E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Urinary Incontinence Due to Overactive Bladder |
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E.1.1.1 | Medical condition in easily understood language |
Urinary Incontinence Due to Overactive Bladder |
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E.1.1.2 | Therapeutic area | Not possible to specify |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
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 |
To evaluate the safety and efficacy of BOTOX for the treatment of urinary incontinence due to OAB in patients 12 to 17 years of age who have not been adequately managed with anticholinergic therapy. To evaluate the safety and efficacy of repeated BOTOX treatments in this patient population. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. written informed consent has been obtained from the legally authorized representative and written minor assent has been obtained, in accordance with local laws and institutional review board (IRB)/independent ethics committee (IEC) requirements
2. written documentation has been obtained in accordance with the relevant country and local privacy requirements, where applicable (eg, Written Authorization for Use and Release of Health and Research Study Information (US sites) and written Data Protection consent (European sites)
3. male or female, aged ≥ 12 years to ≤ 17 years of age at the time of informed consent
4. patient has symptoms of OAB (frequency and urgency) with urinary incontinence for a period of at least 6 months immediately prior to screening, determined by patient history
5. patient experiences a total of ≥ 2 episodes of daytime urinary urgency incontinence in the 2-day patient bladder diary completed during the screening period (daytime is defined as time between waking up to start the day and going to bed to sleep for the
night)
6. patient experiences urinary frequency, defined as an average of ≥ 8 micturitions (toilet voids) per day ie, a total of ≥ 16 micturitions in the 2-day patient bladder diary completed during the screening period
7. patient has not been adequately managed with 1 or more anticholinergic agents for the treatment of OAB in the opinion of the investigator. This includes patients who are still incontinent despite anticholinergic therapy, experiencing intolerable side effects, or are unwilling to continue to take the medication for any reason.
8. patient is willing and able to use CIC to empty the bladder at any time after study treatment if it is determined to be necessary by the investigator
9. patient agrees to a minimum fluid intake of 1500 mL/m2 BSA, not to exceed 3000 mL/m2 BSA per day, during the patient bladder diary completion days at screening and prior to clinic visits during the study
10. negative urine pregnancy test for females who are postmenarche
11. patient is able to complete study requirements including completion of bladder diaries and HRQOL questionnaires (these can also be completed by the parent/legally authorized representative), and is likely to attend study visits in the opinion of the investigator |
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E.4 | Principal exclusion criteria |
1. patient has an uncontrolled systemic disease, or has previous or current diagnosis of malignancy
2. patient has symptoms of OAB due to any known neurological reason (eg, spina bifida, spinal cord injury, or cerebral palsy)
3. patient has a history of 2 or more UTIs treated with antibiotics within 6 months of randomization/day 1 or is taking prophylactic antibiotics to prevent chronic UTI
4. patient has a history or evidence of any pelvic or urological abnormalities, except OAB, including:
o bladder neck surgery resulting in an open bladder neck, or reconstructive surgery of the lower urinary tract (eg, urostomy, urinary diversion, or bladder augmentation)
o anatomical evidence of bladder outlet obstruction (including functional outlet obstruction), urethral or urethral valve obstruction/stricture at screening
o surgery of the urinary tract (including minimally invasive surgery) within 6 months of screening (except those listed above which are exclusionary for any time period)
o circumcision within 1 month of screening
o clinically relevant kidney abnormality, or clinically relevant
vesicoureteric reflux, or disease of the bladder (other than OAB) that may affect bladder function
5. patient has predominance of stress incontinence, or “giggle” incontinence, or any condition other than OAB that in the investigator’s opinion may account for the patient being incontinent
6. patient has unmanaged, unresolved bowel problems (eg, constipation, encopresis)
7. patient currently uses or plans to use medications or therapies to treat symptoms of OAB, including nocturnal enuresis or nocturia.
Patients previously receiving these medications must have discontinued their use prior to the start of the first screening procedure as follows:
o for desmopressin, at least one day prior
o for anticholinergic therapy, at least 7 days prior
o for intravesical anticholinergic therapy, at least 4 weeks prior
o for mirabegron, at least 14 days prior
8. patient currently uses or plans to use an implantable or nonimplantable electrostimulation/neuromodulation device for treatment of OAB. (If a nonimplantable device is used, it must be discontinued at least 7 days prior to the first screening procedure; if a device is implanted, it must be inactive for at least 4 weeks prior to the first screening procedure; neither should be used during the study.)
9. patient plans to start using psychiatric medications or medications for attention deficit hyperactivity disorder during the study. If the patient is already using such medications they should be on a stable dose prior to randomization/day 1 and agree to remain on the same dose during the study if possible when medically indicated.
10. patient uses CIC or an indwelling catheter to manage their OAB
11. patient has had previous or current botulinum toxin therapy of any serotype for any urological condition, or treatment with botulinum toxin of any serotype within 3 months of randomization/day 1 for any other condition or use
12. patient has been treated with intravesical capsaicin or resiniferatoxin within 12 months of screening
13. patient has a PVR urine volume of > 40 mL at screening. The PVR measurement can be repeated once on the same day; the patient is to be excluded if the repeated measure is above 40 mL.
14. patient has a daytime (waking hours) total volume of urine voided > 3000 mL, collected over one daytime period during the 2-day bladder diary collection period prior to randomization/day 1
15. postmenarche female patients of childbearing potential who are pregnant, nursing, or planning to become pregnant during the study (postmenarche female patients must also either be sexually abstinent or use another acceptable form of contraception)
16. patient has known allergy or sensitivity to components of any botulinum toxin preparation (including the study medication preparation), anesthetics or antibiotics to be used during the study
17. patient has hemophilia, or other clotting factor deficiencies, or disorders that cause bleeding diathesis
18. patient cannot withhold any antiplatelet, anticoagulant therapy, or other medications with anticoagulant effects for 3 days prior to randomization/day 1. Note: some medications may need to be withheld for >3 days, per clinical judgment of the investigator
19. patient has any medical condition that may put them at increased risk with exposure to BOTOX including diagnosed myasthenia gravis, Eaton-Lambert syndrome, or amyotrophic lateral sclerosis
20. current enrollment in an investigational drug or device study, or participation in such a study within 30 days of entry into this study (or longer if local requirements specify)
21. patient has a condition or is in a situation which in the investigator's opinion may put the patient at significant risk, may confound the study results, or may interfere significantly with the patient's participation in the study |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy measure is the number of daytime urinary incontinence episodes as recorded in the 2-day bladder diary during the week preceding each study visit. The primary timepoint is week 12 after treatment 1. For patients who receive multiple treatments in this study, the timepoint of main focus is week 12 after each treatment. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Week 12 after each treatment |
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E.5.2 | Secondary end point(s) |
The following secondary efficacy measures will be collected after each treatment using the bladder diary:
• number of daytime micturition episodes
• number of daytime urgency episodes
• presence or absence of night time urinary incontinence
• volume voided per micturition
In addition, the following duration of effect measures are considered secondary efficacy
measures:
• time to patient request and time to patient qualification for retreatment |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Daily after each treatment |
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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 | No |
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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 24 |
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 |
Australia |
Belgium |
Canada |
Czech Republic |
France |
Germany |
Hong Kong |
Italy |
Netherlands |
Norway |
Poland |
South Africa |
Taiwan |
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 | 4 |
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 | 4 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |