Clinical trial NCT01959347: Combined Treatment for Mixed Incontinence
Official title: Effects of Surgical Treatment Enhanced With Exercise for Mixed Urinary Incontinence (ESTEEM)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Urinary Incontinence, Stress
Urinary Incontinence, Urge
Keywords: urinary incontinence
midurethral sling
pelvic floor therapy
Lead sponsor: NICHD Pelvic Floor Disorders Network
Sponsor class: NETWORK
Collaborators: name: Women and Infants Hospital of Rhode Island
name: The Cleveland Clinic
name: Duke University
name: University of Alabama at Birmingham
name: University of New Mexico
name: University of Pennsylvania
name: University of Pittsburgh
name: University of California, San Diego
name: Kaiser Permanente
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: RTI International
First posted: 2013-10-10
Enrollment: 480
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 overarching goal of this randomized trial is to estimate the effect of combined midurethral sling (MUS) and peri-operative behavioral/pelvic floor therapy (BPTx) compared to MUS alone on successful treatment of MUI symptoms in 472 women. Secondary objectives include estimating the effect of combined treatment compared to MUS on improving overactive bladder (OAB) and stress urinary incontinence (SUI) outcomes separately, need for additional treatment, time to failure and identifying predictors of poor outcomes in this MUI population.

A supplemental study, The Human Microbiome Study of ESTEEM, will evaluate the urinary and vaginal microbiome as it relates to women with MUI, their treatment and unaffected controls.

Detailed description: ESTEEM is a multi-center randomized trial of 472 women with MUI who have elected to undergo surgical treatment for SUI. Participants will be randomized to a peri-operative BPTx program+MUS versus MUS alone. The purpose is to compare combined MUS+BPTx versus MUS alone (control) on improving MUI symptoms at 1 year.

Patients will be assigned to one of the two treatment groups. Randomization will be stratified by clinical site and by UUI "severity," which will be defined by the number of urgency urinary IEs on diary.

The primary outcome for this study is the mean change from baseline in UDI-total score at 1 year postoperative. The UDI is a validated, disease-specific, patient-reported outcome (PRO) measure.

Secondary outcomes UUI/OAB outcomes will be measured using the UDI-irritative subscale that measures symptom burden, impact, and changes related to OAB. It is highly responsive to treatment-related change and is able to discriminate among levels of change in all bladder diary variables (urinary urgency, frequency and urge incontinence) and patient ratings of treatment benefit that will characterize how MUS may affect all OAB symptoms individually and as a whole. SUI symptom outcomes will be measured using the UDI-stress subscale to compare SUI outcomes between women randomized to MUS + BPTx versus MUS alone.

Other UUI/OAB outcomes that will be compared between groups include 1) the change in IE frequency and type, number of urgency episodes, urgency severity with voids, number of diurnal voids, and number of nocturnal voids using a bladder diary; 2) patient satisfaction with treatment using the OAB-SAT-q; 3) bother and heal related quality of life using the OAB-q subscale

For analyzing time to failure, "failure" will be defined as initiation of any additional treatment for either SUI or UUI/OAB symptoms during the follow-up period. Subjects lost to follow up will be censored at the time of their last visit.

Quality of life/global impression will be assessed be compared between treatment groups using the a) Incontinence Impact Questionnaire (IIQ), Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ), c) European Quality of Life-5 Dimensions (EQ-5D), d) Adaptation Index and e) Patient Global Impression of Improvement (PGI-I) and Patient Global Impression of Severity (PGI-S).

Safety/additional treatments will be characterized as a) additional re-treatments for SUI or UUI within 12 months of treatment, and type of re-treatment and b) return to OR for sling revision due to worsened OAB symptoms.

To evaluate the association between PFM strength and improvements in UI symptoms, we will objectively assess PFM strength changes using the Peritron Perineometer, and instrument specifically designed for pelvic floor assessment.

Eligibility criteria: Inclusion Criteria:

1. Presence of both SUI and UUI on bladder diary; and \> 2 IEs/3 days

   1. \> 1 Stress IE/3 day diary
   2. \> 1 Urge IE/3 day diary
2. Reporting at least "moderate bother" from UUI item on the UDI "Do you usually experience urine leakage associated with a feeling of urgency, that is a strong sensation of needing to go to the bathroom?"
3. Reporting at least "moderate bother" from SUI item on UDI "Do you usually experience urine leakage related to coughing, sneezing, or laughing"
4. Diagnosis of SUI defined by a positive cough stress test (CST) or urodynamic evaluation within the past 18 months
5. Desires surgical treatment for SUI symptoms
6. Urinary symptoms \>3 months
7. Subjects understand that BPTx is a treatment option for MUI outside of ESTEEM study protocol
8. Urodynamics within past 18 months

Exclusion Criteria:

1. Anterior or apical compartment prolapse at or beyond the hymen (\>0 on POPQ), regardless if patient is symptomatic

   a)Women with anterior or apical prolapse above the hymen (\<0) who do not report vaginal bulge symptoms will be eligible
2. Planned concomitant surgery for anterior vaginal wall or apical prolapse \> 0

   a)Women undergoing only rectocele repair are eligible
3. Women undergoing hysterectomy for any indication will be excluded
4. Active pelvic organ malignancy
5. Age \<21 years
6. Pregnant or plans for future pregnancy in next 12 months, or within 12 months post-partum
7. Post-void residual \>150 cc on 2 occasions, or current catheter use
8. Participation in other trial that may influence results of this study
9. Unevaluated hematuria
10. Prior sling, synthetic mesh for prolapse, implanted nerve stimulator for incontinence
11. Spinal cord injury or advanced/severe neurologic conditions including Multiple Sclerosis, Parkinsons
12. Women on anti-muscarinic therapy will be eligible after 3 week wash-out period
13. Non-ambulatory
14. History of serious adverse reaction to synthetic mesh
15. Not able to complete study assessments per clinician judgment, or not available for 12 month follow-up
16. Women who only report "other IE" on bladder diary, and do not report at minimum 1 stress and 1 urge IE/3 days
17. Diagnosis of and/or history of bladder pain or chronic pelvic pain
18. Women who had intravesical Botox injection within the past 12 months

Primary outcomes:
measure: Change From Baseline UDI Total Score
timeFrame: 3, 6, and 12 Months
Secondary outcomes:
measure: Change From Baseline UDI Stress Score
timeFrame: 3, 6, and 12 Months
measure: Change From Baseline UDI Irritative Score
timeFrame: 3, 6, and 12 Months
measure: Change From Baseline UDI Obstructive Score
timeFrame: 3, 6, and 12 Months
Other outcomes:
measure: Change From Baseline Number of Stress Incontinence Episodes
timeFrame: 2 weeks and 2, 6, and 12 Months
measure: Change From Baseline Number of Urge Incontinence Episodes
timeFrame: 2 weeks and 2, 6, and 12 Months
measure: Change From Baseline Number of Unknown Incontinence Episodes
timeFrame: 2 weeks and 2, 6, and 12 Months
measure: Change From Baseline Total Number of Incontinence Episodes
timeFrame: 2 weeks and 2, 6, and 12 Months
measure: Change From Baseline Number of Wet Pads Per Day
timeFrame: 2 weeks and 2, 6, and 12 Months
measure: Change From Baseline Number of Pads Per Day
timeFrame: 2 weeks and 2, 6, and 12 Months
measure: Change From Baseline Number of Daytime Voids
timeFrame: 2 weeks and 2, 6, and 12 Months
measure: Change From Baseline Number of Nighttime Voids
timeFrame: 2 weeks and 2, 6, and 12 Months
measure: Change From Baseline Number of Urgency Voids Without Incontinence
timeFrame: 2 weeks and 2, 6, and 12 Months
measure: Number of Participants With <8 Voids After Baseline (Normalization of Voiding Frequency)
timeFrame: 2 weeks and 2, 6, and 12 Months
measure: Number of Participants With 50% Reduction in Voids Relative to Baseline (Improved Voiding Frequency)
timeFrame: 2 weeks and 2, 6, and 12 Months
measure: Number of Participants With Greater Number of Voids Relative to Baseline or >8 Voids (Worsening Voiding Frequency)
timeFrame: 2 weeks and 2, 6, and 12 Months
measure: Change From Baseline PISQ-IR NSAPR Score
timeFrame: 3, 6, and 12 Months
measure: Change From Baseline PISQ-IR NSACS Score
timeFrame: 3, 6, and 12 Months
measure: Change From Baseline PISQ-IR NSAGQR Score
timeFrame: 3, 6, and 12 Months
measure: Change From Baseline PISQ-IR NSACI Score
timeFrame: 3, 6, and 12 Months
measure: Change From Baseline PISQ-IR SAAO Score
timeFrame: 3, 6, and 12 Months
measure: Change From Baseline PISQ-IR SAPR Score
timeFrame: 3, 6, and 12 Months
measure: Change From Baseline PISQ-IR SACS Score
timeFrame: 3, 6, and 12 Months
measure: Change From Baseline PISQ-IR SAGQR Score
timeFrame: 3, 6, and 12 Months
measure: Change From Baseline PISQ-IR SACI Score
timeFrame: 3, 6, and 12 Months
measure: Change From Baseline PISQ-IR SAD Score
timeFrame: 3, 6, and 12 Months
measure: Change From Baseline EQ-5D Index Score
timeFrame: 3, 6, and 12 Months
measure: Change From Baseline EQ-5D Visual Analog Scale Score
timeFrame: 3, 6, and 12 Months
measure: Change From Baseline OABq-LF Symptom Severity Score
timeFrame: 3, 6, and 12 Months
measure: Change From Baseline OABq-LF Coping Score
timeFrame: 3, 6, and 12 Months
measure: Change From Baseline OABq-LF Concern Score
timeFrame: 3, 6, and 12 Months
measure: Change From Baseline OABq-LF Sleep Score
timeFrame: 3, 6, and 12 Months
measure: Change From Baseline OABq-LF Social Score
timeFrame: 3, 6, and 12 Months
measure: Change From Baseline OABq-LF HRQL Total Score
timeFrame: 3, 6, and 12 Months
measure: OAB-SATq Satisfaction Score
timeFrame: 3, 6, and 12 Months
measure: OAB-SATq Side Effect Score
timeFrame: 3, 6, and 12 Months
measure: OAB-SATq Endorsement Score
timeFrame: 3, 6, and 12 Months
measure: OAB-SATq Convenience Score
timeFrame: 3, 6, and 12 Months
measure: OAB-SATq Preference Score
timeFrame: 3, 6, and 12 Months
measure: Change From Baseline IIq-LF Physical Activity Score
timeFrame: 3, 6, and 12 Months
measure: Change From Baseline IIq-LF Travel Score
timeFrame: 3, 6, and 12 Months
measure: Change From Baseline IIq-LF Social Relationship Score
timeFrame: 3, 6, and 12 Months
measure: Change From Baseline IIq-LF Emotional Health Score
timeFrame: 3, 6, and 12 Months
measure: Change From Baseline IIq-LF Total Score
timeFrame: 3, 6, and 12 Months
measure: Change From Baseline ADI Hygiene Score
timeFrame: 3, 6, and 12 Months
measure: Change From Baseline ADI Avoidance Score
timeFrame: 3, 6, and 12 Months
measure: Change From Baseline Brink Score
timeFrame: 2 weeks and 2 and 12 Months
measure: Change From Average Peak Muscle Contraction Pressure (cm H2O)
timeFrame: 2 weeks and 2 and 12 Months
measure: PGI-I
timeFrame: 3, 6, and 12 Months
measure: PGI-S
timeFrame: Baseline 3, 6, and 12 Months
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham, Department of Obstetrics and Gynecology
state: Alabama
city: Downey
country: United States
facility: Kaiser Permanente -- Downey
state: California
city: La Jolla
country: United States
facility: University of California at San Diego, UCSD Women's Pelvic Medicine Center
state: California
city: San Diego
country: United States
facility: Kaiser Permanente -- San Diego
state: California
city: Albuquerque
country: United States
facility: University of New Mexico Health Sciences Center, Department of Obstetrics and Gynecology
state: New Mexico
city: Durham
country: United States
facility: Duke University, Duke Division of Urogynecology and Reconstructive Pelvic Surgery
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic, Department OB/GYN
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Magee-Womens Hospital, Department of Obstetrics and Gynecology
state: Pennsylvania
city: Providence
country: United States
facility: Brown/ Women and Infants Hospital of Rhode Island, Center for Women's Pelvic Medicine and Reconstructive Surgery
state: Rhode Island
Study officials:
affiliation: Brown/ Women and Infants Hospital of Rhode Island, Center for Women's Pelvic Medicine and Reconstructive Surgery
name: Vivian W. Sung
role: PRINCIPAL_INVESTIGATOR
affiliation: RTI International
name: Dennis Wallace
role: PRINCIPAL_INVESTIGATOR
References:
citation: Richter HE, Carnes MU, Komesu YM, Lukacz ES, Arya L, Bradley M, Rogers RG, Sung VW, Siddiqui NY, Carper B, Mazloomdoost D, Dinwiddie D, Gantz MG; Eunice Kennedy Shriver National Institute of Child Health and Human Development Pelvic Floor Disorders Network. Association between the urogenital microbiome and surgical treatment response in women undergoing midurethral sling operation for mixed urinary incontinence. Am J Obstet Gynecol. 2022 Jan;226(1):93.e1-93.e15. doi: 10.1016/j.ajog.2021.07.008. Epub 2021 Jul 21.
citation: Sung VW, Richter HE, Moalli P, Weidner AC, Nguyen JN, Smith AL, Dunivan G, Ridgeway B, Borello-France D, Newman DK, Mazloomdoost D, Carper B, Gantz MG; NICHD Pelvic Floor Disorders Network. Characteristics Associated With Treatment Failure 1 Year After Midurethral Sling in Women With Mixed Urinary Incontinence. Obstet Gynecol. 2021 Aug 1;138(2):199-207. doi: 10.1097/AOG.0000000000004444.
citation: Sung VW, Richter HE, Moalli P, Weidner AC, Nguyen JN, Smith AL, Dunivan G, Ridgeway B, Borello-France D, Newman DK, Mazloomdoost D, Carper B, Gantz MG; Eunice Kennedy Shriver National Institute of Child Health and Human Development Pelvic Floor Disorders Network*. Characteristics Associated With Treatment Failure 1 Year After Midurethral Sling in Women With Mixed Urinary Incontinence. Obstet Gynecol. 2020 Sep;136(3):482-491. doi: 10.1097/AOG.0000000000003989.
citation: Sung VW, Borello-France D, Newman DK, Richter HE, Lukacz ES, Moalli P, Weidner AC, Smith AL, Dunivan G, Ridgeway B, Nguyen JN, Mazloomdoost D, Carper B, Gantz MG; NICHD Pelvic Floor Disorders Network. Effect of Behavioral and Pelvic Floor Muscle Therapy Combined With Surgery vs Surgery Alone on Incontinence Symptoms Among Women With Mixed Urinary Incontinence: The ESTEEM Randomized Clinical Trial. JAMA. 2019 Sep 17;322(11):1066-1076. doi: 10.1001/jama.2019.12467.