Refractory Overactive Bladder: Sacral NEuromodulation v. BoTulinum Toxin Assessment (ROSETTA)

Study Overview
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Brief Summary
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The purpose of this randomized, open-label, active-control trial is to compare the effectiveness of intra-detrusor botulinum toxin A (Botox A®, Allergan) versus sacral neuromodulation (InterStim®, Medtronic) for the treatment of refractory urge urinary incontinence. In addition, the study will evaluate select technical attributes of the interventions as well as the effect of these two interventions on other lower urinary tract and pelvic floor symptoms. Hypothesis: InterStim® therapy will result in a greater reduction in daily urge urinary incontinence episodes over the 6-month follow-up period as compared to Botox A® injection. A supplemental study investigates whether biological markers including those related to inflammation and connective tissue remodeling change following treatments with Botox A® and Interstim®.

Detailed Description
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Primary Aim: To compare the change from baseline in the number of urge urinary incontinence episodes (UUIE) over 6 the six month follow-up period in women randomized to sacral neuromodulation (InterStim®) therapy, versus those randomized to intra-detrusor injection with 200 units of botulinum toxin A (Botox A®). Secondary Aims: Long Term Efficacy: To compare the long-term (12 and 24 month) efficacy outcomes in women randomized to sacral neuromodulation(InterStim®) therapy, versus those randomized to intra-detrusor injection with 200 units of botulinum toxin A (Botox A®). Secondary efficacy outcomes, collected at 12 and 24 months as well as 6 months,include adequate control of their urge urinary incontinence, change in bothersome symptoms of urinary urge incontinence (UUI), severity of urge incontinence, urinary frequency, nocturia, subject satisfaction with therapy, quality of life measures and bowel and sexual function. Cost Effectiveness: To compare utilization of medical resources for cost effectiveness analysis and cost-utility between treatment groups. Treatment Safety and Burden: To assess safety profile and treatment burden of both interventions by comparing adverse event incidence between treatment arms, and also by obtaining estimates of incidence of treatment-specific safety and burden outcomes. Safety and burden outcomes for Botox A® injections include receipt of additional injections and intermittent catheterization due to voiding dysfunction/partial urinary retention. Safety and burden outcomes for InterStim® device include infection, pain, lead migration, reprogramming (and reasons for) and surgical revision (and reasons for).

Official Title
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Refractory Overactive Bladder: Sacral NEuromodulation v. BoTulinum Toxin Assessment (ROSETTA)

Conditions
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Urinary Incontinence, Urge

Intervention / Treatment
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* Device: InterStim® device
* Drug: Botox® injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Non-pregnant adult female at least 21 years old, with no plans to become pregnant during the course of the trial) and if of child-bearing potential, with a negative pregnancy test, and if sexually active, must be using medically acceptable contraception. 6 urge urinary incontinence episodes on a 3-day baseline bladder diary, with these urge incontinence episodes representing greater than 50% of the total incontinent episodes recorded. Willing and able to complete all study related items and interviews. Refractory urinary urge urinary incontinence: defined as (1) Persistent symptoms despite at least one or more conservative treatments (e.g. supervised behavioral therapy, supervised physical therapy); and (2)Persistent symptoms despite the use of a minimum of two anticholinergics, or unable to tolerate medication due to side effects, or has a contraindication to taking anticholinergic medication. Currently not on an anticholinergic or antimuscarinic medication (e.g. oxybutynin, tolterodine, and/or fesoterodine) or be willing to stop medication for 3 weeks prior to completing baseline bladder diary and expected to remain off medications through duration of study. Demonstrates ability (or have caregiver demonstrate ability) to perform clean intermittent self-catheterization. Grossly neurologically normal on exam and no gross systemic neurologic conditions believed to affect urinary function. Urodynamic assessment within the previous 18 months prior to enrollment or done after enrollment, prior to randomization. Exclusion Criteria: Neurologic diseases such as multiple sclerosis, Parkinson Disease, CVA within 6 months prior to enrollment, myasthenia gravis, Charcot-Marie-Tooth disease, clinically significant peripheral neuropathy, and complete spinal cord injury. Untreated urinary tract infection (UTI). Any prior use of either study therapy for treatment of urinary urge incontinence (Botox A® or Interstim®). Current participation in any other conflicting interventional research study. PVR >150 ml on 2 occasions within 6 months prior to enrollment (If the PVR value was obtained by ultrasound and was ≥150 ml, the PVR will be confirmed by catheterization which will be the gold standard) Subjects with knowledge of planned MRIs or diathermy, except those allowable per Medtronic guidelines. Current or prior bladder malignancy. Surgically altered detrusor muscle, such as augmentation cystoplasty. Subjects taking aminoglycosides. Currently pregnant or lactating. Subjects who are on ambulatory anticoagulant therapy, including aspirin, who are unable to discontinue treatment for 24 hours prior to bladder injection and staged InterStim® procedure. Serum creatinine level greater than twice the upper limit of normal within the previous year prior to enrollment. Surgical treatment for stress incontinence (sling, Burch or urethral injection) or pelvic organ prolapse recommended or planned at enrollment by study investigator(s). Prior stress incontinence or prolapsed surgery within the last 6 months prior to enrollment. Allergy to lidocaine or bupivacaine. Prior pelvic radiation. Uninvestigated hematuria. Greater than or equal to Stage III vaginal prolapse. Known allergy to Botox A®. Use of a vaginal pessary.

Ages Eligible for Study
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Minimum Age: 21 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: InterStim® device<br>The FSLP InterStim® device is to be done within 3 months of enrolling/consenting. The 1st stage is lead placement into the S3 foramen with best response to stimulation. The 4 electrodes will be tested and set to an amplitude that achieves comfortable stimulation in the vaginal, perineal, or rectal sensation. If =/>50% improvement, participant will then have the 2nd stage IPG implantation, 8-18 days after last FSLP. If there is a technical problem with lead on 1st FSLP, then the participant can have a 2nd FSLP and may go on to have IPG implantation with lead replacement. The 2nd FSLP must be initiated no longer than 1 month since the initiation of the 1st FSLP. If the participant is a non-responder and there is no technical problem, then the lead is removed. | Device: InterStim® device<br>* Eligible subjects will complete baseline assessments, be randomized and scheduled for first stage lead placement (FSLP) InterStim®. The criterion for an initial clinical response to InterStim® therapy will be defined as a ≥50% improvement in the mean number of UUIE/day on a minimum 3 day bladder diary, completed during the 7-14 days following the first stage lead placement (FSLP). Subjects with a ≥ 50% improvement mean number of UUIE/day will be eligible to proceed with implantation of the implantable pulse generator (IPG). Subjects will then be followed monthly to determine the response to therapy.<br>|
| Active Comparator: Botox® injection<br>Total of 200 units of Botox A will be dissolved into 10mL of saline and injected into the bladder within 3 months of enrolling/consenting. Participants determined to have a clinical response at the 1 month visit (post 1st injection) may receive additional injections between 6-24 months. | Drug: Botox® injection<br>* Eligible subjects will complete baseline assessments, be randomized and scheduled for Botox A® injection visit. Subjects who received a Botox A® injection will be assessed for a clinical response, at 1 month from injection, using the same clinical criterion (≥50% improvement in the mean number of UUIE/day on a 3 day bladder diary completed prior to the 1 month visit). Those subjects that experience a clinical response, at one month, will be eligible for a repeat Botox A® injection after 6 months, if they experience degradation of clinical effect, using the PGSC.<br>* Other names: Botox;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Urge Urinary Incontinence (UUI) Episodes | The primary outcome is the change from baseline in mean number of UUI episodes over the first 6-month visit period (1, 2, 3, 4, 5 and 6 month assessments); and is measured using 3-day bladder diaries administered monthly for the first 6 month visit period. | 6 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Improvement of Bladder Function and Urinary Leakage | Proportion of subjects who report adequate improvement of their bladder function and urinary leakage with the Patient Global Impression of Improvement Questionnaire (PGI-I) at 6 months. Adequate improvement is defined as a rating of 1, 2, or 3 (better) on the patient-reported measure of perceived improvement with treatment on a scale of 1 (very much better) to 7 (very much worse). | 6 Months | 
| Change in Overactive Bladder | Change in mean Overactive Bladder Questionnaire Short Form (OABq-SF) score throughout baseline to the first 6-month visit (1, 2, 3, 4, 5, and 6-month assessments). Values range from 0 to 100 with higher scores on the symptom scale indicating greater severity of symptoms and higher scores on the quality of life scale indicating a better quality of life. | 6 Months | 
| Urinary Frequency and Nocturia | Change in mean number of urinary incontinence episodes (any type) and nocturia episodes from baseline over the first 6-month visit period (1, 2, 3, 4, 5, and 6-month assessments) as measured by the 3 day bladder diary. | 6 Months | 
| Severity of Urge Incontinence Symptoms | Severity of urge incontinence symptoms at 6 month visit period as measured by the Sandvik questionnaire. The Sandvik score is a patient-reported measure of incontinence severity as assessed on a scale of slight (1-2), moderate (3-6), severe (8-9), very severe (12) to severe (10-12) using a standard scoring algorithm. | 6 Months | 
| Treatment Satisfaction (OAB-SATq Treatment Satisfaction, Adverse Effects, Treatment Endorsement, and Convenience) | Treatment satisfaction as measured by the mean Overactive Bladder Satisfaction of Treatment Questionnaire (OAB-SATq) score at 6 months (6 month assessment). The OAB-SATq score ranges from 0 to 100 and includes 5 subscales: treatment satisfaction, side effects, treatment endorsement, convenience, and treatment preference, with higher scores reflecting better satisfaction. | 6 months | 
| Treatment Satisfaction (OAB-SATq Treatment Preference) | Treatment preference as measured by the Overactive Bladder Satisfaction of Treatment Questionnaire (OAB-SATq) at 6 months (6 month assessment).OAB-SATq treatment preference is a binary outcome that is classified as yes if a participant answers either Slight preference for the treatment I am receiving now or Definitely prefer the treatment I am receiving now to the question Do you prefer the treatment that you received since entering this study to the treatment you received before the study? | 6 Months | 
| Quality of Life (UDI-SF) | Change from baseline in quality of life measures over the first 6 month visit period (6 month assessment) as measured by the change in mean Urinary Distress Inventory Short Form (UDI-SF) score. The UDI-SF scale has a range from 0 to 100 with higher scores indicating greater distress. | 6 Months | 
| Quality of Life (IIQ-SF) | Change from baseline in quality of life measures over the first 6 month visit period (6 month assessment) as measured by the change in the mean Incontinence Impact Questionnaire short form (IIQ-SF) score. The IIQ-SF scale has a range from 0 to 100 with higher scores indicating a worse quality of life. | 6 Months | 
| Quality of Life (HUI-3) | Change from baseline in quality of life measures over the first 6 month visit period (6 month assessment) as measured by the Health Utility Index, Version 3 (HUI-3). The HUI 3 scale has a range from 0 to 1 with higher scores representing better health. | 6 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Refractory Urinary Urge Incontinence, Botox A®, Interstim® Device