EARLY ONSET AND CONSISTENT RESPONSEOF ONABOTULINUMTOXINA TREATMENT WITH SIGNIFICANT RESOLUTION OFURINARY SYMPTOMS IN FEMALE OVERACTIVE BLADDER PATIENTS WITH URINARYINCONTINENCE IN A MULTICENTER, RANDOMIZED, PLACEBO-CONTROLLED, PHASE4 TRIAL
K. MCCAMMON1, J.GRUENENFELDER 2, V. R. LUCENTE 3, A. OREJUDOS4, T. ABOUSHWAREB 4, D. S. HALE 5;
1Eastern Virginia Med. Sch., Norfolk, VA, 2OrangeCounty Urology Associates, Laguna Hills, CA, 3The Inst.for Female Pelvic Med. & Reconstructive Surgery, Allentown, PA,4Allergan plc, Irvine, CA, 5UrogynecologyAssociates, pc, Indianapolis, IN.
Introduction: In two large,placebo-controlled, phase 3 trials, onabotulinumtoxinA (onabotA) 100Usignificantly reduced urinary incontinence (UI) and improved qualityof life (QOL) at week 12 post-treatment in patients with overactivebladder (OAB). The earliest time to treatment response was notassessed in these trials. A randomized, multicenter,placebo-controlled, phase 4 trial was conducted in OAB patients toassess the efficacy of onabotA, compared with placebo, includingachievement of 100% reduction in incontinence episodes, as early asweek 1 post-treatment.
Objective: We present an interimanalysis of the female subpopulation of this ongoing phase 4post-marketing trial (NCT01945489) to assess the earliest time totreatment response and QOL outcomes with onabotA treatment in OABpatients with UI.
Methods: Female patients whose OAB hadbeen inadequately managed by ≥1 anticholinergic were randomized 1:1to receive onabotA 100U (n=114) or placebo (n=112). This prespecifiedinterim analysis presents data on the female subpopulation up to week12 after treatment. Assessments at weeks 1, 2, 6 and 12 (primary timepoint) post-injection included the mean change from baseline in UIepisodes/day (co-primary endpoint); proportions of patients whoachieved UI reductions of 100% (ie, ″dry;″ co-primary endpoint)and ≥50%; and mean changes from baseline in the urinary symptoms ofmicturition, nocturia and urgency UI episodes/day and theIncontinence-QOL (I-QOL) total summary score. The clinically relevantchange from baseline in I-QOL total score, or minimally importantdifference (MID), was based on published literature1 anddetermined a priori to be a +10 point increase. Adverse events(AEs) were also recorded, including rates of clean intermittentcatheterization (CIC) due to urinary retention. Analysis ofcovariance with treatment and stratification as factors and baselinevalue as a covariate for post baseline visit was used to calculatethe P-values for the continuous parameter. The CochranMantel-Haenszel test was used to calculate the P-values for I-QOL,adjusting for the baseline UI (≤9 vs >9 episodes in a 3-daybladder diary) as randomization stratification factor.
Results:Baseline mean UI episodes/day were 5.4 (onabotA) and 6.0 (placebo).Reductions from baseline in UI episodes/day were significantlygreater in the onabotA group vs placebo as early as week 1 (-2.8 vs-1.9; P=.012), which continued through week 2 (-3.0 vs -1.8; P=.002),week 6 (-3.3 vs -1.6; P<.001), and week 12 (-3.5 vs -1.5; P<.001).Significantly higher proportions of onabotA-treated patients achieved100% UI reduction vs placebo at week 1 (22.8% vs 4.5%), week 2 (25.4%vs 4.5%), week 6 (32.5% vs 5.4%) and week 12 (31.6% vs 4.5%) (P<.001vs placebo for all time points). As early as week 1, a significantlyhigher proportion of onabotA-treated vs placebo patients achieved≥50% UI reduction (57.9% vs 35.7%; P<.001); this continuedthrough week 12 (65.8% vs 36.6%; P<.001). Decreases in the numbersof daily episodes of micturition, nocturia, and urgency UI foronabotA vs placebo were noted as early as week 1 and continuedthrough week 12. Significantly greater improvements in I-QOL score of~1.5 times the MID were observed at week 1 in the onabotA-treatedgroup (15.3 vs 5.6 for placebo; P<.001). Improvements in I-QOLscore were consistently ~2-3 times the MID and significantly greaterthan placebo at weeks 2-12 (P<.001 for all). There were nounexpected safety signals; urinary tract infection was the mostcommon AE (23.0% vs 7.1%). CIC was initiated due to urinary retentionin 7.1% of onabotA-treated patients vs none in the placebogroup.
Conclusions: This female population of OAB patientstreated with onabotA showed significant reductions in UI episodes andclinically relevant improvements in QOL as early as week 1post-treatment. Significantly greater proportion of patients achievedcomplete continence (100% UI reduction) vs placebo as early as week1. The significant decreases in OAB symptoms and improvements in QOLcontinued through the week 12 interim data analysis. OnabotA was welltolerated
References: 1. Urology 1999; 53:71-6.