Forensic Dissection of a Clinical Trial: Lessons Learned in Understanding and Managing Interstitial Cystitis

Management Update

4. RIU0445_07-31.qxd 8/4/10 4:13 PM Page e78 MANAGEMENT UPDATE Forensic Dissection of a Clinical Trial: Lessons Learned in Understanding and Managing Interstitial Cystitis J. Curtis Nickel, MD, FRCSC Department of Urology, Queen’s University, Kingston, Ontario, Canada A pharmaceutical company—sponsored post-registration clinical trial designed to determine the most effective dose of pentosan polysulfate for the treatment of interstitial cystitis (IC) reported negative results. However, because of a priori trial design features, important posthoc analyses were able to answer many of the important clinical issues on the epidemiology, diagnosis, and treatment of IC that to date had remained unanswered. Seven published follow-up reports based on data and outcomes from the original study evaluated the clinical significance of a positive Potassium Sensitivity Test, confirmed the O’Leary-Sant Interstitial Cystitis Symptom Index as a valid and sensitive outcome measure, and determined that doses of pentosan polysulfate higher than the standard US Food and Drug Administration—approved dose of 300 mg/d did not increase efficacy although increased duration of therapy increases the chance of symptom amelioration. Further analyses determined that sexual dysfunction is an important parameter to assess in IC and that successful therapy can improve sexual functioning. Finally, the data showed that symptom severity, quality of life (QoL), and sleep function are interrelated. Consequently, symptom improvement with therapy correlates with improvement in both sleep function and QoL. This post hoc forensic dissection of a clinical trial initially undertaken for simple regulatory reasons has significantly improved our understanding and management of the enigmatic condition we call IC. [Rev Urol. 2010;12(2/3):e78-e85 doi: 10.3909/riu0445] © 2010 MedReviews®, LLC Key words: Interstitial cystitis • Pentosan polysulfate sodium • Potassium sensitivity test hat possible value can a US Food and Drug Administration (FDA)— mandated post-registration clinical trial in interstitial cystitis (IC) have to offer the clinician attempting to understand and manage this enigmatic urologic condition? Despite being a very prevalent, urologic, chronic, pelvic pain syndrome1 that severely impacts patients’ lives,2 only one medical oral therapy, pentosan polysulfate sodium (PPS), is FDA approved for the treatment of this W e78 VOL. 12 NO. 2/3 2010 REVIEWS IN UROLOGY 4. RIU0445_07-31.qxd 8/4/10 4:13 PM Page e79 Managing Interstitial Cystitis condition. The clinical trials that substantiated the treatment claim showed modest improvement with the drug at a dose of 100 mg/d compared with placebo3,4; however, subsequent clinical trials have disputed this efficacy.5,6 One issue raised by both the FDA and practicing clinicians was the choice of dose used in these clinical trials—doses selected on theory rather than pharmacokinetic or clinical data. A randomized, double-blind, doseranging study of PPS for IC was undertaken to answer this question. The study was completed and submitted for publication, but was initially rejected because it was essentially a pharmaceutical company trial with no placebo cohort that yielded negative results with regard to the primary objective. It is hard to believe that only several years ago we as a profession did not realize the importance of publishing negative trial results. Furthermore, the trial was originally designed by a panel of IC “experts,” who were able to include a number of other study parameters into the trial design that eventually allowed for peer-reviewed publication of not only the primary trial but also 7 ancillary post hoc studies that furthered our understanding of IC and its management. This review retrospectively dissects this single clinical trial (which henceforth will be referred to as “The Study”), whose primary objective was to satisfy a regulatory mandate, but which eventually provided more information and data regarding the epidemiology, diagnosis, and treated “natural” history of IC than, to our knowledge, any other published clinical trial on IC to date. The Study The onset of effect and dose-response effect for PPS has never been determined. We designed a study to compare the current recommended dose of PPS with doses 2 to 3 times higher.7 Three hundred and eighty patients from 30 sites were randomized to PPS 100 mg (standard dose), 200 mg, or 300 mg 3 times daily (Elmiron®; Ortho-McNeil-Janssen Pharmaceuticals, Inc., Raritan, NJ) in a double-blind, parallel-group, doubledummy manner for 32 weeks. Study participants were adults with a diagnosis of IC based on a history of IC symptoms (bladder pain, urinary urgency, frequency, and nocturia) for  6 months, or a positive cystoscopic examination (glomerulations and/or Hunner’s ulcers) in addition to bladder pain and urgency of any duration. Subjects on stable medical therapy for IC (eg, analgesics, antidepressants, and antihistamines) were allowed to continue these at their usual doses throughout the study period. However, subjects could not start any antidepressant or antihistamine medications during the trial. The inclusion and exclusion criteria have been previously published.7 The primary endpoint was the O’Leary-Sant Interstitial Cystitis Symptom Index (ICSI), a 4-item questionnaire that has been validated as a reliable symptom questionnaire for IC.8 Scores were tallied for a single summary score indicating mild (0-6), moderate (7-14), and severe (15-20) ment), slightly improved (25%), moderately improved (50%), greatly improved (75%), or symptoms gone (100% improvement). Patients in the last 3 PORIS categories (moderately improved, greatly improved, or symptoms gone) 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. Other outcomes designed into this trial are documented in Table 1. Adverse events were actively collected and recorded during each visit. Primary Objective of The Study The primary objective was to compare the efficacy and safety of the 3 doses of PPS used in the treatment of IC. For all 3 PPS dosages, a clinically significant but similar response was demonstrated (Figure 1). 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  .001 for all doses), but the response to treatment was not dose dependent (no statistically significant difference in response among the 3 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% The duration of therapy appeared to be more important than the dosage. The PORIS scores improved within 4 weeks with 15.8% to 21.1% of all patients classified as responders ( 50% improvement on PORIS) with an increase in responders at each assessment. symptoms. A secondary endpoint was the Patient’s Overall Rating of Symptoms Index (PORIS), an overall scoring system similar to the more familiar Global Response Assessment (GRA). The PORIS had 3 questions that addressed the overall change in IC, pain, and urgency after treatment as worse, no better (0% improve- reported mild, moderate, and severe symptoms, respectively. The duration of therapy appeared to be more important than the dosage. The PORIS scores improved within 4 weeks with 15.8% to 21.1% of all patients classified as responders ( 50% improvement on PORIS) with an increase in responders at each VOL. 12 NO. 2/3 2010 REVIEWS IN UROLOGY e79 4. RIU0445_07-31.qxd 8/4/10 4:13 PM Page e80 Managing Interstitial Cystitis continued Table 1 Outcomes Measured in The Study Measure Outcome Items Scoring ICSI IC-specific symptoms 4 0-20 Higher scores  more severe symptoms;  30% decrease indicates responder PORIS Subjective global assessment 6 Responders  moderately improved, greatly improved, or no symptoms Patient Satisfaction Questionnaire Patient satisfaction 4 No validated scoring; only descriptive SF-12 MSC Mental QoL 6/12 0-100 Higher scores indicating better QoL SF-12 PSC Physical QoL 6/12 0-100 Higher scores indicating better QoL SexFn Sexual functioning 4 0-100 Higher scores indicating better functioning Sleep Scale Sleep functioning 6 0-100 Higher scores indicating better functioning IC, interstitial cystitis; ICSI, O’Leary-Sant Interstitial Cystitis Symptom Index; PORIS, Patient’s Overall Rating of Symptoms Index; QoL, quality of life; SF-12 MSC, Medical Outcomes Study Short Form Mental Symptoms Component; SF-12 PSC, Medical Outcomes Study Short Form Physical Symptoms Component; SexFn, Medical Outcomes Study Sexual Functioning Scale; Sleep Scale, Medical Outcomes Short Form Sleep Index. assessment. 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 (Figure 1). Most adverse events were mild and resolved without intervention; however, there was a significant dose response with respect to adverse events (eg, higher doses were associated with more adverse events). For the primary objective, we learned that, for all 3 dosages of PPS, a similar response was demonstrated. Although believed to be a clinically significant response, there was no placebo group in this study for confirmation. Diagnostic Considerations The difficulty in diagnosing IC in clinical practice has encouraged a search for objective biomarkers of the condition. The potassium sensitivity test (PST), which has been described elsewhere,9 was developed e80 VOL. 12 NO. 2/3 2010 as a possible diagnostic test for IC based on an epithelial dysfunction model of pathogenesis. It was believed that PPS worked by replacing or aiding in the recovery of the individual’s dysfunctional bladder mucus, thereby reducing epithelial permeability. The Study provided an opportunity to administer the PST to a large population of diagnosed patients with IC and thus test its validity as a diagnostic tool.10 In addition, by administering a second PST after the 32-week treatment period and taking an assessment of clinical improvement, we could determine whether successful therapy was associated with an improvement in PST results. A PST was considered negative if neither the water solution nor the potassium solution instilled into the bladder was associated with any urgency or pain. A positive PST was one in which both the analog scales (a 2-point increase for pain or REVIEWS IN UROLOGY urgency) and a questionnaire indicated that the potassium solution was more provocative of symptoms than the water solution. At study entry, 80% of the diagnosed patients with IC were potassium sensitive. Of the patients who responded to PPS therapy, 74.1% showed significant improvement in PST results. Only 39.7% of nonresponders showed improved PST results at study exit. There is considerable disagreement concerning the hypothesis of epithelial dysfunction in IC. Although this analysis was provocative, it did not prove the hypothesis. Similarly, because the greater majority of patients were PST positive, the predictive value in terms of favorable response to heparinoid therapy remains unknown. In this study, we were not able to demonstrate that positive PST predicted therapy outcome; both potassium-positive and potassium-negative groups had 4. RIU0445_07-31.qxd 8/4/10 4:13 PM Page e81 Managing Interstitial Cystitis 14 PPS Mean Score 13 900 mg/d 600 mg/d 300 mg/d 12 11 10 9 8 0 4 8 12 A 16 24 32 Weeks Percentage of Patients 80 PPS (300 mg/d) Trend PPS (300 mg/d) 70 60 50 40 30 20 10 0 4 8 12 B 16 24 32 Weeks Figure 1. (A) O’Leary-Sant Interstitial Cystitis Symptom Index mean scores for all patients randomized to 3 doses of pentosan polysulfate sodium (PPS) for 32 weeks. (B) Percentage of patients receiving 300 mg/d PPS (FDAapproved dose) who reported an improvement in Patient’s Overall Rating of Symptoms Index over 32 weeks of the trial. similar results from therapy. PST may be useful as a diagnostic tool for clinicians who are unsure of the etiology of an individual patient’s urgency, frequency, or pelvic pain. In appropriate clinical situations, a significant response to an intravesical potassium challenge, versus a water challenge, may further suggest the presence of IC. Validation of Outcomes O’Leary-Sant ICSI Validation The O’Leary-Sant ICSI was proposed in 1997 as a uniform outcome measure in IC.8 Although the ICSI had been tested and validated both with a community population and a conve- nience sample of patients with IC,8 it had not yet been validated in any prospective treatment studies. A total of 376 patients enrolled in The Study were included in the analysis.11 In addition to the ICSI and PORIS, Medical Outcome Study (MOS) short form (SF12) mental component summary (MCS) and physical component summary (PCS) quality of life (QoL) assessments (©Medical Outcomes Trust, Hanover, NH) were completed. Results obtained from The Study were used to measure internal consistency, reliability (homogeneity of items in a scale, and the extent to which the scale is free of random error described as the Cronbach coefficient ), construct validity (correlations between scale scores based on known relations such as the SF-12 MCS and PCS), and responsiveness (ability to detect improvement or deterioration that results from therapy or disease progression). In the analysis, the ICSI individual items and score had good variability. Test-retest reliability over a 4-week period was good, and the scale had good internal consistency reliability (Cronbach coefficient , 0.72). Evaluation of the construct validity demonstrated that the individual ICSI items—SF-12 PCS and SF-12 pain question—correlated highly with the ICSI score. It was important to confirm that the ICSI was responsive to clinical improvement so that we could then use it as an outcome in clinical trials. Responsiveness to change was evaluated using a global, patient-generated measure (PORIS). Patients who indicated an improvement in symptoms had a Guyatt statistic of 1.64, which indicated that the instrument was responsive to change. Correspondingly, patients who indicated no change in symptoms had a Guyatt statistic of 0.45, which is within the expected range for a stable population. For every 1-point improvement in the PORIS score, an average improvement of 1.97 was observed in the ICSI score, indicating that the ICSI is associated with clinically meaningful change. This analysis confirmed that the ICSI was a valid, reliable, and responsive measure of IC symptom impact. Responder Analysis A number of post hoc analyses based on The Study required a definition of a responder based on the ICSI. For this post hoc analysis, we used 2 methods to determine the definition of a responder. The first method used the correlation between the PORIS VOL. 12 NO. 2/3 2010 REVIEWS IN UROLOGY e81 4. RIU0445_07-31.qxd 8/4/10 4:13 PM Page e82 Managing Interstitial Cystitis continued and the percentage change in total ICSI score from baseline to the endpoint of The Study. The second method examined various cutoffs of the percentage change of the ICSI for consistent classification with the PORIS. The cutoff point for a responder (first method) on the PORIS (“moderately improved” or 50% improvement) was shown to correspond to a mean change (reduction) of 29.5% in the ICSI and a median reduction of 33%. The predicted value based on a linear regression model shows that the cutoff point on the PORIS corresponds to a 32.1% reduction on the ICSI. These analyses demonstrated that a 30% reduction in the ICSI is a reasonable cutoff point for responders. Using the second method of classification, a 25% to 35% reduction in the ICSI had 75.2% to 75.6% consistent classification with the PORIS. These cutoffs provided acceptable sensitivity and specificity and were consistent with cutoffs obtained using the first method. Therefore, subjects qualified as a responder if they had  30% reduction in ICSI from baseline to study endpoint (week 32 or last observation). Patient Satisfaction The practical reality of designing a clinical trial funded by industry is that the company paying the costs will likely want input into the design. For example, the marketing department wanted to determine whether patients on the intervention were happy with the drug. Although this may be an obvious marketing question, it is certainly something physicians who prescribe the drug should know. To evaluate the relationship between symptom reduction and satisfaction during therapy, a secondary analysis was conducted in 128 subjects treated with PPS 300 mg/d (the FDA-recommended dose) in The e82 VOL. 12 NO. 2/3 2010 Study.12 Along with the other measures, patients completed a treatment satisfaction questionnaire. In this analysis, treatment responders were defined as subjects having  30% reduction in ICSI from baseline to study endpoint (see previous section). A reduction in IC symptoms was associated with significantly higher satisfaction with PPS (P  .05). Responders were more likely to be pleased with the therapy, more likely to state that the time from IC diagnosis until PPS therapy was initiated. Early treatment was defined as treatment initiation  6 months after IC diagnosis, with a subcategory of  3 months after diagnosis. Late treatment was defined as treatment initiation  24 months after IC diagnosis, with a subcategory of  36 months after diagnosis. Of the 128 subjects in the PPS 300 mg/d group, a total of 103 met the definitions for early treatment ( 6 Responders were more likely to be pleased with the therapy, more likely to state that they have benefited from the therapy, and more likely to recommend the therapy. they have benefited from the therapy, and more likely to recommend the therapy. Although this seems intuitive, patient satisfaction, which should really be one of the most important clinical outcomes, did have a positive correlation with improvement in ICSI scores, further validating the ICSI as an outcome parameter. Predictors of Response To date, there have been few successful attempts to find parameters in IC that would predict better response to therapy. Some have suggested that early diagnosis and, in particular, early treatment may result in better months after diagnosis of IC) or late treatment ( 24 months after diagnosis) and were included in the analysis. The early treatment group ( 6 months) had an average improvement in ICSI score of 3.97  0.59 compared with 2.15  0.70 for the late treatment group ( 24 months; P  .0472) (Figure 2). Similar results were seen when examining the ICSI scores at other times from IC diagnosis ( 3 months vs  24 months,  3 months vs  36 months, and  6 months vs  36 months). IC patients who received treatment within 6 months of being diagnosed showed significantly greater improve- Interstitial cystitis patients who received treatment within 6 months of being diagnosed showed significantly greater improvement in symptom severity compared with subjects who received treatment  24 months after diagnosis. response. This analysis evaluated patients in The Study who were randomized to the standard dose (100 mg 3 times per day) to explore whether, after the diagnosis of IC, a shorter time to initiation of treatment with PPS was associated with greater symptom improvement.13 Subjects were categorized as receiving early treatment or late treatment based on REVIEWS IN UROLOGY ment in symptom severity compared with subjects who received treatment  24 months after diagnosis. This study was not intended to explore disease progression or to suggest that the early versus late treatment groups imply different symptom severity on the basis of pathophysiology. Rather, the analysis supports the concept that earlier initiation of IC therapy 4. RIU0445_07-31.qxd 8/4/10 4:13 PM Page e83 Mean Change in ICSI Score From Baseline to Week 32 Managing Interstitial Cystitis 5 * * * 4 3 2 1 0 ⱕ 3 ⱖ 24 ⱕ 3 ⱖ 36 ⱕ 6 ⱖ 24 ⱕ 6 ⱖ 36 Time From IC Diagnosis to Initiation of Treatment (mo) Early Treatment Late Treatment Figure 2. Total mean O’Leary-Sant Interstitial Cystitis Symptom Index (ICSI) score change from baseline to end of study (week 32) in patients with (early  3 and  6 month) and late (  24 and  36 month) treatment from interstitial cystitis (IC) diagnosis. *P  .05 for early treatment versus late treatment. The comparison of  6 months versus  36 months approached statistical significance (P  .0548). Sexual Implications Physicians managing patients with IC have traditionally focused on the pain and voiding symptoms of the condition and, for the most part, have ignored the sexual symptoms. It has been clearly shown that sexual functioning is one of the strongest predictors of poorer QoL in treatment-refractory patients (patients who have failed traditional therapy).14 To our knowledge, no significant treatment effect has ever been observed (or may not have even been looked for) in previous studies and, therefore, a treatment-initiated improvement in sexual functioning could occur. In The Study, the MOS Sexual Functioning Scale (MOS SexFn) (©Medical Outcome Trust), which evaluates libido, arousal, orgasmic, and enjoyment issues associated with sex, was obtained at baseline and during follow-up in the group of patients who received PPS 100 mg 3 times a day (FDA-approved dose and standard dose recommended in clinical practice).15 There were 128 patients in this group (mean age 45 years; 116 women, 12 men). Approximately 40% of patients reported a baseline MOS SexFn score  50 (moderate to severe sexual dysfunction). It was only patients in the treatment responder group (44% of patients who reported a decrease in ICSI of  30%) who experienced improvement in sexual function QoL and Sleep Nocturia is usually the only sleep disturbance reported in epidemiology, cohort, and clinical trials. The fact that a patient may have to awaken to void one or more times a night might have significant implications for health and QoL; however, sleep dysfunction and its impact on the patient are more complex than simply documenting episodes of nocturia. Prior to The Study, Figure 3. Improvement in Medical Outcomes Study (MOS) sexual functioning score and sleep score from baseline to week 32 among treatment responders (n  47) and nonresponders (n  59). Responder defined as a  30% reduction in O’Leary-Sant Interstitial Cystitis Symptom Index. 25 Mean Change From Baseline in MOS Score may provide more benefit to patients who have been diagnosed with IC. (change from baseline of 19.8 in the responder group vs 0.49 in the nonresponder group; P  .0020). There was no change in sexual function over the 32-week trial in the 56% of patients who were not treatment responders (Figure 3). A trend toward improved QoL in treated patients correlated with improvement in sexual functioning. The finding that improvement in IC symptoms was associated with improvement in both sexual functioning and QoL is a very important signal for both physicians and patients. Sexual functioning should be considered as one of the important QoL parameters that must be addressed in managing these patients. P  .0022 P  .0055 19.8 20 15 11.8 10 5 0 1.6 0.49 5 Improvement in MOS Sexual Functioning Score Nonresponder Improvement in MOS Sleep Score Responder VOL. 12 NO. 2/3 2010 REVIEWS IN UROLOGY e83 4. RIU0445_07-31.qxd 8/4/10 4:13 PM Page e84 Managing Interstitial Cystitis continued no evaluation had been performed that exclusively examined the impact of IC on sleep dysfunction, as well as the subsequent effect—either direct or indirect—on health-related QoL. The 128 patients enrolled in The Study received 300 mg/d PPS and were administered a 6-item Short Form Sleep Index (referred to here as the “sleep scale”) adapted from the more comprehensive 12-item MOS Sleep Scale.16,17 This sleep scale examined the following dimensions of sleep: initiation (1 item), maintenance (1 item), respiratory problems (1 item), adequacy (2 items), and somnolence (1 item). The sleep scale was scored from 0 to 100 with higher scores indicating better sleep functioning. The mean change in sleep score for all patients from baseline to the end of The Study was 6.0  1.8 (P  .0011). At the end of the treatment period (week 32), 42% qualified as treatment responders using the definition  30% reduction in ICSI score from baseline whereas 58% were considered nonresponders. At the end of The Study, responders had significant improvements in sleep score compared with baseline (P  .0001). The responders had a mean change from baseline in sleep score of 11.8  3.2 compared with 1.6  2.0 (P  .0055) for the nonresponders (Figure 3). Positive correlations were observed at baseline between the sleep scale and the SF-12 physical and mental components (r  0.43 and r  0.37, respectively; P  .0001). At study endpoint, treatment responders demonstrated a significant improvement in the physical and mental components of the SF-12 whereas nonresponders had a slight worsening of the physical and mental component score. Correlation between sleep and QoL was stronger for the physical component of the SF-12 compared with the mental component. Nocturia, by itself, had little impact on QoL. This study confirmed the association among IC symptoms, sleep dyse84 VOL. 12 NO. 2/3 2010 function, and QoL. Although nocturia itself was associated with minimal impact on QoL, a more comprehensive analysis of sleep dysfunction was strongly correlated with QoL. Patients who responded to treatment had significant improvements in sleep quality as measured by the sleep scale. Responders also showed a significant presently enrolling in which IC patients are randomized to a total of 300 mg/d PPS, 100 mg/d PPS, and placebo.18 This ongoing study, when completed, aims to answer some of the questions remaining due to The Study’s lack of a control group. However, the data from The Study have allowed us to further examine the PST and to Although nocturia itself was associated with minimal impact on quality of life (QoL), a more comprehensive analysis of sleep dysfunction was strongly correlated with QoL. Patients who responded to treatment had significant improvements in sleep quality as measured by the sleep scale. improvement in QoL. These results show that successful therapy for IC can result in improvement in sleep dysfunction and QoL (both physical and mental). Conclusions The major limitation of The Study was the lack of a control group. Another similar study (http://www. ClinicalTrials.gov NCT00399139) is confirm the validity and responsiveness of O’Leary-Sant ICSI. As The Study examined outcome parameters other than symptom response, the impact and associations of disease duration, sexual functioning, patient satisfaction, QoL, and sleep disturbances could be examined (Table 2). We have learned that most patients with a clinical diagnosis of IC have a positive PST, that the ICSI is a valid Table 2 Lessons Learned From Data Analyses Obtained in The Study 1. Increased dose of PPS for IC does not result in an increase in efficacy. 2. Increased duration of PPS therapy for IC results in increased efficacy. 3. The O’Leary-Sant ICSI is a sensitive measure of response to treatment. 4. Patients experiencing a  30% decrease in ICSI can be considered responders. 5. Patient satisfaction with therapy is an important clinical consideration. 6. The majority of patients with a clinical diagnosis of IC have a positive PST. 7. Early treatment is associated with a better response to treatment. 8. IC patients have poor QoL; improvement in symptoms is associated with improvement in QoL. 9. IC patients experience significant sexual dysfunction; improvement in symptoms is associated with improvement in sexual functioning. 10. Nocturia itself is associated with minimal impact on QoL; sleep dysfunction, however, is strongly correlated with QoL; patients who respond to treatment have significant improvements in sleep quality. 11. Do not write off a clinical trial because it was “negative” or was done for “regulatory” purposes. IC, interstitial cystitis; ICSI, O’Leary-Sant Interstitial Cystitis Symptom Index; QoL, quality of life; PPS, pentosan polysulfate sodium; PST, potassium sensitivity test. REVIEWS IN UROLOGY 4. RIU0445_07-31.qxd 8/4/10 4:13 PM Page e85 Managing Interstitial Cystitis and sensitive outcome measure, and that doses higher than the standard FDA-approved dose of 300 mg/d do not increase efficacy. In addition, increased duration of therapy increases the chance of symptom amelioration, sexual dysfunction is an important parameter to assess in IC, and successful therapy can improve sexual functioning. Finally, symptom severity, QoL, and sleep function are interrelated and symptom improvement with therapy correlates with improvement in both sleep function and QoL. This forensic dissection of a clinical trial undertaken for simple regulatory reasons has significantly improved our understanding and management of the enigmatic condition we call IC. The original study and post hoc analyses were supported by Ortho Women’s Health & Urology™, a Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc., Raritan, NJ. Dr. Nickel has been a consultant for Ortho-McNeil Pharmaceuticals and has been an investigator in clinical trials evaluating pentosan polysulfate. Dr. Nickel received no direction, advice, or compensation from OrthoMcNeil in regard to this article, and no industry representative read or edited the manuscript prior to publication. 9. 10. 11. References 1. 2. 3. 4. 5. 6. 7. 8. Nickel JC. Interstitial cystitis: a chronic pelvic pain syndrome. Med Clin North Am. 2004;88: 467-481. Tripp DA, Nickel JC, Fitzgerald MP, et al. Sexual functioning, catastrophizing, depression, and pain, as predictors of quality of life in women suffering from interstitial cystitis/painful bladder syndrome. Urology. 2009;73:987-992. Mulholland SG, Hanno P, Parsons CL, et al. Pentosan polysulfate sodium for therapy of interstitial cystitis: a double-blind placebo-controlled clinical study. Urology. 1990;35:552-558. Parsons CL, Benson G, Childs SJ, et al. A quantitatively controlled method to study prospectively interstitial cystitis and demonstrate the efficacy of pentosanpolysulfate. J Urol. 1993; 150:845-848. Holm-Bentzen M, Jacobsen F, Nerstrøm B, et al. A prospective double-blind clinically controlled multicenter trial of sodium pentosan polysulfate in the treatment of interstitial cystitis and related painful bladder disease. J Urol. 1987;138:503-507. 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. 2003;170:810-815. Nickel JC, Barkin J, Forrest J, et al. Randomized, double-blind, dose-ranging study of pentosan polysulfate sodium for interstitial cystitis. Urology. 2005;65:654-658. O’Leary MP, Sant GR, Fowler FJ, Jr, et al. The interstitial cystitis symptom index and problem index. Urology. 1997;49(suppl 5A):58-63. 12. 13. 14. 15. 16. 17. 18. Parsons CL. Potassium sensitivity test. Tech Urol. 1996;2:171-173. Parsons CL, Forrest J, Nickel JC, et al. Effect of pentosan polysulfate therapy on intravesical potassium sensitivity. Urology. 2002;59: 329-333. 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. 2001;57 (suppl. 6A):62-66. Sand PK, Kaufman DM, Evans RJ, et al. Association between response to pentosan polysulfate sodium therapy for interstitial cystitis and patient questionnaire-based treatment satisfaction. Curr Med Res Opin. 2008;24:2259-2264. Nickel JC. Kaufman DM, Zhang HF, et al. Time to initiation of pentosan polysulfate sodium treatment after interstitial cystitis diagnosis: effect on symptom improvement. Urology. 2008; 71:57-61. Nickel JC, Tripp D, Teal V, et al. Sexual function is a determinant of poor quality of life in women with treatment refractory interstitial cystitis. J Urol. 2007;177:1832-1836. Nickel JC, Parsons CL, Forrest J, et al. Improvement in sexual functioning in patients with interstitial cystitis/painful bladder syndrome. J Sex Med. 2008;5:394-399. Nickel JC, Payne CK, Forrest J, et al. The relationship among symptoms, sleep disturbances, and quality of life in patients with interstitial cystitis. J Urol. 2009;181:2555-2561. Rand Health. Medical Outcomes Study: Sleep scale. http://www.rand.org/health/surveys_tools/ mos/mos_sleep.html. Accessed December 13, 2008. ClinicalTrials.gov. NCT00399139: An effectiveness and safety study of pentosan polysulfate sodium for the treatment of interstitial cystitis. http://clinicaltrials.gov/ct2/show/NCT00399139? termelmiron&rank2. Accessed February 26, 2009. Main Points • Pentosan polysulfate sodium (PPS) is the only US Food and Drug Administration (FDA)–approved oral therapy for the treatment of interstitial cystitis (IC). Clinical trials had shown modest symptom improvement at the 100 mg/d dose, although its efficacy has been disputed in subsequent trials. A randomized, double-blind, dose-ranging study of PPS and IC was undertaken to address these concerns. Duration of therapy appeared to be more important than the dosage. 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 although there was a significant dose response with respect to adverse events (eg, higher doses were associated with more adverse events). • The Study results were used to validate a number of important IC-related outcomes. For example, the analysis confirmed that the O'Leary-Sant IC Symptom Index was a valid, reliable, and, most of all, responsive measure of IC symptoms. Furthermore, it was shown that not only was the actual numeric score important, but also the percentage improvement, where a patient experiencing  30% score improvement could be interpreted as a responder. • Physicians managing patients with IC have traditionally focused on pain and voiding symptoms and have ignored the sexual symptoms. Improvement in IC symptoms was associated with improvement in sexual functioning and quality of life (QoL). Sexual functioning should be considered as one of the important QoL parameters in managing patients. • The Study confirmed the association among IC symptoms, sleep dysfunction, and QoL. Patients who responded to treatment had significant improvements in sleep quality as measured by the sleep scale. Results showed that successful IC therapy improved sleep dysfunction and both mental and physical QoL. VOL. 12 NO. 2/3 2010 REVIEWS IN UROLOGY e85