This is a post hoc analysis of data from a randomised, double-blind, active-controlled, parallel-group, flexible-dose phase IIIb trial conducted at 153 urological centres in Germany; details of the study design and methods were published previously [13]. The study was carried out in accordance with the German Drug Law, the Revised Declaration of Helsinki, and the European Union standards of Good Clinical Practice. The independent ethics committee of the Bavarian State Chamber of Physicians (Munich, Germany) approved the study protocol, the protocol amendment, the information sheet, and the consent form before the start of the study (reference number: 04075; Munich, 15 July 2004).
Patients
Eligibility for the study was determined by the completion of a 7-day micturition diary before randomisation. Men and women (18 years of age or older) with urinary frequency (eight or more micturitions every 24 hours) plus urge incontinence (five or more episodes per week) met the inclusion criteria.
Based on this first diary, subjects with a total daily urine volume of 2.8 L or more, a mean micturition volume of more than 250 mL, and/or a clinically significant bladder outlet obstruction (i.e., postvoid residual urine volume of more than 100 mL) were excluded from participation, as were those with an indwelling catheter or intermittent self-catheterization; urinary tract infection at the screening visit; interstitial cystitis and/or hematuria; contraindications to anticholinergic therapy (e.g., untreated narrow-angle glaucoma, mechanical gastrointestinal stenosis, myasthenia gravis syndrome), tachycardiac arrhythmia, severe psychiatric illnesses, hypersensitivity to trospium or oxybutynin or one of the vehicle ingredients; participation in a bladder training or electrostimulation program, or in another study within the past 30 days. Patients currently receiving drug treatment for UUI were allowed to enter the study following a 14-day washout period prior to study treatment. Concomitant treatments (i.e., other anticholinergic drugs or drugs possessing significant anticholinergic or sympathomimetic effects) as well as drugs that could interact with trospium or oxybutynin were prohibited at all times during the study. However, α-adrenergic blockers were permitted.
Study Design
Having given their written informed consent to the study, patients were randomised on a computer-generated block design ratio (1:1) stratified by centre at the entrance visit to receive 15 mg trospium chloride three times a day (TID) or 2.5 mg oxybutynin hydrochloride TID for 12 weeks. On the basis of the symptoms recorded in a second micturition diary and on the investigator's and patient's impression of the individual's tolerance of the study medication, daily doses could be adjusted upward after four weeks of treatment (at the intermediate visit), to 90 mg trospium (30 mg TID) or 15 mg oxybutynin (5 mg TID) for the following eight weeks. In the case of adverse events (AEs), the increased dosage could be readjusted to the starting point after one week. Patients whose symptoms were managed with the standard dose continued to receive the starting dosage of medication throughout the study. The study ended for each patient after 12 weeks of treatment (final visit).
Efficacy and tolerability assessment
For the post hoc analysis, patients in both treatment groups were stratified to subgroups according to "dose adjustment" or "no dose adjustment".
The primary efficacy variable for the current analysis - as for the parent study - was the absolute reduction in weekly UUI episodes comparing baseline values (i.e., the last week before the entrance visit) with those of treatment week 12 (i.e., the last week before the final visit). This quantitative symptom change was calculated from the patients' 7-day micturition diaries, which had been completed by each patient before randomisation and at treatment week 4 and 12. The intensity of dry mouth, one of the secondary efficacy variables in the parent study, was recorded on an ordinal scale (none, mild, moderate, or severe) and also evaluated from the entrance visit to the intermediate and final visits.
Tolerability was assessed by evaluating the spontaneously reported adverse events, and discontinuations in the subgroups. The association between AEs and treatment was based on physician-assessed causality.
All other efficacy and tolerability assessments conducted in the parent study were described there [13].
Statistical Analysis
The post hoc inferential analysis was performed using the full analysis set (FAS) of the parent study comprising all participants who belonged to the safety population (all patients who were exposed to study medication at least once) and for whom any post-randomisation efficacy data were available. All statistical analyses were descriptive. As normal distribution of the parameters of interest could not be assumed for between-group comparisons, we used the Wilcoxon rank sum test (van Elteren procedure), stratified by study centre for continuous variables. The Hodges-Lehmann point estimator (HLest) was used as a nonparametric estimator. Interval estimates were provided in the form of nonparametric 2-sided 95% CI. The distributions of the observed data are presented by median, quartiles, minimum, and maximum.