Amanda Darekar

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

PURPOSE In 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. MATERIALS AND METHODS Patients 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. RESULTS A 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%). CONCLUSIONS Tanezumab has shown preliminary efficacy in the treatment of pain associated with interstitial cystitis.

Flexible-dose fesoterodine in elderly adults with overactive bladder: results of the randomized, double-blind, placebo-controlled study of fesoterodine in an aging population trial.

To assess the efficacy and safety of flexible‐dose fesoterodine in elderly adults with overactive bladder (OAB).

Evaluation of Cognitive Function in Healthy Older Subjects Treated with Fesoterodine

Abstract Objective: To evaluate the cognitive effects of fesoterodine 4 and 8 mg versus placebo in healthy older adults. Methods: This was an active– and placebo–controlled, double–blind, double–dummy crossover study conducted using healthy volunteers (aged 65–85 years) with baseline Mini–Mental State Examination score ≥ 26. The study comprised 4 treatment periods: fesoterodine 4 mg for 6 days; fesoterodine 4 mg for 3 days followed by fesoterodine 8 mg for 3 days; placebo for 6 days; and placebo for 6 days with alprazolam 1 mg on day 6. The treatment sequence was randomized, with a 3– to 6–day washout between periods. Subjects completed computer–based cognitive assessments and the Rey Auditory Verbal Learning Test on day 1 (before dosing) and day 6 (after dosing) of each period. The primary endpoint was the Detection task; secondary endpoints were the Identification task, 1–card learning task, Continuous Paired Associate Learning task, Groton Maze Learning Task, and the Rey Auditory Verbal Learning Test. Results: Among 18 subjects in the per protocol set, changes from baseline to day 6 with fesoterodine 4 and 8 mg were not significantly different from placebo for any endpoint (P < 0.05); alprazolam produced significant impairment in all endpoints versus placebo (P < 0.05). No serious adverse events were reported; the most common adverse events were dry mouth for fesoterodine and sedation for alprazolam. No sedation was reported with fesoterodine. Conclusion: In healthy older adults, fesoterodine 4 and 8 mg once daily had no statistically significant effects versus placebo on any cognitive function assessed, including memory; alprazolam 1 mg produced statistically significant deterioration.

Long-term safety, tolerability and efficacy of flexible-dose fesoterodine in elderly patients with overactive bladder: open-label extension of the SOFIA trial.

To assess the long‐term safety, tolerability, and efficacy of flexible‐dose fesoterodine in elderly patients with OAB.

Phase III, efficacy and safety study of ertugliflozin monotherapy in people with type 2 diabetes mellitus inadequately controlled with diet and exercise alone

To conduct a phase III study to evaluate the efficacy and safety of ertugliflozin monotherapy in people with type 2 diabetes.

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.

Dose-escalating study of the pharmacokinetics and tolerability of fesoterodine in children with overactive bladder

OBJECTIVE To determine the pharmacokinetics, safety and tolerability of fesoterodine, and assess the utility of 3-day bladder diaries (exploratory objective) in pediatric subjects with neurogenic detrusor overactivity or idiopathic overactive bladder (OAB). METHODS In this 8-week open-label study, subjects (8-17 years, >25 kg) received fesoterodine 4 mg for 4 weeks, then 8 mg for 4 weeks. Blood samples were obtained at weeks 4 and 8. RESULTS Of 21 subjects enrolled, 11 had neurogenic detrusor overactivity and 10 had idiopathic OAB; 1 discontinued (personal reasons). Mean age and weight were 13.2 years and 54.0 kg for boys (n = 12) and 13.1 years and 49.2 kg for girls (n = 9). 5-Hydroxy-methyltolterodine plasma concentrations did not differ by diagnosis and were consistent with predictions based on adult data. Treatment-related adverse events (all mild or moderate) included 1 event each of dry mouth, constipation, dry eyes and blurred vision, and 2 events each of nausea and increased post-void residual volume. Three-day bladder diaries proved feasible. CONCLUSIONS Oral administration of fesoterodine in pediatric subjects (>25 kg) with idiopathic OAB or neurogenic detrusor overactivity produced steady-state plasma 5-hydroxy-methyltolterodine exposures similar to those in adults. The doses given were well tolerated.

Effect of ertugliflozin on glucose control, body weight, blood pressure and bone density in type 2 diabetes mellitus inadequately controlled on metformin monotherapy (VERTIS MET)

We evaluated the efficacy and safety of ertugliflozin, an SGLT2 inhibitor, in type 2 diabetes mellitus (T2DM) inadequately controlled (HbA1c, 7.0%‐10.5%) with metformin monotherapy (≥1500 mg/d for ≥8 weeks).

Measurement of Urethral Closure Function in Women With Stress Urinary Incontinence

PURPOSE We 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. MATERIALS AND METHODS In 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. RESULTS The 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. CONCLUSIONS The 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.

Effects of drug cessation after flexible‐dose fesoterodine in patients with overactive bladder

To determine the course of overactive bladder (OAB) symptoms after 4 weeks of no treatment following a 12‐week study of the efficacy and safety of flexible‐dose fesoterodine in patients with OAB who were enrolled in the UK healthcare system. There are limited data available on the natural time course of OAB symptoms after the cessation of treatment.