AbobotulinumtoxinA is effective in patients with urinary incontinence due to neurogenic detrusor overactivity regardless of spinal cord injury or multiple sclerosis etiology: Pooled analysis of two phase III randomized studies (CONTENT1 and CONTENT2)

Abstract

Background: Neurogenic detrusor overactivity incontinence (NDOI) is often inadequately managed with oral therapy.

Objective: To assess efficacy and safety of abobotulinumtoxinA (aboBoNT-A; Dysport®; Ipsen Ltd.) according to etiology of NDOI.

Design, setting, and participants: Two phase III, randomized, double-blind studies (CONTENT1 [NCT02660138] conducted in Asia, Europe and North America; CONTENT2 [NCT02660359] conducted in the Americas, Asia, Europe and Oceania) both included patients with spinal cord injury (SCI) or multiple sclerosis (MS), with inadequately managed NDOI, regularly performing clean intermittent catheterization (CIC).

Intervention: Patients in CONTENT1 and CONTENT2 received aboBoNT-A injections 600 U (n = 162)/800 U (n = 161), or placebo (n = 162) into the detrusor muscle.

Outcome measurements and statistical analysis: Primary endpoint: mean change from baseline in number of NDOI episodes/week at Week 6. Secondary endpoints: proportion of patients with no NDOI episodes; incontinence-related quality of life (I-QoL); urodynamic parameters; and time-to-retreatment. Safety was also assessed. Statistical analyses were conducted for pooled populations by etiology (aboBoNT-A doses vs. placebo).

Results and limitations: Of 485 randomized patients, 341 (70%) and 144 (30%) had SCI and MS etiologies, respectively. A significant reduction was observed in mean NDOI episodes/week at Week 6 with both aboBoNT-A doses versus placebo in the SCI (all p < 0.001) and MS (all p < 0.01) groups, as well as significant improvements in I-QoL and urodynamic parameters. Median time-to-retreatment was longer in patients with MS (48-62 weeks across doses) than those with SCI (39-44 weeks). Safety data were similar between etiologies. Urinary tract infection was the most frequent adverse event; similar numbers were reported across treatment groups.

Conclusions: AboBoNT-A was well tolerated and significantly improved continence and bladder function, and QoL, in patients with SCI or MS with NDOI performing regular CIC.

Patient summary: AboBoNT-A injections improved QoL, symptoms, and bladder function in patients with SCI or MS with bladder muscle overactivity that causes incontinence.

Keywords: AbobotulinumtoxinA; Botulinum toxin; multiple sclerosis; neurogenic detrusor overactivity incontinence; spinal cord injury.

Figure 1

Change in weekly number NDOI episodes^a in patients with (A) SCI and (B) MS, and proportion of patients^b with different thresholds of improvements from baseline at Week 6 with (C) SCI and (D) MS. *p < 0.05; **p < 0.01; ***p < 0.001. Data in (A) and (B) are LS mean ± SE. Data shown are for the randomized pooled population (DBPC period). ^aBased on the MMRM model to assess difference in change from baseline between each aboBoNT‐A dose group (600 or 800 U) versus placebo at each timepoint (Weeks 2, 6, and 12) with treatment group, visits (Weeks 2, 6, and 12), treatment by‐visit interaction, etiology of NDOI [SCI or MS], prior intradetrusor use [BoNT‐A‐naïve or BoNT‐A‐non‐naïve]), treatment‐by‐visit‐by‐etiology group interaction, study as fixed effect variables, study baseline value as covariate, and patient as a random effect. ^bThe outcomes are based on logistic GLMM model to assess difference between each aboBoNT‐A dose group (600 or 800 U) versus placebo with treatment group, stratification factors, visit (Weeks 2, 6, and 12), treatment‐by‐visit interaction, study baseline‐by‐visit interaction, treatment‐by‐visit‐etiology group interaction, study as fixed effect, and study baseline covariate and patient as random effect. Week 6 data only are presented. AboBoNT‐A, abobotulinumtoxinA; BoNT‐A, botulinum toxin type A; DBPC, double‐blind placebo‐controlled; LS, least square; GLMM, generalized linear mixed model; MMRM, mixed‐model repeated measures; MS, multiple sclerosis; N, number of patients in treatment group; n, number of patients with data; NDOI, neurogenic detrusor overactivity incontinence; SCI, spinal cord injury; SE, standard error; U, units

Figure 2

Change from baseline to Week 6 in I‐QoL total summary score^a in patients with (A) SCI and (B) MS. ***p < 0.001 vs. placebo. Data are LS mean ± SE. Data shown are for the randomized population. ^aBased on the MMRM model to assess difference in change from baseline between each aboBoNT‐A dose group (600 or 800 U) versus placebo with treatment group, visits (Weeks 6 and 12), treatment by‐visit interaction, stratification factors (etiology of NDOI [SCI or MS], prior intradetrusor use [BoNT‐A‐naïve or BoNT‐A‐non‐naïve]), treatment‐by‐visit‐by‐etiology group interaction, study as fixed effect variables, study baseline value as covariates, and patient as a random effect. The statistical model includes Weeks 6 and 12; only Week 6 results are presented. AboBoNT‐A, abobotulinumtoxinA; BoNT‐A, botulinum toxin type A; I‐QoL, incontinence quality of life; LS, least squares; MMRM, mixed‐model repeated measures; MS, multiple sclerosis; N, number of patients in treatment group; n, number of patients with data; NDOI, neurogenic detrusor overactivity incontinence; SCI, spinal cord injury; SE, standard error; U, units

Figure 3

Change from baseline in MCC and MDFP,^a and proportion of patients with no IDC^b at Week 6 in patients with SCI (A, C, E) and MS (B, D, F). **p < 0.01; ***p < 0.001 vs. placebo. Data for (A)–(D) are LS mean ± SE. Data shown are for urodynamic pooled population (DBPC period). ^aBased on an analysis of covariance model to assess difference in change from baseline between each aboBoNT‐A dose group (600 or 800 U) versus placebo at Week 6, with treatment group, stratification factors (etiology of NDOI [SCI or MS], prior intradetrusor use [BoNT‐A naïve or non‐naïve]), study baseline value, study and the treatment‐by‐etiology group interaction as fixed effect variables; ^bBased on logistic regression model to assess difference between each aboBoNT‐A dose group (600 or 800 U) versus placebo at Week 6, with treatment group, stratification factors (etiology of NDOI [SCI or MS], prior intradetrusor use [BoNT‐A naïve or non‐naïve]), study, and treatment‐by‐etiology group interaction as fixed variables. AboBoNT‐A, abobotulinumtoxinA; BoNT‐A, botulinum toxin type A; DBPC, double‐blind placebo‐controlled; IDC, involuntary detrusor contraction; LS, least squares; MCC, maximum cystometric capacity; MDFP, maximum detrusor filling pressure; MS, multiple sclerosis; N, number of patients in treatment group; n, number of evaluable patients; NDOI, neurogenic detrusor overactivity incontinence; SCI; spinal cord injury; SE, standard error; U, units