E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with symptoms of idiopathic overactive bladder (frequency and urgency) and urinary incontinence, whose symptoms have not been adequately managed with anticholinergic therapy |
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E.1.1.1 | Medical condition in easily understood language |
Overactive bladder with Urinary incontinence |
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E.1.1.2 | Therapeutic area | Diseases [C] - Symptoms and general pathology [C23] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 13.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10059617 |
E.1.2 | Term | Overactive bladder |
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 efficacy and safety of BOTOX® 100 U compared with placebo in patients with idiopathic OAB with urinary incontinence whose symptoms have not been adequately managed with 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 | No |
E.3 | Principal inclusion criteria |
1. Written informed consent has been obtained.
2. Written Authorization for Use and Release of Health and Research Study Information (US sites only) has been obtained.
3. Written Data Protection Consent (EU sites only) has been obtained.
4. Written documentation has been obtained in accordance with the relevant country and local privacy requirements, where applicable.
5. Patient is male or female, aged ≥ 18 years old.
6. Patient weighs ≥ 40 kg (88 lbs).
7. Patient has symptoms of idiopathic OAB (frequency and urgency) with urinary incontinence for a period of at least 6 months immediately prior to screening, determined by documented patient history.
8. Patient experiences ≥ 3 episodes of urinary urgency incontinence, with no more than one urgency incontinence-free day, in the 3-day patient bladder diary completed during the screening period (see Section 8.3.2.5 Patient Bladder Diary).
9. Patient experiences urinary frequency, defined as an average of ≥ 8 micturitions (toilet voids) per day i.e. a total ≥ 24 micturitions in the 3-day patient bladder diary completed during the screening period (see Section 8.3.2.5 Patient Bladder Diary).
10. Patient has not been adequately managed with one or more anticholinergic agents for treatment of their overactive bladder symptoms, in the opinion of the investigator.
Not adequately managed is defined as:
• an inadequate response after at least a 4-week period of anticholinergic therapy on an optimized dose(s), i.e., patient was still incontinent despite anticholinergic therapy, or
• limiting side effects after at least a 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.
11. 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.
12. Patient has a negative pregnancy test result if female and of childbearing potential.
13. Patient has a negative urine dipstick reagent strip test at Randomization/Day 1 (for nitrites and leukocyte esterase) and, in the investigator’s opinion, patient is asymptomatic for UTI on day of treatment.
14. Patient is able to complete study requirements including using the toilet without assistance, is able to collect volume voided per micturition measurements over a 24-hour period, complete bladder diaries and questionnaires, and attend all study visits in the opinion of the investigator.
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E.4 | Principal exclusion criteria |
The following are the key exclusion criteria (not exact wording) which ensures patients are not enrolled who are not in the target population:
No. 1: patient has symptoms of OAB due to a known neurological reason (eg. spinal cord injury or multiple sclerosis)
No. 2: patient has predominance of stress incontinence
No. 3: Patient has received anticholinergics or any other medications/therapies to treat symptoms of OAB including nocturia, within 7 days of the start of the screening period procedures.
No. 4: Patient uses CIC or indwelling catheter to mange their urinary incontinence
No. 5: Patient has been treated with any intravesical pharmacologic agent within 12 months of randomisation
No. 6: Patient has had previous or current botulinum toxin therapy of any serotype for any urological condition.
No. 7: Patient has had previous or current botulinum toxin therapy of any serotype for any nonurological condition within 12 weeks of Randomization.
No. 8: Patient has been immunized for any botulinum toxin serotype.
No. 9: Patient has history or evidence of any pelvic or urological abnormalities, bladder surgery or disease, other than ‘overactive bladder’, that may affect bladder function. (Note: list given in protocol)
No. 10: Patient has a history of interstitial cystitis/painful bladder syndrome.
No. 11: Patient has an active genital infection, other than genital warts, either concurrently or within 4 weeks prior to screening.
No. 12: Patient has a history or current diagnosis of bladder cancer or other urothelial malignancy, and/or has uninvestigated suspicious urine cytology results.
No. 13: Patient is male with previous or current diagnosis of prostate cancer or a prostate specific antigen (PSA) level of > 10 ng/mL at screening. Patients with a PSA level of ≥4 ng/mL but ≤ 10 ng/mL must have prostate cancer ruled out to the satisfaction of the investigator according to local site practice.
No. 14: Patient has evidence of urethral and/or bladder outlet obstruction at screening or Randomization.
No. 17: Patient has a 24hour total volume of urine voided > 3000 mL, collected over 24 consecutive hours during the 3-day bladder diary collection period prior to Randomization.
Excluding patients based on potential risks associated with study drug or administration procedure:
No. 15. Patient has a PVR urine volume of > 100 mL at screening.
No. 16. 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.
No. 18: Patient has a history of 2 or more urinary tract infections within 6 months of Randomisation/Day 1 or is taking prophylactic antibiotics toprevent chronic UTIs.
No. 19: Patient has a serum creatinine level > 2 times the upper limit of normal at screening.
No. 20: Patient has current or previous uninvestigated hematuria. Patient with investigated hematuria may enter the study if urological/renal pathology has been ruled out to the satisfaction of the investigator.
No. 21: Patient has hemophilia, or other clotting factor deficiencies, or disorders that cause bleeding diathesis.
No. 22: Patient cannot withhold any antiplatelet, anticoagulant therapy or medications with anticoagulant effects for 3 days prior to Randomization.
No. 23: Patient has a known allergy or sensitivity to any botulinum toxin preparation (including the study medication preparation), anesthetics or antibiotics to be used during the study.
No. 24: Patient has any medical condition that may put them at increased risk with exposure to BOTOX® including diagnosed myasthenia gravis, EatonLambert syndrome, or amyotrophic lateral sclerosis.
No. 27: Patient has any condition or situation which, in the investigator’s opinion, puts the patient at significant risk, could confound the study results, or may interfere significantly with the patient’s participation in the study.
Ensuring do not enrol patients at risk of becoming pregnant:
No. 25: Females who are pregnant, nursing or planning a pregnancy during the study or females of childbearing potential who are unable or unwilling to use a reliable form of contraception during the study (Note: reliable forms are defined in the protocol). |
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E.5 End points |
E.5.1 | Primary end point(s) |
There are two co-primary measures
• Number of episodes of urinary incontinence
• Proportion of patients who have a positive treatment response on the Treatment Benefit Scale (score of either 1 or 2, representing ‘greatly improved’ or ‘improved’)
The primary time point is Week 12 following the first treatment.
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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) |
The secondary efficacy measures are:
Number of micturition episodes
Urinary Incontinence-Specific Quality-of-Life Instrument (I-QOL)
King's Health Questionnaire (KHQ)
Number of urgency episodes. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
These will be measured for the duration of the study. |
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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 | Yes |
E.6.12 | Pharmacoeconomic | Yes |
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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
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 |
Russian Federation |
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 | 6 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |