Followup of Patients With Interstitial Cystitis Responsive to Treatment With Intravesical Bacillus Calmette-Guerin or Placebo
Article Outline
Purpose
We evaluated the longer term response in patients with interstitial cystitis who initially responded to intravesical bacillus Calmette-Guerin or placebo in a randomized clinical trial.
Materials and Methods
Patients with interstitial cystitis who responded positively to treatment with bacillus Calmette-Guerin or placebo after 34 weeks of followup in a double-blind clinical trial were followed for an additional 34 weeks in an observational study to assess response durability. Outcomes at 68 weeks included a patient reported global response assessment, 24-hour voiding diary, and pain, urgency and validated interstitial cystitis symptom indexes.
Results
Of responders to bacillus Calmette-Guerin or placebo in the clinical trial 38 continued extended followup in the observational study. A total of 12 (75%) responders who received placebo and 19 (86%) who received bacillus Calmette-Guerin considered themselves to remain moderately or markedly improved at week 68. Improved symptom outcomes were also generally maintained during followup in the 2 groups.
Conclusions
Most patients who respond to therapy with intravesical bacillus Calmette-Guerin or placebo maintain improved symptoms for up to 68 weeks after the initiation of therapy. However, initial response rates are low and placebo responders demonstrated essentially the same durability of response as bacillus Calmette-Guerin responders. These results argue against the routine use of bacillus Calmette-Guerin in this patient group.
Key Words: bladder, cystitis, interstitial, Mycobacterium bovis, pain, quality of life
Abbreviations and Acronyms: BCG, bacillus Calmette-Guerin, GRA, global response assessment, IC, interstitial cystitis, ICCTG, IC Clinical Trials Group, ICPI, O’Leary-Sant IC Problem Index, ICSI, O’Leary-Sant IC Symptom Index
Interstitial cystitis is a chronic condition characterized by bladder pain and bladder storage symptoms in association with characteristic cystoscopic findings.1 To our knowledge the etiology of this condition is unknown and treatment remains suboptimal. The National Institutes of Health established the ICCTG to perform randomized, controlled clinical trials in patients with IC. The ICCTG recently reported the results of a randomized, double-blind, placebo controlled clinical trial of intravesical BCG.2 After 34 weeks of followup there was no statistically significant difference between BCG and placebo in the rate of responders based on a GRA. A report of extended followup in a previous clinical trial of BCG showed that the beneficial effect was durable at an average of 27 months.3 We report the results of an observational study of a subset of ICCTG clinical trial participants who responded to BCG or placebo to determine whether the effects persisted. These patients remained blinded to their original treatment assignment throughout long-term followup.
Methods
Details of the design of the trial and primary and secondary outcomes were published previously.2 Briefly, women and men who had at least moderate IC symptoms were randomized to intravesical BCG or intravesical saline (placebo) and received up to 6 treatment instillations during a 6 to 10-week period. The 34-week period following randomization comprised the primary randomized portion of the study. The followup of 34 weeks was chosen to correspond to previous studies of BCG3 and make followup comparable for all patients since the duration of treatment could vary somewhat.
At week 34 participants rated their symptoms compared to baseline on a GRA, a 7-point scale ranging from markedly worse to markedly improved. Patients were classified as responders if they reported moderate or marked improvement on the GRA, as supplemented with information on medication use.2 Patients who withdrew from the study without completing the GRA were classified as nonresponders. Responders, who remained blinded to the initial treatment allocation, were invited to participate in followup for an additional 34 weeks. Nonresponders were offered treatment with open label BCG and the results of that study were reported separately. Informed consent was obtained for all participants and the protocol was approved by the institutional review board at each site.
Secondary outcome measures were obtained at baseline, the end of the clinical trial (34 weeks after randomization), the end of the observational phase of the study (68 weeks after randomization) and at select intermediate intervals. The measures were pain and urgency scores, urinary frequency recorded in 24-hour voiding diaries, the University of Wisconsin IC Symptom Inventory,4 and the O’Leary-Sant IC Symptom and Problem Indexes.5 The GRA was also obtained at week 68. The GRA asked respondents to evaluate symptoms compared to when they started this study and we presumed that participants interpreted this to mean at the time of randomization. Adverse events were not assessed during the observational phase.
Since the patients were a subset of the original randomized cohort, the presentation of results is primarily descriptive. Standard 95% CIs were produced for the mean change from weeks 34 to 68 for patients with data available at each time point. A CI that includes zero is consistent with no statistically significant change. The 2-sided Fisher exact test was used to compare proportions between the groups.
Results
The figure shows the disposition of patients in this report. It should be noted that the classification of patients as responders eligible for inclusion in this report was based on the determination of response status at the clinical site. The primary end point of the randomized clinical trial was based on a later central review of responder status and it yielded a slightly different value.2
Patient accounting through all study phases. Clinical site determination of response status at end of randomized clinical trial at week 34 was used to evaluate whether patient was responder eligible for long-term followup or nonresponder eligible for open label BCG. Primary end point of randomized clinical trial was based on central review of responder status.
Of the 44 responders in the clinical trial by clinical site assessment 38 (86%) participated in the observational study. Median age at randomization in these 38 responders was 52 years in those randomized to placebo and 46 years in those assigned to BCG. Approximately 80% of participants were female in each arm. Of placebo responders 11 (69%) were white compared to 21 (95%) BCG responders but this difference had borderline statistical significance (p = 0.065) and the numbers were small. Five patients withdrew during long-term followup, yielding 33 (87%) who were assessed at 68 weeks.
Of 16 responders 12 (75%) from the placebo arm and 19 of 22 from the BCG arm (86%) considered themselves to have remained moderately or markedly improved by the GRA at week 68. This included 6 patients from the placebo arm and 13 from the BCG arm who reported that they remained markedly improved. Note that the 5 patients who withdrew were included in the denominator for these response rates. There was no statistically significant difference between the 2 arms (p = 0.43), although sample sizes were small.
The table lists individual symptoms and the 3 symptom indexes at the beginning (week 34) and end (week 68) of the observational study. For reference the baseline values at randomization in these patients are also shown. The mean values of all of these efficacy outcomes were lower at week 34 than at baseline in these patients, reflecting their status as treatment responders in the randomized trial. Mean changes during followup from weeks 34 to 68 were much smaller than in the randomized trial. Although it appeared that symptom improvements were better maintained in patients who responded to BCG than in responders to placebo, the CIs indicated that all changes were consistent with a mean change of zero. It is important to note that for all secondary efficacy end points sample sizes were small and SDs were large, such that the CIs were wide and the impact of withdrawals may have been large.
Symptom outcomes with time
| Outcome (arm) | Mean ± SD Baseline | Mean ± SD Week 34 | Mean ± SD Week 68 | Mean ± SD Wk 34–68 Change (95% CI) |
|---|---|---|---|---|
| No. pts: | ||||
 Placebo | 16 | 16 | 14 | 14 |
| BCG | 22 | 22 | 19 | 19 |
| Pain: | ||||
| Placebo | 6.2±1.5 | 2.1±1.4 | 3.1±2.2 | 0.8±2.7(−0.6,2.2) |
| BCG | 6.5±1.1 | 2.0±1.5 | 2.3±1.5 | 0.2±1.2(−0.3,0.7) |
| Urgency: | ||||
| Placebo | 6.8±1.3 | 2.9±1.7 | 3.1±2.0 | 0.1±2.1(−1.0,3.2) |
| BCG | 6.8±1.2 | 2.5±1.4 | 2.3±1.6 | −0.2±1.2(−0.7,1.7) |
| 24-Hr frequency: | ||||
| Placebo | 15.1±5.7 | 10.7±3.2 | 12.4±5.2 | 1.5±4.6(−0.9,3.9) |
| BCG | 16.9±5.9 | 11.1±5.5 | 10.4±3.3 | 0.0±3.1⁎(−1.5,1.5) |
| Wisconsin IC Inventory: | ||||
| Placebo | 31.0±7.9 | 12.1±7.7 | 13.8±11.4 | 1.2±7.4†(−2.8,6.2) |
| BCG | 29.8±7.7‡ | 9.1±6.9‡ | 8.1±6.6 | −1.3±5.3(−3.7,1.1) |
| O’Leary-Sant IC Symptom Index: | ||||
| Placebo | 13.1±3.5 | 7.0±3.1 | 8.1±4.4 | 1.1±3.9(−0.9,3.1) |
| BCG | 12.4±3.4 | 6.4±3.3 | 6.4±2.3 | −0.1±2.4⁎(−1.2,1.0) |
| O’Leary-Sant IC Problem Index: | ||||
| Placebo | 12.6±2.5 | 5.5±3.4 | 6.3±3.6 | 0.6±2.8(−0.9,2.1) |
| BCG | 11.5±3.0 | 4.0±3.0 | 4.1±3.1 | −0.2±3.2⁎(−1.7,1.3) |
⁎Total of 17 patients. |
†Total of 13 patients. |
‡Total of 21 patients. |
Discussion
Although we observed no statistically significant beneficial effect of treatment with BCG compared to placebo in the randomized clinical trial with a low response rate in each group, we continued to observe the subset of patients who responded to either treatment to evaluate the duration of effects. Previously Peters et al followed 9 patients who had previously responded to BCG in a randomized clinical trial.3 At a mean followup of 27 months 8 patients (89%) continued to demonstrate improvement compared to pretreatment symptoms. Longer term followup of responders to placebo in that trial was not reported. In the ICCTG trial that we reported most patients who were initially responsive to BCG and participated in the current observational study also maintained responder status and individual improved symptom measures for up to 68 weeks. Thus, although the response rate for BCG was low (21%) in the randomized clinical trial, the positive effect appeared to be durable in most study patients for the period that they were observed.
Interestingly a high proportion of patients who responded to intravesical saline administration also maintained the response for 68 weeks. Although spontaneous symptom remission is frequently mentioned in IC cases, this result is provocative, in that it is distinctly unusual to see long-lasting, dramatic symptom improvement in such refractory cases in the absence of specific therapy. It suggests that the placebo response in IC may also be long term, especially for invasive modes of administration of blinded treatment. Although BCG is considered to have a pharmacological action, we expected that the route of administration with catheterization would likely have a higher placebo effect than an oral medication and accordingly we designed the original randomized clinical trial, expecting a 30% placebo rate. However, the initial placebo response rate was only 12%, similar to the 13% placebo response rate observed in a previous ICCTG trial of oral therapies.6
Few other studies have shown benefits of placebo or sham therapies up to 6 months after treatment. A recent study of transdermal posterior tibial nerve laser therapy for IC, which showed no difference between laser and sham treatments, demonstrated significant improvement in voiding measures, the O’Leary-Sant Symptom Indexes and quality of life 12 weeks after treatment initiation.7 In a trial of microwave thermoablation for benign prostatic hyperplasia a decrease in the mean American Urological Association symptom score was observed by 6 weeks and maintained up to 6 months with larger improvement in the microwave treatment group compared to sham therapy.8 Five of the 35 patients (14%) on sham therapy in that trial had mild symptoms at 6 months, representing a maintained improvement from baseline. A Canadian study of 25 months of followup after placebo therapy for benign prostatic hyperplasia showed a similar long-term placebo effect.9
The magnitude and duration of placebo effects may be affected by treatment blinding. At the end of the randomized portion of the trial at 34 weeks patients were asked to guess their treatment assignments. They were not informed of their actual treatments until all followup through 68 weeks had been completed. All responders who provided a guess as to the assigned treatment guessed that they had been assigned to BCG, whereas two-thirds of nonresponders guessed that they had received placebo. However, there was no evidence that unblinding occurred and it is likely that many responders guessed that they received BCG simply because they improved.
It could be argued that the beneficial effect observed in the BCG and placebo groups was due to hydrodistention from the administration of these agents intravesically. However, only 50 cc placebo or BCG solution was instilled and the mean dwell time for retention was 1.6 and 1.7 hours, respectively. It is generally recognized that hydrodistention that is not performed with the patient under general anesthesia provides no lasting benefits in terms of symptom amelioration. Rather than bladder distention, another possible explanation for the extended effect of BCG and placebo is through the process of learning to postpone urination through holding the instillation. This may provide an effective behavioral therapy that some patients are then able to use in the long term to control the disease. It is also possible that the sustained improvement in the 2 groups was partially due to participation in a clinical trial, work with a caring responsive research coordinator and concentration on bladder symptoms, possibly leading to behavior changes that were not part of the clinical trial protocol. However, to our knowledge there are no published data from a randomized clinical trial on the long-term effects of behavioral modifications in patients with refractory IC.
The major limitation of this study is that it was essentially an observational cohort of a subgroup of patients and, thus, there may have been be selection bias. Although 86% of the responders from the clinical trial participated in this long-term followup, they no longer represent the original randomization and any comparisons of the placebo and BCG arms should be interpreted accordingly. Furthermore, due to the low response rate for the 2 therapies in the original trial the sample size for long-term followup of responders was also small, such that there was limited statistical power for most comparisons.
Conclusions
Most patients who responded to treatment with intravesical BCG or placebo maintained the improvement for up to 68 weeks after the initiation of treatment. However, overall response rates were low and BCG was similar to placebo even at extended followup. These longer term results provide more evidence that that BCG should not be routinely used for IC. The duration of the placebo effect emphasizes the importance of including a placebo group in IC trials, at least until reliably effective therapy is developed.
Appendix. ICCTG Members
Dr. Alan J. Wein (principal investigator), Dr. George W. Drach, Dr. Philip Hanno, Dr. Eric Rovner, Marilou Foy, Gloria McNamara and Lilliam Ribeiro, University of Pennsylvania; Dr. Grannum R. Sant (principal investigator), Dr. Erol Onel, Dr. T. C. Theoharides, Patricia Radgowski and Carolyn Shea-O’Malley, New England Medical Center; Dr. Edward M. Messing (principal investigator), Dr. Robert Mayer, Kay Rust and Elizabeth Smith, University of Rochester; Dr. John Warren (principal investigator), Dr. Toby Chai, Dr. Susan Keay, Linda Horne and Theresa Jackson, University of Maryland; Dr. Daniel J. Culkin (principal investigator), Dr. James F. Donovan, Jr., Lynda Kelsey and Karen Mataranglo, University of Oklahoma; Dr. Ananias C. Diokno (principal investigator), Dr. Kenneth Peters, Eleanor Anton and Loni Lampkins, William Beaumont Hospital; Dr. David Burks (co-principal investigator), Dr. Rifaat Dagher, Michelle Peabody and Jill Sullivan, Henry Ford Hospital; Dr. J. Curtis Nickel (principal investigator), Dr. Alvaro Morales, Joe Downey, Laurel Emerson and Sylvia Robb, Queen’s University; Dr. Christopher K. Payne (principal investigator), Kathryn Azevedo, Dr. Gilbert Rigaud, Dr. Rajesh Shinghal and Debra Clay, Stanford University Medical Center; J. Richard Landis (principal investigator), Kathleen J. Propert (co-principal investigator), Dr. Deborah R. Erickson (University of Kentucky Medical Center), Dr. John T. Farrar, Dr. John E. Tomaszewski, Rosemary A. Madigan, Ted Barrell, Denise Cifelli, James Dattilo, Stephen B. Durborow, Lori Fanelli, Christine Hardy, Raymond W. Hilderbrand, Chris Helker, Gina Norwood, Gargi Parikh, Yanlin Wang and Yawei Zhang, University of Pennsylvania Data Coordinating Center; John W. Kusek, Christopher Mullins and Dr. Leroy M. Nyberg, Jr., National Institute of Diabetes and Digestive and Kidney Diseases; Vicki Ratner, IC Association; Dr. William A. Steers (Chairman of the ICCTG Steering Committee, 1998 to 2001), University of Virginia; and Dr. Harris E. Foster (Chairman of the ICCTG Steering Committee, 2001 to 2004), Yale University.
References
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- A randomized controlled trial of intravesical bacillus Calmette-Guerin for treatment refractory interstitial cystitis. J Urol. 2005;173:1186
- . The efficacy of intravesical bacillus Calmette-Guerin in the treatment of interstitial cystitis: long-term followup. J Urol. 1998;159:1483
- . Psychometric analysis of the University of Wisconsin Interstitial Cystitis Scale: implications for use in randomized clinical trials. J Urol. 1998;159:1085
- . The interstitial cystitis symptom index and problem index. Urology. 1997;49(suppl.):58
- A pilot clinical trial of oral pentosan polysulfate and oral hydroxyzine in patients with interstitial cystitis. J Urol. 2003;170:810
- Transdermal posterior tibial nerve laser therapy is not effective in women with interstitial cystitis. J Urol. 2004;172:1880
- . A high-efficiency microwave thermoablation system for the treatment of benign prostatic hyperplasia: results of a randomized, sham-controlled, prospective, double-blind, multicenter clinical trial. Urology. 1998;51:731
- . Placebo therapy of benign prostatic hyperplasia: a 25-month study (Canadian PROSPECT Study Group). Br J Urol. 1998;81:383
Study received institutional review board approval at each site.
Supported by Cooperative Agreements U01 DK54108, U01 DK54125, U01 DK54127, U01 DK54133, U01 DK54138 and U01 DK54158 from the National Institute for Diabetes and Digestive and Kidney Diseases, and University of Maryland General Clinical Research Center Grant M01 RR 16500, General Clinical Research Centers Program, National Center for Research Resources, National Institutes of Health.
For another article on a related topic see page 764.
PII: S0022-5347(07)02535-9
doi:10.1016/j.juro.2007.09.035
© 2008 American Urological Association. Published by Elsevier Inc. All rights reserved.
Refers to article:
- Abnormal Expression of Differentiation Related Proteins and Proteoglycan Core Proteins in the Urothelium of Patients With Interstitial Cystitis , 14 December 2007