An extended release formulation of trospium chloride was recently developed for the once daily treatment of overactive bladder. We investigated the safety, efficacy and tolerability of 60 mg trospium chloride once daily.
Subjects with overactive bladder were randomized 1:1 to receive 60 mg trospium chloride once daily or placebo in this 12-week multicenter, parallel, double-blind, placebo controlled trial. Primary end points were calculated changes in diary recorded daily urinary frequency and daily urgency urinary incontinence episodes. Secondary end points were urgency severity, volume voided per void and the number of urgency voids per day. Safety was assessed by clinical examination, adverse event monitoring, clinical laboratory values and resting electrocardiograms.
Overall 601 subjects were prescribed trospium once daily (298) or placebo (303). Trospium once daily treatment resulted in significant improvements over placebo in all primary and key secondary efficacy outcomes at weeks 1 through 12. The most common adverse events were dry mouth (trospium 8.7% vs placebo 3%) and constipation (trospium 9.4% vs placebo 1.3%). Central nervous system adverse events were rare (headache with trospium 1.0% vs placebo 2.6%). No clinically meaningful changes in laboratory, physical examination or electrocardiogram parameters were noted.
Trospium once daily provided significant improvements in overactive bladder symptoms (frequency, urgency urinary incontinence and urgency). Efficacy was similar to that seen previously with trospium chloride twice daily, while class effect anticholinergic adverse events occurred at comparatively low levels. Dry mouth was elicited at the lowest reported rate in the oral antimuscarinic drug class.
"To determine the clinical implications of the reduced trospium exposure during concomitant metformin administration, a post hoc analysis was performed on efficacy data reported from two multicentre, randomized, double-blind, placebo-controlled Phase III trials [25, 26]. Comparison of primary efficacy outcomes (average number of toilet voids and urinary urge incontinence [UUI] episodes per day) was conducted between subjects who received both metformin and trospium chloride XR, and an equal number of subjects not on metformin but who received trospium chloride XR only (i.e., 1:1 matching). "
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Overactive bladder (OAB) is often associated with a number of co-morbid medical conditions, including diabetes mellitus. This may necessitate several concomitant treatments, thus creating the potential for drug-drug interactions (DDIs). Trospium is renally eliminated, not metabolized via cytochrome P450; therefore, cytochrome P450 DDIs are unlikely. However, coadministration with another renally eliminated drug (e.g., metformin) may theoretically result in a DDI. OBJECTIVE: The objective of this study was to evaluate the pharmacokinetics (plasma and urine) and safety/tolerability of the coadministration of trospium chloride extended release (XR) and metformin under steady-state conditions in healthy male and female subjects. METHODS: In a single-centre, randomized, open-label, two-group, two-period study in healthy males and females aged 18-45 years, 44 subjects received oral metformin 500 mg twice daily for 3.5 days during one period, and oral trospium chloride XR 60 mg once daily for 10 days, followed by trospium chloride XR 60 mg once daily for 4 days plus metformin 500 mg twice daily for 3.5 days during the other period. The two periods occurred in a crossover fashion, separated by a 3-day washout period. RESULTS: Trospium chloride XR coadministration did not alter metformin steady-state pharmacokinetics. Metformin coadministration reduced trospium steady-state maximum plasma concentration (by 34 %) and area under the concentration-time curve from 0-24 hours (by 29 %). Neither drug's renal clearance was affected. No safety/tolerability issues of concern were observed with coadministration. CONCLUSION: No dosage adjustment is necessary for metformin when coadministered with trospium chloride XR.
Clinical Drug Investigation 01/2013; 33(2). DOI:10.1007/s40261-012-0049-6 · 1.56 Impact Factor
"Thirty-four publications which included a placebo arm were identified in the Chapple meta-analysis . The systematic literature review over the most recent 12 months identified 2 additional studies [9,10]. The 36 studies were identified that met acceptance criteria, and these are listed in Table 1[9-44]. "
[Show abstract][Hide abstract] ABSTRACT: The purpose of this analysis was to characterize the placebo response in antimuscarinic drug trials for OAB, based on changes in commonly-used efficacy endpoints.
Placebo arm data for incontinence episodes, micturitions, voided volume and study characteristics were extracted from randomized placebo controlled antimuscarinic drug trials in OAB, from studies identified in a prior meta-analysis, and from a systematic review of more recently published studies. Relationships between variables were examined using linear regression, and changes in endpoints were analyzed by a meta-analysis approach. The effect of placebo arm size and magnitude of placebo response on probability of successful study outcome was analyzed using an ANOVA model.
Changes in the placebo arms for all 3 endpoints were substantial and statistically significant, and highly heterogeneous. There were significant associations between baseline and change scores for some but not all of the endpoints. More recent studies tended to have more subjects than earlier studies, and there were positive associations between probability of achieving statistically significant results and size of the placebo arm. The magnitude of changes in placebo arms did not appear to influence the likelihood of the study to be statistically significant.
This analysis confirms earlier observation that the placebo response in OAB trials is substantial and highly heterogeneous. There are multiple potential reasons for this; however, these could not be explored in this analysis of study-level data. Two approaches may be used in clinical trials to manage high placebo effect: recruitment of 1) greater numbers of patients and/or 2) more severely affected patients; however, only the former approach is associated with increased probability of successful study outcome.
BMC Medical Research Methodology 02/2009; 9(1):55. DOI:10.1186/1471-2288-9-55 · 2.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Urgency, the primary symptom of overactive bladder (OAB), is thought to be central in driving all other symptoms of OAB, including
frequency, nocturia, and urge urinary incontinence. Although it is defined by the International Continence Society as a sudden
compelling desire to pass urine that is difficult to defer, it remains difficult to describe and measure. Several self-administered
metrics have been developed to measure urgency and have been used to demonstrate the efficacy of antimuscarinic agents in
the treatment of OAB. Urodynamics measures bladder sensation during cystometry, but its role in measuring urgency has not
been well defined. This review discusses scales commonly used to measure urgency and the role of urodynamics in its assessment.
Current Bladder Dysfunction Reports 09/2009; 4(3):155-159. DOI:10.1007/s11884-009-0022-2
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