Combined Treatment for Mixed Incontinence (ESTEEM)

Women and Infants Hospital of Rhode Island, The Cleveland Clinic, Duke University, University of Alabama at Birmingham, University of New Mexico, University of Pennsylvania, University of Pittsburgh, University of California, San Diego, Kaiser Permanente, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), RTI International

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.

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.

MUS can include the TVT™ (mechanical cut mesh only, Gynecare, ETHICON Women's Health & Urology, Somerville, NJ), TVT-O™ (mechanical cut mesh only, Gynecare), or Monarc™ (American Medical Systems, Minnetonka, MN).

MUS is combined with components of behavioral therapy (designed to change behaviors to encourage continence), and pelvic floor muscle therapy (designed to strengthen the pelvic floor muscles, enhance the physiological closure of the bladder neck, and improve coordination). This is done prior to MUS (1 visit) and after MUS for 5 visits at 2, 4, 6, 8 weeks and 6 months.

The Urogenital Distress Inventory (UDI) is a standardized a measure of overactive bladder symptoms and health-related quality of life. The UDI scale has a range from 0 to 300 with higher scores indicating greater distress. The change from baseline outcome is calculated as the difference in score at 3, 6, or 12 months and the score at baseline.

The Urogenital Distress Inventory is a standardized a measure of overactive bladder symptoms and health-related quality of life. The UDI Stress subscale has a range from 0 to 100 with higher scores indicating greater distress. The change from baseline outcome is calculated as the difference in score at 3, 6, or 12 months and the score at baseline.

The Urogenital Distress Inventory is a standardized a measure of overactive bladder symptoms and health-related quality of life. The UDI Irritative subscale has a range from 0 to 100 with higher scores indicating greater distress. The change from baseline outcome is calculated as the difference in score at 3, 6, or 12 months and the score at baseline.

The Urogenital Distress Inventory is a standardized a measure of overactive bladder symptoms and health-related quality of life. The UDI Obstructive subscale has a range from 0 to 100 with higher scores indicating greater distress. The change from baseline outcome is calculated as the difference in score at 3, 6, or 12 months and the score at baseline.

Based on data collected from participant-completed diaries at baseline, 2 weeks, and 2, 6, and 12 months, the outcome variable is computed as the difference in number of stress incontinence episodes at 2 weeks, 2, 6, or 12 months and the number of stress incontinence episodes at baseline.

Based on data collected from participant-completed diaries at baseline, 2 weeks, and 2, 6, and 12 months, the outcome variable is computed as the difference in number of urge incontinence episodes at 2 weeks, 2, 6, or 12 months and the number of urge incontinence episodes at baseline.

Based on data collected from participant-completed diaries at baseline, 2 weeks, and 2, 6, and 12 months, the outcome variable is computed as the difference in number of unknown incontinence episodes at 2 weeks, 2, 6, or 12 months and the number of unknown incontinence episodes at baseline.

Based on data collected from participant-completed diaries at baseline, 2 weeks, and 2, 6, and 12 months, the outcome variable is computed as the difference in total number of incontinence episodes at 2 weeks, 2, 6, or 12 months and the total number of incontinence episodes at baseline.

Based on data collected from participant-completed diaries at baseline, 2 weeks, and 2, 6, and 12 months, the outcome variable is computed as the difference in number of wet pads per day at 2 weeks, 2, 6, or 12 months and the number of wet pads per day at baseline.

Based on data collected from participant-completed diaries at baseline, 2 weeks, and 2, 6, and 12 months, the outcome variable is computed as the difference in total number of pads per day at 2 weeks, 2, 6, or 12 months and the total number of pads per day at baseline.

Based on data collected from participant-completed diaries at baseline, 2 weeks, and 2, 6, and 12 months, the outcome variable is computed as the difference in number of daytime voids at 2 weeks, 2, 6, or 12 months and the number of daytime voids at baseline.

Based on data collected from participant-completed diaries at baseline, 2 weeks, and 2, 6, and 12 months, the outcome variable is computed as the difference in number of nighttime voids at 2 weeks, 2, 6, or 12 months and the number of nighttime voids at baseline.

Based on data collected from participant-completed diaries at baseline, 2 weeks, and 2, 6, and 12 months, the outcome variable is computed as the difference in number of urgency voids without incontinence at 2 weeks, 2, 6, or 12 months and the number of urgency voids without incontinence at baseline.

Based on data collected from participant-completed diaries at baseline, 2 weeks, and 2, 6, and 12 months, for participants with >8 voids at baseline, the outcome is calculated as Yes=no more than 8 voids noted at the time point, No=Otherwise

Based on data collected from participant-completed diaries at baseline, 2 weeks, and 2, 6, and 12 months, the outcome is calculated as Yes=at least 50% reduction in the number of voids between 2 weeks, 2, 6, and 12 months and baseline, No=Otherwise

Number of Participants With Greater Number of Voids Relative to Baseline or >8 Voids (Worsening Voiding Frequency)

Based on data collected from participant-completed diaries at baseline, 2 weeks, and 2, 6, and 12 months, the outcome is calculated as Yes=greater than baseline number of voids at the time point or with greater than 8 voids at the time point, No=Otherwise

The Pelvic Organ Prolapse Incontinence Sexual Questionnaire, IUGA-revised (PISQ-IR) is a questionnaire measuring the impact of incontinence symptoms on sexual function and satisfaction. Using the Rockwood scoring, the PISQ-IR Not Partner Related subscale (NSA-PR) ranges from 0 to 100 with higher scores indicating worse function/satisfaction. The change from baseline outcome is calculated as the difference in score at 3, 6, or 12 months and the score at baseline.

The Pelvic Organ Prolapse Incontinence Sexual Questionnaire, IUGA-revised (PISQ-IR) is a questionnaire measuring the impact of incontinence symptoms on sexual function and satisfaction. Using the Rockwood scoring, the PISQ-IR Not Sexually Active-Condition Specific subscale (NSA-CS) ranges from 0 to 100 with worse scores indicating better function/satisfaction. The change from baseline outcome is calculated as the difference in score at 3, 6, or 12 months and the score at baseline.

The Pelvic Organ Prolapse Incontinence Sexual Questionnaire, IUGA-revised (PISQ-IR) is a questionnaire measuring the impact of incontinence symptoms on sexual function and satisfaction. Using the Rockwood scoring, the PISQ-IR Not Sexually Active-Global Quality Rating subscale (NSA-GQR) ranges from 0 to 100 with higher scores indicating worse function/satisfaction. The change from baseline outcome is calculated as the difference in score at 3, 6, or 12 months and the score at baseline.

The Pelvic Organ Prolapse Incontinence Sexual Questionnaire, IUGA-revised (PISQ-IR) is a questionnaire measuring the impact of incontinence symptoms on sexual function and satisfaction. Using the Rockwood scoring, the PISQ-IR Not Sexually Active-Condition Impact subscale (NSA-CI) ranges from 0 to 100 with higher scores indicating worse function/satisfaction. The change from baseline outcome is calculated as the difference in score at 3, 6, or 12 months and the score at baseline.

The Pelvic Organ Prolapse Incontinence Sexual Questionnaire, IUGA-revised (PISQ-IR) is a questionnaire measuring the impact of incontinence symptoms on sexual function and satisfaction. Using the Rockwood scoring, the PISQ-IR Sexually Active-Arousal, Orgasm subscale (SA-AO) ranges from 0 to 100 with higher scores indicating worse function/satisfaction. The change from baseline outcome is calculated as the difference in score at 3, 6, or 12 months and the score at baseline.

The Pelvic Organ Prolapse Incontinence Sexual Questionnaire, IUGA-revised (PISQ-IR) is a questionnaire measuring the impact of incontinence symptoms on sexual function and satisfaction. Using the Rockwood scoring, the PISQ-IR Sexually Active-Partner Related subscale (SA-PR) ranges from 0 to 100 with higher scores indicating better function/satisfaction. The change from baseline outcome is calculated as the difference in score at 3, 6, or 12 months and the score at baseline.

The Pelvic Organ Prolapse Incontinence Sexual Questionnaire, IUGA-revised (PISQ-IR) is a questionnaire measuring the impact of incontinence symptoms on sexual function and satisfaction. Using the Rockwood scoring, the PISQ-IR Sexually Active-Condition Specific subscale (SA-CS) ranges from 0 to 100 with higher scores indicating better function/satisfaction. The change from baseline outcome is calculated as the difference in score at 3, 6, or 12 months and the score at baseline.

The Pelvic Organ Prolapse Incontinence Sexual Questionnaire, IUGA-revised (PISQ-IR) is a questionnaire measuring the impact of incontinence symptoms on sexual function and satisfaction. Using the Rockwood scoring, the PISQ-IR Sexually Active-Global Quality Rating subscale (SA-GQR) ranges from 0 to 100 with higher scores indicating better function/satisfaction. The change from baseline outcome is calculated as the difference in score at 3, 6, or 12 months and the score at baseline.

The Pelvic Organ Prolapse Incontinence Sexual Questionnaire, IUGA-revised (PISQ-IR) is a questionnaire measuring the impact of incontinence symptoms on sexual function and satisfaction. Using the Rockwood scoring, the PISQ-IR Sexually Active-Condition Impact subscale (SA-CI) ranges from 0 to 100 with higher scores indicating better function/satisfaction. The change from baseline outcome is calculated as the difference in score at 3, 6, or 12 months and the score at baseline.

The Pelvic Organ Prolapse Incontinence Sexual Questionnaire, IUGA-revised (PISQ-IR) is a questionnaire measuring the impact of incontinence symptoms on sexual function and satisfaction. Using the Rockwood scoring, the PISQ-IR Sexually Active-Desire subscale (SA-D) ranges from 0 to 100 with higher scores indicating better function/satisfaction. The change from baseline outcome is calculated as the difference in score at 3, 6, or 12 months and the score at baseline.

EQ-5D is a standardized instrument developed by the EuroQol Group as a measure of health-related quality of life. The index score ranges from 0 to 1 with higher scores indicating a better quality of life. The change from baseline outcome is calculated as the difference in score at 3, 6, or 12 months and the score at baseline.

EQ-5D is a standardized instrument developed by the EuroQol Group as a measure of health-related quality of life. The visual analog scale (VAS) score ranges from 0 to 100 with higher scores indicating a better quality of life. The change from baseline outcome is calculated as the difference in score at 3, 6, or 12 months and the score at baseline.

The Overactive Bladder Questionnaire-Long Form is a standardized a measure of overactive bladder symptoms and health-related quality of life. The OABq-LF Symptom Severity score ranges from 0 to 100 with higher score indicating worse quality of life. The change from baseline outcome is calculated as the difference in score at 3, 6, or 12 months and the score at baseline.

The Overactive Bladder Questionnaire-Long Form is a standardized a measure of overactive bladder symptoms and health-related quality of life. The OABq-LF Coping score ranges from 0 to 100 with higher score indicating better quality of life. The change from baseline outcome is calculated as the difference in score at 3, 6, or 12 months and the score at baseline.

The Overactive Bladder Questionnaire-Long Form is a standardized a measure of overactive bladder symptoms and health-related quality of life. The OABq-LF Concern score ranges from 0 to 100 with higher score indicating better quality of life. The change from baseline outcome is calculated as the difference in score at 3, 6, or 12 months and the score at baseline.

The Overactive Bladder Questionnaire-Long Form is a standardized a measure of overactive bladder symptoms and health-related quality of life. The OABq-LF Sleep score ranges from 0 to 100 with higher score indicating better quality of life. The change from baseline outcome is calculated as the difference in score at 3, 6, or 12 months and the score at baseline.

The Overactive Bladder Questionnaire-Long Form is a standardized a measure of overactive bladder symptoms and health-related quality of life. The OABq-LF Social score ranges from 0 to 100 with higher score indicating better quality of life. The change from baseline outcome is calculated as the difference in score at 3, 6, or 12 months and the score at baseline.

The Overactive Bladder Questionnaire-Long Form is a standardized a measure of overactive bladder symptoms and health-related quality of life. The OABq-LF HRQL score ranges from 0 to 100 with higher score indicating better quality of life. The change from baseline outcome is calculated as the difference in score at 3, 6, or 12 months and the score at baseline.

The Overactive Bladder Satisfaction with Treatment Questionnaire is a standardized a measure of satisfaction with treatment for overactive bladder symptoms. The OAB-SATq Satisfaction score ranges from 0 to 100 with higher scores indicating higher satisfaction.

The Overactive Bladder Satisfaction with Treatment Questionnaire is a standardized a measure of satisfaction with treatment for overactive bladder symptoms. The OAB-SATq Side Effect score ranges from 0 to 100 with higher scores indicating fewer side effects.

The Overactive Bladder Satisfaction with Treatment Questionnaire is a standardized a measure of satisfaction with treatment for overactive bladder symptoms. The OAB-SATq Endorsement score ranges from 0 to 100 with higher scores indicating greater endorsement.

The Overactive Bladder Satisfaction with Treatment Questionnaire is a standardized a measure of satisfaction with treatment for overactive bladder symptoms. The OAB-SATq Convenience score ranges from 0 to 100 with higher scores indicating greater convenience.

The Overactive Bladder Satisfaction with Treatment Questionnaire is a standardized a measure of satisfaction with treatment for overactive bladder symptoms. The preference score is a binary [yes/no] indicator as to whether a subject indicated slight or definite preference for the treatment among women that have had previous treatment for overactive bladder. The outcome is the percentage of participants that prefer the current treatment to previous treatments.

The Incontinence Impact Questionnaire-Long Form is a standardized a measure of health-related quality of life. The IIq-LF Physical Activity score ranges from 0 to 100 with higher scores indicating worse impact. The change from baseline outcome is calculated as the difference in score at 3, 6, or 12 months and the score at baseline.

The Incontinence Impact Questionnaire-Long Form is a standardized a measure of health-related quality of life. The IIq-LF Travel score ranges from 0 to 100 with higher scores indicating worse impact. The change from baseline outcome is calculated as the difference in score at 3, 6, or 12 months and the score at baseline.

The Incontinence Impact Questionnaire-Long Form is a standardized a measure of health-related quality of life. The IIq-LF Social Relationship score ranges from 0 to 100 with higher scores indicating worse impact. The change from baseline outcome is calculated as the difference in score at 3, 6, or 12 months and the score at baseline.

The Incontinence Impact Questionnaire-Long Form is a standardized a measure of health-related quality of life. The IIq-LF Emotional Health score ranges from 0 to 100 with higher scores indicating worse impact. The change from baseline outcome is calculated as the difference in score at 3, 6, or 12 months and the score at baseline.

The Incontinence Impact Questionnaire-Long Form is a standardized a measure of health-related quality of life. The IIq-LF Total score ranges from 0 to 400 with higher scores indicating worse impact. The change from baseline outcome is calculated as the difference in score at 3, 6, or 12 months and the score at baseline.

The Adaptation Index is a standardized measure of health-related quality of life. The ADI Hygiene score ranges from 0 to 100 with higher score indicating worse severity in adaptive behaviors. The change from baseline outcome is calculated as the difference in score at 3, 6, or 12 months and the score at baseline.

The Adaptation Index is a standardized measure of health-related quality of life. The ADI Avoidance score ranges from 0 to 100 with higher score indicating worse severity in adaptive behaviors. The change from baseline outcome is calculated as the difference in score at 3, 6, or 12 months and the score at baseline.

The Brink scale considers three pelvic floor muscle contraction variables: vaginal pressure or muscle force, elevation or vertical displacement of the examiner fingers, and duration of contraction. The score ranges from 3 to 12 with higher scores indicating greater PFM function. The change from baseline outcome is calculated as the difference in score at 3 or 12 months and the score at baseline.

The average peak muscle contraction is measured during a physical exam. The outcome is calculated as the difference in measured value at 3 or 12 months and the score at baseline.

The Patient Global Impression of Improvement (PGI-I) is a patient-reported measure of perceived improvement with treatment, as assessed on a scale of 1 (very much better) to 7 (very much worse). Included here are participants who had improvement as indicated by a rating of 1 (very much better), 2 (much better).

The Patient Global Impression of Severity (PGI-S) is a patient-reported measure of perceived severity of condition, as assessed on a scale of 1 (Normal) to 4 (Severe). Included here are participants who reported Normal or Mild severity as indicated by a rating of 1 or 2.

Inclusion Criteria: Presence of both SUI and UUI on bladder diary; and > 2 IEs/3 days > 1 Stress IE/3 day diary > 1 Urge IE/3 day diary 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?" Reporting at least "moderate bother" from SUI item on UDI "Do you usually experience urine leakage related to coughing, sneezing, or laughing" Diagnosis of SUI defined by a positive cough stress test (CST) or urodynamic evaluation within the past 18 months Desires surgical treatment for SUI symptoms Urinary symptoms >3 months Subjects understand that BPTx is a treatment option for MUI outside of ESTEEM study protocol Urodynamics within past 18 months Exclusion Criteria: 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 Planned concomitant surgery for anterior vaginal wall or apical prolapse > 0 a)Women undergoing only rectocele repair are eligible Women undergoing hysterectomy for any indication will be excluded Active pelvic organ malignancy Age <21 years Pregnant or plans for future pregnancy in next 12 months, or within 12 months post-partum Post-void residual >150 cc on 2 occasions, or current catheter use Participation in other trial that may influence results of this study Unevaluated hematuria Prior sling, synthetic mesh for prolapse, implanted nerve stimulator for incontinence Spinal cord injury or advanced/severe neurologic conditions including Multiple Sclerosis, Parkinsons Women on anti-muscarinic therapy will be eligible after 3 week wash-out period Non-ambulatory History of serious adverse reaction to synthetic mesh Not able to complete study assessments per clinician judgment, or not available for 12 month follow-up Women who only report "other IE" on bladder diary, and do not report at minimum 1 stress and 1 urge IE/3 days Diagnosis of and/or history of bladder pain or chronic pelvic pain Women who had intravesical Botox injection within the past 12 months

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

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

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