OnabotulinumtoxinA for Overactive Bladder
OnabotulinumtoxinA for Overactive Bladder
Details on the two phase 3 placebo-controlled trials (NCT00910845 and NCT00910520) have been previously published. Briefly, patients with idiopathic OAB with three or more UUI episodes over a 3-day period and eight or more micturitions/day were randomised 1 : 1 to receive 20 cystoscopic intradetrusor injections (0.5 ml/injection) of onabotulinumtoxinA 100U or placebo, sparing the trigone.
Patients were inadequately managed by one or more anticholinergic (insufficient efficacy or intolerable side effects); those with a predominance of stress UI were excluded. The number of prior anticholinergic therapies used and the reason for their inadequate management of OAB were recorded. Patients participated in the study for 24 weeks unless they withdrew consent or retreatment occurred. Retreatment was with onabotulinumtoxinA, and could occur from 12 weeks onward if the patient requested it and had at least two UUI episodes over 3 days. Therefore, the true placebo-controlled period was 12 weeks. The period between receipt of initial treatment and retreatment or study exit (if no retreatment) was defined as treatment cycle 1.
A 3-day paper bladder diary was used to collect all OAB symptoms (episodes of incontinence, urgency and micturition). Patients recorded their perception of treatment benefit at each posttreatment visit using the treatment benefit scale (TBS), rating their condition as 'greatly improved', 'improved', 'not changed' or 'worsened'. The number of prior anticholinergics used and the reasons for inadequate management by anticholinergic therapy were also recorded.
The coprimary end-points of change from baseline at week 12 in UI episodes/day and proportion of patients reporting a positive response (rating their condition 'greatly improved' or 'improved') on the TBS were evaluated in the overall pooled population and in subgroups of patients by number of prior anticholinergic therapies (1, 2 or ≥ 3) and the primary reason for inadequate management by their first anticholinergic therapy (insufficient efficacy or intolerable side effects). Change from baseline in urgency episodes and micturition frequency was also assessed. The time to patient request for retreatment was recorded for assessment of duration of treatment.
Adverse events (AEs), postvoid residual (PVR) urine volume and use of clean intermittent catheterisation (CIC) were evaluated at weeks 2, 6 and 12 posttreatment or at any other time depending on clinical need. CIC was initiated if the PVR urine volume was ≥ 200 ml and < 350 ml with associated symptoms (e.g. voiding difficulties or sensation of bladder fullness) or if the PVR urine volume was ≥ 350 ml, regardless of symptoms. The AE of urinary retention was defined as a PVR urine volume ≥ 200 ml that required CIC. The AE of urinary tract infection (UTI) was defined as positive urine culture with bacteriuria count of > 10 colony-forming units/ml, together with leukocyturia of > 5/high power field, even in the absence of symptoms.
Efficacy analyses were conducted using the overall pooled intent-to-treat population (all randomised patients) and safety analyses used the safety population, which comprised all patients who received treatment analysed by actual treatment received.
Daily UI episodes were analysed using an analysis of covariance model, with baseline number of UI episodes as covariates and study site and treatment group as factors. TBS was analysed using the Cochran-Mantel-Haenszel χ method with the number of baseline urgency UI episodes (≤ 9 or > 9) as a stratification factor. Both phase 3 studies were planned to provide 80% overall power to detect a between-group difference in change from baseline in the coprimary study end-points (a difference of 2.3 UI episodes/day, with a standard deviation of 8.5 for UI and a between-group difference of 22% for TBS), assuming an alpha of 0.05.
Methods
Study Design
Details on the two phase 3 placebo-controlled trials (NCT00910845 and NCT00910520) have been previously published. Briefly, patients with idiopathic OAB with three or more UUI episodes over a 3-day period and eight or more micturitions/day were randomised 1 : 1 to receive 20 cystoscopic intradetrusor injections (0.5 ml/injection) of onabotulinumtoxinA 100U or placebo, sparing the trigone.
Patients were inadequately managed by one or more anticholinergic (insufficient efficacy or intolerable side effects); those with a predominance of stress UI were excluded. The number of prior anticholinergic therapies used and the reason for their inadequate management of OAB were recorded. Patients participated in the study for 24 weeks unless they withdrew consent or retreatment occurred. Retreatment was with onabotulinumtoxinA, and could occur from 12 weeks onward if the patient requested it and had at least two UUI episodes over 3 days. Therefore, the true placebo-controlled period was 12 weeks. The period between receipt of initial treatment and retreatment or study exit (if no retreatment) was defined as treatment cycle 1.
Efficacy and Safety Evaluations
A 3-day paper bladder diary was used to collect all OAB symptoms (episodes of incontinence, urgency and micturition). Patients recorded their perception of treatment benefit at each posttreatment visit using the treatment benefit scale (TBS), rating their condition as 'greatly improved', 'improved', 'not changed' or 'worsened'. The number of prior anticholinergics used and the reasons for inadequate management by anticholinergic therapy were also recorded.
The coprimary end-points of change from baseline at week 12 in UI episodes/day and proportion of patients reporting a positive response (rating their condition 'greatly improved' or 'improved') on the TBS were evaluated in the overall pooled population and in subgroups of patients by number of prior anticholinergic therapies (1, 2 or ≥ 3) and the primary reason for inadequate management by their first anticholinergic therapy (insufficient efficacy or intolerable side effects). Change from baseline in urgency episodes and micturition frequency was also assessed. The time to patient request for retreatment was recorded for assessment of duration of treatment.
Adverse events (AEs), postvoid residual (PVR) urine volume and use of clean intermittent catheterisation (CIC) were evaluated at weeks 2, 6 and 12 posttreatment or at any other time depending on clinical need. CIC was initiated if the PVR urine volume was ≥ 200 ml and < 350 ml with associated symptoms (e.g. voiding difficulties or sensation of bladder fullness) or if the PVR urine volume was ≥ 350 ml, regardless of symptoms. The AE of urinary retention was defined as a PVR urine volume ≥ 200 ml that required CIC. The AE of urinary tract infection (UTI) was defined as positive urine culture with bacteriuria count of > 10 colony-forming units/ml, together with leukocyturia of > 5/high power field, even in the absence of symptoms.
Statistical Methods
Efficacy analyses were conducted using the overall pooled intent-to-treat population (all randomised patients) and safety analyses used the safety population, which comprised all patients who received treatment analysed by actual treatment received.
Daily UI episodes were analysed using an analysis of covariance model, with baseline number of UI episodes as covariates and study site and treatment group as factors. TBS was analysed using the Cochran-Mantel-Haenszel χ method with the number of baseline urgency UI episodes (≤ 9 or > 9) as a stratification factor. Both phase 3 studies were planned to provide 80% overall power to detect a between-group difference in change from baseline in the coprimary study end-points (a difference of 2.3 UI episodes/day, with a standard deviation of 8.5 for UI and a between-group difference of 22% for TBS), assuming an alpha of 0.05.
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