Tanezumab Reduces Pain in Women with Interstitial Cystitis/Bladder Pain Syndrome and Patients with Nonurological Associated Somatic Syndromes.

PURPOSE: We performed pooled analyses from 3 small, clinical trials of tanezumab in patients with urological chronic pelvic pain, including chronic prostatitis/chronic pelvic pain syndrome and interstitial cystitis/bladder pain syndrome, to identify patient subpopulations more likely to benefit from tanezumab treatment. MATERIALS AND METHODS: Pooled analyses included data from 208 patients with interstitial cystitis/bladder pain syndrome or chronic prostatitis/chronic pelvic pain syndrome randomized to placebo (104, 65 [62.5%] female) or tanezumab (104, 63 [60.6%] female) who received 1 dose or more of study medication. Data on tanezumab were from study A4091010 (interstitial cystitis/bladder pain syndrome) on 200 µg/kg intravenous, study A4091019 (chronic prostatitis/chronic pelvic pain syndrome) on 20 mg intravenous and study A4091035 (interstitial cystitis/bladder pain syndrome) on 20 mg subcutaneous. Primary study end points were evaluated using analysis of covariance with gender, study and baseline pain as covariates. RESULTS: For pooled analyses least squares mean (SE) change from baseline in 24-hour pain intensity vs placebo was -0.60 (0.24, 90% CI -0.99, -0.20) overall and -0.99 (0.32, p=0.002) and -0.17 (0.36, p=0.650) for females and males, respectively. The improvement in pain intensity was significant (p=0.011) for patients with symptoms suggesting the concomitant presence of nonurological associated somatic syndromes but not for those with pelvic pain symptoms only (p=0.507). CONCLUSIONS: Women with interstitial cystitis/bladder pain syndrome and patients with symptoms suggesting the concomitant presence of nonurological associated somatic syndromes were more likely to experience significant pain reduction with tanezumab than with placebo therapy. In contrast, no difference was reported in response between tanezumab and placebo therapy for men with chronic prostatitis/chronic pelvic pain syndrome symptoms only.

Investigation of a Ca2+ channel α2δ ligand for the treatment of interstitial cystitis: results of a randomized, double-blind, placebo controlled phase II trial.

PURPOSE: We investigated PD-0299685, a Ca(2+) channel α2δ ligand, for interstitial cystitis pain in a randomized, double-blind, placebo controlled phase IIa study. MATERIALS AND METHODS: Patients with interstitial cystitis/bladder pain syndrome received 30 or 60 mg PD-0299685 daily or placebo for 12 weeks. Primary end points were change in average daily worst pain severity score (on an 11-point numerical rating scale) and change in Interstitial Cystitis Symptom Index score from baseline to week 12. Secondary end points included global response assessment, micturition and urgency episode frequency per 24 hours and mean voided volume per micturition. Incidence of adverse events was also assessed. RESULTS: Of 161 patients 54 received 30 mg PD-0299685 daily, 55 received 60 mg PD-0299685 daily and 52 received placebo. At week 12 the 60 mg dose produced a clinically significant reduction in daily worst pain severity score from baseline compared to placebo (treatment difference [90% CI] -0.82 [-1.72, 0.08]). A greater proportion of patients taking 60 mg PD-0299685 daily demonstrated improvement in global response assessment. PD-0299685 had no clinically significant effect on the Interstitial Cystitis Symptom Index score or urinary end points. More patients discontinued due to treatment related adverse events with 30 or 60 mg PD-0299685 daily than with the placebo. CONCLUSIONS: PD-0299685 failed to demonstrate positive proof of concept for the treatment of pain and other urinary end points associated with interstitial cystitis/bladder pain syndrome.

Investigation of the clinical efficacy and safety of pregabalin alone or combined with tolterodine in female subjects with idiopathic overactive bladder.

AIMS: To assess the efficacy and safety of pregabalin alone or in combination with tolterodine extended release (ER) in subjects with idiopathic OAB. METHODS: This 26-week, multicenter, randomized, double-blind, placebo-controlled, three-period crossover study enrolled women aged ≥ 18 years that were diagnosed with OAB and reported ≥ 8 micturitions/24 hr and ≥ 4 urgency episodes/week on 5-day bladder diary at baseline. Subjects were randomized to 1 of 10 treatment sequences and received three of five treatments, each for 4 weeks with 4-week washout periods: standard-dose pregabalin/tolterodine ER (150 mg twice daily [BID]/4 mg once daily [QD], n=102), pregabalin alone (150 mg BID, n=105), tolterodine ER alone (4 mg QD, n=104), low-dose pregabalin/tolterodine ER (75 mg BID/2 mg QD, n=105), and placebo (n=103). Subjects completed 5-day diaries at the end of treatment and washout periods. The primary endpoint was change from baseline to week 4 in mean voided volume (MVV) per micturition. The primary comparison was standard-dose pregabalin/tolterodine ER versus tolterodine ER alone; secondary comparisons were pregabalin alone versus tolterodine ER alone and versus placebo. RESULTS: Baseline-adjusted changes in MVV were significantly greater after treatment with standard-dose pregabalin/tolterodine ER (39.5 ml) versus tolterodine ER alone (15.5 ml; P<0.0001), and with pregabalin alone (27.4 ml) versus tolterodine ER alone (P=0.005) and placebo (11.9 ml; P=0.0006). Treatments were generally well tolerated; discontinuation rates due to adverse events were 4%, 2%, 5%, 0%, and 1% with standard- and low-dose pregabalin/tolterodine ER, pregabalin, tolterodine ER, and placebo, respectively. CONCLUSIONS: Pregabalin, alone or with tolterodine ER may offer an alternative treatment option for idiopathic OAB in women.

Can we predict which patient will fail drug treatment for overactive bladder? A think tank discussion.

The treatment of overactive bladder (OAB) has evolved over the past 20 years to include a number of behavioral, pharmacological, and minimally invasive treatments. After behavioral therapy, pharmacological therapy with antimuscarinics remains the mainstay of treatment. Despite this, a large number of patients will "fail" or be unsatisfied with drugs therapy. It would be extremely helpful to patients and clinicians to be able to predict who those patients are. However, there are a number of barriers. First and foremost are defining "success" and "failure" and this can vary dramatically from one patient to another. Endpoints other than the traditional variables used in clinical trials may be more effective in evaluating treatments and helping to predict outcomes. Along similar lines, there are various definitions for OAB that is "refractory" to conventional treatments and this term needs clarification. In many cases, response to therapy may be affected by factors such as comorbidities, metabolism of drugs, concurrent therapies, etc. These factors are sometimes obvious and sometimes not, and for a variety of reasons it can be quite difficult to predict or determine their effect on outcome. Finally, many patients with OAB include have mixed (stress and urgency) symptoms. It is important to sort out the OAB component of mixed symptoms and mixed urinary incontinence (MUI) when determining effects of therapy.

Preliminary assessment of safety and efficacy in proof-of-concept, randomized clinical trial of tanezumab for chronic prostatitis/chronic pelvic pain syndrome.

OBJECTIVE: To assess the efficacy and safety of tanezumab, a humanized monoclonal antibody directed against the pain-mediating neurotrophin, nerve growth factor, to treat pain and other symptoms of chronic prostatitis/chronic pelvic pain syndrome in a Phase IIa, proof-of-concept clinical trial powered to provide 2-sided 90% confidence interval around the primary endpoint. METHODS: Patients received a single intravenous dose of tanezumab (20 mg) or placebo. The primary efficacy endpoint was the change from baseline to week 6 in average daily numerical rating scale pain score. The secondary endpoints included the change from baseline to week 6 in the National Institutes of Health Chronic Prostatitis Symptom Index and urinary symptoms. Safety was also assessed. RESULTS: Overall, 62 patients were randomized (30 to tanezumab and 32 to placebo). At week 6, tanezumab marginally improved the average daily pain (least-squares mean difference from placebo -0.47, 90% confidence interval -1.150-0.209) and urgency episode frequency (least-squares mean difference from placebo -1.37, 90% confidence interval -3.146-0.401). No difference was seen in the National Institutes of Health chronic prostatitis symptom index total score or micturition frequency at week 6. The most common adverse events were paresthesia and arthralgia. The odds of having a ≥ 30% reduction in pain were 1.75-fold greater (90% confidence interval 0.65-4.69) for patients receiving tanezumab versus placebo. CONCLUSION: Tanezumab might improve symptoms for some patients with chronic prostatitis/chronic pelvic pain syndrome. Although proof of concept was not demonstrated in the present study, additional studies with larger populations and stricter inclusion criteria according to patient phenotype might identify populations in which antinerve growth factor treatment will provide clinical benefit.

Atorvastatin treatment for men with lower urinary tract symptoms and benign prostatic enlargement.

OBJECTIVE: To evaluate the effects of atorvastatin in men with lower urinary tract symptoms (LUTS) and prostatic enlargement due to presumed BPH. METHODS: This was a phase 2, double-blind, randomised, placebo-controlled clinical study. Eligible patients were aged > or =50 yr, with International Prostate Symptom Score (IPSS) > or = 13, total prostate volume (TPV) > or = 30 ml, and maximum urinary flow rate 5-15 ml/s. All patients had serum low-density lipoprotein (LDL) 100-190 mg/dl at baseline. Patients received either atorvastatin 80 mg daily (n=176) or placebo (n=174) for 26 wk. End points included IPSS, TPV, transition zone volume (TZV), maximum urinary flow rate (Q(max)), serum PSA, and lipids. RESULTS: There was no difference between the effects of atorvastatin and placebo on the primary end point of mean change from baseline in IPSS after 26 wk of double-blind treatment (-4.5 vs. -4.3; p=0.263). Similarly, no effect was seen on the lower urinary tract secondary end points including TPV (-1.6 vs. -1.9 ml; p=0.654), TZV (-0.0 vs. -0.8 ml; p=0.421), Q(max) (+1.1 vs. +0.7 ml/s; p=0.612), and PSA (-0.24 vs. -0.14 ng/ml; p=0.235). Atorvastatin had a significant effect on serum lipid levels compared with placebo (eg, LDL: -75.6 vs. -6.1 mg/dl; p<0.001). CONCLUSIONS: Atorvastatin is not effective over 6 mo in the treatment of men with LUTS and prostatic enlargement due to presumed BPH who have serum LDL in the range 100-190 mg/dl.

The impact of targeted training, a dedicated protocol and on-site training material in reducing observer variability of prostate and transition zone dimensions measured by transrectal ultrasonography, in multicentre multinational clinical trials of men with symptomatic benign prostatic enlargement.

OBJECTIVE: To assess the variability of a standardized protocol of transrectal ultrasonography (TRUS), with targeted training, and compare it to the variability in other multicentre clinical trials, as TRUS-estimated total prostate volume (TPV) and transition zone volume (TZV) are considered important efficacy endpoints in assessing new drug therapies for benign prostatic enlargement (BPE), but standardizing TRUS remains a challenge in such studies. PATIENTS AND METHODS: In all, 174 patients with BPE in the placebo arm of a 30-centre clinical trial were analysed at baseline, 13 and 26 weeks with TRUS, to extract TPV and TZV values. All TRUS operators received training in the standardized methods, which was supplemented at the outset by a compact disc-based video. RESULTS: The mean (sd) changes from baseline in TPV at 13 and 26 weeks were - 2.9 (8.9) and -1.9 (8.5) mL, respectively; the respective mean changes from baseline in TZV were -1.2 (6.4) and + 0.7 (7.8) mL. For TPV, 80% of the measurements had differences of + 5.2 to -13.4 mL at 13 weeks, and + 8.0 to - 10.9 mL at 26 weeks. For TZV, 80% of the differences were + 5.8 to - 7.4 at 13 weeks, and + 9.3 to -6.5 mL at 26 weeks. CONCLUSION: The performance of TRUS compared favourably with similar published multicentre studies, which we suggest relates in part to the careful implementation of the protocol. We showed that diligent implementation of a detailed protocol, supplemented by targeted training of investigators and provision of on-site training material, promoted consistent acquisition and successful derivation of key clinical trial endpoints. Quantifying the variability of such endpoints will enable us to track deployment quality for future clinical trials, and will ensure that trials are sufficiently powered to define small changes in prostate size.

Development and validation of a quality-of-life measure for men with nocturia.

OBJECTIVES: To develop and assess the psychometric properties of a short self-report nocturia-specific Quality-of-Life (QOL) questionnaire. METHODS: The Nocturia Quality-of-Life questionnaire (N-QOL) was developed using focus group interviews with men experiencing nocturia. To refine it further and psychometrically validate the questionnaire, 107 men with nocturia (from four urology clinics in the United Kingdom) completed the pilot N-QOL, along with measures of health status and sleep quality. To assess reproducibility, men from one clinic completed the pilot N-QOL again at 1 week. RESULTS: After standard item reduction analyses, 18 items were dropped from the pilot questionnaire. The psychometric properties of the remaining 13-item instrument were tested in accordance with standard criteria. Factor analysis identified two subscales, sleep/energy and bother/concern, loading at 0.5 and greater. The N-QOL overall score and subscales proved to be internally consistent (alpha = 0.84 to 0.90) and reproducible (intraclass correlation coefficient = 0.74 to 0.82). N-QOL scores correlated with sleep quality (P <0.01) as measured by the Pittsburgh Sleep Quality Index and energy/vitality and social functioning (P <0.01) as measured by the SF-36 Health Survey, demonstrating good convergent validity. The N-QOL also demonstrated statistically significant differences between the scores of those experiencing one, two, and three or more episodes of nocturia on an average night, indicating excellent discriminant validity. CONCLUSIONS: These analyses provide support for the psychometric validity of the N-QOL for use in a male population with nocturia.