Demographic diversity of participants in Pfizer sponsored clinical trials in the United States.

The approval of new medicinal agents requires robust efficacy and safety clinical trial data demonstrated to be applicable to population subgroups. Limited data have previously been reported by drug sponsors on the topic of clinical trial diversity. In order to establish a baseline of diversity in our clinical trials that can be used by us and other sponsors, an analysis of clinical trial diversity was conducted covering race, ethnicity, sex, and age. This analysis includes Pfizer interventional clinical trials that initiated enrollment between 2011 through 2020. The data set comprises 213 trials with 103,103 US participants. The analysis demonstrated that overall trial participation of Black or African American individuals was at the US census level (14.3% vs 13.4%), participation of Hispanic or Latino individuals was below US census (15.9% vs 18.5%), and female participation was at US census (51.1% vs 50.8%). The analysis also examined the percentage of trials that achieved racial and ethnic distribution levels at or above census levels. Participant levels above census were achieved in 56.1% of Pfizer trials for Black or African American participants, 51.4% of trials for White participants, 16.0% of trials for Asian participants, 14.2% of trials for Native Hawaiian and Pacific Islander participants, 8.5% of trials for American Indian and Alaska Native participants, and 52.3% of trials for Hispanic or Latino participants. The results presented here provide a baseline upon which we can quantify the impact of our ongoing efforts to improve racial and ethnic diversity in clinical trials.

Characteristics of antimuscarinic responders versus suboptimal responders in a randomized clinical trial of patients with overactive bladder symptoms.

OBJECTIVE: To assess the characteristics of tolterodine extended-release (ER) 4 mg responders and suboptimal responders (≤50% decrease in UUI episodes/24 h) among patients with overactive bladder (OAB), including urgency urinary incontinence (UUI), and identify predictors of a >50% UUI response with fesoterodine 8 mg in tolterodine suboptimal responders. METHODS: Adult patients with OAB symptoms for ≥6 months and ≥8 micturitions, and ≥2 and <15 UUI episodes/24 h at week -2 received open-label tolterodine ER 4 mg during a 2 week run-in. Suboptimal responders after tolterodine treatment (week 0) were randomized to fesoterodine (4 mg for 1 week, 8 mg for weeks 2-12) or placebo once daily. Post-hoc analyses compared the percentage change from week -2 to week 0 in UUI episodes/24 h in tolterodine responders versus suboptimal responders and identified significant predictors of a UUI response at week 12 with fesoterodine 8 mg among tolterodine suboptimal responders. RESULTS: Of 897 patients, 610 (68%) were UUI suboptimal responders during the run-in period. UUI episodes/24 h at week -2 were similar in tolterodine responders and suboptimal responders (4.2 vs. 4.3), but responders showed a significantly greater median percentage decrease in UUI episodes/24 h after tolterodine treatment at week 0 (80.0% versus 15.3%; p < .0001). During double-blind treatment, the percentage of patients with a UUI response at week 12 was significantly greater with fesoterodine (69.9%) than placebo (57.0%; p = .0027). Fesoterodine (vs. placebo), no previous antimuscarinic use before tolterodine run-in, and less UUI severity at baseline were significant predictors of a UUI response. CONCLUSIONS: For patients with OAB, including UUI, who were treated initially with tolterodine and showed a suboptimal UUI response, nearly 70% demonstrated a UUI response with second-line fesoterodine 8 mg. No antimuscarinic use before tolterodine and fewer baseline UUI episodes were significant predictors of a UUI response with fesoterodine.

Development of a predictive model for urgency urinary incontinence.

The ability to set realistic expectations of treatment response in patients with overactive bladder (OAB) can have an impact on patient engagement and adherence to study medication. In order to help set treatment expectations for OAB, a Physician Predictive Tool has been developed based on predictive modelling. Models have been developed utilizing data from eight Phase 3 and 4 fesoterodine clinical trials and these models enable the prediction of individual treatment response in subjects with OAB, based on various baseline characteristics. The data utilized and covariates that were hypothesized to influence treatment response are described. The model selection and development process are also outlined, and the final model and some example results utilizing this model are presented. Finally, we discuss the potential benefits and limitations of such a predictive tool.

Fesoterodine clinical efficacy and safety for the treatment of overactive bladder in relation to patient profiles: a systematic review.

OBJECTIVE: To summarize published evidence on the pharmacology, efficacy, and safety of fesoterodine for the treatment of overactive bladder (OAB) symptoms in relation to patient clinical and demographic profiles. METHODS: A systematic review of published articles on fesoterodine was conducted via a PubMed search. Articles were identified using the search term fesoterodine, with limits of human species and abstract available. Review and meta-analysis articles, validation studies, articles focused on treatment compliance/adherence, meeting abstracts, and articles not focused on oral fesoterodine administration in human subjects were excluded. Data from retained articles were summarized descriptively. RESULTS: Of 137 articles identified, 61 (15 articles on the pharmacology and 46 articles on the efficacy and/or safety of fesoterodine) met inclusion criteria. Superiority trials demonstrated the additional efficacy of fesoterodine 8 mg versus fesoterodine 4 mg and tolterodine extended release 4 mg in treating OAB. Prospective trials in specific patient populations indicated beneficial effects of fesoterodine in elderly patients, vulnerable elderly patients, patients dissatisfied with or with a suboptimal response to previous antimuscarinic therapy, patients with urge urinary incontinence (UUI) or nocturnal urgency, and men with persistent LUTS during alpha-blocker treatment. With two effective doses, the fesoterodine dose can be adjusted to achieve optimal efficacy and tolerability in individual patients. The most common adverse events during fesoterodine treatment are dry mouth and constipation. CONCLUSIONS: Extensive evidence demonstrates the efficacy and safety of fesoterodine in relieving OAB symptoms, including urgency, urinary frequency, UUI, and nocturnal urgency, in patients with various clinical and demographic profiles. Trial results provide valuable information on fesoterodine treatment in specific patient populations, including both elderly and vulnerable elderly patients. Potential limitations of this review are that only English language articles in PubMed were searched and included.

Review of the efficacy and safety of fesoterodine for treating overactive bladder and urgency urinary incontinence in elderly patients.

Overactive bladder (OAB) is a common condition, with prevalence rates increasing with advancing age. Symptoms of OAB, including urgency urinary incontinence (UUI), are associated with various co-morbidities in elderly individuals (e.g., falls and fractures, functional impairment, and depression). The current mainstay of pharmacological therapy for OAB is antimuscarinic agents. Until recently, few studies had specifically evaluated the efficacy and safety of antimuscarinics in the treatment of OAB symptoms in elderly patients. This review summarises available evidence from the medical literature on the efficacy and safety of fesoterodine in elderly patients with OAB symptoms, including UUI. The data from unique placebo-controlled fesoterodine trials of elderly and vulnerable elderly patients, together with age-stratified data from post hoc analyses of fesoterodine trials, demonstrate that treatment with fesoterodine 4 or 8 mg results in statistically and clinically significant improvements in OAB symptoms and patient-reported outcomes in many elderly patients. The data indicate that the efficacy of fesoterodine in elderly patients is comparable with that in younger patients. Fesoterodine is generally well tolerated in elderly and vulnerable elderly patients, with low rates of urinary retention and little evidence of central nervous system events or impaired cognition. The data support a favourable benefit-to-risk ratio for fesoterodine in elderly and medically complex vulnerable elderly patients with OAB.

Superiority of fesoterodine 8 mg vs 4 mg in reducing urgency urinary incontinence episodes in patients with overactive bladder: results of the randomised, double-blind, placebo-controlled EIGHT trial.

OBJECTIVE: To assess the superiority of fesoterodine 8 mg vs 4 mg for improvement in urgency urinary incontinence (UUI) episodes and other diary variables, diary-dry rate (proportion of patients with >0 UUI episodes on baseline diary and 0 UUI episodes on post-baseline diary), and improvements in measures of symptom bother, health-related quality of life (HRQL), and other patient-reported outcomes (PROs). PATIENTS AND METHODS: This was a 12-week, randomised, double-blind, placebo-controlled, multinational trial of men and women aged ≥18 years with overactive bladder (OAB) symptoms including UUI (ClinicalTrials.gov ID NCT01302067). Patients were randomised (2:2:1) to receive fesoterodine 8 mg, fesoterodine 4 mg, or placebo once daily; those randomised to fesoterodine 8 mg started with fesoterodine 4 mg once daily for 1 week, then 8 mg once daily for the remaining 11 weeks. Patients completed bladder diaries at baseline and weeks 4 and 12 and the Patient Perception of Bladder Condition (PPBC), Urgency Perception Scale (UPS), and Overactive Bladder Questionnaire (OAB-q) at baseline and week 12. The primary endpoint was change from baseline to week 12 in UUI episodes per 24 h. RESULTS: At week 12, patients receiving fesoterodine 8 mg (779 patients) had significantly greater reductions from baseline in UUI episodes, micturitions, and urgency episodes than patients receiving fesoterodine 4 mg (790) or placebo (386); diary-dry rate was significantly higher in the fesoterodine 8-mg group vs the fesoterodine 4-mg and placebo groups (all P < 0.05). At week 12, patients receiving fesoterodine 8 mg also had significantly greater improvements in scores on the PPBC, UPS, and all OAB-q scales and domains than patients receiving fesoterodine 4 mg or placebo (all P < 0.01). Patients receiving fesoterodine 4 mg had significantly greater improvements in UUI episodes, urgency episodes, and micturitions; significantly higher diary-dry rates; and significantly greater improvement in PPBC scores and OAB-q scores than patients receiving placebo (all P < 0.05). Dry mouth was the most commonly reported adverse event (AE) in the fesoterodine groups (placebo group, 3.4%; fesoterodine 4-mg group, 12.9%; fesoterodine 8-mg group, 26.1%); most cases were mild or moderate in all treatment groups. Rates of serious AEs and discontinuations due to AEs were low in all groups. CONCLUSIONS: In a 12-week, prospectively designed, superiority trial, fesoterodine 8 mg showed statistically significantly superior efficacy vs fesoterodine 4 mg and placebo, as measured by reductions in UUI episodes and other diary variables, diary-dry dry rate, and improvements in measures of symptom bother, HRQL, and other PROs; clear evidence of dose-dependent efficacy is unique to fesoterodine among antimuscarinics and other oral agents for the treatment of OAB. Fesoterodine 4 mg was significantly more effective than placebo on all outcomes except for improvements in UPS scores. These data support the benefit of having two doses of fesoterodine in clinical practice, with the recommended starting dose of 4 mg for all patients and the fesoterodine 8-mg dose available for patients who require a higher dose to achieve optimal symptom relief.

Effect of fesoterodine on urethral closure function in women with stress urinary incontinence assessed by urethral pressure reflectometry.

INTRODUCTION AND HYPOTHESIS: The aim was to evaluate, using urethral pressure reflectometry (UPR), the effect of fesoterodine on urethral function in women with stress urinary incontinence (SUI). METHODS: Women aged 18 to 65 years were eligible for this randomised, double-blind, placebo-controlled, crossover study if they had had clinically significant SUI or SUI-predominant mixed urinary incontinence for >3 months. Each participant received fesoterodine 4 mg, fesoterodine 8 mg, and placebo once daily for 7 days, with a 7- to 10-day washout between treatments. UPR was performed at baseline and 4 to 8 h after the last dose in each treatment period. Participants completed a 3-day bladder diary before randomisation and during the last 3 days of each treatment period. RESULTS: Of the 22 women randomly assigned and treated, 17 met the criteria for the primary efficacy analyses. No statistically significant differences were seen between fesoterodine 4 mg or fesoterodine 8 mg and placebo in opening urethral pressure (primary endpoint) or other UPR endpoints. No statistically significant differences were seen between either fesoterodine dose and placebo in the change from baseline in the bladder diary variables (total urinary incontinence, SUI, or urgency urinary incontinence episodes per 24 h). Adverse events were reported by 8 participants taking fesoterodine 4 mg, 17 taking fesoterodine 8 mg, and 8 taking placebo. CONCLUSIONS: Fesoterodine did not affect urethral pressure or significantly decrease the number of incontinence episodes in women with SUI. The UPR parameters showed no placebo effect, while there was a placebo effect of 60 % based on the bladder diary.

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.

Evaluation of cognitive function in healthy older subjects treated with fesoterodine.

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.

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.

A new technique for the characterization of chaff elements.

A new technique for the experimental characterization of electromagnetic chaff based on Inverse Synthetic Aperture Radar is presented. This technique allows for the characterization of as few as one filament of chaff in a controlled anechoic environment allowing for stability and repeatability of experimental results. This approach allows for a deeper understanding of the fundamental phenomena of electromagnetic scattering from chaff through an incremental analysis approach. Chaff analysis can now begin with a single element and progress through the build-up of particles into pseudo-cloud structures. This controlled incremental approach is supported by an identical incremental modeling and validation process. Additionally, this technique has the potential to produce considerable savings in financial and schedule cost and provides a stable and repeatable experiment to aid model valuation.

Vacuum switch performance in a 1.2 MJ pulse forming network.

Vacuum switching has been used since the early days of pulsed power to provide a means to controlling the flow of large amounts of current. The attractions of vacuum switches for high energy switching are the vacuum mitigates mechanical shock generated by the discharge, low erosion rates, and rapid recovery for repetitive rate operations. Some of the drawbacks of vacuum switching are typically the requirement of a vacuum system and metal vapor sputtering which eventually renders the switch unusable. SAIC has developed a compact vacuum switch which is capable of conducting a current pulse in excess of 300 kA peak for a duration of approximately 0.5 ms. On a single shot, 150 C have been switched while the amount of action seen by these switches has been as much as 3.65x10(7) A2 s. Switches of this design have been able to conduct up to 20 pulses of this magnitude before failure has occurred. The switch is triggerable down to 80 V potential across the anode and cathode. This paper describes the development of this switch.