| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Idiopathic overactive bladder (symptoms of frequency and urgency) with urinary incontinence. |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 7.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10059617 |
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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 main objective of the study is to evaluate the safety and efficacy of a single treatment of each of 5 doses of BOTOX® compared to BOTOX® Placebo in patients with idiopathic overactive bladder with urinary urge incontinence who have not been adequately managed with anticholinergic therapy. The primary measure is the reduction of weekly frequency of urinary urge incontinence episodes. |
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| E.2.2 | Secondary objectives of the trial |
The study will also evaluate the following secondary measures in the study:
• Number of episodes of micturition
• Number of episodes of nocturia
• Number of episodes of urgency
• 24 hour total volume voided
• Post void residual urine volume
• Urodynamic parameters (which include post void residual volume, volume at first involuntary detrusor contraction, maximum cystometric capacity, peak (amplitude) detrusor pressure following first involuntary detrusor contraction, end fill pressure and detrusor compliance)
• Health outcome measures (which include SF-36, King’s Health Questionnaire (symptoms component only), Incontinence Quality of Life Instrument, EQ-5D, Patient Satisfaction Questionnaire, Patient Global Assessment)
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
All inclusion criteria are listed since they are all equally important.
• Patient is male or female, aged 18 to 85 years old
• Patient weighs ≥ 50 kg (110 lbs)
• Patient has symptoms of idiopathic overactive bladder (frequency and urgency) with urinary urge incontinence for a period of at least 6 months immediately prior to screening day -15, determined by documented patient history
• Patient is able to complete study requirements including electronic bladder diary completion, using the toilet without assistance (patient’s incontinence is not due to inability to reach the toilet) and attend all study visits, in the opinion of the investigator
• Written informed consent has been obtained
• Patient has negative pregnancy test result if female and of child-bearing potential
• Written Data Protection consent has been obtained
• Patient experiences ≥8 episodes of urinary urge incontinence, with no more than one incontinence-free day, determined by completion of patient bladder diary collected over seven consecutive days during the screening period (screening day -14 to randomization day 0)
• Patient experiences urinary frequency, defined as an average of ≥8 micturitions per day (normal voids only), with no more than one micturition-free day, determined by completion of patient bladder diary collected over seven consecutive days during the screening period (screening day -14 through randomization day 0)
• Patient has not been adequately managed with one or more anticholinergic drugs for their overactive bladder symptoms, in the opinion of the investigator. Not adequately managed is defined as an inadequate response to or intolerable side effects after at least one month of anticholinergic therapy on an optimized dose
• Patient is willing to use clean intermittent catheterization (CIC) to empty the bladder or is willing to have an indwelling catheter, if necessary following study treatment
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| E.4 | Principal exclusion criteria |
All exclusion criteria are listed since they are all equally important.
• Patient has symptoms of overactive bladder due to any known neurological reason e.g. spinal cord injury, multiple sclerosis, cerebral vascular accident, Alzheimer’s disease, Parkinson’s disease, etc.
• Patient has received anticholinergic or sympathomimetic medication for the treatment of overactive bladder within 21 days of randomization day 0
• Patient uses clean intermittent catheterization (CIC) to manage their urinary incontinence
• Patient has history or evidence of any pelvic or urological abnormalities, bladder surgery or disease, other than “overactive bladder”, that may impact bladder function. Note: Patient is currently using or has not removed a previously implanted electrostimulation/neuromodulation device for treatment of urinary incontinence (the latest time the device should have been removed is 6 weeks prior to randomization); use of other non-implantable electrostimulatory devices is also exclusionary.
• Patient has history or current diagnosis of bladder cancer or has urine cytology results which may indicate bladder cancer (e.g., suspicious results or diagnostic of malignancy) at screening day -15
• Patient has a post void residual urine volume >200mL at screening day -15
• 24 hour total volume voided > 3000 mL of urine determined by completion of patient bladder diary collected during the seven consecutive days during the screening period (day -14 to day 0)
• Patient has a predominance of stress incontinence, determined by patient history, in the opinion of the investigator
• Patient is male with previous or current diagnosis of prostate cancer. Patients with a PSA level greater than 4.0 ng/mL will require a biopsy to rule out prostate cancer, unless a prostatic biopsy has been performed within the past 12 months
• Patient is male, >40 years of age and has a urine flow rate <12 cc/second at screening day -15
• Patient has serum creatinine level >2 times the upper limit of normal at screening day -15
• Patient has a history of two or more treated urinary tract infections within 6 months of screening day -15
• Patient has urinary infection defined as a bacteriuria count of >105/mL conjoint with leukocyturia >5/hpf at screening day -15
• Patient has asymptomatic urinary infection, defined as positive nitrites, blood and/or leukocyte esterase on urine dipstick reagent strip test at randomization day 0
• Patient has history of unexplained hematuria or unexplained hematuria if >5 RBCs/hpf are present at screening day -15 or randomization day 0)
• Patient has active genital infection, other than genital warts, either concurrently or within 4 weeks prior to screening day -15
• Patient has a history of interstitial cystitis, in the opinion of the investigator
• Patient has evidence of urethral obstruction, in the opinion of the investigator at screening day -15 or randomization day 0
• Patient has a detrusor compliance on urodynamic evaluation of ≤ 20 mL/cmH20 at randomization day 0
• Patient uses anti-platelet or anti-coagulant therapy within 3 days prior to randomization day 0. Note: Some medications can be withheld > 3 days, per clinical judgment of the investigator.
• Patient has hemophilia, or other clotting factor deficiencies or disorders that cause bleeding diathesis
• Patient has previously been treated with any endovesical pharmacologic agent (e.g. capsaicin, resiniferatoxin)
• Patient has had previous or current botulinum toxin therapy of any serotype for any condition
• Patient has a known allergy or sensitivity to any components of the study medication, anesthetics or antibiotics to be used during the study
• Any medical condition that may put the patient at increased risk with exposure to BOTOX® including diagnosed myasthenia gravis, Eaton-Lambert syndrome or amyotropic lateral sclerosis
• Females who are pregnant, nursing or planning a pregnancy during the study or females of child-bearing potential who are unable or unwilling to use a reliable form of contraception during the study
• Current or previous participation in another therapeutic study within 30 days of screening day -15
• 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
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary measure is number of episodes of urinary urge incontinence (episodes to be indicated as urge or stress incontinence episodes as applicable), as recorded by patient bladder diary during 7 consecutive days prior to study visit day 0, and during seven consecutive days immediately prior to weeks 2, 6, 12, 18, 24, 30 and 36 (primary endpoint at week 12).
The primary endpoint for this study is at 12 weeks. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Information not present in EudraCT |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Information not present in EudraCT |
| 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.8.3 |
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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 | Information not present in EudraCT |
| 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 |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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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| End of the trial = last visit of the last subject |
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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 | 11 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
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