The population of the current analysis, which corresponds to the safety population of the parent study, included 828 patients (49.9%) randomised to trospium chloride 45 mg/d and 830 patients (50.1%) randomised to oxybutynin 7.5 mg/d at 153 urological centres in Germany. After four weeks, 29.2% (484 of 1658) had their dose adjusted to the permitted increased (i.e., doubled) dose: 31.5% (261 of 828) of patients in the trospium group, and in 26.9% (223 of 830) of patients in the oxybutynin group. After one week, however, 10.1% (49 of 484) of them (19 in the trospium group and 30 in the oxybuytnin group) had subsequent dose readjustments that returned them to the standard starting dose until the end of treatment.
The FAS population comprised 1608 patients (TC: 810; OXY: 798). No post-randomisation data were available for 50 patients: 18 (2.2%) in the TC-group and 32 (3.9%) in the OXY-group. Patient demographics revealed no clinically relevant differences between the treatment groups. The mean (SD
) age of patients was 61.3 (12.17) years (median: 63 years; range: 20-91 years), 90.3% (n = 1452) were women. Other patient demographics and characteristics were previously reported [13
Urge incontinence episodes
Treatment with either trospium chloride or oxybutynin reduced the total number of UUI episodes per week in the patient population selected by the defined in- and exclusion criteria. Table lists the results of the patients' diaries.
Changes in UUI episodes per week by dose adjustment in the TC-treatment group and the OXY- treatment group (FAS)
In the FAS set, the baseline values of UUI episodes per week (median and mean values) of the "dose adjustment" subgroups were slightly higher than the baseline values of the "no dose adjustment" subgroups in both treatment groups, with the only exception concerning the baseline median values in the oxybutynin "dose adjustment" subgroup. Until the intermediate visit all patients received the standard dose of the relevant medication. At the intermediate visit the patients who fulfilled the criteria for dose adjustment still suffered from a higher number of weekly UUI episodes compared to those patients who needed no dose adjustment. At the final visit the absolute changes in weekly UUI episodes from baseline to week 12 (primary endpoint) showed no relevant differences between the "dose adjustment" subgroups and the "no dose adjustment" subgroups in both treatment groups. Figure illustrates median changes in weekly UUI episodes at each visit for both treatment groups and all subgroups. In the FAS the median change was -11.00 in the "no dose adjustment" TC-subgroup and -10.58 in the "dose adjustment" TC-subgroup; in the oxybutynin treatment group the median change was -10.00 in the "no dose adjustment" subgroup and -9.00 in the "dose adjustment" subgroup. There was no indication whatsoever of a significant difference between the subgroups ("no dose adjustment" and "dose adjustment") in terms of this change neither in the trospium group (P = 0.249) nor in the oxybutynin group (P = 0.349). This is also obvious from the corresponding non-parametric estimator (HLest) for the difference between both subgroups and the corresponding 95% CI.
Changes in UUI episodes per week by dose adjustment (median values, FAS).
Intensity of mouth dryness
The percentage of patients without mouth dryness was comparable between the treatment groups at baseline (trospium: 46.8% [257 of 549; "no dose adjustment"]/49.2% [119 of 242; "dose adjustment"] versus oxybutynin: 45.6% [262 of 575]/45.6% [88 of 193]). At the final visit, the percentage of patients reporting no dry mouth was 19.5% (107 of 549) in the "no dose adjustment" TC-subgroup versus 13.2% (32 of 242) in the "dose adjustment" TC-subgroup, and 8.7% (50 of 575) in the "no dose adjustment" OXY-subgroup versus 4.7% (9 of 193) in the "dose adjustment" OXY-subgroup.
At week 4 and 12, the increase in "dry mouth" intensity was significantly lower (P < 0.001) in the trospium groups than in the oxybutynin groups. The percentage of patients who experienced worsening of dry mouth from baseline to end of study was 57.0% (138 of 242) in the "dose adjustment" TC-subgroup versus 70.5% (136 of 193) in the "dose adjustment" OXY-subgroup, and 47.7% (262 of 549) in the "no dose adjustment" TC-subgroup versus 62.4% (359 of 575) in the "no dose adjustment" OXY-subgroup (Figure ). Thus, patients of both dose adjusted subgroups experienced an approximately 10% higher rate of worsening of mouth dryness than patients of the respective "no dose adjustment" groups at the end of study. The differences between the subgroups were significant for the time period between the intermediate (i.e., time of dose escalation) and the final visit (worsening for TC: 43.4% [105 of 242] in the "dose adjustment" subgroup versus 20.0% [110 of 549] in the "no dose adjustment" subgroup, P < 0.001; OXY: 43.5% [84 of 193] versus 19.5% [112 of 575], P < 0.001), whereas the analysis of the changes from baseline to the end of treatment revealed no significant difference between the "dose adjustment" and the "no dose adjustment" subgroups for both treatment groups (TC: P = 0.049; OXY: P = 0.071).
Changes in intensity of dry mouth by dose adjustment (%, FAS).
The safety population of the parent study comprised 1658 patients. The tolerability assessments of the current analysis based on 1609 patients, i.e., all patients of the safety population minus those patients (n = 49) who had dose readjustment because of AEs (19 [2.3%] in the trospium group and 30 [3.6%] in the oxybutynin group). The main reasons for dose readjustment that were determined to be definitely, probably, or possibly treatment-related were gastrointestinal disorders, such as dry mouth (n = 24), nausea (n = 7), and constipation (n = 3). More patients (n = 17) treated with oxybutynin 15 mg/d experienced the most frequent disorder dry mouth than those receiving trospium 90 mg/d (n = 7). Most cases of dry mouth were moderate to severe.
Regarding the time period between the intermediate visit (i.e., the time of dose escalation) and the final visit, treatment related AEs occurred in 43 out of 809 patients (5.3%) taking trospium and in 58 out of 800 patients (7.3%) taking oxybutynin. Hereby, patients of both dose adjusted subgroups suffered from a slightly higher rate of AEs possibly related to the study medication than those of the "no dose adjustment" subgroups (trospium: 9.5% [23 of 242] versus 3.5% [20 of 567], P < 0.001; oxybutynin: 10.9% [21 of 193] versus 6.1% [37 of 607], P = 0.026). However, this fact did not lead to a higher rate of study discontinuations in the dose adjusted subgroups, neither in the TC-subgroup (5.4% [13 of 242] in the "dose adjustment" subgroup versus 5.1% [29 of 567] in the "no dose adjustment" subgroup, P = 0.880) nor in the OXY-subgroup (6.2% [12 of 193] versus 6.1% [37 of 607], P = 0.951) regarding the same time interval.
Treatment-related AEs were typically anticholinergic in nature, including dry mouth, constipation, nausea, dyspepsia, and diarrhoea. Full details of the tolerability assessments based on the data from the parent study were described previously [13