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

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ClinicalTrials.gov Identifier: NCT01502956
Recruitment Status : Completed
First Posted : January 2, 2012
Last Update Posted : August 24, 2016
Information provided by (Responsible Party):

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 : 380 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
Primary Completion Date : July 2016
Study Completion Date : July 2016

Resource links provided by the National Library of Medicine

U.S. FDA Resources

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 episodes (UUIE) [ Time Frame: Baseline to 6-month visit ]
    The primary outcome is the change from baseline in mean number of UUIE 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. Improvement of Bladder Function [ Time Frame: 6, 12, and 24 month visits ]
    Proportion of subjects who report adequate improvement of their bladder function with the Patient Global Impression of Improvement Questionnaire (PGI-I) at 6, 12, and 24 month visits.

  2. Change in Overactive Bladder [ Time Frame: 6, 12, and 24 month visits ]
    Change from baseline to 6, 12 and 24 month visits in the Overactive Bladder Questionnaire Short Form (OABq-SF).

  3. Urinary Frequency and Nocturia [ Time Frame: 6, 12, and 24 month visits ]
    Change from baseline to 6, 12 and 24 month visits in urinary frequency and nocturia as measured by the 3 day bladder diary and severity of urge incontinence symptoms as measured by the Sandvik questionnaire.

  4. Treatment Satisfaction [ Time Frame: 6, 12, and 24 month visits ]
    The proportion of subjects satisfied with their treatment as measured by the Overactive Bladder Satisfaction of Treatment questionnaire (OAB-SATq) at 6, 12 and 24 month visits.

  5. Quality of Life [ Time Frame: 6, 12, and 24 month visits ]
    Changes from baseline to 6, 12 and 24 month visits in quality of life measures as measured by the Urinary Distress Inventory Short Form (UDI-SF), Incontinence Impact Questionnaire Short Form (IIQ-SF), Pelvic Organ Prolapse/Urinary Incontinence/Sexual Function Questionnaire Short Form (PISQ-SF), St Mark's (Vaizey) questionnaire for bowel incontinence, and the Health Utilities Index Mark 3 (HUI-3).

  6. Cost of Therapies [ Time Frame: Up to 24 months or before if subject does not complete study ]
    The cost of InterStim® therapy and Botox A® therapy as determined by utilization of medical resources for cost-effectiveness analysis.

  7. Safety and Burden of Therapies [ Time Frame: Up to 24 months or before if subject does not complete study ]
    Occurrence of adverse events for InterStim® of infection, pain, decreased efficacy, need for surgical revision and for Botox A® of need for CISC or UTI; proportion of subjects with voiding dysfunction/partial urinary retention requiring catheterization (PVR>300 ml or PVR > 200 ml and symptoms of incomplete voiding); proportion of subjects with Botox A® reinjection or reprogramming of InterStim® device; and proportion of subjects with infection, pain or lead migration of the Interstim® device recorded during follow-up visits.

Eligibility Criteria

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

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01502956

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)
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

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: dwallace, Project Director, NICHD Pelvic Floor Disorders Network
ClinicalTrials.gov Identifier: NCT01502956     History of Changes
Other Study ID Numbers: PFDN 20
U01HD069031 ( U.S. NIH Grant/Contract )
First Posted: January 2, 2012    Key Record Dates
Last Update Posted: August 24, 2016
Last Verified: August 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by dwallace, 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
Signs and Symptoms
Behavioral Symptoms
Elimination Disorders
Mental Disorders
Urinary Bladder Diseases
Botulinum Toxins
Botulinum Toxins, Type A
Acetylcholine Release Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Neuromuscular Agents
Peripheral Nervous System Agents