Botulin-A Toxin Instillations and Overactive Bladder

The primary objective of this pilot study is to evaluate the safety and efficacy of direct instillations of Botulinum-A toxin/DMSO into the bladder via a catheter system as a means of treating women with symptoms of overactive bladder and secondary urinary incontinence. In doing so, we will focus on estimating the percentage of women who experience an improvement in their urinary incontinence symptoms at one month and three months following this novel instillation technique.

Rationale:

To date, the standard treatment for overactive bladder (including detrusor hyperreflexia and detrusor overactivity) consists of oral anticholenergic medications that can have troublesome side effects and variable efficacy. What's more, patients failing pharmacological therapy must either live with their malady or undergo open surgery that is irreversible and carries a prolonged convalescence. The fact remains however that treatment for overactive bladder is necessary to help maintain quality of life and prevent upper urinary tract deterioration. In recent years, cystoscopic-guided injection of Botulinum-A toxin has been used as a novel method of addressing detrusor hyperreflexia and overactivity by blocking acetylcholine transmission at the bladder. The obvious benefits of a more targeted therapy notwithstanding, this method requires the use of a cystoscope, needle delivery of the agent through approximately 30 separate injection sites and either regional or topical intravesical anesthesia for peri-operative pain control. Clearly, the identification of less invasive and more cost effective means of delivering the beneficial effects of Botulinum-A toxin to the bladder muscle has the potential to enhance the overall appeal of this treatment method.

Objectives:

The primary objective of this pilot study is to evaluate the safety and efficacy of direct instillations of Botulinum-A toxin/DMSO into the bladder via a catheter system as a means of treating women with symptoms of overactive bladder and secondary urinary incontinence. In doing so, we will focus on estimating the percentage of women who experience an improvement in their urinary incontinence symptoms at one month and three months following this novel instillation technique.

Study Design:

We are proposing a single center, Phase II pilot study for this investigation. In this proposal, 25 sterile women between 18-90 years of age with urodynamic evidence of detrusor overactivity, hyperreflexia or symptoms of overactive bladder syndrome who lack evidence of infection and stress incontinence will be offered bladder instillation of Botulinum-A toxin with DMSO as a carrier agent if they have failed anticholinergic medications or cannot tolerate the pharmacological side effects. We will use two validated measurement tools for determining urinary incontinence severity. These measurement tools will be administered to each women at baseline and then again at one month and three-month follow-up time points. Our analysis will also focus on identifying and describing adverse events among these women and estimating the percentage of women that experience a successful improvement in their urinary incontinence symptoms.

Study Duration:

Patients will sign an informed consent and be screened for eligibility. Once determined eligible for the study, each patient will be scheduled for baseline evaluation and instillation of Botox/DMSO. Patients will be then followed up at one month and three months. Patients will be removed from the study if they withdraw consent, experience one of the study stopping criteria (in which case the entire study will stop) or when they complete the final follow-up evaluation at three-months.

• Overactive Bladder
• Detrusor Instability
• Detrusor Hyperreflexia of Bladder

Inclusion Criteria:

1. Female patient aged 18 years or older
2. Patient with a history of stress urinary incontinence for at least 12 months
3. Patient with Intrinsic Sphincter Deficiency who demonstrate an abdominal leak point pressure of less than 100 cm of water on urodynamic evaluation
4. Patient with urinary incontinence verified by the Provocation test: a mean urinary leakage of 10 g on screening and baseline visits
5. Patient with positive stress test and/or urodynamic stress incontinence
6. Patient who has failed prior non-invasive treatment (e.g. behavior modification, pelvic floor exercises, biofeedback, electrical stimulation and/or drug therapy)
7. Patient with negative Contigen skin test during screening.
8. Patient who is mentally competent with the ability to understand and comply with the requirements of the study
9. Patient who agrees to be available for the follow-up evaluations as required by the protocol
10. Patient who has given signed informed consent

Exclusion Criteria:

1. Patient with Q-tip angle greater than 30 degrees
2. Patient with Functional Bladder capacity <200 ml as recorded in the baseline Bladder Diary
3. Patient with Post-Void Residual Urine (PVRU) greater than 100 ml on repeated measures. (Patient with a single PVRU of >100 ml and followed by two consecutive PVRU measurements of <100 ml may be included in the study)
4. Patient with vesicoureteral reflux, interstitial cystitis, genitourinary fistulae
5. Patient with predominant urge incontinence
6. Patient with detrusor overactivity on filling cystometry
7. Patient with pelvic organ prolapse stage III or IV, i.e. the most distal part of the prolapse protruding more than 1 cm beyond the hymen (>+1), at straining
8. Patient with urinary incontinence due to neurological disease that is known to affect urinary tract infection
9. Patient with univestigated hematuria
10. Patient with genitourinary malignancies
11. Patient on current medication for stress urinary incontinence, such as alpha-adrenergic agonists or duloxetine, within three weeks prior to completing the baseline Bladder Diary (estrogen therapy on a stable dose for at least two months prior to study start is allowed)
12. Patient who has had bulking therapy for stress urinary incontinence
13. Patient with ongoing complications of prior anti-incontinence surgery
14. Patient who is pregnant, lactating, or planning to become pregnant within the study period
15. Patient who has received pelvic radiation
16. Patient with any condition, which could lead to significant postoperative complications, including current infection and uncontrolled diabetes.
17. Patient who is morbidly obese (defined as BMI > 32 Kg/m2)
18. Patient who is bedridden, institutionalized or in such physical condition that she cannot move to the closest bathroom without assistance from another person
19. Patient with current or acute urinary tract infection, including cystitis or urethritis. (Patient with such infections should be treated with antibiotics, with subsequent urinalysis tests confirming the absence of such infection before study inclusion)
20. Patient with any condition that would preclude treatment due to contraindications and/or warnings in the study product's labeling
21. Patient on concomitant medication with anticoagulant properties (e.g., Warfarin, Heparin, Aspirin, NSAIDs, except for cox-2 inhibitors) within two weeks prior to treatment
22. Patient on immunomodulatory therapy (suppressive or stimulatory)
23. Patient with a known allergy to bovine collagen
24. Patient with known lidocaine hypersensitivity or hypersensitivity to any anesthetics to be used during the treatment session/surgical procedure
25. Patient with a concurrent use of another study product within two weeks prior to study start, or who concurrently participate in any other clinical study
26. Any disease that in the opinion of the Investigator would make the patient unsuitable for the study
27. Patient with a life expectancy of less than 12 months