Clinical trial NCT01502956: Refractory Overactive Bladder: Sacral NEuromodulation v. BoTulinum Toxin Assessment (ROSETTA)
Official title: Refractory Overactive Bladder: Sacral NEuromodulation v. BoTulinum Toxin Assessment (ROSETTA)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Urinary Incontinence, Urge
Keywords: Refractory Urinary Urge Incontinence
Botox A®
Interstim® Device
Lead sponsor: NICHD Pelvic Floor Disorders Network
Sponsor class: NETWORK
Collaborators: name: Duke University
name: University of Alabama at Birmingham
name: University of California, San Diego
name: The Cleveland Clinic
name: Brown University
name: University of New Mexico
name: University of Pennsylvania
name: University of Pittsburgh
name: Oregon Health and Science University
name: RTI International
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2012-01-02
Enrollment: 386
Sex: FEMALE
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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).

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Urge Urinary Incontinence (UUI) Episodes
timeFrame: 6 Months
Secondary outcomes:
measure: Number of Participants With Improvement of Bladder Function and Urinary Leakage
timeFrame: 6 Months
measure: Change in Overactive Bladder
timeFrame: 6 Months
measure: Urinary Frequency and Nocturia
timeFrame: 6 Months
measure: Severity of Urge Incontinence Symptoms
timeFrame: 6 Months
measure: Treatment Satisfaction (OAB-SATq Treatment Satisfaction, Adverse Effects, Treatment Endorsement, and Convenience)
timeFrame: 6 months
measure: Treatment Satisfaction (OAB-SATq Treatment Preference)
timeFrame: 6 Months
measure: Quality of Life (UDI-SF)
timeFrame: 6 Months
measure: Quality of Life (IIQ-SF)
timeFrame: 6 Months
measure: Quality of Life (HUI-3)
timeFrame: 6 Months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham, Department of Obstetrics and Gynecology
state: Alabama
city: La Jolla
country: United States
facility: University of California, San Diego, Women's Pelvic Medicine Center
state: California
city: Albuquerque
country: United States
facility: University of New Mexico Health Sciences Center
state: New Mexico
city: Durham
country: United States
facility: Duke Division of Urogynecology and Reconstructive Pelvic Surgery
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic, Obstretric and Gynecology and Women Health Institute
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University, Kohler Pavilion
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Univesity of Pittsburgh, Magee-Womens Hospital
state: Pennsylvania
city: Providence
country: United States
facility: Women and Infants Hospital of Rhode Island, Center for Women's Pelvic Medicine and Reconstructive Surgery
state: Rhode Island
Study officials:
affiliation: Duke University
name: Cindy Amundsen, MD
role: STUDY_CHAIR
affiliation: University of Alabama at Birmingham
name: Holly Richter, PhD, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Kaiser Permanente, San Diego, CA
name: Shawn A. Menefee, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The Cleveland Clinic
name: Sandip Vasada, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Brown/Women and Infants Hospital of Rhode Island
name: Deborah L. Myers, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of New Mexico
name: Yoko Kumesu, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pennsylvania
name: Lily Arya, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pittsburgh
name: Jerry Lowder, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Oregon Health and Science University
name: W. Thomas Gregory, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: RTI International
name: Dennis Wallace, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: Susan Meikle, MD, MSPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hendrickson WK, Amundsen CL, Rahn DD, Meyer I, Bradley MS, Smith AL, Myers DL, Jelovsek JE, Lukacz ES. Comparison of 100 U With 200 U of Intradetrusor OnabotulinumToxinA for Nonneurogenic Urgency Incontinence. Female Pelvic Med Reconstr Surg. 2021 Mar 1;27(3):140-146. doi: 10.1097/SPV.0000000000001020.
citation: Richter HE, Jelovsek JE, Iyer P, Rogers RG, Meyer I, Newman DK, Bradley MS, Harm-Ernandes I, Dyer KY, Wohlrab K, Mazloomdoost D, Gantz MG; Eunice Kennedy Shriver NICHD Pelvic Floor Disorders Network and the National Institutes of Health Office of Research on Women's Health. Characteristics Associated With Clinically Important Treatment Responses in Women Undergoing Nonsurgical Therapy for Fecal Incontinence. Am J Gastroenterol. 2020 Jan;115(1):115-127. doi: 10.14309/ajg.0000000000000482.
citation: Andy UU, Amundsen CL, Honeycutt E, Markland AD, Dunivan G, Dyer KY, Korbly NB, Bradley M, Vasavada S, Mazloomdoost D, Thomas S; NICHD Pelvic Floor Disorders Network. Sacral neuromodulation versus onabotulinumtoxinA for refractory urgency urinary incontinence: impact on fecal incontinence symptoms and sexual function. Am J Obstet Gynecol. 2019 Nov;221(5):513.e1-513.e15. doi: 10.1016/j.ajog.2019.06.018. Epub 2019 Jun 15.
citation: Komesu YM, Amundsen CL, Richter HE, Erickson SW, Ackenbom MF, Andy UU, Sung VW, Albo M, Gregory WT, Paraiso MF, Wallace D; Eunice Kennedy Shriver National Institute of Child Health and Human Development Pelvic Floor Disorders Network. Refractory urgency urinary incontinence treatment in women: impact of age on outcomes and complications. Am J Obstet Gynecol. 2018 Jan;218(1):111.e1-111.e9. doi: 10.1016/j.ajog.2017.10.006. Epub 2017 Oct 12.
citation: Amundsen CL, Richter HE, Menefee S, Vasavada S, Rahn DD, Kenton K, Harvie HS, Wallace D, Meikle S. The Refractory Overactive Bladder: Sacral NEuromodulation vs. BoTulinum Toxin Assessment: ROSETTA trial. Contemp Clin Trials. 2014 Mar;37(2):272-83. doi: 10.1016/j.cct.2014.01.009. Epub 2014 Jan 30.