Dysport® Treatment of Urinary Incontinence in Adults Subjects With Neurogenic Detrusor Overactivity (NDO) Due to Spinal Cord Injury or Multiple Sclerosis - Study 1

Study Overview
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Brief Summary
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The purpose of this study is to provide confirmatory evidence of the safety and efficacy of two Dysport® (AbobotulinumtoxinA) doses (600 units [U] and 800 U), compared to placebo in reducing urinary incontinence (UI) in adult subjects treated for neurogenic detrusor overactivity (NDO) due to spinal cord injury (SCI) or multiple sclerosis (MS).

Official Title
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A Phase III, Multicentre, Randomised, Double Blind, Parallel Group, Placebo Controlled Study To Assess The Efficacy And Safety Of One Or More Intradetrusor Treatments Of 600 Or 800 Units of Dysport® For The Treatment Of Urinary Incontinence In Subjects With Neurogenic Detrusor Overactivity Due To Spinal Cord Injury Or Multiple Sclerosis

Conditions
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Urinary Incontinence, Overactive Bladder

Intervention / Treatment
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* Biological: Botulinum toxin type A
* Biological: Botulinum toxin type A
* Drug: Placebo
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Urinary Incontinence for at least 3 months prior to Screening as a result of Neurogenic Detrusor Overactivity due to Spinal Cord Injury or Multiple Sclerosis. Subjects with Spinal Cord Injury must have a stable neurological injury at T1 level or below which occurred at least 6 months prior to Screening. Subjects with Multiple Sclerosis must be clinically stable in the investigator's opinion, with no exacerbation (relapse) of MS for at least 3 months prior to Screening. Subjects must have had an inadequate response after at least 4 weeks of oral medications used in the treatment of NDO (e.g. anticholinergics, beta-3 agonists) and/or have intolerable side-effects. Routinely performing Clean Intermittent Catheterization (CIC) to ensure adequate bladder emptying. An average of at least two episodes per day of Urinary Incontinence recorded on the screening bladder diary. Key Exclusion Criteria: Any current condition (other than NDO) that may impact on bladder function. Previous or current, tumour or malignancy affecting the spinal column or spinal cord, or any other unstable cause of SCI. Any condition that will prevent cystoscopic treatment administration or CIC usage, e.g. urethral strictures. Current indwelling bladder catheter, or removal of indwelling bladder catheter less than 4 weeks prior to Screening. BTX-A treatment within 9 months prior to Screening for any urological condition (e.g. detrusor or urethral sphincter treatments). Any neuromodulation/electrostimulation usage for urinary symptoms/incontinence within 4 weeks prior to Screening. Any implanted neuromodulation device must be switched off at least 4 weeks prior to Screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 600 U Dysport® Group<br> | Biological: Botulinum toxin type A<br>* 600 U intra detrusor injection in two treatment periods (Initial and Retreatment phase) delivered at 30 injection points<br>* Other names: Clostridium BTX-A-haemagglutinin complex;|
| Placebo Comparator: 600 U Dysport® Placebo Group<br> | Drug: Placebo<br>* AbobotulinumtoxinA Placebo 600 U intra detrusor injection in two treatment periods (Initial and Retreatment phase) delivered at 30 injection points<br>|
| Experimental: 800 U Dysport® Group<br> | Biological: Botulinum toxin type A<br>* 800 U intra detrusor injection in two treatment periods (Initial and Retreatment phase) delivered at 30 injection points<br>* Other names: Clostridium BTX-A-haemagglutinin complex;|
| Placebo Comparator: 800 U Dysport® Placebo Group<br> | Drug: Placebo<br>* AbobotulinumtoxinA Placebo 800 U intra detrusor injection in two treatment periods (Initial and Retreatment phase) delivered at 30 injection points<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Weekly Number of UI Episodes at Week 6 of DBPC Cycle | The weekly number of UI episodes was measured using a 7-day bladder diary. Bladder diaries that contained data recorded on at least 5 days were included in the analysis. The least square (LS) mean of the change in weekly number of UI episodes at 6 weeks after the first study treatment was calculated using a mixed model repeated measures (MMRM) analysis. | Baseline and Week 6 of DBPC Cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Maximum Cystometric Capacity (MCC) at Week 6 of DBPC Cycle | All subjects had a standardised urodynamic (filling cystometry) assessment at baseline (screening) and again at Week 6 to determine the MCC. The LS mean of the change in MCC at 6 weeks after the first study treatment was calculated using an analysis of covariance (ANCOVA). | Baseline and Week 6 of DBPC Cycle | 
| Mean Change From Baseline in Maximum Detrusor Pressure (MDP) at Week 6 of DBPC Cycle | All subjects had a standardised urodynamic filling cystometry assessment at baseline (screening) and again at Week 6 to determine the MDP. The LS mean of the change in MDP at 6 weeks after the first study treatment was calculated using an ANCOVA. | Baseline and Week 6 of DBPC Cycle | 
| Mean Change From Baseline in Volume at First Involuntary Detrusor Contraction (Vol@1stIDC) at Week 6 of DBPC Cycle | All subjects had a standardised urodynamic (filling cystometry) assessment at baseline (screening) and again at Week 6 to determine the Vol@1stIDC which is the instilled volume when first IDC commences. Subjects who did not exhibit a post-treatment IDC at Week 6 had Vol@1stIDC imputed using the recorded corrected MCC volume at Week 6. The LS mean of the change in Vol@1stIDC at 6 weeks after the first study treatment was calculated using an ANCOVA. | Baseline and Week 6 of DBPC Cycle | 
| Number of Subjects With No Episodes of UI at Week 6 of DBPC Cycle | The weekly number of UI episodes was measured using a 7-day bladder diary. Bladder diaries that contained data recorded on at least 5 days were included in the analysis. The number of subjects with no UI episodes at 6 weeks after the first study treatment was recorded and the percentage of subjects was also calculated from the total number of subjects with any number of UI events at Week 6. | Baseline and Week 6 of DBPC Cycle | 
| Number of Subjects With No IDCs During Storage at Week 6 of DBPC Cycle | All subjects had a standardised urodynamic filling cystometry assessment at baseline (screening) and again at Week 6 to determine the occurrence of IDCs. The number of subjects without IDCs at 6 weeks after the first study treatment was recorded and the percentage of subjects was also calculated from the total number of subjects with data available for analysis at Week 6. | Baseline and Week 6 of DBPC Cycle | 
| Mean Change From Baseline in Incontinence Quality of Life (I-QoL) Questionnaire Total Summary Score at Week 6 of DBPC Cycle | The I-QoL questionnaire is a validated, disease-specific questionnaire designed to measure the effect of UI on subjects' QoL. It consists of 22 items in 3 domains (avoidance and limiting behaviour, psychosocial impact and social embarrassment). Subjects used a 5-point response scale for each of the 22 items with values ranging from 1 (extremely) to 5 (not at all). The total summary score was transformed to a 100 point scale ranging from 0 to 100, with higher scores indicating a better QoL. The LS mean of the change in the I-QoL total summary score at 6 weeks after the first study treatment was calculated using a MMRM analysis. | Baseline and Week 6 of DBPC Cycle | 
| Number of Subjects With a UI Response at Improvement Levels ≥30%, ≥50%, and ≥75% at Week 6 of the DBPC Cycle | The weekly number of UI episodes was measured using a 7-day bladder diary. Bladder diaries that contained data recorded on at least 5 days were included in the analysis. The number of baseline UI episodes was compared with the number of UI episodes at Week 6 to determine the level of response each subject reached, i.e. a decrease of ≥30%, ≥50% or ≥75% . The number of subjects showing an improvement of ≥30%, ≥50% and ≥75% were recorded and the percentage of subjects was also calculated from the total number of subjects with any number of UI events at Week 6. | Baseline and Week 6 of DBPC Cycle | 
| Mean Change From Baseline in Volume Per Void at Week 6 of DBPC Cycle | The volume per void was measured during one 24-hour period of the 7-day bladder diary. The LS mean of the change in volume per void at 6 weeks after the first study treatment was calculated using a MMRM analysis. | Baseline and Week 6 of DBPC Cycle | 
| Median Time Between Treatments | Duration of effect for time between treatments was calculated by: (the date of the first retreatment visit - date of first treatment administration in the DBPC cycle). The median number of days between treatments was determined based on the Kaplan-Meier method. Subjects with no retreatment were censored at the last visit. | Day of first treatment (baseline) and day of retreatment, up to 2 years |