TROSPIUM CHLORIDE (Page 4 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: Carcinogenicity studies with trospium chloride were conducted in mice and rats for 78 weeks and 104 weeks, respectively, at maximally tolerated doses. No evidence of a carcinogenic effect was found in either mice or rats administered up to 200 mg/kg/day (approximately 1 and 16 times, respectively (based on AUC), the expected clinical exposure levels at the maximum recommended human dose (MRHD) of 60 mg.

Mutagenesis: Trospium chloride was not mutagenic nor genotoxic in tests in vitro in bacteria (Ames test) and mammalian cells (L5178Y mouse lymphoma and CHO cells) or in vivo in the mouse micronucleus test.

Impairment of Fertility: No evidence of impaired fertility was observed in rats administered doses up to 200 mg/kg/day (about 16 times the expected clinical exposure at the MRHD, based on AUC).

14 CLINICAL STUDIES

Trospium chloride extended-release capsules were evaluated for the treatment of patients with overactive bladder who had symptoms of urinary frequency, urgency and urge urinary incontinence in two 12-week, randomized, double-blind, placebo-controlled studies. For both studies, entry criteria required the presence of urge incontinence (predominance of urge), at least one incontinence episode per day, and 10 or more micturitions (voids) per day (assessed by 3-day urinary diary). Medical history and data from the baseline urinary diary confirmed the diagnosis. Approximately 88% of the patients enrolled completed the 12-week studies. The mean age was 60 years, and the majority of patients were female (84%) and Caucasian (86%).

The co-primary endpoints in the trials were the mean change from baseline to Week 12 in number of voids/24 hours (reductions in urinary frequency) and the mean change from baseline to Week 12 in number of incontinence episodes/24 hours. Secondary endpoints included mean change from baseline to Week 12 in volume per void.

Study 1 included 592 patients in both trospium chloride extended-release capsules 60 mg and placebo groups. As illustrated in Table 4 and Figures 2 and 3, trospium chloride extended-release capsules demonstrated statistically significantly (p<0.01) greater reductions in the urinary frequency and incontinence episodes, and increases in void volume when compared to placebo starting at Week 1 and maintained through Weeks 4 and 12.

Table 4: Mean (SE) Change from Baseline in Urinary Frequency, Urge Incontinence Episodes and Void Volume in Study 1

Efficacy Endpoint a

Week

Placebo

Trospium Chloride Extended-Release Capsules

P-Value

Urinary frequency / 24 hours (N=300) (N=292)
Mean Baseline012.7 (0.2)12.8 (0.2)
Mean Change from Baseline1-1.2 (0.1)-1.7 (0.1)0.0092
4-1.6 (0.2)-2.4 (0.2)<0.0001
12-2.0 (0.2)-2.8 (0.2)<0.0001
Urge incontinence episodes / week (N=300) (N=292)
Mean Baseline029.0 (1.3)28.8 (1.3)
Mean Change from Baseline1-8.7 (1.0)-13.0 (0.9)0.0003
4-12.2 (1.1)-16.5 (1.2)0.0054
12-13.5 (1.1)-17.3 (1.2)0.0024
Urinary volume / void (mL) (N=300) (N=290)
Mean Baseline0155.9 (3.0)151.0 (2.9)
Mean Change from Baseline112.1 (2.1)21.6 (2.8)0.0036
417.2 (2.5)30.0 (3.1)0.0007
1218.9 (2.8)29.8 (3.2)0.0039

a treatment differences assessed by rank ANOVA for intent-to-treat population, last observation carried forward (ITT:LOCF) data set

Figure 2: Mean Change from Baseline in Urinary Frequency/24 hours by Visit: Study 1

figure-2
(click image for full-size original)

Figure 3: Mean Change from Baseline in Incontinence Episodes/Week by Visit: Study 1

figure-3
(click image for full-size original)

Study 2 included 543 patients in both trospium chloride extended-release capsules 60 mg and placebo groups and was identical in design to Study 1. As illustrated in Table 5 and Figures 4 and 5, trospium chloride extended-release capsules demonstrated statistically significantly (p<0.01) greater reductions in urinary frequency and incontinence episodes, and increases in void volume when compared to placebo at Weeks 4 and 12. However, at Week 1, statistically significant reductions were seen in urinary incontinence episodes and volume void only.

Table 5: Mean (SE) Change from Baseline in Urinary Frequency, Urge Incontinence Episodes and Void Volume in Study 2

Efficacy Endpoint a

Week Placebo Trospium Chloride Extended-Release Capsules P- Value
Urinary Frequency / 24 hours (N=276) (N=267)
Mean Baseline012.9 (0.2)12.8 (0.2)
Mean Change from Baseline1-1.2 (0.2)-1.4 (0.2)0.0759
4-1.7 (0.2)-2.3 (0.2)0.0047
12-1.8 (0.2)-2.5 (0.2)0.0009
Urge incontinence episodes / week (N=276) (N=267)
Mean Baseline028.3 (1.4)28.2 (1.2)
Mean Change from Baseline1-7.3 (1.0)-11.9 (1.0)<0.0001
4-10.6 (1.1)-15.8 (1.1)<0.0001
12-11.3 (1.2)-16.4 (1.3)<0.0001
Urinary volume / void (mL) (N=276) (N=266)
Mean Baseline0151.8 (2.8)149.6 (2.9)
Mean Change from Baseline111.9 (2.5)24.1 (2.4)<0.0001
419.6 (3.1)29.3 (3.0)0.0020
1217.8 (3.3)31.5 (3.4)0.0014

a treatment differences assessed by rank ANOVA for intent-to-treat population, last observation carried forward (ITT:LOCF) data set

Figure 4: Mean Change from Baseline in Urinary Frequency/24 hours by Visit: Study 2

figure-4
(click image for full-size original)

Figure 5: Mean Change from Baseline in Incontinence Episodes/Week by Visit: Study 2

figure-5
(click image for full-size original)

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