- Email: [email protected]
Randomized, double-blind, dose-ranging study of pentosan polysulfate sodium for interstitial cystitis
ADULT UROLOGY
RANDOMIZED, DOUBLE-BLIND, DOSE-RANGING STUDY OF PENTOSAN POLYSULFATE SODIUM FOR INTERSTITIAL CYSTITIS J. CURTIS NICKEL, JACK BARKIN, JOHN FORREST, PHILLIP G. MOSBAUGH, J. HERNANDEZ-GRAULAU, DAVID KAUFMAN, KEITH LLOYD, ROBERT J. EVANS, C. LOWELL PARSONS, AND LINDA E. ATKINSON, ON BEHALF OF THE ELMIRON STUDY GROUP
ABSTRACT Objectives. To compare the current recommended dose of pentosan polysulfate sodium (PPS) with doses two to three times higher. Methods. We evaluated three dosages (300, 600, and 900 mg) of PPS in a randomized, double-blind, double-dummy, parallel-group, multicenter, 32-week study. Adults (n ⫽ 380) with a diagnosis of interstitial cystitis (IC) as determined by a positive cystoscopic examination combined with bladder pain and urgency or a history of IC symptoms for at least 6 months were enrolled. Participants completed the Patient’s Overall Rating of Symptom Index (PORIS) and the O’Leary-Sant Interstitial Cystitis Symptom Index (ICSI) at baseline (ICSI only) and during follow-up visits at 4, 8, 12, 16, 24, and 32 weeks. Results. Mean ICSI scores improved significantly during the 32 weeks for all dosages (baseline 11.2, 11.9, and 11.9 to endpoint 8.2, 8.1, 8.6 for 300, 600, and 900 mg, respectively; P ⬍0.001) but the response to treatment was not dose dependent (no statistically significant difference in response among the three dosages). At baseline, 3.2%, 62.2%, and 34.6% reported mild, moderate, and severe symptoms, respectively, as assessed by the ICSI. At study end, 27.5%, 56.9%, and 15.7% reported mild, moderate, and severe symptoms, respectively. The PORIS scores improved within 4 weeks with 15.8% to 21.1% of all patients classified as responders (50% or greater improvement on PORIS). At 32 weeks, 49.6%, 49.6%, and 45.2% of all patients were responders at a dose of 300, 600, and 900 mg, respectively. Most adverse events were mild and resolved without intervention. Conclusions. For all three dosages of PPS, a clinically significant but similar response was demonstrated. The duration of therapy appears to be more important than the dosage. UROLOGY 65: 654–658, 2005. © 2005 Elsevier Inc.
I
nterstitial cystitis (IC) is a disease manifested by urinary urgency, frequency, and/or pain that occurs in one or more locations throughout the pelvis.1–3 The disease occurs primarily in women and is estimated to affect 0.01% to 0.5% of women.1,4 IC can be severe enough to have a devastating impact on a person’s quality of life,5 but it can also be
associated with moderate symptoms whose effect is less debilitating. Many treatments are available for IC, but it is generally accepted that the results are disappointing, and few have been subjected to rigorous clinical evaluation.6 The oral heparinoid, pentosan polysulfate sodium (PPS), is indicated for the treat-
This study was funded by Ortho-McNeil/ALZA. J. C. Nickel, R. J. Evans, and J. Forrest are paid consultants to, and study investigators funded by, Ortho-McNeil. J. Barkin, P. Mosbaugh, J. Hernandez-Graulau, D. Kaufman, and K. Lloyd are study investigators funded by Ortho-McNeil. C. L. Parsons is a paid consultant to, study investigator funded by, and original patent inventor for the mentioned product. L. E. Atkinson is an employee of ALZA. From Queens University, Kingston, Ontario, Canada; Humber River Regional Hospital, Toronto, Ontario, Canada; Urologic Specialists of Oklahoma, Inc., Tulsa, Oklahoma; Urology of Indiana,
Indianapolis, Indiana; University of Illinois School of Medicine, Peoria, Illinois; Central Park Urology, New York, New York; University of Alabama, Birmingham, Alabama; The Urology Clinic, Greensboro, North Carolina; University of California, San Diego, Medical Center, San Diego, California; and ALZA Corporation, Mountain View, California Reprint requests: J. Curtis Nickel, M.D., Department of Urology, Queen’s University Kingston General Hospital, Victory 4, Kingston, ON K7L 2V7, Canada. E-mail: [email protected] Submitted: July 13, 2004, accepted (with revisions): October 28, 2004
© 2005 ELSEVIER INC. 654
ALL RIGHTS RESERVED
0090-4295/05/$30.00 doi:10.1016/j.urology.2004.10.071
ment of bladder pain or discomfort associated with IC. PPS has been evaluated for the treatment of IC in five randomized, multicenter, double-blind, placebo-controlled studies,7–11 four of which showed greater improvement with PPS than with placebo (P ⫽ 0.03, P ⫽ 0.01, P ⫽ 0.02, and P ⫽ 0.06).7–9,11 The onset of effect and dose-response effect for PPS has never been studied. We designed a study to compare the current recommended dose of PPS with doses two to three times higher. We evaluated three dosages (300, 600, and 900 mg) of PPS in a randomized, double-blind, parallel-group, multicenter, 32-week study.
ENDPOINTS The primary endpoint was the O’Leary-Sant Interstitial Cystitis Symptom Index (ICSI), a four-item questionnaire validated as an outcome parameter in IC.12,13 Scores were tallied for a single summary score indicating mild (0 to 6), moderate (7 to 14), and severe (15 to 20) symptoms. The secondary endpoint was the Patient’s Overall Rating of Symptoms Index (PORIS), which has three questions that address the overall change in IC, pain, and urgency after treatment as worse, no better (0% improvement), slightly improved (25%), moderately improved (50%), greatly improved (75%), or symptoms gone (100% improvement).7,9 Patients in the last three PORIS categories (moderately improved, greatly improved, or no symptoms) were considered to be “responders” to treatment. Patients completed the ICSI at baseline and the PORIS and ICSI at 4, 8, 12, 16, 24, and 32 weeks. Adverse events were actively collected and recorded during each visit.
MATERIAL AND METHODS STUDY DESIGN Patients from 30 sites were randomized to 100, 200, or 300 mg three times daily PPS (Elmiron, Ortho-McNeil Pharmaceutical, Raritan, NJ) in a double-blind, double-dummy manner for 32 weeks. The Institutional Review Board or Research Ethics Board of each study center approved the protocol. Each subject signed a consent form. The study was conducted in accordance with the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, Good Clinical Practices, and the Declaration of Helsinki.
PARTICIPANTS The participants were adults with a diagnosis of IC as determined by either a history of IC symptoms (bladder pain, urinary urgency, frequency, and nocturia) for 6 months or longer or a positive cystoscopic examination (petechial hemorrhages, glomerulations, and/or Hunner’s ulcers) combined with bladder pain and urgency (no minimal duration specified). The cystoscopic examination and hydrodistension were conducted at least 6 weeks before enrollment. All patients had urinalysis findings with no evidence of urinary tract infection; medical history, physical examination, and clinical laboratory test results clinically acceptable to the investigator; and could understand, speak, and read English. Women were required to use contraception or be postmenopausal or surgically sterile. Patients were excluded if they would be using other therapies for IC; were pregnant or lactating; had hepatic disease or significantly abnormal liver function tests; were taking Coumadin, anticoagulants, heparin, tissue plasminogen activator (TPA), streptokinase, or high-dose aspirin (1 g or greater); had aneurysms, thrombocytopenia, hemophilia, gastrointestinal ulcerations, polyps, or diverticula; had a positive stool test for occult blood; had a known hypersensitivity to PPS, microcrystalline cellulose, magnesium stearate, or heparin; had surgery before, during, or within 4 weeks after the study; had a history of bacterial cystitis (within 3 months), neurogenic bladder, pelvic irradiation, chemical cystitis, or carcinoma in the lower abdominal region; had tuberculous cystitis, urinary schistosomiasis, bacterial prostatitis (within 3 months), bladder or ureteral calculi; had clinically significant vaginitis, or obstructive benign prostatic hyperplasia, urethral and/or bladder obstruction; had active genital herpes; had received PPS within 3 months or intravesicular therapy for IC within 30 days; were using Schedule II opioids; had any coexisting medical condition likely to interfere with study procedures; or had taken an investigational drug or device within 30 days. Patients could continue using antidepressants and antihistamines but could not start to use them during the trial. UROLOGY 65 (4), 2005
STATISTICAL ANALYSIS A sample size of 309 assessable patients (103 per group) was planned. This sample size provided 80% power to detect a difference of 1.0 in the mean total ICSI score at endpoint between the 300-mg treatment group and each of the higher dosage groups (based on a two-sample t test with a standard deviation of 2.5, a significance level of alpha ⫽ 0.05, and a 20% attrition rate). The intent-to-treat group included all patients who received at least one dose of medication. The last observation was carried forward to provide complete data at each point. The response to treatment was assessed in the population that completed the trial, as well as the intent-to-treat group. The safety analysis included all treated patients. All statistical tests were two sided and performed using a significance level of 5%. A one-way analysis of variance was used to analyze the baseline ICSI values by dose. A chi-square test for independence was used for the analysis of the proportion of responders (ICSI) by dose. A log-rank test and Wilcoxon test were used to evaluate the time to response according to the ICSI. Fisher’s exact test was used to evaluate the adverse events by dose.
RESULTS A total of 380 patients were enrolled, and 230 (60.5%) completed the 32-week study. Baseline demographics of the enrolled patients were comparable to the group of patients completing the trial. The baseline demographics among the three dosage groups (300, 600, and 900 mg PPS) were comparable (Table I). Nearly all patients had symptoms of IC for at least 6 months, although 27 patients entered the study because of positive cystoscopic findings combined with bladder pain and urgency that may have lasted less than 6 months. The mean duration since diagnosis with IC was 11 months, and approximately 70% of patients had received one or more medications for IC before enrollment. Overall, the responses to the three different dosages (300, 600, and 900 mg/day), as measured by the study endpoints, were not statistically different. Although the mean ICSI scores improved significantly (P ⬍0.001) from baseline (11.2, 11.9, and 11.9) to endpoint (8.2, 8.1, 8.6) for all dosages (300, 600, and 900 mg, respectively), the variabil655
TABLE I. Patient demographics at baseline Dosage (mg/day) Demographic
300
Patients (n) Sex (%) Female Male Age (yr) Mean Range Median time since diagnosis of IC (mo) Mean voids during waking hours (n) Mean voided volume (mL) Severity of symptoms (ICSI) (%) Severe (15–20) Moderate (7–14) Mild (0–6) Naive to medication for IC (%)
128
600 125
900 127
All Patients 380
Completers Only 230
90.6 9.4
88.0 12.0
91.3 8.7
90.0 10.0
88.7 11.3
45.0 19–84 9.5 12.9 127.3
43.5 19–80 8.5 13.4 139.9
44.2 19–81 14.0 13.4 126.0
44.2 17–84 11.0 13.2 130.9
44.9 19–84 11.0 12.0 134.2
26.6 68.5 4.8 36.4
39.2 58.4 2.4 33.6
37.8 59.8 2.4 20.4
34.6 62.2 3.2 30.1
36.0 60.5 3.5 27.0
KEY: IC ⫽ interstitial cystitis; ICSI ⫽ Interstitial Cystitis Symptom Index.
TABLE II. Percentage of patients with 50–100% improvement on PORIS Patients* (n) 300 mg/day 600 mg/day 900 mg/day
4 wk
8 wk
12 wk
16 wk
24 wk
32 wk
335 21.1 17.0 15.8
366 34.2 24.6 35.2
367 38.0 38.5 41.9
367 40.5 42.6 42.7
368 43.8 46.3 46.0
368 49.6 49.6 45.2
KEY: PORIS ⫽ Patient’s Overall Rating of Symptom Index. * Last observation carried forward.
ity by dose was not statistically significant. The time to a response was also not dose dependent. At each dose level, improvements in ICSI scores were seen at the earliest point (4 weeks), with steady improvements over time. When patients were categorized by the severity of their symptoms at baseline according to the ICSI, the responses in those with mild and moderate symptoms were not dose dependent. However, in patients with severe symptoms at baseline, a better response to the 600-mg dose was observed (P ⫽ 0.028). At baseline, 3.2% of all patients reported mild symptoms and 62.2% and 34.6% reported moderate and severe symptoms, respectively, as assessed by the ICSI. During the 32-week study, the percentage of patients receiving each dose who reported severe symptoms decreased steadily, and the percentage receiving each dose reporting mild symptoms increased steadily. This response was not statistically different among the three different dosages. At study end, 27.5% of all patients reported mild symptoms and 56.9% and 15.7% reported moderate and severe symptoms, respectively. The response according to the PORIS scores confirmed that the response to treatment was not dose dependent. The PORIS scores improved within 4 weeks with 15.8% to 21.1% of all patients desig656
nated responders (50% or more improvement). This percentage increased steadily over time. At 32 weeks, 49.6%, 49.6%, and 45.2% of all patients taking 300, 600, and 900 mg, respectively were responders (Table II). The variability in response by dose was not statistically significant. In the subset of 230 patients (60.5%) who completed the 32week trial, an increased responder rate was seen, but this was not dose dependent. Approximately 17% to 23% (depending on dose) of those who completed the study were classified as responders within 4 weeks, and this percentage steadily increased to 59% to 67% by study end. The ICSI correlated well with the PORIS. Patients with a 75% improvement on the PORIS had a 48% mean reduction (indicating improvement in symptoms) in the ICSI score, and patients reporting 100% improvement on the PORIS had a 77% mean reduction in the ICSI score.13 Most adverse events were mild and resolved without intervention or sequelae (Table III). The most common adverse events were diarrhea (25.3%), headache (18.2%), nausea (15.0%), pelvic pain (12.9%), and abdominal pain (12.6%). Alopecia occurred in 5.5% of patients and was typically mild; 3 patients (0.8%) discontinued treatment because of alopecia. Diarrhea, rectal bleedUROLOGY 65 (4), 2005
TABLE III. Drug-related adverse events occurring in more than 2% of patients 300 mg/day Body as a whole Abdominal pain Abdomen enlarged Asthenia Pelvic pain Digestive Diarrhea Dyspepsia Nausea Rectal bleeding Other Alopecia Dizziness Urinary frequency
600 mg/day
900 mg/day
P Value
6.9 1.0 5.0 4.0
9.4 2.8 3.8 0
13.2 2.6 1.8 4.4
NS NS NS NS
14.9 4.0 7.9 4.0
17.9 3.8 8.5 2.8
40.4 4.4 12.3 14.0
⬍0.001 NS NS 0.020
5.0 4.0 4.0
11.3 1.9 2.8
2.6 2.6 1.8
NS NS NS
KEY: NS ⫽ no statistically significant dose relation.
ing, and abdominal pain were dose related (for the first two it was a significant relationship, but for abdominal pain it was a trend only). Most cases of rectal bleeding were mild and consisted of blood in the stool. Other adverse events did not increase significantly with the dosage. No serious drug-related adverse events occurred. Of the 150 patients (39.5%) who discontinued treatment before the end of this 32-week study, 22.4% did so because of adverse effects (primarily diarrhea and abdominal pain), 4.5% did so because of a lack of efficacy, and 12.6% did so for other reasons (eg, noncompliance, protocol violation, lost to follow up, personal reasons). The overall rate of discontinuation was 39.1%, 31.2%, 42.5% in patients taking 300, 600, and 900 mg PPS respectively, and was relatively steady during the 32-week study and was not dose related. Adverse events were the reason for discontinuation of treatment in 18%, 16.8%, and 30.7% of patients taking 300, 600, and 900 mg PPS, respectively, and this was dose dependent (P ⬍0.05). Discontinuations owing to a lack of efficacy occurred in 7.0%, 4.0%, and 2.4% of patients taking 300, 600, and 900 mg PPS, respectively. COMMENT As with many diseases that involve chronic pain, IC is a difficult disease to study. The etiology and pathophysiology are not well understood.1,2,13 Therefore, the goal of treatment is to alleviate the symptoms rather than effect a change in an objective measure of the disease state. We used selfadministered instruments, the ICSI and PORIS, to assess the severity of IC and the response to treatment. The ICSI has been validated for internal consistency, construct validity, and test-retest reliability.12,13 This instrument assesses the patient’s perception of the change in urge, frequency, nocUROLOGY 65 (4), 2005
turia, and pain, the primary symptoms of IC. The PORIS assesses the patient’s perception of the changes in pain, urgency, and overall symptoms of IC.7 Within the range of dosages (300 to 900 mg/day) of PPS studied, no significant differences in the efficacy measurements among dosages was seen. The PORIS and ICSI instruments were administered periodically during the 32-week study to assess the time course of patient response to treatment. PPS seemed to demonstrate a relatively rapid onset of effect, with 16% to 21% of patients classified as responders at the earliest post-treatment point (4 weeks). The onset of effect was not affected by the dose or the severity of symptoms at baseline. The response to PPS in this trial at 12 weeks was similar to that reported in other 3-month trials.7–9 The patient response increased steadily during the remaining time points, with 59% to 67% of patients who completed the study classified as responders at the end of the 32-week study. We evaluated the standard dosage of PPS (300 mg) along with dosages that were two to three times greater (600 and 900 mg). The incidence of adverse events was in the expected range, and most were mild and resolved without intervention. Diarrhea, abdominal pain, and rectal bleeding were dose-related events and were typically mild. The mechanism of action of these adverse effects is unknown. Other adverse events were not dose related. Treatment was discontinued owing to adverse effects in 22.4% of patients, and this was dose related. The limitations of this study included the lack of a comparable placebo group, which would have allowed additional interpretation of the response to treatment, and that the trial became underpowered because of the completion rate of 60% (not wholly unexpected given the length of the trial, severity of 657
illness in most patients, and high doses of PPS). Furthermore, a large majority of patients in this study had moderate to severe symptoms. A better understanding of the treatment effect of PPS may be gained by studying patients at an early stage of the disease. CONCLUSIONS For all three dosages of PPS, a clinically relevant patient response rate was seen. Within the range of dosages studied, no significant differences in the efficacy measurements among the dosages were seen. Dose escalation did not appear to improve the response to treatment. The response appeared to be associated with the duration of therapy rather than the dosage. REFERENCES 1. Nickel JC: Interstitial cystitis: etiology, diagnosis, and treatment. Can Fam Physician 46: 2430 –2440, 2000. 2. Rosamilia A, and Dwyera PL: Pathophysiology of interstitial cystitis. Curr Opin Obstet Gynecol 12: 405– 410, 2000. 3. Propert KJ, Schaeffer AJ, Brensinger CM, et al, for the Interstitial Cystitis Data Base Study Group: A prospective study of interstitial cystitis: results of longitudinal followup of the interstitial cystitis data base cohort. J Urol 163: 1434 – 1439, 2000. 4. Curhan GC, Speizer FE, Hunter DJ, et al: Epidemiology of interstitial cystitis: a population based study. J Urol 161: 549 –552, 1999.
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5. Michael YL, Kawachi I, Stampfer MJ, et al: Quality of life among women with interstitial cystitis. J Urol 164: 423– 427, 2000. 6. Rovner E, Propert KJ, Brensinger C, et al: Treatments used in women with interstitial cystitis: the Interstitial Cystitis Database (ICDB) study experience. Urology 56: 940 –945, 2000. 7. Parsons CL, Benson G, Childs SJ, et al: A quantitatively controlled method to study prospectively interstitial cystitis and demonstrate the efficacy of pentosan polysulfate. J Urol 150: 845– 848, 1993. 8. Mulholland SG, Hanno P, Parsons CL, et al: Pentosan polysulfate sodium for therapy of interstitial cystitis: a double-blind placebo-controlled clinical study. Urology 35: 552–558, 1990. 9. Parsons CL, and Mulholland SG: Successful therapy of interstitial cystitis with pentosanpolysulfate. J Urol 138: 513– 516, 1987. 10. Holm-Bentzen M, Jacobsen F, Nerstrom B, et al: A prospective double-blind clinically controlled multicenter trial of sodium pentosanpolysulfate in the treatment of interstitial cystitis and related painful bladder disease. J Urol 138: 503– 507, 1987. 11. Sant GR, Propert KJ, Hanno PM, et al: A pilot clinical trial of oral pentosan polysulfate and oral hydroxyzine in patients with interstitial cystitis. J Urol 170: 810 – 815, 2003. 12. O’Leary MP, Sant GR, Fowler FJ Jr, et al: The Interstitial Cystitis Symptom Index and Problem Index. Urology 49(suppl 5A): 58 – 63, 1997. 13. Lubeck DP, Whitmore K, Sant GR, et al: Psychometric validation of the O’Leary-Sant Interstitial Cystitis Symptom Index in a clinical trial of pentosan polysulfate sodium. Urology 57(6 suppl 1): 62– 66, 2001.
UROLOGY 65 (4), 2005
RANDOMIZED, DOUBLE-BLIND, DOSE-RANGING STUDY OF PENTOSAN POLYSULFATE SODIUM FOR INTERSTITIAL CYSTITIS J. CURTIS NICKEL, JACK BARKIN, JOHN FORREST, PHILLIP G. MOSBAUGH, J. HERNANDEZ-GRAULAU, DAVID KAUFMAN, KEITH LLOYD, ROBERT J. EVANS, C. LOWELL PARSONS, AND LINDA E. ATKINSON, ON BEHALF OF THE ELMIRON STUDY GROUP
ABSTRACT Objectives. To compare the current recommended dose of pentosan polysulfate sodium (PPS) with doses two to three times higher. Methods. We evaluated three dosages (300, 600, and 900 mg) of PPS in a randomized, double-blind, double-dummy, parallel-group, multicenter, 32-week study. Adults (n ⫽ 380) with a diagnosis of interstitial cystitis (IC) as determined by a positive cystoscopic examination combined with bladder pain and urgency or a history of IC symptoms for at least 6 months were enrolled. Participants completed the Patient’s Overall Rating of Symptom Index (PORIS) and the O’Leary-Sant Interstitial Cystitis Symptom Index (ICSI) at baseline (ICSI only) and during follow-up visits at 4, 8, 12, 16, 24, and 32 weeks. Results. Mean ICSI scores improved significantly during the 32 weeks for all dosages (baseline 11.2, 11.9, and 11.9 to endpoint 8.2, 8.1, 8.6 for 300, 600, and 900 mg, respectively; P ⬍0.001) but the response to treatment was not dose dependent (no statistically significant difference in response among the three dosages). At baseline, 3.2%, 62.2%, and 34.6% reported mild, moderate, and severe symptoms, respectively, as assessed by the ICSI. At study end, 27.5%, 56.9%, and 15.7% reported mild, moderate, and severe symptoms, respectively. The PORIS scores improved within 4 weeks with 15.8% to 21.1% of all patients classified as responders (50% or greater improvement on PORIS). At 32 weeks, 49.6%, 49.6%, and 45.2% of all patients were responders at a dose of 300, 600, and 900 mg, respectively. Most adverse events were mild and resolved without intervention. Conclusions. For all three dosages of PPS, a clinically significant but similar response was demonstrated. The duration of therapy appears to be more important than the dosage. UROLOGY 65: 654–658, 2005. © 2005 Elsevier Inc.
I
nterstitial cystitis (IC) is a disease manifested by urinary urgency, frequency, and/or pain that occurs in one or more locations throughout the pelvis.1–3 The disease occurs primarily in women and is estimated to affect 0.01% to 0.5% of women.1,4 IC can be severe enough to have a devastating impact on a person’s quality of life,5 but it can also be
associated with moderate symptoms whose effect is less debilitating. Many treatments are available for IC, but it is generally accepted that the results are disappointing, and few have been subjected to rigorous clinical evaluation.6 The oral heparinoid, pentosan polysulfate sodium (PPS), is indicated for the treat-
This study was funded by Ortho-McNeil/ALZA. J. C. Nickel, R. J. Evans, and J. Forrest are paid consultants to, and study investigators funded by, Ortho-McNeil. J. Barkin, P. Mosbaugh, J. Hernandez-Graulau, D. Kaufman, and K. Lloyd are study investigators funded by Ortho-McNeil. C. L. Parsons is a paid consultant to, study investigator funded by, and original patent inventor for the mentioned product. L. E. Atkinson is an employee of ALZA. From Queens University, Kingston, Ontario, Canada; Humber River Regional Hospital, Toronto, Ontario, Canada; Urologic Specialists of Oklahoma, Inc., Tulsa, Oklahoma; Urology of Indiana,
Indianapolis, Indiana; University of Illinois School of Medicine, Peoria, Illinois; Central Park Urology, New York, New York; University of Alabama, Birmingham, Alabama; The Urology Clinic, Greensboro, North Carolina; University of California, San Diego, Medical Center, San Diego, California; and ALZA Corporation, Mountain View, California Reprint requests: J. Curtis Nickel, M.D., Department of Urology, Queen’s University Kingston General Hospital, Victory 4, Kingston, ON K7L 2V7, Canada. E-mail: [email protected] Submitted: July 13, 2004, accepted (with revisions): October 28, 2004
© 2005 ELSEVIER INC. 654
ALL RIGHTS RESERVED
0090-4295/05/$30.00 doi:10.1016/j.urology.2004.10.071
ment of bladder pain or discomfort associated with IC. PPS has been evaluated for the treatment of IC in five randomized, multicenter, double-blind, placebo-controlled studies,7–11 four of which showed greater improvement with PPS than with placebo (P ⫽ 0.03, P ⫽ 0.01, P ⫽ 0.02, and P ⫽ 0.06).7–9,11 The onset of effect and dose-response effect for PPS has never been studied. We designed a study to compare the current recommended dose of PPS with doses two to three times higher. We evaluated three dosages (300, 600, and 900 mg) of PPS in a randomized, double-blind, parallel-group, multicenter, 32-week study.
ENDPOINTS The primary endpoint was the O’Leary-Sant Interstitial Cystitis Symptom Index (ICSI), a four-item questionnaire validated as an outcome parameter in IC.12,13 Scores were tallied for a single summary score indicating mild (0 to 6), moderate (7 to 14), and severe (15 to 20) symptoms. The secondary endpoint was the Patient’s Overall Rating of Symptoms Index (PORIS), which has three questions that address the overall change in IC, pain, and urgency after treatment as worse, no better (0% improvement), slightly improved (25%), moderately improved (50%), greatly improved (75%), or symptoms gone (100% improvement).7,9 Patients in the last three PORIS categories (moderately improved, greatly improved, or no symptoms) were considered to be “responders” to treatment. Patients completed the ICSI at baseline and the PORIS and ICSI at 4, 8, 12, 16, 24, and 32 weeks. Adverse events were actively collected and recorded during each visit.
MATERIAL AND METHODS STUDY DESIGN Patients from 30 sites were randomized to 100, 200, or 300 mg three times daily PPS (Elmiron, Ortho-McNeil Pharmaceutical, Raritan, NJ) in a double-blind, double-dummy manner for 32 weeks. The Institutional Review Board or Research Ethics Board of each study center approved the protocol. Each subject signed a consent form. The study was conducted in accordance with the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, Good Clinical Practices, and the Declaration of Helsinki.
PARTICIPANTS The participants were adults with a diagnosis of IC as determined by either a history of IC symptoms (bladder pain, urinary urgency, frequency, and nocturia) for 6 months or longer or a positive cystoscopic examination (petechial hemorrhages, glomerulations, and/or Hunner’s ulcers) combined with bladder pain and urgency (no minimal duration specified). The cystoscopic examination and hydrodistension were conducted at least 6 weeks before enrollment. All patients had urinalysis findings with no evidence of urinary tract infection; medical history, physical examination, and clinical laboratory test results clinically acceptable to the investigator; and could understand, speak, and read English. Women were required to use contraception or be postmenopausal or surgically sterile. Patients were excluded if they would be using other therapies for IC; were pregnant or lactating; had hepatic disease or significantly abnormal liver function tests; were taking Coumadin, anticoagulants, heparin, tissue plasminogen activator (TPA), streptokinase, or high-dose aspirin (1 g or greater); had aneurysms, thrombocytopenia, hemophilia, gastrointestinal ulcerations, polyps, or diverticula; had a positive stool test for occult blood; had a known hypersensitivity to PPS, microcrystalline cellulose, magnesium stearate, or heparin; had surgery before, during, or within 4 weeks after the study; had a history of bacterial cystitis (within 3 months), neurogenic bladder, pelvic irradiation, chemical cystitis, or carcinoma in the lower abdominal region; had tuberculous cystitis, urinary schistosomiasis, bacterial prostatitis (within 3 months), bladder or ureteral calculi; had clinically significant vaginitis, or obstructive benign prostatic hyperplasia, urethral and/or bladder obstruction; had active genital herpes; had received PPS within 3 months or intravesicular therapy for IC within 30 days; were using Schedule II opioids; had any coexisting medical condition likely to interfere with study procedures; or had taken an investigational drug or device within 30 days. Patients could continue using antidepressants and antihistamines but could not start to use them during the trial. UROLOGY 65 (4), 2005
STATISTICAL ANALYSIS A sample size of 309 assessable patients (103 per group) was planned. This sample size provided 80% power to detect a difference of 1.0 in the mean total ICSI score at endpoint between the 300-mg treatment group and each of the higher dosage groups (based on a two-sample t test with a standard deviation of 2.5, a significance level of alpha ⫽ 0.05, and a 20% attrition rate). The intent-to-treat group included all patients who received at least one dose of medication. The last observation was carried forward to provide complete data at each point. The response to treatment was assessed in the population that completed the trial, as well as the intent-to-treat group. The safety analysis included all treated patients. All statistical tests were two sided and performed using a significance level of 5%. A one-way analysis of variance was used to analyze the baseline ICSI values by dose. A chi-square test for independence was used for the analysis of the proportion of responders (ICSI) by dose. A log-rank test and Wilcoxon test were used to evaluate the time to response according to the ICSI. Fisher’s exact test was used to evaluate the adverse events by dose.
RESULTS A total of 380 patients were enrolled, and 230 (60.5%) completed the 32-week study. Baseline demographics of the enrolled patients were comparable to the group of patients completing the trial. The baseline demographics among the three dosage groups (300, 600, and 900 mg PPS) were comparable (Table I). Nearly all patients had symptoms of IC for at least 6 months, although 27 patients entered the study because of positive cystoscopic findings combined with bladder pain and urgency that may have lasted less than 6 months. The mean duration since diagnosis with IC was 11 months, and approximately 70% of patients had received one or more medications for IC before enrollment. Overall, the responses to the three different dosages (300, 600, and 900 mg/day), as measured by the study endpoints, were not statistically different. Although the mean ICSI scores improved significantly (P ⬍0.001) from baseline (11.2, 11.9, and 11.9) to endpoint (8.2, 8.1, 8.6) for all dosages (300, 600, and 900 mg, respectively), the variabil655
TABLE I. Patient demographics at baseline Dosage (mg/day) Demographic
300
Patients (n) Sex (%) Female Male Age (yr) Mean Range Median time since diagnosis of IC (mo) Mean voids during waking hours (n) Mean voided volume (mL) Severity of symptoms (ICSI) (%) Severe (15–20) Moderate (7–14) Mild (0–6) Naive to medication for IC (%)
128
600 125
900 127
All Patients 380
Completers Only 230
90.6 9.4
88.0 12.0
91.3 8.7
90.0 10.0
88.7 11.3
45.0 19–84 9.5 12.9 127.3
43.5 19–80 8.5 13.4 139.9
44.2 19–81 14.0 13.4 126.0
44.2 17–84 11.0 13.2 130.9
44.9 19–84 11.0 12.0 134.2
26.6 68.5 4.8 36.4
39.2 58.4 2.4 33.6
37.8 59.8 2.4 20.4
34.6 62.2 3.2 30.1
36.0 60.5 3.5 27.0
KEY: IC ⫽ interstitial cystitis; ICSI ⫽ Interstitial Cystitis Symptom Index.
TABLE II. Percentage of patients with 50–100% improvement on PORIS Patients* (n) 300 mg/day 600 mg/day 900 mg/day
4 wk
8 wk
12 wk
16 wk
24 wk
32 wk
335 21.1 17.0 15.8
366 34.2 24.6 35.2
367 38.0 38.5 41.9
367 40.5 42.6 42.7
368 43.8 46.3 46.0
368 49.6 49.6 45.2
KEY: PORIS ⫽ Patient’s Overall Rating of Symptom Index. * Last observation carried forward.
ity by dose was not statistically significant. The time to a response was also not dose dependent. At each dose level, improvements in ICSI scores were seen at the earliest point (4 weeks), with steady improvements over time. When patients were categorized by the severity of their symptoms at baseline according to the ICSI, the responses in those with mild and moderate symptoms were not dose dependent. However, in patients with severe symptoms at baseline, a better response to the 600-mg dose was observed (P ⫽ 0.028). At baseline, 3.2% of all patients reported mild symptoms and 62.2% and 34.6% reported moderate and severe symptoms, respectively, as assessed by the ICSI. During the 32-week study, the percentage of patients receiving each dose who reported severe symptoms decreased steadily, and the percentage receiving each dose reporting mild symptoms increased steadily. This response was not statistically different among the three different dosages. At study end, 27.5% of all patients reported mild symptoms and 56.9% and 15.7% reported moderate and severe symptoms, respectively. The response according to the PORIS scores confirmed that the response to treatment was not dose dependent. The PORIS scores improved within 4 weeks with 15.8% to 21.1% of all patients desig656
nated responders (50% or more improvement). This percentage increased steadily over time. At 32 weeks, 49.6%, 49.6%, and 45.2% of all patients taking 300, 600, and 900 mg, respectively were responders (Table II). The variability in response by dose was not statistically significant. In the subset of 230 patients (60.5%) who completed the 32week trial, an increased responder rate was seen, but this was not dose dependent. Approximately 17% to 23% (depending on dose) of those who completed the study were classified as responders within 4 weeks, and this percentage steadily increased to 59% to 67% by study end. The ICSI correlated well with the PORIS. Patients with a 75% improvement on the PORIS had a 48% mean reduction (indicating improvement in symptoms) in the ICSI score, and patients reporting 100% improvement on the PORIS had a 77% mean reduction in the ICSI score.13 Most adverse events were mild and resolved without intervention or sequelae (Table III). The most common adverse events were diarrhea (25.3%), headache (18.2%), nausea (15.0%), pelvic pain (12.9%), and abdominal pain (12.6%). Alopecia occurred in 5.5% of patients and was typically mild; 3 patients (0.8%) discontinued treatment because of alopecia. Diarrhea, rectal bleedUROLOGY 65 (4), 2005
TABLE III. Drug-related adverse events occurring in more than 2% of patients 300 mg/day Body as a whole Abdominal pain Abdomen enlarged Asthenia Pelvic pain Digestive Diarrhea Dyspepsia Nausea Rectal bleeding Other Alopecia Dizziness Urinary frequency
600 mg/day
900 mg/day
P Value
6.9 1.0 5.0 4.0
9.4 2.8 3.8 0
13.2 2.6 1.8 4.4
NS NS NS NS
14.9 4.0 7.9 4.0
17.9 3.8 8.5 2.8
40.4 4.4 12.3 14.0
⬍0.001 NS NS 0.020
5.0 4.0 4.0
11.3 1.9 2.8
2.6 2.6 1.8
NS NS NS
KEY: NS ⫽ no statistically significant dose relation.
ing, and abdominal pain were dose related (for the first two it was a significant relationship, but for abdominal pain it was a trend only). Most cases of rectal bleeding were mild and consisted of blood in the stool. Other adverse events did not increase significantly with the dosage. No serious drug-related adverse events occurred. Of the 150 patients (39.5%) who discontinued treatment before the end of this 32-week study, 22.4% did so because of adverse effects (primarily diarrhea and abdominal pain), 4.5% did so because of a lack of efficacy, and 12.6% did so for other reasons (eg, noncompliance, protocol violation, lost to follow up, personal reasons). The overall rate of discontinuation was 39.1%, 31.2%, 42.5% in patients taking 300, 600, and 900 mg PPS respectively, and was relatively steady during the 32-week study and was not dose related. Adverse events were the reason for discontinuation of treatment in 18%, 16.8%, and 30.7% of patients taking 300, 600, and 900 mg PPS, respectively, and this was dose dependent (P ⬍0.05). Discontinuations owing to a lack of efficacy occurred in 7.0%, 4.0%, and 2.4% of patients taking 300, 600, and 900 mg PPS, respectively. COMMENT As with many diseases that involve chronic pain, IC is a difficult disease to study. The etiology and pathophysiology are not well understood.1,2,13 Therefore, the goal of treatment is to alleviate the symptoms rather than effect a change in an objective measure of the disease state. We used selfadministered instruments, the ICSI and PORIS, to assess the severity of IC and the response to treatment. The ICSI has been validated for internal consistency, construct validity, and test-retest reliability.12,13 This instrument assesses the patient’s perception of the change in urge, frequency, nocUROLOGY 65 (4), 2005
turia, and pain, the primary symptoms of IC. The PORIS assesses the patient’s perception of the changes in pain, urgency, and overall symptoms of IC.7 Within the range of dosages (300 to 900 mg/day) of PPS studied, no significant differences in the efficacy measurements among dosages was seen. The PORIS and ICSI instruments were administered periodically during the 32-week study to assess the time course of patient response to treatment. PPS seemed to demonstrate a relatively rapid onset of effect, with 16% to 21% of patients classified as responders at the earliest post-treatment point (4 weeks). The onset of effect was not affected by the dose or the severity of symptoms at baseline. The response to PPS in this trial at 12 weeks was similar to that reported in other 3-month trials.7–9 The patient response increased steadily during the remaining time points, with 59% to 67% of patients who completed the study classified as responders at the end of the 32-week study. We evaluated the standard dosage of PPS (300 mg) along with dosages that were two to three times greater (600 and 900 mg). The incidence of adverse events was in the expected range, and most were mild and resolved without intervention. Diarrhea, abdominal pain, and rectal bleeding were dose-related events and were typically mild. The mechanism of action of these adverse effects is unknown. Other adverse events were not dose related. Treatment was discontinued owing to adverse effects in 22.4% of patients, and this was dose related. The limitations of this study included the lack of a comparable placebo group, which would have allowed additional interpretation of the response to treatment, and that the trial became underpowered because of the completion rate of 60% (not wholly unexpected given the length of the trial, severity of 657
illness in most patients, and high doses of PPS). Furthermore, a large majority of patients in this study had moderate to severe symptoms. A better understanding of the treatment effect of PPS may be gained by studying patients at an early stage of the disease. CONCLUSIONS For all three dosages of PPS, a clinically relevant patient response rate was seen. Within the range of dosages studied, no significant differences in the efficacy measurements among the dosages were seen. Dose escalation did not appear to improve the response to treatment. The response appeared to be associated with the duration of therapy rather than the dosage. REFERENCES 1. Nickel JC: Interstitial cystitis: etiology, diagnosis, and treatment. Can Fam Physician 46: 2430 –2440, 2000. 2. Rosamilia A, and Dwyera PL: Pathophysiology of interstitial cystitis. Curr Opin Obstet Gynecol 12: 405– 410, 2000. 3. Propert KJ, Schaeffer AJ, Brensinger CM, et al, for the Interstitial Cystitis Data Base Study Group: A prospective study of interstitial cystitis: results of longitudinal followup of the interstitial cystitis data base cohort. J Urol 163: 1434 – 1439, 2000. 4. Curhan GC, Speizer FE, Hunter DJ, et al: Epidemiology of interstitial cystitis: a population based study. J Urol 161: 549 –552, 1999.
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5. Michael YL, Kawachi I, Stampfer MJ, et al: Quality of life among women with interstitial cystitis. J Urol 164: 423– 427, 2000. 6. Rovner E, Propert KJ, Brensinger C, et al: Treatments used in women with interstitial cystitis: the Interstitial Cystitis Database (ICDB) study experience. Urology 56: 940 –945, 2000. 7. Parsons CL, Benson G, Childs SJ, et al: A quantitatively controlled method to study prospectively interstitial cystitis and demonstrate the efficacy of pentosan polysulfate. J Urol 150: 845– 848, 1993. 8. Mulholland SG, Hanno P, Parsons CL, et al: Pentosan polysulfate sodium for therapy of interstitial cystitis: a double-blind placebo-controlled clinical study. Urology 35: 552–558, 1990. 9. Parsons CL, and Mulholland SG: Successful therapy of interstitial cystitis with pentosanpolysulfate. J Urol 138: 513– 516, 1987. 10. Holm-Bentzen M, Jacobsen F, Nerstrom B, et al: A prospective double-blind clinically controlled multicenter trial of sodium pentosanpolysulfate in the treatment of interstitial cystitis and related painful bladder disease. J Urol 138: 503– 507, 1987. 11. Sant GR, Propert KJ, Hanno PM, et al: A pilot clinical trial of oral pentosan polysulfate and oral hydroxyzine in patients with interstitial cystitis. J Urol 170: 810 – 815, 2003. 12. O’Leary MP, Sant GR, Fowler FJ Jr, et al: The Interstitial Cystitis Symptom Index and Problem Index. Urology 49(suppl 5A): 58 – 63, 1997. 13. Lubeck DP, Whitmore K, Sant GR, et al: Psychometric validation of the O’Leary-Sant Interstitial Cystitis Symptom Index in a clinical trial of pentosan polysulfate sodium. Urology 57(6 suppl 1): 62– 66, 2001.
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