An adaptive randomized clinical trial in interstitial cystitis/bladder pain syndrome evaluating efficacy of ASP3652 and the relationship between disease characteristics and Hunner's lesions.

PURPOSE: The primary purpose of this study was to evaluate the effect of the fatty acid amide hydrolase (FAAH) inhibitor ASP3652 on efficacy and safety in patients with Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS). The secondary purpose was to evaluate phenotyping based on Hunner's lesions (HL). METHODS: In this randomized trial, adult female patients with moderate/severe IC/BPS received 12 weeks of treatment with an oral dose of ASP3652 (50, 150, or 300 mg twice daily) or placebo. A Bayesian model was employed using accumulating data to adjust the randomization probability and to analyze the primary efficacy variable (change from baseline to end of treatment in Mean Daily Pain [MDP; range 0-10]). Study outcomes and patient characteristics of patients with and without HL (HL+ and HL-) were compared. RESULTS: In total, 287 patients were randomized. The 300 mg dose group (n = 97) showed the largest effect, i.e., a mean change from baseline to end of treatment of -1.73 in MDP. However, the mean difference from placebo was 0.02. The probability that this dose was better than placebo was 13.5%. Adverse event incidence was low and similar between study groups. HL+ patients were older and had more severe symptoms than HL-. An association was suggested in HL+ patients between changes in micturition frequency and MDP (R = 0.41 [95% CI 0.18, 0.63]), which was not observed in HL- (R = 0.04 [95% CI -0.16, 0.29]). CONCLUSION: ASP3652 was safe and well tolerated, but did not show efficacy in IC/BPS. The observed differences between HL+ and HL- suggest that IC/BPS diagnosis and treatment may be approached differently in these two phenotypes. TRIAL REGISTRATION: EudraCT number 2011-004555-39, date of registration: 2012-05-07.

A combined proof of concept and dose finding study with multiple endpoints: A Bayesian adaptive design in chronic prostatitis/chronic pelvic pain syndrome.

There is a need for identifying effective drugs or terminating ineffective drugs as early as possible to optimize efficient and cost effective drug development. The aim of the proposed trial was to simultaneously establish Proof of Concept (PoC) and dose finding (DF) for a new drug with a novel mode of action in a new indication. We simulated and executed an adaptive allocation design to investigate the effects of a drug on male patients suffering from chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). This manuscript describes the clinical trial simulations and primary analysis results. A Bayesian adaptive allocation procedure was employed to allocate patients to treatment using a normal dynamic linear model. The study was to stop early for efficacy if the probability of a clinically significant difference between an experimental arm and placebo was at least 90%. The study was to stop for futility if the probability that the maximum effective dose was better than placebo by at least the futility difference was less than 20%. During the execution phase the study was stopped early, that is 32% less than planned maximum sample size, due to futility. The final results confirmed that the predefined stopping rules were met. In conclusion, the simulations showed that, if the drug was effective, this adaptive design could accomplish both the goals of PoC and DF. However, the study stopped early for futility in line with the simulation predictions for stopping. This resulted in the early stopping of a trial recruiting patients on ineffective treatment.

Fatty Acid Amide Hydrolase Inhibitor Treatment in Men With Chronic Prostatitis/Chronic Pelvic Pain Syndrome: An Adaptive Double-blind, Randomized Controlled Trial.

OBJECTIVE: To examine the effect of a peripherally active fatty acid amide hydrolase (FAAH) inhibitor ASP3652 on safety and efficacy outcomes in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Inhibition of FAAH is hypothesized to reduce the excitability of urinary tract afferents including nociceptors. MATERIALS AND METHODS: In this adaptive, randomized, double-blind, placebo-controlled study, adult male patients with moderate to severe CP/CPPS were treated for 12 weeks with an oral dose of ASP3652 (25, 75, 150, or 300 mg twice daily, or 300 mg once daily), or placebo. A Bayesian model was used for adaptive prospective modeling of randomization, study continuation decisions, and analysis of the efficacy variables. RESULTS: The study was stopped for futility at preplanned interim analysis when 239 patients were randomized (226 were included in the intention-to-treat set): the 25 mg group showed the largest reduction of the primary end point National Institutes of Health Chronic Prostatitis Symptom Index total score (7.0 points), but the placebo group showed a mean reduction of 7.3 points (difference: 0.3 [95% confidence interval: -1.9, 2.6]). Micturition outcomes improved compared with placebo in all ASP3652 groups; for example, in the 300 mg twice daily group, voiding frequency decreased by -1.10 (95% CI: -2.0, -0.2) voids/24 hours vs placebo. Safety outcomes were comparable across the treatment groups. CONCLUSION: ASP3652 was generally safe and well-tolerated. It did not show efficacy on pain symptoms in patients with CP/CPPS. However, the results indicate that FAAH inhibition may attenuate lower urinary tract symptoms. Dedicated studies in patients with lower urinary tract dysfunction are needed to confirm this.

The Burden of Bladder Pain in Five European Countries: A Cross-sectional Study.

OBJECTIVE: To estimate the burden of illness associated with bladder pain in 5 European countries: France, Germany, Italy, Spain, and the United Kingdom. PATIENTS AND METHODS: Patients with a diagnosis of bladder pain (ie, unpleasant sensation, pain, pressure, or discomfort related to the urinary bladder) were identified from data collected by the cross-sectional National Health and Wellness Survey performed in 2013. Propensity score matching was used to construct a comparator group without bladder pain (1 case: 2 controls). Assessments were performed for several outcomes including health-related quality of life (HRQoL; 36-item Short-Form, version 2), work-related function (Work Productivity and Activity Impairment questionnaire), employment status, and all-cause healthcare resource use. RESULTS: We identified 275 patients with a physician diagnosis of bladder pain, 274 of whom were successfully matched to 548 controls without bladder pain. Compared with matched controls, patients with bladder pain had significantly impaired HRQoL (mental component summary: 38.5 vs 44.5; physical component summary: 38.9 vs 47.8; P <.001). Overall work productivity loss was significantly greater in patients with bladder pain compared with matched controls (41.7% vs 21.5%; P <.001). Patients with bladder pain were also significantly more likely to use all-cause healthcare resources and make more visits to healthcare providers in the previous 6 months than matched controls (P <.001 for all outcomes). CONCLUSION: Bladder pain is associated with a considerable burden in Europe in terms of impaired HRQoL and work productivity, and increased healthcare resource use.

National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) symptom evaluation in multinational cohorts of patients with chronic prostatitis/chronic pelvic pain syndrome.

BACKGROUND: The assessment of patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) in everyday practice and clinical studies relies on National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) scores for symptom appraisal, inclusion criteria for clinical trials, follow-up, and response evaluation. OBJECTIVE: We investigated multiple databases of CP/CPPS patients to determine the prevalence and impact of pain locations and types to improve our strategy of individualized phenotypically guided treatment. DESIGN, SETTING, AND PARTICIPANTS: Four major databases with CPSI scores for nonselected CP/CPPS clinic patients from Canada, Germany, Italy, and the United States. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Individual question scores and subtotal and total scores of CPSI were described and correlated with each other. Ordinal regression analysis was performed to define pain severity categories. RESULTS AND LIMITATIONS: A total of 1563 CP/CPPS patients were included. Perineal pain/discomfort was the most prevalent pain symptom (63%) followed by testicular pain (58%), pain in the pubic area (42%) and penis (32%); reports of pain during ejaculation and voiding were 45% and 43%, respectively. European patients had a significantly higher number of pain localizations and symptoms compared with North American patients (p<0.001). Severity of pain correlated well with frequency of pain (r = 0.645). No specific pain localization/type was associated with more severe pain. Correlation of pain domain with quality of life (QoL) (r = 0.678) was higher than the urinary domain (r = 0.320). Individually, pain severity (r = 0.627) and pain frequency (r = 0.594) correlated better with QoL than pain localization (r = 0.354). Pain severity categories results for NIH-CPSI item 4 (0-10 numerical rating scale for average pain) were mild, 0-3; moderate, 4-6; severe, 7-10; CPSI pain domain (0-21): mild, 0-7; moderate, 8-13; and severe, 14-21. CONCLUSIONS: Pain has more impact on QoL than urinary symptoms. Pain severity and frequency are more important than pain localization/type. Cut-off levels for disease severity categories have been identified that will prove valuable in symptom assessment and the development of therapeutic strategies.

The selective estrogen receptor alpha agonist Org 37663 induces estrogenic effects but lacks antirheumatic activity: a phase IIa trial investigating efficacy and safety of Org 37663 in postmenopausal female rheumatoid arthritis patients receiving stable background methotrexate or sulfasalazine.

OBJECTIVE: Multiple lines of evidence suggest that sex hormones may play a role in the pathogenesis or clinical expression of rheumatoid arthritis (RA). Studies on the effects of exogenous estrogens in RA patients have yielded contradictory results. We undertook this study to determine the effects of the selective estrogen receptor alpha (ERalpha) agonist Org 37663 in patients with RA, in terms of both its estrogenic effects and its ability to ameliorate disease activity. METHODS: A 10-week, multicenter, randomized, double-blind, placebo-controlled, parallel group, dose-finding, proof-of-concept trial was initiated to obtain data on the efficacy and safety of Org 37663 in postmenopausal female patients with RA who were receiving background treatment with either methotrexate or sulfasalazine. Patients were randomized to receive placebo or Org 37663 at doses of 4 mg/day, 15 mg/day, or 50 mg/week. The primary efficacy variable was the Disease Activity Score in 28 joints (DAS28). RESULTS: Org 37663 induced a clear biologic, estrogenic response in several organ systems, including a dose-related increase in levels of sex hormone binding globulin. However, the DAS28 decreased similarly for all treatment groups including placebo, indicating lack of clinical efficacy of Org 37663 in this trial. CONCLUSION: The observed lack of clinical benefit in RA patients treated with an ERalpha agonist, in association with a clear biologic response to the study drug, provides evidence that a biologically relevant ERalpha-mediated estrogenic effect is not associated with a clinically relevant effect on RA symptoms and signs.

Intranasal administration of recombinant human cartilage glycoprotein-39 as a treatment for rheumatoid arthritis: a phase II, multicentre, double-blind, randomised, placebo-controlled, parallel-group, dose-finding trial.

BACKGROUND: Autoantigen-specific immunotherapy by mucosal tolerance induction via the intranasal route is an attractive therapeutic option for the treatment of autoimmune diseases, including rheumatoid arthritis (RA). Human cartilage glycoprotein-39 (HC gp-39) has been identified as a potential key autoantigen in RA. Based on animal studies, intranasal administration of the autoantigen is hypothesised to induce immunological tolerance in patients with RA and to ameliorate disease activity. In a phase I/IIA clinical trial in patients with RA, intranasal application of HC gp-39 was safe and well tolerated. OBJECTIVE: To investigate the efficacy of intranasally administered fully human, recombinant HC gp-39 (Org 39141) by a large clinical study. METHODS: In a 13-week multicentre, double-blind, randomised, placebo-controlled, parallel-group, dose-finding, proof-of-concept trial, patients with RA (disease-modifying antirheumatic drug (DMARD) naive or after washout of DMARD treatment) were randomised to receive either intranasal applications of placebo or HC gp-39 in doses of 30, 150, 300 or 600 microg, once a week. The primary efficacy variable was the 28 joint count Disease Activity Score (DAS28). RESULTS: During the treatment period the DAS28 decreased similarly for all treatment groups-including placebo-indicating lack of efficacy of intranasal HC gp-39 treatment in the current setting. Safety variables were similar for all study groups. CONCLUSION: It was concluded that with the treatment protocol used (dose levels and frequency of dosing), intranasal treatment with Org 39141 was safe but did not result in more clinical improvement than in placebo-treated patients.

Decrease of disease activity under ineffective therapy in DMARD-naive patients with early rheumatoid arthritis: role of antibody profiles and carriage of the HLA shared epitope in predicting decrease of disease activity.

OBJECTIVE: To evaluate whether the baseline presence of rheumatoid arthritis (RA)-associated biomarkers could define subgroups of patients that are more prone to show a spontaneous decrease of RA disease activity. In a previous placebo-controlled phase II trial that failed to show any superiority of the experimental compound versus placebo, a remarkable decrease of such disease activity was observed despite the lack of effective treatment. METHODS: A subgroup of 83 disease modifying antirheumatic drug-naive RA patients with disease duration < 3 years was analyzed. Rheumatoid factor (RF), anti-citrullinated protein/peptide antibodies (ACPA), and HLA shared epitope (SE) were determined at baseline. RESULTS: RF-positive patients tended to have higher levels of disease activity at baseline compared to RF-negative patients [Disease Activity Score (DAS) 6.12 vs 5.65, p = 0.02 at screening], but the decrease in disease activity was similar in both subgroups (DAS -1.23 vs -1.07). In contrast, ACPA-positive patients showed similar baseline disease activity scores compared to ACPA-negative patients, but tended to show a smaller decrease of disease activity than patients without ACPA (Delta DAS -1.53 vs -0.79, p = 0.013). Presence of the HLA-SE seemed not to have any effect on the baseline DAS or on the spontaneous decrease of DAS. CONCLUSION: The predictive value of baseline RA-associated biomarkers for spontaneous decrease of disease activity under placebo or ineffective treatment is limited. Yet the data analyzed here might be useful for the design of future placebo-controlled trials in RA.

Intranasal administration of recombinant human cartilage glycoprotein-39. A phase I escalating cohort study in patients with rheumatoid arthritis.

OBJECTIVE: To investigate safety and tolerability and pilot efficacy of repeated single doses of Org39141 in patients with active rheumatoid arthritis (RA). Org 39141 is recombinant human cartilage glycoprotein-39, intended to induce mucosal tolerance upon intranasal administration. METHODS: RA patients with moderate disease activity were treated for 4 weeks and followed for another 8 weeks. The trial had a sequential cohort design: RA patients in the first cohort received 4 intranasal doses (one per week) of either 25 microg Org 39141 or placebo; in subsequent cohorts, treatment with 125microg, 625 microg, or 3125 microg Org39141 was compared to placebo. Safety was evaluated by means of reporting adverse events, standard laboratory testing, and nose examination. The primary efficacy endpoint was RA disease activity as measured by the Disease Activity Score 28 (DAS28). RESULTS: A total of 36 patients were randomized. Org39141 was well tolerated, and no severe or serious adverse events (AE) were reported. In the pooled placebo group, a decrease in DAS28 was observed, but to a lesser extent than in the Org 39141 treatment groups. After 4 weeks of treatment, the mean decrease in DAS in the 625 microg Org 39141 treatment group (-24%) was statistically (p = 0.02) and clinically (EULAR criteria) significantly larger than in the pooled placebo group (-3%). Once-weekly intranasal treatment with Org39141 was well tolerated, and no serious or severe AE were reported. A trend towards efficacy was observed. Our results are encouraging for further clinical development of Org39141.