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Efficacy and safety of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in a randomized, double-blind, comparative Phase III study in Japan
J Infect Chemother xxx (2018) 1e9
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Original Article
Efficacy and safety of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in a randomized, double-blind, comparative Phase III study in Japan* Hiroshige Mikamo a, Kazuhiro Tateda b, Katsunori Yanagihara c, Shinya Kusachi d, Yoshio Takesue e, Takashi Miki f, Yuki Oizumi f, Kazuaki Gamo f, *, Atsuki Hashimoto f, Junko Toyoshima f, Kenichi Kato f a
Department of Clinical Infectious Diseases, Aichi Medical University, Nagakute, Aichi, Japan Department of Microbiology and Infectious Diseases, Toho University School of Medicine, Tokyo, Japan c Department of Laboratory Medicine, Nagasaki University Hospital, Nagasaki, Japan d Department of Surgery, Toho University Ohashi Medical Center, Tokyo, Japan e Hyogo College of Medicine Hospital, Hyogo, Japan f Astellas Pharma, Inc., Tokyo, Japan b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 26 March 2018 Received in revised form 18 May 2018 Accepted 23 May 2018 Available online xxx
We assessed the efficacy and safety of fidaxomicin, a narrow-spectrum macrocyclic antibiotic, for treating inpatients with Clostridioides (Clostridium) difficile infection (CDI) in Japan. The objective was to demonstrate the non-inferior efficacy of fidaxomicin versus vancomycin. This Phase III, vancomycin-controlled, double-blind, parallel-group study enrolled adults with CDI. Patients were randomly assigned to receive fidaxomicin (200 mg twice daily, orally) or vancomycin (125 mg four-times daily, orally) for 10 days. The primary endpoint was global cure rate of CDI (proportion of patients cured at end of treatment with no recurrence during 28-day follow-up). Non-inferiority margin of 10% was pre-specified. Two-hundred and twelve patients were randomized and received treatment at 82 hospitals. Global cure rate was 67.3% (70/104) with fidaxomicin and 65.7% (71/108) with vancomycin: difference 1.2% [95% confidence interval (CI) 11.3e13.7]. Non-inferiority was not demonstrated. Post-hoc analysis in full analysis set patients who received at least 3 days' treatment revealed a higher global cure rate for fidaxomicin [70/97 (72.2%)] than vancomycin [71/106 (67.0%)]: difference 4.6% (95% CI 7.9e17.1). Recurrence rate in the full analysis set for recurrence was lower in fidaxomicin- [17/87 (19.5%)] than vancomycin-treated [24/95 (25.3%)] patients. Adverse event incidences and profiles were similar for both treatments. Though non-inferiority was not demonstrated for fidaxomicin versus vancomycin, global cure rate was numerically higher and recurrence rate lower for fidaxomicin than vancomycin. Fidaxomicin could be an option for the treatment of CDI in an era of reduced antibiotic susceptibility, and to reduce the incidence of recurrence in Japanese patients. ClinicalTrials.gov Identifier: NCT02179658. © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Clostridioides (Clostridium) difficile infection Fidaxomicin Global clinical cure Japan Recurrence Vancomycin
* All authors meet the ICMJE authorship criteria, and have made substantial contributions to all of the following: the conception and design of the study, or acquisition of data, or analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; and final approval of the version to be submitted. * Corresponding author. Astellas Pharma, Inc., 2-5-1, Nihonbashi-Honcho, Chuo-Ku, Tokyo 103-8411, Japan. E-mail address: [email protected] (K. Gamo).
1. Introduction Clostridioides (Clostridium) difficile is the primary pathogenic cause of infectious diarrhea that develops after hospitalization and antibiotic treatment [1,2]. C. difficile infection (CDI) is toxin mediated and associated with broad-spectrum antibiotic use [1,2], which
https://doi.org/10.1016/j.jiac.2018.05.010 1341-321X/© 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Mikamo H, et al., Efficacy and safety of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in a randomized, double-blind, comparative Phase III study in Japan, J Infect Chemother (2018), https://doi.org/10.1016/ j.jiac.2018.05.010
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H. Mikamo et al. / J Infect Chemother xxx (2018) 1e9
disrupts the gut microbiota and enables overgrowth of C. difficile and subsequent infection [3]. Other risk factors for CDI include advanced age, hospitalization and serious underlying illness [2,4]. Clinical symptoms range from mild diarrhea to more severe abdominal pain, fever and leukocytosis, or severe, complicated CDI with the development of pseudomembranous colitis or toxic megacolon [2]. Although epidemiological studies of CDI in Japan are limited, 30-day all-cause mortality rates of 13e15% [5,6] and recurrence rates of 14e46% have been reported in Japanese patients [6e8]. Metronidazole and vancomycin are currently recommended by the Japanese Association for Infectious Diseases for the treatment of CDI [9]. However, the incidence of recurrence is estimated to be up to 25% with these agents [10,11]. The high recurrence rates have been postulated to be a consequence of disruption of the gut microbiota [12,13]. In two prospective, double-blind, randomized, parallel-group, non-inferiority registration studies in the US, Canada and Europe, the narrow-spectrum macrocyclic antibiotic fidaxomicin was noninferior for initial clinical cure of CDI, and was associated with significantly lower recurrence rates and higher sustained clinical cure compared with vancomycin [14,15]. The aim of the present study was to evaluate the efficacy, safety and pharmacokinetics (PK) of fidaxomicin for the treatment of CDI in a hospital setting in Japan, with the objective of investigating whether non-inferiority of fidaxomicin versus vancomycin is confirmed in Japanese patients.
undertaken at 82 centers in Japan between June 2014 and September 2016. The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice and International Conference of Harmonization guidelines. Patients provided written informed consent. Hospitalized patients with CDI were screened and were eligible for inclusion if they were aged 20 years and had not received antibiotic treatment for CDI, or had treatment failure after 3 days of metronidazole therapy before providing informed consent. All patients had symptomatic CDI: diarrhea defined as 4 episodes of unformed bowel movements (UBMs) within 24 h before randomization and presence of C. difficile toxin A/B confirmed in stool within 96 h using the study centers' usual toxin detection kit before randomization. Key exclusion criteria were: life-threatening or fulminant CDI; paralytic ileus or toxic megacolon; prior use of fidaxomicin; concomitant use of any antibiotic intended for CDI treatment; 2 prior episodes of CDI within 3 months before study entry; and requirement for antidiarrheal drugs (e.g. loperamide). 2.2. Randomization and masking
2. Patients and methods
Patients were randomly assigned to treatment (1:1 allocation) using dynamic allocation with a biased-coin minimization approach with study center and prior occurrence of CDI as allocation factors to minimize bias. Active and placebo treatments were administered using a double-dummy method to ensure that trial personnel and investigators assessing outcomes were blinded to treatment assignment throughout the trial.
2.1. Study design and population
2.3. Procedures
This Phase III, randomized, vancomycin-controlled, double-blind, parallel-group study of fidaxomicin in patients with CDI was
Patients assigned to fidaxomicin received one fidaxomicin 200 mg tablet orally twice daily and vancomycin placebo orally
Table 1 Study populations and analyses. Study population
Definition
Analyses
Full analysis set, FAS
All randomized patients who met the criteria for symptomatic Clostridioides (Clostridium) difficile infection, received at least one dose of study drug and were assessed for at least one efficacy endpoint during the treatment period As the FAS, but only including patients who achieved clinical cure at the end of treatment Patients in the FAS who met the inclusion criteria; did not violate the exclusion criteria; for treatment failure evaluation, they received at least 3 days of treatment (at least six doses of fidaxomicin or its matching placebo and at least 12 doses of vancomycin or its matching placebo); for cure evaluation, they received at least 16 doses of fidaxomicin or its matching placebo and at least 32 doses of vancomycin or its matching placebo; had cure assessment at end of treatment; and had no protocol deviations, including the use of prohibited or restricted concomitant drugs As the PPS, but only including patients who achieved clinical cure at the end of treatment and met the following criteria: were assessed as having no recurrence during the period from 25 to 31 days after end of treatment or recurrence within 31 days after end of treatment; and did not take any drug that could confound the assessment of recurrence Patients from the PPS-R and PPS who were not cured All patients who received the study drug and who had at least one blood/stool sample assessed for drug concentration All patients who received at least one dose of study drug Patients in the FAS who received at least 3 days of treatment (at least six doses of fidaxomicin or its matching placebo and at least 12 doses of vancomycin or its matching placebo) As the mFAS, but only including patients who achieved clinical cure at the end of treatment
Primary analysis population for clinical efficacy (cure, global cure and resolution of diarrhea) and microbiological efficacy
Full analysis set for recurrence, FAS-R Per-protocol set, PPS
Per-protocol set for recurrence, PPS-R
Per-protocol set for global cure, PPS-G Pharmacokinetic analysis set, PKAS
Safety analysis set, SAF Modified full analysis set, mFAS
Modified full analysis set for recurrence, mFAS-R
Recurrence Clinical efficacy (cure and resolution of diarrhea) and microbiological efficacy
Recurrence
Clinical efficacy in terms of global cure Pharmacokinetic parameters in blood and stool
Safety assessments Post-hoc analyses for clinical efficacy (cure, global cure and resolution of diarrhea) and microbiological efficacy Post-hoc analysis of recurrence
Please cite this article in press as: Mikamo H, et al., Efficacy and safety of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in a randomized, double-blind, comparative Phase III study in Japan, J Infect Chemother (2018), https://doi.org/10.1016/ j.jiac.2018.05.010
H. Mikamo et al. / J Infect Chemother xxx (2018) 1e9
four-times daily for 10 days. Patients assigned to vancomycin received one fidaxomicin placebo tablet twice daily and reconstituted vancomycin powder four-times daily (500 mg/day) for 10 days. Efficacy assessments followed previously published procedures [15]. Clinical cure of CDI was assessed at the end of treatment (EOT) and defined by the resolution of diarrhea (i.e. 3 episodes of UBMs for 2 consecutive days), with maintenance of resolution by EOT and no further requirement for CDI therapy at EOT. Patients who did not achieve cure at EOT were considered treatment failures and discontinued from the study. Recurrence, assessed throughout the 28day follow-up period in patients who met the criteria for clinical cure, was defined by more frequent UBMs than at EOT per 24-h period within 4 weeks after cessation of therapy, presence of C. difficile toxin A/B in stool and a need for retreatment of CDI according to the investigator's opinion. Blood samples for pharmacokinetic (PK) analysis were collected 3e5 h after the first dose of treatment on Day 1 and last dose at EOT. Feces samples for PK analysis were collected from the first defecation within 24 h after the last dose of fidaxomicin at EOT. Plasma and fecal concentrations of fidaxomicin and its primary metabolite, OP-1118, were determined using validated liquid chromatography tandem mass spectrometry at a central facility. Stool samples for microbiological analysis were collected at screening, at EOT and at the follow-up visit. Samples were evaluated for C. difficile detection by culture. Microbiological response
3
was evaluated at EOT and at the follow-up visit. Minimum inhibitory concentrations (MICs) were determined by an agar plate dilution method in accordance with Clinical and Laboratory Standards Institute (CLSI) M11-A8 and M100-S24 [16,17]. Isolated C. difficile were characterized using multilocus sequence typing (MLST), with sequences compared against those in the Center for Genomic Epidemiology (CGE) database, available at https://cge.cbs. dtu.dk//services/MLST/. Analyses were performed by LSI Medience Corporation. 2.4. Endpoints The primary efficacy endpoint was global cure rate of CDI (proportion of all treated patients who were cured at EOT and had no recurrence during follow up). This was assessed in the full analysis set (FAS), adjusting for prior occurrence of CDI. Secondary endpoints included the global cure rate of CDI in populations other than the FAS; clinical cure rate of CDI (proportion of patients who were cured at EOT); recurrence rate of CDI (proportion of patients who were cured at EOT and had recurrence during the follow-up period); time to recurrence of CDI [time (days) from the final day of treatment to recurrence]; time to resolution of diarrhea [time (days) from the start of treatment to resolution of diarrhea]; and microbiological efficacy (change in C. difficile carriage between pre-treatment and post-treatment). Patients with microbiological eradication were those with cultured C. difficile at
Fig. 1. Participant flow chart. There were 15 patients (16 deviations) in the fidaxomicin group and 17 patients (18 deviations) in the vancomycin group with major protocol deviations. Two patients in the vancomycin group had violations of the inclusion/exclusion criteria. Six patients in the fidaxomicin group and four patients in the vancomycin group had dose and dosage regimen violations. Eight patients in the fidaxomicin group and 11 patients in the vancomycin group had concomitant drug/therapy violations. Two patients in the fidaxomicin group and one patient in the vancomycin group had serious adverse event reporting violations. FAS-R, full analysis set for recurrence; mFAS, modified full analysis set; mFAS-R, modified full analysis set for recurrence; PKAS, pharmacokinetic analysis set; PPS, per-protocol set; PPS-G, per-protocol set for global cure; PPS-R, per-protocol set for recurrence.
Please cite this article in press as: Mikamo H, et al., Efficacy and safety of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in a randomized, double-blind, comparative Phase III study in Japan, J Infect Chemother (2018), https://doi.org/10.1016/ j.jiac.2018.05.010
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H. Mikamo et al. / J Infect Chemother xxx (2018) 1e9
screening and ‘eradication’, ‘presumed eradication’ or ‘colonization’ after treatment. Eradication occurred if there was an improvement or resolution of clinical symptoms and C. difficile was absent in stool. Presumed eradication occurred if there was an improvement or resolution of clinical symptoms in the absence of a CDI test result. Colonization occurred if there was an improvement or resolution of clinical symptoms but C. difficile remained present in feces. PK was assessed by determining plasma and fecal concentrations of fidaxomicin and OP-1118. Safety was assessed up to the end of the 28-day follow-up period after treatment initiation and was based on treatmentemergent adverse events (AEs), mortality, routine test results and vital sign measurements.
2.5. Statistical analyses Global cure rates for fidaxomicin and vancomycin were assumed to be 75.5% and 63.8%, respectively, with reference to previously published results [18]. Based on the assumption of a one-sided a level of 0.025, 1:1 allocation ratio, 10% non-inferiority margin, and allowing for withdrawal of 10% of patients, a total of 210 patients (105 per treatment group) were needed to have 90% power in the present study. The primary population for clinical efficacy (cure, global cure and resolution of diarrhea) and microbiological efficacy analyses was the FAS. Study populations are described in Table 1. The modified FAS (mFAS) and mFAS for recurrence (mFAS-R) were used
Table 2 Patient demographics and baseline characteristics (FAS). Characteristic
Gender, n (%) Female Age, years Mean (SD) Median (range) Age category (years), n (%) <65 65e<75 75 Height, cm Mean (SD) Median (range) Weight, kg Mean (SD) Median (range) BMI, kg/m2 Mean (SD) Median (range) CDI severitya, n (%) Mild/moderate Severe Antibiotic use for CDI before screening, n (%) None Metronidazoleb Prior CDI, n (%) No Yes Prior CDI 3 months before screening, n (%) No Yes No. UBMs on the day of registration, n Mean (SD) Median (range) Renal function eGFRc (mL/min/1.73 m2), n (%) <30 30e<60 60e<90 90 eCCLd (mL/min), n (%) <30 30e<50 50e<80 80 Missing Hepatic functione, n (%) Grade 1 Grade 2
Fidaxomicin
Vancomycin
(n ¼ 104)
(n ¼ 108)
56 (53.8)
54 (50.0)
74.0 (13.5) 76.5 (26e93)
75.0 (12.5) 78.0 (21e92)
17 (16.3) 26 (25.0) 61 (58.7) n ¼ 103 155.96 (9.35) 155.50 (135.0e177.6) n ¼ 99 52.55 (14.09) 52.60 (23.5e103.7) n ¼ 98 21.45 (5.00) 21.03 (11.8e39.3)
18 (16.7) 16 (14.8) 74 (68.5) n ¼ 107 155.92 (10.59) 156.00 (125.0e180.5) n ¼ 104 50.74 (11.41) 50.00 (29.4e90.8) n ¼ 104 20.83 (4.00) 20.68 (14.4e32.5)
79 (76.0) 25 (24.0)
86 (79.6) 22 (20.4)
99 (95.2) 5 (4.8)
105 (97.2) 3 (2.8)
90 (86.5) 14 (13.5)
92 (85.2) 16 (14.8)
92 (88.5) 12 (11.5) n ¼ 100 5.8 (6.3) 4.0 (0e60)
96 (88.9) 12 (11.1) n ¼ 104 5.6 (3.9) 5.0 (0e29)
16 24 39 25
(15.4) (23.1) (37.5) (24.0)
18 27 35 28
(16.7) (25.0) (32.4) (25.9)
22 19 34 23 6
(22.4) (19.4) (34.7) (23.5)
19 25 39 21 4
(18.3) (24.0) (37.5) (20.2)
96 (92.3) 8 (7.7)
101 (93.5) 7 (6.5)
BMI, body mass index. eCCL, creatinine clearance. CDI, Clostridioides (Clostridium) difficile infection. eGFR, estimated glomerular filtration rate. SD, standard deviation. UBMs, unformed bowel movements. a Severe CDI defined as creatinine >1.5 mg/dL, white blood cell count >15000/mL or body temperature >38.5 C at baseline. b Treatment for 3 days but failed to achieve clinical improvement. c eGFR calculated according to: 194 age0.287 creatinine1.094 ( 0.739 for women). d eCCL calculated according to: [(140 age) body weight in kg] ÷ [72 creatinine] (x 0.85 for women). e According to NCI-CTCAE Grade, ver 4.03. Grade 2 defined as laboratory test values meeting any of the following criteria before the start of treatment: ALP >2.5 upper limit of normal (ULN), AST >3 ULN, ALT >3 ULN, or total bilirubin >1.5 ULN.
Please cite this article in press as: Mikamo H, et al., Efficacy and safety of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in a randomized, double-blind, comparative Phase III study in Japan, J Infect Chemother (2018), https://doi.org/10.1016/ j.jiac.2018.05.010
H. Mikamo et al. / J Infect Chemother xxx (2018) 1e9
in post-hoc analyses to identify any influence on efficacy outcomes of early treatment discontinuation. Patients with missing data for clinical cure and recurrence of CDI were considered failure for clinical cure and to have CDI recurrence. Global cure of CDI was derived from the cure and recurrence of CDI imputed for missing values. Plasma and fecal concentrations below the lower limit of quantification were treated as zero. Data are reported for the FAS, unless otherwise stated, and summarized with descriptive statistics. For global cure, cure, recurrence and microbiological efficacy, the rate and corresponding 95% confidence interval (CI) for each treatment group were calculated. Between-treatment differences and 95% CIs were then determined. Non-inferiority of fidaxomicin versus vancomycin was demonstrated in the primary analysis of global cure rate when the lower limit of the 95% CI for the difference between treatments was
a
5
above 10%. Analysis of between-group differences was calculated using the ManteleHaenszel estimator based on whether patients had a prior episode of CDI. For time to CDI recurrence and resolution of diarrhea, KaplaneMeier estimates were calculated and comparisons made between treatment groups using the logrank test. All analyses were performed using SAS® Drug Development 4.5 (SAS Institute) and SAS System Release 9.4. All reported P values were two-sided, and the significance level was P < 0.05. 3. Results 3.1. Participants Of 227 patients who were screened, 215 eligible patients were enrolled and randomized; 106 to fidaxomicin and 109 to
b
Fig. 2. (a) Clinical efficacy outcomes of Clostridioides (Clostridium) difficile infection treatment with fidaxomicin and vancomycin in the primary analysis population (FAS and FAS-R). Vertical bars represent 95% confidence intervals. Difference (95% confidence interval [CI]) between fidaxomicin and vancomycin groups and the 95%CI calculated using the MantelHaenszel estimator based on prior occurrence of C. difficile infection in the FAS. FAS, full analysis set. FAS-R, full analysis set for recurrence. aFAS. bFAS-R. (b) Clinical efficacy outcomes of Clostridioides (Clostridium) difficile infection treatment with fidaxomicin and vancomycin in secondary analysis populations (PPS, PPS-G, PPS-R, mFAS and mFAS-R). Vertical bars represent 95% confidence intervals. Difference (95% confidence interval [CI]) between fidaxomicin and vancomycin groups and the 95%CI calculated using the Mantel-Haenszel estimator based on prior occurrence of C. difficile infection. mFAS, modified full analysis set. mFAS-R, modified full analysis set for recurrence. PPS, per-protocol set. PPS-G, perprotocol set for global cure. PPS-R, per-protocol set for recurrence.
Table 3 Global cure rate of Clostridioides (Clostridium) difficile infection (CDI). Value
Global cure rate of CDI, n (%) 95% CI Difference in global cure rate of CDI, %a 95% CI
FAS
PPS-G
mFAS
Fidaxomicin (n ¼ 104)
Vancomycin (n ¼ 108)
Fidaxomicin (n ¼ 85)
Vancomycin (n ¼ 95)
Fidaxomicin (n ¼ 97)
Vancomycin (n ¼ 106)
70 (67.3) 58.3e76.3 1.2 11.3e13.7
71 (65.7) 56.8e74.7
63 (74.1) 64.8e83.4 3.9 9.1e16.8
66 (69.5) 60.2e78.7
70 (72.2) 63.2e81.1 4.6 7.9e17.1
71 (67.0) 58.0e75.9
CI, confidence interval. FAS, full analysis set. mFAS, modified full analysis set. PPS-G, per-protocol set for global cure. a Calculated difference (fidaxomicin e vancomycin) obtained using the Mantel-Haenszel estimator.
a
b
Fig. 3. (a) KaplaneMeier plot of the time from the last day of dosing to Clostridioides (Clostridium) difficile infection recurrence, full analysis set for recurrence (FAS-R). Patients with missing data for recurrence of CDI were considered to have CDI recurrence; the time to recurrence was defined as the date of last evaluation minus the date of last study drug administration plus one. (b) KaplaneMeier plot of the time from the start of treatment to resolution of diarrhea, full analysis set (FAS). Patients with missing data for resolution of diarrhea were considered ‘failure’ and the time to no resolution of diarrhea was defined as the date of evaluation for cure of CDI minus the date of first study drug administration plus one.
Please cite this article in press as: Mikamo H, et al., Efficacy and safety of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in a randomized, double-blind, comparative Phase III study in Japan, J Infect Chemother (2018), https://doi.org/10.1016/ j.jiac.2018.05.010
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H. Mikamo et al. / J Infect Chemother xxx (2018) 1e9
vancomycin (Fig. 1). Of the randomized patients, 2 in the fidaxomicin group and 1 in the vancomycin group withdrew before receiving treatment. All remaining patients tested positive for C. difficile toxin A/B and were included in the FAS and SAF. The two treatment groups did not differ significantly with respect to baseline characteristics (Table 2). 3.2. Efficacy The primary endpoint of global cure rate of CDI in the FAS was 67.3% with fidaxomicin and 65.7% with vancomycin (Fig. 2a, Table 3), with a treatment difference of 1.2% (95% CI 11.3e13.7). The lower limit of the 95% CI for this difference was not above the non-inferiority margin of 10%, therefore non-inferiority was not demonstrated. The global cure rate at the end of the study was higher with fidaxomicin than vancomycin when analyzed in the PPS-G (Fig. 2b, Table 3), with a treatment difference of 3.9% (95% CI 9.1e16.8). Similarly, fidaxomicin was numerically superior to vancomycin in relation to the post-hoc analysis of global cure rate in the mFAS: treatment difference 4.6% (95% CI 7.9e17.1) (Fig. 2b, Table 3). In the FAS, cure rates of CDI at EOT were 83.7% with fidaxomicin and 88.0% with vancomycin (Fig. 2a), with a treatment difference of 4.4%. The cure rates of CDI in the PPS (Fig. 2b) and mFAS (Fig. 2b) were higher and treatment differences were smaller than in the FAS. During the follow-up period, the recurrence rates were 19.5% with fidaxomicin and 25.3% with vancomycin, with a treatment difference of 4.9% in the FAS-R (Fig. 2a). The recurrence rates in
the PPS-R (Fig. 2b) and mFAS-R (Fig. 2b) were the same or lower and treatment differences greater than in the FAS. The time taken after EOT for the first 10% of patients to experience a recurrence in the FAS-R (primary analysis) population (Fig. 3a) was 11 days in the fidaxomicin group and 8 days in the vancomycin group. No treatment differences were observed (P ¼ 0.330). The median time from the start of treatment to resolution of diarrhea in the FAS was 4 days in the fidaxomicin group and 3 days in the vancomycin group; P ¼ 0.342 (Fig. 3b). In the FAS, microbiological eradication of C. difficile after treatment was similar for fidaxomicin and vancomycin [87.8% (79/90) versus 90.1% (91/101), respectively; Table 4]. At the follow-up visit, the microbiological eradication rate was maintained in 80.8% (59/ 73) fidaxomicin-treated patients and in 77.6% (66/85) vancomycintreated patients in the FAS-R (Table 4). 3.3. Pharmacokinetic analysis Plasma and fecal PK concentrations of fidaxomicin and OP-1118 are given in Table 5. Mean (standard deviation) plasma concentrations of fidaxomicin and OP-1118 following fidaxomicin administration were 54.68 (73.75) ng/mL and 135.55 (199.18) ng/mL, respectively, at EOT. 3.4. Safety The incidence of AEs was 70.2% (73/104) in the fidaxomicin group and 70.4% (76/108) in the vancomycin group (Table 6). Safety findings
Table 4 Microbiological efficacy outcomes after treatment of Clostridioides (Clostridium) difficile infection with fidaxomicin and vancomycin in the primary analysis population (FAS and FAS-R). Outcomes were measured at the end of treatment in the FAS and at the follow-up visit in the FAS-R. Outcome, n (%)
Eradicationa Presumed eradicationa Colonizationa Persistence Presumed persistenceb Unknownb No. patients, nc Eradication ratec 95% CI Difference in eradication rate, %d 95% CI
FAS
FAS-R
Fidaxomicin (n ¼ 104)
Vancomycin (n ¼ 108)
Fidaxomicin (n ¼ 87)
Vancomycin (n ¼ 95)
56 (53.8) 17 (16.3) 6 (5.8) 1 (1.0) 10 (9.6) 14 (13.5) 90 79 (87.8) 81.0e94.5
77 (71.3) 13 (12.0) 1 (0.9) 3 (2.8) 7 (6.5) 7 (6.5) 101 91 (90.1) 84.3e95.9 2.3 11.2e6.6
25 (30.1) 3 (3.6) 31 (37.3) 10 (12.0) 4 (4.8) 10 (12.0) 73 59 (80.8) 71.8e89.9
21 (22.8) 4 (4.3) 41 (44.6) 14 (15.2) 5 (5.4) 7 (7.6) 85 66 (77.6) 68.8e86.5 3.2 9.5e15.8
CI, confidence interval. FAS, full analysis set. FAS-R, full analysis set for recurrence. a Eradication, presumed eradication and colonization were assessed as eradiation. b Persistence and presumed persistence were assessed as persistence. c Patients with unknown results were excluded from the calculation of the eradication rate. d Difference (fidaxomicin e vancomycin) and 95% CI calculated using normal approximation.
Table 5 Plasma and fecal concentrations of fidaxomicin and OP-1118 after the first dose and end of treatment (PKAS). Fidaxomicin
No. patients, n Mean (SD) concentration in plasma, ng/mL No. patients, n Mean (SD) concentration in feces, mg/g
OP-1118
First dose
End of treatment
First dose
End of treatment
102 41.77 (46.27) e e
90 54.68 (73.75) 57 1984.98 (1368.16)
102 72.77 (65.49) e e
90 135.55 (199.18) 57 1458.09 (1131.88)
PKAS, pharmacokinetic analysis set. SD, standard deviation. Blood samples were obtained 3e5 h after the first dose of treatment on Day 1 and the last dose at end of treatment. Feces samples were obtained at the first defecation within 24 h after the last dose of fidaxomicin at end of treatment. The lower limit of quantification of fidaxomicin and OP-1118 in plasma was 0.20 ng/mL for both molecules, and in feces, 10.00 ng/mL and 50.00 ng/mL, respectively.
Please cite this article in press as: Mikamo H, et al., Efficacy and safety of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in a randomized, double-blind, comparative Phase III study in Japan, J Infect Chemother (2018), https://doi.org/10.1016/ j.jiac.2018.05.010
H. Mikamo et al. / J Infect Chemother xxx (2018) 1e9 Table 6 Adverse events reported during the study (SAF). Patients, n (%)
Fidaxomicin (n ¼ 104)
Vancomycin (n ¼ 108)
Any AE Grade 1a Grade 2a Grade 3a Grade 4a Grade 5a Any treatment-related AEb Deathc Treatment-related death Any serious AEd Any AE leading to treatment discontinuation Grade 1a, Grade 2a Grade 3a Grade 4a Grade 5a AE by preferred termf Clostridioides (Clostridium) difficile colitis Urinary tract infection Constipation Pyrexia Dermatitis contact Nausea Back pain Vomiting Malaise Delirium Hemorrhoids Pruritus Contusion Erythema Skin exfoliation Diarrhea Dizziness Febrile neutropenia Hepatic function abnormal Liver function test abnormal
73 (70.2) 13 (12.5) 36 (34.6) 15 (14.4) 6 (5.8) 3 (2.9) 9 (8.7) 3 (2.9) 0 16 (15.4) 6 (5.8)e 0 1 (1.0) 2 (1.9) 3 (2.9) 0
76 (70.4) 11 (10.2) 38 (35.2) 22 (20.4) 3 (2.8) 2 (1.9) 9 (8.3) 2 (1.9) 0 14 (13.0) 1 (0.9) 0 0 1 (0.9) 0 0
13 (12.5) 3 (2.9) 6 (5.8) 5 (4.8) 4 (3.8) 4 (3.8) 4 (3.8) 3 (2.9) 1 (1.0) 3 (2.9) 3 (2.9) 3 (2.9) 3 (2.9) 3 (2.9) 3 (2.9) 2 (1.9) 1 (1.0) 1 (1.0) 1 (1.0) 0
21 (19.4) 11 (10.2) 7 (6.5) 6 (5.6) 3 (2.8) 2 (1.9) 1 (0.9) 4 (3.7) 4 (3.7) 2 (1.9) 2 (1.9) 2 (1.9) 1 (0.9) 1 (0.9) 1 (0.9) 3 (2.8) 3 (2.8) 3 (2.8) 3 (2.8) 3 (2.8)
AE, adverse event. SAF, safety analysis set. a If a patient had multiple AEs, but with differing grades, the patient was counted only once with the highest grade. b AEs considered possibly or probably related to study drug or AEs for which a causal relationship with study drug was missing. c None of the deaths was related to study drug or Clostridioides (Clostridium) difficile infection. d Serious AE defined as AE considered by the investigator or the sponsor to result in death, or be life-threatening, causing persistent or significant disability/incapacity or substantial disruption to the ability to conduct normal daily activities, cause congenital anomaly or birth defect, require hospitalization or prolongation of hospitalization, or other medically important event. e Vomiting (Grade 1) and delusion (Grade 2) were reported in one patient. f Occurring in 2% of patients in any treatment group and regardless of relationship to study drug.
were similar for both treatments, except that the incidence of any AE leading to treatment discontinuation was higher for fidaxomicin [5.8% (6/104)] than vancomycin [0.9% (1/108)]. Any AE leading to treatment discontinuation were 7 events in 6 patients in the fidaxomicin group [ventricular fibrillation (Grade 4), duodenal ulcer hemorrhage (Grade 3), vomiting (Grade 1), general physical health deterioration (Grade 3), liver carcinoma ruptured (Grade 4), delusion (Grade 2) and peripheral artery aneurysm (Grade 4)] and 1 patient in the vancomycin group [pancreatic leak (Grade 3)] (Table 6). 3.5. Clostridioides (Clostridium) difficile isolates For 191 strains of C. difficile isolated at screening, the MIC90 of fidaxomicin was 0.12 (range 0.004e0.5) mg/mL. The MIC90 was 0.5 (range 0.25e2) mg/mL for vancomycin and 1 (range 0.12e2) mg/mL for metronidazole (Table 7). The most commonly identified
7
Table 7 Antibiotic susceptibility test results for 191 C. difficile isolates cultured at screening (FAS). Test antibiotic
MIC50 (mg/mL)
MIC90 (mg/mL)
Range (mg/mL)
Ampicillin Clindamycin Fidaxomicin Meropenem Metronidazole Moxifloxacin Vancomycin
1 128 0.06 2 0.5 32 0.50
2 >128 0.12 4 1 >128 0.50
0.5, 8 1, >128 0.004, 0.5 1, 8 0.12, 2 1, >128 0.25, 2
MIC50, minimum inhibitory concentration at which 50% of isolates were inhibited. MIC90, minimum inhibitory concentration at which 90% of isolates were inhibited.
sequence types were 17, 8 and 2 (Fig. 4). The hypervirulent strain type 1 was detected on a single occasion. 4. Discussion This multicenter study, conducted in Japan, assessed the efficacy of fidaxomicin for the treatment of CDI. The findings demonstrated that twice-daily dosing with fidaxomicin was associated with a treatment difference of 1.2% compared with four-times daily vancomycin in relation to the primary endpoint e the rate of global cure (without recurrence) at study end e but did not achieve the study's pre-defined non-inferiority margin in the primary analysis population. In the present study, more fidaxomicin-treated patients than vancomycin-treated patients withdrew prematurely from treatment (especially within the first 3 days) owing to adverse events, protocol deviations and either the patient's or investigator's request to withdraw, which may have impaired the direct comparison of efficacy in the treatment groups. To allow for this imbalance, pre-defined secondary (PPS-G) and post-hoc (mFAS) analyses were performed in patients who received at least 3 days of treatment. Regardless of treatment group, the cure and global cure rates were higher in the mFAS than in the FAS and the recurrence rate in the mFAS-R was similar to that in the FAS-R. In particular, in the mFAS, the cure rate for fidaxomicin was 5% higher than in the FAS and was similar to that for vancomycin. The lower limit of the 95% CI for the difference in global cure rate in the mFAS was 7.9%, which was above the non-inferiority margin of 10%. The 3-day threshold was based on in-vitro gut modeling data, which demonstrated clearance of C. difficile viable cells, toxins and spores after 2e4 days of starting fidaxomicin treatment [19]. In previous fidaxomicin studies, a threshold of at least 3 days of treatment in per-protocol populations was used for the evaluation of clinical cure [14,15]. Compared with two registration studies of fidaxomicin in non-Japanese populations [14,15], in which rates of initial cure were 88.2% and 87.7%, global (sustained) cure were 74.6% and 76.6%, and recurrence rates were 15.4% and 12.7%, the corresponding cure rates among fidaxomicin-treated patients in the present study were somewhat lower and the recurrence rate somewhat higher (83.7%, 67.3% and 19.5%, respectively). The clinical cure rates with fidaxomicin were high (>80%) across the studies, and recurrence rates were lower and global cure rates higher for fidaxomicin-than vancomycin-treated patients [14,15]. The time to resolution of diarrhea was similar between treatment groups, and the time to CDI recurrence was longer with fidaxomicin than vancomycin across all three studies [14,15]. Moreover, the high rate of microbiological eradication of C. difficile in the fidaxomicin group (EOT: 87.8% and follow-up visit: 80.8%) supported clinical outcomes.
Please cite this article in press as: Mikamo H, et al., Efficacy and safety of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in a randomized, double-blind, comparative Phase III study in Japan, J Infect Chemother (2018), https://doi.org/10.1016/ j.jiac.2018.05.010
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Fig. 4. Sequence types (ST) and their frequencies in 191 strains of Clostridioides (Clostridium) difficile identified by multilocus sequence typing (MLST) analysis at screening, full analysis set (FAS). aOther sequence types identified were: 1, 6, 11, 13, 26, 27, 35, 42, 47, 49, 53, 59, 67, 82, 98, 100, 182 and non-typable.
A difference between the populations in the present study and those of the previous, non-Japanese studies, which may contribute to the observed differences in treatment outcomes, is that our study enrolled only hospitalized patients, whereas in the previous studies, only 59.4% and 68.2%, respectively, were inpatients [14,15]. The previous studies found lower cure rates among inpatients compared with outpatients, regardless of treatment [14,15]. Potential reasons for worse outcomes in inpatients include the tendency for these patients to be elderly and have severe or complicated infections [20]. Additionally, a greater proportion of inpatients with CDI compared with outpatients with CDI have a serious underlying disease other than CDI [20] and use concomitant medications that carry a risk of CDI [20], while hospitalized patients are at risk of exposure to C. difficile spores [2] and subsequent re-infection. The overall incidence of treatment-related AEs was low (8.7%) and similar in the two treatment groups. The safety profile of fidaxomicin treatment in the present study was similar to that in previous studies in non-Japanese populations [14,15]. There is no evidence for a different safety profile for fidaxomicin in Caucasian and Japanese populations [21]. Regarding the distribution of C. difficile strains in this study, common strains were sequence types (ST) 17, 8 and 2, corresponding to PCR ribotypes (RT) 018, 002/159 and 014/020/076/220 [22]. This is consistent with previous reports in Japan/Asia [23]. Strains ST1 and ST11, corresponding to RT027/036 and RT078 [22], respectively, are highly represented among clinical isolates in the United States and Europe [24], although they were each identified only once in our study. A key strength of the present study is that it provides evidence of clinical outcomes, and information on the safety of fidaxomicin in a large population of hospitalized patients with CDI in Japan. A potential limitation was the absence of outpatients enrolled into the study, which may have impacted the range of C. difficile strains present and consequently, the outcome of treatment. Metronidazole and vancomycin are the only agents currently approved for the treatment of CDI in Japan, but are associated with a substantial risk of recurrence [10,11]. Additionally, alternative
CDI-targeted antibiotics are needed in response to the trend for decreased susceptibility to these agents [25]. In the epidemiological study monitoring antimicrobial resistance surveillance pre- and post-introduction of fidaxomicin, Freeman et al. [24] showed that fidaxomicin susceptibility was retained post-introduction. In this Phase III study, fidaxomicin showed a high cure rate of CDI in hospitalized patients in Japan; however, fidaxomicin noninferiority compared with vancomycin was not demonstrated in the primary analysis population. Furthermore, fidaxomicin was associated with a lower rate of recurrence numerically than vancomycin in all study populations analyzed. Fidaxomicin could be an option for the treatment of CDI and to reduce the risk of recurrence in Japanese patients. Conflicts of interest Hiroshige Mikamo has received research funding from Sumitomo Dainippon Pharma Co., Ltd, Taisho Toyama Pharmaceutical Co., Ltd, Daiichi Sankyo Co., Ltd, Pfizer Co., Ltd, Astellas, Inc., MSD K.K., Toyama Chemical Co., Ltd, MIYARISAN Pharmaceutical Co., Ltd, Shionogi & Co. Ltd., and consulting and lecture fees from Sumitomo Dainippon Pharma Co., Ltd, Taisho Toyama Pharmaceutical Co., Ltd, Daiichi Sankyo Co., Ltd, Pfizer Co., Ltd, MSD K.K., Astellas Pharma, Inc., and MIYARISAN Pharmaceutical Co., Ltd. Katsunori Yanagihara has received lecture fees from Pfizer Japan, Inc., Daiichi-Sankyo Co., Ltd, Astellas Pharma, Inc., Taisho Toyama Pharmaceutical Co., Ltd, Asahi Kasei Pharma Co., Ltd, and BD Japan, research fees from Taisho Toyama Pharmaceutical Co., Ltd, Meiji Seika Pharma Co., Ltd, KYORIN Pharmaceutical Co., Ltd, and Roche Diagnostics K.K., and research grants from Dainippon Sumitomo Pharma Co., Ltd, MSD Japan, Daiichi-Sankyo Co., Ltd, Astellas Pharma, Inc., Pfizer Japan, Inc., Taisho Toyama Pharmaceutical Co., Ltd, and Biofermin Seiyaku Co., Ltd. Shinya Kusachi has received research funding from Sumitomo Dainippon Pharma Co., Ltd, Taisho Toyama Pharmaceutical Co., Ltd, Daiichi-Sankyo Co., Ltd, Pfizer Co., Ltd, Astellas Pharma Inc., MSD K.K., Shionogi & Co., Ltd, Japan Blood Products Organization and Takeda Pharma Co., Ltd, and personal fees from Sumitomo
Please cite this article in press as: Mikamo H, et al., Efficacy and safety of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in a randomized, double-blind, comparative Phase III study in Japan, J Infect Chemother (2018), https://doi.org/10.1016/ j.jiac.2018.05.010
H. Mikamo et al. / J Infect Chemother xxx (2018) 1e9
Dainippon Pharma Co., Ltd, Taisho Toyama Pharmaceutical Co., Ltd, Daiichi-Sankyo Co., Ltd, Pfizer Co., Ltd, MSD K.K., Astellas Pharma, Inc., and Takeda Pharma Co., Ltd. Yoshio Takesue has received grants from Dainippon Sumitomo Pharma Co., Ltd, and Shionogi & Co., Ltd, and lecture fees from Astellas Pharma, Inc. Taisho Toyama Pharmaceutical Co., Ltd, and MSD Japan. Takashi Miki, Yuki Oizumi, Kazuaki Gamo, Atsuki Hashimoto, Junko Toyoshima, and Kenichi Kato are employees of Astellas Pharma, Inc., Japan. Kazuhiro Tateda has no conflicts of interest to declare.
[11]
[12]
[13]
Acknowledgments
[14]
The study was funded by Astellas Pharma, Inc. Medical writing support was provided by Rhian Harper Owen, PhD, for Cello Health MedErgy (Europe), funded by Astellas Pharma, Inc.
[15]
[16]
References [1] Takahashi M, Mori N, Bito S. Multi-institution case-control and cohort study of risk factors for the development and mortality of Clostridium difficile infections in Japan. BMJ Open 2014;4. e005665. [2] Rupnik M, Wilcox MH, Gerding DN. Clostridium difficile infection: new developments in epidemiology and pathogenesis. Nat Rev Microbiol 2009;7: 526e36. [3] Buffie CG, Bucci V, Stein RR, McKenney PT, Ling L, Gobourne A, et al. Precision microbiome reconstitution restores bile acid-mediated resistance to Clostridium difficile. Nature 2015;517:205e8. [4] Hookman P, Barkin JS. Clostridium difficile associated infection, diarrhea and colitis. World J Gastroenterol 2009;15:1554e80. [5] Honda H, Yamazaki A, Sato Y, Dubberke ER. Incidence and mortality associated with Clostridium difficile infection at a Japanese tertiary care center. Anaerobe 2014;25:5e10. [6] Kobayashi K, Sekiya N, Ainoda Y, Kurai H, Imamura A. Adherence to clinical practice guidelines for the management of Clostridium difficile infection in Japan: a multicenter retrospective study. Eur J Clin Microbiol Infect Dis 2017;36:1947e53. [7] Hikone M, Ainoda Y, Tago S, Fujita T, Hirai Y, Takeuchi K, et al. Risk factors for recurrent hospital-acquired Clostridium difficile infection in a Japanese university hospital. Clin Exp Gastroenterol 2015;8:191e6. [8] Mikamo H, Aoyama N, Sawata M, Fujimoto G, Dorr MB, Yoshinari T. The effect of bezlotoxumab for prevention of recurrent Clostridium difficile infection (CDI) in Japanese patients. J Infect Chemother 2018;24:123e9. [9] Ohnishi K, Ainoda Y, Imamura A, Iwabuchi S, Okuda M, Nakano T. JAID/JSC guidelines for infection treatment 2015-intestinal infections. J Infect Chemother 2018;24:1e17. [10] Aguado JM, Anttila VJ, Galperine T, Goldenberg SD, Gwynn S, Jenkins D, et al. Highlighting clinical needs in Clostridium difficile infection: the views of
[17]
[18] [19]
[20]
[21]
[22]
[23] [24]
[25]
9
European healthcare professionals at the front line. J Hosp Infect 2015;90: 117e25. Heimann SM, Vehreschild JJ, Cornely OA, Wisplinghoff H, Hallek M, Goldbrunner R, et al. Economic burden of Clostridium difficile associated diarrhoea: a cost-of-illness study from a German tertiary care hospital. Infection 2015;43:707e14. Lewis BB, Buffie CG, Carter RA, Leiner I, Toussaint NC, Miller LC, et al. Loss of microbiota-mediated colonization resistance to Clostridium difficile infection with oral vancomycin compared with metronidazole. J Infect Dis 2015;212: 1656e65. Isaac S, Scher JU, Djukovic A, Jimenez N, Littman DR, Abramson SB, et al. Shortand long-term effects of oral vancomycin on the human intestinal microbiota. J Antimicrob Chemother 2017;72:128e36. Louie TJ, Miller MA, Mullane K, Weiss K, Lentnek A, Golan Y, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011;364: 422e31. Cornely OA, Crook DW, Esposito R, Poirier A, Somero MS, Weiss K, et al. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis 2012;12:281e9. Clinical and Laboratory Standards Institute. Methods for antimicrobial susceptibility testing of anaerobic bacteria: approved standarddeighth edition. CLSI document M11eA8. Wayne, PA, USA: CLSI; 2012. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing, 24th informational supplement. Wayne, PA, USA: CLSI document M100-S24; 2014. Mullane KM, Gorbach S. Fidaxomicin: first-in-class macrocyclic antibiotic. Expert Rev Anti Infect Ther 2011;9:767e77. Chilton CH, Crowther GS, Freeman J, Todhunter SL, Nicholson S, Longshaw CM, et al. Successful treatment of simulated Clostridium difficile infection in a human gut model by fidaxomicin first line and after vancomycin or metronidazole failure. J Antimicrob Chemother 2014;69:451e62. Khanna S, Pardi DS, Aronson SL, Kammer PP, Orenstein R, St Sauver JL, et al. The epidemiology of community-acquired Clostridium difficile infection: a population-based study. Am J Gastroenterol 2012;107:89e95. Oshima H, Yamazaki T, Benner L, Miki T, Michon I, Wojtkowski T, et al. Comparison of the safety, tolerability, and pharmacokinetics of fidaxomicin in healthy Japanese and caucasian subjects. Clin Drug Invest 2015;35: 375e84. Griffiths D, Fawley W, Kachrimanidou M, Bowden R, Crook DW, Fung R, et al. Multilocus sequence typing of Clostridium difficile. J Clin Microbiol 2010;48: 770e8. Riley TV, Kimura T. The epidemiology of Clostridium difficile infection in Japan: a systematic review. Infect Dis Ther 2018;7:39e70. Freeman J, Vernon J, Pilling S, Morris K, Nicholson S, Shearman S, et al. The ClosER study: results from a three-year pan-European longitudinal surveillance of antibiotic resistance among prevalent Clostridium difficile ribotypes, 2011e2014. Clin Microbiol Infect 2017;0. pii: S1198eS1743X(17)305700 [Epub ahead of print]. Peng Z, Jin D, Kim HB, Stratton CW, Wu B, Tang Y-W, et al. Update on antimicrobial resistance in Clostridium difficile: resistance mechanisms and antimicrobial susceptibility testing. J Clin Microbiol 2017;55:1998e2008.
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Original Article
Efficacy and safety of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in a randomized, double-blind, comparative Phase III study in Japan* Hiroshige Mikamo a, Kazuhiro Tateda b, Katsunori Yanagihara c, Shinya Kusachi d, Yoshio Takesue e, Takashi Miki f, Yuki Oizumi f, Kazuaki Gamo f, *, Atsuki Hashimoto f, Junko Toyoshima f, Kenichi Kato f a
Department of Clinical Infectious Diseases, Aichi Medical University, Nagakute, Aichi, Japan Department of Microbiology and Infectious Diseases, Toho University School of Medicine, Tokyo, Japan c Department of Laboratory Medicine, Nagasaki University Hospital, Nagasaki, Japan d Department of Surgery, Toho University Ohashi Medical Center, Tokyo, Japan e Hyogo College of Medicine Hospital, Hyogo, Japan f Astellas Pharma, Inc., Tokyo, Japan b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 26 March 2018 Received in revised form 18 May 2018 Accepted 23 May 2018 Available online xxx
We assessed the efficacy and safety of fidaxomicin, a narrow-spectrum macrocyclic antibiotic, for treating inpatients with Clostridioides (Clostridium) difficile infection (CDI) in Japan. The objective was to demonstrate the non-inferior efficacy of fidaxomicin versus vancomycin. This Phase III, vancomycin-controlled, double-blind, parallel-group study enrolled adults with CDI. Patients were randomly assigned to receive fidaxomicin (200 mg twice daily, orally) or vancomycin (125 mg four-times daily, orally) for 10 days. The primary endpoint was global cure rate of CDI (proportion of patients cured at end of treatment with no recurrence during 28-day follow-up). Non-inferiority margin of 10% was pre-specified. Two-hundred and twelve patients were randomized and received treatment at 82 hospitals. Global cure rate was 67.3% (70/104) with fidaxomicin and 65.7% (71/108) with vancomycin: difference 1.2% [95% confidence interval (CI) 11.3e13.7]. Non-inferiority was not demonstrated. Post-hoc analysis in full analysis set patients who received at least 3 days' treatment revealed a higher global cure rate for fidaxomicin [70/97 (72.2%)] than vancomycin [71/106 (67.0%)]: difference 4.6% (95% CI 7.9e17.1). Recurrence rate in the full analysis set for recurrence was lower in fidaxomicin- [17/87 (19.5%)] than vancomycin-treated [24/95 (25.3%)] patients. Adverse event incidences and profiles were similar for both treatments. Though non-inferiority was not demonstrated for fidaxomicin versus vancomycin, global cure rate was numerically higher and recurrence rate lower for fidaxomicin than vancomycin. Fidaxomicin could be an option for the treatment of CDI in an era of reduced antibiotic susceptibility, and to reduce the incidence of recurrence in Japanese patients. ClinicalTrials.gov Identifier: NCT02179658. © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Clostridioides (Clostridium) difficile infection Fidaxomicin Global clinical cure Japan Recurrence Vancomycin
* All authors meet the ICMJE authorship criteria, and have made substantial contributions to all of the following: the conception and design of the study, or acquisition of data, or analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; and final approval of the version to be submitted. * Corresponding author. Astellas Pharma, Inc., 2-5-1, Nihonbashi-Honcho, Chuo-Ku, Tokyo 103-8411, Japan. E-mail address: [email protected] (K. Gamo).
1. Introduction Clostridioides (Clostridium) difficile is the primary pathogenic cause of infectious diarrhea that develops after hospitalization and antibiotic treatment [1,2]. C. difficile infection (CDI) is toxin mediated and associated with broad-spectrum antibiotic use [1,2], which
https://doi.org/10.1016/j.jiac.2018.05.010 1341-321X/© 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Mikamo H, et al., Efficacy and safety of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in a randomized, double-blind, comparative Phase III study in Japan, J Infect Chemother (2018), https://doi.org/10.1016/ j.jiac.2018.05.010
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disrupts the gut microbiota and enables overgrowth of C. difficile and subsequent infection [3]. Other risk factors for CDI include advanced age, hospitalization and serious underlying illness [2,4]. Clinical symptoms range from mild diarrhea to more severe abdominal pain, fever and leukocytosis, or severe, complicated CDI with the development of pseudomembranous colitis or toxic megacolon [2]. Although epidemiological studies of CDI in Japan are limited, 30-day all-cause mortality rates of 13e15% [5,6] and recurrence rates of 14e46% have been reported in Japanese patients [6e8]. Metronidazole and vancomycin are currently recommended by the Japanese Association for Infectious Diseases for the treatment of CDI [9]. However, the incidence of recurrence is estimated to be up to 25% with these agents [10,11]. The high recurrence rates have been postulated to be a consequence of disruption of the gut microbiota [12,13]. In two prospective, double-blind, randomized, parallel-group, non-inferiority registration studies in the US, Canada and Europe, the narrow-spectrum macrocyclic antibiotic fidaxomicin was noninferior for initial clinical cure of CDI, and was associated with significantly lower recurrence rates and higher sustained clinical cure compared with vancomycin [14,15]. The aim of the present study was to evaluate the efficacy, safety and pharmacokinetics (PK) of fidaxomicin for the treatment of CDI in a hospital setting in Japan, with the objective of investigating whether non-inferiority of fidaxomicin versus vancomycin is confirmed in Japanese patients.
undertaken at 82 centers in Japan between June 2014 and September 2016. The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice and International Conference of Harmonization guidelines. Patients provided written informed consent. Hospitalized patients with CDI were screened and were eligible for inclusion if they were aged 20 years and had not received antibiotic treatment for CDI, or had treatment failure after 3 days of metronidazole therapy before providing informed consent. All patients had symptomatic CDI: diarrhea defined as 4 episodes of unformed bowel movements (UBMs) within 24 h before randomization and presence of C. difficile toxin A/B confirmed in stool within 96 h using the study centers' usual toxin detection kit before randomization. Key exclusion criteria were: life-threatening or fulminant CDI; paralytic ileus or toxic megacolon; prior use of fidaxomicin; concomitant use of any antibiotic intended for CDI treatment; 2 prior episodes of CDI within 3 months before study entry; and requirement for antidiarrheal drugs (e.g. loperamide). 2.2. Randomization and masking
2. Patients and methods
Patients were randomly assigned to treatment (1:1 allocation) using dynamic allocation with a biased-coin minimization approach with study center and prior occurrence of CDI as allocation factors to minimize bias. Active and placebo treatments were administered using a double-dummy method to ensure that trial personnel and investigators assessing outcomes were blinded to treatment assignment throughout the trial.
2.1. Study design and population
2.3. Procedures
This Phase III, randomized, vancomycin-controlled, double-blind, parallel-group study of fidaxomicin in patients with CDI was
Patients assigned to fidaxomicin received one fidaxomicin 200 mg tablet orally twice daily and vancomycin placebo orally
Table 1 Study populations and analyses. Study population
Definition
Analyses
Full analysis set, FAS
All randomized patients who met the criteria for symptomatic Clostridioides (Clostridium) difficile infection, received at least one dose of study drug and were assessed for at least one efficacy endpoint during the treatment period As the FAS, but only including patients who achieved clinical cure at the end of treatment Patients in the FAS who met the inclusion criteria; did not violate the exclusion criteria; for treatment failure evaluation, they received at least 3 days of treatment (at least six doses of fidaxomicin or its matching placebo and at least 12 doses of vancomycin or its matching placebo); for cure evaluation, they received at least 16 doses of fidaxomicin or its matching placebo and at least 32 doses of vancomycin or its matching placebo; had cure assessment at end of treatment; and had no protocol deviations, including the use of prohibited or restricted concomitant drugs As the PPS, but only including patients who achieved clinical cure at the end of treatment and met the following criteria: were assessed as having no recurrence during the period from 25 to 31 days after end of treatment or recurrence within 31 days after end of treatment; and did not take any drug that could confound the assessment of recurrence Patients from the PPS-R and PPS who were not cured All patients who received the study drug and who had at least one blood/stool sample assessed for drug concentration All patients who received at least one dose of study drug Patients in the FAS who received at least 3 days of treatment (at least six doses of fidaxomicin or its matching placebo and at least 12 doses of vancomycin or its matching placebo) As the mFAS, but only including patients who achieved clinical cure at the end of treatment
Primary analysis population for clinical efficacy (cure, global cure and resolution of diarrhea) and microbiological efficacy
Full analysis set for recurrence, FAS-R Per-protocol set, PPS
Per-protocol set for recurrence, PPS-R
Per-protocol set for global cure, PPS-G Pharmacokinetic analysis set, PKAS
Safety analysis set, SAF Modified full analysis set, mFAS
Modified full analysis set for recurrence, mFAS-R
Recurrence Clinical efficacy (cure and resolution of diarrhea) and microbiological efficacy
Recurrence
Clinical efficacy in terms of global cure Pharmacokinetic parameters in blood and stool
Safety assessments Post-hoc analyses for clinical efficacy (cure, global cure and resolution of diarrhea) and microbiological efficacy Post-hoc analysis of recurrence
Please cite this article in press as: Mikamo H, et al., Efficacy and safety of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in a randomized, double-blind, comparative Phase III study in Japan, J Infect Chemother (2018), https://doi.org/10.1016/ j.jiac.2018.05.010
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four-times daily for 10 days. Patients assigned to vancomycin received one fidaxomicin placebo tablet twice daily and reconstituted vancomycin powder four-times daily (500 mg/day) for 10 days. Efficacy assessments followed previously published procedures [15]. Clinical cure of CDI was assessed at the end of treatment (EOT) and defined by the resolution of diarrhea (i.e. 3 episodes of UBMs for 2 consecutive days), with maintenance of resolution by EOT and no further requirement for CDI therapy at EOT. Patients who did not achieve cure at EOT were considered treatment failures and discontinued from the study. Recurrence, assessed throughout the 28day follow-up period in patients who met the criteria for clinical cure, was defined by more frequent UBMs than at EOT per 24-h period within 4 weeks after cessation of therapy, presence of C. difficile toxin A/B in stool and a need for retreatment of CDI according to the investigator's opinion. Blood samples for pharmacokinetic (PK) analysis were collected 3e5 h after the first dose of treatment on Day 1 and last dose at EOT. Feces samples for PK analysis were collected from the first defecation within 24 h after the last dose of fidaxomicin at EOT. Plasma and fecal concentrations of fidaxomicin and its primary metabolite, OP-1118, were determined using validated liquid chromatography tandem mass spectrometry at a central facility. Stool samples for microbiological analysis were collected at screening, at EOT and at the follow-up visit. Samples were evaluated for C. difficile detection by culture. Microbiological response
3
was evaluated at EOT and at the follow-up visit. Minimum inhibitory concentrations (MICs) were determined by an agar plate dilution method in accordance with Clinical and Laboratory Standards Institute (CLSI) M11-A8 and M100-S24 [16,17]. Isolated C. difficile were characterized using multilocus sequence typing (MLST), with sequences compared against those in the Center for Genomic Epidemiology (CGE) database, available at https://cge.cbs. dtu.dk//services/MLST/. Analyses were performed by LSI Medience Corporation. 2.4. Endpoints The primary efficacy endpoint was global cure rate of CDI (proportion of all treated patients who were cured at EOT and had no recurrence during follow up). This was assessed in the full analysis set (FAS), adjusting for prior occurrence of CDI. Secondary endpoints included the global cure rate of CDI in populations other than the FAS; clinical cure rate of CDI (proportion of patients who were cured at EOT); recurrence rate of CDI (proportion of patients who were cured at EOT and had recurrence during the follow-up period); time to recurrence of CDI [time (days) from the final day of treatment to recurrence]; time to resolution of diarrhea [time (days) from the start of treatment to resolution of diarrhea]; and microbiological efficacy (change in C. difficile carriage between pre-treatment and post-treatment). Patients with microbiological eradication were those with cultured C. difficile at
Fig. 1. Participant flow chart. There were 15 patients (16 deviations) in the fidaxomicin group and 17 patients (18 deviations) in the vancomycin group with major protocol deviations. Two patients in the vancomycin group had violations of the inclusion/exclusion criteria. Six patients in the fidaxomicin group and four patients in the vancomycin group had dose and dosage regimen violations. Eight patients in the fidaxomicin group and 11 patients in the vancomycin group had concomitant drug/therapy violations. Two patients in the fidaxomicin group and one patient in the vancomycin group had serious adverse event reporting violations. FAS-R, full analysis set for recurrence; mFAS, modified full analysis set; mFAS-R, modified full analysis set for recurrence; PKAS, pharmacokinetic analysis set; PPS, per-protocol set; PPS-G, per-protocol set for global cure; PPS-R, per-protocol set for recurrence.
Please cite this article in press as: Mikamo H, et al., Efficacy and safety of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in a randomized, double-blind, comparative Phase III study in Japan, J Infect Chemother (2018), https://doi.org/10.1016/ j.jiac.2018.05.010
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H. Mikamo et al. / J Infect Chemother xxx (2018) 1e9
screening and ‘eradication’, ‘presumed eradication’ or ‘colonization’ after treatment. Eradication occurred if there was an improvement or resolution of clinical symptoms and C. difficile was absent in stool. Presumed eradication occurred if there was an improvement or resolution of clinical symptoms in the absence of a CDI test result. Colonization occurred if there was an improvement or resolution of clinical symptoms but C. difficile remained present in feces. PK was assessed by determining plasma and fecal concentrations of fidaxomicin and OP-1118. Safety was assessed up to the end of the 28-day follow-up period after treatment initiation and was based on treatmentemergent adverse events (AEs), mortality, routine test results and vital sign measurements.
2.5. Statistical analyses Global cure rates for fidaxomicin and vancomycin were assumed to be 75.5% and 63.8%, respectively, with reference to previously published results [18]. Based on the assumption of a one-sided a level of 0.025, 1:1 allocation ratio, 10% non-inferiority margin, and allowing for withdrawal of 10% of patients, a total of 210 patients (105 per treatment group) were needed to have 90% power in the present study. The primary population for clinical efficacy (cure, global cure and resolution of diarrhea) and microbiological efficacy analyses was the FAS. Study populations are described in Table 1. The modified FAS (mFAS) and mFAS for recurrence (mFAS-R) were used
Table 2 Patient demographics and baseline characteristics (FAS). Characteristic
Gender, n (%) Female Age, years Mean (SD) Median (range) Age category (years), n (%) <65 65e<75 75 Height, cm Mean (SD) Median (range) Weight, kg Mean (SD) Median (range) BMI, kg/m2 Mean (SD) Median (range) CDI severitya, n (%) Mild/moderate Severe Antibiotic use for CDI before screening, n (%) None Metronidazoleb Prior CDI, n (%) No Yes Prior CDI 3 months before screening, n (%) No Yes No. UBMs on the day of registration, n Mean (SD) Median (range) Renal function eGFRc (mL/min/1.73 m2), n (%) <30 30e<60 60e<90 90 eCCLd (mL/min), n (%) <30 30e<50 50e<80 80 Missing Hepatic functione, n (%) Grade 1 Grade 2
Fidaxomicin
Vancomycin
(n ¼ 104)
(n ¼ 108)
56 (53.8)
54 (50.0)
74.0 (13.5) 76.5 (26e93)
75.0 (12.5) 78.0 (21e92)
17 (16.3) 26 (25.0) 61 (58.7) n ¼ 103 155.96 (9.35) 155.50 (135.0e177.6) n ¼ 99 52.55 (14.09) 52.60 (23.5e103.7) n ¼ 98 21.45 (5.00) 21.03 (11.8e39.3)
18 (16.7) 16 (14.8) 74 (68.5) n ¼ 107 155.92 (10.59) 156.00 (125.0e180.5) n ¼ 104 50.74 (11.41) 50.00 (29.4e90.8) n ¼ 104 20.83 (4.00) 20.68 (14.4e32.5)
79 (76.0) 25 (24.0)
86 (79.6) 22 (20.4)
99 (95.2) 5 (4.8)
105 (97.2) 3 (2.8)
90 (86.5) 14 (13.5)
92 (85.2) 16 (14.8)
92 (88.5) 12 (11.5) n ¼ 100 5.8 (6.3) 4.0 (0e60)
96 (88.9) 12 (11.1) n ¼ 104 5.6 (3.9) 5.0 (0e29)
16 24 39 25
(15.4) (23.1) (37.5) (24.0)
18 27 35 28
(16.7) (25.0) (32.4) (25.9)
22 19 34 23 6
(22.4) (19.4) (34.7) (23.5)
19 25 39 21 4
(18.3) (24.0) (37.5) (20.2)
96 (92.3) 8 (7.7)
101 (93.5) 7 (6.5)
BMI, body mass index. eCCL, creatinine clearance. CDI, Clostridioides (Clostridium) difficile infection. eGFR, estimated glomerular filtration rate. SD, standard deviation. UBMs, unformed bowel movements. a Severe CDI defined as creatinine >1.5 mg/dL, white blood cell count >15000/mL or body temperature >38.5 C at baseline. b Treatment for 3 days but failed to achieve clinical improvement. c eGFR calculated according to: 194 age0.287 creatinine1.094 ( 0.739 for women). d eCCL calculated according to: [(140 age) body weight in kg] ÷ [72 creatinine] (x 0.85 for women). e According to NCI-CTCAE Grade, ver 4.03. Grade 2 defined as laboratory test values meeting any of the following criteria before the start of treatment: ALP >2.5 upper limit of normal (ULN), AST >3 ULN, ALT >3 ULN, or total bilirubin >1.5 ULN.
Please cite this article in press as: Mikamo H, et al., Efficacy and safety of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in a randomized, double-blind, comparative Phase III study in Japan, J Infect Chemother (2018), https://doi.org/10.1016/ j.jiac.2018.05.010
H. Mikamo et al. / J Infect Chemother xxx (2018) 1e9
in post-hoc analyses to identify any influence on efficacy outcomes of early treatment discontinuation. Patients with missing data for clinical cure and recurrence of CDI were considered failure for clinical cure and to have CDI recurrence. Global cure of CDI was derived from the cure and recurrence of CDI imputed for missing values. Plasma and fecal concentrations below the lower limit of quantification were treated as zero. Data are reported for the FAS, unless otherwise stated, and summarized with descriptive statistics. For global cure, cure, recurrence and microbiological efficacy, the rate and corresponding 95% confidence interval (CI) for each treatment group were calculated. Between-treatment differences and 95% CIs were then determined. Non-inferiority of fidaxomicin versus vancomycin was demonstrated in the primary analysis of global cure rate when the lower limit of the 95% CI for the difference between treatments was
a
5
above 10%. Analysis of between-group differences was calculated using the ManteleHaenszel estimator based on whether patients had a prior episode of CDI. For time to CDI recurrence and resolution of diarrhea, KaplaneMeier estimates were calculated and comparisons made between treatment groups using the logrank test. All analyses were performed using SAS® Drug Development 4.5 (SAS Institute) and SAS System Release 9.4. All reported P values were two-sided, and the significance level was P < 0.05. 3. Results 3.1. Participants Of 227 patients who were screened, 215 eligible patients were enrolled and randomized; 106 to fidaxomicin and 109 to
b
Fig. 2. (a) Clinical efficacy outcomes of Clostridioides (Clostridium) difficile infection treatment with fidaxomicin and vancomycin in the primary analysis population (FAS and FAS-R). Vertical bars represent 95% confidence intervals. Difference (95% confidence interval [CI]) between fidaxomicin and vancomycin groups and the 95%CI calculated using the MantelHaenszel estimator based on prior occurrence of C. difficile infection in the FAS. FAS, full analysis set. FAS-R, full analysis set for recurrence. aFAS. bFAS-R. (b) Clinical efficacy outcomes of Clostridioides (Clostridium) difficile infection treatment with fidaxomicin and vancomycin in secondary analysis populations (PPS, PPS-G, PPS-R, mFAS and mFAS-R). Vertical bars represent 95% confidence intervals. Difference (95% confidence interval [CI]) between fidaxomicin and vancomycin groups and the 95%CI calculated using the Mantel-Haenszel estimator based on prior occurrence of C. difficile infection. mFAS, modified full analysis set. mFAS-R, modified full analysis set for recurrence. PPS, per-protocol set. PPS-G, perprotocol set for global cure. PPS-R, per-protocol set for recurrence.
Table 3 Global cure rate of Clostridioides (Clostridium) difficile infection (CDI). Value
Global cure rate of CDI, n (%) 95% CI Difference in global cure rate of CDI, %a 95% CI
FAS
PPS-G
mFAS
Fidaxomicin (n ¼ 104)
Vancomycin (n ¼ 108)
Fidaxomicin (n ¼ 85)
Vancomycin (n ¼ 95)
Fidaxomicin (n ¼ 97)
Vancomycin (n ¼ 106)
70 (67.3) 58.3e76.3 1.2 11.3e13.7
71 (65.7) 56.8e74.7
63 (74.1) 64.8e83.4 3.9 9.1e16.8
66 (69.5) 60.2e78.7
70 (72.2) 63.2e81.1 4.6 7.9e17.1
71 (67.0) 58.0e75.9
CI, confidence interval. FAS, full analysis set. mFAS, modified full analysis set. PPS-G, per-protocol set for global cure. a Calculated difference (fidaxomicin e vancomycin) obtained using the Mantel-Haenszel estimator.
a
b
Fig. 3. (a) KaplaneMeier plot of the time from the last day of dosing to Clostridioides (Clostridium) difficile infection recurrence, full analysis set for recurrence (FAS-R). Patients with missing data for recurrence of CDI were considered to have CDI recurrence; the time to recurrence was defined as the date of last evaluation minus the date of last study drug administration plus one. (b) KaplaneMeier plot of the time from the start of treatment to resolution of diarrhea, full analysis set (FAS). Patients with missing data for resolution of diarrhea were considered ‘failure’ and the time to no resolution of diarrhea was defined as the date of evaluation for cure of CDI minus the date of first study drug administration plus one.
Please cite this article in press as: Mikamo H, et al., Efficacy and safety of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in a randomized, double-blind, comparative Phase III study in Japan, J Infect Chemother (2018), https://doi.org/10.1016/ j.jiac.2018.05.010
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H. Mikamo et al. / J Infect Chemother xxx (2018) 1e9
vancomycin (Fig. 1). Of the randomized patients, 2 in the fidaxomicin group and 1 in the vancomycin group withdrew before receiving treatment. All remaining patients tested positive for C. difficile toxin A/B and were included in the FAS and SAF. The two treatment groups did not differ significantly with respect to baseline characteristics (Table 2). 3.2. Efficacy The primary endpoint of global cure rate of CDI in the FAS was 67.3% with fidaxomicin and 65.7% with vancomycin (Fig. 2a, Table 3), with a treatment difference of 1.2% (95% CI 11.3e13.7). The lower limit of the 95% CI for this difference was not above the non-inferiority margin of 10%, therefore non-inferiority was not demonstrated. The global cure rate at the end of the study was higher with fidaxomicin than vancomycin when analyzed in the PPS-G (Fig. 2b, Table 3), with a treatment difference of 3.9% (95% CI 9.1e16.8). Similarly, fidaxomicin was numerically superior to vancomycin in relation to the post-hoc analysis of global cure rate in the mFAS: treatment difference 4.6% (95% CI 7.9e17.1) (Fig. 2b, Table 3). In the FAS, cure rates of CDI at EOT were 83.7% with fidaxomicin and 88.0% with vancomycin (Fig. 2a), with a treatment difference of 4.4%. The cure rates of CDI in the PPS (Fig. 2b) and mFAS (Fig. 2b) were higher and treatment differences were smaller than in the FAS. During the follow-up period, the recurrence rates were 19.5% with fidaxomicin and 25.3% with vancomycin, with a treatment difference of 4.9% in the FAS-R (Fig. 2a). The recurrence rates in
the PPS-R (Fig. 2b) and mFAS-R (Fig. 2b) were the same or lower and treatment differences greater than in the FAS. The time taken after EOT for the first 10% of patients to experience a recurrence in the FAS-R (primary analysis) population (Fig. 3a) was 11 days in the fidaxomicin group and 8 days in the vancomycin group. No treatment differences were observed (P ¼ 0.330). The median time from the start of treatment to resolution of diarrhea in the FAS was 4 days in the fidaxomicin group and 3 days in the vancomycin group; P ¼ 0.342 (Fig. 3b). In the FAS, microbiological eradication of C. difficile after treatment was similar for fidaxomicin and vancomycin [87.8% (79/90) versus 90.1% (91/101), respectively; Table 4]. At the follow-up visit, the microbiological eradication rate was maintained in 80.8% (59/ 73) fidaxomicin-treated patients and in 77.6% (66/85) vancomycintreated patients in the FAS-R (Table 4). 3.3. Pharmacokinetic analysis Plasma and fecal PK concentrations of fidaxomicin and OP-1118 are given in Table 5. Mean (standard deviation) plasma concentrations of fidaxomicin and OP-1118 following fidaxomicin administration were 54.68 (73.75) ng/mL and 135.55 (199.18) ng/mL, respectively, at EOT. 3.4. Safety The incidence of AEs was 70.2% (73/104) in the fidaxomicin group and 70.4% (76/108) in the vancomycin group (Table 6). Safety findings
Table 4 Microbiological efficacy outcomes after treatment of Clostridioides (Clostridium) difficile infection with fidaxomicin and vancomycin in the primary analysis population (FAS and FAS-R). Outcomes were measured at the end of treatment in the FAS and at the follow-up visit in the FAS-R. Outcome, n (%)
Eradicationa Presumed eradicationa Colonizationa Persistence Presumed persistenceb Unknownb No. patients, nc Eradication ratec 95% CI Difference in eradication rate, %d 95% CI
FAS
FAS-R
Fidaxomicin (n ¼ 104)
Vancomycin (n ¼ 108)
Fidaxomicin (n ¼ 87)
Vancomycin (n ¼ 95)
56 (53.8) 17 (16.3) 6 (5.8) 1 (1.0) 10 (9.6) 14 (13.5) 90 79 (87.8) 81.0e94.5
77 (71.3) 13 (12.0) 1 (0.9) 3 (2.8) 7 (6.5) 7 (6.5) 101 91 (90.1) 84.3e95.9 2.3 11.2e6.6
25 (30.1) 3 (3.6) 31 (37.3) 10 (12.0) 4 (4.8) 10 (12.0) 73 59 (80.8) 71.8e89.9
21 (22.8) 4 (4.3) 41 (44.6) 14 (15.2) 5 (5.4) 7 (7.6) 85 66 (77.6) 68.8e86.5 3.2 9.5e15.8
CI, confidence interval. FAS, full analysis set. FAS-R, full analysis set for recurrence. a Eradication, presumed eradication and colonization were assessed as eradiation. b Persistence and presumed persistence were assessed as persistence. c Patients with unknown results were excluded from the calculation of the eradication rate. d Difference (fidaxomicin e vancomycin) and 95% CI calculated using normal approximation.
Table 5 Plasma and fecal concentrations of fidaxomicin and OP-1118 after the first dose and end of treatment (PKAS). Fidaxomicin
No. patients, n Mean (SD) concentration in plasma, ng/mL No. patients, n Mean (SD) concentration in feces, mg/g
OP-1118
First dose
End of treatment
First dose
End of treatment
102 41.77 (46.27) e e
90 54.68 (73.75) 57 1984.98 (1368.16)
102 72.77 (65.49) e e
90 135.55 (199.18) 57 1458.09 (1131.88)
PKAS, pharmacokinetic analysis set. SD, standard deviation. Blood samples were obtained 3e5 h after the first dose of treatment on Day 1 and the last dose at end of treatment. Feces samples were obtained at the first defecation within 24 h after the last dose of fidaxomicin at end of treatment. The lower limit of quantification of fidaxomicin and OP-1118 in plasma was 0.20 ng/mL for both molecules, and in feces, 10.00 ng/mL and 50.00 ng/mL, respectively.
Please cite this article in press as: Mikamo H, et al., Efficacy and safety of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in a randomized, double-blind, comparative Phase III study in Japan, J Infect Chemother (2018), https://doi.org/10.1016/ j.jiac.2018.05.010
H. Mikamo et al. / J Infect Chemother xxx (2018) 1e9 Table 6 Adverse events reported during the study (SAF). Patients, n (%)
Fidaxomicin (n ¼ 104)
Vancomycin (n ¼ 108)
Any AE Grade 1a Grade 2a Grade 3a Grade 4a Grade 5a Any treatment-related AEb Deathc Treatment-related death Any serious AEd Any AE leading to treatment discontinuation Grade 1a, Grade 2a Grade 3a Grade 4a Grade 5a AE by preferred termf Clostridioides (Clostridium) difficile colitis Urinary tract infection Constipation Pyrexia Dermatitis contact Nausea Back pain Vomiting Malaise Delirium Hemorrhoids Pruritus Contusion Erythema Skin exfoliation Diarrhea Dizziness Febrile neutropenia Hepatic function abnormal Liver function test abnormal
73 (70.2) 13 (12.5) 36 (34.6) 15 (14.4) 6 (5.8) 3 (2.9) 9 (8.7) 3 (2.9) 0 16 (15.4) 6 (5.8)e 0 1 (1.0) 2 (1.9) 3 (2.9) 0
76 (70.4) 11 (10.2) 38 (35.2) 22 (20.4) 3 (2.8) 2 (1.9) 9 (8.3) 2 (1.9) 0 14 (13.0) 1 (0.9) 0 0 1 (0.9) 0 0
13 (12.5) 3 (2.9) 6 (5.8) 5 (4.8) 4 (3.8) 4 (3.8) 4 (3.8) 3 (2.9) 1 (1.0) 3 (2.9) 3 (2.9) 3 (2.9) 3 (2.9) 3 (2.9) 3 (2.9) 2 (1.9) 1 (1.0) 1 (1.0) 1 (1.0) 0
21 (19.4) 11 (10.2) 7 (6.5) 6 (5.6) 3 (2.8) 2 (1.9) 1 (0.9) 4 (3.7) 4 (3.7) 2 (1.9) 2 (1.9) 2 (1.9) 1 (0.9) 1 (0.9) 1 (0.9) 3 (2.8) 3 (2.8) 3 (2.8) 3 (2.8) 3 (2.8)
AE, adverse event. SAF, safety analysis set. a If a patient had multiple AEs, but with differing grades, the patient was counted only once with the highest grade. b AEs considered possibly or probably related to study drug or AEs for which a causal relationship with study drug was missing. c None of the deaths was related to study drug or Clostridioides (Clostridium) difficile infection. d Serious AE defined as AE considered by the investigator or the sponsor to result in death, or be life-threatening, causing persistent or significant disability/incapacity or substantial disruption to the ability to conduct normal daily activities, cause congenital anomaly or birth defect, require hospitalization or prolongation of hospitalization, or other medically important event. e Vomiting (Grade 1) and delusion (Grade 2) were reported in one patient. f Occurring in 2% of patients in any treatment group and regardless of relationship to study drug.
were similar for both treatments, except that the incidence of any AE leading to treatment discontinuation was higher for fidaxomicin [5.8% (6/104)] than vancomycin [0.9% (1/108)]. Any AE leading to treatment discontinuation were 7 events in 6 patients in the fidaxomicin group [ventricular fibrillation (Grade 4), duodenal ulcer hemorrhage (Grade 3), vomiting (Grade 1), general physical health deterioration (Grade 3), liver carcinoma ruptured (Grade 4), delusion (Grade 2) and peripheral artery aneurysm (Grade 4)] and 1 patient in the vancomycin group [pancreatic leak (Grade 3)] (Table 6). 3.5. Clostridioides (Clostridium) difficile isolates For 191 strains of C. difficile isolated at screening, the MIC90 of fidaxomicin was 0.12 (range 0.004e0.5) mg/mL. The MIC90 was 0.5 (range 0.25e2) mg/mL for vancomycin and 1 (range 0.12e2) mg/mL for metronidazole (Table 7). The most commonly identified
7
Table 7 Antibiotic susceptibility test results for 191 C. difficile isolates cultured at screening (FAS). Test antibiotic
MIC50 (mg/mL)
MIC90 (mg/mL)
Range (mg/mL)
Ampicillin Clindamycin Fidaxomicin Meropenem Metronidazole Moxifloxacin Vancomycin
1 128 0.06 2 0.5 32 0.50
2 >128 0.12 4 1 >128 0.50
0.5, 8 1, >128 0.004, 0.5 1, 8 0.12, 2 1, >128 0.25, 2
MIC50, minimum inhibitory concentration at which 50% of isolates were inhibited. MIC90, minimum inhibitory concentration at which 90% of isolates were inhibited.
sequence types were 17, 8 and 2 (Fig. 4). The hypervirulent strain type 1 was detected on a single occasion. 4. Discussion This multicenter study, conducted in Japan, assessed the efficacy of fidaxomicin for the treatment of CDI. The findings demonstrated that twice-daily dosing with fidaxomicin was associated with a treatment difference of 1.2% compared with four-times daily vancomycin in relation to the primary endpoint e the rate of global cure (without recurrence) at study end e but did not achieve the study's pre-defined non-inferiority margin in the primary analysis population. In the present study, more fidaxomicin-treated patients than vancomycin-treated patients withdrew prematurely from treatment (especially within the first 3 days) owing to adverse events, protocol deviations and either the patient's or investigator's request to withdraw, which may have impaired the direct comparison of efficacy in the treatment groups. To allow for this imbalance, pre-defined secondary (PPS-G) and post-hoc (mFAS) analyses were performed in patients who received at least 3 days of treatment. Regardless of treatment group, the cure and global cure rates were higher in the mFAS than in the FAS and the recurrence rate in the mFAS-R was similar to that in the FAS-R. In particular, in the mFAS, the cure rate for fidaxomicin was 5% higher than in the FAS and was similar to that for vancomycin. The lower limit of the 95% CI for the difference in global cure rate in the mFAS was 7.9%, which was above the non-inferiority margin of 10%. The 3-day threshold was based on in-vitro gut modeling data, which demonstrated clearance of C. difficile viable cells, toxins and spores after 2e4 days of starting fidaxomicin treatment [19]. In previous fidaxomicin studies, a threshold of at least 3 days of treatment in per-protocol populations was used for the evaluation of clinical cure [14,15]. Compared with two registration studies of fidaxomicin in non-Japanese populations [14,15], in which rates of initial cure were 88.2% and 87.7%, global (sustained) cure were 74.6% and 76.6%, and recurrence rates were 15.4% and 12.7%, the corresponding cure rates among fidaxomicin-treated patients in the present study were somewhat lower and the recurrence rate somewhat higher (83.7%, 67.3% and 19.5%, respectively). The clinical cure rates with fidaxomicin were high (>80%) across the studies, and recurrence rates were lower and global cure rates higher for fidaxomicin-than vancomycin-treated patients [14,15]. The time to resolution of diarrhea was similar between treatment groups, and the time to CDI recurrence was longer with fidaxomicin than vancomycin across all three studies [14,15]. Moreover, the high rate of microbiological eradication of C. difficile in the fidaxomicin group (EOT: 87.8% and follow-up visit: 80.8%) supported clinical outcomes.
Please cite this article in press as: Mikamo H, et al., Efficacy and safety of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in a randomized, double-blind, comparative Phase III study in Japan, J Infect Chemother (2018), https://doi.org/10.1016/ j.jiac.2018.05.010
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H. Mikamo et al. / J Infect Chemother xxx (2018) 1e9
Fig. 4. Sequence types (ST) and their frequencies in 191 strains of Clostridioides (Clostridium) difficile identified by multilocus sequence typing (MLST) analysis at screening, full analysis set (FAS). aOther sequence types identified were: 1, 6, 11, 13, 26, 27, 35, 42, 47, 49, 53, 59, 67, 82, 98, 100, 182 and non-typable.
A difference between the populations in the present study and those of the previous, non-Japanese studies, which may contribute to the observed differences in treatment outcomes, is that our study enrolled only hospitalized patients, whereas in the previous studies, only 59.4% and 68.2%, respectively, were inpatients [14,15]. The previous studies found lower cure rates among inpatients compared with outpatients, regardless of treatment [14,15]. Potential reasons for worse outcomes in inpatients include the tendency for these patients to be elderly and have severe or complicated infections [20]. Additionally, a greater proportion of inpatients with CDI compared with outpatients with CDI have a serious underlying disease other than CDI [20] and use concomitant medications that carry a risk of CDI [20], while hospitalized patients are at risk of exposure to C. difficile spores [2] and subsequent re-infection. The overall incidence of treatment-related AEs was low (8.7%) and similar in the two treatment groups. The safety profile of fidaxomicin treatment in the present study was similar to that in previous studies in non-Japanese populations [14,15]. There is no evidence for a different safety profile for fidaxomicin in Caucasian and Japanese populations [21]. Regarding the distribution of C. difficile strains in this study, common strains were sequence types (ST) 17, 8 and 2, corresponding to PCR ribotypes (RT) 018, 002/159 and 014/020/076/220 [22]. This is consistent with previous reports in Japan/Asia [23]. Strains ST1 and ST11, corresponding to RT027/036 and RT078 [22], respectively, are highly represented among clinical isolates in the United States and Europe [24], although they were each identified only once in our study. A key strength of the present study is that it provides evidence of clinical outcomes, and information on the safety of fidaxomicin in a large population of hospitalized patients with CDI in Japan. A potential limitation was the absence of outpatients enrolled into the study, which may have impacted the range of C. difficile strains present and consequently, the outcome of treatment. Metronidazole and vancomycin are the only agents currently approved for the treatment of CDI in Japan, but are associated with a substantial risk of recurrence [10,11]. Additionally, alternative
CDI-targeted antibiotics are needed in response to the trend for decreased susceptibility to these agents [25]. In the epidemiological study monitoring antimicrobial resistance surveillance pre- and post-introduction of fidaxomicin, Freeman et al. [24] showed that fidaxomicin susceptibility was retained post-introduction. In this Phase III study, fidaxomicin showed a high cure rate of CDI in hospitalized patients in Japan; however, fidaxomicin noninferiority compared with vancomycin was not demonstrated in the primary analysis population. Furthermore, fidaxomicin was associated with a lower rate of recurrence numerically than vancomycin in all study populations analyzed. Fidaxomicin could be an option for the treatment of CDI and to reduce the risk of recurrence in Japanese patients. Conflicts of interest Hiroshige Mikamo has received research funding from Sumitomo Dainippon Pharma Co., Ltd, Taisho Toyama Pharmaceutical Co., Ltd, Daiichi Sankyo Co., Ltd, Pfizer Co., Ltd, Astellas, Inc., MSD K.K., Toyama Chemical Co., Ltd, MIYARISAN Pharmaceutical Co., Ltd, Shionogi & Co. Ltd., and consulting and lecture fees from Sumitomo Dainippon Pharma Co., Ltd, Taisho Toyama Pharmaceutical Co., Ltd, Daiichi Sankyo Co., Ltd, Pfizer Co., Ltd, MSD K.K., Astellas Pharma, Inc., and MIYARISAN Pharmaceutical Co., Ltd. Katsunori Yanagihara has received lecture fees from Pfizer Japan, Inc., Daiichi-Sankyo Co., Ltd, Astellas Pharma, Inc., Taisho Toyama Pharmaceutical Co., Ltd, Asahi Kasei Pharma Co., Ltd, and BD Japan, research fees from Taisho Toyama Pharmaceutical Co., Ltd, Meiji Seika Pharma Co., Ltd, KYORIN Pharmaceutical Co., Ltd, and Roche Diagnostics K.K., and research grants from Dainippon Sumitomo Pharma Co., Ltd, MSD Japan, Daiichi-Sankyo Co., Ltd, Astellas Pharma, Inc., Pfizer Japan, Inc., Taisho Toyama Pharmaceutical Co., Ltd, and Biofermin Seiyaku Co., Ltd. Shinya Kusachi has received research funding from Sumitomo Dainippon Pharma Co., Ltd, Taisho Toyama Pharmaceutical Co., Ltd, Daiichi-Sankyo Co., Ltd, Pfizer Co., Ltd, Astellas Pharma Inc., MSD K.K., Shionogi & Co., Ltd, Japan Blood Products Organization and Takeda Pharma Co., Ltd, and personal fees from Sumitomo
Please cite this article in press as: Mikamo H, et al., Efficacy and safety of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in a randomized, double-blind, comparative Phase III study in Japan, J Infect Chemother (2018), https://doi.org/10.1016/ j.jiac.2018.05.010
H. Mikamo et al. / J Infect Chemother xxx (2018) 1e9
Dainippon Pharma Co., Ltd, Taisho Toyama Pharmaceutical Co., Ltd, Daiichi-Sankyo Co., Ltd, Pfizer Co., Ltd, MSD K.K., Astellas Pharma, Inc., and Takeda Pharma Co., Ltd. Yoshio Takesue has received grants from Dainippon Sumitomo Pharma Co., Ltd, and Shionogi & Co., Ltd, and lecture fees from Astellas Pharma, Inc. Taisho Toyama Pharmaceutical Co., Ltd, and MSD Japan. Takashi Miki, Yuki Oizumi, Kazuaki Gamo, Atsuki Hashimoto, Junko Toyoshima, and Kenichi Kato are employees of Astellas Pharma, Inc., Japan. Kazuhiro Tateda has no conflicts of interest to declare.
[11]
[12]
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Acknowledgments
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The study was funded by Astellas Pharma, Inc. Medical writing support was provided by Rhian Harper Owen, PhD, for Cello Health MedErgy (Europe), funded by Astellas Pharma, Inc.
[15]
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References [1] Takahashi M, Mori N, Bito S. Multi-institution case-control and cohort study of risk factors for the development and mortality of Clostridium difficile infections in Japan. BMJ Open 2014;4. e005665. [2] Rupnik M, Wilcox MH, Gerding DN. Clostridium difficile infection: new developments in epidemiology and pathogenesis. Nat Rev Microbiol 2009;7: 526e36. [3] Buffie CG, Bucci V, Stein RR, McKenney PT, Ling L, Gobourne A, et al. Precision microbiome reconstitution restores bile acid-mediated resistance to Clostridium difficile. Nature 2015;517:205e8. [4] Hookman P, Barkin JS. Clostridium difficile associated infection, diarrhea and colitis. World J Gastroenterol 2009;15:1554e80. [5] Honda H, Yamazaki A, Sato Y, Dubberke ER. Incidence and mortality associated with Clostridium difficile infection at a Japanese tertiary care center. Anaerobe 2014;25:5e10. [6] Kobayashi K, Sekiya N, Ainoda Y, Kurai H, Imamura A. Adherence to clinical practice guidelines for the management of Clostridium difficile infection in Japan: a multicenter retrospective study. Eur J Clin Microbiol Infect Dis 2017;36:1947e53. [7] Hikone M, Ainoda Y, Tago S, Fujita T, Hirai Y, Takeuchi K, et al. Risk factors for recurrent hospital-acquired Clostridium difficile infection in a Japanese university hospital. Clin Exp Gastroenterol 2015;8:191e6. [8] Mikamo H, Aoyama N, Sawata M, Fujimoto G, Dorr MB, Yoshinari T. The effect of bezlotoxumab for prevention of recurrent Clostridium difficile infection (CDI) in Japanese patients. J Infect Chemother 2018;24:123e9. [9] Ohnishi K, Ainoda Y, Imamura A, Iwabuchi S, Okuda M, Nakano T. JAID/JSC guidelines for infection treatment 2015-intestinal infections. J Infect Chemother 2018;24:1e17. [10] Aguado JM, Anttila VJ, Galperine T, Goldenberg SD, Gwynn S, Jenkins D, et al. Highlighting clinical needs in Clostridium difficile infection: the views of
[17]
[18] [19]
[20]
[21]
[22]
[23] [24]
[25]
9
European healthcare professionals at the front line. J Hosp Infect 2015;90: 117e25. Heimann SM, Vehreschild JJ, Cornely OA, Wisplinghoff H, Hallek M, Goldbrunner R, et al. Economic burden of Clostridium difficile associated diarrhoea: a cost-of-illness study from a German tertiary care hospital. Infection 2015;43:707e14. Lewis BB, Buffie CG, Carter RA, Leiner I, Toussaint NC, Miller LC, et al. Loss of microbiota-mediated colonization resistance to Clostridium difficile infection with oral vancomycin compared with metronidazole. J Infect Dis 2015;212: 1656e65. Isaac S, Scher JU, Djukovic A, Jimenez N, Littman DR, Abramson SB, et al. Shortand long-term effects of oral vancomycin on the human intestinal microbiota. J Antimicrob Chemother 2017;72:128e36. Louie TJ, Miller MA, Mullane K, Weiss K, Lentnek A, Golan Y, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011;364: 422e31. Cornely OA, Crook DW, Esposito R, Poirier A, Somero MS, Weiss K, et al. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis 2012;12:281e9. Clinical and Laboratory Standards Institute. Methods for antimicrobial susceptibility testing of anaerobic bacteria: approved standarddeighth edition. CLSI document M11eA8. Wayne, PA, USA: CLSI; 2012. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing, 24th informational supplement. Wayne, PA, USA: CLSI document M100-S24; 2014. Mullane KM, Gorbach S. Fidaxomicin: first-in-class macrocyclic antibiotic. Expert Rev Anti Infect Ther 2011;9:767e77. Chilton CH, Crowther GS, Freeman J, Todhunter SL, Nicholson S, Longshaw CM, et al. Successful treatment of simulated Clostridium difficile infection in a human gut model by fidaxomicin first line and after vancomycin or metronidazole failure. J Antimicrob Chemother 2014;69:451e62. Khanna S, Pardi DS, Aronson SL, Kammer PP, Orenstein R, St Sauver JL, et al. The epidemiology of community-acquired Clostridium difficile infection: a population-based study. Am J Gastroenterol 2012;107:89e95. Oshima H, Yamazaki T, Benner L, Miki T, Michon I, Wojtkowski T, et al. Comparison of the safety, tolerability, and pharmacokinetics of fidaxomicin in healthy Japanese and caucasian subjects. Clin Drug Invest 2015;35: 375e84. Griffiths D, Fawley W, Kachrimanidou M, Bowden R, Crook DW, Fung R, et al. Multilocus sequence typing of Clostridium difficile. J Clin Microbiol 2010;48: 770e8. Riley TV, Kimura T. The epidemiology of Clostridium difficile infection in Japan: a systematic review. Infect Dis Ther 2018;7:39e70. Freeman J, Vernon J, Pilling S, Morris K, Nicholson S, Shearman S, et al. The ClosER study: results from a three-year pan-European longitudinal surveillance of antibiotic resistance among prevalent Clostridium difficile ribotypes, 2011e2014. Clin Microbiol Infect 2017;0. pii: S1198eS1743X(17)305700 [Epub ahead of print]. Peng Z, Jin D, Kim HB, Stratton CW, Wu B, Tang Y-W, et al. Update on antimicrobial resistance in Clostridium difficile: resistance mechanisms and antimicrobial susceptibility testing. J Clin Microbiol 2017;55:1998e2008.
Please cite this article in press as: Mikamo H, et al., Efficacy and safety of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in a randomized, double-blind, comparative Phase III study in Japan, J Infect Chemother (2018), https://doi.org/10.1016/ j.jiac.2018.05.010