Reduced-dose Botox for Urgency Incontinence Among Elder Females

Study Overview
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Brief Summary
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The purpose of this study is to study the treatment of urgency urinary incontinence (UUI), specifically among women 70 years and older, by comparing reduced versus standard dose of onabotulinumtoxinA (BTX; trade name BOTOX(c)) injection in the bladder.

Detailed Description
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The purpose of this quadruple-masked, randomized-controlled study is to study the treatment of urgency urinary incontinence (UUI) specifically among older women with low- versus standard-dose of onabotulinumtoxinA (BTX) via: symptom-specific and health-related quality of life (QOL; Aim 1), patient-reported and clinical outcome measures including adverse events (Aim 2), qualitative experience with focused interviews (Aim 3) and cost burden and economic impact (Aim 4). This study is an active collaboration between researchers in Gynecology, Urology, and Geriatrics at Dartmouth Hitchcock Medical Center (DHMC) and at 5 other centers; University of Alabama (UAB), University of Pittsburgh (U Pitt), University of Texas Southwestern (UTSW), Kaiser Permanente of Southern California (KPSCP), and Oregon Health & Sciences University (OHSU). The investigators also have collaborators at Stanford University and University of Connecticut, though those sites are not recruiting participants.

Official Title
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Reduced-dose onabotuLinumtoxinA for Urgency Incontinence Among Elder Females (RELIEF): A Randomized Controlled Comparative Effectiveness Trial With Embedded Qualitative and Costing Analyses

Conditions
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Overactive Bladder, Urinary Incontinence in Old Age, Urgency Urinary Incontinence

Intervention / Treatment
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* Drug: Botox 50 Unit Injection
* Drug: Botox 100 Unit Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult female at least 70 years old at date of enrollment Urge-predominant mixed urinary incontinence (urge>stress per the MESA questionnaire) On average 2 or more urgency or insensible incontinence episodes per day per patient report Refractory urinary urgency incontinence, defined as Persistent symptoms despite trial of one or more conservative treatments (e.g. behavioral therapy, physical therapy, home Kegel exercises); participants not required to have attempted first line therapies if deemed not feasible or appropriate by provider with input of participant/caregiver. Persistent symptoms despite the use of anticholinergic and/or beta-3 agonist medication; or inability to tolerate medication due to side effects, or has a contraindication to taking medication, or is unable to afford the cost of the medication. Currently not on an anticholinergic or beta-3 agonist medication or is willing to stop medication for 3 weeks prior to completing baseline bladder tally, with plan to remain off medication through duration of the study. Currently not actively using sacral neuromodulation therapy (either has not tried, or unit has been off for 4 weeks prior to baseline bladder tally and will remain turned off for the duration of the study). It is permissible for participants to continue self-led conservative therapies during participation in the study, including Kegel exercises, avoidance of bladder irritants, and urge suppression. Willing and able to complete all study-related items, with assistance of caregiver(s) if needed. Demonstrates awareness of possible need for catheterization in event of post-injection urinary retention & acknowledges risks of catheterization. Participant does not need to demonstrate ability to perform self-catheterization. Grossly neurologically normal on exam and no gross systemic neurologic conditions believed to affect urinary function. Patients with a diagnosis of Parkinson's disease or diabetes may be eligible provided they have a grossly normal neurologic exam and otherwise fulfill the inclusion/exclusion criteria. Exclusion Criteria: Lack of capacity to provide consent. Will be assessed if needed per judgment of the site PI and study staff, with use of optional questionnaire. Baseline persistently elevated post-void residual [PVR] (>150mL on 2 occasions in the 6 weeks prior to enrollment). If the PVR was obtained via bladder scanner with measurements differing by more than 100mL, or if there is concern about the accuracy of the scanner, it will be confirmed via catheterization which will be considered the gold standard. Need for BTX injection to take place in the Operating Room or under sedation. (Of note, for repeat injection under the protocol, patients may have OR injection if indicated due to pain with initial BTX injection.) Previous treatment with intravesical BTX in the last 12 months or use of sacral neuromodulation therapy within the past 4 weeks (unit may remain implanted, but should remain off for duration of the study). Untreated symptomatic urinary tract infection (UTI). Eligible once UTI treatment complete and symptoms resolved. Known bladder abnormality, including current or prior bladder malignancy, carcinoma in situ or untreatable cystitis (e.g. eosinophilic cystitis); prior major bladder surgery that would alter the detrusor muscle, such as augmentation cystoplasty; or hematuria that has not been evaluated. Neurogenic detrusor overactivity or neurologic disease that may impact bladder function, including stroke, multiple sclerosis, peripheral neuropathy, spinal cord injury. Conditions such as Parkinson's disease and diabetes are acceptable provided normal bladder emptying and grossly normal neurologic function. Concurrent BTX use for other indication, participants cannot exceed 300 units BTX in a 3 month period. Participants who may have conflict between study BTX administration and administration for other purposes may be excluded from participation if there is concern that study drug administration will be compromised. Concurrent use of BTX for another indication that would not exceed 300 units in a 3 month period, or that can have time of administration of the other BTX adjusted to avoid excessive dose, is acceptable; for instance, for migraines. Greater than stage 2 pelvic floor prolapse, uncorrected or persistent despite pessary use (leading edge of prolapse not greater than 1cm beyond the hymen). Ongoing pessary use is permissible. Patients may have had a prior repair for pelvic organ prolapse. (see chart review of recent exam or perform brief exam while collecting post-void residual) Planned prolapse or stress incontinence surgery; would defer enrollment to >3 months post-operative. Allergy or intolerance to lidocaine or BTX. Participation in another research study that could conflict with the RELIEF study, in estimation of the site PI.

Ages Eligible for Study
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Minimum Age: 70 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Botox: Standard dose<br>The standard dose of 100 units of botox will be injected into the bladder. | Drug: Botox 100 Unit Injection<br>* Participants will be randomized to either receive a standard does (100 units) or low dose (50 units) of botox one time.If a particParticipants will be randomized to either receive a standard dose (100 units) or low dose (50 units) of onabotulinumtoxinA. If a participant has decreased symptom relief, after 3 months post injection, they may receive repeat injection up to twice during the 12 month follow-up period.<br>* Other names: OnabotulinumtoxinA 100 Unit;|
| Experimental: Botox: Low dose<br>A lower dose of 50 units of botox will be injected into the bladder. | Drug: Botox 50 Unit Injection<br>* Participants will be randomized to either receive a standard dose (100 units) or low dose (50 units) of onabotulinumtoxinA. If a participant has decreased symptom relief, after 3 months post injection, they may receive repeat injection up to twice during the 12 month follow-up period.<br>* Other names: OnabotulinumtoxinA 50 Unit Injection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in symptom specific quality of life and bother over time. | The Overactive bladder questionnaire (OABq-SF), is a validated and reliable patient-centered quality of life questionnaire. The OABq-SF is based on a continuous sore of 0-100, with higher score translating to greater bother. | Baseline, monthly post-injection through 12 months post-injection; primary outcome is at 3 months post-injection. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptom severity | Urogential Distress Inventory (UDI-6). The UDI-6 has a cut off score of 33.33 to distinguish women who are symptomatic versus asymptomatic. UDI-6 scores that are greater than 33.33 indicated higher distress caused by urinary incontinence symptoms. | Baseline, 3, 6, & 12 months post injection. Results will be compared at the end of the 12 months. | 
| Symptom bother | Incontinence impact questionnaire (IIQ). The IIQ has a cut off score of 9.52. This score distinguish women who are symptomatic and asymptomatic. | Baseline, 3, 6, & 12 months post injection. Results will be compared at the end of the 12 months. | 
| Change in number of urgency urinary incontinence (UUI) episodes per day. | Participants will keep a bladder tally for 3 days and results will be compared from baseline to 1, 3, and 6 months post injected to determine if there has been a change in the number of urgency urinary incontinence episodes. | Baseline, and 1, 3, and 6 months post injection | 
| Change in Global Symptom Improvement | Participants will be asked to complete the Patient Global Impression of Improvement (PGI-I) scale. The PGI-I scale is a one item assessment with responses ranging from very much better to very much worse. | Baseline,3, 6, & 12 months post injection | 
| Goal setting and attainment | Participants will express 3-5 goals and goal attainment will be assessed with the Patient Global Impression of Improvement Survey (PGI-I Scale). The PGI-I scale is a one item assessment with responses ranging from very much better to very much worse. | Baseline & 3 months post injection. | 
| Change in general health-related quality of life as measure by the Health Utility Index-3 | Participants will complete the Health Utilities Index (HUI). The HUI measure health status, reporting health-related quality of life, and producing utility scores. The score ranges from 0.00 (dead) to 1.00 (perfect health). | Baseline, 3 6 and 12 months | 
| Depression | Patient Health Questionnaire-9 (PHQ-9) is a 10 item scale with scores ranging from 1(minimal depression) to 27 (severe depression). | Baseline, 3, 6 and 12 months post injection. Results will be compared at the end of the 3 month post injection. | 
| Procedural discomfort and adverse events | Urinary retention, post-void residual & duration of voiding dysfunction; urinary tract infection, unscheduled clinic/emergency department visits and any adverse events assessed using the Clavien-Dindo scale,which has been validated for use in urology setting. | Day of injection and monthly through 12 months | 
| Qualitative experience of BTX treatment and adverse events | Using novel focused interview for a subset of participants. Participants will be interviewed before injection and 3 months post injection. | Baseline & 3 months post injection | 
| Survey of economic burden | Incontinence Resource Use Questionnaire measures the amount of use of various incontinence products. Questions include the number of incontinence protection items used per week. | Baseline, 3 & 12 months. Results will be compared at the end of the 12 months. | 

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