| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with urinary incontinence due to neurogenic detrusor overactivity as a result of spinal cord injury or multiple sclerosis who have not been adequately managed with anticholinergic therapy and have neurological respiratory impairment. |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10046543 |
| E.1.2 | Term | Urinary incontinence |
|
| 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 2 dose levels of BOTOX® (200 U or 300 U) compared to placebo 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 and have neurological respiratory impairment. |
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| E.2.2 | Secondary objectives of the trial | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient is male or female, aged 18 to 80 years old.
2. Patient weighs ≥ 50 kg (110 lbs).
3. Written informed consent has been obtained.
4. Written Authorization for Use and Release of Health and Research Study Information (US sites only) has been obtained.
5. Written Data Protection Consent (European sites only) has been obtained.
6. Written documentation has been obtained in accordance with the relevant country and local privacy requirements, where applicable.
7. Patient has urinary incontinence as a result of neurogenic detrusor overactivity for a period of at least 3 months prior to Screening Day -21 as a result of spinal cord injury (SCI) or multiple sclerosis (MS), determined by documented patient history. In addition:
• Spinal cord injured patients must have a stable neurological injury between cervical level 5 (C5) and cervical level 8 (C8), inclusively as determined by the neurological definition of SCI; complete or incomplete. The spinal cord injury must have occurred ≥ 12 months prior to Screening Day -21.
• Multiple sclerosis patients must be clinically stable, in the investigator’s opinion, for ≥ 3 months prior to Screening and through Randomization/Day 1. Patients must have an Expanded Disability Status Scale (EDSS) score between 7.0 and 8.0, inclusively.
8. Patient has the ability to perform acceptable and reproducible pulmonary function testing as determined by the investigator and pulmonologist.
9. Patient has a Forced Vital Capacity (FVC) between 50% and 80% of predicted value on two separate testing days during Screening (Day -21 to Day -1). Note: The difference between the largest FVC observed on each testing day must not exceed 20%. There should be at least 7 days between the two screening PFTs and the second PFT must occur within 0-5 days prior to Randomization/Day 1 Visit.
10. Patient has detrusor overactivity (defined as a phasic rise in bladder pressure during the filling phase as determined by urodynamics) demonstrated during the Screening period (Day -21 to -1) ) or Randomization/Day 1.
11. Patient is able to complete study requirements and attend all study visits (telephone and clinic), in the opinion of the investigator.
12. 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 to or intolerable side effects while taking an optimized dose for at least one month.
13. For patients taking anticholinergic medication for their neurogenic overactive bladder, dose is stable and patient is willing to maintain same dosing during study participation.
14. Patient has a negative pregnancy test result if female and of childbearing potential.
15. Both MS and SCI patients must be willing to use IC to empty the bladder and maintain an established catheterization frequency throughout the study. Caregiver may perform IC for patient, if patient is unable to do this. (Indwelling catheters and suprapubic catheters are not permitted).
16. Patient experiences ≥ 4 episodes of urinary incontinence (leakage) over 3 days determined by completion of a bladder diary during the Screening period. |
|
| E.4 | Principal exclusion criteria |
1. 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
2. Patient has been immunized for any botulinum toxin serotype.
3. Patient has history or evidence of any significant pelvic or urological abnormality including but not limited to the following (described in protocol):
- 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 due to a - pathologic condition or 2) is uninvestigated.
- interstitial cystitis in the opinion of the investigator
- bladder stones within 6 months of Screening Day - 21
- 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 Day -21)
4. Patient is male with previous or current diagnosis of prostate cancer. Patients with a PSA level greater than 4.0 ng/mL at Screening Day -21 will require a biopsy to rule out prostate cancer, unless a prostatic biopsy has been performed within the past 12 months.
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 the investigator at Randomization/Day 1. Suspicious urine cytology abnormalities require the investigator’s assessment that the findings are not indicative of malignancy.
6. Patient has discontinued anticholinergic medication for the treatment of overactive bladder < 21 days prior to Randomization/Day 1.
7. Patient has an untreated or symptomatic (e.g. fever, recent change in neurological status) urinary tract infection (UTI) on Randomization/Day 1.
8. Patient has a post void residual volume above 150 mL for patients who micturate or have a mixed catheterization/spontaneous micturition pattern.
9. Patient has an active genital infection, other than genital warts, within 4 weeks prior to Screening Day -21.
10. Patient has an acute respiratory tract infection at during (Screening Day -21 to Day -1) or Randomization/Day 1. Patient may qualify for re-screening upon clinical resolution and stabilization (one month, or longer based on the investigator’s opinion, has elapsed after clinical resolution without recurrent symptoms).
11. Patient has a clinically significant abnormal CXR finding. Patient may qualify for re-screening upon resolution, or the CXR finding is no longer considered clinically significant.
12. Patient has clinically significant intrinsic lung disease (e.g. sarcoidosis, pulmonary fibrosis, bronchiectasis).
13. Asthmatics, whose disease is not stable (i.e., have had exacerbation(s) of asthma within 3 months prior to Screening Day -21). Note: Stable, preventative respiratory medications/therapy are permitted.
14. Patient has an acute exacerbation of COPD within 3 months prior to Screening Day -21.
15. Patient has had a pulmonary embolus (PE) within 6 months of Screening Day -21, or a history of recurrent pulmonary emboli (i.e., a diagnosis of PE on more than one occasion per lifetime).
16. Patient has aspiration pneumonia, aspiration pneumonitis or acute respiratory failure within 12 months prior to Screening Day -21.
17. Patient requires supplemental oxygen and/or ventilatory support.
18. Patient has evidence of carbon dioxide (CO2) retention as indicated by serum bicarbonate level greater than the upper limit of normal (reference range) at Screening Day -21.
19. Patient has used any antiplatelet 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 (refer to Section 8.2.2 Prohibited Medications/Treatments for details).
20. Patient has hemophilia or other clotting factor deficiencies or disorders that may cause bleeding diatheses.
21. Patient is currently using, or plans to use, an implanted or non-implantable electrostimulation/neuromodulation device for treatment of overactive bladder.
22. Patient is currently being treated with an intrathecal baclofen pump.
23. Patient has a known allergy or sensitivity to any component of the study medication, anesthetics or antibiotics or any other products associated with the injection and general study procedures.
24. 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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• Number of episodes of urinary incontinence as recorded in the patient bladder diary
• Number of episodes of voiding and method (catheterization or voluntary) as recorded in the patient bladder diary
• Urodynamic parameters, as detailed in the protocol. Urodynamic studies will be conducted according to International Continence Society (ICS) standard guidelines (Homma et al, 2002) and results will be assessed by an independent central urodynamic reviewer. |
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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 | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Information not present in EudraCT |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| 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 | Information not present in EudraCT |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 2 |
| 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 |
|
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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