E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Urinary incontinence due to neurogenic detrusor overactivity (NDO) resulting from multiple sclerosis (MS) |
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E.1.1.1 | Medical condition in easily understood language |
Urinary incontinence resulting from multiple sclerosis (MS) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10046543 |
E.1.2 | Term | Urinary incontinence |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Evaluate the safety and efficacy of 100 U BOTOX compared to placebo injected into the detrusor for the treatment of urinary incontinence due to NDO resulting from MS, in patients who are not catheterizing at baseline, and whose symptoms have not been adequately managed with an anticholinergic therapy. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
As part of a post-licensing commitment to the Irish Medicines Board, approximately 40 patients will be enrolled into an injection paradigm subset in which patients will receive treatment administered as 20 injections of 0.5mL instead of 30 injections of 1mL. The objective is to evaluate this additional intradetrusor injection paradigm. The study design for these patients will be identical in all other respects; the only difference will be the injection paradigm.
This sub-study is included within the main protocol and therefore there is no separate title, date or version.
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E.3 | Principal inclusion criteria |
1) patient has multiple sclerosis, determined by documented patient history
- patient’s MS is clinically stable for ≥ 3 months prior to screening, in the investigator’s opinion
- patient has an Expanded Disability Status Scale (EDSS) score of ≤ 6.5
2) patient has NDO for a period of at least 3 months prior to screening, determined by documented patient history
- the presence of an involuntary detrusor contraction (IDC) must also be demonstrated during the urodynamic assessment in the screening period or day 1 (prior to randomization)
3) patient has not been adequately managed with one or more anticholinergics for their urinary incontinence, in the opinion of the investigator. Not adequately managed is defined as meeting one of the following:
- an inadequate response after at least a 4-week period of anticholinergic therapy on an optimized dose(s), ie, the patient was still incontinent despite anticholinergic therapy
- limiting side effects after at least a 2-week period of anticholinergic therapy on an optimized
dose(s)
4) for patients taking anticholinergic medication for their NDO at study entry, dose is stable and patient is willing to maintain the same dose during study participation
5) for patients not taking anticholinergics for their NDO at study entry, anticholinergics must have been discontinued at least 7 days prior to any screening procedures and anticholinergic treatment must not be commenced during the study
6) patient experiences ≥ 3 and ≤ 60 episodes of urinary incontinence, with no more than one incontinence-free day, as recorded in the 3-day bladder diary completed during the screening period |
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E.4 | Principal exclusion criteria |
1) patient currently uses clean intermittent catheterization (CIC) (at any frequency), or indwelling catheter, to manage their urinary incontinence
2) per investigator judgment, patient should be using CIC to empty their bladder even if currently not doing so
3) patient is unable or unwilling to use CIC post-treatment, if required
4) patient has had previous or current botulinum toxin therapy of any serotype for any urological condition
5) patient has had previous or current botulinum toxin therapy of any serotype for any non-urological condition within 12 weeks of randomization/day 1
6) patient has history or evidence of any pelvic or urological abnormalities including but not limited to the following:
- elevated serum creatinine > 2 times the upper limit of normal
- current or previous uninvestigated hematuria (patients with investigated hematuria may enter the study if urological/renal pathology has been ruled out to the satisfaction of the investigator)
- interstitial cystitis in the opinion of the investigator
- bladder stones and/or bladder stone surgery at the time of screening or within 6 months prior to screening
- surgery or bladder disease other than detrusor overactivity that may impact bladder function with the exception of surgeries > 1 year from screening for stress incontinence, uterine prolapse, rectocele, or cystocele
- urethral and/or bladder outlet obstruction, in the opinion of the investigator
7) patient has 24-hour total volume of urine voided > 3000 mL, collected over 24 consecutive hours during the 3-day bladder diary collection period during screening
8) patient has a post-void residual (PVR) urine volume of >150 mL at screening. Note: the PVR measurement can be repeated once; the patient is to be excluded if the repeated measure is above 150 mL
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy measure is the number of episodes of urinary incontinence as recorded by the patient in the 3 day bladder diary completed in the week prior to each study visit. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
- Maximum Cystometric Capacity (MCC, mL) by urodynamics as determined by the independent central reviewer
- maximum detrusor pressure during the first Involuntary Detrusor Contraction (IDC, PmaxIDC) (cm H2O) by urodynamics as determined by the independent central reviewer
- I-QOL total summary score as completed by the patient |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Urodynamics: Week 6 after treatment 1
I-QOL: Week 6, 12, 24 after treatment 1 if only one treatment; Week 6, 12, within the qualification period for treatment 2 and 6 weeks after treatment 2 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 21 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Canada |
Czech Republic |
France |
Poland |
Portugal |
Russian Federation |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 16 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 16 |