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

• ClinicalTrials.gov Identifier: NCT01502956
• Recruitment Status: Completed
• First Posted: January 2, 2012
• Results First Posted: March 8, 2018
• Last Update Posted: May 2, 2018
• Sponsor: NICHD Pelvic Floor Disorders Network
• Collaborators: Duke University; University of Alabama at Birmingham; University of California, San Diego; The Cleveland Clinic; Brown University; University of New Mexico; University of Pennsylvania; University of Pittsburgh; Oregon Health and Science University; RTI International; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Information provided by (Responsible Party): NICHD Pelvic Floor Disorders Network

Study Description

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®.

Condition or disease	Intervention/treatment	Phase
Urinary Incontinence, Urge	Device: InterStim® device; Drug: Botox® injection	Phase 3

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).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 386 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Refractory Overactive Bladder: Sacral NEuromodulation v. BoTulinum Toxin Assessment (ROSETTA)
• Study Start Date: February 2012
• Actual Primary Completion Date: July 2016
• Actual Study Completion Date: July 2016

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: InterStim® device; 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; 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.
Active Comparator: Botox® injection; 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; 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.; Other Name: Botox

Outcome Measures

Primary Outcome Measures :

1. Number of Urge Urinary Incontinence (UUI) Episodes [ Time Frame: 6 Months ]
   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.

Secondary Outcome Measures :

1. Number of Participants With Improvement of Bladder Function and Urinary Leakage [ Time Frame: 6 Months ]
   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).
2. Change in Overactive Bladder [ Time Frame: 6 Months ]
   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.
3. Urinary Frequency and Nocturia [ Time Frame: 6 Months ]
   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.
4. Severity of Urge Incontinence Symptoms [ Time Frame: 6 Months ]
   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.
5. Treatment Satisfaction (OAB-SATq Treatment Satisfaction, Adverse Effects, Treatment Endorsement, and Convenience) [ Time Frame: 6 months ]
   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. Treatment Satisfaction (OAB-SATq Treatment Preference) [ Time Frame: 6 Months ]
   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?"
7. Quality of Life (UDI-SF) [ Time Frame: 6 Months ]
   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.
8. Quality of Life (IIQ-SF) [ Time Frame: 6 Months ]
   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.
9. Quality of Life (HUI-3) [ Time Frame: 6 Months ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 21 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Alabama

University of Alabama at Birmingham, Department of Obstetrics and Gynecology

Birmingham, Alabama, United States, 35249-7333

United States, California

University of California, San Diego, Women's Pelvic Medicine Center

La Jolla, California, United States, 92037

United States, New Mexico

University of New Mexico Health Sciences Center

Albuquerque, New Mexico, United States, 87131-0001

United States, North Carolina

Duke Division of Urogynecology and Reconstructive Pelvic Surgery

Durham, North Carolina, United States, 277707

United States, Ohio

Cleveland Clinic, Obstretric and Gynecology and Women Health Institute

Cleveland, Ohio, United States, 44194

United States, Oregon

Oregon Health and Science University, Kohler Pavilion

Portland, Oregon, United States, 97239

United States, Pennsylvania

University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

Univesity of Pittsburgh, Magee-Womens Hospital

Pittsburgh, Pennsylvania, United States, 15213

United States, Rhode Island

Women and Infants Hospital of Rhode Island, Center for Women's Pelvic Medicine and Reconstructive Surgery

Providence, Rhode Island, United States, 02903

Sponsors and Collaborators

NICHD Pelvic Floor Disorders Network

Duke University

University of Alabama at Birmingham

University of California, San Diego

The Cleveland Clinic

Brown University

University of New Mexico

University of Pennsylvania

University of Pittsburgh

Oregon Health and Science University

RTI International

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Study Chair: Cindy Amundsen, MD; Duke University
• Principal Investigator: Holly Richter, PhD, MD; University of Alabama at Birmingham
• Principal Investigator: Shawn A. Menefee, MD; Kaiser Permanente, San Diego, CA
• Principal Investigator: Sandip Vasada, MD; The Cleveland Clinic
• Principal Investigator: Deborah L. Myers, MD; Brown/Women and Infants Hospital of Rhode Island
• Principal Investigator: Yoko Kumesu, MD; University of New Mexico
• Principal Investigator: Lily Arya, MD; University of Pennsylvania
• Principal Investigator: Jerry Lowder, MD; University of Pittsburgh
• Principal Investigator: W. Thomas Gregory, MD; Oregon Health and Science University
• Principal Investigator: Dennis Wallace, PhD; RTI International
• Principal Investigator: Susan Meikle, MD, MSPH; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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. Erratum In: Am J Gastroenterol. 2021 May 1;116(5):1100.

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. Erratum In: Am J Obstet Gynecol. 2023 Jan;228(1):124-125.

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.

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.

• Responsible Party: NICHD Pelvic Floor Disorders Network
• ClinicalTrials.gov Identifier: NCT01502956
• Other Study ID Numbers: PFDN 20; U01HD069031 ( U.S. NIH Grant/Contract )
• First Posted: January 2, 2012
• Results First Posted: March 8, 2018
• Last Update Posted: May 2, 2018
• Last Verified: April 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by NICHD Pelvic Floor Disorders Network:

Refractory Urinary Urge Incontinence; Botox A®; Interstim® Device

Additional relevant MeSH terms:

Urinary Incontinence; Urinary Bladder, Overactive; Urinary Incontinence, Urge; Urination Disorders; Urologic Diseases; Lower Urinary Tract Symptoms; Urological Manifestations; Urinary Bladder Diseases; Botulinum Toxins, Type A; Neuromuscular Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Acetylcholine Release Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Cholinergic Agents; Neurotransmitter Agents