E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
NEUROGENIC DETRUSOR OVERACTIVITY |
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E.1.1.1 | Medical condition in easily understood language |
Bladder Overactivity due to neurologic pathology |
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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 | 15.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10012547 |
E.1.2 | Term | Detrusor hyperreflexia |
E.1.2 | System Organ Class | 100000004857 |
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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 |
The primary study objective is to assess the efficacy of a single dose of Dysport (750 U) compared to placebo for the improvement in the daily incontinence episode frequency (IEF) for each administration mode (15 or 30 injection sites). |
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E.2.2 | Secondary objectives of the trial |
The secondary study objective is to assess the change over time in urodynamic parameters (manocystometric measurements according to the 'Good Urodynamic Practice' of the ICS) quality of life, catheterisations and the response to treatment following treatment with a single dose of Dysport (750 U) compared to placebo for each administration mode (15 or 30 injection sites), as well as the pain induced by the injection procedure. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
(10 Written informed consent prior to any study related procedures.
(2) Male or female subjects aged 18 to 70, inclusive.
(3) Urinary incontinence as a result of NDO due to documented SCI or MS as defined by the ICS guidelines.
(4) Inadequate response or refractory to anticholinergic medication used to treat neurogenic overactive bladder.
(5) The dose and class of anticholinergic treatment, if any, must be fixed for the duration of the study and stable at randomisation visit.
(6a) Have documented SCI or MS (both complete and incomplete SCIs and relevant MS with confirmed NDO as defined by ICS guidelines will be included in this study).
(7) Have documented urinary tract exploration at screening. If not, lower urinary tract echography shall be conducted prior to baseline.
(8) Have a minimum average of two incontinence episodes per day calculated as the average daily IEF over the 3 days preceding the baseline visit (three consecutive 24 hour periods).
(9) Subject, family member or care giver is willing and able to perform CIC for the duration of the study.
(10) Have an exclusive and well trained voiding mode by clean self
catheterisation before baseline.
(11) Be able to complete all study requirements including completing a daily voiding diary and to attend all scheduled study visits, in the opinion of the Investigator.
(12a) Female subjects of child-bearing potential must have a negative pregnancy test result and be willing to use reliable contraceptive measures for the duration of the study (i.e. oral contraceptives and spermicide, when used in combination with condoms, etc as a ‘double barrier method’).
(13) Botulinum toxin naïve for intra-detrusor injections and have no previous treatment with BTX of any type, within 3 months prior to study entry for any other condition. |
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E.4 | Principal exclusion criteria |
(1) Greater than 3 L diuresis per day based on the average over the 3 days preceding the baseline visit (three consecutive 24 hour periods).
(2a) Previous or current diagnosis of bladder disease and urethral disease or surgery, or prostate cancer (prostate specific antigen of >10 ng/mL).
Subjects with serum prostate specific antigen concentrations >4 ng/mL and <10 ng/mL must have prostate cancer excluded.
(3) Clinical symptomatic urinary tract infection at screening visit without adapted antibiotherapy.
(4) History of NDO due to an aetiology other than SCI or MS.
(5) History of stress incontinence.
(6) Significant baseline renal and/or urinary tract pathology
(e.g. hydronephrosis, stones, renal mass) at screening.
(7) History of unexplained haematuria.
(8) Known history of interstitial cystitis, uninvestigated haematuria,
mullerian duct cysts, and urethral obstruction due to
stricture/valves/sclerosis of urethral tumour, radiation cystitis, genitorurinary tuberculosis, or bladder calculi.
(9) Current indwelling catheter, or removal of chronic catheter <1 month prior to randomisation visit.
(10) Any medical condition that may increase their risk of exposure to BTX including diagnosed myasthenia gravis, Lambert-Eaton Syndrome, amyotrophic lateral sclerosis or any other disease that might interfere with neuromuscular function.
(11) Any condition or situation which, in the Investigator's opinion, puts the subject at significant risk, may confound the study results, or may significantly interfere with the subject's participation in the study.
(12) History of allergy or intolerance to local anaesthetics (lidocaine, xylocaine etc).
(13) History of chronic drug or alcohol abuse.
(14) Previous treatment with any endovesical pharmacologic agent including detrusor BTX injection.
(15) Have previously undergone urethral stent placement or sphincterotomy.
(16) Use of medications with anti-platelet or anticoagulant effects (except Low Molecular Weight Heparin) within 10 days of randomisation. (Low Molecular Weight Heparin is standard of care after SCI until 2 to 3 months post injury; for post SCI subjects it will be stopped 24 hours before and for 48 hours after each bladder injection).
(17) Use of medications that affect neuromuscular transmission, such as curare-like depolarising agents, lincosamides, polymyxins,
anticholinesterases and aminoglycoside antibiotics.
(18) Concurrent therapy which, in the Investigator's opinion, would interfere with the evaluation of study medication safety or efficacy.
(19) Receipt of any experimental drug or use of any experimental device within 30 days prior to the screening visit.
(20) Nursing or lactating female subjects.
(21) Known hypersensitivity to botulinum toxin (BTX) or to any components in the study drug formulation (including cow’s milk protein). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Mean change from baseline in the averaged daily frequency of episodes of urinary incontinence (calculated as the average daily IEF over the 3 days preceding each 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) |
- Urodynamic examination: manocystometric measurements.
- Quality of Life assessment.
- Pain prior to and after administration of study treatment.
- Clean self catheterisations per day.
- Physician's global assessment of the treatment response as
compared with baseline. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Urodynamic examination / Quality of Life assessment / Clean self catheterisations per day / Physician's global assessment : Day 14, Day 42 and Day 84
- Pain: prior to and after the cystoscopic intra-detrusor
injection of study treatment (at baseline)
|
|
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 | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 4 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 22 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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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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 | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |