Efficacy of Botulinum Toxin Type A for the Treatment of Non-neurogenic Urinary Urge Incontinence

Study Overview
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Brief Summary
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Non-neurogenic urinary urge incontinence (UUI) is a common quality of life disorder that causes people to feel an urgent need to urinate. Standard treatment for UUI includes behavior modification, pelvic floor exercises, anticholinergic medication, and less commonly, sacral neuromodulation. Unfortunately anticholinergic therapy is only moderately effective. Botulinum toxin A (BTA or Botox©) may be a useful treatment in patients that do not respond to standard therapy. Botulinum toxin A has been used in other studies to improve symptoms in neurogenic urinary incontinence, and a variety of lower urinary tract disorders. BTA has been used in other studies to improve the symptoms in urinary incontinence, migraines, spinal cord injuries and a variety of lower urinary tract disorders. However, the treatment of non-neurogenic urinary urge incontinence has not been examined in a well-controlled study. The primary purpose of this study is to determine the efficacy of botulinum toxin A (BTA) in the treatment of non-neurogenic urinary urge incontinence (UUI). The secondary objectives are to examine the side effects associated with BTA treatment and the impact this treatment has on patients' quality of life.

Detailed Description
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Introduction: Non-neurogenic urinary urge incontinence (UUI) is a common quality of life disorder that becomes more prevalent with age. It is described as a condition that causes people to feel an urgent need to urinate due to muscle spasms in the bladder. Factors such as infection, inflammation, strokes, and dementia can stimulate the bladder to create spasms and cause urine loss. Overactive bladder refers to the symptom complex of urinary frequency, urgency and or nocturia with or without incontinence. Overactive bladder is a disorder of the storage phase of the bladder affecting approximately 16.9% of the US women, increasing to 31% after age 75. Standard treatment for UUI includes behavior modification, pelvic floor exercises, anticholinergic medication, and less commonly, sacral neuromodulation. Unfortunately anticholinergic therapy is only moderately effective and causes bothersome side effects, particularly at higher doses. Sacral neuromodulation therapy is currently unavailable in Saskatchewan with the closest treatment centre being located in Calgary. Botulinum toxin A (BTA or Botox©) may be a useful treatment in patients that do not respond to standard therapy. Botulinum toxin A has been used in other studies to improve symptoms in neurogenic urinary incontinence, migraines following spinal cord injuries, and a variety of lower urinary tract disorders. This product has been approved by FDA for treatments of the following conditions: two eye muscle disorders (blepharospasm and strabismus in December 1989), severe underarm sweating (primary axillary hyperhydrosis), brow furrow and frown lines (April 2002) and other cosmetic purposes (July 2004). For the treatment of UUI, BTA is injected into the detrusor muscle of the bladder which is the muscle of the bladder that squeezes urine towards the outlet. BTA has been used in other studies to improve the symptoms in urinary incontinence and a variety of lower urinary tract disorders, however, the treatment for non-neurogenic urinary urge incontinence has not been examined in a well-controlled study. Research Purpose and Objectives: The primary purpose of this study is to determine the efficacy of BTA in the treatment of non-neurogenic UUI. The secondary objectives are to examine the side effects associated with BTA treatment and the impact this treatment has on patients' quality of life. Research Methods: This study employs a 12 month, double-blinded, randomized, partial cross-over design. The first 6 months of the study, subjects will be randomized to receive either detrusor injection of BTA or a placebo injection. In the remaining six months, subjects in the control group will be offered the detrusor injection of BTA. All 36 subjects will be followed for the remaining 6 months. Study Procedures and Protocol Pre-injection Assessment: The pre-injection and assessment stage includes an evaluation of the medical history and physical exam. Previous therapy and medication will be disclosed to the physician. The investigator will ensure the subject meets the inclusion criteria, has had urinalysis and a pregnancy test if under 50 years old. Day of the Procedure: On the day of the surgery, the study pharmacist will randomize subjects using a random numbers table. The study doctor, nurses, and subjects will be blinded to treatment allocation. Ancef 1gm, or in the case of penicillin allergy, cipro 400 mg, will be given by intravenous. A local anaesthetic will be instilled at the end of the cystoscopy (40 ml 1% lidocaine) and sedation will be provided as required. Fifteen minutes will lapse before beginning the procedure. Using a 30 degree rigid scope and minimally invasive cystoscopic technique, 10 injections at 10 U/ml per injection (altogether 100 U of BTA) will be injected into the bladder wall, sparing the trigone.3,4 Subjects assigned to the placebo condition will receive injections of a saline at a similar frequency as the BTA injections. Subjects will be observed for 60 minutes post procedure and then discharged home. This is the standard protocol for other BTA procedures performed on an outpatient basis in the RQHR. Catheter supplies will be provided upon discharge. Follow-up Schedule: Four to Six Weeks Post-Procedure: The primary and secondary measures will be assessed. Three Months post-procedure: The same procedures will be repeated as at the four-to-six week assessment. Six Months post-procedure: The four-to-six week assessment will be performed, and symptoms of retention or residual since the last visit will be discussed. A cystoscopy will be performed to study culture/urinalysis, measure desire and capacity, and show incontinence. Study allocation will be revealed at six months, and BTA injection will be offered to subjects that had received the placebo. Nine Months: The four-to-six week procedures are repeated. Twelve Months: The four-to-six week procedures are repeated. Potential Significance: Current anticholinergic therapy for non neurogenic UUI has limitations. In addition to significant systemic side effects, studies have shown that only 50% of patients improve with anticholinergic therapy, and that improvement does not always involve continence. Thus, detrusor injection of BTA may be a safe and efficacious therapy for patients who have failed standard therapy with anticholinergic medication and allow for an improved quality of life.

Official Title
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Efficacy of Botulinum Toxin A Intradetrusor Injections for the Treatment of Non-neurogenic Urinary Urge Incontinence- A Randomized Double-Blind Control Trial

Conditions
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Urinary Urge Incontinence

Intervention / Treatment
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* Drug: Botulinum Toxins, Type A
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female subjects, greater than 17 years of age Written informed consent has been obtained Ability to follow study instructions and likely to complete all required visits Written authorization for Use and Release of Health and Research Study Information has been obtained Subject meets the following criteria: clinical diagnosis of urinary urge incontinence with resistance to or intolerance of anticholinergic medication Anticholinergic medications allowed Willingness and ability to use self-catheterization if necessary Exclusion Criteria: Uncontrolled clinically significant medical condition other than the condition under evaluation Known allergy or sensitivity to any of the components in the study medication Females with a positive pregnancy test, or who are breast-feeding, planning a pregnancy during the study, who think that they may be pregnant at the start of the study Concurrent participation in another investigational drug or device study Treatment with botulinum toxin of any serotype for urological condition prior to enrolment in study (if applicable) Any medical condition that may put the subject at increased risk with exposure to botulinum toxin A including diagnosed myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, or any other disorder that might interfere with neuromuscular function Any condition or situation that, in the investigator's opinion, may put the subject at significant risk, confound the study results, or interfere significantly with the subject's participation in the study Symptomatic urinary retention or post-void residual of >200ml Anticoagulation therapy within 3 days of injection procedure Familial bleeding disorder UUI secondary to neurologic disease Myasthenia gravis Previous bladder pathology (e.g. transitional cell carcinoma)

Ages Eligible for Study
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Minimum Age: 17 Years
Maximum Age: 80 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
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebos<br>Placebo injected into the detrusor at Day 1, | Drug: Placebos<br>* Placebos injected into the detrusor at Day 1, followed by injection of botulinum toxin Type A 100U after 24 weeks has elapsed from previous treatment, if requested/qualified.<br>|
| Experimental: Botulinum Toxins, Type A<br>Botulinum Toxins, Type A 100U injected into the detrusor at Day 1 | Drug: Botulinum Toxins, Type A<br>* Botulinum Toxins, Type A 100U injected into the detrusor at Day 1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Maximum Capacity at Cystoscopy Between Baseline and 6 Month Follow-up | Cystoscopy is a test performed with a cystoscope, a narrow tube with a tiny camera at its tip, inserted into the urethra and bladder to see the inside of the bladder and urethra. Maximum bladder capacity--the amount of liquid or gas the bladder can hold under anesthesia. Without anesthesia, capacity is limited by either pain or a severe urge to urinate. | Baseline to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Incontinence Episodes Between Baseline and 6 Week Follow-up | Incontinence- involuntary leakage of urine | Baseline to 6 weeks | 
| Change in Incontinence Episodes Between Baseline and 3 Month Follow-up | Incontinence- involuntary leakage of urine | Baseline to 3 month | 
| Change in Incontinence Episodes Between Baseline and 6 Month Follow-up | Incontinence- involuntary leakage of urine | Baseline to 6 month | 
| Change in Incontinence Episodes Between Baseline and 9 Month Follow-up | Incontinence- involuntary leakage of urine | Baseline to 9 months | 
| Change in Incontinence Episodes Between Baseline and 12 Month Follow-up | Incontinence- involuntary leakage of urine | Baseline and 12 months | 
| Change in Incontinence Episodes Between Baseline and 24 Months Follow-up | Incontinence- involuntary leakage of urine | Baseline and 24 months | 
| Change in Number of Daytime Voids Between Baseline and 6 Week Follow-up | Frequency of daily urination | Baseline to 6 weeks | 
| Change in Number of Daytime Voids Between Baseline and 3 Month Follow-up | Frequency of daily urination | Baseline to 3 month | 
| Change in Number of Daytime Voids Between Baseline and 6 Month Follow-up | Frequency of daily urination | Baseline to 6 months | 
| Change in Number of Daytime Voids Between Baseline and 9 Month Follow-up | Frequency of daily urination | Baseline to 9 months | 
| Change in Number of Daytime Voids Between Baseline and 12 Month Follow-up | Frequency of daily urination | Baseline to 12 months | 
| Change in Number of Daytime Voids Between Baseline and 24 Month Follow-up | Frequency of daily urination | Baseline to 24 months | 
| Change in Number of Night Voids Between Baseline and 6 Week Follow-up | Frequency of night voiding | Baseline to 6 weeks | 
| Change in Number of Night Voids Between Baseline and 3 Month Follow-up | Frequency of night voiding | Baseline to 3 months | 
| Change in Number of Night Voids Between Baseline and 6 Month Follow-up | Frequency of night voiding | Baseline to 6 months | 
| Change in Number of Night Voids Between Baseline and 9 Month Follow-up | Frequency of night voiding | Baseline and 9 months | 
| Change in Number of Night Voids Between Baseline and 12 Month Follow-up | Frequency of night voiding | Baseline to 12 months | 
| Change in Number of Night Voids Between Baseline and 24 Months Follow-up | Frequency of night voiding | Baseline and 24 months | 
| Subjective Benefit Assessment at 6 Weeks | Self assessed description of how well they believed the Botulinum Toxin type A was working. The patients' subjective assessment of the treatment's efficacy was obtained verbally using a four-point rating scale. Rating options were: dry (complete response), improvement (> 50% reduction in incontinence), partial response (≤ 50% reduction in incontinence), no response to treatment. | Baseline to 6 weeks | 
| Subjective Benefit Assessment at 3 Months | Self assessed description of how well they believed the Botulinum Toxin type A was working. The patients' subjective assessment of the treatment's efficacy was obtained verbally using a four-point rating scale. Rating options were: dry (complete response), improvement (> 50% reduction in incontinence), partial response (≤ 50% reduction in incontinence), no response to treatment. | Baseline to 3 months | 
| Subjective Benefit Assessment at 6 Months | Self assessed description of how well they believed the Botulinum Toxin type A was working.The patients' subjective assessment of the treatment's efficacy was obtained verbally using a four-point rating scale. Rating options were: dry (complete response), improvement (> 50% reduction in incontinence), partial response (≤ 50% reduction in incontinence), no response to treatment. | Baseline to 6 months | 
| Change in Incontinence Impact Questionnaire From Baseline to 6 Weeks Follow-up | Disease specific validated quality of life measure. Health-related quality of life measures for women with urinary incontinence. Incontinences Impact Questionnaire - 7 (IIQ-7) The IIQ-7 is 7-point scale used to rate a patients' life and the affect of accidental urine loss on activities, relationships, and feelings. Item responses are assigned values of 0 for not at all, 1 for slightly, 2 for moderately, and 3 for greatly. The average score of items responded to is calculated. The average, which ranges from 0 to 3, is multiplied by 33 1/3 to put scores on a scale of 0 to 100. | Baseline to 6 weeks | 
| Change in Incontinence Impact Questionnaire From Baseline to 3 Months Follow-up | Disease specific validated quality of life measure. Health-related quality of life measures for women with urinary incontinence. Incontinences Impact Questionnaire - 7 (IIQ-7) The IIQ-7 is 7-point scale used to rate a patients' life and the affect of accidental urine loss on activities, relationships, and feelings. Item responses are assigned values of 0 for not at all, 1 for slightly, 2 for moderately, and 3 for greatly. The average score of items responded to is calculated. The average, which ranges from 0 to 3, is multiplied by 33 1/3 to put scores on a scale of 0 to 100. | Baseline to 3 months | 
| Change in Incontinence Impact Questionnaire From Baseline to 6 Months Follow-up | Disease specific validated quality of life measure. Health-related quality of life measures for women with urinary incontinence. Incontinences Impact Questionnaire - 7 (IIQ-7) The IIQ-7 is 7-point scale used to rate a patients' life and the affect of accidental urine loss on activities, relationships, and feelings. Item responses are assigned values of 0 for not at all, 1 for slightly, 2 for moderately, and 3 for greatly. The average score of items responded to is calculated. The average, which ranges from 0 to 3, is multiplied by 33 1/3 to put scores on a scale of 0 to 100. | Baseline to 6 months | 
| Change in Urogenital Distress Inventory From Baseline to 6 Week Follow-up | Disease specific quality of life measure. Health-related quality of life measures for women with urinary incontinence. Urogenital Distress Inventory - 6 (UDI-6) The UDI-6 is a 6-point scale that asks patients to respond to questions rating whether they experience and how much they are bothered by UUI. Item responses are assigned values of 0 for not at all, 1 for slightly, 2 for moderately, and 3 for greatly. The average score of items responded to is calculated. Higher scores reflect greater distress associated with symptoms. The average, which ranges from 0 to 3, is multiplied by 33 1/3 to put scores on a scale of 0 to 100. | Baseline to 6 weeks | 
| Change in Urogenital Distress Inventory From Baseline to 3 Months Follow-up | Disease specific quality of life measure. Health-related quality of life measures for women with urinary incontinence. The UDI-6 is a 6-point scale that asks patients to respond to questions rating whether they experience and how much they are bothered by UUI. Item responses are assigned values of 0 for not at all, 1 for slightly, 2 for moderately, and 3 for greatly. The average score of items responded to is calculated. Higher scores reflect greater distress associated with symptoms. The average, which ranges from 0 to 3, is multiplied by 33 1/3 to put scores on a scale of 0 to 100. | Baseline to 3 months | 
| Change in Urogenital Distress Inventory From Baseline to 6 Months Follow-up | Disease specific quality of life measure. Health-related quality of life measures for women with urinary incontinence. The UDI-6 is a 6-point scale that asks patients to respond to questions rating whether they experience and how much they are bothered by UUI. Item responses are assigned values of 0 for not at all, 1 for slightly, 2 for moderately, and 3 for greatly. The average score of items responded to is calculated. Higher scores reflect greater distress associated with symptoms. The average, which ranges from 0 to 3, is multiplied by 33 1/3 to put scores on a scale of 0 to 100. | Baseline to 6 months | 
| Change in Patient Perception of Bladder Condition From Baseline to 6 Weeks | Disease specific validated quality of life measures. A single-item global measure for patients with overactive bladder. Patient Perception of Bladder Condition (PPBC) The PPBC is a single-item, 6-point scale that asks patients to rate their subjective impression of their current bladder problems. It has been shown to have concurrent and discriminant validity as well as responsiveness to treatment. Patients are asked to rate their perceived bladder condition on a 6-point scale ranging from 1 no problems at all, 2 some very minor problems. 3 some minor problems, 4(some) moderate problems, 5 severe problems, and 6 many severe problems. A higher score indicates a more negative impression of current bladder problems. | Baseline to 6 weeks | 
| Change in Patient Perception of Bladder Condition From Baseline to 3 Months | Disease specific validated quality of life measures. A single-item global measure for patients with overactive bladder. Patient Perception of Bladder Condition (PPBC) The PPBC is a single-item, 6-point scale that asks patients to rate their subjective impression of their current bladder problems. It has been shown to have concurrent and discriminant validity as well as responsiveness to treatment. Patients are asked to rate their perceived bladder condition on a 6-point scale ranging from 1 no problems at all, 2 some very minor problems. 3 some minor problems, 4(some) moderate problems, 5 severe problems, and 6 many severe problems. A higher score indicates a more negative impression of current bladder problems. | Baseline to 3 months | 
| Change in Patient Perception of Bladder Condition From Baseline to 6 Months | Disease specific validated quality of life measures. A single-item global measure for patients with overactive bladder. Patient Perception of Bladder Condition (PPBC) The PPBC is a single-item, 6-point scale that asks patients to rate their subjective impression of their current bladder problems. It has been shown to have concurrent and discriminant validity as well as responsiveness to treatment. Patients are asked to rate their perceived bladder condition on a 6-point scale ranging from 1 no problems at all, 2 some very minor problems. 3 some minor problems, 4(some) moderate problems, 5 severe problems, and 6 many severe problems. A higher score indicates a more negative impression of current bladder problems. | Baseline to 6 months | 
| Change in Indevus Urgency Severity Scale From Baseline to 6 Weeks | A disease specific quality of life measure. A self reported measure that assesses urinary urgency severity associated with overactive bladder. Indevus Urgency Severity Scale (IIUS) The IIUS is a single item scale designed to describe urinary urges. The scale is rated through the patient's urge: none (0 points), mild (1), moderate (2) and severe (3). A higher score represents more urinary urges. | Baseline to 6 weeks | 
| Change in Indevus Urgency Severity Scale From Baseline to 3 Months | A disease specific quality of life measure. A self reported measure that assesses urinary urgency severity associated with overactive bladder. Indevus Urgency Severity Scale (IIUS) The IIUS is a single item scale designed to describe urinary urges. The scale is rated through the patient's urge: none (0 points), mild (1), moderate (2) and severe (3). A higher score represents more urinary urges. | Baseline to 3 months | 
| Change in Indevus Urgency Severity Scale From Baseline to 6 Months | A disease specific quality of life measure. A self reported measure that assesses urinary urgency severity associated with overactive bladder. Indevus Urgency Severity Scale (IIUS) The IIUS is a single item scale designed to describe urinary urges. The scale is rated through the patient's urge: none (0 points), mild (1), moderate (2) and severe (3). A higher score represents more urinary urges. | Baseline to 6 months | 
| 24 Hour Pad Weight (gm) at 3 Months | weight of pad (in gm) worn for 24 hours to detect urine loss | 3 months | 
| 24 Hour Pad Weight (gm) at 9 Months | weight of pad (in gm) worn for 24 hours to detect urine loss | 9 months | 
| Frequency of Urinary Tract Infections From Baseline to 6 Months | Frequency of urinary tract infections from baseline to 6 month-follow-up | Baseline to 6 months | 
| Frequency of Participants Needing Self-catheterization From Baseline to 6 Month Follow-up | Frequency of participants needing self-catheterization from baseline to 6 month follow-up. | Baseline to 6 months | 
| Frequency of Participants With Urinary Tract Infections From Baseline to 6 Months | Frequency of particiapnts with urinary tract infections from baseline to 6 month-follow-up | Baseline to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Urinary incontinence, urge, detrusor hyperreflexia, detrusor instability, non-neurogenic, Female Urogenital Diseases and Pregnancy Complications, Female Urogenital Diseases, Urologic Diseases, Urination Disorders, Urinary Incontinence