (renin-angiotensin-aldosterone and sympathetic nervous system), and an increase in renal blood flow. These effects result in improved renal function, thereby providing the therapeutic rationale for treatment of HRS with terlipressin.5, 19, 26
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Vasopressins are direct systemic vasoconstrictors (mediated by V1 receptor-activation on vascular smooth muscle) and antidiuretics (mediated by V2 receptor-activation in the renal collecting duct system). The distribution and density of vasopressin receptors accounts for the various pharmacological effects, which are concentration-dependent, with V1 receptor-mediated vasoconstriction occurring at higher concentrations. The V2 receptor-mediated antidiuresis reaches a maximum effect at lower concentrations. At the dose of terlipressin used to treat HRS patients, the strong V1-mediated vasoconstrictor activity is the pharmacodynamic mechanism responsible for its clinical activity.24 (See Section 11 for description of terlipressin)
Nonclinical Studies
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The nonclinical pharmacology data in various animal species, including relevant models of liver disease, have consistently demonstrated that terlipressin decreases splanchnic blood flow and portal pressure, increases peripheral vascular resistance and effective arterial volume, and increases renal perfusion. The hemodynamic effects of terlipressin in numerous animal models are consistent with the effects reported in a large number of clinical studies and with the proposed mechanism of action of terlipressin in HRS patients (vasoconstriction of the dilated splanchnic arterial bed and increased arterial volume resulting in an increase in renal perfusion and improved renal function). The nonclinical and clinical pharmacokinetics studies have demonstrated that the pharmacokinetic profile of terlipressin following intravenous (IV) administration is similar in animals and in humans. In all studies, detectable plasma concentrations of both terlipressin and lysine-vasopressin are achieved after IV administration of terlipressin, and the plasma concentrations appear to increase with increasing dose administered. Terlipressin and lysinevasopressin are rapidly eliminated in all species studied. Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol Single-dose studies were conducted in mice, rats and dogs. Repeat-dose studies (7 and 28 days) were conducted in rats and dogs. Overall, the clinical signs in rats and dogs were generally consistent with the pharmacologic effects of terlipressin and correlated with terlipressin dose level. No significant signs were observed during the 2-week recovery period in the 28-day studies. There was no necrosis observed at the injection site in rats or dogs.24
Clinical Studies
5.4.1.
Pharmacokinetics and Pharmacodynamics
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No formal drug interaction studies have been performed, but in-vitro studies demonstrated that terlipressin does not have either inhibitory or induction potential on a broad array of cytochrome p450 isoenzymes.24
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The pharmacokinetics of terlipressin are complex and can be described by second-order kinetics. After IV administration of terlipressin, the glycyl residues of terlipressin are cleaved by endogenous tissues proteases. Thus, terlipressin levels in the blood decrease rather rapidly and the pharmacologically active metabolite lysine-vasopressin is released gradually from tissues into the circulation.
5.4.2.
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The similarity in elimination half-life and clearance in HRS patients in study OT-0401 and healthy volunteers may be explained by the ubiquitous nature of the enzymes responsible for the metabolism of terlipressin and other peptides. Vasopressin is metabolized at the C- and Nterminus, as well as by disulfide bond cleavage, by various peptidases and proteases that are detectable in almost all human tissues; however, the majority of terlipressin metabolism occurs in liver and kidney tissues. 16, 24, 27 Healthy Volunteers
5.4.3.
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After administration of 7.5 µg/kg terlipressin, maximum plasma concentration of terlipressin was seen within 5 minutes.17 By 120 minutes, terlipressin was virtually absent and the maximal concentration of lysine-vasopressin observed. The mean elimination half-life of terlipressin was 24 ± 2 minutes and volume of distribution was 15.5 ± 4.5 L. The half life for distribution and elimination of terlipressin was determined to be 8 and 50 minutes 34 respectively, after administration of a single dose of 5, 10 or 20 µg/kg terlipressin.34 The distribution volume was 0.7 L/kg body weight and plasma clearance was 9 ml/kg/min. Only 1% of the injected terlipressin was found in urine, which indicates that terlipressin was almost completely metabolized in the body. Lysine-vasopressin reached highest plasma concentrations 60 to 120 minutes after terlipressin administration. Plasma levels of lysine-vasopressin remained constant over a period of 4 - 6 hours. Patients with HRS Type 1
A population-based sparse sampling pharmacokinetic (PK) strategy was utilized in patients with HRS type 1 enrolled in the previous phase 3 study (OT-0401). Analyses of samples from 29 patients indicate that terlipressin and lysine-vasopressin plasma concentrations appear to increase with dose. Mean maximum terlipressin concentrations of 62.1 ng/mL were observed immediately after dosing, then decayed rapidly with a mean half-life of 1.08 hours and returned to baseline within the 6 hour dosing interval. Mean maximum lysine-vasopressin steady-state Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol plasma levels of 1.06 ng/mL were seen peaking at approximately 2-hours post dose, and were still measurable in 2/3 of patients at 5.4 hours post-dose (mean 0.15 ng/mL). Due to the short half-life and rapid clearance of terlipressin and lysine-vasopressin in HRS patients, the chance of any significant drug accumulation after several days of treatment with terlipressin is very low. Clinical Efficacy in Hepatorenal Syndrome Type 1 (Study OT-0401)
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5.4.4.
Study OT-0401, was a phase 3, double-blind, randomized, placebo-controlled, multicenter international trial in which 112 patients with HRS type 1 were randomized 1:1 to receive terlipressin or placebo, with concomitant albumin administration recommended in both treatment arms.
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Study OT-0401 was designed using a more stringent version of the standard HRS reversal endpoint (at least one SCr value ≤ 1.5 mg/dL) to include assessment of the durability of response. The resulting primary endpoint was called “Treatment Success” and required an initial reduction of SCr to ≤ 1.5 mg/dL followed by a confirmatory SCr measurement of < 1.5 mg/dL 48 hours after the initial HRS reversal and an additional SCr value < 2.5 mg/dL at Day 14, without intervening liver transplant or dialysis. The primary endpoint, Treatment Success at Day 14, favored terlipressin but did not attain statistical significance (25% vs. 13%; p = 0.093).42
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Using the established endpoint of HRS reversal (at least one SCr value ≤ 1.5 mg/dL), the incidence of HRS reversal on treatment was significantly higher in terlipressin-treated patients (34%) compared with placebo-treated patients (13%; p = 0.008). In terlipressin-treated patients, HRS reversal typically occurred between Days 3 and 7, but continued to occur until Day 14. In addition, the terlipressin-treated patients had a statistically significant reduction in SCr concentrations from baseline to end of treatment relative to the control group (- 0.7 mg/dL; p = 0.009). The results demonstrated that terlipressin is superior to placebo for HRS reversal and for improving renal function when administered concomitantly with the standard background therapy of albumin. Albumin alone had a modest effect on HRS reversal, supporting its continued use as part of standard medical therapy for HRS.
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Although terlipressin improves renal function, it does not affect the underlying severe liver disease, and thus can only be expected to have a modest effect on overall survival. In Study OT0401 no significant differences in overall and transplant-free survival at Day 180 were observed between the terlipressin and control groups (42.9% with terlipressin vs. 37.5% with placebo; p = 0.84). In addition to study OT-0401, the medical literature on treatment of HRS type 1 with terlipressin includes several additional randomized, controlled studies.2, 23, 29, 33, 47 Data from these studies consistently showed improvements in renal function, as measured by HRS reversal and/or reduction of SCr, in 33% to 100% of patients studied. In addition, three recent meta-analyses, which include the results of OT-0401, support the efficacy of terlipressin for the treatment of HRS.14, 20, 40 (Figure 1)
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol Forest Plots Of Random Effects Meta-Analyses On Terlipressin Plus Albumin Versus Albumin For Patients With HRS.20
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Figure 1:
Forest plots of random effects meta-analyses on terlipressin plus albumin versus albumin for patients with HRS. The outcome measures are reversal of HRS and improved renal function. The included patients received terlipressin alone or with albumin versus no intervention or albumin.20
5.4.5.
Clinical Safety in Study OT-0401
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In study OT-0401, the majority of patients in both treatment arms experienced at least one adverse event (AE) (Table 2). The incidence of serious adverse events (SAEs) was identical between treatment groups. The most common AE in the terlipressin-treated patients included vomiting, hepatic failure, nausea, abdominal pain, and anemia.24
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Three terlipressin-treated patients (5%) experienced non-fatal ischemic AEs leading to treatment withdrawal (myocardial infarction, livedo reticularis, cyanosis of peripheral extremities).
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There were no treatment-related deaths reported and the majority of deaths in both treatment arms were due to the underlying liver disease.
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol Table 2:
Overview of Safety Data – Study OT-0401
Safety Parameter
Terlipressin (N = 56) n (%)
Placebo (N = 55) n (%)
All
52 (92.9)
49 (89.1)
Treatment-related
18 (32.1)
Serious Adverse Events All
37 (66.1) 5 (8.9)
Deaths up to 180 days All
Withdrawal due to Adverse Event All Treatment-related
5.4.6.
Other Parameters in Study OT-0401
5.4.6.1.
Antigenicity
36 (65.5)
32 (57.1)
35 (63.6)
0 (0.0)
0 (0.0)
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12 (21.8)
1 (1.8)
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Adverse Events
3 (5.4)
2 (3.6)
3 (5.4)
0 (0.0)
5.4.6.2.
QT Effects
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No significant levels of antibody were detectable in the serum of HRS type 1 patients treated with terlipressin.
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Electrocardiogram (ECG) data from HRS type 1 patients were analyzed for effects on QT. The QT interval decreased from baseline in both treatment groups with a more marked decrease in the placebo group. This resulted in a mean difference in change from baseline in QTcF between terlipressin and placebo of 7.8 msec, which was not statistically significant. Known and Potential Risks
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5.4.6.3.
Terlipressin is a vasoconstrictor and should be used with caution in patients with coronary artery disease as it may cause myocardial ischemia. It should not be used in patients with unstable angina or recent acute myocardial infarction. Torsade de pointes, QT prolongation and ventricular fibrillation have been rarely reported in the post-marketing setting outside the United States (US). Ischemic events (cardiac, gastrointestinal, and skin) have occurred following administration of terlipressin. Manifestations may include angina, ECG changes, peripheral cyanosis and extremity pain. Terlipressin should be permanently discontinued if an ischemic event occurs. Due to its constrictive effects on smooth muscle, terlipressin should be used with caution in patients with severe asthma or chronic obstructive pulmonary disease (COPD). Terlipressin Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol causes significant increases in uterine activity and reduction in endometrial blood flow that can result in fetal harm and spontaneous abortion.
5.5.
Study Rationale
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Hepatorenal syndrome type 1 is a serious orphan disease complicating decompensated chronic liver disease with cirrhosis; the optimal treatment for the underlying cause of HRS type 1 is liver transplantation.19 However, many patients will not survive long enough to receive a liver transplant and therapy, which may provide a bridge to transplantation, is badly needed. Furthermore, pre-transplant renal impairment is associated with increased post-transplant complications and a decrease in the net benefit of liver transplantation.32, 46 Conversely, HRS reversal is associated with improved overall survival42 and therapy, which reverses HRS type 1 appears likely to be associated with improved post-transplant outcomes.38 In those patients who are not candidates for liver transplantation, HRS reversal facilitates their medical management and may provide the survival time needed for improvement in underlying liver disease (e.g., alcoholic hepatitis). At present, there are no approved drug therapies for HRS type 1 in the US, Australia, or Canada.
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Increased understanding of the pathophysiology of HRS type 1 has demonstrated that vasoconstrictive drug therapy may reverse HRS type 1.41 While a number of vasoconstrictor drugs (e.g., midodrine, ornipressin, vasopressin, norepinephrine) have been studied as treatment for HRS type 1, most have either been studied in small numbers of patients outside randomized and placebo-controlled trials,3, 49 studied retrospectively,13, 45 or have not shown evidence of efficacy with an acceptable risk-benefit profile.22 Terlipressin has been extensively studied in patients with cirrhosis as therapy for esophageal variceal hemorrhage (EVH), and more recently, as therapy for HRS type 1.12, 43 Terlipressin is approved in many countries for the treatment of esophageal variceal hemorrhage, and in several countries for the treatment of HRS (France, Ireland, Spain, Mexico, South Korea, Taiwan, India, and Portugal), but is not approved for any indication in the USA, Canada, Australia, Japan and South Africa.
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Four randomized, controlled trials of terlipressin in HRS type 129, 33, 42, 47 along with recent meta-analyses of these and other trials, support the role of terlipressin in HRS type 1.14, 20, 40 The largest of the randomized placebo-controlled trials studied 112 patients with HRS type 1 treated with terlipressin or placebo as part of the Orphan Therapeutics clinical development program.42 While this pivotal trial demonstrated a clinically and statistically significant effect of terlipressin (versus placebo) on the rate of HRS reversal, the accepted and standard clinical endpoint applied in the literature,41 the study-specific primary endpoint, the incidence of “Treatment Success at Day 14”, yielded less robust results (see Section 5.4.4). Overall, data from this pivotal study and the existing literature provide evidence that terlipressin is effective in reversing HRS type 1, but as agreed with the FDA, a confirmatory phase 3 placebo-controlled trial is needed. This trial, in combination with existing data, will provide the level of evidence necessary to define the risk-benefit of terlipressin in patients with HRS type 1 and endeavor to obtain regulatory approval for its use to satisfy the unmet medical need. 5.5.1.
Primary Endpoint Rationale
The primary endpoint of “Confirmed HRS Reversal” is based on the clinical endpoint of HRS reversal (one SCr value of ≤ 1.5 mg/dL) the standard endpoint utilized in the literature and HRS Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol treatment guidelines.41 In agreement with FDA, confirmation of HRS reversal has been incorporated into the primary endpoint through documentation of a second SCr value of ≤ 1.5 mg/dL at least 48 hours later. 5.5.2.
Dosing Regimen and Recommended Co-treatment with Albumin
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The terlipressin dosing regimen used in study OT-0401 was 1 mg every 6 hours increased to 2 mg every 6 hours if SCr values decreased < 30% after 3 days. Study medication was administered for 2 days post-response or up to 14 days. If a patient’s SCr value was at or above baseline on Day 7, then study medication was to be discontinued.
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The dosing regimen studied in study OT-0401 was based on a substantial body of evidence from 11 literature studies where effective doses of terlipressin in HRS type 1 ranged from 2 to 12 mg/day.24 Additional dosing information was derived from the approved dosage in foreign labeling (1-2 mg every 4-6 hours, i.e., 4-12 mg/day) for esophageal variceal hemorrhage (EVH), a condition that affects patients with cirrhosis and portal hypertension, a population substantially similar to the HRS patient population.
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The 1 mg dose was shown to be the appropriate starting dose in study OT-0401, as only a small proportion of patients who achieved HRS reversal required a dose increase to 2 mg (3 out of 19 responders). In the randomized, controlled TAHRS study, all 6 patients who received an initial terlipressin dose of 0.5 mg q4h required dose increases whereas only one of the 17 patients who received an initial dose of 1 mg q4h required a dose increase to 2 mg q4h.24 Two of the 9 patients who achieved HRS reversal in TAHRS required the 2 mg dose.
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The dosing regimen in study OT-0401 had a less frequent dosing interval and lower daily dose intensity than the TAHRS Study regimen, but resulted in similar efficacy (34% vs. 39%) and a lower rate of SAEs (66% vs. 91%) and withdrawals due to AEs (5% vs. 22%) in terlipressintreated patients.
EP
The duration of therapy is to be at least 2 days post-response or up to 14 days. This duration of treatment was used historically in studies of terlipressin in HRS and was also shown to be an appropriate duration of treatment based on Study OT-0401. In OT-0401, HRS reversal commonly occurred between Days 3 and 7 (range 2-14 days) and the mean maximal decrease in SCr in all terlipressin patients was observed after approximately 7 days. However, HRS reversal continued to occur up to Treatment Day 14.
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Based on the finding in study OT-0401, that patients without any SCr decrease by Day 4 did not achieve HRS reversal, a change to the duration of therapy is being made for this study. Protocol IK-4001-HRS-301) specifies that these patients must be discontinued on Day 4, rather than on Day 7. In keeping with standard medical practice and current guidelines, it is strongly recommended that albumin be administered to all patients in both study arms. Albumin doses recommended by the IAC are 1 g/kg initially (maximum 100 g) and 20-40 g/day thereafter as clinically indicated.41 It is recommended (if clinically appropriate) that the albumin dose is kept constant during the study drug administration period.
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6.
OBJECTIVES
6.1.
Primary Objective
6.2.
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The primary objective of this study is to confirm the efficacy and safety of intravenous terlipressin versus placebo in the treatment of adult subjects with HRS type 1 receiving standard of care albumin therapy. Efficacy will be demonstrated by confirmed HRS reversal (two SCr values ≤ 1.5 mg/dL at least 48 hrs apart while on treatment).
Secondary Objective(s)
6.3.
Efficacy Variables
6.3.1.
Primary Efficacy Variables
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Secondary objectives of this study are to demonstrate that terlipressin improves renal function and reverses HRS type 1 compared to placebo.
The primary efficacy evaluation will be based on the following:
Confirmed HRS Reversal: the percentage of subjects with two SCr values of ≤ 1.5 mg/dL, at least 48 hours apart, on treatment, (see Section 13.5.1 for details of endpoint definition) 6.3.2.
Secondary Efficacy Variables
Secondary efficacy analyses will be based on the following:
Renal Function: change from baseline through end of treatment in SCr values
•
HRS Reversal: the percentage of subjects with at least one SCr value ≤ 1.5 mg/dL on treatment
•
Transplant-free survival up to 90 days, defined as the time (in days) that each subject survives without liver transplantation from the day of randomization
•
Overall survival up to 90 days, defined as the time (in days) that each subject survives from the day of randomization
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6.3.3.
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•
Other Efficacy Variables
Additional efficacy analyses will be based on the following: •
Glomerular Filtration Rate: change from baseline through end of treatment in GFR calculated using both the Modification of Diet in Renal Disease (MDRD) and CockcroftGault equations
•
Fractional excretion of sodium: change from baseline through end of treatment in calculated fractional excretion of sodium
•
HRS type 1 recurrence until transplantation, hospital discharge, or Day 14, whichever occurs first
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol Dialysis free survival up to 90 days: defined as the time (in days) that each subject survives without dialysis from the day of randomization
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7.
INVESTIGATIONAL PLAN
7.1.
Overall Study Design and Plan: Description
SC
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This is a phase 3, randomized, double-blind, placebo-controlled, multicenter study of intravenous terlipressin administered to subjects with HRS type 1. All subjects who consent to study participation must undergo an in-hospital screening/qualification period of no less than 48 hours to establish the diagnosis of HRS type 1. Written informed consent will be obtained by the principal investigator or sub-investigator from the subject or legally-authorized representative prior to the subject qualification form being completed. Qualified subjects are then randomized in a 1:1 ratio to receive either terlipressin or placebo, stratified by qualifying SCr (< 3.6 mg/dL or ≥ 3.6 mg/dL) and alcoholic hepatitis (present or not). Approximately 150 subjects will be enrolled at 40 - 55 sites in the US and 0 - 10 sites in Canada.
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Subjects will receive up to 14 days of study treatment intravenously every 6 hours (maximum of 15 or 16 days allowed if HRS reversal is first achieved on Days 13 or 14, respectively). Subjects will be contacted on Days 30 (± 7), 60 (± 14), and 90 (± 14) for assessment of survival, renal replacement therapy (RRT) and transplantation. (Figure 2) Subjects will participate in four assessment phases, which includes screening, pretreatment, active, and follow-up assessment phases (see Section 13.2). Schematic Diagram of Trial Design
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Figure 2:
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8.
STUDY POPULATION
8.1.
Population Rationale
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The study population consists of adult subjects with cirrhosis, ascites, and a diagnosis of HRS type 1 based on the 2007 IAC diagnostic criteria.4, 41
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Subjects will be stratified by alcoholic hepatitis (present or not). Alcoholic hepatitis, which results from excessive alcohol consumption, is a well characterized, specific condition, which may complicate cirrhosis and may be a precipitating factor for HRS type 1. In subjects with underlying cirrhosis, alcoholic hepatitis is generally associated with acute-on-chronic liver failure and a poor prognosis. Subjects with alcoholic hepatitis are not candidates for liver transplantation since a six month period of abstinence from alcohol is usually required prior to transplant eligibility. In Study OT-0401, absence of alcoholic hepatitis was a significant predictor for 180-Day Survival. However, some subjects with alcoholic hepatitis improve with appropriate care over a time period similar to that in this proposed study. Treated complications associated with alcoholic hepatitis, such as HRS type 1, may improve coincident with the improvement in the underlying decompensated liver disease. For these reasons, randomization stratified by the presence or absence of alcoholic hepatitis is important to promote an equal distribution of subjects with this diagnosis between treatment groups.
8.2.
TE D
Subjects will also be stratified by qualifying serum creatinine (< 3.6 mg/dL or ≥ 3.6 mg/dL). Qualifying serum creatinine is a prognostic factor for survival and HRS reversal. Excluding subjects with a baseline serum creatinine of > 7 mg/dL (an exclusion criterion for this study), 3.6 mg/dL (N =106) was the mean baseline serum creatinine of subjects enrolled in the Study OT-0401.
Number of subjects to be studied
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Approximately 150 Subjects with HRS type 1 will be enrolled at approximately 40 - 55 investigational sites located in the US and 0 - 10 sites in Canada. Subjects will not be replaced.
Inclusion criteria
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8.3.
Subjects must meet all of the following inclusion criteria to be eligible to enrollment: 1. Written informed consent by subject or legally authorized representative 2. At least 18 years of age 3. Cirrhosis and ascites
4. Rapidly progressive reduction in renal function characterized by: − SCr ≥ 2.5 mg/dL
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol − Doubling of SCr within 2 weeks (or for observations of shorter duration, SCr values over time meeting slope-based criteria for proportional increases likely to be representative of at least a doubling within 2 weeks; see Appendix A)
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Note: Refer to Appendix A for a nomogram intended for use in situations when the SCr value has increased rapidly over a short period of time but has not yet doubled within 2 weeks. The nomogram may be used to determine whether the patient’s SCr values are consistent with a trajectory with a slope likely to be representative of at least a doubling within 2 weeks (SCr values must be documented for a minimum of 4 days).
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In situations where the time elapsed between SCr values is greater than 2 weeks, the investigator must contact the Medical Hotline maintained by the sponsor to discuss patient eligibility. The qualification form, including all available SCr data must be completed by the investigator and forwarded to the sponsor for review and approval prior to enrollment. All communications between investigators and the sponsor regarding a patient’s eligibility, including reasons supporting inclusion in the trial, will be documented. 5. No sustained improvement in renal function (< 20% decrease in SCr and SCr ≥ 2.25 mg/dL) 48 hours after both diuretic withdrawal and the beginning of plasma volume expansion with albumin: Note: Albumin doses recommended by the IAC are 1 g/kg on the first day (maximum 100 g) and 20 - 40 g/day thereafter as clinically indicated.41 It is recommended (if clinically appropriate) that the albumin dose is kept constant during the study drug administration period.
•
Note: The qualifying SCr value is the SCr value at least 48 hrs after both diuretic withdrawal (if applicable) and the beginning of albumin fluid challenge. The qualifying SCr value must be ≥ 2.25 mg/dL AND at least 80% of the diagnostic (prefluid challenge) SCr value.
Exclusion criteria
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8.4.
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•
If any of the following exclusion criteria are met, the subject will not be enrolled:
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1. Serum creatinine > 7 mg/dL 2. Shock •
Note: Hypotension (MAP < 70 mm Hg or a decrease > 40 mm Hg in systolic blood pressure from baseline) with evidence of hypoperfusion abnormalities despite adequate fluid resuscitation.11, 37, 44
3. Sepsis or systemic inflammatory response syndrome (SIRS) •
Note: SIRS: Presence of 2 or more of the following findings: temperature > 38°C or < 36°C; heart rate > 90/min; respiratory rate of > 20/min or a PaCO2 of < 32 mm Hg; white blood cell count of > 12,000 cells/µL or < 4,000/ µL.7, 37
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol •
Note: Sepsis: Documented infection and systemic inflammatory response syndrome.7, 37
4. < 2 days anti-infective therapy for documented or suspected infection 5. Proteinuria > 500 mg/day
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6. Hematuria or microhematuria (> 50 red blood cells per high power field) 7. Clinically significant casts on urinalysis, including granular casts •
Note: Urine sediment examination is required to exclude presence of granular casts and other clinically significant casts (e.g., red blood cell [RBC] casts).
8. Evidence of intrinsic or parenchymal renal disease (including acute tubular necrosis)
SC
9. Obstructive uropathy or other renal pathology on ultrasound or other medical imaging 10. Current or recent treatment (within 4 weeks) with nephrotoxic drugs, e.g., aminoglycosides, nonsteroidal anti-inflammatory drugs (NSAID) Note: Up to 3 doses of an NSAID within the prior month (prescription or over the counter) is acceptable
•
Note: Use of short-term (< 2 weeks) oral neomycin for acute encephalopathy is acceptable.
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•
11. Current or recent (within 4 weeks) renal replacement therapy
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12. Superimposed acute liver failure/injury due to factors other than alcoholic hepatitis, including acute viral hepatitis, drugs, medications (e.g., acetaminophen), or other toxins (e.g., mushroom [Amanita] poisoning) 13. Current or recent treatment (within 48 hours) with octreotide, midodrine, vasopressin, dopamine or other vasopressors 14. Severe cardiovascular disease as judged by investigator
EP
15. Estimated life expectancy of less than 3 days 16. Confirmed pregnancy
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17. Known allergy or sensitivity to terlipressin or another component of the study treatment 18. Participation in other clinical research studies involving the evaluation of other investigational drugs or devices within 30 days of randomization. NOTE: It is recognized that clinical judgment is a component of individual subject assessment, particularly in critically ill subjects with multi-organ disease. If, in the opinion of the investigator, a subject clinically meets the criteria for HRS type 1 but appears to demonstrate a potential deviation from the inclusion or exclusion criteria listed above, the investigator must contact the sponsor or designee to discuss subject eligibility. All communications, including reasons supporting inclusion in the study, will be documented.
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8.5.
Subject Withdrawal criteria
adverse event(s)
•
abnormal laboratory value(s)
•
abnormal test procedure result(s)
•
protocol violation
•
withdrawal of consent
•
lost to follow-up
•
administrative problems
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•
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Subjects have the right to discontinue treatment and/or withdraw from the study at any time without prejudice. The investigator may discontinue any subject at any time for any reason. If study treatment or protocol-specified assessments are discontinued, the reason will be recorded and the sponsor should be notified promptly. Reasons for terminating participation in the clinical study may include the following:
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It is imperative to obtain complete follow-up data for all randomized subjects, whether or not they received their assigned study treatment or discontinued study medication prematurely. Every attempt should be made to collect follow-up information, including required laboratory tests and mortality assessments, except for those subjects who specifically withdraw consent for release of such information. Subjects withdrawn from treatment due to an adverse event should be followed until the event resolves or stabilizes.
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9.
PROTOCOL DEVIATIONS
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This study will be conducted as described in this protocol, except for an emergency situation in which the protection, safety, and well being of the subject requires immediate intervention that deviates from the protocol, based on the judgment of the investigator (or a responsible, appropriately trained professional designated by the investigator). In the event of a significant deviation from the protocol due to an emergency, accident, or error, the investigator or designee must contact the sponsor, or their agent, at the earliest possible time by telephone. This will allow an early joint decision regarding the subject’s continuation in the study. The investigator and the sponsor will document this decision. The IRB or Independent Ethics Committee (IEC) will be informed of all protocol deviations by the investigator in accordance with the IRB or IEC established procedure. No deviations from the protocol of any type will be made without complying with all the IRB or IEC established procedures.
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10.
TREATMENT OF SUBJECTS
10.1.
Terlipressin
10.1.1.
Initial Dosing
RI PT
Each subject will be assigned a blinded study kit containing study medication and commercially available sterile normal saline for reconstitution. Under no circumstance is it permitted to treat a subject with study medication from a kit that was not specifically assigned to him/her.
10.1.2.
SC
Blinded terlipressin for injection will be administered intravenously as a slow bolus injection over 2 minutes at a dose of 1 mg (1 vial) every 6 hours (4 mg/day). Dose Modifications
M AN U
If on Day 4 of therapy (after a minimum of 10 doses), serum creatinine has decreased, but by less than 30% from the baseline value, the dose will be increased to 2 mg every 6 hours (8 mg/d). The dose will not be increased if the subject has coronary artery disease; or in the clinical setting of circulatory overload, pulmonary edema, or treatment-refractory bronchospasm. If in the investigator’s judgment, a dose increase is not advisable or otherwise justified in the individual subject, the reason(s) for not increasing the dose of study medication will be documented on the case report form (CRF).
10.2.
Placebo
TE D
If dosing is interrupted due to a non-ischemic adverse event, terlipressin may be restarted, at the discretion of the investigator, at the same or lower dose (i.e., 0.5-1 mg q6h).
The dosing regimen for blinded placebo medication is identical to the above described blinded terlipressin for injection regimen.
Blinding
EP
10.3.
10.4.
AC C
This study will be double-blinded using matching 6-mL placebo glass vials containing lyophilized mannitol without the active ingredient terlipressin, and 6-mL vials with lyophilized mannitol as the inert carrier compound containing 1 mg terlipressin acetate.
Randomization
Subjects will be randomly assigned via an interactive voice response system (IVRS) to treatment groups in order to minimize bias based upon subject selection and baseline characteristics. Subjects will be stratified by qualifying SCr (< 3.6 mg/dL or ≥ 3.6 mg/dL) and presence/absence of alcoholic hepatitis and equally randomized (1:1) to receive either active terlipressin or matching placebo. Each investigational site will receive kits of blinded, labeled active and placebo vials each numbered with unique, randomized kit identification numbers. The kit labels will include treatment disclosure areas in case of the need for emergency unblinding in the event that definite Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol knowledge of the study medication is essential for the medical treatment of the subject (see Section 12.1.2). The randomization codes will be generated by an independent statistician and will not be accessible to the sponsor, investigator, or other site personnel (unless required during a medical emergency) during the trial period.
Retreatment
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10.5.
Discontinuation of Treatment
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10.6.
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If judged by the investigator to be potentially beneficial, subjects who demonstrated at least a 30% decrease in SCr from baseline value during the initial treatment cycle and subsequently develop recurrence of HRS type 1 (as defined by 2007 IAC criteria), may be retreated once with the initially assigned blinded study medication for a maximum of 14 days (treatment and study procedures are identical to the initial therapy). The subject must meet the same inclusion/ exclusion criteria (Sections 8.3 and 8.4) and the sponsor must be contacted prior to initiation of retreatment. Subjects are not re-randomized for the retreatment cycle.
Treatment will continue until at least two SCr values ≤ 1.5 mg/dL have been obtained at least 48 hours apart, or up to 14 days (maximum of 15/16 days if SCr first reaches 1.5 mg/dL on Day 13/14, respectively). If on Day 4 (after a minimum of 10 doses), SCr is at or above the baseline value, study medication will be discontinued. Treatment must be discontinued when the subject is to undergo RRT or transplantation.
TE D
Dosing must be permanently discontinued if an ischemic event occurs.
Concomitant Medication
10.7.1.
Recommended Concomitant Medication
10.7.1.1.
Albumin
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10.7.
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In keeping with standard medical practice and current guidelines, it is strongly recommended that albumin be administered to all subjects in both study arms. Albumin doses recommended by the IAC following the albumin fluid challenge are 20-40 g/day as clinically indicated.41 It is recommended (if clinically appropriate) that the albumin dose is kept constant during the study drug administration period. 10.7.1.2.
Prohibited or Discouraged Concomitant Medications
The following medications are prohibited or strongly discouraged during treatment with study medication. (Table 3)
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol Table 3:
Prohibited/Discouraged Concomitant Medications Prohibited Concomitant Medications
Octreotide Prostaglandin analogs (e.g., misoprostol) NSAIDs (e.g., ibuprofen, naproxen, diclofenac) Discouraged Concomitant Medications
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Midodrine and other vasopressive drugs including vasopressin, dopamine, dobutamine, norepinephrine
10.8.
SC
Diuretics are strongly discouraged unless medically required for fluid overload
Treatment Compliance
10.9.
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The treatment, dosage and time of administration for each dose of study drug will be documented. A monitor will review subject source documents and drug accountability records to assess treatment compliance on an ongoing basis during site visits.
Medical Hotline
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The sponsor will maintain a 24-hour Medical Hotline for investigators to discuss patient issues including enrollment eligibility, unblinding, and retreatment. All Hotline communications will be documented.
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11.
STUDY DRUG MATERIAL AND MANAGEMENT
11.1.
Description of Terlipressin for Injection
Figure 3:
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Single-use, sterile 6-mL vials containing a lyophilized solid of 1 mg terlipressin acetate (equivalent to 0.85 mg terlipressin free base) with 10 mg mannitol as a bulking agent/stabilizer will be provided by the sponsor. The batch number will be documented in the trial master file. Lucassin® (Terlipressin for Injection)
Molecular Formula: C52 H74 N16 O15 S2
H Gly Gly
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Structure:
1227.4 daltons
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Molecular Weight:
Gly
Tyr
Cys
Phe
Cys
Gln
Asn
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Pro Lys
Gly
Homogenous lyophilized white to off-white solid
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Appearance:
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H2 N
Solubility:
Clear, colorless solution in saline
Vials:
Colorless glass vials containing 11 mg of a white to off-white solid, 1 mg active ingredient and 10 mg mannitol.
The active ingredient, N-[N-(N-glycylglycyl)glycyl]-8-L-lysinevasopressin, is a synthetically manufactured hormonogen of 8-lysine vasopressin, composed of 12 amino acids and having the characteristic ring structure of a cyclic nonapeptide with a disulfide bridge between the fourth and the ninth amino acid. Three glycyl-amino acids are substituted at position 1 (cysteine) of 8lysine-vasopressin. By this N-terminal extension of 8-lysine-vasopressin the metabolic Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol degradation rate of the active ingredient is significantly reduced, because the glycyl molecules inhibit rapid N-terminal enzymatic degradation.
11.2.
Packaging and Labeling
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Single-use, sterile 6-mL vials of a lyophilized solid containing 1 mg of terlipressin acetate (equivalent to 0.85 mg terlipressin free base) with mannitol or matching placebo (mannitol only) will be provided to the sites in kits of 36 vials each. Study drug labels will comply with local regulatory requirements, including sponsor name and address, protocol number, kit number, storage conditions and US IND caution statement.
11.3.
Study Drug Storage and Preparation
SC
Commercially available 5-mL vials of sterile 0.9% sodium chloride for injection will be provided to the sites for reconstitution of the terlipressin or matching placebo.
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Study drug should be stored in a secure location at 15ºC - 25ºC until reconstitution and can be stored up to 24 hours at refrigerated storage conditions (2ºC - 8ºC) once reconstituted with the sterile 0.9% NaCl solution provided. Access will be strictly limited to the investigators and their designees. 11.3.1.
Reconstitution
11.3.2.
Administration
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Study drug must be reconstituted with the provided sterile 0.9 % sodium chloride solution (5mL).
Reconstituted study drug should be administered via a slow bolus (IV push over 2 minutes). See Section 10.1 for details. After study drug administration the line should be flushed with saline.
Study Drug Accountability
EP
11.4.
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The investigator or designee must maintain an inventory record of study medication administered to assure the regulatory authorities and the sponsor that the investigational new drug will not be dispensed to any person who is not a subject under the terms and conditions set forth in this protocol. Neither the investigators nor any designees may provide study medication to any subject not formally enrolled in this protocol. The study medication supplied for use in this study is to be prescribed only by the principal investigator or named sub-investigators and may not be used for any purpose other than that outlined in this protocol. All unused investigational product will be handled as outlined in the pharmacy manual. Periodic review of drug accountability records will be conducted by investigational site monitors. Final review and reconciliation of the accountability records will be performed by the sponsor.
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RANDOMIZATION, BREAKING OF BLINDED CODES
12.1.
Randomization and blinding
12.1.1.
Randomization
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12.
The investigator will complete the subject qualification form along with the required supportive documentation (including SCr values during hospitalization and details of albumin fluid challenge administration and diuretic withdrawal) and forward to the sponsor for review and approval of subject enrollment.
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Randomization will occur only after a diagnosis of HRS type 1 is established, written informed consent has been obtained from the subject or representative and subject eligibility is confirmed. Once a subject is randomized, the subject is considered a study participant. Even if study medication is not subsequently administered, the subject must be followed-up for mortality assessments. Approximately 150 subjects will be randomized via an IVRS. Each successive subject will be assigned a unique identification number. Allocation will be made to one of two treatment groups, i.e., terlipressin or placebo in a 1:1 ratio. Both treatment groups will be studied concurrently. Randomization will be stratified by qualifying SCr (< 3.6 mg/dL or ≥ 3.6 mg/dL) and alcoholic hepatitis (present or not). 12.1.2.
Blinding of Study Medications
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The active and placebo vials will be labeled with single panel labels comprised of the randomized identification numbers for each kit to maintain the blinding of the randomized treatments. The kits will be labeled with identification number specific two-part tear-off labels with emergency treatment disclosure panels. At the time of randomization, the tear-off portion of the kit label will be detached and affixed to the drug accountability log.
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The study medication labels will bear the sponsor name and address, protocol number, kit number, directions for refrigerated storage, and the US Investigational New Drug (IND) caution statement. For sites outside of the US, additional country-specific required labeling will be added. 12.1.3.
Unblinding of Treatment Assignment
Unblinding of treatment assignment should be done only in the event that definite knowledge of the study medication is essential for the medical treatment of the subject. In the event that unblinding of an individual subject is required, the site pharmacist will be able to unblind the study code by swabbing the identification label from the pre-packaged study medication kit assigned to the subject. The sponsor must be immediately informed of any unblinding and the site must document the date and reason for unblinding in writing.
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13.
ASSESSMENTS AND PROCEDURES
13.1.
Schedule of Assessments and Procedures
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Table 4 presents the schedule of assessments and procedures to be performed during the study.
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IK-4001-HRS-301 Protocol Schedule of Assessments Pre-Treatment Period
X
Informed Consent
X
Verification of Study Qualification
X
Randomization
X
Medical History
Days 1-14
X
Prior Medications
X
Concomitant Meds
X
2
Height 12-lead ECG Child-Pugh Score Blood sample for genetic markers
3
PK sampling Study Medication Administration5 Vital Signs (BP, HR)
6
Serum Creatinine & BUN7 8
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Weight
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Physical Exam
Serum Electrolytes
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Diagnosis of HRS type 1 established
Study Entry Baseline Assessment
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Screening Period
Study Assessment
Active Study Period
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Table 4:
X
X
X X X X X X X
X4 <-------X------>
X
<-------X------>
X
<-------X------>
X
<-------X------>
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Follow-up Period (days from 1st dose)1 30 day (± 7 days)
60 day (± 14 days)
90 day (± 14 days)
ACCEPTED MANUSCRIPT
IK-4001-HRS-301 Protocol
Screening Period
Study Assessment
Encephalopathy Score
8
X
8
X
ALT, AST, ALP, Protein, Albumin, Bilirubin9
X
9
INR
X
9
CBC & Differential9 9
Spot Urine Creatinine & Sodium
Serious Adverse Event11 HRS type 1 Recurrence Assessment Mortality Assessment Renal Replacement Therapy Assessment Transplantation Assessment 1
<-------X------> <-------X------> <-------X------>
X
<-------X------>
X
<-------X------>
X
<-------X------>
X
<-------X------>
EP
Nonserious Adverse Event
10
90 day (± 14 days)
<-------X------>
X
AC C
MELD Score (sponsor calculation)
9
TE D
Fractional Excretion of Sodium (sponsor calculation) 9
60 day (± 14 days)
<-------X------>
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Serum Glucose, Calcium, Magnesium
Days 1-14
30 day (± 7 days)
SC
GFR (sponsor calculation)
Study Entry Baseline Assessment
Active Study Period
RI PT
Pre-Treatment Period
Follow-up Period (days from 1st dose)1
<-------X------> <-------X------>
<---X-->
<-------X------->
<-X12->
<-----------------------------------X----------------------------------> <-----------------------------------X----------------------------------> <-----------------------------------X---------------------------------->
Follow-up assessments must also be completed for subjects randomized but not treated with study medication Concomitant medications include Albumin, IV solutions and blood products 3 Optional 4 Pre-determined PK time points are randomly assigned as described in Section 13.5.5 5 Maximum treatment 15/16 days if HRS reversal first achieved on Day 13/14 6 Vital sign measurements: Time points for FIRST DOSE ONLY: Pre dose & Post dose at 5 min, 30 min, 1 hr, 2 hr, 4 hr: Time points all other doses: Pre dose & 2
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IK-4001-HRS-301 Protocol Post dose at 5 min and 2 hr Must be performed at least once daily during active treatment AND until Day 14 (regardless of treatment status) or discharge, whichever occurs first 8 Once daily during treatment days 9 Treatment Days 1, 3 and 7 and at treatment termination. 10 Up to 7 days post end of treatment 11 Up to 30 days post end of treatment 12 Up to 30 days post end of treatment based on SAE data
AC C
EP
TE D
M AN U
SC
RI PT
7
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13.2.
Study Assessment Phases
13.2.1.
Subject Screening Phase
SC
RI PT
The screening period occurs prior to enrollment and consists of establishing the diagnosis of HRS type 1 as per guidelines and standard medical practice and confirming eligibility for study participation. The investigator will complete the subject qualification form along with the required supportive documentation (including SCr values during hospitalization and details of albumin fluid challenge administration and diuretic withdrawal) and forward to the sponsor for review and approval of subject enrollment. Written informed consent will be obtained by the principal investigator or sub-investigator from the subject or legally-authorized representative prior to the subject qualification form being completed. Subjects screened but not enrolled in the trial for any reason should be recorded on the screening log. These subjects are not considered study participants and no additional follow-up is required. Pre-Treatment Phase
M AN U
13.2.2.
The pre-treatment period occurs prior to administration of study medication and includes collection of baseline assessments.
13.2.3.
TE D
The qualifying SCr value (SCr value at least 48 hrs after both diuretic withdrawal and the beginning of albumin fluid challenge) is considered the baseline SCr and must be drawn no more than 8 hours prior to start of study medication. The qualifying SCr value must be ≥ 2.25 mg/dL AND at least 80% of the diagnostic (pre-fluid challenge) SCr value. If there is a delay in subject randomization, then the qualifying/baseline SCr value must be redrawn so that the value is collected within 8 hours prior to the start of study medication. Other baseline assessments must be performed no more than 24 hours prior to start of study medication. Active Study Phase (14 Days)
EP
The active study period extends from the initiation of study treatment through Day 14 (Day 15/16 as described in Section 10.1) or discharge from the hospital for any reason, whichever occurs first. Study medication will be administered as described in Section 10. See Table 4 for the Schedule of Assessments during the active study period. Follow-up Phase
AC C
13.2.4.
The follow-up period begins after the end of the study treatment and concludes 90 days following the start of treatment. All subjects will be contacted by telephone for follow-up on Days 30 (± 7), 60 (± 14), and 90 (± 14) to assess survival, RRT, and transplant status. Study days will be counted from first day of study medication administration (or from randomization for those subjects who do not receive study medication).
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13.3.
Detail of Safety Assessments and Procedures
•
at baseline with the physical examination
•
prior to each dose of study medication
•
first dose only: post dose at 5 min, 30 min, 1hr, 2hr, 4hr
•
all other doses: post dose at 5 minutes and 2 hours
RI PT
13.3.1. Vital Sign Measurements Vital sign measurements include heart rate and blood pressure and will be recorded during the following time points:
West Haven Criteria for Semiquantitative Grading of Mental State15
M AN U
Table 5:
SC
13.3.2. Encephalopathy Score Clinically detectable encephalopathy is to be assessed prior to study drug administration and daily during study medication administration using the clinical criteria described in Table 5.
Trivial lack of awareness Euphoria or anxiety Shortened attention span Impaired performance of addition
Grade 2
Lethargy or apathy Minimal disorientation for time or place Subtle personality change Inappropriate behavior Impaired performance of subtraction
Grade 3
Somnolence to semi-stupor, but responsive to verbal stimuli Confusion Gross disorientation
Grade 4
Coma (unresponsive to verbal or noxious stimuli)
AC C
EP
TE D
Grade 1
13.3.3.
Model for End-Stage Liver Disease (MELD) Score
Model for end-stage liver disease (MELD) scores will be calculated by the sponsor based on SCr, bilirubin and INR values at baseline and treatment Days 1, 3, 7 and treatment termination. 13.3.4.
Adverse Events
All adverse events (serious and non-serious) will be assessed and recorded beginning with initiation of study medication administration (treatment-emergent) until seven (7) days after discontinuation of study medication. Serious adverse events will be assessed and recorded until 30 days after discontinuation of study medication. Deaths will be reported up to 90 days in all
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol subjects randomized (including randomized subjects who did not receive study medication for any reason). Those events that are serious in nature must be reported to the Sponsor or its designee for safety reporting in an expedited manner (see Section 14 for definitions and reporting requirements).
Detail of Laboratory Assessments and Procedures
13.4.1.
Local Laboratory at Investigational Site
RI PT
13.4.
13.4.1.1.
Serum Electrolytes & Biochemistry
SC
The laboratory tests specified in this section will be performed in the laboratory at the investigational site.
•
creatinine
•
BUN
M AN U
The following assessments are required at baseline, then once daily during treatment (max 16 days) and daily until Day 14 or hospital discharge (whichever occurs first), regardless of treatment status:
If SCr and/or BUN assessments are performed more than once daily as part of the subject’s medical care, all values are to be recorded on the CRF.
•
sodium
•
potassium
•
chloride
•
CO2
TE D
The following assessments are required at baseline, then once daily during treatment with study medication (max 16 days):
total bilirubin
AC C
•
EP
The following assessments are required at baseline and on Treatment Days 1, 3, 7, and, whenever possible, at treatment termination: •
alkaline phosphatase (ALP)
•
alanine amino transferase (ALT; SGPT)
•
aspartate amino transferase (AST; SGOT)
•
total protein
•
albumin
•
magnesium
•
calcium
•
glucose
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Hematology
•
INR
•
complete blood count and differential
13.4.1.3.
RI PT
The following assessments are required at baseline and on Treatment Days 1, 3, 7, and, whenever possible, at treatment termination:
Urine
spot sodium
•
spot creatinine
Detail of Efficacy Assessments and Procedures
M AN U
13.5.
•
SC
The following assessments are required at baseline and on Treatment Days 1, 3, 7, and, whenever possible at treatment termination:
Serum creatinine must be collected at baseline, once daily during treatment (see Section 13.4.1.1); and then once daily (regardless of treatment status) until Day 14 or hospital discharge, whichever occurs first. If SCr assessments are performed more than once daily as part of the subject’s medical care, all values obtained each day will be recorded on the CRF. Serum creatinine values obtained after liver transplantation or RRT will be excluded from the efficacy evaluation. 13.5.1.
Primary Efficacy Variables
TE D
Confirmed HRS Reversal: The percentage of subjects with two SCr values of ≤ 1.5 mg/dL at least 48 hours apart, on treatment, and without intervening RRT or liver transplant.
EP
The time window in which the second and confirmatory SCr value of ≤ 1.5 mg/dL can occur is a minimum of 40 hours (i.e., 48 hours minus an 8 hour window) from the first SCr value of ≤ 1.5 mg/dL and a maximum of 24 hours after the last dose of study medication (i.e., “on treatment”). In the event of liver transplantation or hospital discharge (alive) less than 48 hours after HRS reversal (i.e., the first SCr value of ≤ 1.5 mg/dL), a second and confirmatory SCr value at least 22 hours (i.e., 24 hours minus a 2 hour window) later is acceptable.
AC C
The two SCr values of ≤ 1.5 mg/dL values on treatment do not have to be sequential but any intervening values must not be ≥ 1.8 mg/dL. All SCr values recorded each day will be evaluated. The date and time of the first observed SCr value of ≤ 1.5 mg/dL on treatment (HRS reversal) will be used for calculating the time window for the confirmatory SCr value. The first SCr value of ≤ 1.5 mg/dL occurring during the time window for confirmation will be selected as the second and confirmatory value. Any SCr values obtained post liver transplantation (defined as time subject is transferred from ward to the operating room [OR]) or post-RRT (defined as the time RRT is started) will be excluded from the efficacy analysis.
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol Secondary Efficacy Variables
13.5.2.
Secondary efficacy analyses will be performed in a nested sequential manner in the following order: •
Renal Function
RI PT
Repeated measures analysis of change from baseline through end of treatment in renal function assessed by the daily serum creatinine values.
− SCr values from baseline through end of treatment (up to 24 hours after the last dose) will be used in the analysis. For each subject, the on-treatment mean daily SCr value will be calculated and used in the analysis. Any SCr values obtained post liver transplantation or RRT will be excluded from analysis. HRS Reversal
SC
•
•
Transplant-Free Survival
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− Incidence of HRS Reversal is defined as at least one SCr value of ≤ 1.5 mg/dL on treatment (up to 24 hours after the last dose of study medication). Any SCr values obtained post liver transplantation or RRT will be excluded from the analysis. − Transplant-Free Survival up to 90 days, defined as the time (in days) that each subject survives without liver transplantation from the day of randomization. •
Overall Survival
13.5.3.
TE D
− Overall Survival up to 90 days, defined as the time (in days) that each subject survives from the day of randomization. Other Efficacy Variables
Additional analyses will be based on the following: •
Glomerular Filtration Rate (GFR)
Fractional excretion of sodium (FENa)
AC C
•
EP
− Repeated measures analysis of change from baseline through end of treatment in the mean daily sponsor-calculated GFR using both MDRD and Cockcroft-Gault equations. − Repeated measures analysis of change from baseline through end of treatment in sponsor-calculated fractional excretion of sodium (measured at baseline and on Treatment Days 1, 3, 7 and end of treatment).
•
HRS Type 1 Recurrence until transplantation, hospital discharge, or Day 14, whichever occurs first. − Incidence of HRS type 1 recurrence defined as a SCr value of ≥ 2.5 mg/dL in the absence of other causes of renal impairment as described in the IAC 2007 criteria. − Any subject with a SCr value of ≥ 2.5 mg/dL after achieving two SCr values of ≤ 1.5 mg/dL (confirmed HRS reversal), but prior to transplant/discharge/day 14
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RI PT
will be assessed for HRS type 1 recurrence. Hepatorenal Syndrome type 1 recurrence is another episode of HRS type 1 as per the protocol inclusion/ exclusion criteria (see Sections 8.3 and 8.4). The investigator will determine whether the subject has had a recurrence of HRS type 1. If the investigator cannot exclude a recurrence of HRS type 1, then the subject will be considered to have HRS type 1 recurrence. − Recurrence of HRS type 1 during the follow-up period (after discharge or Day 14) will also be assessed based upon the investigator’s opinion and SAE data collected up to 30 days post end of treatment.
13.5.4.
Dialysis free survival up to 90 days: defined as the time (in days) that each subject survives without dialysis from the day of randomization
SC
•
Other Exploratory Analyses
M AN U
Other exploratory, sensitivity and subgroup analyses will be performed as appropriate. Examples of potential exploratory analyses include: Time to Transplantation up to 90 days summarized descriptively for only those subjects who undergo transplantation. Time to transplantation will be summarized as a continuous variable by treatment group, with descriptive statistics such as N, mean, standard deviation, median, minimum and maximum.
•
Transplant-free survival and overall survival of responders versus non-responders for the endpoints of Confirmed HRS Reversal and HRS Reversal.
•
Evaluation of efficacy outcomes for baseline prognostic factors.
TE D
•
13.5.5.
Pharmacokinetics
EP
In order to characterize the pharmacokinetics of terlipressin, as well as to examine the influence potential covariates, blood samples will be obtained from all subjects for determination of terlipressin and its metabolite lysine-vasopressin if possible. In consideration of the subjects’ conditions, a sparse sampling approach will be used to collect blood samples from each subject. The data will be subject to population pharmacokinetic analysis using NONMEM.
AC C
A baseline sample will be taken from all subjects prior to receipt of any medications. Three additional samples will be taken based on randomization assignments during the first dosing interval on Day 1. The first time point will be randomly assigned from one of the 6 time points of TIMEPOINT A, the second time point from one of the 4 time points of TIMEPOINT B, and third time from one of the 4 time points of TIMEPOINT C for each subject. The assigned blood collection time points will be provided to the sites at the time of randomization. •
TIMEPOINT A (~ 0.083 hr): 5, 6, 7, 8, 9, 10 min (± 1 min)
•
TIMEPOINT B (early phase): 0.5, 1, 1.5, and 2 hr (± 5 min)
•
TIMEPOINT C (late phase): 3, 3.5, 4 and 5 hr (± 10 min)
If study medication is discontinued due to a serious AE, an additional blood sample will be taken at the time of discontinuation, if feasible. Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol Sites will be instructed as to the importance of maintaining adequate records with respect to the time of dosing and the obtaining of the blood samples, as to the proper labeling of containers, the importance of prompt and proper sample processing, and storage of samples.
RI PT
Blood samples (7mL each) will be processed within 30 min, following sample collection and handling procedures provided by the sponsor. Plasma will be stored under controlled conditions at -20°C prior to shipment to the analytical site for analysis.
SC
A previously developed population PK model will be used to characterize pharmacokinetics of terlipressin and its active metabolite lysine-vasopressin if quantifiable in HRS type 1 subjects and also to evaluate covariate factors that may affect terlipressin pharmacokinetic parameters. Terlipressin and lysine-vasopressin data will be fitted simultaneously to a linear threecompartment PK model. Exposure and response relationship will be explored using an appropriate PK- PD model such as linear or Emax model. Cmax, or AUC will be used as the drug exposure and MAP, BP, and HR will be used as a response endpoint.
Optional Sub-Study for Biomarker Genetic Assessments
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13.6.
All subjects will be invited to participate in a biomarker genetic evaluation. Blood samples for this evaluation will be collected on a voluntary basis; participation in this project will not affect participation in the main study. Samples will be used only for research purposes to identify potential biomarkers which may reflect treatment response, hemodynamic effects, or the benefitrisk of terlipressin treatment. Subjects must provide additional informed consent in order to participate in this portion of the study. In the event that a site’s IRB does not approve this portion of the study, this section will not be applicable. Genetic Assessments
TE D
13.6.1.
EP
Whole blood for DNA analysis will be collected from consenting subjects. Genetic samples collected for analysis of DNA sequence variations will be double coded (i.e., an independent code will be added to the first standard code to increase data protection). The plans for analysis of DNA samples include, but are not limited to, single nucleotide polymorphisms (SNPs) in the promoter region of the vasopressin V1 receptor gene and genome wide association scans to study genetic variation at other single nucleotide polymorphism levels.
AC C
All specimens collected for this portion of the study will be destroyed 15 years after the completion of the study unless keeping the specimens longer than the 15 year period is required by regulatory authorities. These samples will be used for research purposes only. Specific use of the specimens as described above is governed by the sponsor to ensure the appropriate use of the samples. The sampling procedures, storage conditions and shipment instructions for participating sites will be provided in the Laboratory Manual. The total additional volume of blood loss for biomarker genetic assessments will be approximately 10 mL per subject.
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ADVERSE EVENTS
14.1.
Definitions
14.1.1.
Adverse Event
RI PT
14.
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment.
14.1.2.
SC
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Serious Adverse Event
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A serious adverse event is any untoward medical occurrence that at any dose: results in death
•
is life-threatening, i.e., the subject was, in the opinion of the investigator, at immediate risk of death from the event as it occurred (It does not include an event that, had it occurred in a more severe form, might have caused death.)
•
results in persistent or significant disability/incapacity
•
requires in-patient hospitalization or prolongs hospitalization
•
is a congenital anomaly/birth defect
•
is another medically significant event that, based upon appropriate medical judgment, may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed above (e.g., allergic bronchospasm requiring intensive treatment in an emergency room or home, blood dyscrasias or convulsions that do not result in hospitalization, or the development of drug dependency or drug abuse)
EP
TE D
•
AC C
A distinction is to be drawn between serious and severe adverse events. A severe adverse event may not be serious and a serious adverse event need not be considered severe. The term “severe” is used to describe the intensity of a specific event (as in mild, moderate, severe). However, the event itself may be of minor medical significance (e.g., severe headache). This is not the same as “serious,” which is based on subject/event outcome or action criteria usually associated with events that pose a threat to a subject’s life or functioning.
14.2.
Severity And Causality Assessments For Adverse Events
14.2.1.
Severity Assessment
Adverse experiences will be graded on a 3-point scale and reported as indicated on the case report form. The intensity of an adverse experience is defined as follows: Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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Discomfort noticed, but no disruption to daily activity.
2 = Moderate: Discomfort sufficient to reduce or affect normal daily activity. 3 = Severe:
Study Medication Causality
RI PT
14.2.2.
Inability to work or perform normal daily activity.
Relationship of an adverse experience to treatment will be assessed as follows:
1 = Unrelated: an AE that is clearly and incontrovertibly due to extraneous causes (disease, environment, etc.) and does not meet the criteria for ‘possible’ or ‘probable.’
SC
2 = Possible: the connection between the AE and study treatment appears unlikely, but cannot be ruled out with certainty. An AE may be considered ‘possibly related’ if it has at least two of the following: 1. It follows a reasonable temporal sequence from administration of study medication.
M AN U
2. It may readily have been produced by the subject's clinical state or by environmental or toxic factors. 3. It follows a known response pattern to study product.
3 = Probable: an AE that is considered to be related to study treatment with a high degree of certainty. An AE may be considered probably related to test product if: 1. It follows a reasonable temporal sequence from administration of study treatment. It cannot be reasonably explained by the known characteristics of the subject's clinical state
TE D
2. It follows a known pattern of response to study treatment. 3. It reappears upon re-challenge.
Collection, Recording and Reporting of Adverse Events
14.3.1.
Adverse Event Recording
EP
14.3.
AC C
Adverse events will be collected beginning with the administration (includes retreatment) of study drug (treatment-emergent). The investigator will assess the seriousness and intensity (severity) of all adverse events and the causal relationship to study medication Non-serious adverse events will be assessed and recorded on the Case Report Form for the time period from the start of administration of study medication until 7 days after discontinuation of study medication, regardless of causal relationship to study medication. All serious adverse events (SAE) will be assessed and recorded on the Case Report Form for the time period from the start of administration of study medication up to 30 days post end of study medication administration regardless of causal relationship to study medication. The Serious Adverse Event Report (SAER) form must be completed and submitted to the sponsor within 24 hours of awareness of the SAE. Deaths All deaths that occur up to 90 days will be reported as serious adverse events, regardless of underlying cause or causal relationship to study medication. Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol Hospitalizations Planned hospital admissions and/or planned surgical operations for an illness or disease, which existed before the subject was randomized are not to be considered adverse events (e.g., rehospitalization for liver transplantation). However, baseline conditions, which deteriorate during the clinical study may be considered adverse events.
RI PT
Following the initial hospital discharge, all rehospitalizations within 30 days post end of treatment (except for planned hospital admissions or procedures as described above) are to be recorded as SAEs. Rehospitalizations will require an investigator assessment and opinion regarding possible recurrence of HRS type 1. Complications of the Disease
SC
Complications frequently associated with HRS type 1 are expected to occur, but should still be recorded as AEs or SAEs as applicable, for example esophageal variceal hemorrhage (EVH), hepatic encephalopathy, sepsis, pneumonia, urinary tract infection (UTI) etc.
14.3.2.
M AN U
Since HRS type 1 is the indication under investigation worsening/aggravation of HRS during the active treatment period (including non-response) will not be recorded as an SAE unless HRS is the cause of death or results in a subsequent rehospitalization due to suspected recurrence Procedure for Serious Adverse Event Reporting
EP
TE D
The investigator must complete the Serious Adverse Event Report (SAER) form for each serious adverse event and all deaths, regardless of causal relationship to study medication. The SAER must be submitted to the Sponsor (or designee) within 24 hours from the point in time when the study staff becomes aware of the SAE. The information provided must be sufficient to allow for independent medical assessment of the event and should include information on concomitant medications, results of relevant laboratory and diagnostic tests, and relevant medical history. The Sponsor (or designee) will contact the investigator should it be necessary to clarify any information. The investigator should provide any additional follow-up information regarding the SAE as soon as it becomes available. All serious adverse events should be followed until resolution or stabilization.
AC C
Any SAE must be reported on a Serious Adverse Event form to Ikaria Therapeutics LLC within 24 hours of an Investigator becoming aware of the event by fax to: Drug safety and Surveillance Fax: +1-908-238-6635
The initial SAE form does not need to be signed by the Investigator; however, a signed SAE form is required within 72 hours of faxing to Ikaria Therapeutics LLC. The initial fax by the Investigator will include a detailed description of the event including start and stop dates, causality assessment by the Investigator, and supported as needed with written copies of medical records, autopsy reports, and other appropriate documents. The investigator must also report SAEs to their local IRB/IEC as required by their institution.
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15.
STATISTICAL PLAN
SC
RI PT
This is a randomized, double-blind, placebo-controlled, multicenter study of intravenous terlipressin in subjects with HRS type 1. All subjects who consent to study participation must undergo an in-hospital screening/qualification period of no less than 48 hours prior to enrollment in order to establish the diagnosis of HRS type 1. Written informed consent will be obtained by the principal investigator or sub-investigator from the subject or legally-authorized representative prior to the subject qualification form being completed. Qualified subjects are then randomized in a 1:1 ratio to receive either terlipressin or placebo, stratified by qualifying SCr (< 3.6 mg/dL or ≥ 3.6 mg/dL) and alcoholic hepatitis (present or not). Approximately 150 subjects are planned to be enrolled at 40 - 55 sites in the United States and 0 - 10 sites in Canada.
15.1.
M AN U
Randomization will be done dynamically using an IVRS stratified by qualifying SCr (< 3.6 mg/dL or ≥ 3.6 mg/dL) and alcoholic hepatitis (present or not). Subjects will receive up to 14 days of study medication (maximum 16 days in pre-specified cases, see Section 10.4), administered intravenously 4 times per day. A Data Safety Monitoring Board (DSMB) will review safety data throughout the study as outlined in the DSMB charter.
Safety Variables
Safety variables will include the following: adverse events
•
serious adverse events, including deaths
•
general safety profile
TE D
•
The general safety profile will include vital signs; change from baseline through end of treatment in MELD score, encephalopathy score and laboratory parameters other than SCr.
15.2.
AC C
EP
Adverse events will be collected during treatment and up to 7 days post end of treatment. Serious adverse events will be collected up to 30 days post end of treatment. Deaths up to 90 days will be reported as SAEs. Adverse events will be classified by Medical Dictionary for Drug Regulatory Activities (MedDRA) system organ class, preferred term, severity, and seriousness, as well as by the investigator's assessment of the relationship of the adverse event to the study medication.
Subject Accounting and Baseline Characteristics
A summary of the study completion status and reasons for discontinuation will be provided for each treatment group. Baseline characteristics (age, gender, race, etc.) will be summarized. The number of subjects with medical conditions within each body system will be reported. Summaries of the extent of exposure and protocol deviations will also be provided.
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15.3.
Statistical Methodology
15.3.1.
Sample Size Calculation
15.3.2.
RI PT
In the OT-0401 study, for subjects with baseline SCr ≤ 7 mg/dL, the confirmed HRS reversal rate in the placebo group was 12.5% (7/56). The rate for terlipressin was 36% (18/50). Onehundred-and-fifty subjects (75 subjects per group) will provide 90% power to detect a statistically significant (p ≤ 0.05 two-sided test) difference between the two treatment groups. Patient Populations
15.3.2.1.
Intention to Treat (ITT) Population
SC
The populations that will be utilized for this study are defined below.
15.3.2.2.
M AN U
The ITT population is defined as all randomized subjects who had at least one baseline assessment. Treatment classification will be based on the randomized treatment. The ITT population defined in this way complies with the ITT principle expressed in ICH E-9. This will be the primary population for analysis of efficacy endpoints. Safety Population
The safety population is defined as all randomized subjects who received at least one dose of study medication (terlipressin or placebo). Treatment classification will be based on the actual treatment received. Per Protocol (PP) Population
TE D
15.3.2.3.
The PP population is defined as all subjects in the ITT population who did not have any major protocol violations (including receiving the wrong study treatment). Major protocol violations will be defined prior to unblinding.
Statistical Analyses
AC C
15.3.3.
EP
A blinded data review meeting will be held prior to database lock. All protocol violations will be reviewed by the study team to determine which violations disqualify the subject from the PP population. Criteria determined to disqualify one subject will be applied consistently to all other subjects.
All statistical analyses will be performed and summary tables and data listings will be prepared using SAS® software version 9.1.3 or higher. All statistical tests will be two-sided with a final significance level of 0.05, unless stated otherwise. When the assumptions for the planned testing methods do not hold, transformations or nonparametric methods may be employed. 15.3.4.
Demographic and Baseline Characteristics
All variables concerning demographic and baseline characteristics will be summarized by treatment group and overall to describe the study population. This will include a summary of the incidence of alcoholic hepatitis at baseline. The analyses will be presented for all subjects in the safety and ITT populations.
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol Continuous variables will be summarized by N, mean, standard deviation, median, minimum and maximum, and a p-value based on the overall F-test from an ANOVA with factor treatment. Categorical variables will be summarized by frequency, percent and a p-value based on a Cochran-Mantel-Haenszel (CMH) chi-square Test. Efficacy Analyses
RI PT
15.3.5.
All efficacy endpoints will be analyzed primarily in the ITT population. Data from the initial treatment course will be utilized in the analyses. Any re-treatment courses will be evaluated separately.
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SC
The primary efficacy variable of incidence of subjects with Confirmed HRS Reversal (see Section 13.5.1 for details of endpoint definition) will be summarized by treatment group and analyzed using the Cochran-Mantel-Haenszel (CMH) chi-square test stratified by qualifying SCr (< 3.6 mg/dL or ≥ 3.6 mg/dL) and alcoholic hepatitis (present or not). If the proportion of subjects with treatment success is small (expected cell counts less than 5), Fisher’s Exact test will be used instead of the CMH test. If the primary endpoint is found significant, the pre-specified secondary efficacy endpoints will be analyzed in a sequential manner at the 0.05 level of significance. Testing will stop if a secondary endpoint is not significant. The following are the secondary endpoints:
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1. Change from baseline through end of treatment in renal function (serum creatinine). This endpoint will be analyzed using repeated measures analysis of covariance (ANCOVA), with treatment as a main effect and the baseline qualifying serum creatinine and day as a covariate. A treatment by day interaction will be added to the model if the interaction is found significant at 0.1 level. If treatment by day interaction is significant, p-values for treatment differences within each day will be produced, but the primary test of the treatment effect will be the overall treatment effect p-value. If the treatment by day interaction is significant, this analysis will also be performed without the interaction.
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2. Incidence of HRS Reversal, defined as at least one SCr ≤ 1.5 mg/dL on treatment. This endpoint will be analyzed similarly to the primary endpoint.
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3. Transplant-Free Survival up to 90 days, defined as the time (in days) that each subject survives without liver transplantation from the day of randomization. Data after transplantation will be considered as censored at the time of transplantation. This variable will be analyzed using a two-sample log rank test stratified by qualifying SCr (< 3.6 mg/dL or ≥ 3.6 mg/dL) and alcoholic hepatitis (present or not). A graphical summary of product limit estimates of the survival distribution will also be provided by treatment group, as estimated in Proc Lifetest (SAS®).
4. Overall Survival at 90 days, defined as the time (in days) that each subject survives from the day of randomization. This variable will be analyzed using a two-sample log rank test stratified by qualifying SCr (< 3.6 mg/dL or ≥ 3.6 mg/dL) and alcoholic hepatitis (present or not).
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol A graphical summary of product limit estimates of the survival distribution will also be provided by treatment group, as estimated in Proc Lifetest (SAS®).
15.3.5.1.
Other Efficacy Variables
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Hepatorenal syndrome type 1 recurrence until transplantation, hospital discharge, or Day 14, whichever occurs first.
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Incidence of HRS type 1 recurrence is defined as a SCr ≥ 2.5 mg/dL in the absence of other causes of renal impairment as described in the IAC 2007 criteria after achievement of confirmed HRS reversal (see Section 13.5.1 for endpoint definition). This variable will be presented descriptively by N, frequency and percentages.
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Other continuous variables such as GFR, FENa, which are measured on several days during the study, will be analyzed by repeated measures ANCOVA, with treatment as a main effect, and day, and strata as covariates. Treatment by strata and treatment by day interactions will be added to the model if found significant at the 0.1 level of significance. If treatment by day interaction is significant, p-values for treatment differences within a day will be produced, but the primary test for treatment effect will be the overall treatment differences.
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Dialysis-Free Survival up to 90 days, defined as the time (in days) that each subject survives without dialysis from the day of randomization. Data after dialysis will be considered as censored at the time of dialysis. This variable will be analyzed using a two-sample log rank test stratified by qualifying serum creatinine (< 3.6 mg/dL or ≥ 3.6 mg/dL) and alcoholic hepatitis (present or not). A graphical summary of product limit estimates of the survival distribution will also be provided by treatment group, as estimated in Proc Lifetest (SAS®). Efficacy data by subgroups of demographic and baseline variables as appropriate, as well as study site will be summarized.
Time to Transplantation up to 90 days summarized descriptively for only those subjects who undergo transplantation. Time to transplantation will be summarized as a continuous variable by treatment group, with descriptive statistics such as N, mean, standard deviation, median, minimum and maximum.
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Other exploratory, sensitivity and subgroup analyses will be performed as appropriate. Examples of potential exploratory analyses include:
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Transplant-free survival and overall survival of responders versus non-responders for the endpoints of Confirmed HRS Reversal and HRS Reversal.
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Evaluation of efficacy outcomes for baseline prognostic factors.
15.3.5.2.
Safety Analysis
The analysis for the frequency of adverse events will be assessed using Fisher’s Exact Test. These variables will be summarized by frequency, percent, and the p-value based on the statistical test. Change from baseline in MELD score, encephalopathy score and BUN will be analyzed similarly to the change from baseline in renal function (see Section 13.3). Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol The vital signs of systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate and mean arterial pressure (MAP) will be assessed as individual values, daily averages, maximum and minimum values. Changes from baseline will be evaluated similarly to other continuous safety variables.
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Other continuous safety variables (e.g., labs) will be analyzed using an analysis of variance on change from baseline, with treatment as a main effect and qualifying SCr (< 3.6 mg/dL or ≥ 3.6 mg/dL) and alcoholic hepatitis (present or not) as blocking factors. Other categorical safety variables (e.g., lab shifts) will be analyzed using the CMH test stratified by qualifying SCr (< 3.6 mg/dL or ≥ 3.6 mg/dL) and alcoholic hepatitis (present or not). 15.3.6.
Pharmacokinetics
15.3.7.
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Pharmacokinetic variables will be analyzed separately and described in a separate analysis plan. Definition of Time Points
15.3.8.
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Baseline: For evaluations that are collected at multiple occasions prior to initiation of study medication, the latest non-missing evaluation will be considered the "Baseline" evaluation for analysis. In most cases baseline will be defined as Day 0 of the study period, but a pre-study period value will be utilized instead if the Day 0 value is missing. Study Day 1 will be defined as the first calendar day that study medication is administered during the study period. Missing Data
15.3.9.
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No imputation will be made for missing data.
Procedure for Amendments to Statistical Plan
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It is intended that all statistical analyses specified in this protocol will be performed. However, study observations or analysis results may suggest the need for additional, or changes to the statistical analyses of the collected study data. In either case, deviations (subtractions or additions) from the planned statistical analysis will be fully described in the final clinical study report. The statistical plan can be amended and the reasons for amendments will be documented. Furthermore, any additional analyses performed beyond those specified in this protocol will be descriptive in nature and will not include hypothesis testing for the purposes of inferential conclusions.
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16.
DATA MANAGEMENT
16.1.
Data Collection
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A Case Report Form will be used to collect all subject data and assessments. The modules are pre-treatment/baseline, 14, 30, 60 and 90 days. Case Report Forms (electronic or paper) are to be completed for all subjects. All paper forms are to be completed in black ink or typed, in English. All electronic forms are to be completed in English.
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Correction(s) of data on the paper CRF should be made by crossing out the incorrect data (in a manner that leaves the previous entry identifiable) and writing the correct values next to those crossed out. Each correction must be initialed, dated, and explained where necessary, by the individual making the correction.
16.2.
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Refer to study specific CRF completion guidelines for further details.
Records Retention
Food and Drug Administration regulations require all investigators participating in clinical drug trials to maintain detailed clinical data for one of the following periods: at least two years following the date on which a New Drug Application is approved by the FDA, or
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two years after the sponsor notifies the investigator that no further application is to be filed with the FDA.
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Similarly, International Conference on Harmonisation (ICH) guidelines require that essential documents be retained until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product.
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To comply with these requirements, the investigator will not dispose of any records relevant to this study without either (1) written permission from the sponsor or (2) providing an opportunity for the sponsor to collect such records. The investigator shall take responsibility for maintaining adequate and accurate hard copy source documents of all observations and data generated during this study, including any data clarification forms (DCFs) received from the sponsor. Such documentation is subject to inspection by the Sponsor or its agents, the FDA and/or other regulatory agencies.
16.3.
Inspection of Records
In compliance with local regulations, US Federal regulations and ICH GCP guidelines, it is required that the Investigator and institution permit authorized representatives of the Sponsor, the regulatory agency(s), and the IRB/IEC direct access to review the subject’s original medical records for verification of study-related procedures and data. Direct access includes examining, analyzing, verifying, and reproducing any records and reports that are important to the evaluation Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol of the study. The Investigator is obligated to inform the subject and obtain their consent to permit named representatives to have access to his/her study-related records without violating the confidentiality of the subject.
16.4.
Retention of Records/Critical Documents
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In compliance with ICH GCPs and applicable regulatory requirements, copies of all records (e.g., informed consent documents, laboratory data slips, source documents, IND safety reports, test article dispensing records, etc.) which support case report forms of this study, must be retained in the files of the responsible Investigator for a minimum of two years following notification by Sponsor that all investigations at all sites are completed, terminated, or discontinued, or that the Food and Drug Administration has approved the New Drug Application. If the Investigator retires, relocates, or for other reasons withdraws from the responsibility of keeping the study records, custody must be transferred to a person who will accept the responsibility. Ikaria must be notified in writing of the name and address of the new custodian.
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17.
QUALITY CONTROL AND QUALITY ASSURANCE
17.1.
Study Monitoring
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The sponsor has ethical, legal and scientific obligations to carefully follow this study in a detailed and orderly manner in accordance with established research principles and applicable regulations. The investigator, as part of his responsibilities, is expected to cooperate with the sponsor in ensuring that the study adheres to the protocol and GCP requirements.
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As part of a concerted effort to fulfill these obligations (maintain current personal knowledge of the progress of the study), the sponsor's monitor will visit the center(s) during the study in accordance with the Monitoring Plan set forth for this trial as well as maintain frequent telephone and written communication. The investigator will permit the sponsor to monitor the study as frequently as is deemed necessary and provide access to medical records to ensure that data are being recorded adequately, that data are verifiable and that protocol adherence is satisfactory.
Auditing
The sponsor may conduct audits at the study center(s). Audits will include, but not be limited to, drug supply, presence of required documents, the informed consent process, and comparison of case report forms with source documents. The investigator agrees to participate with audits conducted at a reasonable time in a reasonable manner.
17.3.
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Regulatory authorities worldwide may also audit the investigator during or after the study. The investigator should contact the sponsor immediately if this occurs, and must fully cooperate with regulatory authority audits conducted at a reasonable time in a reasonable manner.
Ethics and Responsibility
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This study will be conducted in compliance with the protocol, with the sponsor’s standard operating procedures and/or guidelines, with the FDA regulations, with the ICH GCP guidelines and with the Declaration of Helsinki.
Informed Consent
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Written informed consent will be obtained from all subjects (or their guardian or legal representative) before any study-related procedures (including any pre-treatment study-specific procedures) are performed. The investigator(s) has both ethical and legal responsibility to ensure that each subject being considered for inclusion in this study is given a full explanation of the protocol. This shall be documented on a written informed consent form, which shall be approved by the same IRB or IEC responsible for approval of this protocol. Each informed consent form shall include the elements required by FDA regulations in 21 Code of Federal Regulations (CFR) Part 50 and ICH Guidance E6, Section 4.8. The investigator agrees to obtain approval from the Sponsor of any written informed consent form used in the study, preferably prior to submission to the IRB or IEC. Once the appropriate essential information has been provided to the subject and fully explained by the investigators (or a qualified designee) and it is felt that the subject understands the Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol implications of participating, the subject and the investigator (or designee) shall sign the IRB or IEC-approved written informed consent form. The subject shall be given a copy of the signed informed consent form, and the original shall be kept in the site’s regulatory file. A second copy may be filed in the subject's medical record, if allowed by the institution.
Institutional Review Board/Independent Ethics Committee
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17.5.
Confidentiality
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This protocol and the written informed consent form shall be submitted to the IRB or IEC identified with this responsibility at the research facility. Notification in writing of approval must come from the IRB or IEC chairman or secretary, to the investigator, either as a letter or as a copy of the appropriate section of the IRB or IEC meeting minutes where this protocol and associated informed consent form were discussed. The investigator will not participate in the decision. If the investigator is an IRB or IEC member, the written approval must indicate such non-participation. The investigator will submit status reports to the IRB or IEC at least annually (when applicable). The IRB or IEC must be notified by the investigator in writing of the interruption and/or completion of the study; the investigator must promptly report to the IRB or IEC all changes in research (protocol amendments) and will not make such changes without IRB or IEC approval except where necessary to eliminate apparent immediate hazards to human subjects. In these cases, the IRB or IEC must be notified within five days of the change. The investigator will promptly report to the IRB or IEC all unanticipated problems involving risk to subjects or others. The investigator is required to maintain an accurate and complete record of all written correspondence to and received from the IRB or IEC and must agree to share all such documents and reports with the sponsor.
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All information generated in this study will be considered confidential and will not be disclosed to any persons not directly concerned with the study without written prior permission from the sponsor. However, authorized regulatory officials and sponsor personnel will be allowed full access to the records. All medications provided and subject bodily fluids and/or other materials collected shall be used solely in accordance with this protocol, unless otherwise agreed to in writing by the sponsor.
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Only initials and/or unique subject numbers in case report forms will identify subjects. Their full names may, however, be made known to a product regulatory agency or other authorized official if necessary.
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18.
REGISTRATION OF STUDY AND PUBLICATION OF DATA
This trial will be registered at the publicly accessible Web site www.clinicaltrials.gov. Registration at other publicly accessible registries will be performed as required.
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The results of this study will be published and/or presented at scientific meetings in accordance with usual and customary academic, editorial and ethical practices and requirements. To ensure inclusion of complete and reliable data and to allow the protection of any proprietary information, the investigator agrees to submit any manuscripts or abstracts to Ikaria Therapeutics LLC for review prior to submission.
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19.
REFERENCES
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1. Alessandria C, Ozdogan O, Guevara M, et al. MELD score and clinical type predict prognosis in hepatorenal syndrome: relevance to liver transplantation. Hepatology. 2005 Jun;41(6):1282-9. 2. Alessandria C, Ottobrelli A, Debernardi-Venon W, et al. Noradrenalin vs terlipressin in patients with hepatorenal syndrome: a prospective, randomized, unblinded, pilot study. J Hepatol. 2007 Oct;47(4):499-505. 3. Angeli P, Violpin R, Gerunda G, et al. Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide. Hepatology. 1999 Jun;29(6):1690-7.
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4. Arroyo V, Ginès P, Gerbes AL, et al. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club. Hepatology. 1996 Jan;23(1):164-76..
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5. Arroyo V, Terra C, Ginès P. New treatments of hepatorenal syndrome. Semin Liver Dis. 2006 Aug;26(3):254-64. 6. Blei AT, Großmann RJ, Gusberg R, Conn H. Comparison of vasopressin and triglycyllysine vasopressin on splanchnic and systemic hemodynamics in dogs. Dig Dis Sci. 1980 Sep;25(9):688-94.
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7. Bone RC, Balk RA, Cerra FB, et al, Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. Chest 2009 Nov;136(5 Suppl):e28. 8. Briglia AE, Anania, FA. Hepatorenal syndrome. Definition, pathophysiology, and intervention. Crit Care Clin. 2002 Apr;18(2):345-73 9. Cárdenas A. Hepatorenal syndrome: a dreaded complication of end-stage liver disease. Am J Gastroenterol. 2005 Feb;100(2):460-7.
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10. Cárdenas A, Ginès P. Therapy insight: management of hepatorenal syndrome. Gastroenterol & Hepatol. 2006 Jun;3(6):338-48.
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11. Dellinger RP, Levy MM, Carlet JM, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: Crit Care Med. 2008 Jan;36(1):296-327. 12. Döhler KD. Vasopressin analogues in the treatment of hepatorenal syndrome and gastrointestinal haemorrhage. Best Practice & Research Clinical Anaesthesiology. 2008 Jun;22(2):335-50 13. Esrailian E, Pantagco ER, Kyulo NL, Hu K-Q, Runyon BA. Octreotide/midodrine therapy significantly improves renal function and 30-day survival in patients with type 1 hepatorenal syndrome. Dig Dis Sci. 2007 Mar;52(3):742-8. 14. Fabrizi F, Dixit V, Messa P, Martin P. Terlipressin for hepatorenal syndrome: A metaanalysis of randomized trials. Int J Artif Organs. 2009 Mar;32(3):133-40.
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol 15. Ferenci P, Lockwood A,Mullen K, Weissenborn K, Blei A. Hepatic encephalopathydefinition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology. 2002 Mar;35(3):716-21.
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16. Fjellestad-Paulsen A, Lundin S. Metabolism of vasopressin, oxytocin and their analogues [Mpa1, D-Arg8]-vasopressin (dDAVP) and [Mpa1, D-Tyr(Et)2, Thr4, Orn8]oxytocin (antocin) in human kidney and liver homogenates. Regul Pept. 1996 Nov 14;67(1):27-32. 17. Forsling ML, Aziz LA, Miller M, Davis R, Donovan B. Conversion of triglycylvasopressin to lysine vasopressin in man. J. Endocr. 1980 May;85(2):237-44.
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18. Ginès A, Escorsell A, Ginès P, et al. Incidence, Predictive Factors, and Prognosis of the Hepatorenal Syndrome in Cirrhosis With Ascites. Gastroenterology. 1993 Jul;105(1):229-36.
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19. Ginès P, Guevara M, Arroyo V, Rhodes J. Hepatorenal syndrome. Lancet. 2003;362:1819-1827. 20. Gluud LL, Christensen K, Christensen E, Krag A. Systematic review of randomized trials on vasoconstrictor drugs for hepatorenal syndrome. Hepatology. 2010 Feb;51(2):576-84. 21. Gonwa TA, Klintmalm GB, Levy M, Jennings LS, Goldstein RM, Husberg BS. Impact of pretransplant renal function on survival after liver transplantation. Transplantation. 1995 Feb 15;59(3):361-5.
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22. Guevara M, Ginès P, Fernandez-Esparrach G, et al. Reversibility of hepatorenal syndrome by prolonged administration of ornipressin and plasma volume expansion. Hepatology. 1998 Jan;27(1):35-41. 23. Hadengue A, Gadano A, Moreau R, et al. Beneficial effect of the 2-day administration of terlipressin in patients with cirrhosis and hepatorenal syndrome. J. Hepatol. 1998 Oct;29(4):565-70.
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24. IK-4001 Lucassin® (terlipressin). [Investigator’s Brochure] Clinton, NJ: Ikaria Therapeutics LLC. Version 3. 2010.
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25. Kiser TH, MacLaren R, Fish DN. Treatment of hepatorenal syndrome. Pharmacotherapy. 2009 Oct;29(10):1196-211. 26. Kiszka-Kanowitz M, Henriksen JH, Hansen EF, Møller S, Bendtsen F. Effects of terlipressin on blood volume distribution in patients with cirrhosis. Scand J Gastroenterol. 2004 May;39(5):486-92. 27. Lauson HD. Metabolism of antidiuretic hormones. Am J Med. 1967 May;42(5):713-44. 28. Lucey MR, Mathurin P, Morgan TR. Alcoholic Hepatitis. NEJM. 2009 Jun 25;360(26):2758-69. 29. Martín-Llahí M, Pépin MN, Guevara M, et al. Terlipressin and albumin versus albumin in patients with cirrhosis and hepatorenal syndrome. A randomized study. Gastroenterol. 2008 May;134(5):1352-9. Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol 30. McCormick PA, Donnelly C. Management of hepatorenal syndrome. Pharmacology & Therapeutics. 2008 Jul;119(1):1-6. 31. Moreau R, Durand F, Poynard T, et al. Terlipressin in patients with cirrhosis and type 1 hepatorenal syndrome: a retrospective multicenter study. Gastroenterology 2002 Apr;122(4):923-30.
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32. Nair S, Verma S, Thuluvath PJ. Pretransplant renal function predicts survival in patients undergoing orthotopic liver transplantation. Hepatology. 2002 May;35(5):1179-85. 33. Neri S, Pulvirenti D, Malaguarnera M, et al. Terlipressin and albumin in patients with cirrhosis and type 1 hepatorenal syndrome. Dig Dis Sci. 2008 Mar;53(3):830-5.
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34. Nilsson G, Lindblom P, Ohlin M, Berling R, Vernersson E. Pharmacokinetics of terlipressin after iv doses to healthy volunteers. Drugs Exptl. Clin. Res. 1990;16(6):30714.
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35. Plate. Studies on the localization and kinetics of metabolism of synthetic vasopressin slow release preparation triglycyl-lysine-vasopressin [thesis]. Hanover Germany: Hanover School of Medicine, Department of Gastroenterology and Hepatology, 1995. 36. Pliska V, Chard T, Rudinger J, Forsling ML. In vivo activation of synthetic hormonogens of lysine vasopressin: N-glycyl-glycyl-glycyl-(8-lysine) vasopressin in the cat. Acta Endocrinol. 1976 Mar;81(3):474-81. 37. Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP. The natural history of the systemic inflammatory response system (SIRS). A prospective study. JAMA. 1995 Jan 11;273(2):117-23.
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38. Restuccia T, Ortega R, Guevara M, et al. Effects of treatment of hepatorenal syndrome before transplantation on posttransplantation outcome. A case-control study. J Hepatol. 2004 Jan;40(1):140-6.
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39. Ruiz R, Barri YM, Jenning LW, et al. Hepatorenal syndrome: a proposal for kidney after liver transplantation (KALT). Liver Transpl. 2007 Jun;13(6):838-43.
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40. Sagi SV, Mittal S, Kasturi KS, Sood GK. Terlipressin therapy for reversal of type 1 hepatorenal syndrome: A meta-analysis of randomized controlled trials. J Gastro Hep. 2010 Jan 14. 41. Salerno F, Gerbes A, Ginès P, Wong F, Arroyo V. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. A concensus workshop of The International Ascites Club. Gut. 2007 Sep;56(9):1310-18. 42. Sanyal AJ, Boyer T, Garcia-Tsao G, et al. A randomized, prospective, double-blind placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome. Gastroenterology. 2008 May;134(5):1360-8. 43. Saner FH, Canbay A, Gerken G, Broelsch CE. Pharmacology, clinical efficacy and safety of terlipressin in esophageal varices bleeding, septic shock and hepatorenal syndrome. Expert Rev. Gastroenterol. Hepatol. 2007 Dec;1(2):207-17. 44. Sessler CN, Perry JC, Varney KL. Management of severe sepsis and septic shock. Curr Opin Crit Care. 2004 Oct;10(5):354-63. Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol 45. Skagen C, Einstein M, Lucey MR, Said A. Combination treatment with octreotide, midodrine, and albumin improves survival in patients with type 1 and type 2 hepatorenal syndrome. J Clin Gastroenterol. 2009 Aug;43(7):680-5.
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46. Sharma P, Schaubel DE, Guidinger MK, Merion RM. Effect of pretransplant serum creatinine on the survival benefit of liver transplantation. Liver Transpl. 2009 Dec;15(12):1808-13. 47. Solanki P, Chawla A, Garg R, Gupta R, Jain M, Sarin SK. Beneficial effects of terlipressin in hepatorenal syndrome: a prospective, randomized placebo-controlled clinical trial. J Gastroenterol Hepatol. 2003 Feb;18(2):152-6.
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48. Wisniewski K, Alagarsamy S, Taki H, Miampamba M, Laporte R, Galyean R, et al. Synthesis and biological activity of terlipressin and its putative metabolites. In: Blondelle SE, ed. Understanding Biology using Peptides. Proceedings of the Nineteenth American Peptide Symposium. Vol. 9. New York, NY: Springer; 2005:489-490.
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49. Wong F, Pantea L, Sniderman K. Midodrine, octreotide, albumin, and tips in selected patients with cirrhosis and type 1 hepatorenal syndrome. Hepatology. 2004 Jul;40(1):5564.
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APPENDIX A. STUDY IK-4001-HRS-301: NOMOGRAM TO DETERMINE CRITERION FOR SCr DOUBLING OVER TWO WEEKS
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The nomogram is intended for use in situations when the SCr value has increased rapidly over a shorter period of time but has not yet doubled within 2 weeks.
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To fulfill Inclusion Criterion No. 4, subjects must have rapidly progressive reduction in renal function characterized by: 1) SCr ≥ 2.5 mg/dL and 2) doubling of SCr within 2 weeks (or SCr values over time indicating a trajectory with a slope likely to be representative of at least a doubling within 2 weeks). For ease of calculation, these trajectories are estimated by relating a certain required “fold increase in SCr” to the elapsed time in days between two measured values (see Figure 4 and Table 6 below); greater proportional increases in SCr are required for observations of shorter duration. As noted in the nomogram, a 1.5 fold increase between the SCr values must be achieved within 4 days of observation. The required fold increase in SCr between SCr values progressively rises from 4 days of observation up to a 2 fold increase by 14 days observation.
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Figure 4: Nomogram to Determine Criterion for SCr Doubling Over Two Weeks
Table 6: Elapsed Time in Days and Required Fold Increase in SCr Fold increase in creatinine
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1.50
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Elapsed time (days)
1.54
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1.58
7
1.62
8
1.67
9
1.71
10
1.76
11
1.82
12
1.88
13
1.94
14
2.00
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PII: DOI: Reference:
S1542-3565(16)30437-2 10.1016/j.cgh.2016.07.016 YJCGH 54837
To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 15 July 2016 Please cite this article as: Wong F, Pappas SC, Boyer TD, Sanyal AJ, Bajaj JS, Escalante S, Jamil K, on behalf of the REVERSE Investigators, Terlipressin Improves Renal Function and Reverses Hepatorenal Syndrome in Patients with Systemic Inflammatory Response Syndrome, Clinical Gastroenterology and Hepatology (2016), doi: 10.1016/j.cgh.2016.07.016. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Terlipressin Improves Renal Function and Reverses Hepatorenal Syndrome in Patients with Systemic Inflammatory Response Syndrome
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Short title: SIRS and Response to Terlipressin in HRS
Florence Wong,* Stephen Chris Pappas,‡ Thomas D. Boyer,§ Arun J. Sanyal,║ Jasmohan S. Bajaj,║ Shannon Escalante,¶ Khurram Jamil,¶ on behalf of the
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REVERSE Investigators
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*Department of Medicine, University of Toronto, Toronto, Ontario, Canada; ‡Orphan Therapeutics, Lebanon, New Jersey; §Department of Medicine, University of Arizona, Tucson, Arizona; ║Department of Medicine, Virginia Commonwealth University, Richmond, Virginia; ¶Ikaria Therapeutics LLC/a Mallinckrodt Company, Hampton,
Funding
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New Jersey
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This study was sponsored by Ikaria Therapeutics LLC/a Mallinckrodt Company. The
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sponsor participated in the design and conduct of the study, interpretation of study data, and writing of this report.
Abbreviations used in this paper: CHRSR, complete hepatorenal syndrome reversal; HRS-1, hepatorenal syndrome type 1; SCr, serum creatinine; SIRS, systemic inflammatory response syndrome.
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ACCEPTED MANUSCRIPT Address correspondence to: Florence Wong, 9EB/222 Toronto General Hospital, 200 Elizabeth Street, Toronto M5G2C4, ON, Canada. Telephone: 1-416-3403834; fax: 1-416-3405019; e-mail: [email protected].
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Conflicts of Interest
Florence Wong is a consultant for Ikaria Therapeutics LLC/a Mallinckrodt Company, has served on the advisory board for Grifols Inc., and has received grant support
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from Gilead Sciences. Stephen Chris Pappas is a consultant for Orphan
Therapeutics and Ikaria Therapeutics LLC/a Mallinckrodt Company. Thomas D.
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Boyer is a consultant for Ikaria Therapeutics LLC/a Mallinckrodt Company. Arun J. Sanyal has stock options in Genfit; has served as a consultant for AbbVie Inc., AstraZeneca, Exalenz Bioscience Ltd., FibroGen Inc., Genfit, Immuron Ltd, Ikaria Therapeutics LLC/a Mallinckrodt Company, Nimbus Therapeutics, Nitto Denko
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Corporation, Salix Pharmaceuticals, Takeda Pharmaceutical Company, and Tobira Therapeutics; and has been an unpaid consultant for Echosens and Intercept Pharmaceuticals. Jasmohan S. Bajaj has served as a consultant for Grifols Inc.,
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Norgine, and Salix Pharmaceuticals; his institution has received grants from Grifols
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Inc. and Salix Pharmaceuticals. Shannon Escalante and Khurram Jamil are employees of Ikaria Therapeutics LLC/a Mallinckrodt Company.
Acknowledgments
The authors would like to thank the REVERSE study investigators and study participants, as well as Peter Teuber, PhD, of Orphan Therapeutics for assistance with analysis and interpretation of the study data, and Michael Morren, MBA, RPh, of Peloton Advantage, LLC, for administrative and publishing support.
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Author Contributions Florence Wong, Stephen Chris Pappas, Thomas D. Boyer, Arun J. Sanyal, Jasmohan S. Bajaj, and Khurram Jamil collected data. Florence Wong, Stephen C.
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Pappas, Thomas D. Boyer, Arun J. Sanyal, Jasmohan S. Bajaj, and Khurram Jamil analyzed and interpreted the data. Shannon Escalante provided statistical analysis and support. Florence Wong, Stephen C. Pappas, Thomas D. Boyer, Arun J. Sanyal,
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Jasmohan S. Bajaj, and Khurram Jamil drafted the manuscript. All authors have read
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and approved the final version submitted and accept responsibility for its content.
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ACCEPTED MANUSCRIPT ABSTRACT BACKGROUND & AIMS: Patients with systemic inflammatory response syndrome (SIRS) along with decompensated cirrhosis and renal dysfunction have a poor prognosis and a lower response to treatment. We evaluated the effect of SIRS on
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the response of hepatorenal syndrome type 1 (HRS1) to terlipressin.
METHODS: We performed a retrospective study of data from a trial of the effects of
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terlipressin (1 mg every 6 hours or placebo with concomitant albumin) in 198 patients with HRS1, performed at 50 investigational sites in the United States and 2 in
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Canada from October 2010 through February 2013. We identified patients with 2 or more criteria for SIRS, without untreated infections (28 received terlipressin and 30 received placebo), as well as patients with less than 2 criteria for SIRS (controls). Primary endpoints included HRS reversal (a decrease in serum level of creatinine to
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≤1.5 mg/dL), confirmed HRS reversal (defined as 2 serum creatinine levels ≤1.5 mg/dL, ≥ 48 hours apart), and survival for 90 days after treatment.
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RESULTS: Baseline characteristics were similar between groups, apart from slightly
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higher white blood cell counts and heart rates, and slightly lower serum levels of bicarbonate in patients with SIRS vs without SIRS. HRS was reversed in 42.9% of patients who received terlipressin with SIRS (12/28) vs 6.7% of patients who received placebo (2/30) (P=.0018); confirmed HRS reversal occurred in 32.1% of patients who received terlipressin with SIRS (9/28) vs 3.3% who received placebo (1/30) (P=.0048). A larger proportion of patients with SIRS who received terlipressin survived for 90 days without a transplant (13/28, 46.4%) than patients with SIRS who received placebo (7/30, 23.3%) (P=.076).
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Conclusion: In an analysis of data from a placebo-controlled study, we found that terlipressin improved renal function and reversed HRS in a higher proportion of
ClincialTrials.gov, number NCT01143246.
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patients with HRS1 and SIRS than patients who received albumin plus placebo.
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Keywords: HRS-1; renal dysfunction; REVERSE trial; cirrhosis
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ACCEPTED MANUSCRIPT The systemic inflammatory response syndrome (SIRS) is a non-specific inflammatory response to various insults such as trauma, ischemia, or infection.1 SIRS occurs frequently in patients with decompensated cirrhosis,2,3 possibly related to increased translocation of bacteria and their breakdown products across the gut
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wall,4 independent of an obvious infection.5 Many of these bacterial products can stimulate the production of various inflammatory cytokines from immune cells.6.
Pathophysiologically, many of these cytokines can initiate an inflammatory cascade,
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resulting in a pro-coagulant response, especially in the microcirculation. This
ultimately leads to the development of micro-thrombi and loss of circulatory integrity,7
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contributing to the development of multi-organ failure in patients with SIRS.8 Indeed, the severity of the systemic inflammation and the magnitude of the immune response have been identified as predictors of poor patient outcome.2,9
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Hepatorenal syndrome type 1 (HRS-1) is a unique form of acute kidney injury observed in advanced cirrhosis and ascites10 with a high mortality risk if left untreated.11 Traditionally, the pathogenesis of HRS-1 is attributed to abnormal
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hemodynamics of decompensated cirrhosis,12 which ultimately lead to decreased
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renal blood flow and reduced glomerular filtration. The fact that treatments aimed at correcting the hemodynamic abnormalities do not reverse the majority of cases of HRS-113,14 suggests that other pathogenetic factors may also be involved. It has been proposed that inflammation with various inflammatory cytokines can induce changes in the renal microcirculation and bring about an increase in oxidative stress, thereby causing renal tubular damage, especially in the presence of infection.16 Bacterial infections, the most common precipitant of HRS-1 in cirrhosis,17 are associated with an intense inflammatory response. Therefore, it is plausible that the
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ACCEPTED MANUSCRIPT presence of SIRS in patients with cirrhosis and HRS-1 may adversely affect the response to vasoconstrictor therapy, although this has never been reported.
The REVERSE study was a phase 3, randomized, placebo-controlled study of
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patients with decompensated cirrhosis and HRS-1 treated with terlipressin or
placebo, both with concomitant albumin. Since patients with ≥2 SIRS criteria without a current uncontrolled infection were included, an evaluation of this subgroup was
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considered important, particularly because of concern for the inadvertent enrollment of patients with covert sepsis and the reported poorer prognosis of patients with ≥2
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SIRS criteria.3. Thus, the aims of this post-hoc study were 1) to evaluate the effects of SIRS on the response to terlipressin in patients with decompensated cirrhosis and HRS-1, and 2) to determine the effects of SIRS on the 90-day survival of these
Methods
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patients.
This study employs the data collected in the REVERSE study (clinical trial
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registration identifier NCT01143246; ClinicalTrials.gov), which was conducted at 50
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investigational sites in the United States and 2 in Canada from October 2010 to February 2013. The REVERSE study design, protocol, and ethical oversight have previously been described.18 Briefly, patients with HRS-1, as defined by the International Club of Ascites,12 without uncontrolled infection, were included and randomized to receive terlipressin, 1 mg every 6 hours or placebo via slow intravenous bolus injections for up to 16 days, together with albumin 20 to 40 g/d for both treatment groups. The terlipressin dose was doubled after a minimum of 10 doses on Day 4 if the serum creatinine (SCr) had not decreased by at least 30%
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ACCEPTED MANUSCRIPT from the baseline value. The study endpoints included HRS-1 reversal, defined as a decrease in SCr to ≤1.5 mg/dL while on treatment, confirmed HRS-1 reversal (CHRSR), defined as 2 SCr levels of ≤1.5 mg/dL at least 48 hours apart while on treatment, and 90-day survival. Patients were then followed for 90 days to evaluate
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the rates of liver transplantation and renal replacement therapy, as well as survival. The study also collected 3 of the 4 SIRS parameters1 at enrollment, namely, a heart rate of >90 beats/min, a white blood cell count of <4 or >12 x 109/L, and a serum
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bicarbonate of <21 mmol/L, which was used as a surrogate for partial arterial
pressure of CO2 of <32 mm Hg.19 The fourth parameter, body temperature, was
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subsequently requested and available for 129 patients. Patients were separated into those meeting ≥2 SIRS criteria and those meeting <2 SIRS criteria at enrollment; they were evaluated with respect to response to terlipressin treatment and 90-day
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survival.
All authors had access to the study data and reviewed and approved the final
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manuscript.
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Statistical Analysis
All efficacy analyses were based on the intent-to-treat population, defined as all randomized patients who had ≥1 baseline assessment. The safety population was defined as all randomized patients who received ≥1 dose of study medication (terlipressin or placebo). The incidence rates for patients with HRS reversal and CHRSR were analyzed using the Cochran-Mantel-Haenszel chi-square test. An analysis of variance with main effect treatment for continuous variables and a Cochran-Mantel-Haenszel test for general association for discrete variables were
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ACCEPTED MANUSCRIPT used for comparisons of the SIRS group versus the non-SIRS group and terlipressin versus placebo within groups (see Tables 1 and 2). Transplant-free and overall survival at 90 days were analyzed using a 2-sample log rank test stratified by qualifying SCr level. SCr changes from baseline to the end of treatment were
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evaluated using a repeated measures analysis of covariance, with treatment as a main effect and qualifying SCr level and day as covariates. The frequency of adverse
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events and other safety events were summarized descriptively.
Results
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196 patients who fulfilled all inclusion criteria were enrolled. Of these, 97 patients were randomized to receive terlipressin and 99 to receive placebo. In all, 58 patients (30%) met ≥2 SIRS criteria and were termed “the SIRS group” (terlipressin: n=28, placebo: n=30). The remaining 138 patients were termed “the non-SIRS group,” 69
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(50%) were randomized to receive terlipressin and 69 (50%) to receive placebo.
Baseline demographic and laboratory data for all the patients are shown in Table 1.
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All patients who had infections in the 14 days prior to enrollment had received
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appropriate antibiotics and did not have sepsis at the time of enrollment. There was no significant difference in the acute-on-chronic liver failure grade or the proportion of patients on antibiotics between the SIRS and Non-SIRS subgroups at baseline (Supplementary Table 1). Significantly more patients in the SIRS subgroup (19/58 [32.8%]) had alcoholic hepatitis versus the non-SIRS group (26/138 [18.8%]; P = .035). A significantly higher mean [±SD] heart rate (85 [±13] vs. 77 [±12] beats/min; P = .0001), significantly higher mean [±SD] white blood cell count (9.9 [±7.6] vs. 6.8 [±2.8] x 109/L; P = .0001), and significantly lower mean [±SD] serum bicarbonate (17
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ACCEPTED MANUSCRIPT [±3] vs. 20 [±4] mmol/L; P = .0001) were observed in the SIRS group versus the nonSIRS group. However, no difference in the baseline mean [±SD] temperature (36.5°C [± .4] vs. 36.6°C [± .6]; P = NS) was observed between the two groups of
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patients.
HRS-1 Treatment Response
Terlipressin was administered for a mean (±SD) duration of 6.0 (±4.9) days (SIRS
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group: 7.8 [±6.8] days; non-SIRS group: 5.3 [±3.9] days), and placebo was
administered for a mean (±SD) duration of 5.9 (±4.1) days (SIRS group: 7.2 [±4.5]
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days; non-SIRS group: 5.8 [±3.8] days). Overall, 22.4% (13/58) of patients in the SIRS group and 32.6% (45/138) in the non-SIRS group received their assigned treatment for ≤3 days (P = .17) because of liver transplant, initiation of renal replacement therapy, adverse events, or lack of response. The total terlipressin or
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placebo doses administered in the SIRS group were higher than those administered in the non-SIRS group (Table 2), but there was no significant difference in mean doses of albumin used. This appeared to be related to more patients in the non-SIRS
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group discontinuing the study drug either at Day 4 because of a lack of response
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(SCr at or above baseline after 3 days of treatment) or because of adverse events (Supplementary Table 2).
Amongst the SIRS patients, despite the fact that both SIRS subgroups received similar doses of terlipressin or placebo and albumin, there was a significantly higher rate of HRS-1 reversal in response to terlipressin compared to placebo (Figure 1A). Such a difference was not observed between the terlipressin versus the placebo subgroups in the non-SIRS patients (Figure 1A). The same improved renal
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ACCEPTED MANUSCRIPT response with terlipressin compared with placebo was also noted among the SIRS group with respect to confirmed HRS reversal (Figure 1B). Furthermore, only the SIRS group but not the non-SIRS group showed a significantly greater mean reduction in SCr with terlipressin between end-of-treatment and baseline (Figure
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1C).
Other Clinical Outcomes
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Many complications were recorded during the study period. However, the overall frequency of adverse events and serious adverse events was similar between the
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SIRS group and the non-SIRS group. During the study, 6 patients in the SIRS group (terlipressin: n=3 [10.7%]; placebo: n=3 [10%]) and 18 (13%) patients in the nonSIRS group (terlipressin: n=15 (21.7%); placebo: n=3 (4.6%) discontinued treatment because of adverse events (Supplementary Table 2). Table 3 shows the important
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severe adverse events that occurred during the treatment period. No significant difference was observed between the SIR and non-SIRS groups with respect to the
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Survival
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frequency of clinically important adverse events.
In the SIRS group, 2 patients who received terlipressin underwent a liver transplant up to Day 90 compared with 8 patients who received placebo. In the non-SIRS group, 27 patients receiving terlipressin and 24 receiving placebo underwent a liver transplant up to Day 90. The overall 90-day survival was not significantly different between the SIRS and non-SIRS groups, irrespective of whether patients received terlipressin or placebo. However, there was a trend toward an improved 90-day transplant-free survival in the SIRS group who received terlipressin (46.4% [13/28]
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ACCEPTED MANUSCRIPT versus those who received placebo (23.3% [7/30]; P = .076). No such trend was observed in the non-SIRS group between patients receiving terlipressin versus placebo (Figure 2). Causes of death included multi-organ failure, end-stage liver
between the SIRS versus the non-SIRS groups.
DISCUSSION
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disease, infection, respiratory failure, and renal failure, with no differences observed
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SIRS is known to occur in a significant number of patients with decompensated cirrhosis,2,3 and is associated with a negative impact on patient outcome,2,20
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especially in patients with renal dysfunction.3 The REVERSE study,21 a treatment study for HRS-1, did not show a greater efficacy for terlipressin plus albumin versus placebo plus albumin in reversing HRS-1, contrary to expectations. The question is then raised as to whether the presence of SIRS could have contributed to the
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negative outcome in the REVERSE study.21 Therefore, it was necessary to compare the response to terlipressin plus albumin in patients with HRS-1 and SIRS versus those without SIRS. The results demonstrate that patients with HRS-1 and SIRS had
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an improved response to terlipressin plus albumin compared with placebo plus
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albumin, whereas no such difference was observed in the non-SIRS group. Furthermore, the presence of SIRS also had a positive impact on renal function in patients who received terlipressin plus albumin, with significantly more patients achieving CHRSR. There was also a trend toward increased 90-day transplant-free survival in the same patients, compared with those who received placebo plus albumin as well as those in the non-SIRS group.
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ACCEPTED MANUSCRIPT These unexpected findings seem to contradict previously published reports of SIRS conferring a negative impact on patient outcomes.2,3 However, a recent small study demonstrating the effectiveness of terlipressin in improving renal function and reversing HRS-1 in patients with cirrhosis and sepsis22 seems to support our
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findings, as these patients by definition had to have significant inflammation.
Although SIRS has been withdrawn from the latest SEPSIS 3 definition,23 we feel that these findings related to SIRS are important in this population of patients, as the
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presence of SIRS represents a subgroup with inflammation and therefore may behave differently. The mechanisms whereby SIRS could improve the renal
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response to terlipressin plus albumin are not obvious. The SIRS and non-SIRS groups had similar severity of renal dysfunction at enrollment. Their infection history and antibiotic use in the immediate pre-enrollment period were also similar. It is possible that the longer treatment duration in the SIRS group, and therefore a higher
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total terlipressin dose together with a higher albumin dose, could have contributed to the improved renal function in the SIRS group. However, the reported elimination half-life for terlipressin is 50 minutes and the effective half-life of terlipressin is 6
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hours.24 There are no published data to support a hypothesis that a higher
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cumulative dose of terlipressin will yield an improved renal response. The lack of increased effects on regional hemodynamics with higher doses of terlipressin has been reported in an animal model of sepsis.25 The fact that terlipressin 2 mg, administered as a bolus intravenously in cirrhotic patients, provides the same portal hypotensive effect as a terlipressin 1 mg bolus dose26 also suggests that there are minimal additional effects with higher doses in humans. However, this will need to be formally studied.
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ACCEPTED MANUSCRIPT The fact that the presence of SIRS improved the renal response to terlipressin in patients with HRS-1 is an intriguing observation. Terlipressin improves renal function in HRS-1 by virtue of its vasoconstrictive effects on the systemic and the splanchnic circulations. In the systemic circulation, terlipressin induces arterial vasoconstriction
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and increases the systemic vascular resistance.24 The improvement in mean arterial pressure and hence renal perfusion pressure can improve the renal circulation and glomerular filtration. Indeed, an increase in mean arterial pressure has been
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identified as a predictor of renal response to terlipressin in patients with HRS-127,28 Terlipressin also induces vasoconstriction in the mesenteric arterioles, thereby
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reducing portal inflow and hence portal pressure29 However, in the presence of SIRS, terlipressin appears to produce and enhance renal response that may not be entirely explained by a possible reduction in portal pressure or an increase in renal
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perfusion pressure alone.
The presence of SIRS is associated with increased levels of various inflammatory cytokines.30 Patients with cirrhosis have higher levels of circulating endotoxins,
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possibly related to increased bacterial translocation across the gut wall as a result of
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portal hypertension,31 and increased intestinal permeability. The bacterial stimulus promotes the production of many pro-inflammatory cytokines, especially tumornecrosis factor-α and interleukin 632 and substances that cause vasodilatation such as nitric oxide. The bacterial translocation tends to worsen with progression of cirrhosis, occurring in at least 30% of patients with decompensated cirrhosis.4 Therefore, it is feasible that with the likely reduction of portal pressure with terlipressin, there may a reduction of bacterial translocation, with consequent reduction in endotoxemia and in production of pro-inflammatory cytokines. It is
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ACCEPTED MANUSCRIPT possible that the reduction in pro-inflammatory cytokines with terlipressin is amplified in the presence of SIRS. Alternatively, it has been suggested that terlipressin may have a direct anti-inflammatory action independent of it portal hypotensive effect.33
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It has been suggested that the effects of terlipressin are enhanced in the presence of infection and increased inflammation, independent of changes in pro-inflammatory cytokine levels.34 Using isolated aortic rings from animals with cirrhosis induced by
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bile duct ligation, terlipressin abolished the hyporesponsive reaction to
vasoconstrictors to a much greater degree in the presence of lipopolysaccharide, a
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product of gram-negative bacteria, compared with those without a lipopolysaccharide challenge.34 This exaggerated response with terlipressin in the presence of infection or inflammation mimics the enhanced renal response to terlipressin that we have observed with our patients with HRS-1. This may have been sufficient to lead to an
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improved 90-day transplant-free survival in the SIRS group who received terlipressin.
It appears that a subset of cirrhotic patients with HRS-1 and SIRS but without
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uncontrolled infection may benefit from receiving terlipressin. A limitation of the study
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is that it was not designed to evaluate the mechanisms involved in this improved renal response in the presence of SIRS. Thus, we can only propose the possible explanations for the results. SIRS, in the absence of infection, may prove to be an additional predictive factor that identifies a subgroup of patients with HRS-1 who would benefit from treatment with terlipressin.
In conclusion, SIRS is common in patients with advanced cirrhosis, ascites, and HRS-1. Despite being more ill, the proportion of patients with HRS-1 and SIRS in this
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ACCEPTED MANUSCRIPT study who responded to treatment with terlipressin was significantly greater than that for patients with SIRS who received placebo, and also for patients without SIRS.
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Future studies should explore the possible mechanisms involved.
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ACCEPTED MANUSCRIPT Figure Legends
Figure 1. Renal outcomes in response to treatment between the SIRS and nonSIRS groups: (A) percentage of patients with HRS-1 reversal, defined as 1 SCr
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reading of ≤1.5 mg/dL while on treatment, (B) percentage of patients with confirmed HRS-1 reversal, defined as 2 SCr readings of ≤1.5 mg/dL at least 48 hours apart while on treatment, and (C) the mean decrease in SCr in mg/dL. HRS-1, hepatorenal
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syndrome type 1; SCr, serum creatinine; SIRS, systemic inflammatory response
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syndrome.
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ACCEPTED MANUSCRIPT Figure 2. Transplant-free survival up to 90 days in the SIRS and non-SIRS groups,
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further separated by treatment assignment.
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ACCEPTED MANUSCRIPT 18. Boyer TD, Medicis JJ, Pappas SC, et al. A randomized, placebo-controlled, double-blind study to confirm the reversal of hepatorenal syndrome type 1 with terlipressin: the REVERSE trial design. Open Access J Clin Trials 2012;4:39-49. 19. Centor RM. Serum total carbon dioxide. In: Walker HK, Hall WD, Hurst JW,
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ACCEPTED MANUSCRIPT 27. Boyer TD, Sanyal AJ, Garcia-Tsao G, et al. Predictors of response to terlipressin plus albumin in hepatorenal syndrome (HRS) type 1: relationship of serum creatinine to hemodynamics. J Hepatol 2011;55:315-321. 28. Nazar A, Pereira GH, Guevara M, et al. Predictors of response to therapy with
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ACCEPTED MANUSCRIPT Table 1. Baseline Patient Demographics and Blood Levels a
SIRS group
b
Terlipressin
Placebo
Terlipressin
Placebo
28
30
69
69
56.3 (± 8.0)
54.1 (± 7.9)
55.6 (± 8.6)
55.2 (± 8.8)
Sex, male : female
13:15
22:8
39:30
45:24
Alcoholic hepatitis
7 (25)
12 (40)
13 (18.8)
13 (18.8)
MAP, mm Hg (± SD)
74.6 (± 11.5)
76.4 (± 10.8)
76.1 (± 12.0)
75.0 (± 10.5)
Heart rate, beats/min
83 (± 15)
86 (± 10)
78 (± 12)
76 (± 12)
n
13
20
45
51
o
C (± SD)
36.7 (± .4)
36.5 (± .4)
SCr, mg/dL (± SD)
3.7 (± 1.2)
3.7 (± 1.1)
Patients with SCr
16 (57.1)
14 (46.7)
n Age, y (± SD)
(± SD)
3.7 (± 1.1)
27 (39.1)
37 (46.4)
132 (± 5)
132 (± 6)
132 (± 6)
12.6 (± 11.7)
10.8 (± 11.2)
10.7 (± 10.3)
12.6 (± 13.4)
10.3 (± 7.4)
9.5 (± 7.9)
7.1 (± 2.9)
6.5 (± 2.7)
< .0001
< .0001
132 (± 7)
(± SD) -
Serum HCO3 , mmol/L
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3.5 (± 1.0)
(± SD) WBC count x 10 /L
17 (± 3)
17 (± 3)
21 (± 4)
19 (± 4)
10.4 (± 1.83)
10.5 (± 1.88)
10.5 (± 1.80)
10.3 (± 1.67)
19 (67.9)
20 (66.7)
47 (68.1)
43 (62.3)
33.2 (± 7.4)
32.3 (± 5.7)
33.6 (± 5.8)
32.8 (± 5.4)
Pneumonia
0 (0)
1 (3.3)
6 (8.7)
2 (2.9)
Urinary tract
5 (17.9)
6 (20.0)
20 (29)
13 (18.8)
6 (21.4)
4 (13.3)
8 (11.6)
13 (18.8)
24
27
62
63
9.8±3.06
9.4±2.02
9.8±2.07
9.7±2.07
(± SD) Child-Pugh score
Child-Pugh class C, n (%)
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MELD score (± SD)
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(± SD)
Infection in the
previous 14 days, n (%)
infection Spontaneous bacterial peritonitis CLIF-SOFA Score (n) (±SD)
c
.0001
36.6 (± .6)
(± SD) Serum bilirubin, mg/dL
c
.0349
36.5 (± .5)
≥3.6 mg/dL, n (%) Serum sodium, mEq/L
SC
Temperature
P value
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Parameter
Non-SIRS group
23
c
c
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HCO3 , bicarbonate; MAP, mean arterial pressure; MELD, model for end-stage liver disease; SCr, serum creatinine; SIRS, systemic inflammatory response syndrome. a
Patients who met ≥2 SIRS criteria.
b
Patients who met <2 SIRS criteria.
c
SIRS versus non-SIRS, analysis of variance, with main effect treatment for continuous variables and
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a Cochran-Mantel-Haenszel test for general association for discrete variables.
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Table 2. Treatment Information and Medication Doses Used in the Study SIRS group Placebo
28
30
7.8 (± 6.8)
7.2 (± 4.5)
.73
34.7 (± 43.2)
36.1 (± 33.5)
.900
Total albumin dose, g (± SD)
197.8 (± 162.79)
293.1 (± 232.05)
.101
Mean daily albumin dose, g
48.9 (± 31.14)
48.0 (± 17.06)
83.1 (± 13.77)
74.2 (± 12.06)
7.6 (± 16.56)
2.5 (± 1.63)
N Treatment duration, days
value
69
5.3 (± 3.9)
5.8 (± 3.8)
.4918
.0068
23.3 (± 22.8)
.8076
.0067
181.5 (± 145.66)
222.3 (± 162.98)
.1513
.0836
.892
50.2 (± 23.62)
51.3 (± 27.82)
.8120
.5859
.014
80.7 (± 12.20)
75.3 (± 11.10)
.0095
.9395
−2.2 (± 11.08)
.012
4.6 (± 13.33)
.2 (± 10.53)
.0394
.9308
3.4 (± 1.80)
.090
3.2 (± 1.99)
3.6 (± 2.04)
.1930
.2370
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placebo) dose, mg (± SD)
mm Hg (± SD) ∆ MAP from baseline to end of SCr at end of treatment, mg/dL (± SD)
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treatment, mm Hg (± SD)
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(± SD) MAP at end of treatment,
valueb
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22.2 (± 25.9)
value
P a
Placebo
(± SD) Total treatment (terlipressin/
P
Terlipressin
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Terlipressin
a
SC
Parameter
Non-SIRS group
P
a
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∆ MAP, change in mean arterial pressure; SCr, serum creatinine; SIRS, systemic inflammatory response syndrome. Terlipressin versus placebo, analysis of variance, with main effect treatment for continuous variables and a Cochran-Mantel-Haenszel test for general
association for discrete variables. b
SIRS versus non-SIRS, analysis of variance, with main effect treatment for continuous variables and a Cochran-Mantel-Haenszel test for general association
for discrete variables.
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Non-SIRS group
Placebo
Terlipressin
Placebo
25
30
68
65
4 (16.0)
1 (3.3)
8 (11.8)
4 (6.2)
Infection, n (%)
7 (28)
3 (10.0)
6 (8.8)
8 (12.3)
Respiratory events, n (%)c
4 (16)
6 (20.0)
Hypotension n (%)b
0 (0)
4 (13.0)
N Multi-organ failure, n (%)
SIRS, systemic inflammatory response syndrome. a
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Terlipressin
9 (13.2)
6 (9.2)
2 (2.9)
1 (1.5)
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Included pulmonary edema, respiratory failure, pleural effusion, pulmonary hypertension, acute
respiratory distress syndrome, obstructive airway disorder, aspiration pneumonia. b
As reported by the investigator; a general guidance was provided to define hypotension as mean
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arterial pressure <70 mm Hg or decrease >40 mm Hg in systolic blood pressure from baseline.
26
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Supplementary Table 1. ACLF Grade and Antibiotic Use at Baseline by SIRS and Non-SIRS and Treatment Groups SIRS groupa
n
Terlipressin Placebo
Total
28
30
58
0
1 (3.6)
0
1 (1.7)
1
9 (32.1)
15 (50.0) 24 (41.4)
2
12 (42.9)
12 (40.0) 24 (41.4)
3
6 (21.4)
3 (10.0)
17 (60.7)
17 (56.7) 34 (58.6)
P valuec
Terlipressin
Placebo
Total
69
69
138
0
1 (0.7)
ACLF grade,
n (%)
1 (1.4)
33 (47.8)
35 (50.7) 68 (49.3)
23 (33.3)
18 (26.1) 41 (29.7)
12 (17.4)
16 (23.2) 28 (20.3)
.7949
40 (58.0)
43 (62.3) 83 (60.1)
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Antibiotic use
.3096
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9 (15.5)
SC
n (%)
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Parameter
Non-SIRS groupb
a
Patients who met ≥2 SIRS criteria. Patients who met <2 SIRS criteria.
b
Comparing terlipressin versus placebo using Fisher's exact test.
d
Comparing SIRS total versus non-SIRS total using Fisher’s exact test.
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ACLF, acute-on-chronic liver failure; SIRS, systemic inflammatory response syndrome.
1
P valuec P valued
.5455
.3136
.7282
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Supplementary Table 2. Reasons for Discontinuation of Study Treatment by the SIRS Group (Intent-to-Treat Population) SIRS groupa
n
Terlipressin
Placebo
Terlipressin
Placebo
28
30
69
69
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Reason for discontinuation, n (%)
Non-SIRS groupb
3 (10.7)
3 (10.0)
15 (21.7)
3 (4.3)
Confirmed HRS reversal
9 (32.1)
2 (6.7)
11 (15.9)
12 (17.4)
1 (3.3)
0 (0)
0 (0)
0 (0)
4 (5.8)
11 (15.9)
SC
Adverse event
0 (0)
Other
4 (14.3)
Physician decision
2 (7.1)
4 (13.3)
3 (4.3)
7 (10.1)
Protocol violation
0 (0)
0 (0)
0 (0)
1 (1.4)
1 (3.6)
4 (13.3)
3 (4.3)
3 (4.3)
4 (14.3)
3 (10.0)
7 (10.1)
7 (10.1)
1 (3.6)
2 (6.7)
1 (1.4)
3 (4.3)
4 (14.3)
8 (26.7)
14 (20.3)
16 (23.2)
0 (0)
3 (10.0)
11 (15.9)
6 (8.7)
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Death
Received maximum duration of randomized study
Renal replacement therapy
SCr at or above baseline value Transplant
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Request of patient or legally authorized representative
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medication treatment per protocol
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HRS, hepatorenal syndrome; SCr, serum creatinine; SIRS, systemic inflammatory response syndrome. a Patients who met ≥2 SIRS criteria. b Patients who met <2 SIRS criteria.
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol
1.
TITLE PAGE
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TERLIPRESSIN, LUCASSIN® IK-4001-HRS-301 A MULTI-CENTER, RANDOMIZED, PLACEBOCONTROLLED, DOUBLE-BLIND STUDY TO CONFIRM THE REVERSAL OF HEPATORENAL SYNDROME TYPE I WITH LUCASSIN® (TERLIPRESSIN) (REVERSE TRIAL)
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FORMERLY ORPHAN THERAPEUTICS PROTOCOL NUMBER OT-1001
Document type:
Clinical Study Protocol
Development phase:
Phase 3
IND number:
Ikaria Therapeutics LLC
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Company/Sponsor:
07 June 2010
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Release date:
68,582
6 Route 173 Clinton, NJ 08809 Telephone: 908-238-6600
This confidential document is the property of Ikaria Therapeutics LLC. No unpublished information contained herein may be disclosed without prior written approval from Ikaria Therapeutics LLC. Access to this document must be restricted to relevant parties.
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EMERGENCY CONTACT INFORMATION Name
Address and Telephone number
Study Lead
Diane Stebbins
6 State Route 173 Clinton, NJ 08809 Office: 908-238-6647
Medical Lead
Khurram Jamil, MD
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Role in Study
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6 State Route 173 Clinton, NJ 08809 Office: 908-238-6416
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INVESTIGATOR’S AGREEMENT
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I have read the attached protocol entitled “A Multi-Center, Randomized, Placebo-Controlled, Double-Blind Study To Confirm The Reversal Of Hepatorenal Syndrome Type 1 with Lucassin® (Terlipressin) (REVERSE Trial)” and agree to abide by all provisions set forth therein. I agree to comply with the International Conference on Harmonization (ICH) Tripartite Guideline on Good Clinical Practice (GCP), the ethical principles stated in the latest version of the Declaration of Helsinki, and the applicable local and international regulations, whichever provide the greater protection of the individual.
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I agree to ensure that the confidential information contained in this document will not be used for any purpose other than the evaluation or conduct of the clinical investigation without the prior written consent of Sponsor, Ikaria Therapeutics LLC.
Signature
Sponsor Statement
Date
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Principal Investigator
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Signature
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This study protocol was subject to critical review and has been approved by the following Sponsor representative.
Khurram Jamil, MD 6 Route 173 Clinton, NJ 08809
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2.
SYNOPSIS
Name of Sponsor/Company: Ikaria Therapeutics LLC
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Name of Investigational Product: Lucassin® Name of Active Ingredient: Terlipressin
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Title of Study: A Multi-Center Randomized, Placebo-Controlled, Double-Blind Study to Confirm the Reversal of Hepatorenal Syndrome Type 1 with Lucassin® (Terlipressin) (REVERSE Trial) (Formerly Orphan Therapeutics Protocol Number OT-1001)
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Study center(s): 40 - 55 sites in the United States and 0 - 10 in Canada
Phase of development: Phase 3
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Studied period (years): Estimated date first subject enrolled: October 2010 Estimated date last subject enrolled: February 2012 Duration of Treatment: up to14 days (maximum of 15/16 days if HRS reversal first achieved on Day 13/14) Duration of Study: (including all follow-up assessments): 90 days Estimated Study Completion Date: May 2012
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Objectives: Primary: To confirm the efficacy and safety of intravenous terlipressin versus placebo in the treatment of subjects with hepatorenal syndrome (HRS) type 1 receiving standard of care albumin therapy. Secondary: To demonstrate that terlipressin improves renal function and reverses HRS type 1 compared to placebo.
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Methodology: Placebo-controlled, double-blind, randomized, multicenter study. 1:1 randomization to terlipressin (Lucassin®) 1 mg IV q6h versus placebo. Number of subjects (planned): Approximately 150 subjects Diagnosis and main criteria for inclusion: Adult subjects with cirrhosis, ascites, and a diagnosis of HRS type 1 based on the 2007 International Ascites Club (IAC) diagnostic criteria. Main Inclusion Criteria: Subjects ≥ 18 years of age with cirrhosis, ascites, and rapidly progressive reduction in renal function (e.g., doubling of serum creatinine within 2 weeks) to a serum creatinine (SCr) ≥ 2.5 mg/dL without sustained improvement in renal function (< 20% decrease in SCr and SCr ≥ 2.25 mg/dL) 48 hours after both diuretic withdrawal and the beginning of plasma volume expansion with albumin.
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Exclusion Criteria: SCr level > 7 mg/dL; shock; sepsis or systemic inflammatory response syndrome (SIRS); < 2 days antiinfective therapy for documented/suspected infection; proteinuria > 500 mg/day; hematuria or microhematuria (> 50 red blood cells per high power field); clinically significant casts on urinalysis, including granular casts; evidence of intrinsic or parenchymal renal disease (including acute tubular necrosis); obstructive uropathy or other renal pathology on ultrasound or other medical imaging; current or recent treatment (within 4 weeks) with nephrotoxic drugs; current or recent (within 4 weeks) renal replacement therapy (RRT); superimposed acute liver injury due to factors other than acute alcoholic hepatitis including acute viral hepatitis, drugs, medications, or other toxins; current or recent treatment (within 48 hours) with octreotide, midodrine, vasopressin, dopamine or other vasopressors; severe cardiovascular disease as judged by investigator; estimated life expectancy of less than 3 days; confirmed pregnancy; known allergy or sensitivity to terlipressin or any component of study medication; participation in other clinical research involving investigational drugs or devices within 30 days
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Investigational product, dosage and mode of administration: Single-use, sterile 6-mL vials containing a lyophilized solid of 1 mg terlipressin acetate (equivalent to 0.85 mg terlipressin free base) with 10 mg mannitol as a bulking agent/stabilizer. Each vial will be reconstituted with 5 mL of sterile 0.9% sodium chloride solution. The following dosing scheme will be utilized for both terlipressin and matching placebo: Initial Dosing: Blinded Lucassin® (terlipressin for injection) or placebo will be administered intravenously as a slow bolus injection over 2 minutes at a dose of 1 mg (1 vial) every 6 hours (4 mg/day). Dose Modifications: • If on Day 4 of therapy (after a minimum of 10 doses), serum creatinine has decreased, but by less than 30% from the baseline value, the dose will be increased to 2 mg every 6 hours (8 mg/d). • The dose will not be increased if the subject has coronary artery disease; or in the clinical setting of circulatory overload, pulmonary edema, or treatment-refractory bronchospasm. • If dosing is interrupted due to a non-ischemic adverse event, study medication may be restarted, at the discretion of the investigator, at the same or lower dose (i.e., 0.5-1 mg q6h). Treatment Discontinuation: • Treatment will continue until at least two SCr values ≤ 1.5 mg/dL have been obtained at least 48 hours apart, or up to a maximum of 14 days (maximum of 15/16 days if SCr first reaches 1.5 mg/dL on Day 13/14, respectively). • If on Day 4 (after a minimum of 10 doses) SCr is at or above baseline value, study medication will be discontinued. • Treatment must be discontinued when the subject is to undergo RRT or transplantation. • Dosing must be permanently discontinued if an ischemic event occurs. Retreatment: If judged by the investigator to be potentially beneficial, subjects who demonstrated at least a 30% reduction in SCr during initial treatment who develop recurrence of HRS type 1 may be retreated once with the initially assigned study medication. To qualify for retreatment the subject must again meet the study inclusion/exclusion criteria. Duration of treatment: The active treatment period is 14 days (exception: 15 or 16 days as described above), with one
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol retreatment cycle allowed. Subjects will be contacted for follow-up assessments on Days 30, 60 and 90. Reference therapy, dosage and mode of administration: Matching placebo vials (containing 11 mg mannitol) that are identical in appearance to terlipressin for injection vials. Each vial will be reconstituted with 5 mL of sterile 0.9% sodium chloride solution.
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Criteria for evaluation: Primary Efficacy Endpoint: Confirmed HRS Reversal - the percentage of subjects with two serum creatinine (SCr) values ≤ 1.5 mg/dL, at least 48 hours apart, on treatment Secondary Efficacy Endpoints:
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•
Renal function: change from baseline through end of treatment in SCr values HRS Reversal: the percentage of subjects with at least one SCr value ≤ 1.5 mg/dL on treatment Transplant-free Survival up to 90 days, defined as the time (in days) that each subject survives without liver transplantation from the day of randomization. Overall Survival up to 90 days, defined as the time (in days) that each subject survives from the day of randomization
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• • •
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Other Efficacy Endpoints: • Glomerular filtration rate (GFR): change from baseline through end of treatment in GFR using both MDRD and Cockcroft-Gault equations • Fractional excretion of sodium (FENa): change from baseline through end of treatment in FENa • HRS type 1 recurrence until transplantation, hospital discharge, or Day 14, whichever occurs first. • Dialysis free survival up to 90 days: defined as the time (in days) that each subject survives without dialysis from the day of randomization Safety: • Non-serious adverse events up to 7 days post end of treatment • Serious adverse events up to 30 days post end of treatment • General safety profile, including vital signs and laboratory tests • Mortality up to 90 days Pharmacokinetics: • Population PK using sparse sampling approach. One baseline sample and additional three sparse samples during the 1st dose period on Day 1 will be collected. The time points for sample collection will be randomly assigned at the time of randomization. A previously developed population PK model will be used to characterize the pharmacokinetics of terlipressin and lysine-vasopressin in HRS subjects. • The relationship between drug exposure (AUC or Cmax) and response (SCr, MAP, and HR) during the treatment with terlipressin will also be explored. Exploratory Biomarker (optional): Exploratory analysis of gene expression for receptor polymorphism (DNA) as a biomarker for terlipressin treatment effects.
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Statistical methods: The primary efficacy endpoint for this study is the incidence of confirmed HRS Reversal defined as the percentage of subjects with two SCr values of ≤ 1.5 mg/dL, at least 48 hrs apart, on treatment (see Section 13.5.1). The intent-to-treat (ITT) population, excluding any SCr values obtained posttransplantation or post-renal replacement therapy, will be used for analysis; Subjects will be stratified by qualifying SCr (< 3.6 mg/dL or ≥ 3.6 mg/dL) and alcoholic hepatitis (present or not). The primary efficacy endpoint will be analyzed in the ITT population using a Cochran-Mantel-Haenszel (CMH) chisquare test stratified for SCr and alcoholic hepatitis (present or not). Secondary efficacy variables that are similar to the primary endpoint will be analyzed similarly using the CMH test. The pre-specified secondary endpoints will be analyzed in a sequential fashion. Change from baseline in variables (such as SCr) through end of treatment will be analyzed using repeated measures analysis of covariance. Subgroup analysis by pre-specified criteria and other exploratory analyses are planned. In the OT-0401 study, for subjects with baseline SCr ≤ 7 mg/dL, the confirmed HRS reversal rate in the placebo group was 12.5% (7/56). The rate for terlipressin was 36% (18/50). One-hundred-and-fifty subjects (75 subjects per group) will provide 90% power to detect a statistically significant (p ≤ 0.05 two-sided test) difference between the two treatment groups. A Data Safety Monitoring Board (DSMB) will review safety and mortality data as per DSMB charter.
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TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES
1.
TITLE PAGE ..............................................................................................................1
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3.
EMERGENCY CONTACT INFORMATION ................................................................................2 INVESTIGATOR’S AGREEMENT ...............................................................................................3 SYNOPSIS ...................................................................................................................4
3.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .................8
4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................15
5.
INTRODUCTION ......................................................................................................18
5.1.
Hepatorenal Syndrome ...............................................................................................18
5.2.
Terlipressin Background .............................................................................................19
5.3.
Nonclinical Studies .....................................................................................................19
5.4.
Clinical Studies ...........................................................................................................20
5.4.1.
Pharmacokinetics and Pharmacodynamics .................................................................20
5.4.2.
Healthy Volunteers .....................................................................................................20
5.4.3.
Patients with HRS Type 1...........................................................................................20
5.4.4.
Clinical Efficacy in Hepatorenal Syndrome Type 1 (Study OT-0401) ......................21
5.4.5.
Clinical Safety in Study OT-0401 ..............................................................................22
5.4.6.
Other Parameters in Study OT-0401 ..........................................................................23
5.4.6.1.
Antigenicity ................................................................................................................23
5.4.6.2.
QT Effects ...................................................................................................................23
5.4.6.3.
Known and Potential Risks .........................................................................................23
5.5.1. 5.5.2. 6.
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2.
Study Rationale ...........................................................................................................24 Primary Endpoint Rationale .......................................................................................24
Dosing Regimen and Recommended Co-treatment with Albumin ............................25 OBJECTIVES .............................................................................................................26
6.1.
Primary Objective .......................................................................................................26
6.2.
Secondary Objective(s) ...............................................................................................26
6.3.
Efficacy Variables ......................................................................................................26
6.3.1.
Primary Efficacy Variables.........................................................................................26
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol Secondary Efficacy Variables.....................................................................................26
6.3.3.
Other Efficacy Variables ............................................................................................26
7.
INVESTIGATIONAL PLAN .....................................................................................28
7.1.
Overall Study Design and Plan: Description ..............................................................28
8.
STUDY POPULATION .............................................................................................29
8.1.
Population Rationale ...................................................................................................29
8.2.
Number of subjects to be studied................................................................................29
8.3.
Inclusion criteria .........................................................................................................29
8.4.
Exclusion criteria ........................................................................................................30
8.5.
Subject Withdrawal criteria ........................................................................................32
9.
PROTOCOL DEVIATIONS ......................................................................................33
10.
TREATMENT OF SUBJECTS ..................................................................................34
10.1.
Terlipressin .................................................................................................................34
10.1.1.
Initial Dosing ..............................................................................................................34
10.1.2.
Dose Modifications .....................................................................................................34
10.2.
Placebo ........................................................................................................................34
10.3.
Blinding ......................................................................................................................34
10.4.
Randomization ............................................................................................................34
10.5.
Retreatment .................................................................................................................35
10.6.
Discontinuation of Treatment .....................................................................................35
10.7.
Concomitant Medication ............................................................................................35
10.7.1.
Recommended Concomitant Medication ...................................................................35
10.7.1.1.
Albumin ......................................................................................................................35
10.7.1.2.
Prohibited or Discouraged Concomitant Medications ................................................35
10.8.
Treatment Compliance................................................................................................36
11. 11.1.
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6.3.2.
Medical Hotline ..........................................................................................................36
STUDY DRUG MATERIAL AND MANAGEMENT .............................................37 Description of Terlipressin for Injection ....................................................................37
11.2.
Packaging and Labeling..............................................................................................38
11.3.
Study Drug Storage and Preparation ..........................................................................38
11.3.1.
Reconstitution .............................................................................................................38
11.3.2.
Administration ............................................................................................................38
11.4.
Study Drug Accountability .........................................................................................38
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol RANDOMIZATION, BREAKING OF BLINDED CODES .....................................39
12.1.
Randomization and blinding .......................................................................................39
12.1.1.
Randomization ............................................................................................................39
12.1.2.
Blinding of Study Medications ...................................................................................39
12.1.3.
Unblinding of Treatment Assignment ........................................................................39
13.
ASSESSMENTS AND PROCEDURES ....................................................................40
13.1.
Schedule of Assessments and Procedures ..................................................................40
13.2.
Study Assessment Phases ...........................................................................................44
13.2.1.
Subject Screening Phase .............................................................................................44
13.2.2.
Pre-Treatment Phase ...................................................................................................44
13.2.3.
Active Study Phase (14 Days) ....................................................................................44
13.2.4.
Follow-up Phase .........................................................................................................44
13.3.
Detail of Safety Assessments and Procedures ............................................................45
13.3.1.
Vital Sign Measurements ............................................................................................45
13.3.2.
Encephalopathy Score ................................................................................................45
13.3.3.
Model for End-Stage Liver Disease (MELD) Score ..................................................45
13.3.4.
Adverse Events ...........................................................................................................45
13.4.
Detail of Laboratory Assessments and Procedures ....................................................46
13.4.1.
Local Laboratory at Investigational Site.....................................................................46
13.4.1.1.
Serum Electrolytes & Biochemistry ...........................................................................46
13.4.1.2.
Hematology.................................................................................................................47
13.4.1.3.
Urine ...........................................................................................................................47
13.5.
Detail of Efficacy Assessments and Procedures .........................................................47
13.5.1.
Primary Efficacy Variables.........................................................................................47
13.5.2.
Secondary Efficacy Variables.....................................................................................48
13.5.3.
Other Efficacy Variables ............................................................................................48
13.5.4.
Other Exploratory Analyses .......................................................................................49
13.5.5.
Pharmacokinetics ........................................................................................................49
13.6.
Optional Sub-Study for Biomarker Genetic Assessments ..........................................50
13.6.1.
Genetic Assessments ..................................................................................................50
14.
ADVERSE EVENTS..................................................................................................51
14.1.
Definitions ..................................................................................................................51
14.1.1.
Adverse Event .............................................................................................................51
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14.2.
Severity And Causality Assessments For Adverse Events ........................................51
14.2.1.
Severity Assessment ...................................................................................................51
14.2.2.
Study Medication Causality........................................................................................52
14.3.
Collection, Recording and Reporting of Adverse Events ...........................................52
14.3.1.
Adverse Event Recording ...........................................................................................52
14.3.2.
Procedure for Serious Adverse Event Reporting ........................................................53
15.
STATISTICAL PLAN................................................................................................54
15.1.
Safety Variables ..........................................................................................................54
15.2.
Subject Accounting and Baseline Characteristics ......................................................54
15.3.
Statistical Methodology ..............................................................................................55
15.3.1.
Sample Size Calculation .............................................................................................55
15.3.2.
Patient Populations .....................................................................................................55
15.3.2.1.
Intention to Treat (ITT) Population ............................................................................55
15.3.2.2.
Safety Population ........................................................................................................55
15.3.2.3.
Per Protocol (PP) Population ......................................................................................55
15.3.3.
Statistical Analyses .....................................................................................................55
15.3.4.
Demographic and Baseline Characteristics ................................................................55
15.3.5.
Efficacy Analyses .......................................................................................................56
15.3.5.1.
Other Efficacy Variables ............................................................................................57
15.3.5.2.
Safety Analysis ...........................................................................................................57
15.3.6.
Pharmacokinetics ........................................................................................................58
15.3.7.
Definition of Time Points ...........................................................................................58
15.3.8.
Missing Data ...............................................................................................................58
15.3.9.
Procedure for Amendments to Statistical Plan ...........................................................58
16.
DATA MANAGEMENT ...........................................................................................59
16.2.
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14.1.2.
Data Collection ...........................................................................................................59 Records Retention .......................................................................................................59
16.3.
Inspection of Records .................................................................................................59
16.4.
Retention of Records/Critical Documents ..................................................................60
17.
QUALITY CONTROL AND QUALITY ASSURANCE .........................................61
17.1.
Study Monitoring ........................................................................................................61
17.2.
Auditing ......................................................................................................................61
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17.4.
Informed Consent .......................................................................................................61
17.5.
Institutional Review Board/Independent Ethics Committee ......................................62
17.6.
Confidentiality ............................................................................................................62
18.
REGISTRATION OF STUDY AND PUBLICATION OF DATA ...........................63
19.
REFERENCES ...........................................................................................................64
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APPENDIX A. STUDY IK-4001-HRS-301: NOMOGRAM TO DETERMINE CRITERION FOR SCr DOUBLING OVER TWO WEEKS ....................................68
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LIST OF TABLES Abbreviations and Specialist Terms ...........................................................................15
Table 2:
Overview of Safety Data – Study OT-0401 ...............................................................23
Table 3:
Prohibited/Discouraged Concomitant Medications ....................................................36
Table 4:
Schedule of Assessments ............................................................................................41
Table 5:
West Haven Criteria for Semiquantitative Grading of Mental State15 .......................45
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Table 1:
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LIST OF FIGURES Forest Plots Of Random Effects Meta-Analyses On Terlipressin Plus Albumin Versus Albumin For Patients With HRS.20 .................................................22
Figure 2:
Schematic Diagram of Trial Design ...........................................................................28
Figure 3:
Lucassin® (Terlipressin for Injection) ........................................................................37
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Figure 1:
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol
4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
The following abbreviations and specialist terms are used in this study protocol. Table 1:
Abbreviations and Specialist Terms Explanation
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine amino transferase, also known as SGPT
ANCOVA
analysis of covariance
AST
aspartate amino transferase, also known as SGOT
AUC
area under the curve
BP
blood pressure
BUN
blood urine nitrogen
CBC
complete blood count
CFR
Code of Federal Regulations
Cmax
maximum concentration
CMH
Cochran-Mantel-Haenszel
CO2
carbon dioxide
chronic obstructive pulmonary disease
CRF
case report form
d
day
EC ECG Emax EVH
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DSMB
data clarification form
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DCF
DNA
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COPD
dL
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Abbreviation or specialist term
deciliter deoxyribonucleic acid Data Safety Monitoring Board Ethics Committee electrocardiogram maximum effect esophageal variceal hemorrhage
FENa
fractional excretion of sodium
FDA
Food and Drug Administration
FU
follow-up
GCP
Good Clinical Practice
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol Explanation
GFR
glomerular filtration rate
h
hour
HR
heart rate
HRS
hepatorenal syndrome
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IND
Investigational New Drug
INR
International Normalized Ratio
IRB
Institutional Review Board
ITT
intent-to-treat
IV
intravenous
IVRS
Interactive Voice Response System
MAP
mean arterial pressure
MedRA
Medical Dictionary for Regulatory Activities
MELD
model for end-stage liver disease
MDRD
modification of diet in renal disease
NSAIDs
nonsteroidal anti-inflammatory drugs polymerase chain reaction
PK
pharmacokinetic
PD
pharmacodynamic
RRT SAE SAER SBP
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RNA
per protocol
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RBC
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PCR
q6h
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Abbreviation or specialist term
once every six hours red blood cell ribonucleic acid renal replacement therapy serious adverse event serious adverse event report systolic blood pressure
SCr
serum creatinine
SGOT
serum glutamic-oxaloacetic transaminase, also known as AST
SGPT
serum glutamic-pyruvic transaminase, also known as ALT
SmPC
summary of product characteristics
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol Explanation
SNPs
single nucleotide polymorphisms
TBD
to be determined
TIPS
transjugular intrahepatic portosystemic shunt
US
United States
UTI
urinary tract infection
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Abbreviation or specialist term
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5.
INTRODUCTION
5.1.
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This protocol describes the procedures and instructions for this randomized, double-blind, placebo-controlled phase 3 study. This study is designed to evaluate the efficacy and safety of intravenous Lucassin® (terlipressin) versus placebo for the treatment of type 1 hepatorenal syndrome (HRS) in subjects receiving standard of care albumin therapy. This study will be conducted in compliance with International Conference of Harmonization (ICH) / Good Clinical Practices (GCP) including the Declaration of Helsinki and all applicable regulatory requirements.
Hepatorenal Syndrome
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Hepatorenal syndrome is a rare syndrome of marked renal dysfunction in patients with cirrhosis, decompensated liver disease, and portal hypertension.4, 5, 9, 10, 19 Hepatorenal syndrome is characterized by functional renal failure (very low renal perfusion and glomerular filtration rates) in the absence of underlying kidney pathology. Hepatorenal syndrome is at one end of a spectrum of functional renal abnormalities caused by severe vasoconstriction of the renal circulation leading to a pronounced reduction in glomerular filtration rate (GFR). Hepatorenal syndrome type 1 is characterized by a rapid progressive renal impairment and has a very poor prognosis with > 80% mortality within 3 months.1, 18, 25, 31
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Patients with HRS have a hyperdynamic circulation characterized by arterial hypotension and very low systemic vascular resistance; in the splanchnic circulation, there is marked arterial vasodilation, which is responsible for impairment in circulatory function and homeostatic activation of the endogenous vasoconstrictor systems. In the early stages of decompensated cirrhosis, renal blood flow is maintained within normal limits due to an increased production of systemic and renal vasodilators (mainly prostaglandins). As cirrhosis progresses, the effect of circulating vasoconstrictors overcomes the effect of renal vasodilators, resulting in severe renal vasoconstriction and a reduction in GFR. In some patients, precipitating factors (including bacterial infections) worsen circulatory dysfunction and aggravate renal vasoconstriction. Once renal vasoconstriction occurs, intra-renal mechanisms perpetuate HRS since hypoperfusion leads to an imbalance in local vasoactive systems that, in turn, cause more vasoconstriction.10
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The diagnostic criteria for HRS were originally described by a consensus workshop of the International Ascites Club in 1996 and were updated in 2007.4, 41 Hepatorenal syndrome is a diagnosis of exclusion; other causes of renal failure, e.g., shock, parenchymal kidney disease, nephrotoxic drugs, and volume depletion must be ruled out. Hepatorenal syndrome type 1 is characterized by rapidly progressive renal failure, e.g., a doubling of the serum creatinine (SCr) concentration to ≥ 2.5 mg/dL in less than 2 weeks. At present, there is no approved pharmacological therapy for the treatment of HRS type 1 in the USA, Canada or Australia. The only curative treatment for HRS type 1 and the underlying endstage cirrhosis is liver transplantation.8, 19, 30 However, not all patients are candidates for liver transplantation and liver transplantation is not universally available. For those who are transplant candidates, a suitable organ may not be found quickly enough. Furthermore, even when an organ is available, the presence of uncorrected HRS type 1 worsens the outcome of liver transplantation.21, 39 One retrospective case-control study suggests that HRS patients treated with vasopressin analogues before liver transplant have a post-transplant outcome similar to that of Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol patients with no HRS pre-transplant.38 Thus, even in the best possible clinical scenario, there is a high need for effective medical therapy to reverse HRS type 1; in the absence of access to transplant, medical therapy is the only alternative.
5.2.
Terlipressin Background
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Substantial data available from many published clinical investigations in the literature provide compelling evidence suggesting that administration of terlipressin improves renal function in patients with HRS.14, 20, 29, 42 In HRS patients with hyperdynamic circulation, the strong V1 receptor-mediated vasoconstrictor activity of terlipressin, particularly in the splanchnic area, results in an increase in effective arterial volume, an increase in mean arterial pressure (MAP), normalization of endogenous vasoconstrictor systems (renin-angiotensin-aldosterone and sympathetic nervous system), and an increase in renal blood flow. These effects result in improved renal function, thereby providing the therapeutic rationale for treatment of HRS with terlipressin.5, 19, 26
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Terlipressin is a synthetic vasopressin analog that acts on vasopressin receptors, both as a prodrug for lysine-vasopressin and probably with pharmacologic activity on its own, albeit of lower potency than lysine-vasopressin. The duration of action of terlipressin is longer than that of vasopressin and is due to cleavage of the N-terminal glycyl residues of terlipressin) by various tissue peptidases, resulting in gradual release of the pharmacologically active metabolite lysinevasopressin.
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Vasopressins are direct systemic vasoconstrictors (mediated by V1 receptor-activation on vascular smooth muscle) and antidiuretics (mediated by V2 receptor-activation in the renal collecting duct system). The distribution and density of vasopressin receptors accounts for the various pharmacological effects, which are concentration-dependent, with V1 receptor-mediated vasoconstriction occurring at higher concentrations. The V2 receptor-mediated antidiuresis reaches a maximum effect at lower concentrations. At the dose of terlipressin used to treat HRS patients, the strong V1-mediated vasoconstrictor activity is the pharmacodynamic mechanism responsible for its clinical activity.24 (See Section 11 for description of terlipressin)
Nonclinical Studies
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The nonclinical pharmacology data in various animal species, including relevant models of liver disease, have consistently demonstrated that terlipressin decreases splanchnic blood flow and portal pressure, increases peripheral vascular resistance and effective arterial volume, and increases renal perfusion. The hemodynamic effects of terlipressin in numerous animal models are consistent with the effects reported in a large number of clinical studies and with the proposed mechanism of action of terlipressin in HRS patients (vasoconstriction of the dilated splanchnic arterial bed and increased arterial volume resulting in an increase in renal perfusion and improved renal function). The nonclinical and clinical pharmacokinetics studies have demonstrated that the pharmacokinetic profile of terlipressin following intravenous (IV) administration is similar in animals and in humans. In all studies, detectable plasma concentrations of both terlipressin and lysine-vasopressin are achieved after IV administration of terlipressin, and the plasma concentrations appear to increase with increasing dose administered. Terlipressin and lysinevasopressin are rapidly eliminated in all species studied. Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol Single-dose studies were conducted in mice, rats and dogs. Repeat-dose studies (7 and 28 days) were conducted in rats and dogs. Overall, the clinical signs in rats and dogs were generally consistent with the pharmacologic effects of terlipressin and correlated with terlipressin dose level. No significant signs were observed during the 2-week recovery period in the 28-day studies. There was no necrosis observed at the injection site in rats or dogs.24
Clinical Studies
5.4.1.
Pharmacokinetics and Pharmacodynamics
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No formal drug interaction studies have been performed, but in-vitro studies demonstrated that terlipressin does not have either inhibitory or induction potential on a broad array of cytochrome p450 isoenzymes.24
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The pharmacokinetics of terlipressin are complex and can be described by second-order kinetics. After IV administration of terlipressin, the glycyl residues of terlipressin are cleaved by endogenous tissues proteases. Thus, terlipressin levels in the blood decrease rather rapidly and the pharmacologically active metabolite lysine-vasopressin is released gradually from tissues into the circulation.
5.4.2.
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The similarity in elimination half-life and clearance in HRS patients in study OT-0401 and healthy volunteers may be explained by the ubiquitous nature of the enzymes responsible for the metabolism of terlipressin and other peptides. Vasopressin is metabolized at the C- and Nterminus, as well as by disulfide bond cleavage, by various peptidases and proteases that are detectable in almost all human tissues; however, the majority of terlipressin metabolism occurs in liver and kidney tissues. 16, 24, 27 Healthy Volunteers
5.4.3.
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After administration of 7.5 µg/kg terlipressin, maximum plasma concentration of terlipressin was seen within 5 minutes.17 By 120 minutes, terlipressin was virtually absent and the maximal concentration of lysine-vasopressin observed. The mean elimination half-life of terlipressin was 24 ± 2 minutes and volume of distribution was 15.5 ± 4.5 L. The half life for distribution and elimination of terlipressin was determined to be 8 and 50 minutes 34 respectively, after administration of a single dose of 5, 10 or 20 µg/kg terlipressin.34 The distribution volume was 0.7 L/kg body weight and plasma clearance was 9 ml/kg/min. Only 1% of the injected terlipressin was found in urine, which indicates that terlipressin was almost completely metabolized in the body. Lysine-vasopressin reached highest plasma concentrations 60 to 120 minutes after terlipressin administration. Plasma levels of lysine-vasopressin remained constant over a period of 4 - 6 hours. Patients with HRS Type 1
A population-based sparse sampling pharmacokinetic (PK) strategy was utilized in patients with HRS type 1 enrolled in the previous phase 3 study (OT-0401). Analyses of samples from 29 patients indicate that terlipressin and lysine-vasopressin plasma concentrations appear to increase with dose. Mean maximum terlipressin concentrations of 62.1 ng/mL were observed immediately after dosing, then decayed rapidly with a mean half-life of 1.08 hours and returned to baseline within the 6 hour dosing interval. Mean maximum lysine-vasopressin steady-state Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol plasma levels of 1.06 ng/mL were seen peaking at approximately 2-hours post dose, and were still measurable in 2/3 of patients at 5.4 hours post-dose (mean 0.15 ng/mL). Due to the short half-life and rapid clearance of terlipressin and lysine-vasopressin in HRS patients, the chance of any significant drug accumulation after several days of treatment with terlipressin is very low. Clinical Efficacy in Hepatorenal Syndrome Type 1 (Study OT-0401)
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5.4.4.
Study OT-0401, was a phase 3, double-blind, randomized, placebo-controlled, multicenter international trial in which 112 patients with HRS type 1 were randomized 1:1 to receive terlipressin or placebo, with concomitant albumin administration recommended in both treatment arms.
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Study OT-0401 was designed using a more stringent version of the standard HRS reversal endpoint (at least one SCr value ≤ 1.5 mg/dL) to include assessment of the durability of response. The resulting primary endpoint was called “Treatment Success” and required an initial reduction of SCr to ≤ 1.5 mg/dL followed by a confirmatory SCr measurement of < 1.5 mg/dL 48 hours after the initial HRS reversal and an additional SCr value < 2.5 mg/dL at Day 14, without intervening liver transplant or dialysis. The primary endpoint, Treatment Success at Day 14, favored terlipressin but did not attain statistical significance (25% vs. 13%; p = 0.093).42
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Using the established endpoint of HRS reversal (at least one SCr value ≤ 1.5 mg/dL), the incidence of HRS reversal on treatment was significantly higher in terlipressin-treated patients (34%) compared with placebo-treated patients (13%; p = 0.008). In terlipressin-treated patients, HRS reversal typically occurred between Days 3 and 7, but continued to occur until Day 14. In addition, the terlipressin-treated patients had a statistically significant reduction in SCr concentrations from baseline to end of treatment relative to the control group (- 0.7 mg/dL; p = 0.009). The results demonstrated that terlipressin is superior to placebo for HRS reversal and for improving renal function when administered concomitantly with the standard background therapy of albumin. Albumin alone had a modest effect on HRS reversal, supporting its continued use as part of standard medical therapy for HRS.
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Although terlipressin improves renal function, it does not affect the underlying severe liver disease, and thus can only be expected to have a modest effect on overall survival. In Study OT0401 no significant differences in overall and transplant-free survival at Day 180 were observed between the terlipressin and control groups (42.9% with terlipressin vs. 37.5% with placebo; p = 0.84). In addition to study OT-0401, the medical literature on treatment of HRS type 1 with terlipressin includes several additional randomized, controlled studies.2, 23, 29, 33, 47 Data from these studies consistently showed improvements in renal function, as measured by HRS reversal and/or reduction of SCr, in 33% to 100% of patients studied. In addition, three recent meta-analyses, which include the results of OT-0401, support the efficacy of terlipressin for the treatment of HRS.14, 20, 40 (Figure 1)
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol Forest Plots Of Random Effects Meta-Analyses On Terlipressin Plus Albumin Versus Albumin For Patients With HRS.20
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Figure 1:
Forest plots of random effects meta-analyses on terlipressin plus albumin versus albumin for patients with HRS. The outcome measures are reversal of HRS and improved renal function. The included patients received terlipressin alone or with albumin versus no intervention or albumin.20
5.4.5.
Clinical Safety in Study OT-0401
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In study OT-0401, the majority of patients in both treatment arms experienced at least one adverse event (AE) (Table 2). The incidence of serious adverse events (SAEs) was identical between treatment groups. The most common AE in the terlipressin-treated patients included vomiting, hepatic failure, nausea, abdominal pain, and anemia.24
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Three terlipressin-treated patients (5%) experienced non-fatal ischemic AEs leading to treatment withdrawal (myocardial infarction, livedo reticularis, cyanosis of peripheral extremities).
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There were no treatment-related deaths reported and the majority of deaths in both treatment arms were due to the underlying liver disease.
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol Table 2:
Overview of Safety Data – Study OT-0401
Safety Parameter
Terlipressin (N = 56) n (%)
Placebo (N = 55) n (%)
All
52 (92.9)
49 (89.1)
Treatment-related
18 (32.1)
Serious Adverse Events All
37 (66.1) 5 (8.9)
Deaths up to 180 days All
Withdrawal due to Adverse Event All Treatment-related
5.4.6.
Other Parameters in Study OT-0401
5.4.6.1.
Antigenicity
36 (65.5)
32 (57.1)
35 (63.6)
0 (0.0)
0 (0.0)
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12 (21.8)
1 (1.8)
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Adverse Events
3 (5.4)
2 (3.6)
3 (5.4)
0 (0.0)
5.4.6.2.
QT Effects
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No significant levels of antibody were detectable in the serum of HRS type 1 patients treated with terlipressin.
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Electrocardiogram (ECG) data from HRS type 1 patients were analyzed for effects on QT. The QT interval decreased from baseline in both treatment groups with a more marked decrease in the placebo group. This resulted in a mean difference in change from baseline in QTcF between terlipressin and placebo of 7.8 msec, which was not statistically significant. Known and Potential Risks
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5.4.6.3.
Terlipressin is a vasoconstrictor and should be used with caution in patients with coronary artery disease as it may cause myocardial ischemia. It should not be used in patients with unstable angina or recent acute myocardial infarction. Torsade de pointes, QT prolongation and ventricular fibrillation have been rarely reported in the post-marketing setting outside the United States (US). Ischemic events (cardiac, gastrointestinal, and skin) have occurred following administration of terlipressin. Manifestations may include angina, ECG changes, peripheral cyanosis and extremity pain. Terlipressin should be permanently discontinued if an ischemic event occurs. Due to its constrictive effects on smooth muscle, terlipressin should be used with caution in patients with severe asthma or chronic obstructive pulmonary disease (COPD). Terlipressin Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol causes significant increases in uterine activity and reduction in endometrial blood flow that can result in fetal harm and spontaneous abortion.
5.5.
Study Rationale
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Hepatorenal syndrome type 1 is a serious orphan disease complicating decompensated chronic liver disease with cirrhosis; the optimal treatment for the underlying cause of HRS type 1 is liver transplantation.19 However, many patients will not survive long enough to receive a liver transplant and therapy, which may provide a bridge to transplantation, is badly needed. Furthermore, pre-transplant renal impairment is associated with increased post-transplant complications and a decrease in the net benefit of liver transplantation.32, 46 Conversely, HRS reversal is associated with improved overall survival42 and therapy, which reverses HRS type 1 appears likely to be associated with improved post-transplant outcomes.38 In those patients who are not candidates for liver transplantation, HRS reversal facilitates their medical management and may provide the survival time needed for improvement in underlying liver disease (e.g., alcoholic hepatitis). At present, there are no approved drug therapies for HRS type 1 in the US, Australia, or Canada.
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Increased understanding of the pathophysiology of HRS type 1 has demonstrated that vasoconstrictive drug therapy may reverse HRS type 1.41 While a number of vasoconstrictor drugs (e.g., midodrine, ornipressin, vasopressin, norepinephrine) have been studied as treatment for HRS type 1, most have either been studied in small numbers of patients outside randomized and placebo-controlled trials,3, 49 studied retrospectively,13, 45 or have not shown evidence of efficacy with an acceptable risk-benefit profile.22 Terlipressin has been extensively studied in patients with cirrhosis as therapy for esophageal variceal hemorrhage (EVH), and more recently, as therapy for HRS type 1.12, 43 Terlipressin is approved in many countries for the treatment of esophageal variceal hemorrhage, and in several countries for the treatment of HRS (France, Ireland, Spain, Mexico, South Korea, Taiwan, India, and Portugal), but is not approved for any indication in the USA, Canada, Australia, Japan and South Africa.
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Four randomized, controlled trials of terlipressin in HRS type 129, 33, 42, 47 along with recent meta-analyses of these and other trials, support the role of terlipressin in HRS type 1.14, 20, 40 The largest of the randomized placebo-controlled trials studied 112 patients with HRS type 1 treated with terlipressin or placebo as part of the Orphan Therapeutics clinical development program.42 While this pivotal trial demonstrated a clinically and statistically significant effect of terlipressin (versus placebo) on the rate of HRS reversal, the accepted and standard clinical endpoint applied in the literature,41 the study-specific primary endpoint, the incidence of “Treatment Success at Day 14”, yielded less robust results (see Section 5.4.4). Overall, data from this pivotal study and the existing literature provide evidence that terlipressin is effective in reversing HRS type 1, but as agreed with the FDA, a confirmatory phase 3 placebo-controlled trial is needed. This trial, in combination with existing data, will provide the level of evidence necessary to define the risk-benefit of terlipressin in patients with HRS type 1 and endeavor to obtain regulatory approval for its use to satisfy the unmet medical need. 5.5.1.
Primary Endpoint Rationale
The primary endpoint of “Confirmed HRS Reversal” is based on the clinical endpoint of HRS reversal (one SCr value of ≤ 1.5 mg/dL) the standard endpoint utilized in the literature and HRS Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol treatment guidelines.41 In agreement with FDA, confirmation of HRS reversal has been incorporated into the primary endpoint through documentation of a second SCr value of ≤ 1.5 mg/dL at least 48 hours later. 5.5.2.
Dosing Regimen and Recommended Co-treatment with Albumin
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The terlipressin dosing regimen used in study OT-0401 was 1 mg every 6 hours increased to 2 mg every 6 hours if SCr values decreased < 30% after 3 days. Study medication was administered for 2 days post-response or up to 14 days. If a patient’s SCr value was at or above baseline on Day 7, then study medication was to be discontinued.
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The dosing regimen studied in study OT-0401 was based on a substantial body of evidence from 11 literature studies where effective doses of terlipressin in HRS type 1 ranged from 2 to 12 mg/day.24 Additional dosing information was derived from the approved dosage in foreign labeling (1-2 mg every 4-6 hours, i.e., 4-12 mg/day) for esophageal variceal hemorrhage (EVH), a condition that affects patients with cirrhosis and portal hypertension, a population substantially similar to the HRS patient population.
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The 1 mg dose was shown to be the appropriate starting dose in study OT-0401, as only a small proportion of patients who achieved HRS reversal required a dose increase to 2 mg (3 out of 19 responders). In the randomized, controlled TAHRS study, all 6 patients who received an initial terlipressin dose of 0.5 mg q4h required dose increases whereas only one of the 17 patients who received an initial dose of 1 mg q4h required a dose increase to 2 mg q4h.24 Two of the 9 patients who achieved HRS reversal in TAHRS required the 2 mg dose.
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The dosing regimen in study OT-0401 had a less frequent dosing interval and lower daily dose intensity than the TAHRS Study regimen, but resulted in similar efficacy (34% vs. 39%) and a lower rate of SAEs (66% vs. 91%) and withdrawals due to AEs (5% vs. 22%) in terlipressintreated patients.
EP
The duration of therapy is to be at least 2 days post-response or up to 14 days. This duration of treatment was used historically in studies of terlipressin in HRS and was also shown to be an appropriate duration of treatment based on Study OT-0401. In OT-0401, HRS reversal commonly occurred between Days 3 and 7 (range 2-14 days) and the mean maximal decrease in SCr in all terlipressin patients was observed after approximately 7 days. However, HRS reversal continued to occur up to Treatment Day 14.
AC C
Based on the finding in study OT-0401, that patients without any SCr decrease by Day 4 did not achieve HRS reversal, a change to the duration of therapy is being made for this study. Protocol IK-4001-HRS-301) specifies that these patients must be discontinued on Day 4, rather than on Day 7. In keeping with standard medical practice and current guidelines, it is strongly recommended that albumin be administered to all patients in both study arms. Albumin doses recommended by the IAC are 1 g/kg initially (maximum 100 g) and 20-40 g/day thereafter as clinically indicated.41 It is recommended (if clinically appropriate) that the albumin dose is kept constant during the study drug administration period.
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6.
OBJECTIVES
6.1.
Primary Objective
6.2.
RI PT
The primary objective of this study is to confirm the efficacy and safety of intravenous terlipressin versus placebo in the treatment of adult subjects with HRS type 1 receiving standard of care albumin therapy. Efficacy will be demonstrated by confirmed HRS reversal (two SCr values ≤ 1.5 mg/dL at least 48 hrs apart while on treatment).
Secondary Objective(s)
6.3.
Efficacy Variables
6.3.1.
Primary Efficacy Variables
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Secondary objectives of this study are to demonstrate that terlipressin improves renal function and reverses HRS type 1 compared to placebo.
The primary efficacy evaluation will be based on the following:
Confirmed HRS Reversal: the percentage of subjects with two SCr values of ≤ 1.5 mg/dL, at least 48 hours apart, on treatment, (see Section 13.5.1 for details of endpoint definition) 6.3.2.
Secondary Efficacy Variables
Secondary efficacy analyses will be based on the following:
Renal Function: change from baseline through end of treatment in SCr values
•
HRS Reversal: the percentage of subjects with at least one SCr value ≤ 1.5 mg/dL on treatment
•
Transplant-free survival up to 90 days, defined as the time (in days) that each subject survives without liver transplantation from the day of randomization
•
Overall survival up to 90 days, defined as the time (in days) that each subject survives from the day of randomization
EP
AC C
6.3.3.
TE D
•
Other Efficacy Variables
Additional efficacy analyses will be based on the following: •
Glomerular Filtration Rate: change from baseline through end of treatment in GFR calculated using both the Modification of Diet in Renal Disease (MDRD) and CockcroftGault equations
•
Fractional excretion of sodium: change from baseline through end of treatment in calculated fractional excretion of sodium
•
HRS type 1 recurrence until transplantation, hospital discharge, or Day 14, whichever occurs first
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol Dialysis free survival up to 90 days: defined as the time (in days) that each subject survives without dialysis from the day of randomization
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•
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7.
INVESTIGATIONAL PLAN
7.1.
Overall Study Design and Plan: Description
SC
RI PT
This is a phase 3, randomized, double-blind, placebo-controlled, multicenter study of intravenous terlipressin administered to subjects with HRS type 1. All subjects who consent to study participation must undergo an in-hospital screening/qualification period of no less than 48 hours to establish the diagnosis of HRS type 1. Written informed consent will be obtained by the principal investigator or sub-investigator from the subject or legally-authorized representative prior to the subject qualification form being completed. Qualified subjects are then randomized in a 1:1 ratio to receive either terlipressin or placebo, stratified by qualifying SCr (< 3.6 mg/dL or ≥ 3.6 mg/dL) and alcoholic hepatitis (present or not). Approximately 150 subjects will be enrolled at 40 - 55 sites in the US and 0 - 10 sites in Canada.
M AN U
Subjects will receive up to 14 days of study treatment intravenously every 6 hours (maximum of 15 or 16 days allowed if HRS reversal is first achieved on Days 13 or 14, respectively). Subjects will be contacted on Days 30 (± 7), 60 (± 14), and 90 (± 14) for assessment of survival, renal replacement therapy (RRT) and transplantation. (Figure 2) Subjects will participate in four assessment phases, which includes screening, pretreatment, active, and follow-up assessment phases (see Section 13.2). Schematic Diagram of Trial Design
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Figure 2:
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8.
STUDY POPULATION
8.1.
Population Rationale
RI PT
The study population consists of adult subjects with cirrhosis, ascites, and a diagnosis of HRS type 1 based on the 2007 IAC diagnostic criteria.4, 41
M AN U
SC
Subjects will be stratified by alcoholic hepatitis (present or not). Alcoholic hepatitis, which results from excessive alcohol consumption, is a well characterized, specific condition, which may complicate cirrhosis and may be a precipitating factor for HRS type 1. In subjects with underlying cirrhosis, alcoholic hepatitis is generally associated with acute-on-chronic liver failure and a poor prognosis. Subjects with alcoholic hepatitis are not candidates for liver transplantation since a six month period of abstinence from alcohol is usually required prior to transplant eligibility. In Study OT-0401, absence of alcoholic hepatitis was a significant predictor for 180-Day Survival. However, some subjects with alcoholic hepatitis improve with appropriate care over a time period similar to that in this proposed study. Treated complications associated with alcoholic hepatitis, such as HRS type 1, may improve coincident with the improvement in the underlying decompensated liver disease. For these reasons, randomization stratified by the presence or absence of alcoholic hepatitis is important to promote an equal distribution of subjects with this diagnosis between treatment groups.
8.2.
TE D
Subjects will also be stratified by qualifying serum creatinine (< 3.6 mg/dL or ≥ 3.6 mg/dL). Qualifying serum creatinine is a prognostic factor for survival and HRS reversal. Excluding subjects with a baseline serum creatinine of > 7 mg/dL (an exclusion criterion for this study), 3.6 mg/dL (N =106) was the mean baseline serum creatinine of subjects enrolled in the Study OT-0401.
Number of subjects to be studied
EP
Approximately 150 Subjects with HRS type 1 will be enrolled at approximately 40 - 55 investigational sites located in the US and 0 - 10 sites in Canada. Subjects will not be replaced.
Inclusion criteria
AC C
8.3.
Subjects must meet all of the following inclusion criteria to be eligible to enrollment: 1. Written informed consent by subject or legally authorized representative 2. At least 18 years of age 3. Cirrhosis and ascites
4. Rapidly progressive reduction in renal function characterized by: − SCr ≥ 2.5 mg/dL
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol − Doubling of SCr within 2 weeks (or for observations of shorter duration, SCr values over time meeting slope-based criteria for proportional increases likely to be representative of at least a doubling within 2 weeks; see Appendix A)
RI PT
Note: Refer to Appendix A for a nomogram intended for use in situations when the SCr value has increased rapidly over a short period of time but has not yet doubled within 2 weeks. The nomogram may be used to determine whether the patient’s SCr values are consistent with a trajectory with a slope likely to be representative of at least a doubling within 2 weeks (SCr values must be documented for a minimum of 4 days).
M AN U
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In situations where the time elapsed between SCr values is greater than 2 weeks, the investigator must contact the Medical Hotline maintained by the sponsor to discuss patient eligibility. The qualification form, including all available SCr data must be completed by the investigator and forwarded to the sponsor for review and approval prior to enrollment. All communications between investigators and the sponsor regarding a patient’s eligibility, including reasons supporting inclusion in the trial, will be documented. 5. No sustained improvement in renal function (< 20% decrease in SCr and SCr ≥ 2.25 mg/dL) 48 hours after both diuretic withdrawal and the beginning of plasma volume expansion with albumin: Note: Albumin doses recommended by the IAC are 1 g/kg on the first day (maximum 100 g) and 20 - 40 g/day thereafter as clinically indicated.41 It is recommended (if clinically appropriate) that the albumin dose is kept constant during the study drug administration period.
•
Note: The qualifying SCr value is the SCr value at least 48 hrs after both diuretic withdrawal (if applicable) and the beginning of albumin fluid challenge. The qualifying SCr value must be ≥ 2.25 mg/dL AND at least 80% of the diagnostic (prefluid challenge) SCr value.
Exclusion criteria
EP
8.4.
TE D
•
If any of the following exclusion criteria are met, the subject will not be enrolled:
AC C
1. Serum creatinine > 7 mg/dL 2. Shock •
Note: Hypotension (MAP < 70 mm Hg or a decrease > 40 mm Hg in systolic blood pressure from baseline) with evidence of hypoperfusion abnormalities despite adequate fluid resuscitation.11, 37, 44
3. Sepsis or systemic inflammatory response syndrome (SIRS) •
Note: SIRS: Presence of 2 or more of the following findings: temperature > 38°C or < 36°C; heart rate > 90/min; respiratory rate of > 20/min or a PaCO2 of < 32 mm Hg; white blood cell count of > 12,000 cells/µL or < 4,000/ µL.7, 37
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol •
Note: Sepsis: Documented infection and systemic inflammatory response syndrome.7, 37
4. < 2 days anti-infective therapy for documented or suspected infection 5. Proteinuria > 500 mg/day
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6. Hematuria or microhematuria (> 50 red blood cells per high power field) 7. Clinically significant casts on urinalysis, including granular casts •
Note: Urine sediment examination is required to exclude presence of granular casts and other clinically significant casts (e.g., red blood cell [RBC] casts).
8. Evidence of intrinsic or parenchymal renal disease (including acute tubular necrosis)
SC
9. Obstructive uropathy or other renal pathology on ultrasound or other medical imaging 10. Current or recent treatment (within 4 weeks) with nephrotoxic drugs, e.g., aminoglycosides, nonsteroidal anti-inflammatory drugs (NSAID) Note: Up to 3 doses of an NSAID within the prior month (prescription or over the counter) is acceptable
•
Note: Use of short-term (< 2 weeks) oral neomycin for acute encephalopathy is acceptable.
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•
11. Current or recent (within 4 weeks) renal replacement therapy
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12. Superimposed acute liver failure/injury due to factors other than alcoholic hepatitis, including acute viral hepatitis, drugs, medications (e.g., acetaminophen), or other toxins (e.g., mushroom [Amanita] poisoning) 13. Current or recent treatment (within 48 hours) with octreotide, midodrine, vasopressin, dopamine or other vasopressors 14. Severe cardiovascular disease as judged by investigator
EP
15. Estimated life expectancy of less than 3 days 16. Confirmed pregnancy
AC C
17. Known allergy or sensitivity to terlipressin or another component of the study treatment 18. Participation in other clinical research studies involving the evaluation of other investigational drugs or devices within 30 days of randomization. NOTE: It is recognized that clinical judgment is a component of individual subject assessment, particularly in critically ill subjects with multi-organ disease. If, in the opinion of the investigator, a subject clinically meets the criteria for HRS type 1 but appears to demonstrate a potential deviation from the inclusion or exclusion criteria listed above, the investigator must contact the sponsor or designee to discuss subject eligibility. All communications, including reasons supporting inclusion in the study, will be documented.
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8.5.
Subject Withdrawal criteria
adverse event(s)
•
abnormal laboratory value(s)
•
abnormal test procedure result(s)
•
protocol violation
•
withdrawal of consent
•
lost to follow-up
•
administrative problems
M AN U
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•
RI PT
Subjects have the right to discontinue treatment and/or withdraw from the study at any time without prejudice. The investigator may discontinue any subject at any time for any reason. If study treatment or protocol-specified assessments are discontinued, the reason will be recorded and the sponsor should be notified promptly. Reasons for terminating participation in the clinical study may include the following:
AC C
EP
TE D
It is imperative to obtain complete follow-up data for all randomized subjects, whether or not they received their assigned study treatment or discontinued study medication prematurely. Every attempt should be made to collect follow-up information, including required laboratory tests and mortality assessments, except for those subjects who specifically withdraw consent for release of such information. Subjects withdrawn from treatment due to an adverse event should be followed until the event resolves or stabilizes.
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9.
PROTOCOL DEVIATIONS
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This study will be conducted as described in this protocol, except for an emergency situation in which the protection, safety, and well being of the subject requires immediate intervention that deviates from the protocol, based on the judgment of the investigator (or a responsible, appropriately trained professional designated by the investigator). In the event of a significant deviation from the protocol due to an emergency, accident, or error, the investigator or designee must contact the sponsor, or their agent, at the earliest possible time by telephone. This will allow an early joint decision regarding the subject’s continuation in the study. The investigator and the sponsor will document this decision. The IRB or Independent Ethics Committee (IEC) will be informed of all protocol deviations by the investigator in accordance with the IRB or IEC established procedure. No deviations from the protocol of any type will be made without complying with all the IRB or IEC established procedures.
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10.
TREATMENT OF SUBJECTS
10.1.
Terlipressin
10.1.1.
Initial Dosing
RI PT
Each subject will be assigned a blinded study kit containing study medication and commercially available sterile normal saline for reconstitution. Under no circumstance is it permitted to treat a subject with study medication from a kit that was not specifically assigned to him/her.
10.1.2.
SC
Blinded terlipressin for injection will be administered intravenously as a slow bolus injection over 2 minutes at a dose of 1 mg (1 vial) every 6 hours (4 mg/day). Dose Modifications
M AN U
If on Day 4 of therapy (after a minimum of 10 doses), serum creatinine has decreased, but by less than 30% from the baseline value, the dose will be increased to 2 mg every 6 hours (8 mg/d). The dose will not be increased if the subject has coronary artery disease; or in the clinical setting of circulatory overload, pulmonary edema, or treatment-refractory bronchospasm. If in the investigator’s judgment, a dose increase is not advisable or otherwise justified in the individual subject, the reason(s) for not increasing the dose of study medication will be documented on the case report form (CRF).
10.2.
Placebo
TE D
If dosing is interrupted due to a non-ischemic adverse event, terlipressin may be restarted, at the discretion of the investigator, at the same or lower dose (i.e., 0.5-1 mg q6h).
The dosing regimen for blinded placebo medication is identical to the above described blinded terlipressin for injection regimen.
Blinding
EP
10.3.
10.4.
AC C
This study will be double-blinded using matching 6-mL placebo glass vials containing lyophilized mannitol without the active ingredient terlipressin, and 6-mL vials with lyophilized mannitol as the inert carrier compound containing 1 mg terlipressin acetate.
Randomization
Subjects will be randomly assigned via an interactive voice response system (IVRS) to treatment groups in order to minimize bias based upon subject selection and baseline characteristics. Subjects will be stratified by qualifying SCr (< 3.6 mg/dL or ≥ 3.6 mg/dL) and presence/absence of alcoholic hepatitis and equally randomized (1:1) to receive either active terlipressin or matching placebo. Each investigational site will receive kits of blinded, labeled active and placebo vials each numbered with unique, randomized kit identification numbers. The kit labels will include treatment disclosure areas in case of the need for emergency unblinding in the event that definite Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol knowledge of the study medication is essential for the medical treatment of the subject (see Section 12.1.2). The randomization codes will be generated by an independent statistician and will not be accessible to the sponsor, investigator, or other site personnel (unless required during a medical emergency) during the trial period.
Retreatment
RI PT
10.5.
Discontinuation of Treatment
M AN U
10.6.
SC
If judged by the investigator to be potentially beneficial, subjects who demonstrated at least a 30% decrease in SCr from baseline value during the initial treatment cycle and subsequently develop recurrence of HRS type 1 (as defined by 2007 IAC criteria), may be retreated once with the initially assigned blinded study medication for a maximum of 14 days (treatment and study procedures are identical to the initial therapy). The subject must meet the same inclusion/ exclusion criteria (Sections 8.3 and 8.4) and the sponsor must be contacted prior to initiation of retreatment. Subjects are not re-randomized for the retreatment cycle.
Treatment will continue until at least two SCr values ≤ 1.5 mg/dL have been obtained at least 48 hours apart, or up to 14 days (maximum of 15/16 days if SCr first reaches 1.5 mg/dL on Day 13/14, respectively). If on Day 4 (after a minimum of 10 doses), SCr is at or above the baseline value, study medication will be discontinued. Treatment must be discontinued when the subject is to undergo RRT or transplantation.
TE D
Dosing must be permanently discontinued if an ischemic event occurs.
Concomitant Medication
10.7.1.
Recommended Concomitant Medication
10.7.1.1.
Albumin
EP
10.7.
AC C
In keeping with standard medical practice and current guidelines, it is strongly recommended that albumin be administered to all subjects in both study arms. Albumin doses recommended by the IAC following the albumin fluid challenge are 20-40 g/day as clinically indicated.41 It is recommended (if clinically appropriate) that the albumin dose is kept constant during the study drug administration period. 10.7.1.2.
Prohibited or Discouraged Concomitant Medications
The following medications are prohibited or strongly discouraged during treatment with study medication. (Table 3)
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol Table 3:
Prohibited/Discouraged Concomitant Medications Prohibited Concomitant Medications
Octreotide Prostaglandin analogs (e.g., misoprostol) NSAIDs (e.g., ibuprofen, naproxen, diclofenac) Discouraged Concomitant Medications
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Midodrine and other vasopressive drugs including vasopressin, dopamine, dobutamine, norepinephrine
10.8.
SC
Diuretics are strongly discouraged unless medically required for fluid overload
Treatment Compliance
10.9.
M AN U
The treatment, dosage and time of administration for each dose of study drug will be documented. A monitor will review subject source documents and drug accountability records to assess treatment compliance on an ongoing basis during site visits.
Medical Hotline
AC C
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The sponsor will maintain a 24-hour Medical Hotline for investigators to discuss patient issues including enrollment eligibility, unblinding, and retreatment. All Hotline communications will be documented.
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11.
STUDY DRUG MATERIAL AND MANAGEMENT
11.1.
Description of Terlipressin for Injection
Figure 3:
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Single-use, sterile 6-mL vials containing a lyophilized solid of 1 mg terlipressin acetate (equivalent to 0.85 mg terlipressin free base) with 10 mg mannitol as a bulking agent/stabilizer will be provided by the sponsor. The batch number will be documented in the trial master file. Lucassin® (Terlipressin for Injection)
Molecular Formula: C52 H74 N16 O15 S2
H Gly Gly
M AN U
Structure:
1227.4 daltons
SC
Molecular Weight:
Gly
Tyr
Cys
Phe
Cys
Gln
Asn
TE D
Pro Lys
Gly
Homogenous lyophilized white to off-white solid
AC C
Appearance:
EP
H2 N
Solubility:
Clear, colorless solution in saline
Vials:
Colorless glass vials containing 11 mg of a white to off-white solid, 1 mg active ingredient and 10 mg mannitol.
The active ingredient, N-[N-(N-glycylglycyl)glycyl]-8-L-lysinevasopressin, is a synthetically manufactured hormonogen of 8-lysine vasopressin, composed of 12 amino acids and having the characteristic ring structure of a cyclic nonapeptide with a disulfide bridge between the fourth and the ninth amino acid. Three glycyl-amino acids are substituted at position 1 (cysteine) of 8lysine-vasopressin. By this N-terminal extension of 8-lysine-vasopressin the metabolic Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol degradation rate of the active ingredient is significantly reduced, because the glycyl molecules inhibit rapid N-terminal enzymatic degradation.
11.2.
Packaging and Labeling
RI PT
Single-use, sterile 6-mL vials of a lyophilized solid containing 1 mg of terlipressin acetate (equivalent to 0.85 mg terlipressin free base) with mannitol or matching placebo (mannitol only) will be provided to the sites in kits of 36 vials each. Study drug labels will comply with local regulatory requirements, including sponsor name and address, protocol number, kit number, storage conditions and US IND caution statement.
11.3.
Study Drug Storage and Preparation
SC
Commercially available 5-mL vials of sterile 0.9% sodium chloride for injection will be provided to the sites for reconstitution of the terlipressin or matching placebo.
M AN U
Study drug should be stored in a secure location at 15ºC - 25ºC until reconstitution and can be stored up to 24 hours at refrigerated storage conditions (2ºC - 8ºC) once reconstituted with the sterile 0.9% NaCl solution provided. Access will be strictly limited to the investigators and their designees. 11.3.1.
Reconstitution
11.3.2.
Administration
TE D
Study drug must be reconstituted with the provided sterile 0.9 % sodium chloride solution (5mL).
Reconstituted study drug should be administered via a slow bolus (IV push over 2 minutes). See Section 10.1 for details. After study drug administration the line should be flushed with saline.
Study Drug Accountability
EP
11.4.
AC C
The investigator or designee must maintain an inventory record of study medication administered to assure the regulatory authorities and the sponsor that the investigational new drug will not be dispensed to any person who is not a subject under the terms and conditions set forth in this protocol. Neither the investigators nor any designees may provide study medication to any subject not formally enrolled in this protocol. The study medication supplied for use in this study is to be prescribed only by the principal investigator or named sub-investigators and may not be used for any purpose other than that outlined in this protocol. All unused investigational product will be handled as outlined in the pharmacy manual. Periodic review of drug accountability records will be conducted by investigational site monitors. Final review and reconciliation of the accountability records will be performed by the sponsor.
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RANDOMIZATION, BREAKING OF BLINDED CODES
12.1.
Randomization and blinding
12.1.1.
Randomization
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12.
The investigator will complete the subject qualification form along with the required supportive documentation (including SCr values during hospitalization and details of albumin fluid challenge administration and diuretic withdrawal) and forward to the sponsor for review and approval of subject enrollment.
M AN U
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Randomization will occur only after a diagnosis of HRS type 1 is established, written informed consent has been obtained from the subject or representative and subject eligibility is confirmed. Once a subject is randomized, the subject is considered a study participant. Even if study medication is not subsequently administered, the subject must be followed-up for mortality assessments. Approximately 150 subjects will be randomized via an IVRS. Each successive subject will be assigned a unique identification number. Allocation will be made to one of two treatment groups, i.e., terlipressin or placebo in a 1:1 ratio. Both treatment groups will be studied concurrently. Randomization will be stratified by qualifying SCr (< 3.6 mg/dL or ≥ 3.6 mg/dL) and alcoholic hepatitis (present or not). 12.1.2.
Blinding of Study Medications
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The active and placebo vials will be labeled with single panel labels comprised of the randomized identification numbers for each kit to maintain the blinding of the randomized treatments. The kits will be labeled with identification number specific two-part tear-off labels with emergency treatment disclosure panels. At the time of randomization, the tear-off portion of the kit label will be detached and affixed to the drug accountability log.
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EP
The study medication labels will bear the sponsor name and address, protocol number, kit number, directions for refrigerated storage, and the US Investigational New Drug (IND) caution statement. For sites outside of the US, additional country-specific required labeling will be added. 12.1.3.
Unblinding of Treatment Assignment
Unblinding of treatment assignment should be done only in the event that definite knowledge of the study medication is essential for the medical treatment of the subject. In the event that unblinding of an individual subject is required, the site pharmacist will be able to unblind the study code by swabbing the identification label from the pre-packaged study medication kit assigned to the subject. The sponsor must be immediately informed of any unblinding and the site must document the date and reason for unblinding in writing.
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13.
ASSESSMENTS AND PROCEDURES
13.1.
Schedule of Assessments and Procedures
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Table 4 presents the schedule of assessments and procedures to be performed during the study.
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IK-4001-HRS-301 Protocol Schedule of Assessments Pre-Treatment Period
X
Informed Consent
X
Verification of Study Qualification
X
Randomization
X
Medical History
Days 1-14
X
Prior Medications
X
Concomitant Meds
X
2
Height 12-lead ECG Child-Pugh Score Blood sample for genetic markers
3
PK sampling Study Medication Administration5 Vital Signs (BP, HR)
6
Serum Creatinine & BUN7 8
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Weight
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Physical Exam
Serum Electrolytes
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Diagnosis of HRS type 1 established
Study Entry Baseline Assessment
SC
Screening Period
Study Assessment
Active Study Period
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Table 4:
X
X
X X X X X X X
X4 <-------X------>
X
<-------X------>
X
<-------X------>
X
<-------X------>
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Follow-up Period (days from 1st dose)1 30 day (± 7 days)
60 day (± 14 days)
90 day (± 14 days)
ACCEPTED MANUSCRIPT
IK-4001-HRS-301 Protocol
Screening Period
Study Assessment
Encephalopathy Score
8
X
8
X
ALT, AST, ALP, Protein, Albumin, Bilirubin9
X
9
INR
X
9
CBC & Differential9 9
Spot Urine Creatinine & Sodium
Serious Adverse Event11 HRS type 1 Recurrence Assessment Mortality Assessment Renal Replacement Therapy Assessment Transplantation Assessment 1
<-------X------> <-------X------> <-------X------>
X
<-------X------>
X
<-------X------>
X
<-------X------>
X
<-------X------>
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Nonserious Adverse Event
10
90 day (± 14 days)
<-------X------>
X
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MELD Score (sponsor calculation)
9
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Fractional Excretion of Sodium (sponsor calculation) 9
60 day (± 14 days)
<-------X------>
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Serum Glucose, Calcium, Magnesium
Days 1-14
30 day (± 7 days)
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GFR (sponsor calculation)
Study Entry Baseline Assessment
Active Study Period
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Pre-Treatment Period
Follow-up Period (days from 1st dose)1
<-------X------> <-------X------>
<---X-->
<-------X------->
<-X12->
<-----------------------------------X----------------------------------> <-----------------------------------X----------------------------------> <-----------------------------------X---------------------------------->
Follow-up assessments must also be completed for subjects randomized but not treated with study medication Concomitant medications include Albumin, IV solutions and blood products 3 Optional 4 Pre-determined PK time points are randomly assigned as described in Section 13.5.5 5 Maximum treatment 15/16 days if HRS reversal first achieved on Day 13/14 6 Vital sign measurements: Time points for FIRST DOSE ONLY: Pre dose & Post dose at 5 min, 30 min, 1 hr, 2 hr, 4 hr: Time points all other doses: Pre dose & 2
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IK-4001-HRS-301 Protocol Post dose at 5 min and 2 hr Must be performed at least once daily during active treatment AND until Day 14 (regardless of treatment status) or discharge, whichever occurs first 8 Once daily during treatment days 9 Treatment Days 1, 3 and 7 and at treatment termination. 10 Up to 7 days post end of treatment 11 Up to 30 days post end of treatment 12 Up to 30 days post end of treatment based on SAE data
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7
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13.2.
Study Assessment Phases
13.2.1.
Subject Screening Phase
SC
RI PT
The screening period occurs prior to enrollment and consists of establishing the diagnosis of HRS type 1 as per guidelines and standard medical practice and confirming eligibility for study participation. The investigator will complete the subject qualification form along with the required supportive documentation (including SCr values during hospitalization and details of albumin fluid challenge administration and diuretic withdrawal) and forward to the sponsor for review and approval of subject enrollment. Written informed consent will be obtained by the principal investigator or sub-investigator from the subject or legally-authorized representative prior to the subject qualification form being completed. Subjects screened but not enrolled in the trial for any reason should be recorded on the screening log. These subjects are not considered study participants and no additional follow-up is required. Pre-Treatment Phase
M AN U
13.2.2.
The pre-treatment period occurs prior to administration of study medication and includes collection of baseline assessments.
13.2.3.
TE D
The qualifying SCr value (SCr value at least 48 hrs after both diuretic withdrawal and the beginning of albumin fluid challenge) is considered the baseline SCr and must be drawn no more than 8 hours prior to start of study medication. The qualifying SCr value must be ≥ 2.25 mg/dL AND at least 80% of the diagnostic (pre-fluid challenge) SCr value. If there is a delay in subject randomization, then the qualifying/baseline SCr value must be redrawn so that the value is collected within 8 hours prior to the start of study medication. Other baseline assessments must be performed no more than 24 hours prior to start of study medication. Active Study Phase (14 Days)
EP
The active study period extends from the initiation of study treatment through Day 14 (Day 15/16 as described in Section 10.1) or discharge from the hospital for any reason, whichever occurs first. Study medication will be administered as described in Section 10. See Table 4 for the Schedule of Assessments during the active study period. Follow-up Phase
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13.2.4.
The follow-up period begins after the end of the study treatment and concludes 90 days following the start of treatment. All subjects will be contacted by telephone for follow-up on Days 30 (± 7), 60 (± 14), and 90 (± 14) to assess survival, RRT, and transplant status. Study days will be counted from first day of study medication administration (or from randomization for those subjects who do not receive study medication).
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13.3.
Detail of Safety Assessments and Procedures
•
at baseline with the physical examination
•
prior to each dose of study medication
•
first dose only: post dose at 5 min, 30 min, 1hr, 2hr, 4hr
•
all other doses: post dose at 5 minutes and 2 hours
RI PT
13.3.1. Vital Sign Measurements Vital sign measurements include heart rate and blood pressure and will be recorded during the following time points:
West Haven Criteria for Semiquantitative Grading of Mental State15
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Table 5:
SC
13.3.2. Encephalopathy Score Clinically detectable encephalopathy is to be assessed prior to study drug administration and daily during study medication administration using the clinical criteria described in Table 5.
Trivial lack of awareness Euphoria or anxiety Shortened attention span Impaired performance of addition
Grade 2
Lethargy or apathy Minimal disorientation for time or place Subtle personality change Inappropriate behavior Impaired performance of subtraction
Grade 3
Somnolence to semi-stupor, but responsive to verbal stimuli Confusion Gross disorientation
Grade 4
Coma (unresponsive to verbal or noxious stimuli)
AC C
EP
TE D
Grade 1
13.3.3.
Model for End-Stage Liver Disease (MELD) Score
Model for end-stage liver disease (MELD) scores will be calculated by the sponsor based on SCr, bilirubin and INR values at baseline and treatment Days 1, 3, 7 and treatment termination. 13.3.4.
Adverse Events
All adverse events (serious and non-serious) will be assessed and recorded beginning with initiation of study medication administration (treatment-emergent) until seven (7) days after discontinuation of study medication. Serious adverse events will be assessed and recorded until 30 days after discontinuation of study medication. Deaths will be reported up to 90 days in all
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol subjects randomized (including randomized subjects who did not receive study medication for any reason). Those events that are serious in nature must be reported to the Sponsor or its designee for safety reporting in an expedited manner (see Section 14 for definitions and reporting requirements).
Detail of Laboratory Assessments and Procedures
13.4.1.
Local Laboratory at Investigational Site
RI PT
13.4.
13.4.1.1.
Serum Electrolytes & Biochemistry
SC
The laboratory tests specified in this section will be performed in the laboratory at the investigational site.
•
creatinine
•
BUN
M AN U
The following assessments are required at baseline, then once daily during treatment (max 16 days) and daily until Day 14 or hospital discharge (whichever occurs first), regardless of treatment status:
If SCr and/or BUN assessments are performed more than once daily as part of the subject’s medical care, all values are to be recorded on the CRF.
•
sodium
•
potassium
•
chloride
•
CO2
TE D
The following assessments are required at baseline, then once daily during treatment with study medication (max 16 days):
total bilirubin
AC C
•
EP
The following assessments are required at baseline and on Treatment Days 1, 3, 7, and, whenever possible, at treatment termination: •
alkaline phosphatase (ALP)
•
alanine amino transferase (ALT; SGPT)
•
aspartate amino transferase (AST; SGOT)
•
total protein
•
albumin
•
magnesium
•
calcium
•
glucose
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Hematology
•
INR
•
complete blood count and differential
13.4.1.3.
RI PT
The following assessments are required at baseline and on Treatment Days 1, 3, 7, and, whenever possible, at treatment termination:
Urine
spot sodium
•
spot creatinine
Detail of Efficacy Assessments and Procedures
M AN U
13.5.
•
SC
The following assessments are required at baseline and on Treatment Days 1, 3, 7, and, whenever possible at treatment termination:
Serum creatinine must be collected at baseline, once daily during treatment (see Section 13.4.1.1); and then once daily (regardless of treatment status) until Day 14 or hospital discharge, whichever occurs first. If SCr assessments are performed more than once daily as part of the subject’s medical care, all values obtained each day will be recorded on the CRF. Serum creatinine values obtained after liver transplantation or RRT will be excluded from the efficacy evaluation. 13.5.1.
Primary Efficacy Variables
TE D
Confirmed HRS Reversal: The percentage of subjects with two SCr values of ≤ 1.5 mg/dL at least 48 hours apart, on treatment, and without intervening RRT or liver transplant.
EP
The time window in which the second and confirmatory SCr value of ≤ 1.5 mg/dL can occur is a minimum of 40 hours (i.e., 48 hours minus an 8 hour window) from the first SCr value of ≤ 1.5 mg/dL and a maximum of 24 hours after the last dose of study medication (i.e., “on treatment”). In the event of liver transplantation or hospital discharge (alive) less than 48 hours after HRS reversal (i.e., the first SCr value of ≤ 1.5 mg/dL), a second and confirmatory SCr value at least 22 hours (i.e., 24 hours minus a 2 hour window) later is acceptable.
AC C
The two SCr values of ≤ 1.5 mg/dL values on treatment do not have to be sequential but any intervening values must not be ≥ 1.8 mg/dL. All SCr values recorded each day will be evaluated. The date and time of the first observed SCr value of ≤ 1.5 mg/dL on treatment (HRS reversal) will be used for calculating the time window for the confirmatory SCr value. The first SCr value of ≤ 1.5 mg/dL occurring during the time window for confirmation will be selected as the second and confirmatory value. Any SCr values obtained post liver transplantation (defined as time subject is transferred from ward to the operating room [OR]) or post-RRT (defined as the time RRT is started) will be excluded from the efficacy analysis.
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol Secondary Efficacy Variables
13.5.2.
Secondary efficacy analyses will be performed in a nested sequential manner in the following order: •
Renal Function
RI PT
Repeated measures analysis of change from baseline through end of treatment in renal function assessed by the daily serum creatinine values.
− SCr values from baseline through end of treatment (up to 24 hours after the last dose) will be used in the analysis. For each subject, the on-treatment mean daily SCr value will be calculated and used in the analysis. Any SCr values obtained post liver transplantation or RRT will be excluded from analysis. HRS Reversal
SC
•
•
Transplant-Free Survival
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− Incidence of HRS Reversal is defined as at least one SCr value of ≤ 1.5 mg/dL on treatment (up to 24 hours after the last dose of study medication). Any SCr values obtained post liver transplantation or RRT will be excluded from the analysis. − Transplant-Free Survival up to 90 days, defined as the time (in days) that each subject survives without liver transplantation from the day of randomization. •
Overall Survival
13.5.3.
TE D
− Overall Survival up to 90 days, defined as the time (in days) that each subject survives from the day of randomization. Other Efficacy Variables
Additional analyses will be based on the following: •
Glomerular Filtration Rate (GFR)
Fractional excretion of sodium (FENa)
AC C
•
EP
− Repeated measures analysis of change from baseline through end of treatment in the mean daily sponsor-calculated GFR using both MDRD and Cockcroft-Gault equations. − Repeated measures analysis of change from baseline through end of treatment in sponsor-calculated fractional excretion of sodium (measured at baseline and on Treatment Days 1, 3, 7 and end of treatment).
•
HRS Type 1 Recurrence until transplantation, hospital discharge, or Day 14, whichever occurs first. − Incidence of HRS type 1 recurrence defined as a SCr value of ≥ 2.5 mg/dL in the absence of other causes of renal impairment as described in the IAC 2007 criteria. − Any subject with a SCr value of ≥ 2.5 mg/dL after achieving two SCr values of ≤ 1.5 mg/dL (confirmed HRS reversal), but prior to transplant/discharge/day 14
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RI PT
will be assessed for HRS type 1 recurrence. Hepatorenal Syndrome type 1 recurrence is another episode of HRS type 1 as per the protocol inclusion/ exclusion criteria (see Sections 8.3 and 8.4). The investigator will determine whether the subject has had a recurrence of HRS type 1. If the investigator cannot exclude a recurrence of HRS type 1, then the subject will be considered to have HRS type 1 recurrence. − Recurrence of HRS type 1 during the follow-up period (after discharge or Day 14) will also be assessed based upon the investigator’s opinion and SAE data collected up to 30 days post end of treatment.
13.5.4.
Dialysis free survival up to 90 days: defined as the time (in days) that each subject survives without dialysis from the day of randomization
SC
•
Other Exploratory Analyses
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Other exploratory, sensitivity and subgroup analyses will be performed as appropriate. Examples of potential exploratory analyses include: Time to Transplantation up to 90 days summarized descriptively for only those subjects who undergo transplantation. Time to transplantation will be summarized as a continuous variable by treatment group, with descriptive statistics such as N, mean, standard deviation, median, minimum and maximum.
•
Transplant-free survival and overall survival of responders versus non-responders for the endpoints of Confirmed HRS Reversal and HRS Reversal.
•
Evaluation of efficacy outcomes for baseline prognostic factors.
TE D
•
13.5.5.
Pharmacokinetics
EP
In order to characterize the pharmacokinetics of terlipressin, as well as to examine the influence potential covariates, blood samples will be obtained from all subjects for determination of terlipressin and its metabolite lysine-vasopressin if possible. In consideration of the subjects’ conditions, a sparse sampling approach will be used to collect blood samples from each subject. The data will be subject to population pharmacokinetic analysis using NONMEM.
AC C
A baseline sample will be taken from all subjects prior to receipt of any medications. Three additional samples will be taken based on randomization assignments during the first dosing interval on Day 1. The first time point will be randomly assigned from one of the 6 time points of TIMEPOINT A, the second time point from one of the 4 time points of TIMEPOINT B, and third time from one of the 4 time points of TIMEPOINT C for each subject. The assigned blood collection time points will be provided to the sites at the time of randomization. •
TIMEPOINT A (~ 0.083 hr): 5, 6, 7, 8, 9, 10 min (± 1 min)
•
TIMEPOINT B (early phase): 0.5, 1, 1.5, and 2 hr (± 5 min)
•
TIMEPOINT C (late phase): 3, 3.5, 4 and 5 hr (± 10 min)
If study medication is discontinued due to a serious AE, an additional blood sample will be taken at the time of discontinuation, if feasible. Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol Sites will be instructed as to the importance of maintaining adequate records with respect to the time of dosing and the obtaining of the blood samples, as to the proper labeling of containers, the importance of prompt and proper sample processing, and storage of samples.
RI PT
Blood samples (7mL each) will be processed within 30 min, following sample collection and handling procedures provided by the sponsor. Plasma will be stored under controlled conditions at -20°C prior to shipment to the analytical site for analysis.
SC
A previously developed population PK model will be used to characterize pharmacokinetics of terlipressin and its active metabolite lysine-vasopressin if quantifiable in HRS type 1 subjects and also to evaluate covariate factors that may affect terlipressin pharmacokinetic parameters. Terlipressin and lysine-vasopressin data will be fitted simultaneously to a linear threecompartment PK model. Exposure and response relationship will be explored using an appropriate PK- PD model such as linear or Emax model. Cmax, or AUC will be used as the drug exposure and MAP, BP, and HR will be used as a response endpoint.
Optional Sub-Study for Biomarker Genetic Assessments
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13.6.
All subjects will be invited to participate in a biomarker genetic evaluation. Blood samples for this evaluation will be collected on a voluntary basis; participation in this project will not affect participation in the main study. Samples will be used only for research purposes to identify potential biomarkers which may reflect treatment response, hemodynamic effects, or the benefitrisk of terlipressin treatment. Subjects must provide additional informed consent in order to participate in this portion of the study. In the event that a site’s IRB does not approve this portion of the study, this section will not be applicable. Genetic Assessments
TE D
13.6.1.
EP
Whole blood for DNA analysis will be collected from consenting subjects. Genetic samples collected for analysis of DNA sequence variations will be double coded (i.e., an independent code will be added to the first standard code to increase data protection). The plans for analysis of DNA samples include, but are not limited to, single nucleotide polymorphisms (SNPs) in the promoter region of the vasopressin V1 receptor gene and genome wide association scans to study genetic variation at other single nucleotide polymorphism levels.
AC C
All specimens collected for this portion of the study will be destroyed 15 years after the completion of the study unless keeping the specimens longer than the 15 year period is required by regulatory authorities. These samples will be used for research purposes only. Specific use of the specimens as described above is governed by the sponsor to ensure the appropriate use of the samples. The sampling procedures, storage conditions and shipment instructions for participating sites will be provided in the Laboratory Manual. The total additional volume of blood loss for biomarker genetic assessments will be approximately 10 mL per subject.
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ADVERSE EVENTS
14.1.
Definitions
14.1.1.
Adverse Event
RI PT
14.
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment.
14.1.2.
SC
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Serious Adverse Event
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A serious adverse event is any untoward medical occurrence that at any dose: results in death
•
is life-threatening, i.e., the subject was, in the opinion of the investigator, at immediate risk of death from the event as it occurred (It does not include an event that, had it occurred in a more severe form, might have caused death.)
•
results in persistent or significant disability/incapacity
•
requires in-patient hospitalization or prolongs hospitalization
•
is a congenital anomaly/birth defect
•
is another medically significant event that, based upon appropriate medical judgment, may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed above (e.g., allergic bronchospasm requiring intensive treatment in an emergency room or home, blood dyscrasias or convulsions that do not result in hospitalization, or the development of drug dependency or drug abuse)
EP
TE D
•
AC C
A distinction is to be drawn between serious and severe adverse events. A severe adverse event may not be serious and a serious adverse event need not be considered severe. The term “severe” is used to describe the intensity of a specific event (as in mild, moderate, severe). However, the event itself may be of minor medical significance (e.g., severe headache). This is not the same as “serious,” which is based on subject/event outcome or action criteria usually associated with events that pose a threat to a subject’s life or functioning.
14.2.
Severity And Causality Assessments For Adverse Events
14.2.1.
Severity Assessment
Adverse experiences will be graded on a 3-point scale and reported as indicated on the case report form. The intensity of an adverse experience is defined as follows: Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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Discomfort noticed, but no disruption to daily activity.
2 = Moderate: Discomfort sufficient to reduce or affect normal daily activity. 3 = Severe:
Study Medication Causality
RI PT
14.2.2.
Inability to work or perform normal daily activity.
Relationship of an adverse experience to treatment will be assessed as follows:
1 = Unrelated: an AE that is clearly and incontrovertibly due to extraneous causes (disease, environment, etc.) and does not meet the criteria for ‘possible’ or ‘probable.’
SC
2 = Possible: the connection between the AE and study treatment appears unlikely, but cannot be ruled out with certainty. An AE may be considered ‘possibly related’ if it has at least two of the following: 1. It follows a reasonable temporal sequence from administration of study medication.
M AN U
2. It may readily have been produced by the subject's clinical state or by environmental or toxic factors. 3. It follows a known response pattern to study product.
3 = Probable: an AE that is considered to be related to study treatment with a high degree of certainty. An AE may be considered probably related to test product if: 1. It follows a reasonable temporal sequence from administration of study treatment. It cannot be reasonably explained by the known characteristics of the subject's clinical state
TE D
2. It follows a known pattern of response to study treatment. 3. It reappears upon re-challenge.
Collection, Recording and Reporting of Adverse Events
14.3.1.
Adverse Event Recording
EP
14.3.
AC C
Adverse events will be collected beginning with the administration (includes retreatment) of study drug (treatment-emergent). The investigator will assess the seriousness and intensity (severity) of all adverse events and the causal relationship to study medication Non-serious adverse events will be assessed and recorded on the Case Report Form for the time period from the start of administration of study medication until 7 days after discontinuation of study medication, regardless of causal relationship to study medication. All serious adverse events (SAE) will be assessed and recorded on the Case Report Form for the time period from the start of administration of study medication up to 30 days post end of study medication administration regardless of causal relationship to study medication. The Serious Adverse Event Report (SAER) form must be completed and submitted to the sponsor within 24 hours of awareness of the SAE. Deaths All deaths that occur up to 90 days will be reported as serious adverse events, regardless of underlying cause or causal relationship to study medication. Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol Hospitalizations Planned hospital admissions and/or planned surgical operations for an illness or disease, which existed before the subject was randomized are not to be considered adverse events (e.g., rehospitalization for liver transplantation). However, baseline conditions, which deteriorate during the clinical study may be considered adverse events.
RI PT
Following the initial hospital discharge, all rehospitalizations within 30 days post end of treatment (except for planned hospital admissions or procedures as described above) are to be recorded as SAEs. Rehospitalizations will require an investigator assessment and opinion regarding possible recurrence of HRS type 1. Complications of the Disease
SC
Complications frequently associated with HRS type 1 are expected to occur, but should still be recorded as AEs or SAEs as applicable, for example esophageal variceal hemorrhage (EVH), hepatic encephalopathy, sepsis, pneumonia, urinary tract infection (UTI) etc.
14.3.2.
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Since HRS type 1 is the indication under investigation worsening/aggravation of HRS during the active treatment period (including non-response) will not be recorded as an SAE unless HRS is the cause of death or results in a subsequent rehospitalization due to suspected recurrence Procedure for Serious Adverse Event Reporting
EP
TE D
The investigator must complete the Serious Adverse Event Report (SAER) form for each serious adverse event and all deaths, regardless of causal relationship to study medication. The SAER must be submitted to the Sponsor (or designee) within 24 hours from the point in time when the study staff becomes aware of the SAE. The information provided must be sufficient to allow for independent medical assessment of the event and should include information on concomitant medications, results of relevant laboratory and diagnostic tests, and relevant medical history. The Sponsor (or designee) will contact the investigator should it be necessary to clarify any information. The investigator should provide any additional follow-up information regarding the SAE as soon as it becomes available. All serious adverse events should be followed until resolution or stabilization.
AC C
Any SAE must be reported on a Serious Adverse Event form to Ikaria Therapeutics LLC within 24 hours of an Investigator becoming aware of the event by fax to: Drug safety and Surveillance Fax: +1-908-238-6635
The initial SAE form does not need to be signed by the Investigator; however, a signed SAE form is required within 72 hours of faxing to Ikaria Therapeutics LLC. The initial fax by the Investigator will include a detailed description of the event including start and stop dates, causality assessment by the Investigator, and supported as needed with written copies of medical records, autopsy reports, and other appropriate documents. The investigator must also report SAEs to their local IRB/IEC as required by their institution.
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15.
STATISTICAL PLAN
SC
RI PT
This is a randomized, double-blind, placebo-controlled, multicenter study of intravenous terlipressin in subjects with HRS type 1. All subjects who consent to study participation must undergo an in-hospital screening/qualification period of no less than 48 hours prior to enrollment in order to establish the diagnosis of HRS type 1. Written informed consent will be obtained by the principal investigator or sub-investigator from the subject or legally-authorized representative prior to the subject qualification form being completed. Qualified subjects are then randomized in a 1:1 ratio to receive either terlipressin or placebo, stratified by qualifying SCr (< 3.6 mg/dL or ≥ 3.6 mg/dL) and alcoholic hepatitis (present or not). Approximately 150 subjects are planned to be enrolled at 40 - 55 sites in the United States and 0 - 10 sites in Canada.
15.1.
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Randomization will be done dynamically using an IVRS stratified by qualifying SCr (< 3.6 mg/dL or ≥ 3.6 mg/dL) and alcoholic hepatitis (present or not). Subjects will receive up to 14 days of study medication (maximum 16 days in pre-specified cases, see Section 10.4), administered intravenously 4 times per day. A Data Safety Monitoring Board (DSMB) will review safety data throughout the study as outlined in the DSMB charter.
Safety Variables
Safety variables will include the following: adverse events
•
serious adverse events, including deaths
•
general safety profile
TE D
•
The general safety profile will include vital signs; change from baseline through end of treatment in MELD score, encephalopathy score and laboratory parameters other than SCr.
15.2.
AC C
EP
Adverse events will be collected during treatment and up to 7 days post end of treatment. Serious adverse events will be collected up to 30 days post end of treatment. Deaths up to 90 days will be reported as SAEs. Adverse events will be classified by Medical Dictionary for Drug Regulatory Activities (MedDRA) system organ class, preferred term, severity, and seriousness, as well as by the investigator's assessment of the relationship of the adverse event to the study medication.
Subject Accounting and Baseline Characteristics
A summary of the study completion status and reasons for discontinuation will be provided for each treatment group. Baseline characteristics (age, gender, race, etc.) will be summarized. The number of subjects with medical conditions within each body system will be reported. Summaries of the extent of exposure and protocol deviations will also be provided.
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15.3.
Statistical Methodology
15.3.1.
Sample Size Calculation
15.3.2.
RI PT
In the OT-0401 study, for subjects with baseline SCr ≤ 7 mg/dL, the confirmed HRS reversal rate in the placebo group was 12.5% (7/56). The rate for terlipressin was 36% (18/50). Onehundred-and-fifty subjects (75 subjects per group) will provide 90% power to detect a statistically significant (p ≤ 0.05 two-sided test) difference between the two treatment groups. Patient Populations
15.3.2.1.
Intention to Treat (ITT) Population
SC
The populations that will be utilized for this study are defined below.
15.3.2.2.
M AN U
The ITT population is defined as all randomized subjects who had at least one baseline assessment. Treatment classification will be based on the randomized treatment. The ITT population defined in this way complies with the ITT principle expressed in ICH E-9. This will be the primary population for analysis of efficacy endpoints. Safety Population
The safety population is defined as all randomized subjects who received at least one dose of study medication (terlipressin or placebo). Treatment classification will be based on the actual treatment received. Per Protocol (PP) Population
TE D
15.3.2.3.
The PP population is defined as all subjects in the ITT population who did not have any major protocol violations (including receiving the wrong study treatment). Major protocol violations will be defined prior to unblinding.
Statistical Analyses
AC C
15.3.3.
EP
A blinded data review meeting will be held prior to database lock. All protocol violations will be reviewed by the study team to determine which violations disqualify the subject from the PP population. Criteria determined to disqualify one subject will be applied consistently to all other subjects.
All statistical analyses will be performed and summary tables and data listings will be prepared using SAS® software version 9.1.3 or higher. All statistical tests will be two-sided with a final significance level of 0.05, unless stated otherwise. When the assumptions for the planned testing methods do not hold, transformations or nonparametric methods may be employed. 15.3.4.
Demographic and Baseline Characteristics
All variables concerning demographic and baseline characteristics will be summarized by treatment group and overall to describe the study population. This will include a summary of the incidence of alcoholic hepatitis at baseline. The analyses will be presented for all subjects in the safety and ITT populations.
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol Continuous variables will be summarized by N, mean, standard deviation, median, minimum and maximum, and a p-value based on the overall F-test from an ANOVA with factor treatment. Categorical variables will be summarized by frequency, percent and a p-value based on a Cochran-Mantel-Haenszel (CMH) chi-square Test. Efficacy Analyses
RI PT
15.3.5.
All efficacy endpoints will be analyzed primarily in the ITT population. Data from the initial treatment course will be utilized in the analyses. Any re-treatment courses will be evaluated separately.
M AN U
SC
The primary efficacy variable of incidence of subjects with Confirmed HRS Reversal (see Section 13.5.1 for details of endpoint definition) will be summarized by treatment group and analyzed using the Cochran-Mantel-Haenszel (CMH) chi-square test stratified by qualifying SCr (< 3.6 mg/dL or ≥ 3.6 mg/dL) and alcoholic hepatitis (present or not). If the proportion of subjects with treatment success is small (expected cell counts less than 5), Fisher’s Exact test will be used instead of the CMH test. If the primary endpoint is found significant, the pre-specified secondary efficacy endpoints will be analyzed in a sequential manner at the 0.05 level of significance. Testing will stop if a secondary endpoint is not significant. The following are the secondary endpoints:
TE D
1. Change from baseline through end of treatment in renal function (serum creatinine). This endpoint will be analyzed using repeated measures analysis of covariance (ANCOVA), with treatment as a main effect and the baseline qualifying serum creatinine and day as a covariate. A treatment by day interaction will be added to the model if the interaction is found significant at 0.1 level. If treatment by day interaction is significant, p-values for treatment differences within each day will be produced, but the primary test of the treatment effect will be the overall treatment effect p-value. If the treatment by day interaction is significant, this analysis will also be performed without the interaction.
EP
2. Incidence of HRS Reversal, defined as at least one SCr ≤ 1.5 mg/dL on treatment. This endpoint will be analyzed similarly to the primary endpoint.
AC C
3. Transplant-Free Survival up to 90 days, defined as the time (in days) that each subject survives without liver transplantation from the day of randomization. Data after transplantation will be considered as censored at the time of transplantation. This variable will be analyzed using a two-sample log rank test stratified by qualifying SCr (< 3.6 mg/dL or ≥ 3.6 mg/dL) and alcoholic hepatitis (present or not). A graphical summary of product limit estimates of the survival distribution will also be provided by treatment group, as estimated in Proc Lifetest (SAS®).
4. Overall Survival at 90 days, defined as the time (in days) that each subject survives from the day of randomization. This variable will be analyzed using a two-sample log rank test stratified by qualifying SCr (< 3.6 mg/dL or ≥ 3.6 mg/dL) and alcoholic hepatitis (present or not).
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol A graphical summary of product limit estimates of the survival distribution will also be provided by treatment group, as estimated in Proc Lifetest (SAS®).
15.3.5.1.
Other Efficacy Variables
RI PT
Hepatorenal syndrome type 1 recurrence until transplantation, hospital discharge, or Day 14, whichever occurs first.
SC
Incidence of HRS type 1 recurrence is defined as a SCr ≥ 2.5 mg/dL in the absence of other causes of renal impairment as described in the IAC 2007 criteria after achievement of confirmed HRS reversal (see Section 13.5.1 for endpoint definition). This variable will be presented descriptively by N, frequency and percentages.
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Other continuous variables such as GFR, FENa, which are measured on several days during the study, will be analyzed by repeated measures ANCOVA, with treatment as a main effect, and day, and strata as covariates. Treatment by strata and treatment by day interactions will be added to the model if found significant at the 0.1 level of significance. If treatment by day interaction is significant, p-values for treatment differences within a day will be produced, but the primary test for treatment effect will be the overall treatment differences.
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Dialysis-Free Survival up to 90 days, defined as the time (in days) that each subject survives without dialysis from the day of randomization. Data after dialysis will be considered as censored at the time of dialysis. This variable will be analyzed using a two-sample log rank test stratified by qualifying serum creatinine (< 3.6 mg/dL or ≥ 3.6 mg/dL) and alcoholic hepatitis (present or not). A graphical summary of product limit estimates of the survival distribution will also be provided by treatment group, as estimated in Proc Lifetest (SAS®). Efficacy data by subgroups of demographic and baseline variables as appropriate, as well as study site will be summarized.
Time to Transplantation up to 90 days summarized descriptively for only those subjects who undergo transplantation. Time to transplantation will be summarized as a continuous variable by treatment group, with descriptive statistics such as N, mean, standard deviation, median, minimum and maximum.
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Other exploratory, sensitivity and subgroup analyses will be performed as appropriate. Examples of potential exploratory analyses include:
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Transplant-free survival and overall survival of responders versus non-responders for the endpoints of Confirmed HRS Reversal and HRS Reversal.
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Evaluation of efficacy outcomes for baseline prognostic factors.
15.3.5.2.
Safety Analysis
The analysis for the frequency of adverse events will be assessed using Fisher’s Exact Test. These variables will be summarized by frequency, percent, and the p-value based on the statistical test. Change from baseline in MELD score, encephalopathy score and BUN will be analyzed similarly to the change from baseline in renal function (see Section 13.3). Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol The vital signs of systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate and mean arterial pressure (MAP) will be assessed as individual values, daily averages, maximum and minimum values. Changes from baseline will be evaluated similarly to other continuous safety variables.
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Other continuous safety variables (e.g., labs) will be analyzed using an analysis of variance on change from baseline, with treatment as a main effect and qualifying SCr (< 3.6 mg/dL or ≥ 3.6 mg/dL) and alcoholic hepatitis (present or not) as blocking factors. Other categorical safety variables (e.g., lab shifts) will be analyzed using the CMH test stratified by qualifying SCr (< 3.6 mg/dL or ≥ 3.6 mg/dL) and alcoholic hepatitis (present or not). 15.3.6.
Pharmacokinetics
15.3.7.
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Pharmacokinetic variables will be analyzed separately and described in a separate analysis plan. Definition of Time Points
15.3.8.
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Baseline: For evaluations that are collected at multiple occasions prior to initiation of study medication, the latest non-missing evaluation will be considered the "Baseline" evaluation for analysis. In most cases baseline will be defined as Day 0 of the study period, but a pre-study period value will be utilized instead if the Day 0 value is missing. Study Day 1 will be defined as the first calendar day that study medication is administered during the study period. Missing Data
15.3.9.
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No imputation will be made for missing data.
Procedure for Amendments to Statistical Plan
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It is intended that all statistical analyses specified in this protocol will be performed. However, study observations or analysis results may suggest the need for additional, or changes to the statistical analyses of the collected study data. In either case, deviations (subtractions or additions) from the planned statistical analysis will be fully described in the final clinical study report. The statistical plan can be amended and the reasons for amendments will be documented. Furthermore, any additional analyses performed beyond those specified in this protocol will be descriptive in nature and will not include hypothesis testing for the purposes of inferential conclusions.
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16.
DATA MANAGEMENT
16.1.
Data Collection
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A Case Report Form will be used to collect all subject data and assessments. The modules are pre-treatment/baseline, 14, 30, 60 and 90 days. Case Report Forms (electronic or paper) are to be completed for all subjects. All paper forms are to be completed in black ink or typed, in English. All electronic forms are to be completed in English.
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Correction(s) of data on the paper CRF should be made by crossing out the incorrect data (in a manner that leaves the previous entry identifiable) and writing the correct values next to those crossed out. Each correction must be initialed, dated, and explained where necessary, by the individual making the correction.
16.2.
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Refer to study specific CRF completion guidelines for further details.
Records Retention
Food and Drug Administration regulations require all investigators participating in clinical drug trials to maintain detailed clinical data for one of the following periods: at least two years following the date on which a New Drug Application is approved by the FDA, or
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two years after the sponsor notifies the investigator that no further application is to be filed with the FDA.
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Similarly, International Conference on Harmonisation (ICH) guidelines require that essential documents be retained until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product.
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To comply with these requirements, the investigator will not dispose of any records relevant to this study without either (1) written permission from the sponsor or (2) providing an opportunity for the sponsor to collect such records. The investigator shall take responsibility for maintaining adequate and accurate hard copy source documents of all observations and data generated during this study, including any data clarification forms (DCFs) received from the sponsor. Such documentation is subject to inspection by the Sponsor or its agents, the FDA and/or other regulatory agencies.
16.3.
Inspection of Records
In compliance with local regulations, US Federal regulations and ICH GCP guidelines, it is required that the Investigator and institution permit authorized representatives of the Sponsor, the regulatory agency(s), and the IRB/IEC direct access to review the subject’s original medical records for verification of study-related procedures and data. Direct access includes examining, analyzing, verifying, and reproducing any records and reports that are important to the evaluation Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol of the study. The Investigator is obligated to inform the subject and obtain their consent to permit named representatives to have access to his/her study-related records without violating the confidentiality of the subject.
16.4.
Retention of Records/Critical Documents
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In compliance with ICH GCPs and applicable regulatory requirements, copies of all records (e.g., informed consent documents, laboratory data slips, source documents, IND safety reports, test article dispensing records, etc.) which support case report forms of this study, must be retained in the files of the responsible Investigator for a minimum of two years following notification by Sponsor that all investigations at all sites are completed, terminated, or discontinued, or that the Food and Drug Administration has approved the New Drug Application. If the Investigator retires, relocates, or for other reasons withdraws from the responsibility of keeping the study records, custody must be transferred to a person who will accept the responsibility. Ikaria must be notified in writing of the name and address of the new custodian.
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17.
QUALITY CONTROL AND QUALITY ASSURANCE
17.1.
Study Monitoring
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The sponsor has ethical, legal and scientific obligations to carefully follow this study in a detailed and orderly manner in accordance with established research principles and applicable regulations. The investigator, as part of his responsibilities, is expected to cooperate with the sponsor in ensuring that the study adheres to the protocol and GCP requirements.
17.2.
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As part of a concerted effort to fulfill these obligations (maintain current personal knowledge of the progress of the study), the sponsor's monitor will visit the center(s) during the study in accordance with the Monitoring Plan set forth for this trial as well as maintain frequent telephone and written communication. The investigator will permit the sponsor to monitor the study as frequently as is deemed necessary and provide access to medical records to ensure that data are being recorded adequately, that data are verifiable and that protocol adherence is satisfactory.
Auditing
The sponsor may conduct audits at the study center(s). Audits will include, but not be limited to, drug supply, presence of required documents, the informed consent process, and comparison of case report forms with source documents. The investigator agrees to participate with audits conducted at a reasonable time in a reasonable manner.
17.3.
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Regulatory authorities worldwide may also audit the investigator during or after the study. The investigator should contact the sponsor immediately if this occurs, and must fully cooperate with regulatory authority audits conducted at a reasonable time in a reasonable manner.
Ethics and Responsibility
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This study will be conducted in compliance with the protocol, with the sponsor’s standard operating procedures and/or guidelines, with the FDA regulations, with the ICH GCP guidelines and with the Declaration of Helsinki.
Informed Consent
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Written informed consent will be obtained from all subjects (or their guardian or legal representative) before any study-related procedures (including any pre-treatment study-specific procedures) are performed. The investigator(s) has both ethical and legal responsibility to ensure that each subject being considered for inclusion in this study is given a full explanation of the protocol. This shall be documented on a written informed consent form, which shall be approved by the same IRB or IEC responsible for approval of this protocol. Each informed consent form shall include the elements required by FDA regulations in 21 Code of Federal Regulations (CFR) Part 50 and ICH Guidance E6, Section 4.8. The investigator agrees to obtain approval from the Sponsor of any written informed consent form used in the study, preferably prior to submission to the IRB or IEC. Once the appropriate essential information has been provided to the subject and fully explained by the investigators (or a qualified designee) and it is felt that the subject understands the Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol implications of participating, the subject and the investigator (or designee) shall sign the IRB or IEC-approved written informed consent form. The subject shall be given a copy of the signed informed consent form, and the original shall be kept in the site’s regulatory file. A second copy may be filed in the subject's medical record, if allowed by the institution.
Institutional Review Board/Independent Ethics Committee
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17.5.
Confidentiality
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This protocol and the written informed consent form shall be submitted to the IRB or IEC identified with this responsibility at the research facility. Notification in writing of approval must come from the IRB or IEC chairman or secretary, to the investigator, either as a letter or as a copy of the appropriate section of the IRB or IEC meeting minutes where this protocol and associated informed consent form were discussed. The investigator will not participate in the decision. If the investigator is an IRB or IEC member, the written approval must indicate such non-participation. The investigator will submit status reports to the IRB or IEC at least annually (when applicable). The IRB or IEC must be notified by the investigator in writing of the interruption and/or completion of the study; the investigator must promptly report to the IRB or IEC all changes in research (protocol amendments) and will not make such changes without IRB or IEC approval except where necessary to eliminate apparent immediate hazards to human subjects. In these cases, the IRB or IEC must be notified within five days of the change. The investigator will promptly report to the IRB or IEC all unanticipated problems involving risk to subjects or others. The investigator is required to maintain an accurate and complete record of all written correspondence to and received from the IRB or IEC and must agree to share all such documents and reports with the sponsor.
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All information generated in this study will be considered confidential and will not be disclosed to any persons not directly concerned with the study without written prior permission from the sponsor. However, authorized regulatory officials and sponsor personnel will be allowed full access to the records. All medications provided and subject bodily fluids and/or other materials collected shall be used solely in accordance with this protocol, unless otherwise agreed to in writing by the sponsor.
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Only initials and/or unique subject numbers in case report forms will identify subjects. Their full names may, however, be made known to a product regulatory agency or other authorized official if necessary.
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18.
REGISTRATION OF STUDY AND PUBLICATION OF DATA
This trial will be registered at the publicly accessible Web site www.clinicaltrials.gov. Registration at other publicly accessible registries will be performed as required.
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The results of this study will be published and/or presented at scientific meetings in accordance with usual and customary academic, editorial and ethical practices and requirements. To ensure inclusion of complete and reliable data and to allow the protection of any proprietary information, the investigator agrees to submit any manuscripts or abstracts to Ikaria Therapeutics LLC for review prior to submission.
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19.
REFERENCES
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1. Alessandria C, Ozdogan O, Guevara M, et al. MELD score and clinical type predict prognosis in hepatorenal syndrome: relevance to liver transplantation. Hepatology. 2005 Jun;41(6):1282-9. 2. Alessandria C, Ottobrelli A, Debernardi-Venon W, et al. Noradrenalin vs terlipressin in patients with hepatorenal syndrome: a prospective, randomized, unblinded, pilot study. J Hepatol. 2007 Oct;47(4):499-505. 3. Angeli P, Violpin R, Gerunda G, et al. Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide. Hepatology. 1999 Jun;29(6):1690-7.
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4. Arroyo V, Ginès P, Gerbes AL, et al. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club. Hepatology. 1996 Jan;23(1):164-76..
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5. Arroyo V, Terra C, Ginès P. New treatments of hepatorenal syndrome. Semin Liver Dis. 2006 Aug;26(3):254-64. 6. Blei AT, Großmann RJ, Gusberg R, Conn H. Comparison of vasopressin and triglycyllysine vasopressin on splanchnic and systemic hemodynamics in dogs. Dig Dis Sci. 1980 Sep;25(9):688-94.
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7. Bone RC, Balk RA, Cerra FB, et al, Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. Chest 2009 Nov;136(5 Suppl):e28. 8. Briglia AE, Anania, FA. Hepatorenal syndrome. Definition, pathophysiology, and intervention. Crit Care Clin. 2002 Apr;18(2):345-73 9. Cárdenas A. Hepatorenal syndrome: a dreaded complication of end-stage liver disease. Am J Gastroenterol. 2005 Feb;100(2):460-7.
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10. Cárdenas A, Ginès P. Therapy insight: management of hepatorenal syndrome. Gastroenterol & Hepatol. 2006 Jun;3(6):338-48.
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11. Dellinger RP, Levy MM, Carlet JM, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: Crit Care Med. 2008 Jan;36(1):296-327. 12. Döhler KD. Vasopressin analogues in the treatment of hepatorenal syndrome and gastrointestinal haemorrhage. Best Practice & Research Clinical Anaesthesiology. 2008 Jun;22(2):335-50 13. Esrailian E, Pantagco ER, Kyulo NL, Hu K-Q, Runyon BA. Octreotide/midodrine therapy significantly improves renal function and 30-day survival in patients with type 1 hepatorenal syndrome. Dig Dis Sci. 2007 Mar;52(3):742-8. 14. Fabrizi F, Dixit V, Messa P, Martin P. Terlipressin for hepatorenal syndrome: A metaanalysis of randomized trials. Int J Artif Organs. 2009 Mar;32(3):133-40.
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol 15. Ferenci P, Lockwood A,Mullen K, Weissenborn K, Blei A. Hepatic encephalopathydefinition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology. 2002 Mar;35(3):716-21.
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16. Fjellestad-Paulsen A, Lundin S. Metabolism of vasopressin, oxytocin and their analogues [Mpa1, D-Arg8]-vasopressin (dDAVP) and [Mpa1, D-Tyr(Et)2, Thr4, Orn8]oxytocin (antocin) in human kidney and liver homogenates. Regul Pept. 1996 Nov 14;67(1):27-32. 17. Forsling ML, Aziz LA, Miller M, Davis R, Donovan B. Conversion of triglycylvasopressin to lysine vasopressin in man. J. Endocr. 1980 May;85(2):237-44.
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18. Ginès A, Escorsell A, Ginès P, et al. Incidence, Predictive Factors, and Prognosis of the Hepatorenal Syndrome in Cirrhosis With Ascites. Gastroenterology. 1993 Jul;105(1):229-36.
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19. Ginès P, Guevara M, Arroyo V, Rhodes J. Hepatorenal syndrome. Lancet. 2003;362:1819-1827. 20. Gluud LL, Christensen K, Christensen E, Krag A. Systematic review of randomized trials on vasoconstrictor drugs for hepatorenal syndrome. Hepatology. 2010 Feb;51(2):576-84. 21. Gonwa TA, Klintmalm GB, Levy M, Jennings LS, Goldstein RM, Husberg BS. Impact of pretransplant renal function on survival after liver transplantation. Transplantation. 1995 Feb 15;59(3):361-5.
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22. Guevara M, Ginès P, Fernandez-Esparrach G, et al. Reversibility of hepatorenal syndrome by prolonged administration of ornipressin and plasma volume expansion. Hepatology. 1998 Jan;27(1):35-41. 23. Hadengue A, Gadano A, Moreau R, et al. Beneficial effect of the 2-day administration of terlipressin in patients with cirrhosis and hepatorenal syndrome. J. Hepatol. 1998 Oct;29(4):565-70.
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24. IK-4001 Lucassin® (terlipressin). [Investigator’s Brochure] Clinton, NJ: Ikaria Therapeutics LLC. Version 3. 2010.
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25. Kiser TH, MacLaren R, Fish DN. Treatment of hepatorenal syndrome. Pharmacotherapy. 2009 Oct;29(10):1196-211. 26. Kiszka-Kanowitz M, Henriksen JH, Hansen EF, Møller S, Bendtsen F. Effects of terlipressin on blood volume distribution in patients with cirrhosis. Scand J Gastroenterol. 2004 May;39(5):486-92. 27. Lauson HD. Metabolism of antidiuretic hormones. Am J Med. 1967 May;42(5):713-44. 28. Lucey MR, Mathurin P, Morgan TR. Alcoholic Hepatitis. NEJM. 2009 Jun 25;360(26):2758-69. 29. Martín-Llahí M, Pépin MN, Guevara M, et al. Terlipressin and albumin versus albumin in patients with cirrhosis and hepatorenal syndrome. A randomized study. Gastroenterol. 2008 May;134(5):1352-9. Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol 30. McCormick PA, Donnelly C. Management of hepatorenal syndrome. Pharmacology & Therapeutics. 2008 Jul;119(1):1-6. 31. Moreau R, Durand F, Poynard T, et al. Terlipressin in patients with cirrhosis and type 1 hepatorenal syndrome: a retrospective multicenter study. Gastroenterology 2002 Apr;122(4):923-30.
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32. Nair S, Verma S, Thuluvath PJ. Pretransplant renal function predicts survival in patients undergoing orthotopic liver transplantation. Hepatology. 2002 May;35(5):1179-85. 33. Neri S, Pulvirenti D, Malaguarnera M, et al. Terlipressin and albumin in patients with cirrhosis and type 1 hepatorenal syndrome. Dig Dis Sci. 2008 Mar;53(3):830-5.
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34. Nilsson G, Lindblom P, Ohlin M, Berling R, Vernersson E. Pharmacokinetics of terlipressin after iv doses to healthy volunteers. Drugs Exptl. Clin. Res. 1990;16(6):30714.
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35. Plate. Studies on the localization and kinetics of metabolism of synthetic vasopressin slow release preparation triglycyl-lysine-vasopressin [thesis]. Hanover Germany: Hanover School of Medicine, Department of Gastroenterology and Hepatology, 1995. 36. Pliska V, Chard T, Rudinger J, Forsling ML. In vivo activation of synthetic hormonogens of lysine vasopressin: N-glycyl-glycyl-glycyl-(8-lysine) vasopressin in the cat. Acta Endocrinol. 1976 Mar;81(3):474-81. 37. Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP. The natural history of the systemic inflammatory response system (SIRS). A prospective study. JAMA. 1995 Jan 11;273(2):117-23.
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38. Restuccia T, Ortega R, Guevara M, et al. Effects of treatment of hepatorenal syndrome before transplantation on posttransplantation outcome. A case-control study. J Hepatol. 2004 Jan;40(1):140-6.
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39. Ruiz R, Barri YM, Jenning LW, et al. Hepatorenal syndrome: a proposal for kidney after liver transplantation (KALT). Liver Transpl. 2007 Jun;13(6):838-43.
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40. Sagi SV, Mittal S, Kasturi KS, Sood GK. Terlipressin therapy for reversal of type 1 hepatorenal syndrome: A meta-analysis of randomized controlled trials. J Gastro Hep. 2010 Jan 14. 41. Salerno F, Gerbes A, Ginès P, Wong F, Arroyo V. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. A concensus workshop of The International Ascites Club. Gut. 2007 Sep;56(9):1310-18. 42. Sanyal AJ, Boyer T, Garcia-Tsao G, et al. A randomized, prospective, double-blind placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome. Gastroenterology. 2008 May;134(5):1360-8. 43. Saner FH, Canbay A, Gerken G, Broelsch CE. Pharmacology, clinical efficacy and safety of terlipressin in esophageal varices bleeding, septic shock and hepatorenal syndrome. Expert Rev. Gastroenterol. Hepatol. 2007 Dec;1(2):207-17. 44. Sessler CN, Perry JC, Varney KL. Management of severe sepsis and septic shock. Curr Opin Crit Care. 2004 Oct;10(5):354-63. Final 1.0 - 07 June 2010 Ikaria Therapeutics LLC
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ACCEPTED MANUSCRIPT IK-4001-HRS-301 Protocol 45. Skagen C, Einstein M, Lucey MR, Said A. Combination treatment with octreotide, midodrine, and albumin improves survival in patients with type 1 and type 2 hepatorenal syndrome. J Clin Gastroenterol. 2009 Aug;43(7):680-5.
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46. Sharma P, Schaubel DE, Guidinger MK, Merion RM. Effect of pretransplant serum creatinine on the survival benefit of liver transplantation. Liver Transpl. 2009 Dec;15(12):1808-13. 47. Solanki P, Chawla A, Garg R, Gupta R, Jain M, Sarin SK. Beneficial effects of terlipressin in hepatorenal syndrome: a prospective, randomized placebo-controlled clinical trial. J Gastroenterol Hepatol. 2003 Feb;18(2):152-6.
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48. Wisniewski K, Alagarsamy S, Taki H, Miampamba M, Laporte R, Galyean R, et al. Synthesis and biological activity of terlipressin and its putative metabolites. In: Blondelle SE, ed. Understanding Biology using Peptides. Proceedings of the Nineteenth American Peptide Symposium. Vol. 9. New York, NY: Springer; 2005:489-490.
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49. Wong F, Pantea L, Sniderman K. Midodrine, octreotide, albumin, and tips in selected patients with cirrhosis and type 1 hepatorenal syndrome. Hepatology. 2004 Jul;40(1):5564.
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APPENDIX A. STUDY IK-4001-HRS-301: NOMOGRAM TO DETERMINE CRITERION FOR SCr DOUBLING OVER TWO WEEKS
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The nomogram is intended for use in situations when the SCr value has increased rapidly over a shorter period of time but has not yet doubled within 2 weeks.
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To fulfill Inclusion Criterion No. 4, subjects must have rapidly progressive reduction in renal function characterized by: 1) SCr ≥ 2.5 mg/dL and 2) doubling of SCr within 2 weeks (or SCr values over time indicating a trajectory with a slope likely to be representative of at least a doubling within 2 weeks). For ease of calculation, these trajectories are estimated by relating a certain required “fold increase in SCr” to the elapsed time in days between two measured values (see Figure 4 and Table 6 below); greater proportional increases in SCr are required for observations of shorter duration. As noted in the nomogram, a 1.5 fold increase between the SCr values must be achieved within 4 days of observation. The required fold increase in SCr between SCr values progressively rises from 4 days of observation up to a 2 fold increase by 14 days observation.
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Figure 4: Nomogram to Determine Criterion for SCr Doubling Over Two Weeks
Table 6: Elapsed Time in Days and Required Fold Increase in SCr Fold increase in creatinine
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1.50
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Elapsed time (days)
1.54
6
1.58
7
1.62
8
1.67
9
1.71
10
1.76
11
1.82
12
1.88
13
1.94
14
2.00
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5
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