| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Overactive Bladder and Urinary Incontinence |
|
| E.1.1.1 | Medical condition in easily understood language |
| Overactive Bladder and Urinary Incontinence |
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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 | LLT |
| E.1.2 | Classification code | 10059617 |
| E.1.2 | Term | Overactive bladder |
| 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 |
| To evaluate the efficacy and safety of intradetrusor BOTOX® 100 U compared to placebo in patients with OAB and urinary incontinence whose symptoms have not been adequately managed with anticholinergic therapy and are solifenacin naïve |
|
| E.2.2 | Secondary objectives of the trial |
| To compare the treatment effects of BOTOX® and solifenacin. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient is male or female, aged ≥ 18 years old.
2. Patient weighs ≥ 40 kg (88 lbs).
3. Patient has OAB and urinary incontinence for a period of at least 6 months immediately prior to screening, determined by documented patient history
4. Patient experiences ≥ 3 episodes of urinary urgency incontinence, with no more than 1 urinary urgency incontinence-free day, in the 3-day patient bladder diary completed during the screening period (see Section 6.3.4 Bladder Diary).
5. Patient experiences urinary frequency, defined as an average of ≥ 8 micturitions (toilet voids) per day ie, a total of ≥ 24 micturitions in the 3-day patient bladder diary completed during the screening period (see Section 6.3.4 Bladder Diary).
6. Patient has not been adequately managed with one or more anticholinergic agent for treatment of their OAB symptoms, in the opinion of the investigator. Not adequately managed is defined as:
o an inadequate response after at least a documented 4-week period of anticholinergic therapy on an optimized dose(s) ie, patient was still incontinent despite anticholinergic therapy, or
o limiting side effects after at least a documented 2-week period of anticholinergic therapy on an optimized dose(s).
An optimized dose is defined as an approved dose for the indication of OAB
7. Patient is willing to use clean intermittent catheterization (CIC) to empty the bladder at any time after study treatment, if it is determined to be necessary by the investigator |
|
| E.4 | Principal exclusion criteria |
1. Patient has symptoms of OAB due to any known neurological reason (eg, spinal cord injury, multiple sclerosis, cerebrovascular accident, Alzheimer’s disease, Parkinson’s disease, etc)
2. Patient has a predominance of stress incontinence, in the opinion of the investigator, determined by patient history
3. Patient has had previous or current therapy for OAB with solifenacin (any dose).
4. patient has received anticholinergics or any other medications or therapies to treat symptoms of OAB, including nocturia, within 7 days of the start of the screening period procedures
5. Patient uses CIC or indwelling catheter to manage their urinary incontinence.
6. Patient has a 24-hour total volume of urine voided > 3000 mL, collected over 24 consecutive hours during the 3-day bladder diary collection period prior to randomization/day 1
7.Patient has had previous or current botulinum toxin therapy of any serotype for any urological condition (or for any other condition within 12 weeks of randomization/day 1).
8. Patient has a history or evidence of uncontrolled narrow-angle glaucoma.
9. Patient has received therapy with ketoconazole or other potent cytochrome P450 3A4 (CYP3A4) inhibitors, within 7 days of the start of the screening period procedures.
10. Patient has serum creatinine level > 2 times the upper limit of normal at screening.
11. Patient has liver function tests (bilirubin, aspartate aminotransferase [AST], alanine aminotransferase [ALT]) > 1.5 times the upper limit of normal at screening.
12. Patient has decreased gastrointestinal motility, in the opinion of the investigator.
13. Patient has a known hypersensitivity to solifenacin, one of its components, including lactose, or to any other anticholinergics
14. Patient has a history of congenital or acquired QT prolongation
15. patient has history or evidence of any pelvic or urological abnormalities, bladder surgery or disease, other than OAB, that may affect bladder function including but not limited to:
o bladder stones and/or bladder stone surgery at the time of screening or within 6 months prior to screening
o surgery (including minimally invasive surgery) within 1 year of screening for stress incontinence, uterine prolapse, rectocele, or cystocele
o current or planned use of an electrostimulation/neuromodulation device (including posterior tibial nerve stimulation) for treatment of urinary incontinence (if a device is still implanted it must be inactive 4 weeks prior to randomization/day 1 and for the duration of the study); use of other nonimplantable electrostimulatory devices are also exclusionary.
16. Patient has evidence of urethral and/or bladder outlet obstruction, in the opinion of the investigator at screening or randomization/day 1
17. Patient has a PVR urine volume of > 100 mL at screening. The PVR measurement can be repeated once; the patient is to be excluded if the repeated measure is above 100 mL.
18. Patient has had urinary retention or an elevated PVR urine volume that has been treated with an intervention (such as catheterization) within 6 months of screening. Note: voiding difficulties as a result of surgical procedures that resolved within 24 hours are not exclusionary
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
There are 2 co-primary efficacy measures:
1. 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
2. proportion of patients who have 100% reduction (incontinence free/dry) from study baseline (ie, baseline prior to intradetrusor treatment 1) in urinary incontinence
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary timepoint is week 12 after intradetrusor treatment 1.
|
|
| E.5.2 | Secondary end point(s) |
The secondary measures include:
1. proportion of patients who have a positive treatment response on the Treatment Benefit Scale (TBS) (score of either 1 or 2, representing ‘greatly improved’ or ‘improved’)
2. number of micturition episodes
3. number of nocturia episodes (voids that interrupt night sleep)
4. mean KHQ domain scores for 2 of the 7 multi-item KHQ domains (‘Role Limitations’ and ‘Social Limitations’)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The secondary end point timepoint is week 12 after intradetrusor treatment 1. |
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 31 |
| 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 |
| Canada |
| European Union |
| United States |
|
| 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
|
|
| 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 | 1 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 24 |
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