Efficacy of Botulinum Toxin A Injection for Neurogenic Detrusor Overactivity and Urinary Incontinence: A Randomized, Double-Blind Trial

Efficacy of Botulinum Toxin A Injection for Neurogenic Detrusor Overactivity and Urinary Incontinence: A Randomized, Double-Blind Trial

Purpose

We determined the efficacy of onabotulinumtoxinA for neurogenic detrusor overactivity secondary to spinal cord injury or multiple sclerosis.

Materials and Methods

In a prospective, double-blind, multicenter study 57 patients 18 to 75 years old with neurogenic detrusor overactivity secondary to spinal cord injury or multiple sclerosis and urinary incontinence (defined as 1 or more occurrences daily) despite current antimuscarinic treatment were randomized to onabotulinumtoxinA 300 U (28) or placebo (29) via cystoscopic injection at 30 intradetrusor sites, sparing the trigone. Patients were offered open label onabotulinumtoxinA 300 U at week 36 and followed a further 6 months while 24 each in the treatment and placebo groups received open label therapy. The primary efficacy parameter was daily urinary incontinence frequency on 3-day voiding diary at week 6. Secondary parameters were changes in the International Consultation on Incontinence Questionnaire and the urinary incontinence quality of life scale at week 6. Diary and quality of life evaluations were also done after open label treatment.

Results

The mean daily frequency of urinary incontinence episodes was significantly lower for onabotulinumtoxinA than for placebo at week 6 (1.31 vs 4.76, p <0.0001), and for weeks 24 and 36. Improved urodynamic and quality of life parameters for treatment vs placebo were evident at week 6 and persisted to weeks 24 to 36. The most common adverse event in each group was urinary tract infection.

Conclusions

In adults with antimuscarinic refractory neurogenic detrusor overactivity and multiple sclerosis onabotulinumtoxinA is well tolerated and provides clinically beneficial improvement for up to 9 months.

Key Words: urinary bladder, neurogenic, botulinum toxin type A, urinary incontinence, multiple sclerosis, spinal cord injuries

Abbreviations and Acronyms: AE, adverse event, BoNT-A, onabotulinumtoxinA, ICIQ, International Consultation on Incontinence Questionnaire, I-QOL, UI QOL Scale, MS, multiple sclerosis, NDO, neurogenic detrusor overactivity, QOL, quality of life, SCI, spinal cord injury, UI, urinary incontinence

 

Urinary dysfunction, including UI, is common in patients with SCI or MS.¹, ², ³, ⁴, ⁵ First line treatment for NDO secondary to SCI or MS is usually antimuscarinic medication with or without intermittent catheterization to accomplish bladder emptying.⁶

Patients with NDO may have an incomplete response to pharmacotherapy.⁷ Also, adverse effects may limit antimuscarinic use,⁷ particularly since patients with NDO typically require higher doses than patients with idiopathic detrusor overactivity.⁶ Investigational agents such as capsaicin and resiniferatoxin are not widely applicable and invasive surgical procedures such as bladder myomectomy, intestinal augmentation or urinary diversion may be the only alternative in some instances.⁶

In 2000 the use of intradetrusor BoNT-A for NDO was first reported.⁸ It provides significant improvement in patients with NDO, including those refractory to antimuscarinics.⁹, ¹⁰, ¹¹, ¹², ¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷, ¹⁸ However, in the literature there is a paucity of randomized, placebo controlled trials of BoNT-A in patients with NDO.¹⁹, ²⁰ We determined the efficacy of intravesical BoNT-A in patients with NDO and UI secondary to SCI or MS.

Back to Article Outline

Materials and Methods

This prospective, randomized, double-blind study was performed across Canada in 7 centers from October 2006 to April 2009. The study enrolled men and women 18 to 75 years old with NDO secondary to SCI or MS who had UI (1 or more episodes daily) despite current antimuscarinic treatment based on a 3-day baseline voiding diary during the 1 to 2-week screening period. Patients were asked to record intake and voided volume, void type, voiding need strength, and incontinence episodes and severity.

Additional study inclusion criteria were normal renal function assessed by the investigator by serum chemistry and renal ultrasound, and stability on a stable dose of medication for NDO for 1 month or greater. Exclusion criteria were a history of transurethral sphincterotomy, bladder neck or prostatic resection, or bladder surgery and chronic indwelling catheter use.

Patients were randomized to receive 1 intravesical injection cycle of BoNT-A 300 U diluted in 30 ml of normal saline or saline placebo administered via a flexible or rigid cystoscopic injection needle at 30 sites and sparing the trigone (day 0). Study medication was administered using local, regional or general anesthesia at investigator discretion. Antimuscarinics were discontinued at week 3 and could be resumed at 50% of the previous dose at week 4 and at the full dose at week 6. At week 36 all patients were offered open label BoNT-A 300 U.

After study enrollment patients were randomized using sequential treatment assignment numbers linked to treatment codes allocated at random by a randomization schedule prepared on a balanced 1:1 basis. Personnel who did not perform injections loaded the syringes with study medication to maintain double-blind status.

Evaluations

In addition to a 3-day voiding diary, multichannel urodynamics with subtracted detrusor pressure were done at baseline.²¹ Telephone followups were performed at weeks 1, 3 and 4, and patients attended clinic visits at weeks 6, 24 and 36. Evaluations at followup visits consisted of urodynamics, ICIQ²² and I-QOL²³ to assess the impact of UI on QOL, a 3-day voiding diary completed before the visit, AE assessment and concomitant medication use. After open label treatment patients were followed an additional 6 months with voiding diary and questionnaire evaluations at weeks 48 and 60.

The primary efficacy parameter was the number of UI episodes daily based on a 3-day voiding diary at week 6. Secondary efficacy parameters were changes in urodynamics and questionnaires at week 6, and the daily frequency of UI episodes, urodynamics and questionnaires at other time points.

Statistical Methods

Sample size estimation was based on certain assumptions, including a week 6 mean change from baseline of 0.75 UI episodes, an SD of 0.85 UI episodes, α = 0.05 and β = 0.20. To detect a difference of 0.75 between treatment groups in the mean change from baseline in the number of UI episodes and assuming a 20% dropout rate it was necessary to enroll 56 patients, that is 28 per group. The calculation assumed a 2-sample procedure using 2-sided statistical testing.

Efficacy and safety analysis was done on an intent to treat basis in all patients who were exposed to at least 1 dose of study treatment and had at least 1 posttreatment efficacy measure available. All statistical tests were 2-sided and interpreted at a 5% significance level. Continuous variables were tested using ANCOVA with the baseline value as the covariate or with rank ANCOVA if the necessary assumptions for parametric testing were not satisfied. The Student t test (or Wilcoxon rank sum test when data were nonparametric) was used if baseline was not an influence in the model. Categorical (nominal) variables were compared between the groups using the chi-square test (or Fisher’s exact test for nonparametric data). Ordinal variables were compared using rank ANCOVA or the Wilcoxon rank sum test when no adjustment for baseline value was required. The last observation carried forward technique was applied for missing efficacy and questionnaire data only if patients discontinued the study due to AEs. Data imputation was not applied for patients who discontinued for other reasons. Data are shown as the mean ± SD or the median and IQR, as appropriate.

Ethics

The study was performed in accordance with the ethical principles of the Declaration of Helsinki. The study protocol and informed consent form were approved by the institutional review board at each study center before study initiation. Written informed consent was obtained from all patients before performing study procedures.

Back to Article Outline

Results

A total of 58 patients were randomized (fig. 1). However, 1 patient who subsequently refused to complete the study procedures and continue the study did not receive study treatment. Thus, analysis included 28 patients with BoNT-A and 29 with placebo who were randomized and received treatment. A total of 27 BoNT-A and 25 placebo recipients completed the study to week 36, of whom 24 per group received open label BoNT-A and completed the study.

• 
  • View Large Image
  • Download to PowerPoint

• Patient disposition. Asterisk indicates 1 patient in BoNT-A group who underwent open label treatment at week 36 but was not ready for treatment at appropriate time and withdrew from study.

Mean patient age was 42.8 years (range 32 to 50) and 34 of the 57 patients (60%) were male (table 1). NDO was secondary to SCI in 38 patients and to MS in 19. The BoNT-A and placebo groups were similar at baseline in demographics, urinary symptoms and urodynamic findings.

Table 1. Demographic and baseline characteristics

Efficacy

Voiding diary 

The mean daily frequency of UI episodes was significantly lower in the BoNT-A group than in the placebo group at weeks 6 (1.3 ± 1.3 vs 4.8 ± 2.9, p <0.0001), 24 and 36. After open label BoNT-A treatment each group had a significant decrease from baseline in the mean daily number of UI episodes (table 2).

Table 2. Voiding diary results at study time points

The group median of the patient percent decrease from baseline in the daily frequency of UI episodes was significantly greater for BoNT-A than for placebo at weeks 6, 24 and 36. In the open label phase each group also had a significant median percent decrease from baseline in the mean daily frequency of UI episodes at weeks 48 and 60 (table 2).

Urodynamics 

Improvement in urodynamic parameters in the BoNT-A group was evident at week 6 compared with that in the placebo group and it persisted to week 24. In patients with BoNT-A vs placebo median reflex detrusor volume at first contraction was significantly higher at week 6, median maximum detrusor pressure during filling was significantly lower at weeks 6, 24 and 36, and median volume at maximum detrusor pressure during filling and median maximum cystometric capacity²⁴ were significantly higher at weeks 6 and 24 (table 3). As determined by the clinician, filling volume was considered the volume at which high detrusor pressure, large volume or uncontrolled voiding occurred.²⁴

Table 3. Key parameters on multichannel urodynamics at baseline, and after BoNT-A and placebo

Questionnaires 

BoNT-A treatment was associated with improved QOL on ICIQ and I-QOL. Recipients of BoNT-A vs placebo had significantly more favorable scores on assessment of the frequency of urine leakage (UI) and the amount of urine leakage at weeks 6 and 24, and interference of urine leakage with life at weeks 6 and 36. Each group had significant improvement from baseline on all 3 assessments after open label treatment.

On ICIQ question 1 (UI frequency) significant differences extended to week 24. At weeks 24 and 36 in the BoNT-A group 65.2% and 33.3% of patients, respectively, reported fewer than 2 to 3 leakage episodes weekly vs 3.8% at baseline. Complete continence was reported by 10.7% of patients with BoNT-A vs none with placebo at week 24 and in 19% vs 26% in the open label phase at week 48.

There were no significant between group differences in the proportion of patients with leakage at baseline. However, at week 6 compared with placebo significantly fewer patients with BoNT-A reported experiencing UI when asleep (39% vs 72%, p <0.05), when physically active or exercising (29% vs 66%, p <0.01) and for no obvious reason (29% vs 55%, p <0.05).

Baseline mean I-QOL total QOL scores were 39.4 in the BoNT-A group and 46.8 in the placebo group. Significantly greater improvement from baseline in I-QOL total scores were seen for BoNT-A than for placebo at weeks 6, 24 and 36. Significant improvement from baseline was also seen in the 2 groups after open label treatment.

Antimuscarinics

At baseline 21 of 28 patients (75%) in the BoNT-A group vs 18 of 29 (62%) in the placebo group were on antimuscarinics (p = 0.3950). At week 6 in the BoNT-A group 14 of 21 patients (67%) had resumed antimuscarinics vs 17 of 18 (94%) in the placebo group (p = 0.0489). Seven of the 14 patients (50%) with BoNT-A who restarted antimuscarinics continued with 50% of the original dose vs 2 of 17 (12%) with placebo (p = 0.0439). The others who restarted antimuscarinics received the full dose.

Safety and Tolerability

Table 4 lists AEs that developed in 5% or greater of patients. Urinary tract infection was the most common AE and it occurred at a similar rate in the 2 groups. Muscle weakness was reported by 3 patients with BoNT-A. A male with SCI and quadriplegia reported mild arm weakness and difficult transfers lasting 3 days to 3 weeks after injection. A female with SCI and paraplegia reported upper body weakness and transfer difficulty starting 6 weeks after injection and lasting for 2 weeks. These events were considered probably and possibly treatment related, respectively. A patient with SCI reported transient left arm weakness several months after injection, which was considered unrelated.

Table 4. AEs that developed in 5% or more of patients