Ginsberg NDO: Phase 3 OnabotulinumtoxinA for Urinary Incontinence from Neurogenic Detrusor Overactivity
Ginsberg NDO was a 52-week international, multicenter, double-blind randomized trial of intradetrusor onabotulinumtoxinA 200 U, 300 U or placebo in 416 patients with multiple sclerosis or spinal cord injury and urinary incontinence from neurogenic detrusor overactivity, with the change in weekly incontinence episodes at week 6 as the primary endpoint. Both doses reduced weekly episodes by 21 and 23 versus 9 with placebo (each P < 0.001).[1]
- Design and population
- International, multicenter, double-blind, placebo-controlled randomized trial. 416 adults with urinary incontinence from neurogenic detrusor overactivity (multiple sclerosis 227, spinal cord injury 189) and 14 or more incontinence episodes per week.
- Arms
- Intradetrusor onabotulinumtoxinA 200 U versus onabotulinumtoxinA 300 U versus placebo
- Report and follow-up
- 2012 · Primary endpoint at week 6 within a 52-week trial
| Endpoint | Results | Effect | Finding |
|---|---|---|---|
| Mean change from baseline in weekly urinary incontinence episodes at week 6; each dose versus placebo | 21 fewer per week (n=135) vs 23 fewer per week (n=132) vs 9 fewer per week (n=149) | P <0.001 |
Harms: Clean intermittent catheterization started for urinary retention, patients not catheterizing at baseline: 35% vs 42% vs 10%; Most common adverse events: Urinary tract infection and urinary retention.
Design
Eligible patients had urinary incontinence from neurogenic detrusor overactivity with 14 or more episodes per week; 227 had multiple sclerosis and 189 had spinal cord injury. The groups comprised 135 patients on 200 U, 132 on 300 U and 149 on placebo.[1] Allergan sponsored the trial, registered as NCT00311376 (study 191622-515).[2] The label describes the patients in the two registration trials as having an inadequate response to or intolerance of at least one anticholinergic.[3]
The primary endpoint was the change from baseline in mean weekly urinary incontinence episodes at week 6. Secondary endpoints were maximum cystometric capacity, maximum detrusor pressure during the first involuntary detrusor contraction and the Incontinence Quality of Life (I-QOL) total score.[1]
Results
At week 6, 200 U reduced mean weekly incontinence by 21 episodes and 300 U by 23, against 9 with placebo (each P < 0.001). Maximum cystometric capacity, maximum detrusor pressure at the first involuntary contraction and the I-QOL total score improved significantly more than with placebo for both doses (each P < 0.001).[1]
Median time to patient request for re-treatment was 256 days with 200 U, 254 days with 300 U and 92 days with placebo. The trial identified no clinically relevant benefit in efficacy or duration of the 300 U dose over 200 U.[1]
In the open-label extension for completers of either of two 52-week phase 3 trials (this one and its replicate, Cruz 2011), 200 U reduced incontinence by 3.2 to 4.1 episodes per day across six treatments, with a median duration of effect of 9.0 months; results with 300 U were similar.[4] Volume per void nearly doubled after treatment and I-QOL improvements stayed above twice the minimally important difference.[4] Among 227 patients who completed four years, the decrease at week 6 stayed between 3.5 and 3.8 episodes per day from a baseline of 4.3. Each year at week 6, 86.6% to 94.1% of these four-year completers had a reduction in episodes of at least 50% and 43.6% to 57.4% had a 100% reduction.[5] Patients received 1.4 to 1.5 treatments per year; the median duration of effect was at least 9.0 months (range 3.0 to 49.2), and 26.0% or more had an effect of 12 months or longer.[5]
Surgery and treatment delivery
The trial compared 200 U and 300 U with placebo.[1] The labeled adult neurogenic dose is 200 U, injected cystoscopically into the detrusor, avoiding the trigone, as 30 injections of 1 mL (about 6.7 U) about 1 cm apart and about 2 mm deep.[3] The bladder is instilled with enough saline for visualization without overdistension, a final 1 mL of saline clears the needle, and the patient is observed for at least 30 minutes.[3] The label requires no urinary tract infection at treatment, prophylactic antibiotics (except aminoglycosides) from 1 to 3 days before to 1 to 3 days after the procedure, and discontinuation of antiplatelet therapy at least 3 days before. Repeat injection is considered when the effect wanes and no sooner than 12 weeks after the previous injection.[3]
In the extension, patients were treated as needed on their request, at least 12 weeks after the previous treatment and above a prespecified incontinence-episode threshold.[4]
Adverse events
Urinary tract infection and urinary retention were the most common adverse events. Among patients not catheterizing at baseline, 10% on placebo, 35% on 200 U and 42% on 300 U began clean intermittent catheterization for retention.[1] In the extension, de novo catheterization rates were 29.5%, 3.4% and 6.0% over treatments 1 to 3 with 200 U (43.0%, 15.0% and 4.8% with 300 U) and 0% for treatments 4 to 6; urinary tract infection and urinary retention remained the most common events without new safety signals.[4] In the four-year completers, urinary tract infection incidence did not rise with time.[5]
The label reports pooled data from the two placebo-controlled trials. Within 12 weeks, urinary tract infection occurred in 24% with 200 U versus 17% with placebo, urinary retention in 17% versus 3% and hematuria in 4% versus 3%. Among patients not catheterizing at baseline, 30.6% (33/108) catheterized for retention with 200 U versus 6.7% (7/104) with placebo; the rate was 31% (27/86) versus 5% (4/88) in multiple sclerosis and 27% (6/22) versus 19% (3/16) in spinal cord injury. Autonomic dysreflexia occurred in 1.5% with 200 U versus 0.4% with placebo.[3] The AUA/SUFU guideline reports annualized multiple sclerosis exacerbation rates in this trial of 0.22 with placebo, 0.14 with 200 U and 0.37 with 300 U.[6]
Limitations
The comparator was placebo; the trial did not compare onabotulinumtoxinA with an anticholinergic, with augmentation cystoplasty or with a lower dose. The 100 U dose was later tested separately in the label's post-approval study of noncatheterizing patients with multiple sclerosis (100 U, n = 66; placebo, n = 78).[3] The primary endpoint was measured at week 6, and the re-treatment endpoint was time to patient request.[1] The long-term reports are uncontrolled and enrolled only completers.[4][5]
In conversation
- Parallel to Nitti OAB Trial (2012). Same toxin and route tested in idiopathic OAB at 100 U; this trial used 200 U and 300 U in neurogenic detrusor overactivity.
- Parallel to Nitti OAB Trial (2012). Same drug and sponsor, placebo-controlled phase 3 design; Ginsberg studied neurogenic detrusor overactivity at higher doses, this trial idiopathic OAB at 100 U.
The replicate trial of Cruz enrolled 275 patients (multiple sclerosis 154, spinal cord injury 121) and used 30 injections that avoided the trigone. At week 6, 200 U and 300 U reduced weekly episodes by 21.8 and 19.4 versus 13.2 with placebo (P < 0.01), and, among patients not using catheterization at baseline, 12%, 30% and 42% on placebo, 200 U and 300 U began catheterization after treatment.[7] Both trials found no clinically relevant efficacy or duration advantage for 300 U.[1][7]
Guidelines and approvals
- AUA/SUFU (2021). In patients with neurogenic lower urinary tract dysfunction from spinal cord injury or multiple sclerosis who are refractory to oral medications, clinicians should recommend onabotulinumtoxinA to improve bladder storage parameters, decrease incontinence episodes and improve quality of life measures . The supporting text lists this trial among the randomized trials behind the statement and finds no efficacy difference between 200 U and 300 U. For patients who void spontaneously, clinicians must discuss the risk of urinary retention and the potential need for intermittent catheterization before selecting botulinum toxin therapy .[6]
- EAU Neuro-Urology (limited update, March 2026). Use botulinum toxin A injections in the detrusor to reduce neurogenic detrusor overactivity if antimuscarinic therapy is ineffective . The text cites this trial for repeat injections without loss of efficacy.[8]
- FDA (August 24, 2011). OnabotulinumtoxinA approved for adults with urinary incontinence due to detrusor overactivity associated with a neurologic condition (for example spinal cord injury or multiple sclerosis) who have an inadequate response to or are intolerant of an anticholinergic.[9]
Report history
| Published | Report | Cutoff | Headline results | Citation |
|---|---|---|---|---|
| 2012-04-12 | Phase 3 trial, 52 weeks · primary | — | Mean change from baseline in weekly urinary incontinence episodes at week 6; each dose versus placebo: 21 fewer per week (n=135) vs 23 fewer per week (n=132) vs 9 fewer per week (n=149); P <0.001 Change in maximum cystometric capacity; each dose versus placebo: Significantly greater improvement than placebo with both doses.; P <0.001 Change in maximum detrusor pressure during the first involuntary detrusor contraction; each dose versus placebo: Significantly greater improvement than placebo with both doses.; P <0.001 Change in Incontinence Quality of Life total score; each dose versus placebo: Significantly greater improvement than placebo with both doses.; P <0.001 Median time to patient request for re-treatment: 256 days vs 254 days vs 92 days; — | Ginsberg D, Gousse A, Keppenne V, et al. "Phase 3 Efficacy and Tolerability Study of OnabotulinumtoxinA for Urinary Incontinence From Neurogenic Detrusor Overactivity." *J Urol.* 2012;187(6):2131-2139. doi:10.1016/j.juro.2012.01.125 DOI |
| 2015-11-24 | Extension, up to four years · updated | — | Change from study baseline in incontinence episodes per day at week 6 after each of six 200 U treatments: 3.2 to 4.1 fewer per day; — Descriptive Overall median duration of effect: 9.0 months; — Descriptive Volume per void after treatment: Consistently increased, nearly doubling after treatment.; — Descriptive Incontinence Quality of Life total score: Improvements consistently greater than twice the minimally important difference.; — Descriptive | Kennelly M, Dmochowski R, Schulte-Baukloh H, et al. "Efficacy and Safety of OnabotulinumtoxinA Therapy Are Sustained Over 4 Years of Treatment in Patients With Neurogenic Detrusor Overactivity: Final Results of a Long-Term Extension Study." *Neurourol Urodyn.* 2017;36(2):368-375. doi:10.1002/nau.22934 DOI |
| 2016-06-02 | Four-year completers · secondary | — | Decrease in urinary incontinence episodes per day at week 6, by treatment year: Decrease ranged from 3.5 to 3.8 episodes per day across 4 years from a baseline of 4.3 per day (3.4 to 3.9 across the 200 U-only and 300/200 U cohorts).; — Descriptive Reduction in incontinence episodes of at least 50% and of 100%, by treatment year: At least 50%: 87.6% to 92.1%; 100%: 46.3% to 53.2% (86.6% to 94.1% and 43.6% to 57.4% across the 200 U-only and 300/200 U cohorts).; — Descriptive Overall median duration of effect: At least 9.0 months (range 3.0 to 49.2); 26.0% or more had an effect of 12 months or longer.; — Descriptive OnabotulinumtoxinA treatments per year: 1.4 to 1.5 treatments per year.; — Descriptive | Rovner E, Kohan A, Chartier-Kastler E, et al. "Long-Term Efficacy and Safety of OnabotulinumtoxinA in Patients With Neurogenic Detrusor Overactivity Who Completed 4 Years of Treatment." *J Urol.* 2016;196(3):801-808. doi:10.1016/j.juro.2016.04.046 DOI |
References
1. Ginsberg D, Gousse A, Keppenne V, et al. "Phase 3 Efficacy and Tolerability Study of OnabotulinumtoxinA for Urinary Incontinence From Neurogenic Detrusor Overactivity." J Urol. 2012;187(6):2131-2139. doi:10.1016/j.juro.2012.01.125
2. ClinicalTrials.gov. Safety and Efficacy Study of Botulinum Toxin Type A for the Treatment of Neurogenic Overactive Bladder. Identifier NCT00311376.
3. Allergan. BOTOX (onabotulinumtoxinA) for injection: Prescribing Information. Revised 11/2023. Sections 2.3, 5, 6.1 and 14.1.
4. Kennelly M, Dmochowski R, Schulte-Baukloh H, et al. "Efficacy and Safety of OnabotulinumtoxinA Therapy Are Sustained Over 4 Years of Treatment in Patients With Neurogenic Detrusor Overactivity: Final Results of a Long-Term Extension Study." Neurourol Urodyn. 2017;36(2):368-375. doi:10.1002/nau.22934
5. Rovner E, Kohan A, Chartier-Kastler E, et al. "Long-Term Efficacy and Safety of OnabotulinumtoxinA in Patients With Neurogenic Detrusor Overactivity Who Completed 4 Years of Treatment." J Urol. 2016;196(3):801-808. doi:10.1016/j.juro.2016.04.046
6. Ginsberg DA, Boone TB, Cameron AP, et al. "The AUA/SUFU Guideline on Adult Neurogenic Lower Urinary Tract Dysfunction: Treatment and Follow-Up." J Urol. 2021;206(5):1106-1113. doi:10.1097/JU.0000000000002239
7. Cruz F, Herschorn S, Aliotta P, et al. "Efficacy and Safety of OnabotulinumtoxinA in Patients With Urinary Incontinence Due to Neurogenic Detrusor Overactivity: A Randomised, Double-Blind, Placebo-Controlled Trial." Eur Urol. 2011;60(4):742-750. doi:10.1016/j.eururo.2011.07.002
8. Blok B, Hamid R, Hentzen C, et al. EAU Guidelines on Neuro-Urology. Limited update. Arnhem: EAU Guidelines Office; March 2026. Section 3.4.2.e.
9. U.S. Food and Drug Administration. Supplement approval letter, BLA 103000/5232 (BOTOX). August 24, 2011.