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

NCT ID: NCT01502956

Last Updated: 2018-05-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 386 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-02-29
• Study Completion Date: 2016-07-31

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).

Conditions

Urinary Incontinence, Urge

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

InterStim® device

Intervention Type: 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.

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.

Group Type: ACTIVE_COMPARATOR

Botox® injection

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DEVICE

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.

Intervention Type: DRUG

Other Intervention Names

Botox

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.

• Minimum Eligible Age: 21 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Duke University

OTHER

Sponsor Role: collaborator

University of Alabama at Birmingham

OTHER

Sponsor Role: collaborator

University of California, San Diego

OTHER

Sponsor Role: collaborator

The Cleveland Clinic

OTHER

Sponsor Role: collaborator

Brown University

OTHER

Sponsor Role: collaborator

University of New Mexico

OTHER

Sponsor Role: collaborator

University of Pennsylvania

OTHER

Sponsor Role: collaborator

University of Pittsburgh

OTHER

Sponsor Role: collaborator

Oregon Health and Science University

OTHER

Sponsor Role: collaborator

RTI International

OTHER

Sponsor Role: collaborator

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

NIH

Sponsor Role: collaborator

NICHD Pelvic Floor Disorders Network

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Cindy Amundsen, MD

Role: STUDY_CHAIR

Duke University

Holly Richter, PhD, MD

Role: PRINCIPAL_INVESTIGATOR

University of Alabama at Birmingham

Shawn A. Menefee, MD

Role: PRINCIPAL_INVESTIGATOR

Kaiser Permanente, San Diego, CA

Sandip Vasada, MD

Role: PRINCIPAL_INVESTIGATOR

The Cleveland Clinic

Deborah L. Myers, MD

Role: PRINCIPAL_INVESTIGATOR

Brown/Women and Infants Hospital of Rhode Island

Yoko Kumesu, MD

Role: PRINCIPAL_INVESTIGATOR

University of New Mexico

Lily Arya, MD

Role: PRINCIPAL_INVESTIGATOR

University of Pennsylvania

Jerry Lowder, MD

Role: PRINCIPAL_INVESTIGATOR

University of Pittsburgh

W. Thomas Gregory, MD

Role: PRINCIPAL_INVESTIGATOR

Oregon Health and Science University

Dennis Wallace, PhD

Role: PRINCIPAL_INVESTIGATOR

RTI International

Susan Meikle, MD, MSPH

Role: PRINCIPAL_INVESTIGATOR

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

Locations

University of Alabama at Birmingham, Department of Obstetrics and Gynecology

Birmingham, Alabama, United States

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

La Jolla, California, United States

University of New Mexico Health Sciences Center

Albuquerque, New Mexico, United States

Duke Division of Urogynecology and Reconstructive Pelvic Surgery

Durham, North Carolina, United States

Cleveland Clinic, Obstretric and Gynecology and Women Health Institute

Cleveland, Ohio, United States

Oregon Health and Science University, Kohler Pavilion

Portland, Oregon, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

Univesity of Pittsburgh, Magee-Womens Hospital

Pittsburgh, Pennsylvania, United States

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

Providence, Rhode Island, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 33620895 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31895722 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31211964 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 29031894 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 24486637 (View on PubMed)

Other Identifiers

U01HD069031

Identifier Type: NIH

Identifier Source: secondary_id

View Link

PFDN 20

Identifier Type: -

Identifier Source: org_study_id