Botulin-A Toxin Instillations and Overactive Bladder

Study Overview
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Brief Summary
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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.

Detailed Description
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Rationale: To date, the standard treatment for overactive bladder (including detrusor hyperreflexia and detrusor overactivity) consists of oral anticholinergic 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.

Official Title
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Botulin-A Toxin/Dimethyl Sulfoxide Bladder Instillations for Treatment of Voiding Dysfunction Secondary to Detrusor Hyperreflexia and Detrusor Instability in Women

Conditions
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Overactive Bladder, Detrusor Instability, Detrusor Hyperreflexia

Intervention / Treatment
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* Drug: Botulinum-A toxin
* Drug: Dimethyl sulfoxide (DMSO)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female patient aged 18 years or older Patient with a history of stress urinary incontinence for at least 12 months Patient with Intrinsic Sphincter Deficiency who demonstrate an abdominal leak point pressure of less than 100 cm of water on urodynamic evaluation Patient with urinary incontinence verified by the Provocation test: a mean urinary leakage of 10 g on screening and baseline visits Patient with positive stress test and/or urodynamic stress incontinence Patient who has failed prior non-invasive treatment (e.g. behavior modification, pelvic floor exercises, biofeedback, electrical stimulation and/or drug therapy) Patient with negative Contigen skin test during screening. Patient who is mentally competent with the ability to understand and comply with the requirements of the study Patient who agrees to be available for the follow-up evaluations as required by the protocol Patient who has given signed informed consent Exclusion Criteria: Patient with Q-tip angle greater than 30 degrees Patient with Functional Bladder capacity <200 ml as recorded in the baseline Bladder Diary 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) Patient with vesicoureteral reflux, interstitial cystitis, genitourinary fistulae Patient with predominant urge incontinence Patient with detrusor overactivity on filling cystometry 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 Patient with urinary incontinence due to neurological disease that is known to affect urinary tract infection Patient with uninvestigated hematuria Patient with genitourinary malignancies 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) Patient who has had bulking therapy for stress urinary incontinence Patient with ongoing complications of prior anti-incontinence surgery Patient who is pregnant, lactating, or planning to become pregnant within the study period Patient who has received pelvic radiation Patient with any condition, which could lead to significant postoperative complications, including current infection and uncontrolled diabetes. Patient who is morbidly obese (defined as BMI > 32 Kg/m2) Patient who is bedridden, institutionalized or in such physical condition that she cannot move to the closest bathroom without assistance from another person 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) Patient with any condition that would preclude treatment due to contraindications and/or warnings in the study product's labeling Patient on concomitant medication with anticoagulant properties (e.g., Warfarin, Heparin, Aspirin, Nonsteroidal anti-inflammatory drugs (NSAIDs), except for cox-2 inhibitors) within two weeks prior to treatment Patient on immunomodulatory therapy (suppressive or stimulatory) Patient with a known allergy to bovine collagen Patient with known lidocaine hypersensitivity or hypersensitivity to any anesthetics to be used during the treatment session/surgical procedure 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 Any disease that in the opinion of the Investigator would make the patient unsuitable for the study Patient with a life expectancy of less than 12 months

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Botox/DMSO Solution<br>Subjects received Botulinum-A toxin and Dimethyl sulfoxide solution. The first 3 subjects in Phase 1 underwent bladder instillation of 50 cc of the solution utilizing 200 units of botulinum-A toxin and 50cc DMSO. The next 6 subjects in the Phase 1 trial received 300 units of botulinum-A toxin and 50cc DMSO. All subjects in the Phase 2 trial received 300 units of botulinum-A toxin and 50cc DMSO. | Drug: Botulinum-A toxin<br>* A simple bladder catheterization in the office with a standard urinary catheter and instill the Botulinum-A toxin/DMSO solution.<br>* Other names: Xeomin;Drug: Dimethyl sulfoxide (DMSO)<br>* Subjects received 50 cc of DMSO in an aqueous solution for intravesical instillation with botulinum-A toxin. Each cc contained 0.54 gm DMSO.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Number of Incontinent Episodes During 24 Hours | The study coordinator instructed the subject to keep record of any incontinence episodes during the 24-hour period prior to their baseline and follow-up visits. | baseline, 1 month, 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median 24 Hour Pad Weight | Prior to baseline and follow-up visits, the study coordinator weighed standard pads provided to the subject for the study time period. The study coordinator instructed the subject to bring in any pads used during the 24-hour period prior to baseline and follow up visits. The study coordinator recorded the 24-hour pad weights into the study dataset. | baseline, 1 month, 3 months | 
| Blaivas-Groutz Anti-Incontinence Score at Baseline | The Blaivas-Groutz Anti-incontinence scale was used as a measure of urinary incontinence. This scale combines information on the number of incontinent episodes in a 24-hour period, 24-hour pad weights, and a qualitative rating by the patient into a single score ranging from 0 to 6. This score is then used to categorize incontinence as none (0), mild (1-2), moderate (3-4), or severe (5-6). | baseline | 
| Blaivas-Groutz Anti-Incontinence Score at 1 Month | The Blaivas-Groutz Anti-incontinence scale was used as a measure of urinary incontinence. This scale combines information on the number of incontinent episodes in a 24-hour period, 24-hour pad weights, and a qualitative rating by the patient into a single score ranging from 0 to 6. This score is then used to categorize incontinence as none (0), mild (1-2), moderate (3-4), or severe (5-6). | 1 month after treatment | 
| Blaivas-Groutz Anti-Incontinence Score at 3 Months | The Blaivas-Groutz Anti-incontinence scale was used as a measure of urinary incontinence. This scale combines information on the number of incontinent episodes in a 24-hour period, 24-hour pad weights, and a qualitative rating by the patient into a single score ranging from 0 to 6. This score is then used to categorize incontinence as none (0), mild (1-2), moderate (3-4), or severe (5-6). | 3 months after treatment | 
| Mean Number of Pads Per Day |  | baseline, 1 month, 3 months | 
| Postvoid Residual |  | baseline, 1 month, 3 months | 
| Urine Culture |  | baseline, 1 month, 3 months | 
| Urinary Urgency at Baseline | Urinary urgency was measured by the Indevus Urgency Severity Scale (IUSS). The IUSS asks patients to assess the severity of 'urgency' at each void. The scale employs the following wording: Degree of urgency is meant to describe your urge to urinate. Sometimes you may feel a very strong urge to urinate and at other times, you may feel a milder urge prior to the onset of a toilet void. Rate this feeling by circling 0, 1, 2, or 3, defined as: 0: NONE - no urgency, 1: MILD - awareness of urgency, but it is easily tolerated and you can continue with your usual activity or tasks, 2: MODERATE - enough urgency discomfort that it interferes with or shortens your usual activity or tasks, 3: SEVERE - extreme urgency discomfort that abruptly stops all activity or tasks. | baseline | 
| Urinary Urgency at 1 Month | Urinary urgency was measured by the Indevus Urgency Severity Scale (IUSS). The IUSS asks patients to assess the severity of 'urgency' at each void. The scale employs the following wording: Degree of urgency is meant to describe your urge to urinate. Sometimes you may feel a very strong urge to urinate and at other times, you may feel a milder urge prior to the onset of a toilet void. Rate this feeling by circling 0, 1, 2, or 3, defined as: 0: NONE - no urgency, 1: MILD - awareness of urgency, but it is easily tolerated and you can continue with your usual activity or tasks, 2: MODERATE - enough urgency discomfort that it interferes with or shortens your usual activity or tasks, 3: SEVERE - extreme urgency discomfort that abruptly stops all activity or tasks. | 1 month after treatment | 
| Urinary Urgency at 3 Months | Urinary urgency was measured by the Indevus Urgency Severity Scale (IUSS). The IUSS asks patients to assess the severity of 'urgency' at each void. The scale employs the following wording: Degree of urgency is meant to describe your urge to urinate. Sometimes you may feel a very strong urge to urinate and at other times, you may feel a milder urge prior to the onset of a toilet void. Rate this feeling by circling 0, 1, 2, or 3, defined as: 0: NONE - no urgency, 1: MILD - awareness of urgency, but it is easily tolerated and you can continue with your usual activity or tasks, 2: MODERATE - enough urgency discomfort that it interferes with or shortens your usual activity or tasks, 3: SEVERE - extreme urgency discomfort that abruptly stops all activity or tasks. | 3 months after treatment | 
| Median Urogenital Distress Inventory (UDI-6) Scores | The UDI-6 was one measure of urinary-associated quality of life. The UDI-6 questionnaire has 6 items, scored from 0 (not at all) to 3 (greatly), with total scores ranging from 0 to 18, a higher score indicating greater distress. | baseline, 1 month, 3 months | 
| Bothersomeness | The bothersomeness refers to the question: On a scale of 1-10 (0 is not at all; 10 is intolerable), how badly does loss of urinary control bother you? | baseline, 1 month, 3 months | 
| Incontinence Impact Questionnaire-short Form (IIQ-7) Scores | The IIQ-7 was one measure of urinary-associated quality of life. The IIQ-7 questionnaire has 7 items, scored from 0 (not at all) to 3 (greatly), with total scores ranging from 0 to 21, a higher score indicating greater distress. | baseline, 1 month, 3 months |