|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Neurogenic detrusor overactivity as a result of spinal cord injury, in patients with urinary incontinence, who have not been adequately managed with anticholinergic therapy.
|E.1.2 Medical condition or disease under investigation
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|To explore the dose dependent response to 50 U, 100 U and 200 U BOTOX® when injected into the detrusor for the treatment of urinary incontinence caused by neurogenic detrusor overactivity in patients who have not been adequately managed with anticholinergic therapy
|Secondary objectives of the trial
|Trial contains a sub-study
|Principal inclusion criteria
|1. Patient is male or female, aged 18 to 80 years old.
2. Patient weighs ≥ 40 kg (88 lb).
3. Written informed consent has been obtained.
4. Written Data Protection Consent (European sites only) has been obtained.
5. Written documentation has been obtained in accordance with the relevant country and local privacy requirements, where applicable.
6. Patient has urinary incontinence as a result of neurogenic detrusor overactivity for a period of at least 3 months prior to screening as a result of spinal cord injury, determined by documented patient history. In addition patients must have a stable neurological injury level at T1 or below (cervical injuries are excluded) occurring ≥ 6 months prior to screening.
7. Patient has detrusor overactivity (defined as a phasic rise in bladder pressure during the filling phase determined by urodynamics) demonstrated during the screening period or Day 1 (prior to randomization).
8. Patient is able to complete study requirements including bladder diary completion and attend all study visits, in the opinion of the investigator.
9. Patient has not been adequately managed with one or more anticholinergics for their urinary incontinence, in the opinion of the investigator. Not adequately managed is defined as an inadequate response or intolerable side effects after at least one month of anticholinergic therapy on an optimized dose.
10. For patients taking anticholinergic medication for their neurogenic overactive bladder, dose is stable and patient is willing to maintain same dosing during study participation.
11. Patient has a negative pregnancy result if female and of childbearing potential.
The following criteria are also required for entry into the study at Randomization/Day 1:
12. Patient experiences > 14 episodes of urinary incontinence per week determined by completion of patient bladder diary (7 consecutive days) during the screening period with:
• A minimum of 5 days of diary completion within the 7 day diary completion period
• No more than 2 incontinent-free days within the 7 day diary completion period
13. Patient currently uses, or is willing to use, clean intermittent catheterization (CIC) to empty the bladder (indwelling catheter is not permitted). Patients currently on CIC should be willing to maintain an established CIC frequency throughout the study. Caregiver may perform CIC.
14. Patients with a negative urine culture result must take an antibiotic medication for 3 days immediately prior to Randomization/Day 1 and agree to continue antibiotic medication for at least 3 days following treatment. Patients with a positive urine culture result indicating urinary tract infection (UTI) must take an antibiotic to which the identified organism is sensitive for at least 5 days immediately prior to Randomization/Day 1 and continue for 3 days following the procedure (or longer as needed) and patient is asymptomatic for UTI on day of treatment. A UTI is defined as either a positive urine culture result with a bacteriuria count of > 105 CFU/mL conjoint with a leukocyturia > 5/hpf at screening or a positive urine culture that, in the investigator’s opinion, requires antibiotic therapy.
|Principal exclusion criteria
|1. Patient has history or evidence of any pelvic or urological abnormalities including but not limited to the following:
• elevated serum creatinine > 2 times the upper limit of normal (reference range)
• history of or current hematuria, 1) if the hematuria is determined to be a pathologic condition or 2) is uninvestigated
• interstitial cystitis in the opinion of the investigator
• bladder stones within 6 months of screening
• surgery or bladder disease other than detrusor overactivity that may impact bladder function with the exception of surgeries for bladder stones (> 6 months) and stress incontinence, uterine prolapse, rectocele, or cystocele (>1 year) from screening
2. Patient has had previous or current botulinum toxin therapy of any serotype for any urological condition or, treatment within 3 months of Randomization/Day 1 for any other condition or use.
3. Patient has been immunized for any botulinum toxin serotype.
4. Patient discontinued anticholinergic medication for overactive bladder < 21 days prior to Randomization/Day 1.
5. Patient has a history or current diagnosis of bladder cancer or has urine cytology results which may indicate bladder cancer not ruled out by investigator at Randomization/Day 1. Suspicious urine cytology abnormalities require the investigator’s assessment to ensure that the findings are not indicative of malignancy.
6. Patient is male with previous or current diagnosis of prostate cancer or a PSA > 10 ng/ml. Patients with a PSA > 4 ng/ml but < 10 ng/ml must have prostate cancer ruled out to the satisfaction of the investigator according to local site practice.
7. Patient has 24 hour total volume voided > 3000 mL of urine determined by completion of patient bladder diary collected over one consecutive 24 hour period during the 7 day diary collection period prior to Randomization/Day1.
8. For patients who micturate or have a mixed catheterization/spontaneous micturition pattern, patient has a post void residual volume above 200 mL.
9. Patient has an active genital infection, other than genital warts, either concurrently or within 4 weeks prior to screening.
10. Patient uses any anti-platelet or anticoagulant therapy or is using medications with anticoagulative effects within 3 days prior to treatment. Some medications may need to be withheld for > 3 days per clinical judgment of the investigator.
11. Patient has hemophilia or other clotting factor deficiencies or disorders that cause bleeding diatheses.
12. Patient has had concurrent treatment or treatment within 6 months of Randomization/Day 1 with capsaicin or resiniferatoxin.
13. Patient is currently using or plans to use an implanted or non-implantable electrostimulation/neuromodulation device for treatment of overactive bladder.
14. Patient has a known allergy or sensitivity to any components of the study medication, anesthetics or antibiotics or any other products associated with the treatment and general study procedures.
15. Patient has any medical condition that may put the patient at increased risk with exposure to BOTOX® including diagnosed myasthenia gravis, Eaton-Lambert syndrome or amyotrophic lateral sclerosis.
16. Patient is female and pregnant, nursing or planning a pregnancy during the study, or of childbearing potential and unable or unwilling to use a reliable form of contraception during the study.
17. Patient is currently or has previously participated in another therapeutic or device study within 30 days of screening.
18. 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.
|E.5 End points
|Primary end point(s)
|Number of episodes of urinary incontinence as recorded by patient bladder diary during the 7 days prior to each study visit. Primary timepoint is at Week 6 following the first treatment
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
| Information not present in EudraCT
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Trial has a data monitoring committee
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
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months