Ian W. Mills

Proof of Concept Trial of Tanezumab for the Treatment of Symptoms Associated With Interstitial Cystitis

PURPOSEnIn this randomized, double-blind, placebo controlled phase 2 study we investigated tanezumab, a humanized monoclonal antibody that specifically inhibits nerve growth factor as a treatment for interstitial cystitis pain.nnnMATERIALS AND METHODSnPatients with interstitial cystitis received a single intravenous dose of 200 μg/kg tanezumab or placebo. Patients recorded daily pain scores (on an 11-point numerical rating scale) 7 days before attending study visits and completed a urinary symptom diary for 3 of those days. Patients also completed the Interstitial Cystitis Symptom Index questionnaire and a global response assessment. The primary end point was change in average daily numerical rating scale pain score from baseline to week 6. Secondary end points included global response assessment, Interstitial Cystitis Symptom Index score, micturition and urgency episode frequency per 24 hours, and mean voided volume per micturition. The incidence of adverse events was also assessed.nnnRESULTSnA total of 34 patients received tanezumab and 30 received placebo. At week 6 tanezumab produced a significant reduction from baseline in average daily pain score vs placebo (treatment difference [LS mean, 90% CI] was -1.4 [-2.2, -0.5]). A significantly higher proportion of patients on tanezumab responded as improved in the global response assessment and tanezumab also significantly reduced urgency episode frequency vs placebo. Tanezumab had no significant effect on Interstitial Cystitis Symptom Index score, micturition frequency or mean voided volume per micturition. The most common adverse events were headache (tanezumab 20.6%, placebo 16.7%) and paresthesia (tanezumab 17.6%, placebo 3.3%).nnnCONCLUSIONSnTanezumab has shown preliminary efficacy in the treatment of pain associated with interstitial cystitis.

Neural Control of the Lower Urinary Tract: Peripheral and Spinal Mechanisms

This review deals with individual components regulating the neural control of the urinary bladder. This article will focus on factors and processes involved in the two modes of operation of the bladder: storage and elimination. Topics included in this review include: (1) The urothelium and its roles in sensor and transducer functions including interactions with other cell types within the bladder wall (“sensory web”), (2) The location and properties of bladder afferents including factors involved in regulating afferent sensitization, (3) The neural control of the pelvic floor muscle and pharmacology of urethral and anal sphincters (focusing on monoamine pathways), (4) Efferent pathways to the urinary bladder, and (5) Abnormalities in bladder function including mechanisms underlying comorbid disorders associated with bladder pain syndrome and incontinence. Neurourol. Urodynam. 29: 128–139, 2010.

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. Neurourol. Urodynam. 29:652–657, 2010.

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

OBJECTIVEnTo 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.nnnMETHODSnPatients 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.nnnRESULTSnOverall, 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.nnnCONCLUSIONnTanezumab 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.

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

To assess the efficacy and safety of pregabalin alone or in combination with tolterodine extended release (ER) in subjects with idiopathic OAB.

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

PURPOSEnWe 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.nnnMATERIALS AND METHODSnPooled 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.nnnRESULTSnFor 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).nnnCONCLUSIONSnWomen 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.

Measurement of Urethral Closure Function in Women With Stress Urinary Incontinence

PURPOSEnWe assessed the use of urethral pressure reflectometry in detecting pressure increases in the female urethra and compared the usefulness of urethral pressure reflectometry vs urethral pressure profilometry in a pharmacodynamic intervention study.nnnMATERIALS AND METHODSnIn this randomized, double-blind, placebo controlled, crossover study 17 women with stress urinary incontinence or mixed urinary incontinence received 4 mg esreboxetine or placebo for 7 to 9 days followed by a washout period before crossing over treatments. Urethral pressure reflectometry and urethral pressure profilometry were performed before and at the end of each treatment period.nnnRESULTSnThe urethral opening pressure measured with urethral pressure reflectometry increased significantly compared to placebo by 13.7 cm H(2)O (p <0.0001) with an observed within subject standard deviation of 5.4. The increase in maximum urethral closure pressure was 8.4 cm H(2)O compared to placebo (p = 0.06) and for maximum urethral pressure the increase was 9.9 cm H(2)O (p = 0.04). However, the within subject SD for these parameters was higher at 11.4 and 12.2, respectively, implying lower power for these analyses. While receiving esreboxetine patients had significantly fewer incontinence episodes and reported a treatment benefit (global impression of change) compared to placebo.nnnCONCLUSIONSnThe opening pressure measured with urethral pressure reflectometry was less variable compared to the parameters measured with urethral pressure profilometry (maximum urethral closure pressure and maximum urethral pressure). Consequently using urethral pressure reflectometry would result in a more efficient study design when investigating pharmacological effects on the urethra in future studies. We also found that esreboxetine was well tolerated, and had a positive and clinically relevant effect on urethral closure function and symptoms of stress urinary incontinence.

Investigation of a Ca2+ Channel α2δ Ligand for the Treatment of Interstitial Cystitis: Results of a Randomized, Double-Blind, Placebo Controlled Phase II Trial

PURPOSEnWe investigated PD-0299685, a Ca(2+) channel α2δ ligand, for interstitial cystitis pain in a randomized, double-blind, placebo controlled phase IIa study.nnnMATERIALS AND METHODSnPatients 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.nnnRESULTSnOf 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.nnnCONCLUSIONSnPD-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.

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

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.