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TOVIAZ®Clinical Studies (fesoterodine fumarate)

14 CLINICAL STUDIES

14.1 Adult Overactive Bladder

The efficacy of Toviaz extended-release tablets was evaluated in two, Phase 3, randomized, double-blind, placebo-controlled, 12-week studies for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. Entry criteria required that patients have symptoms of overactive bladder for ≥6-months duration, at least 8 micturitions per day, and at least 6 urinary urgency episodes or 3 urge incontinence episodes per 3-day diary period. Patients were randomized to a fixed dose of Toviaz 4 or 8 mg/day or placebo. In one of these studies, 290 patients were randomized to an active control arm (an oral antimuscarinic agent). For the combined studies, a total of 554 patients received placebo, 554 patients received Toviaz 4 mg/day, and 566 patients received Toviaz 8 mg/day. The majority of patients were Caucasian (91%) and female (79%) with a mean age of 58 years (range 19–91 years).

The primary efficacy endpoints were the mean change in the number of urge urinary incontinence episodes per 24 hours and the mean change in the number of micturitions (frequency) per 24 hours. An important secondary endpoint was the mean change in the voided volume per micturition.

Results for the primary endpoints and for mean change in voided volume per micturition from the two 12-week clinical studies of Toviaz are reported in Table 10.

Table 10: Mean Baseline and Change From Baseline to Week 12 for Urge Urinary Incontinence Episodes, Number of Micturitions, and Volume Voided per Micturition
Study 1Study 2
ParameterPlacebo
N=279
Toviaz
4mg/day
N=265
Toviaz
8mg/day
N=276
Placebo
N=266
Toviaz
4mg/day
N=267
Toviaz
8mg/day
N=267
vs. = versus
*
Only those patients who were urge incontinent at baseline were included for the analysis of number of urge incontinence episodes per 24 hours: In Study 1, the number of these patients was 211, 199, and 223 in the placebo, Toviaz 4 mg/day and Toviaz 8 mg/day groups, respectively. In Study 2, the number of these patients was 205, 228, and 218, respectively.
Number of urge incontinence episodes per 24 hours*
  Baseline3.73.83.73.73.93.9
  Change from baseline-1.20-2.06-2.27-1.00-1.77-2.42
  p-value vs. placebo-0.001<0.001-<0.003<0.001
Number of micturitions per 24 hours
  Baseline12.011.611.912.212.912.0
  Change from baseline-1.02-1.74-1.94-1.02-1.86-1.94
  p-value vs. placebo-<0.001<0.001-0.032<0.001
Voided volume per micturition (mL)
  Baseline150160154159152156
  Change from baseline10273381733
  p-value vs. placebo-<0.001<0.001-0.150<0.001

Figures 1–4: The following figures show change from baseline over time in number of micturitions and urge urinary incontinence episodes per 24 h in the two studies.

Figure 1

Figure 2

Figure 3

Figure 4

A reduction in number of urge urinary incontinence episodes per 24 hours was observed for both doses as compared to placebo as early as two weeks after starting Toviaz therapy.

14.2 Pediatric Neurogenic Detrusor Overactivity

The efficacy of Toviaz was evaluated in Study 3 (NCT01557244), a Phase 3, randomized, open-label study consisting of a 12-week efficacy phase followed by a 12-week safety extension phase in pediatric patients from 6 years to 17 years of age. Two cohorts were studied. Cohort 1 (patients weighing greater than 25 kg) received a fixed dose of Toviaz 4 mg or Toviaz 8 mg tablets orally once daily, or once daily. In the safety extension phase, patients randomized to the active comparator were switched to Toviaz 4 mg or Toviaz 8 mg once daily. For study inclusion, patients were required to have stable neurological disease and clinically or urodynamically-demonstrated NDO. Cohort 2 patients weighing less than 25 kg received an investigational fesoterodine formulation.

During the 12-week efficacy phase, 124 patients (69 males and 55 females) were randomized to receive Toviaz 4 mg (N=42), Toviaz 8 mg (N=42), or active comparator (N=40) orally once daily. The majority of patients were Caucasian (52%) or Asian (44%) with a mean age of 11 years (range 6 years to 17 years) and a mean weight of 42.8 kg (range 25.1 to 96.0 kg).

Primary Endpoint

The primary efficacy endpoint was the mean change from baseline in maximum cystometric bladder capacity (MCBC) at Week 12.

Treatment with Toviaz 4 mg or 8 mg daily resulted in improvements from baseline to Week 12 in the primary efficacy endpoint, MCBC, for pediatric patients, with numerically higher changes from baseline for Toviaz 8 mg daily than for Toviaz 4 mg daily.

Results for the primary endpoint MCBC are reported in Table 11.

Table 11: Mean Baseline and Change From Baseline to Week 12 for Maximum Cystometric Bladder Capacity (mL) in Pediatric NDO Patients Receiving Toviaz 4 mg or Toviaz 8 mg and Weighing More Than 25 kg in Study 3
Toviaz 4 mgToviaz 8 mg
CI = confidence interval
Baseline is defined as the last available measurement prior to the start of treatment.
N is the number of patients who took at least one dose and provided a valid value for MCBC at baseline.
*
Least squares mean change and 95% CI are based on an analysis of covariance model with terms for treatment group, baseline maximum cystometric bladder capacity and baseline weight. Last observation carried forward/baseline observation carried forward was used for imputing missing values at Week 12.
N4141
Baseline195.1173.3
Change from baseline
(95% CI)*
58.1
(28.8, 87.4)
83.4
(54.2, 112.5)

Secondary Endpoints

Results for other urodynamic secondary efficacy endpoints and selected secondary efficacy endpoints derived from patient urinary diaries are reported in Tables 12 and 13, respectively.

Table 12: Summary of Baseline and Change From Baseline to Week 12 in Secondary Urodynamic Endpoints in Pediatric NDO Patients Weighing Greater Than 25 kg in Study 3
Toviaz 4 mgToviaz 8 mg
CI = confidence interval; IDC = involuntary detrusor contractions
Baseline is defined as the last available measurement prior to the start of treatment.
N is the number of patients who took at least one dose and provided valid endpoint data at baseline .
*
Least squares mean change and 95% CI are based on an analysis of covariance model with terms for treatment group, baseline (for the endpoint being analyzed) and baseline weight. Last observation carried forward/baseline observation carried forward was used for imputing missing values at Week 12.
Detrusor pressure at maximum bladder capacity (cmH2O)
N4041
Baseline26.527.2
Change from Baseline
(95% CI)*
-2.9
(-7.6, 1.9)
-1.6
(-6.3, 3.1)
Number and percentage of patients with IDC at Baseline but not at Week 12 (n (%))
N4141
n (%)9 (22.0)18 (43.9)
Bladder volume at first IDC (mL)
N2636
Baseline88.688.5
Change from Baseline
(95% CI)*
30.5
(2.4, 58.6)
26.1
(2.2, 49.9)
Bladder compliance (mL/cmH20)
N4040
Baseline13.810.1
Change from Baseline
(95% CI)*
6.4
(-0.5, 13.3)
5.4
(-1.5, 12.3)
Table 13: Mean Baseline and Change From Baseline to Week 12 in Selected Secondary Bladder-Diary Endpoints in Pediatric NDO Patients Weighing Greater Than 25 kg in Study 3
Toviaz 4 mgToviaz 8 mg
CI = confidence interval
Baseline is defined as the last available measurement prior to the start of treatment.
N is the number of patients who took at least one dose and provided valid endpoint data at baseline.
*
Only patients with >0 incontinence episodes at baseline are included.
Least squares mean change and 95% CI are based on an analysis of covariance model with terms for treatment group, baseline (for the endpoint being analyzed) and baseline weight. Last observation carried forward/baseline observation carried forward was used for imputing missing values at Week 12.
Number of incontinence episodes per 24 hours*
N3333
Baseline2.82.7
Change from Baseline
(95% CI)
-0.5
(-0.9, 0.0)
-0.9
(-1.4, -0.4)
Maximum catheterized urine volume per 24 hours (mL)
N3632
Baseline222.5164.7
Change from Baseline
(95% CI)
31.6
(-9.3, 72.6)
51.0
(8.1, 93.8)
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