Safety and Effectiveness of a Non-invasive Neuromodulation Device on Urgency Urinary Incontinence in Overactive Bladder

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the change from baseline between the active and sham treatment groups in the treatment of urgency (urinary) incontinence episodes (leaks).

Official Title
-----------------
Multi-center, Prospective, Randomized, Double-blind, Sham-controlled Clinical Study to Evaluate Safety and Effectiveness of a Transcutaneous, High-frequency, Amplitude-modulated, Non-invasive Neuromodulation Device on Urgency Urinary Incontinence in Subjects With Overactive Bladder (OAB)

Conditions
-----------------
Overactive Bladder

Intervention / Treatment
-----------------
* Device: (VERV™ System)
* Device: Sham version of (VERV™ System)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males and Females, at least 18 years of age Failure on primary OAB treatment, such as behavior modification or fluid/diet management, AND at least one (1) anti-cholinergic drug (unless patient was contra-indicated for anti-cholinergic use) Symptoms of overactive bladder for at least 6 months An average of one (1) or more urgency (urinary) incontinence episodes per 24-hours, over a 3-day period, confirmed by the 3-day baseline voiding diary, with a maximum of 12 urgency (urinary) incontinence episodes per 24-hours Dexterity and ability to place and operate the device Females of child-bearing capability agrees to use a reliable form of birth control for the duration of the trial An average of eight (8) or more voids per 24-hours, over a 3-day period, confirmed by the 3-day baseline voiding diary Willing and capable of understanding and complying with all requirements of the protocol, including proper completion of the baseline voiding diary Signed and dated the IRB-approved Informed Consent document. Exclusion Criteria: Dysfunctional voiding symptoms unrelated to OAB, such as clinically significant bladder outlet obstruction, and urinary retention (pvr > 100 cc) Morbidly obese, defined as having Body Mass Index (BMI) > 40 kg/m2 Stress predominant mixed urinary incontinence Neurological disease affecting urinary bladder function, including but not limited to Parkinson's disease, multiple sclerosis, stroke, spinal cord injury and uncontrolled epilepsy. Pelvic surgery (such as sub-urethral sling, pelvic floor repair) within the past 6 months Intravesical or urethral sphincter Botulinum Toxin Type A injections within the past 12 months Any neuromodulation therapy for overactive bladder within the past 3 months Failure to respond to previous neuromodulation therapy for overactive bladder Leading edge of any vaginal prolapse is beyond hymenel ring. Prior peri-urethral or transurethral bulking agent injections for bladder problems within the past 12 months. Any skin conditions affecting treatment or assessment of the treatment sites History of lower back surgery or injury that could impact placement of the patch, or where underlying scar tissue or nerve damage may impact treatment. Presence of an implanted electro-medical device (e.g. pacemaker, defibrillator, InterStim®, etc.), or any metallic implant in the lower back. Pregnant, nursing, suspected to be pregnant (by urine pregnancy method), or plans to become pregnant during the course of the study. Known latex allergies, or allergies or hypersensitivity to patch materials that will be in contact with the body (e.g., hydrogel, acrylic-based adhesive, polyurethane). Uncontrolled diabetes and/or diabetes with peripheral neuropathy. Current Urinary Tract Infection (UTI) or history of recurrent UTIs (>3 UTIs in the past year). History of lower tract genitourinary malignancies within the last 6 months or any previous pelvic radiation. Any clinically significant systemic disease or condition that in the opinion of the Investigator would make the patient unsuitable for the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active Treatment group<br>VERV™ System | Device: (VERV™ System)<br>* Active electrode patches are worn for 12 weeks, one per week. The patch is placed by the subject. All subjects will have access to active patches for 9 months after the sham-controlled 12-week portion of the study is complete.<br>* Other names: Non-invasive neurostimulation device;|
| Sham Comparator: Sham Treatment Group<br>Sham version of (VERV™ System) | Device: Sham version of (VERV™ System)<br>* Inactive (sham) electrode patches are worn for 12 weeks, one per week. The patch is placed by the subject. All subjects will have access to active patches for 9 months after the sham-controlled 12-week portion of the study is complete.<br>* Other names: Inactive Non-invasive neurostimulation device;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate Proportion of Responders Based on the Change From Baseline in Mean Urgency (Urinary) Incontinence Episodes (Leaks) Between the Active and Sham Treatment Groups | The primary objective of the randomized phase of the study is to evaluate the 12 week change from baseline in mean urgency (urinary) incontinence episodes (leaks) between the active and sham treatment groups. The mean of the number of urinary incontinence episodes over 24 hours is defined as the mean of the number of UIEs recorded per 24 hour period for three consecutive days (via a 3-day diary). The primary objective of the open label phase of the study is to evaluate and confirm the continued efficacy of the VERV™ System for long-term use. The primary objective was assessed with rate of responders, where responder was defined as a subject who achieved a decrease of ≥50% in mean urgency urinary incontinence episodes at 12 weeks compared to baseline. | 12 weeks (Randomized Phase) and 12 Months (Open Label) | 
| Evaluate the Median Change From Baseline in Mean Urgency (Urinary) Incontinence Episodes (Leaks) Between the Active and Sham Treatment Groups | The primary objective of the randomized phase of the study is to evaluate the 12 week and 12 month median change from baseline in mean urgency (urinary) incontinence episodes (leaks) between treatment groups. The mean of the number of urinary incontinence episodes over 24 hours is defined as the mean of the number of UIEs recorded per 24 hour period for three consecutive days (via a 3-day diary). Mean urinary frequency episodes calculated for each patient during time period. The median change in frequency was then calculated for each treatment group. Distribution of changes from baseline were then assessed prospectively for normality using the Kolmogorov - Smirnoff test. Since departure from normality was actually observed in the distribution, the Wilcoxon Rank-Sum test was performed to compare the median change between treatment groups and the p-values for the test of equality of medians were reported along with the medians. | 12 weeks (Randomized Phase) and 12 Months (Open Label) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure Change in the Median of the Mean Urinary Frequency | Evaluate the 12 week change from baseline in median urinary frequency between the active and sham treatment groups. Mean urinary frequency episodes calculated for each patient during time period. The median change in frequency was then calculated for each treatment group. Distribution of changes from baseline were then assessed prospectively for normality using the Kolmogorov - Smirnoff test. Since departure from normality was actually observed in the distribution, the Wilcoxon Rank-Sum test was performed to compare the median change between treatment groups and the p-values for the test of equality of medians were reported along with the medians. | 12 weeks and 12 Months | 
| Measure Median Change in Mean Volume Per Void | Evaluate the 12 week median change from baseline in mean volume (ml) per void between the active and sham treatment groups | 12 weeks | 
| Measure Decrease in the Median Change From Baseline in Mean Urgency Episodes | Evaluate the 12 week change from baseline in median for mean number of urgency episodes between the active and sham treatment groups. Patients were required to complete seven 3-day voiding diaries throughout the course of the study. The voiding diary collected the following information: amount voided (in ml); urgency associated with each toileted void , approximate time of leak, and presence of urge preceding leak.The mean number of urgency episodes over 24 hours was then calculated for each patient during the observation period. The change in median for the mean of the number of urgency episodes over 24 hours) for each treatment group was then calculated. Distribution of changes from baseline were assessed prospectively using the Kolmogorov - Smirnoff test. The Wilcoxon Rank-Sum test was performed to compare the median change between treatment groups and the p-values for the test of equality of medians were reported along with the medians. | 12 weeks | 
| Measure Improvement in the Median of the Mean OAB-Symptom Composite Score | OAB Symptom Composite Score (OAB-SCS) is a composite symptom score of toilet voids, urgency severity and urge urinary incontinence combining the Indevus Urgency Severity Scale (IUSS) for capture of urgency severity per toilet void with 24-hour frequency and UUI episodes. IUSS Score/void and/or UUI is assigned an OAB-SCS Point/Void: 0(none)=1, 1(mild/easily tolerated)=2, 2(moderate discomfort interfering with activities)=3, 3(severe/extreme urgency discomfort that abruptly stopped all activity or tasks)=4, UUI without void=5. Overall OAB-SCS Score is calculated for each day by multiplying the OAB-SCS Points/Void and/or UUIs by the number of events meeting criteria and adding the individual scores together. The minimum overall OAB-SCS score in a 24 hour period would be a 1 (representing a single mild void with a OAB -SCS Point/Void score of 0). The score would increase based upon the number voids/events and overall severity each event. Medians calculated for each treatment group. | 12 weeks | 
| Change in Median Total Health Related Quality of Life (HRQL) of OAB-q From Baseline (Screening) to Week 12 | The OAB-q is validated to measure symptom bother and life impact due to OAB. It consists of an 8-item Bother Scale to assess individual symptoms and a 25-item HRQL scale that in turn consists of 4 subscales (coping-8 items, concern-7 items, sleep-5 items and social-5 items) to assess impact on life. Responses for each item in the Bother Scale range from 1 (bothered not at all by the symptom) to 6 (Bothered A Very Great Deal). Scores are then added generating an overall Bother Score (severity) ranging from 8 to 48. For HRQL, individual responses range between 1-None of the Time to a 6-All of the Time. Subscale scores range from 8-48 (coping) 7-42 (concern), 5-30 (sleep) and 5-30 (social). Subscale scores are then added to generate the HRQL ranging between 25-150. Raw HRQL scores are transformed for standardization purposes as follows: ((Highest Possible Score-Actual Raw Score)/Range of Scores)*1 00 so that scores could range from 0 (All of the Time) to 100 (None of the Time). | 12 Weeks (Randomized Phase) and 12 Months (Open Label). | 
| Change in Patient Perception of Bladder Condition (PPBC) From Baseline (Screening Period) to Week 12 as Defined as an Improvement in Severity. | PPBC is a 6-point scale (from 'no problems at all' to 'many severe problems') describing the problem level of the bladder condition at that moment. Improvement is defined as a reduction in the number and/or severity of observed problems. | 12 Weeks (Randomized Phase) and 12 Months (Open Label Phase) | 
| Assessment of Treatment Benefit Scale (TBS) | TBS is a patient-reported outcome comprised of a 4-point scale of checkboxes to describe the change in condition during treatment (greatly improved to worsened). Improvement was defined as a change in the patient's assessment of overall condition to improved or greatly improved over the course of treatment. Analysis was based upon the number of patients who reported an improvement in condition. | 12 Weeks | 
| Assessment of Improvement as Measure by Overactive Bladder Satisfaction With Treatment Questionnaire (OAB-SAT) | Overall satisfaction with treatment was assessed (OAB-SAT-q) an 11 question list with multiple scaled checkboxes to allow the subject to rate the treatment with regard to satisfaction, bother from side effects, treatment endorsement, and convenience. | 12 weeks | 
| Change Clinical Global Impressions at 12 Weeks | CGI is an Investigator assessment, which rates the severity of illness at baseline on a scale of 1 (normal, not ill at all) to 7 (Amongst the most extremely ill patients), and then rates improvement at 12 weeks on a scale of 1 (very much improved) to 10 (very much worse). The analysis was based upon the number of patients that much and very much improved. | 12 weeks (Randomized Phase) and 12 Months (Open Label Phase) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Urinary Incontinence, Overactive Bladder, Frequency, Urgency