Effects of Surgical Treatment Enhanced With Exercise for Mixed Urinary Incontinence (ESTEEM)
Phase: PHASE3
Conditions: Urinary Incontinence, Stress, Urinary Incontinence, Urge
Sponsor: NICHD Pelvic Floor Disorders Network

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CONFIDENTIAL 
 
 
Pelvic Floor Disorders Network 
 
Protocol 
 
Effects of Surgical Treatment Enhanced with Exercise for Mixed Urinary Incontinence (ESTEEM) 
 
Short title: Combined treatment for mixed incontinence 
 
 
 
 
Concept Proposal:  Approved by Steering Committee 7/22/2011 
Mini Protocol:   Approved by Steering Committee 7/19/2012 
Protocol: Approved by Steering Committee 10/11/2012 
 
 
Revised: February 12, 2014 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
The information contained within this document is not to be disclosed in any way without 
the prior permission of the Protocol Chair(s), or the PFDN NICHD Program Scientist and 

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Protocol Chair: 
Vivian W. Sung 
Brown/Women and Infants Hospital 
Division of Urogynecology 
695 Eddy Street, lower level 
Providence, RI 02906 
vsung@wihri.org 
(401) 274-1122 x 8740 
 
 
Protocol Committee: 
Brown/Women and Infants: Deborah L. Myers (Co-Chair) 
Cleveland Clinic: Beri Ridgeway 
Duke University Medical Center: Alison Weidner 
University of Alabama at Birmingham: Holly Richter 
University of California-San Diego: Emily Lukacz 
University of New Mexico: Gena Dunivan  
University of Pennsylvania: Ariana Smith, Diane Newman 
University of Pittsburgh: Pamela Moalli, Diane Borello-France 
RTI DCC: Marie Gantz 
NIH/NICHD: Susan Meikle  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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ABBREVIATIONS 
 
ABC 
Anticholinergic versus Botox Comparison trial 
ATLAS 
Ambulatory Treatments for Leakage Associated with Stress Incontinence trial 
BBUSQ 
Birmingham Bowel Urinary Symptom Questionnaire 
BD 
Bladder diary 
BE- DRI 
Behavior Enhances Drug Reduction of Incontinence trial 
BPTx 
Behavioral/pelvic floor therapy 
CDF 
Cumulative distribution function 
CST 
Cough stress test 
DCC 
Data Coordinating Center 
DO 
Detrusor overactivity 
DSMB 
Data and Safety Monitoring Board 
EQ-5D 
European Quality of Life-5 Dimensions 
HRQOL 
Health related quality of life 
IE 
Incontinence episode 
ICI 
International Consultation on Incontinence 
ICS 
International Continence Society 
IIQ 
Incontinence Impact Questionnaire 
IRB 
Institutional Review Board 
ITT 
Intention-to-treat 
IUGA 
International Urogynecological Association 
MESA 
Medical, Epidemiologic, and Social Aspects of Aging 
MID 
Minimum important difference 
MIMOSA 
Mixed Incontinence: Medical or Surgical Approach trial 
MSM 
Medical Safety Monitor 
MUI 
Mixed urinary incontinence 
MUS 
Mid-urethral sling 
OAB 
Overactive bladder 
OAB-q 
Overactive Bladder Questionnaire 
OAB-q-SS 
Overactive Bladder Questionnaire-Symptom subscale 
OAB-SAT-q 
Overactive Bladder Questionnaire-Satisfaction with Treatment Questionnaire 
OPTIMAL 
Operations and Pelvic Muscle Training in the Management of Apical Support Loss 
trial 
PFD 
Pelvic floor disorder 
PFDI 
Pelvic Floor Disorder Inventory 
PFDN 
Pelvic Floor Disorders Network 
PFMT 
Pelvic floor muscle training 
PGI-I 
Patient Global Impression- Improvement 
PGI-S 
Patient Global Impression-Severity 
PISQ 
Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire  
POPQ 
Pelvic Organ Prolapse Quantification system 
PVR 
Postvoid residual 
QoL 
Quality of life 
QUID 
Questionnaire for Urinary Incontinence Diagnosis  
RCT 
Randomized controlled trial 
RUBI 
Refractory idiopathic urge incontinence and botulinum A injection trial 
SAE 
Serious adverse event 
SD 
Standard deviation 
SISTEr 
Stress Incontinence Surgical Treatment Efficacy Trial 

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SUI 
Stress urinary incontinence 
TOMUS 
Trial of Mid-Urethral Slings 
TOT 
Transobturator tape sling 
TVT 
Tension-free vaginal tape sling  
TVT-O 
Tension-free vaginal tape obturator 
UDE 
Urodynamic evaluation 
UDI 
Urogenital Distress Inventory 
UI 
Urinary incontinence 
UIE 
Urinary incontinence episode  
UITN 
Urinary Incontinence Treatment Network 
UUI 
Urge urinary incontinence 
ValUE 
Value of Urodynamic Evaluation trial 
VPFMC 
Voluntary pelvic floor muscle contraction 
3IQ 
3 Incontinence Questions Assessment Tool 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
 
1. Study Aims ......................................................................................................................................... 7 
1.1. Primary Aim: ................................................................................................................................ 7 
1.2. Secondary Aims: .......................................................................................................................... 7 
1.3. Exploratory Aims: ......................................................................................................................... 7 
2. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ...................................................... 8 
2.1. Disease/Condition Background: ................................................................................................... 8 
2.2. Challenges with definitions........................................................................................................... 9 
2.3. Current treatment strategies for MUI: Challenges and old assumptions ....................................... 9 
2.4. Behavioral/pelvic floor muscle therapy (BPTx) ........................................................................... 10 
2.5. Anti-incontinence surgical treatment outcomes in women with MUI ........................................... 10 
2.6. Limitations of existing MUS trials for the MUI population ............................................................ 12 
2.7. MIMOSA Trial: First Network trial attempt focused on MUI population ....................................... 13 
2.8. Summary of known and potential risks and benefits of study treatment ..................................... 13 
2.9. Significance of proposed study / Rationale for combined surgical and BPTx approach .............. 13 
2.10. Innovation ................................................................................................................................ 13 
3. STUDY DESIGN .............................................................................................................................. 14 
3.1. Description of study design (See Figure 2, Study flow diagram) ................................................ 14 
3.2 Masking issues ........................................................................................................................... 15 
3.3. Randomization and Stratification................................................................................................ 15 
3.4. Outcomes .................................................................................................................................. 16 
3.4.1.a Rationale for using UDI as primary study outcome......................................................... 18 
3.4.1.b. Rationale for timing of primary outcome: ....................................................................... 19 
3.4.1.c. Management of subjects who request additional treatment for SUI and/or OAB after MUS:
 .................................................................................................................................................. 19 
3.4.2. Secondary outcomes ........................................................................................................... 20 
3.4.2.a. Urge urinary incontinence/overactive bladder symptom outcomes ................................ 20 
3.4.2.b. Stress urinary incontinence symptom outcomes ........................................................... 20 
3.4.3. Other outcomes ................................................................................................................... 21 
3.4.3.a. Other UUI/OAB outcomes ............................................................................................. 21 
3.4.3.b. Time to failure ............................................................................................................... 21 
3.4.3.c. Quality of life/global impression ..................................................................................... 21 
3.4.3.d. Safety/additional treatment ........................................................................................... 21 
4.1. Eligibility Criteria/Rationale for inclusion/exclusion ..................................................................... 25 
4.2. Inclusion Criteria ........................................................................................................................ 27 
4.3. Exclusion Criteria ....................................................................................................................... 27 
4.4. Screening for Eligibility ............................................................................................................... 28 
5. DESCRIPTION OF STUDY INTERVENTIONS ................................................................................ 30 

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5.1. Midurethral sling procedure (both groups) .................................................................................. 30 
5.2. Background for BPTx intervention .............................................................................................. 31 
5.2.1. What is the evidence for behavioral/lifestyle modification? .................................................. 31 
5.2.2. What is the evidence for bladder training/urge suppression? ............................................... 32 
5.2.3. What is the evidence for Pelvic Floor Muscle Training (PFMT)? .......................................... 33 
5.2.4. What is the best approach to PFMT for treatment of urinary incontinence? ......................... 33 
5.3. What is the best “control” group for this study? .......................................................................... 34 
5.5. Patient management and follow-up ............................................................................................ 37 
5.5.1. Baseline Procedures ........................................................................................................... 37 
5.5.2. Postoperative visits and procedures .................................................................................... 38 
6.1. Sample size estimates ............................................................................................................... 40 
6.1.1. Primary aim and secondary aims: ....................................................................................... 40 
6.1.2. Potential limitations of the UDI and primary outcome:.......................................................... 41 
6.1.3. Management of women who drop out prior to receiving MUS .............................................. 41 
6.2. Statistical analysis plan .............................................................................................................. 41 
6.2.1. Primary aim ......................................................................................................................... 41 
6.2.2. Secondary aims ................................................................................................................... 42 
6.2.3. Exploratory aims .................................................................................................................. 42 
6.3. Interim data monitoring .............................................................................................................. 46 
7. Ethical Concerns/Safety ................................................................................................................... 46 
7.1. Ethical Concerns ........................................................................................................................ 46 
7.2. Informed Consent ...................................................................................................................... 46 
7.3. Data Safety Monitoring Board .................................................................................................... 47 
7.4. Reporting of serious adverse events .......................................................................................... 47 
7.5. Adverse events .......................................................................................................................... 47 
8. Feasibility ......................................................................................................................................... 47 
9. References ....................................................................................................................................... 48 
 
10. ESTEEM Ancillary Study: Goals among women with mixed urinary incontinence undergoing midurethral 
sling surgery randomized to behavioral therapy or no behavioral therapy (GloW).................................54 
 
 
 
 
 
 
 
 
 
 
 

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1. Study Aims 
 
Mixed urinary incontinence (MUI), defined as both stress urinary incontinence (SUI) and urge urinary 
incontinence (UUI), is a challenging condition and there are limited trials evaluating interventions that can 
optimize treatment outcomes. 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 OAB and SUI outcomes 
separately, need for additional treatment, time to failure and identifying predictors of poor outcomes in this 
MUI population. 
 
1.1. Primary Aim: 
 
To assess whether combined MUS + peri-operative BPTx is superior to MUS alone for improving 
MUI symptoms at 1 year in women electing surgical treatment.  
 
Primary Outcome: Change in severity of MUI symptoms at 1 year following MUS measured using the 
Urogenital Distress Inventory (UDI).2   
 
Primary Null Hypothesis: There is no difference in the change in MUI symptoms between women receiving 
combined MUS+BPTx versus MUS alone at 1 year following MUS surgery. 
 
Primary Alternative Hypothesis: Combined MUS+BPTx is superior to MUS alone for improving change in 
MUI symptoms at 1 year following MUS surgery. 
 
1.2. Secondary Aims: 
1. OAB symptom outcomes: To assess whether combined MUS+BPTx  is superior to MUS alone 
for improving change in OAB symptoms at 1 year in women electing surgical treatment. 
-OAB symptoms will be measured using UDI-irritative subscale scores 
 
Secondary Alternative Hypothesis: Combined MUS+BPTx is superior to MUS alone for improving 
change in OAB symptoms in women with MUI at 1 year following MUS surgery.  
 
2. SUI symptom outcomes: To assess whether combined MUS+BPTx is superior to MUS alone for 
improving change in SUI symptoms at 1 year in women electing surgical treatment for MUI. 
-SUI symptoms will be measured using the UDI-stress subscale. 
 
Secondary Alternative Hypothesis: Combined MUS+BPTx is superior to MUS alone for improving 
change in SUI symptoms in women with MUI at 1 year following MUS surgery.  
 
1.3. Exploratory Aims: 
1. Secondary urinary outcomes: To assess whether combined MUS+BPTx is superior to MUS 
alone for improving the number of urgency and urge incontinence episodes on bladder diary at 1 
year following MUS surgery. 
 
2. Time to failure: To compare time to failure between MUS+BPTx versus MUS alone. 
-Failure will be defined as initiation of any additional treatment for lower urinary tract symptoms (SUI, 
UUI/OAB, or voiding dysfunction). 

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3. Predictors of poor outcomes: To develop models to identify predictors of change of MUI, OAB, 
and SUI outcomes measured using the UDI between baseline and 1 year post-treatment. 
 
4. Quality of life and global impression: To compare quality of life outcomes and Patient Global 
Impression-Improvement (PGI-I)3, Patient Global Impression-Severity (PGI-S)3 between groups 
 
5. Safety and additional treatments: To describe rates of reoperation (sling revision) for worsening 
OAB symptoms after MUS and to compare the proportion of women in each group initiating 
additional treatment for SUI and/or OAB, and the types of additional treatment (BPTx, medications, 
other)  
 
 
 
6.  Minimally important difference (MID) and clinical definitions: To determine MIDs and 
clinically meaningful definitions of MUI that predict clinical outcomes using cut-offs and combinations 
of standardized measures 
 
 
7. Pelvic floor muscle strengthening:  To compare pelvic floor muscle strength changes between 
women randomized to combined MUS+BPTx versus MUS alone and to estimate associations 
between pelvic floor muscle strength improvement and UI symptoms. We will also explore predictors 
of unsuccessful pelvic floor muscle strengthening. 
 
8. Cost-effectiveness analysis: To determine the cost effectiveness of combined midurethral sling 
(MUS) and peri-operative behavioral/pelvic floor therapy (BPTx) compared to MUS alone for the 
treatment of MUI symptoms 
2. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
2.1. Disease/Condition Background:   
 
Up to 50% of women with incontinence have mixed urinary incontinence (MUI); a complex condition 
that is significantly challenging for patients, clinicians and researchers.4-6 For patients, the combination of 
UUI and SUI is more bothersome compared to either condition alone.7-9 For clinicians, treatment of MUI is 
challenging due to higher failure rates, as interventions designed to benefit one symptom often do not 
benefit the other. For clinicians and researchers, the lack of a clinically useful definition of MUI10 and the 
frequent exclusion of MUI patients from randomized trials11 pose challenges for determining best treatment 
approaches.  The wide variability of patient symptoms and terminology, ranging from “stress-predominant”, 
“urge-predominant”, “OAB -wet” or “OAB-dry”, further complicates data interpretation and patient 
management. The current definitions and treatment approaches have failed to provide significant progress 
in the treatment of this bothersome condition.  
 
 
OAB 
MUI 
SUI 
UUI 
Figure 1. Conceptual model of MUI. Adapted from 
Katsumi et al1 

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2.2. Challenges with definitions 
 
There is significant variability and controversy regarding the “best” definition of MUI: essentially there 
is an absence of a universal definition.10-15  Based on the name alone, it makes sense that “MUI” includes 
symptoms of both SUI and UUI/OAB. The International Urogynecological Association (IUGA)/International 
Continence Society (ICS) joint terminology report defines OAB based on symptoms alone as “urgency with 
or without urgency incontinence, usually with frequency and nocturia”: women can be “OAB-wet” or “OAB-
dry”.  MUI is defined by the same group as “the complaint of involuntary leakage associated with urgency 
and also with exertion, effort, sneezing, or coughing”.16 Clinical challenges with this definition include: 1) it 
excludes women who may have significant urgency and/or frequency without UUI; 2) it excludes women 
who have detrusor overactivity in the absence of sensory urgency; and 3) many women do not experience 
SUI or UUI based on these clear cut definitions.  Purely “objective” measures such as urodynamic 
evaluation (UDE) also do not provide a clear and consistent definition. Further complicating the issue is the 
lack of consensus and evidence regarding the pathophysiology of MUI. Some experts argue the two 
conditions should be considered as having completely different pathological processes,12 whereas others 
argue that at least in a subset of women, they are directly linked (e.g. proximal urethral funneling causing 
detrusor overactivity). 
 
Brubaker et al and the Urinary Incontinence Treatment Network (UITN) attempted to develop an 
empirically derived definition of MUI in 2009.10 Using data from the Stress Incontinence Surgical Treatment 
Efficacy Trial (SISTEr trial), a randomized trial comparing fascial sling to Burch colposuspension,17 the 
investigators used a series of regressions and attempted to define cut-off values for a variety of 
standardized measures that could predict clinical outcomes. Standardized measures included the Medical, 
Epidemiologic and Social Aspects of Aging (MESA),18 the Urogenital Distress Inventory (UDI),2 urodynamic 
studies and a 3-day urinary diary. The investigators created threshold definitions using the MESA (which 
measures the frequency of SUI and/or UUI), the UDI (which measures the presence and degree of bother 
for SUI and UUI), and UDE (defined as presence of urodynamic SUI and detrusor overactivity with or 
without associated leakage). These definitions were evaluated against the trial’s clinical outcome, a 
composite outcome divided into SUI success (negative cough stress test, no SUI re-treatment, and negative 
MESA SUI) and overall success (stress criteria plus no leakage on diary or pad test). After testing 12 
different definitions for MUI, the authors were unable to identify a definition that could accurately reflect 
clinical outcomes and proposed that both subcomponents of SUI and UUI should be individually described 
instead of using a one-dimensional descriptor. One limitation is that the SISTEr trial included only women 
with pure SUI or stress-predominant MUI. 
 
 
In a second attempt, Brubaker et al used data from the UITN Behavior Enhances Drug Reduction of 
Incontinence (BE-DRI) to again explore operational definitions of MUI, using various thresholds and 
combinations of the MESA, UDI and 7-day voiding diary.19 They were unable to identify strict cut-off values 
for any of these baseline measures that could predict the study’s primary outcome (success defined as a 
70% reduction in incontinence episodes). Because of this, the authors again recommended using distinct 
descriptions of both urgency and stress subcomponents when characterizing subjects with MUI until better 
definitions are developed. One limitation is that the BE-DRI population included primarily women with urge-
predominant MUI.  
 
2.3. Current treatment strategies for MUI: Challenges and old assumptions 
 
Based on expert opinion, the primary treatment strategy for MUI typically begins with segregation of 
symptoms and focus on the most bothersome symptom (SUI vs UUI).  Although many women may clearly 
have one condition that is more bothersome, many have equally bothersome symptoms, or cannot 
determine which condition is “most bothersome”. Behavioral/pelvic floor therapy (BPTx) has been shown to 
be effective for all types of incontinence20, and some experts suggest that BPTx should be the first 
treatment for MUI, regardless of which symptom is more bothersome because it is minimally invasive. Other 
authors support the first-line use of anti-muscarinics for MUI, despite that the improvement over placebo 

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has been shown to be only modest,21 side effects are common, and discontinuation is high, ranging from 
43%-83% within the first 30 days of initial prescription.22   
 
  
 
Although intuitively it makes sense that non-surgical options should be offered first, these 
recommendations are based on the following assumptions for MUI:  
 
1. OAB and SUI are separate and unrelated conditions  
 
-There is some evidence to suggest that at least in a subset of women, these 2 conditions may be 
related (proximal urethral funneling causing detrusor overactivity) 
 
2. Treatment should always be initiated in a stepwise, sequential fashion 
 
-There has been little evidence evaluating the potential benefit of combined treatments, and thus the 
old paradigm of following stepwise treatment remains unproven 
 
3. Surgical treatment should be reserved for women with SUI-predominant MUI because it will 
worsen OAB symptoms 
 
-Most studies suggesting worsening of OAB symptoms included traditional bladder neck slings and 
colposuspension and not MUS 
 
4. All women would prefer to take long-term medications over undergoing a surgical intervention  
 
-Adherence to anticholinergics is poor 
 
 
Clinically, many women with MUI become dissatisfied with conservative treatment and/or the need to take a 
medication long-term. In practice, there can be much “cross-over” due to patient dissatisfaction when the 
outcomes of treatment are focused on only one symptom. Many women with “urge-predominant” MUI who 
have tried BPTx and/or anti-muscarinic therapy will go on to choose surgical treatment for SUI after 
becoming dissatisfied with the results. Women with equally bothersome OAB and SUI components 
commonly choose surgery, with or without a trial of BPTx.  This “traditional” treatment paradigm for MUI has 
not resulted to significant advances and we are now challenged to consider new paradigms for MUI.   
 
2.4. Behavioral/pelvic floor muscle therapy (BPTx) 
 
BPTx includes 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. A recent Cochrane review of pelvic 
floor muscle exercise found that these treatments were effective for both SUI and MUI compared to placebo 
or no treatment, but women with pure SUI may have better outcomes.20 The UITN study BE-DRI by Burgio 
et al evaluated whether combined anti-muscarinic therapy with behavioral therapy would increase the 
number of women who could discontinue drug therapy while sustaining a significant reduction in UUI.23 BE-
DRI included women with pure UUI or UUI-predominant MUI. Although the addition of behavioral therapy 
did not improve drug therapy discontinuation, the study found that the combination of behavioral training 
and drug therapy yielded improved urinary outcomes compared to drug therapy alone. Specific to the MUI 
population, there is a paucity of literature evaluating whether combined therapies including BPTx that are 
designed to simultaneously treat both components (bothersome SUI and bothersome UUI) will improve a 
patient’s outcome and perception of her condition.      
 
2.5. Anti-incontinence surgical treatment outcomes in women with MUI 
 
Although “traditional teaching” is that women with MUI should not undergo anti-incontinence surgery 
for SUI due to potential risk of worsening OAB, this is not supported by recent literature for MUS outcomes.  
There continues to be accumulating evidence regarding the efficacy of midurethral sling (MUS) for the 
treatment of MUI (See Table 1). The MUS has proven to be highly effective for SUI treatment with cure 
rates up to 80% at 1 year24 and there is more recent evidence supporting improved OAB outcomes also.
 
 

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A systematic review by Jain et al in 2011 including six randomized trials and seven prospective 
studies reported that the overall cure rate of urgency and the UUI component of MUI after MUS was 30-
85% at a follow-up of a few months to 5 years.25  Whether authors consider MUS to be helpful or hurtful for 
MUI often depends on the point of view of a paper, and may also be highly dependent on the definitions 
used to define “persistent OAB.”  Some studies report that more than 50% of women with MUI experience 
complete resolution or improvement of OAB symptoms after MUS treatment.26 However, other studies 
report that MUI is a risk factor for failure of both SUI and OAB outcomes27 or that MUS may exacerbate 
OAB symptoms. One study reported a failure rate of 42% compared to 12% for SUI outcomes in women 
with baseline MUI compared to those with SUI alone.28  Whether there may be specific patient 
characteristics that are associated with resolution or exacerbation of OAB symptoms also remains unclear. 
 
The Trial of Mid-Urethral Slings (TOMUS) by Richter et al for the UITN randomized 597 women with 
pure SUI or SUI-predominant MUI (based on MESA scores) to retropubic versus transobturator MUS.24  
Success was a composite outcome, defined as: 1) negative CST; 2) negative pad test; 3) no retreatment for 
SUI; 4) no self-reported leakage on 3-day voiding diary; 4) no self-reported SUI symptoms; 5) no self-
reported retreatment of SUI. At baseline, 70/589 (12%) had detrusor overactivity on UDE, but overall mean 
urge scores on MESA were low (5.9-6.6 + 4 points). One year postoperatively, 11% had persistent UUI 
(defined as any MESA urge item response of “sometimes” or “often” or post-operative initiation of anti-
muscarinic treatment for UUI).  The rate of de novo UUI was 1/597 (0.002%). The UDI-irritative subscale 
scores improved from a mean of 41.2 (25.4), to 9.2 (15.2), and 8.9 (15.1) at baseline, 6 and 12 months, 
respectively suggesting improvement in OAB symptoms (unpublished data, personal communication). 
Higher baseline MESA urge scores increased the risk of overall (objective and subjective) sling failure.29 In 
a planned secondary analysis evaluating UDE predictors, detrusor overactivity on preoperative UDE was 
not a risk factor for objective or subjective failure.30  
 
Barber et al performed a second trial also comparing retropubic versus transobturator MUS for 
SUI.27, 31 Although women with baseline detrusor overactivity were excluded, 71% had baseline UUI based 
on the UUI item on the PFDI-20 questionnaire32.  At 1 year postoperative 31% of women reported 
bothersome UUI and 4-10% had new or worsened UUI. 45% of women were failures, defined as a 
composite outcome of “abnormal bladder function” defined as: 1) incontinence symptoms of any type; 2) 
positive CST; 3) retreatment for SUI; 4) postoperative urinary retention.  Overall, 79% reported Patient-
Global Impression of Improvement3 (PGI-I) scores as “much better/very much better”. The 2 UDI-irritative 
items in the UDI-6 (UUI and frequency) improved from a median of 3 points at baseline to 0 points at 12 
months, also suggesting improvement in OAB symptoms (unpublished data, personal communication). In a 
secondary analysis, baseline UUI was not a risk factor for recurrent UI 1 year postoperatively, but 
preoperative use of anti-muscarinic medications was. However, 53% (10/19) of women taking anti-
muscarinics at baseline were no longer taking them 1 year postoperatively.  
 
A secondary analysis by Palva et al of another randomized trial comparing retropubic versus 
transobturator MUS evaluated the prevalence of urinary urgency symptoms after MUS.33 In the original 
inclusion criteria, only women with a “detrusor instability score” < 7 (suggesting pure SUI) were included. 
However, the authors found that despite this inclusion criteria, a considerable proportion of women reported 
at least slightly bothersome urinary frequency and UUI on the UDI-6 (~75% reported urinary frequency and 
66% had UUI at baseline that was at least “somewhat bothersome”). At 36 months postoperatively, 51-60% 
were “cured” of urinary frequency and 73-75% were cured of UUI based on UDI-6 responses. The rate of de 
novo urgency was 3.1-4.5% at 12 months and 5.6-6.2% at 36 months. The authors go so far as to conclude 
that MUS “can be recommended in cases of mixed incontinence”. 
 
Abdel-fattah performed an RCT comparing two transobturator MUS including 341 women with pure 
SUI or SUI-predominant MUI. In a secondary analysis evaluating only the subset of women with urodynamic 
MUI, (n=83/341, 24%), 52% of women were cured of urgency, 23% had persistent urgency, and 25% had 
worsened urgency.34 58% were cured of UUI, 24% had persistent UUI, and 19% had worsened UUI at 12 
months postoperative.  At 12 months, 75% of women with MUI experienced overall “cure” of incontinence 
based on the PGI-I < 2, although in their original report of their primary trial findings, preoperative UUI was a 
risk factor for sling failure by PGI-I.35 

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In summary, recent secondary analyses of trials have suggested that over half of women may 
experience improvement and/or “cure” of OAB symptoms after MUS; however, to date there has not been a 
study focused on strategies to improve outcomes in women with MUI undergoing surgery. 
 
Table 1. Randomized trials reporting midurethral sling outcomes in women with MUI*† 
First 
Author 
No. 
Pts 
Inclusion 
criteria 
Primary 
objective 
% MUI at 
baseline  
Follow-
up 
% postop OAB 
and definition 
De novo 
OAB 
Other 
relevant 
findings 
Richter,24, 
29, 30 
597 
Pure SUI / SUI-
predom by 
MESA 
TVT vs 
TVT-O or 
Monarc  
-12% DO  
1 year 
10-12% persistent 
UUI (by MESA or 
treatment) 
0.002% 
New UUI  
-MESA urge 
score risk 
factor for 
failure 
-Baseline 
DO not risk 
factor 
 
Barber27, 
31 
170 
Urodynamic 
SUI and no DO 
TVT vs 
Monarc 
-71% UUI  
(PFDI) 
 
-14% 
preop 
anticholin 
1 year 
-31% UUI postop 
(PFDI) 
 
-4-10% new/worse 
UUI (PFDI)   
-16% anticholin 
postop 
4-10% 
New / 
worse UUI  
-79% “Cure” 
by PGI-I <2 
Palva33 
267 
Pure SUI / SUI-
predom by 
“detrusor 
instability 
score” 
 
TVT vs 
TVT-O 
-75% 
frequency 
(UDI) 
 
-66% UUI 
(UDI)  
1 year  
&  
3 year 
-1 year: 
22% frequency 
13% UUI (UDI) 
 
-3 years: 
36% frequency 
21% UUI  (UDI) 
-1 year: 
3-4.5% 
 
-3 years: 
5.6-6.2% 
-Only 
provides 
postop 
prevalence 
of sxs,  
-unclear % 
“persistent” 
or “cured” 
Abdel-
fattah34-36 
341 
 
Pure SUI / SUI-
predom 
(undefined) 
TVT-O vs 
ARIS  
-24% DO 
(N=83)  
 
-18% prior 
antimusc 
1 year 
By BBUSQ: 
-23% persistent 
urgency  
-25% worsening 
urgency 
 
-24% persistent 
UUI  
-19% worsened 
UUI 
-~25% worsened 
OAB taking 
anticholinergics 
4.3% UUI 
-52% Cure 
urgency 
-58% Cure 
UUI 
-75% “cure” 
by PGI-I < 2. 
 
 
*Excludes small, under-powered RCTs 
†TVT™ (Tension free-vaginal tape, Gynecare, Ethicon Inc); TVT-O™ (Gynecare TVT™ Obturator System, 
Ethicon Inc); Monarc™ (American Medical Systems, Inc), ARIS® (Transobturator Sling System, Coloplast 
Pty Ltd) 
 
2.6. Limitations of existing MUS trials for the MUI population 
 
The existing MUS RCT data are limited because they do not focus on women with MUI and the 
inclusion criteria almost always require one condition to be “predominant” or “more bothersome” (e.g. SUI-
predominant for most surgical trials and UUI-predominant for most medication trials). Thus, women with 
equally bothersome symptoms are typically excluded, or may feel pressured to “choose” a most bothersome 
condition in order to qualify for a trial. In addition, many MUS trials use a composite outcome to define 
failure (e.g. any self-reported incontinence or incontinence on diary) and therefore it is difficult to tease out 

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SUI and OAB outcomes separately, which is highly important when counseling a patient with MUI. Finally, 
ancillary studies from existing trials are underpowered to determine SUI and OAB outcomes separately.  
2.7. MIMOSA Trial: First Network trial attempt focused on MUI population 
 
In 2009 the UITN published on their experience with the “Mixed Incontinence: Medical or Surgical 
Approach” (MIMOSA) trial.37 MIMOSA was designed as a pragmatic clinical trial randomizing women to 
nonsurgical treatment (pharmacological therapy and behavioral therapy) versus surgical treatment (MUS 
including TVT, TOT, TVT-O, fascial sling and Burch). After 4-5 months of enrollment as a feasibility study, 
27 women were randomized out of 1190 women screened and the study was stopped due to low 
enrollment. The investigators felt recruitment was challenging at least in part due to the divergent treatment 
approaches, but also because of the practical trial design and strict inclusion criteria.  
Based on unpublished data from MIMOSA: of 24 women randomized with complete follow-up data 
at 6 months, 71% met criteria of optimal outcome (defined as score < 2 on PGI-I and a score of < 2 on PGI-
S), suggesting that surgical treatment may improve MUI symptoms at least in the short term. 
 
To avoid the challenges encountered in MIMOSA, the ESTEEM protocol team carefully designed 
our treatment to ensure a fair perception of treatment arms in an efficacy trial design, and carefully selected 
inclusion criteria that would not be overly strict, yet still allow recruitment of a MUI population (See Section 
4.2, Inclusion Criteria). 
2.8. Summary of known and potential risks and benefits of study treatment 
 
BPTx has been shown to be beneficial when used for the treatment of MUI. Other than time and 
effort commitment and potential discomfort from a pelvic exam, the risks of BPTx are extremely low. MUS 
has been shown to be an effective treatment for SUI, and recent evidence suggests possible benefit for MUI 
populations also. However, there are women with MUI who report persistent or worse UUI/OAB symptoms 
after MUS and this is one potential risk. The remaining risks of MUS are not expected to be different for the 
ESTEEM population compared to previous studies including pure-SUI or SUI-predominant MUI subjects. 
2.9. Significance of proposed study / Rationale for combined surgical and BPTx approach 
 
In summary, at least three gaps of knowledge contribute to the clinical challenge of treating women 
with MUI who desire SUI surgery. First, there is a lack of data to guide counseling on expected outcomes, 
particularly for the OAB component after MUS (what happens to OAB symptoms after MUS?). Second, 
while persistent / worsened OAB symptoms after surgery are associated with patient dissatisfaction, there 
have been essentially no trials evaluating how to best treat this component peri-operatively (how do we 
improve OAB outcomes after MUS? Can combined treatment improve outcomes for MUI?). Third, there is 
little data on what factors may increase the risk of MUS “failure” in this population (who should or should not 
get a MUS if they have MUI?).  ESTEEM will provide the needed information to address these gaps. 
 
Patients with MUI who ultimately elect surgery for SUI are often hopeful that their overall urinary 
condition will improve, but as surgeons we currently cannot assure patients this will be the outcome. 
Treatments that can optimize both OAB and SUI outcomes in this population are needed.  Studies have 
demonstrated potential clinical benefit of initiating perioperative physical therapy after other procedures  
including prostatectomy38, 39 and orthopedic procedures40.  Perioperative BPTx combined with MUS may 
have similar effects on improving OAB outcomes in women with  MUI. The index surgery may serve as a 
“teachable moment” that can be used to reinforce principles and adherence of BPTx to optimize outcomes, 
and/or an opportunity to affect postoperative tissue remodeling and neuromuscular dysfunction.   
2.10. Innovation 
 
This proposal is innovative for several reasons. First, it studies a population of women who are often 
excluded from clinical intervention trials but are at high risk for failing segregated SUI and UUI treatments. 
Second, in contrast to the historical paradigm of initiating treatments separately and stepwise for SUI and 
UUI, we will evaluate the effect of a combined surgical and non-surgical approach to optimize treatment 
outcomes.  Third, this study will provide critical information regarding OAB outcomes after MUS and will be 

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powered to allow reporting of OAB and SUI outcomes separately after treatment.  Finally, we will gain 
important predictive information regarding which patients may experience improvement, worsening, or no 
change in their OAB symptoms. At the completion of this study, we will understand whether a combined 
behavioral/surgical treatment approach is superior to surgery alone and will have predictive information that 
will be directly applicable to the clinical care of patients with this challenging condition.  
3. STUDY DESIGN  
3.1. Description of study design (See Figure 2, Study flow diagram) 
 
Figure 2. Study flow diagram 
 
 
 
ESTEEM is a 3-stage, 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. 
Stage 1: preoperative BPTx versus control  
Stage 2: All participants will undergo a MUS   
Stage 3: postoperative BPTx versus control  (based on initial randomization) 
MUI; surgery planned 
Consent/enrollment 
Baseline evaluation 
Randomization (N=472)  
Pre-operative BPTx  
(1 visit) 
Midurethral sling 
Midurethral sling 
Post-operative BPTx 
5 visits  
(2, 4, 6, 8 wks, 6 mo postop) 
Postoperative Assessments (Both groups): 
2, 8 wks: Clinic visit  
3 mo, 6 mo, 12 mo: Clinic visit, outcomes  
BPTx intervention 
Control 

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3.2 Masking issues 
 
It is not feasible to mask the patients or interventionists to the BPTx intervention due to the nature of 
the treatment being studied. The team considered “sham” visits with interventionists; however, based on 
expert interventionist opinion, sham interventions for UI involving the pelvic floor are extremely difficult to 
design in a way that is convincing yet maintains the integrity of the intervention itself. We also considered 
using “general massage” as a potential control group; however, there is some evidence suggesting that 
psychological stress is associated with OAB and irritative symptoms which could potentially contaminate the 
control group.41 Issues of adherence (or over-adherence) in the massage group are also possible, as 
women could schedule these independently from the study. For these reasons, the team decided it was not 
feasible to incorporate any sham procedures in the control group. 
 
Study surgeons and outcome assessors will be masked to treatment assignment. All outcome 
measures will be collected by masked outcome assessors. Study coordinators / clinical staff performing 
objective measurement of PFM strength will be masked (Aim 7).  All patient-reported outcomes (PROs) will 
be administered prior to other clinical assessments or procedures. 
 
Table 2. Masking in ESTEEM 
 
Study individual 
Masking 
Study participant 
No 
Interventionist 
No 
Outcome assessors 
(includes clinical staff 
performing PFM 
measurement) 
Yes 
Study surgeon 
Yes 
 
 
Efforts will be made by unmasked research assistant/staff members to remind the patient that the 
surgeon is masked to her treatment assignment. If she desires additional treatment, it is likely the surgeon 
would offer BPTx as additional treatment and she will be reminded that she can decline additional BPTx 
without revealing to her surgeon that she received the BPTx intervention. Such methods have been 
effective for past PFDN trials (e.g. OPTIMAL trial42).  
3.3. Randomization and Stratification  
Patients will be assigned to one of the two treatment groups with a randomization sequence 
prepared and maintained centrally by the Data Coordinating Center (DCC). Allocation to the treatment 
groups will be 1:1. Randomly ordered permuted blocks will be used, with block sizes known only by the 
DCC. The web-based data management system will provide the treatment assignment for each participant 
as she is randomized. Thus, the allocation sequence will be concealed from clinical site staff.  
Randomization will be stratified by clinical site. It is important that UUI “severity” is comparable in 
both groups as it is a potential risk factor for treatment failure. Therefore, randomization will also be 
stratified based on UUI “severity” which will be defined by the number of urgency urinary incontinence 
episodes (IEs) on diary. This will ensure that women who have more frequent, or more “severe” UUI are 
equally distributed between the two groups. SUI severity is less of an issue because all subjects will be 
receiving the same treatment for SUI.  
 
Burgio et al,43 identified risk factors for unsuccessful behavioral treatment of urge/urge-predominant 
MUI.  Women who had >10 IE/week on a 7-day diary diary at baseline were much less likely to be 
completely continent after behavioral treatment. Therefore, for a 3-day diary, this would translate into ~4 IEs 
on a 3-day diary as a potential risk factor for treatment failure.  

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There is limited data to support stratification based on presence of preoperative DO on UDE.  One 
study found that up to 38% will have resolution of DO after MUS.44  Other studies suggest that baseline DO 
is a risk factor for postoperative UUI.45 Still other studies even suggest that baseline DO is associated with 
greater improvement in OAB symptoms postoperatively. Choe et al evaluated 132 women with MUI who 
underwent MUS and found a higher proportion of women with preoperative DO had complete resolution of 
OAB symptoms postoperatively compared to those without DO (37% vs. 18%).46 A secondary analysis of 
TOMUS data supported that more severe UUI (by MESA score) was a risk factor for non-SUI sling failure 
after MUS (or failure due to UUI);29 however, baseline DO was not a risk factor (28% vs 21% objective 
failure for women with and without DO, respectively).30  
 
Based on the existing evidence, the team reached consensus that women should be stratified based 
on a cutoff of > 4 urge IEs on 3-day diary. The team agreed that there was insufficient data regarding 
preoperative DO to stratify by this variable; however, this data will be collected for exploratory analyses.  
 
3.4. Outcomes  
 
Figure 3. ESTEEM outcomes 
 
 
3.4.1. Detailed Description of Primary Study Outcome 
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. A PRO is 
a measurement of any aspect of a patient’s health status that comes directly from the patient (without 
interpretation by the physician, researcher, other). In clinical trials, symptom indices and quality of life PRO 
instruments are being increasingly used as primary outcomes and supported by federal agencies.37, 47, 48  
The long form of the UDI is a 19 item, validated UI symptom specific questionnaire with 3 subscales: 
stress, irritative, and obstructive symptoms.2  Higher scores represent more severe disease or bother from 
the patient perspective. Construct validity (convergent) was originally established by demonstrating 
significant correlation between the overall UDI and its subscale scores with the number of IEs on 7-day 
diary and pad tests. Criterion validity was established by correlating total and subscale scores with 
physician diagnoses. The UDI can effectively discriminate between known UI clinical groups and diagnoses 
(specifically genuine SUI, urodynamic detrusor overactivity, or mixed) and is responsive to change. These 
are some minimum qualities needed for valid interpretation of a PRO in a clinical trial. 
Although it is fairly simple to determine the statistical significance of a change in a symptom index, 
placing the magnitude of these changes in a context that is meaningful for patients is more difficult. The 
 
Aims  
 
 
 
 
 
 
 
Outcomes 
 
Primary Aim  
 
 
 
 
 
 
Primary  
Treatment of MUI symptoms  
 
 
 
 
Total MUI symptom score (UDI) 
 
Secondary Aims 
 
 
 
 
 
 
Secondary 
Other urinary treatment benefits 
 
 
 
 
OAB symptoms (UDI-irritative) 
 
 
 
 
 
 
 
 
 
SUI symptoms (UDI-stress) 
 
Exploratory Aims 
 
 
 
 
 
 
Exploratory 
Other potential treatment benefits 
 
 
 
 
Diary 
 
 
 
 
 
 
 
 
 
Quality of life, global impression 
 
 
 
 
 
 
 
 
 
Need for additional treatments 
 
 
 
 
 
 
 
 
 
Time to failure 
 
 
 
 
 
 
 
 
 

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minimum important difference (MID) of a measure is a score change that should reflect a clinically 
meaningful response to treatment and represents the “between group criterion” that needs to be met or 
exceeded in order for study results to be considered clinically meaningful. From the patient perspective, 
MID can be defined as “the smallest difference in score in the domain of interest which patients perceive as 
beneficial...” 49 It is useful for interpreting questionnaire results for both within-group and between-group 
differences and represents the magnitude of benefit for which trials should be powered to minimize type 1 
and type 2 errors. Although no single approach to determine MID is perfect, a combination of approaches is 
often used to determine a reasonable range of MID scores. Importantly, there are published MID ranges for 
the total UDI score and its subscales for urge predominant and pure stress/stress predominant urinary 
incontinence populations. 
Table 3 summarizes the relevant published MID data for the UDI. Dyer et al used the BE-DRI study 
population to determine MID values for the UDI and UDI-irritative subscale.50  The BE-DRI population 
included 94% subjects with urge-predominant MUI based on bladder diary with a baseline mean UDI total 
score of 120 (49) points and UDI-irritative subscale score of 58 (22) points.  Using anchor based methods, 
the authors recommend an MID of -35 for total UDI and -15 for UDI-irritative scores for this population. 
Barber et al used the Ambulatory Treatments for Leakage Associated with Stress Incontinence Trial 
(ATLAS) study population and determined MID values for the UDI total and UDI–stress subscales.51 This 
population was pure/stress-predominant MUI, undergoing conservative treatment for SUI. The baseline 
mean UDI score was lower at 80 (40) points and UDI-stress was 47 (19) points. Based on their findings, the 
authors recommend an MID of -11 and -8 for the UDI total and stress subscale scores respectively. 
 
Table 3. Published MIDs for the Urogenital Distress Inventory 
 
Trial/Author 
Population 
Endpoint/ 
intervention 
UDI 
component 
Anchor-based 
MID 
Distribution-
based MID 
(1/2 SD) 
Recommended 
MID 
BE-DRI, 
Dyer50 
Pure urge/Urge-
predominant MUI 
8 month 
Meds +/- 
BPTx 
UDI-total 
 
-45 to -36 
-25 
-35 
UDI-irritative 
-20 to -18 
-11 
-15 
ATLAS, 
Barber51 
Pure SUI/SUI 
predominant MUI 
3 month 
Pessary vs 
BPTx vs both 
UDI-total 
-22.6 to -6.4 
-21.9 to -18.8 
-11 
UDI-stress 
-16.5 to -4.6 
-10.6 to -9.1 
-8 
 
 
 
Published MIDs are important for estimating sample size and interpreting findings, however there are at 
least 3 different ways we can analyze the UDI scores: 
 
#1. Compare postoperative mean UDI scores between groups at 1 year 
 
#2. Compare mean changes (delta) in UDI scores from baseline to 1-year between groups 
(preferred, see below) 
#3. Dichotomize “success” and “failure” as women who achieved a 35 point improvement versus 
those who did not (also known as “responder analysis”) 
 
 
We chose not to dichotomize our outcome for many reasons (option #3). Dichotomizing women as 
“success” or “failure” based on MID could simplify interpretation; however, using purely a responder 
analysis approach has limitations and some authors recommend avoiding this for primary analyses in 
trials.52 One disadvantage of responder analysis is reduced power and efficiency compared to analysis on 
the original scale, primarily due to the loss of information associated with lumping groups together.  
Particularly relevant to ESTEEM, some women could have worse scores compared to baseline and this 
information would be lost because they would be grouped with those who may have “slightly” improved, but 

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just not enough to be classified as a “success”. Also relevant to ESTEEM, if both groups worsened but one 
group “worsened less”, this information would also be lost using this approach. 
 
Because the trial is randomized and we will be stratifying by UUI severity, we would expect the 
baseline UDI scores to be similar between groups. If the average baseline score is the same in the two 
groups, then comparing  the mean change in UDI score between groups (option #2) is mathematically 
equivalent to comparing post-operative UDI scores at 1 year between groups (option #1). However, option 
#2 has some advantages in that (1) if baseline scores are not the same in the two groups, comparing the 
mean change in UDI score between groups at 12 months will account for that baseline difference, and (2) 
UDI scores typically have a distribution that is highly skewed, but differences from baseline should be close 
enough to being normally distributed that analysis methods that assume a normal distribution can be used.   
3.4.1.a Rationale for using UDI as primary study outcome 
Due to limitations in how to best define successful treatment of MUI, the investigators had extensive 
discussion around whether an objective, subjective, or composite outcome would be best for this trial. The 
team agreed that the primary outcome must remain true to the clinical question and be clinically relevant in 
capturing both potential benefit and harm of both the control and the intervention for this trial.  It is critical 
that the outcome is meaningful from the patient perspective and will be able to capture OAB improvement, 
worsening, or no change in symptoms. The team discussed using bladder diary, patient global impression, 
or OAB PROs. Arguments against each of these were based on the following rationale: 
 
1. Problems with using bladder diary as primary outcome:  
a. Diary does not capture a meaningful patient outcome- It is becoming clear that typical clinical trial 
endpoints such as reduction in IEs, voided volumes, etc do not capture what is meaningful to patients. 
Counting IEs on diary likely does not capture what is important to a patient (e.g. having 3 large urge leaks a 
day may be more bothersome than having 20 small stress leaks or having 20 urgency associated voids may 
be more bothersome than having 1 UUI episode). In addition, diary IEs do not correlate perfectly with 
patient satisfaction.53 Finally, bladder diaries have been shown to be less reliable in women with MUI, 
particularly for the SUI component.54 
b. Diary cutoffs to define improvement for MUI are unknown-What percent improvement for the SUI 
component and for the UUI component is clinically important for a woman with MUI? Any cutoffs chosen 
would be arbitrary.  
c. Using IEs on bladder diary as a primary outcome would require a minimum number of IEs 
(approximately 3-4 IE/3days) at baseline to be able to detect a change. The protocol team felt that setting 
such strict inclusion criteria would be too limiting to allow recruitment of a good range of MUI severity (see 
Inclusion Criteria, Section 4.2).  
For all of these reasons, the team decided against using bladder diary IEs as the primary outcome 
and to instead focus on measures that can capture outcomes from the patient perspective. 
 
2. Problems with using global impression measure as primary outcome 
A patient’s overall/global impression of improvement would be reflective of her overall urinary 
condition. Although this outcome would seemingly be ideal for capturing a meaningful outcome, for our trial 
it could potentially introduce bias. Because it is not feasible to mask subjects in ESTEEM to the intervention 
(BPTx), a single, subjective global impression item would be subject to bias. For example, if subjects in the 
control group were more likely to ask for additional treatment and report they were not “improved” because 
they knew there was another potential treatment available that they did not receive, this would bias our 
study towards a higher failure rate in the control group (making our intervention seem more effective than it 
really is). The challenges of masking or designing a sham procedure for the control group for ESTEEM have 
already been noted above (Section 3.2). 
 
3. Problems with using OAB PRO measure as primary outcome 

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Finally, we considered using an OAB PRO as the primary outcome, such as the Overactive Bladder 
Questionnaire (OAB-q)55 or the UDI-irritative subscale.  However, these do not account for SUI symptoms, 
which are part of the MUI symptom constellation. In addition, it is still unclear whether patients with MUI are 
at risk of sling failure for SUI and at least 2 studies suggest this may be the case.27, 28 Finally, there are 
some women with MUI who may not be able to clearly distinguish all UI episodes as stress- or urge- related 
and the team felt it would be important to also capture these symptoms. Finally, specifically regarding the 
OAB-q, there is less validity data in a MUI population compared to the UDI. 
 
For all of these reasons, using the UDI as the primary outcome is ideal and it has all of the 
characteristics that are important for a MUI population: 
1. The overall UDI score includes both a stress and irritative subscale, allowing us to 
comprehensively capture both SUI and OAB symptom outcomes. 
2. It captures a meaningful outcome from the patient perspective, incorporating both the presence 
and bother of SUI and OAB symptoms.  
3. It includes 3 UI items that are not necessarily specific to stress or urge and thus can help capture 
UI episodes for which patients cannot clearly distinguish as SUI or UUI. 
4. It can capture both improvement and worsening of preexisting symptoms, but also the 
development of new urinary symptoms.56 
 
Because MUI includes both SUI and UUI, it is important to be able to report SUI and OAB outcomes 
separately. There is no clinical rationale for assuming that one component, or that one subscale of the UDI 
is more important to women than another. Therefore, the UDI-stress subscale and UDI-irritative subscale 
will be important secondary outcomes for which ESTEEM will be powered to detect differences and each 
will have a priori analysis plans (see Section 6, Statistical Considerations).  
3.4.1.b. Rationale for timing of primary outcome: 
 
There was significant discussion regarding the best timing for the primary outcome. In framing this 
question, the group considered at which time-point would a difference in outcome lead to recommendation 
of BPTx as part of clinical practice. Long-term outcomes of 1 year and/or more are “standard” for surgical 
trials and are important to determine if a surgical treatment is worthwhile. However, outcomes for BPTx 
trials are often shorter, between 3-6 months and there was concern that longer time points may miss 
improvements which may not be sustained over time.  Clinically, women with MUI who ultimately have 
persistent OAB symptoms seem to experience a re-occurrence of these symptoms within 3-6 months of the 
index MUS surgery and therefore, many investigators felt it was important for the outcome to be at least 6 
months or greater.  
 
Based on these considerations, the primary outcome will be the change in UDI score from baseline 
and 12 months postoperative, given the intervention is the combination of BPTx and surgery, with Time 0 = 
the time of surgery. Note that if a participant is randomized but surgery is not performed, then Time 0 will be 
the planned surgery date. A secondary outcome will include time to failure; therefore, we will be able to 
detect any potential early differences that are not sustained at 12 months (See Section 6, Statistical 
Analysis). Additional assessments will be made at 3 and 6 months postoperatively, which will allow for 
shorter-term assessments of BPTx effects.  
 
3.4.1.c. Management of subjects who request additional treatment for SUI and/or OAB after MUS: 
 
The overarching goal of ESTEEM is to evaluate the effect of combined treatment on improving both 
SUI and UUI outcomes in women with MUI. Therefore, any request for additional treatment for any lower 
urinary tract symptoms (SUI, UUI/OAB, voiding dysfunction) before the 1 year outcome for either of these 
symptoms will be considered treatment failure.  The team agreed it would be difficult to withhold additional 
treatment from either group for the 1 year study duration; however, any additional treatment should be 
initiated after the acute postoperative recovery period. Clinically, some women may experience immediate 

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exacerbation of OAB symptoms after MUS followed by improvement, whereas other women may 
experience initial improvement but then recurrence of OAB symptoms several months later. Therefore, the 
team came to a consensus that any additional treatment should be deferred until 3 months postoperatively 
when OAB symptoms would be expected to have reached a baseline. This will allow enough time for 
complete physical and tissue recovery from the surgical procedure, will allow for assessment of potential 
BPTx early benefits, and will provide information on the natural course of OAB symptoms in the early 
postoperative period which is important for clinical counseling and decision-making. Any subjects receiving 
additional treatment prior to the 3 month time point will be considered a protocol deviation. 
In the event that a randomized participant decides not to undergo surgery but then later changes her 
mind and has MUS surgery, the surgery will be considered additional treatment. For purposes of calculating 
follow up windows, the date of the original planned surgery that did not occur will be Time 0.  
Subjects who initiate additional treatment will be asked to complete all primary and secondary 
outcome measures prior to initiation of additional treatment. The type of additional treatment will not be 
limited and will be left to the physician’s clinical judgment. This may include (but is not limited to) behavioral 
and/or pelvic floor therapy, continence pessary, medical therapy, other procedure-based treatments 
(posterior tibial nerve stimulation, Botox), and surgical (sling revision, re-placement, sacral 
neuromodulation). Statistical models designed to specifically account for subjects who initiate additional 
treatment will be used. Please see Section 6, Statistical Considerations section for details on how the 
analysis of primary and secondary outcomes measured at 1 year will account for any additional treatment 
requests for SUI and/or OAB if initiated prior to the 1 year time point.  
 
3.4.2. Secondary outcomes 
Consistent with Brubaker et al who emphasized the importance of characterizing the OAB and SUI 
components separately for MUI populations, we will ensure adequate power of our trial to detect differences 
in OAB and SUI symptom outcomes separately. 
 
3.4.2.a. Urge urinary incontinence/overactive bladder symptom outcomes 
Because the primary clinical problem in this population is the potential for persistent or worsening 
OAB after MUS, it is highly important to capture and report on the cardinal symptoms of OAB from the 
patient perspective. The UDI-irritative subscale measures symptom burden, impact, and changes related to 
OAB which are important aspects that cannot be directly observed or otherwise measured. 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. 
Particularly for ESTEEM, this comprehensive OAB measure will be important to understanding how MUS 
may affect all OAB symptoms individually and as a whole.  
 
3.4.2.b. Stress urinary incontinence symptom outcomes 
 
It is also important to be able to report on SUI outcomes separately. The majority of studies have not 
demonstrated significant differences in efficacy for SUI outcomes for subjects who had MUI preoperatively; 
however the majority of studies only had small subsets of women with MUI. Two studies have suggested 
worse SUI outcomes in women with MUI at baseline (see section 2.4 above). One study by Paick et al 
evaluated 274 women, of which 73 had MUI and reported cure rates for SUI to be 78% for the MUI group 
and 95% for the pure SUI group.57 They also reported that maximal urethral pressure at baseline was 
associated with a greater risk of persistent OAB, suggesting the possibility that profound urethral 
dysfunction may contribute to persistent symptoms. A study by Gleason et al using data from the University 
of Alabama including 534 women with MUS found that women with MUI had higher rates of SUI compared 
to women with SUI only (36% vs 16%, p<.001) with an adjusted OR = 2.7 (95% CI 1.7, 4.2) (unpublished 
data). In addition, because BPTx can also treat SUI, it is important to know if women randomized to 

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MUS+BPTx have improved SUI symptom outcomes as well. Therefore, as a secondary outcome, we will 
also compare SUI outcomes between women randomized to MUS + BPTx versus MUS alone. SUI 
symptoms will be measured using the UDI-stress subscale.  
3.4.3. Other outcomes 
3.4.3.a. Other UUI/OAB outcomes 
i. Bladder diary – We will assess the change in IE frequency and type, number of urgency episodes, 
urgency severity with voids, number of diurnal voids, and number of nocturnal voids and compare these 
variables between groups at 6 months and 1 year.  
 
ii. Overactive Bladder treatment satisfaction (OAB-SAT-q)58-The OAB-SAT-q is an 11 item 
instrument designed to assess patient satisfaction with treatment in a clinical setting. There are three 3-item 
subscales (Satisfaction, Side Effects, Endorsement) and two single items (Convenience, Preference). 
Response options are presented on 4-, 5-, and 6-point Likert scales. It has demonstrated good 
psychometric properties in OAB/UUI patients receiving anticholinergic and anticholinergic + behavioral 
therapies. We will compare change from baseline in OAB-SAT-q scores at 6 months and 1 year between 
treatment groups. 
 
iii.  Overactive Bladder Questionnaire-Symptom subscale (OAB-q) – The OAB-q is a validated, 
responsive questionnaire that includes 8 symptom bother items (SS) and 25 health related quality of life 
(HRQOL) items of 4 subscales (coping, concern, sleep, and social interaction).55 In a systematic review of 
UI questionnaires by Avery et al, the OAB-q was rated as “grade A”, highest recommendation specifically 
for OAB symptoms.59  Each item is rated on a 6-point Likert scale ranging from “not at all bothered” to “a 
very great deal bothered” for symptom items and “none of the time” to “all of the time” for HRQOL items. 
Subscales are summed and transformed into scores ranging from 0-100 with higher bother scores 
indicating increasing symptom bother and higher HRQOL scores indicating better quality of life.60,61 We will 
compare change from baseline in OAB-q scores at 6 months and 1 year between treatment groups. 
 
3.4.3.b. Time to failure 
 
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.  
 
 
3.4.3.c. Quality of life/global impression 
We will compare change from baseline in the scores below at 6 months and 1 year between treatment 
groups. 
 
a) Incontinence Impact Questionnaire (IIQ) 
 
b) Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ) 62 
 
c) European Quality of Life-5 Dimensions (EQ-5D)63 
 
d) Adaptation Index 
 
e) Patient Global Impression of Improvement (PGI-I)3 and Patient Global Impression of Severity 
 
(PGI-S)3:  
 
3.4.3.d. Safety/additional treatment 
 
a) additional re-treatments for SUI or UUI within 12 months of treatment, and type of re-treatment 
 
b) return to OR for sling revision due to worsened OAB symptoms  
 

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3.4.3.e. Pelvic floor muscle (PFM) strength 
 
PFM strength has traditionally been measured subjectively by a clinician or interventionist using the 
Brink score in many previous studies, including Network studies. However, because this is a subjective 
measure, it may be subject to bias. Although there are many trials showing symptom improvement with 
pelvic floor therapy20, there are limited studies evaluating the association between PFM strength and 
improvements in UI symptoms. To contribute to the literature about this issue, in ESTEEM we will 
objectively assess PFM strength changes using the Peritron Perineometer. Peritron is an advanced 
pressure biofeedback perineometer specifically designed for pelvic floor assessment. Pelvic floor muscle 
contraction creates pressure in the sensor that is transferred and displayed on a “Readout Unit” which is 
small and handheld.  
 
 
FIGURE 4. Peritron Perineometer 
 
Example: Peritron 9300 Device (www.win-health.com/perineomter.html) 
 
After a thorough search of the literature and discussion with other experts in the field, the protocol 
investigators concluded that the Peritron device has adequate evidence to support its validity, including test-
retest reliability and inter-rater reliability, for both baseline and maximum contraction pressure 
measurements. In addition, studies support its reliability in “normal”, continent controls as well as women 
with UI. 
Studies evaluating the Peritron’s reliability properties are in Table 4. A study by Hundley et al 
supports the reliability of measurements from this device in postmenopausal, parous women (inter-rater 
reliability for baseline and maximum pressure 0.78 to 0.88).64  This is supported in normative women as well 
(correlation r=0.83).65 The Peritron device provides a potential method of determining an objective measure 
of PFM strength.  Measurement using the Peritron device will be standardized and Principal Investigators at 
each site will be trained on how to use the device and will be responsible for training their clinical staff and 
for quality assurance of Peritron use. Clinical staff performing the Peritron measurements will be masked to 
the intervention the subject received. PFM measures (Maximum squeeze amplitude and duration of 
squeeze), will be performed at baseline, at the first post-operative visit after surgery (2 weeks), 8 weeks, 
and at the primary endpoint (12 months) – See Assessment Table 11. Changes in squeeze measures from 
baseline at 8 weeks and 12 months will be compared between treatment groups. 
 
 
 
 
 
 
 

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Table 4. Validity properties of Peritron device 
 
 
 
Author 
(year) 
N 
Subject 
characteristics 
 Study aims 
Peritron Findings 
Kerschan-
Schindal et al 
(2002)66 
37 
 
 
Postmenopausal 
all with UI 
(28 SUI; 5 UUI; 4 
MUI) 
 
 
1. To examine the test-
retest reliability of several 
PFM  measures.  
 
2. To correlate findings 
between different 
measures. 
Peritron Reliability: 
-ICC for max contraction = 0.97 
-ICC for mean contraction over 5 
seconds = 0.95 
-Correlation between max force and 
mean contraction force over 5s =  r 
=0.95. 
Correlations with other measures: 
- urine stop test r = 0.88 max force  
- digital exam r = 0.70 max force 
- pad tests r = -0.33 and -0.28 for max  
Hundley et al 
(2005)64 
100  
Mean age 48 (22 to 
85) yrs 
 
46% 
postmenopausal 
 
1.To compare Brink 
scores with Peritron 
measurement 
 
2. Determine intra- and 
inter-rater reliability for the 
Peritron. 
Peritron Reliability: 
-Interrater reliability max pressure, r = 
0.88 
Brink Reliability: 
-Interrater Brink for total score = 0.68, 
pressure = 0.68, vertical displacement = 
0.58, and squeeze duration = 0.44 
Correlations with other measures: 
- Brink pressure r =0.67  
Bo et al, 200565 
20  
“Normals” 
PT students 
Mean age 25.1 (21-
38) yrs. 
To assess whether max 
vaginal squeeze pressure 
differed when measured 
with 2 different sized 
probes. 
Peritron Reliability: 
Test-retest: r2 = 0.83  
Frawley et al 
(2006)67 
20  
19 female PT (1 
unable to contract) 
 
Age range 25-65 
yrs 
 
 
Some parous 
subjects reported 
mild UI and/or 
prolapse 
1. To determine the intra-
therapist reliability for 
digital muscle testing and 
vaginal manometry on 
max voluntary contraction 
and endurance. 
 
2. To establish how 
reliability varied with 
different tools and different 
testing positions. 
Peritron Reliability: 
-Test-retest for Max pressure: r=0.91 to 
0.96 across positions (supine lowest at 
0.91). 
-pressure endurance r=0.05 to 0.41with 
hooklying the lowest 
Rahmani et al 
(2009)68 
15 
20-50 yrs 
1. Test-retest reliability 
Peritron Reliability: 
-Test-retest (same day) Max pressure: 
ICC=.95 
-Test-retest (same day) Endurance: 
ICC=.94 
-Test-retest (between-days) Max 
pressure: ICC=.88 
-Test-retest (between day) Endurance: 
ICC=.83 
 
 
 
3.4.3.f. Cost-effectiveness outcomes 
The cost-effectiveness analysis will be conducted from a societal perspective and will be expressed as 
incremental cost required to produce one additional unit of quality-adjusted life year (QALY). Data on each 
subject’s use of medical and non-medical resources, related to urinary incontinence will be collected during 

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the follow up period. Direct and indirect costs of the treatment of urinary incontinence with combined 
midurethral sling (MUS) and peri-operative behavioral/pelvic floor therapy (BPTx) compared to MUS alone 
and women’s preference for health states for improvement in urinary incontinence will be estimated.  
We plan to capture incremental direct health care, direct non-medical, and indirect resource use related to 
study interventions and complications and other urinary incontinence management (such as other UI 
treatment, UI products and management of side effects).  Costs will be estimated using the resource costing 
method.   Direct medical service use collected from each study case report form and direct non-medical and 
indirect costs collected from patient questionnaires are monetized by multiplying the number of units of each 
resource use by the average unit cost of this item in dollars. Detailed individual cost data will not be 
collected.  This method allows a consistent capture of resource use when costs are incurred across multiple 
health systems or payers. Detailed case report forms, that include the interventions performed (e.g. 
midurethral sling surgery and behavioral/pelvic floor therapy sessions) and clinical events (e.g. 
complications and additional treatment) will be completed by the study coordinator at study visits. Patient 
questionnaire on direct non-medical costs (e.g. pads, laundry) and indirect costs (e.g. time, lost productivity) 
will be completed at study visits 3, 6  and 12 months.  Data from medical resource types (physician visits, 
behavioral/pelvic floor therapy sessions, medications, hospital admissions and emergency room visits) will 
be collected. Cost for each direct medical service use, direct non-medical items, and indirect items will be 
assigned based on national Medicare reimbursement rates or other standardized unit costs as indicated in 
the following Table 5.  
 
Table 5:  Resource utilization data collection and price data source, by utilization category 
Service  
Source Documentation 
Price Weight  
Surgery: midurethral sling 
Case Report Form 
Medicare reimbursement 
Behavioral/pelvic floor 
therapy 
Case Report Form 
Medicare reimbursement 
Medication 
Case Report Form 
Drug Red Book 
Physician visit 
Case Report Form 
Medicare reimbursement 
Complication: surgery 
Case Report Form 
Medicare reimbursement  
Complication: hospitalization  Case Report Form 
Medicare reimbursement  
Complication: ER visit  
Case Report Form 
Medicare reimbursement 
UI products 
Questionnaire 
Average national cost 
UI laundry / dry cleaning 
Questionnaire 
Average cost 
Time 
Questionnaire 
Average cost 
Lost Productivity 
Questionnaire 
Average cost 
 
Rationale for using the EQ-5D to measure Utility Values 
 
The European Quality of Life-5 Dimensions (EQ-5D) (EuroQol Group, http://www.euroqol.org), preference-
based utility index algorithm will be used to calculate each subject’s utility index.69  This instrument will be 
collected at baseline and follow up study visits (3, 6, and 12 months). The EQ-5D has 5 attributes (mobility, 
self-care, usual activities, pain/discomfort and anxiety/depression) with 3 levels each for a possible 243 
unique health states.  The EQ-5D scoring Function is based on the time-tradeoff method with UK Scores 
ranging from  -0.59 to1.00 and US Scores from -0.11 to 1.00.   This instrument has been previously 
validated in women with urinary incontinence (Penn preliminary data, Tables 6 and 7) and used in women 
with urinary incontinence.70, 71 These data will be used to compare change in QALYs between the two 
treatment groups. We are choosing to use a general scale to calculate change in utilities (rather than 
condition-specific) to allow for comparison of cost-effectiveness results with other interventions and 
diseases.  
 

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A questionnaire to measure direct non-medical costs (e.g. pads, laundry) and indirect costs (e.g. time, lost 
productivity) will be administered.  Based on similar questionnaires used in SISTEr17 and ValUE72 studies, 
this instrument should take approximately 15 minutes for a subject to complete at baseline and 3, 6 and 12 
months. 
 
Table 6: Mean utility preference scores for women with urge incontinence, stress incontinence and 
mixed incontinence.   
 
UUI 
(n = 40) 
MUI 
(108) 
SUI 
(n=54) 
p-valuea 
HUI-3 
0.78 ± 0.23 
0.79 ± 0.24 
0.86 ± 0.15 
0.29 
EQ-5D 
0.71 ± 0.23 
0.73 ± 0.26 
0.81 ± 0.16 
 
 0.02 
SF-6D 
0.76 ± 0.12 
0.74 ± 0.12 
0.81 ± 0.11 
0.02 
VAS b 
0.78 ± 0.15 
0.78 ± 0.16 
0.80 ± 0.14 
0.63 
UUI = urge incontinence  SUI = stress incontinence, MUI = mixed urge and stress incontinence                                  
a Kruskal Wallis      b VAS scores were divided by 100 to enhance comparability 
 
Table 7: Utility preference score correlations with symptom severity and condition-specific HRQOL 
measures 
 
HUI-3 
EQ-5D 
SF-6D 
VAS 
 
r- valuea 
r-valuea 
r-valuea 
r-valuea 
     PFDI-20 score 
-0.32 
-0.42 
-0.37 
-0.22 
Bladder subscore 
-0.16  
-0.26  
-0.24  
-0.23  
     PFIQ-7 score 
-0.45 
-0.48 
-0.50 
-0.32  
Bladder subscore 
-0.29 
-0.31  
-0.41   
-0.26  
Lower scores on the HUI-3, EQ-5D, SF-6D and VAS represent worse utility values while higher scores 
on the PFDI, ISI and PFIQ represent worse symptom severity and quality of life.  a Spearman correlation 
 
4. SELECTION OF PARTICIPANTS 
Adult women aged 21 or older with bothersome MUI (defined as bothersome SUI and UUI) will be eligible.  
 
4.1. Eligibility Criteria/Rationale for inclusion/exclusion 
4.1.1. Defining the ESTEEM MUI population 
 
For ESTEEM, women must demonstrate both subjective bothersome SUI and UUI and objective 
documentation of both conditions. The team wanted to ensure that our eligibility criteria would identify the 
appropriate MUI population, but wanted to avoid overly strict criteria that may hinder recruitment such as in 
MIMOSA.  
However, as already discussed, the MUI population is difficult to define. Currently, an instrument that 
can clearly segregate SUI versus UUI symptoms and assess the magnitude of bother that is predictive of 
clinical outcomes for MUI does not exist. Therefore, defining our inclusion criteria for this MUI population is 
critical, but we recognize that whatever criteria are selected may not be considered to be strictly “evidence-
based”.   
We reviewed the literature on common definitions of SUI and UUI used in previous clinical trials to 
help determine our criteria. Trials for SUI often use a subjective report of SUI in combination with a positive 
cough stress test (CST). CST has a 90-100% test-retest reliability.73 For OAB and UUI, trials often use 
bladder diary to document the diagnosis. More invasive UDE has not been shown to predict treatment 
outcomes for SUI and has a reliability similar to the CST72, 74, 75. For OAB, DO is a urodynamic observation 
but most often is not documented on UDE.76 There is poor agreement between OAB symptoms and DO and 
the presence of DO does not predict outcomes of a variety of OAB treatments.77 Therefore, trials have 

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moved away from strictly using UDE parameters as criteria and similarly, we will not use strictly UDE 
parameters as inclusion in ESTEEM. 
Because no single measure captures our criteria of providing subjective and objective 
documentation of both conditions, we will use a combination to define MUI in ESTEEM. This includes 
subjective documentation of at least moderately bothersome SUI and UUI on UDI, objective documentation 
of both SUI and UUI on diary, and objective documentation of SUI by CST or UDE.  
The team reviewed bladder diary criteria for existing SUI and UUI trials (summarized in Table 8). 
Ultimately the goal of ESTEEM is to capture those women who have MUI that are most clinically 
challenging because it is unclear which to treat first and for which a MUS potentially could be efficacious, 
detrimental, or neutral. It is not the patient who has severe UUI who needs sacral neuromodulation that we 
are interested in recruiting for ESTEEM. In addition, unlike previous UUI trials, because our primary 
outcome is not defined by diary improvement, the diary will be utilized only to document the presence of 
both SUI and UUI IEs. Therefore, the number of IEs does not have to be set “so high” solely to allow 
demonstration of outcome improvement.  
Therefore the team decided that at least 2 incontinence episodes must be documented on a 3-day 
diary: a minimum of 1 documented episode of SUI and 1 documented episode of UUI would be appropriate 
for documenting MUI. In addition, patients must also report at least moderate bother from both SUI and UUI 
on the UDI to be eligible and desire surgical treatment of SUI symptoms. This will allow appropriate 
documentation of both conditions, but would not be overly strict so as to exclude women on either the mild 
or severe end of the spectrum. 
 
4.1.2. Targeting a population that is distinct from TOMUS 
 
There were significant improvements in the UDI-irritative subscale scores in the TOMUS trial. Ideally 
we want to target a population with more severe urge symptoms, since additional effects of BPTx would be 
difficult to detect in a population too similar to TOMUS. In general the MESA urge score in TOMUS was low 
at a mean of 5 points. Requiring documentation of UUI on diary and report of at least “moderate bother” 
from UUI on the UDI will help to ensure a more severe UUI population (with MUI) than TOMUS. 
 
 
Table 8. Bladder diary inclusion criteria for other relevant trials 
 
Study 
Interventions 
Inclusion 
Final population diary 
characteristics 
Outcome definition 
UUI trials utilizing diary for inclusion 
Burgio-BE-DRI23 
Tolterodine/BPT vs 
Tolterodine alone 
>7 UIEs on 7-day 
diary and UUI>SUI on 
MESA 
1% UUI 7-13 IE/wk 
1% UUI >14 IE/wk 
30% MUI 7-13 IE/wk 
68% MUI >14 IE/wk 
70% reduction IEs, no 
other UUI treatment, 
withdrawal of antichol 
at 8 months 
Visco-ABC78 
Anticholinergic vs 
Botox 
>5 UIEs on 3-day 
diary and 
>50% UIE/IE 
Mean (SD) 
IEs/day: 5.6 (3) 
Urge IEs/day: 5.0 (2.7) 
Stress IEs/day: 0.8 (1.0) 
Other IEs/day: 0.1 (.4) 
Mean voids/day: 7.9 (3) 
Mean voids/night: 1.6 
(1.3) 
Change in IEs on 3-
day diary monthly, 
from 1-6 months 
Amundsen-
ROSETTA 
Interstim vs Botox 
> 6 urge IEs/3-day 
diary 
- 
Change in IEs on 3-
day diary 
Other relevant trials that did not utilize diary for inclusion 

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Brubaker-
MIMOSA37 
Initial surgical 
treatment vs initial 
non-surgical 
treatment 
No BD  
-MESA urge>stress 
or urge score > 7 and 
moderate or great 
bother on UDI-6 and 
moderate or severe 
UI on PGI-S 
- 
PGI-I >much better 
and PGI-S normal or 
mild 
Nager-ValUE72 
Basic office eval vs 
eval + UDS 
No BD 
MESA stress> urge, 
+CST 
 
>70% reduction in UDI 
and PGI-I > much 
better 
Richter-TOMUS24 
Retropubic vs 
transobturator MUS 
No BD 
MESA stress> urge, 
+CST 
Median IE/d = 2.7 
10th-90th %=(0.7-6.7) 
1) neg CST; 2) neg 
pad test; 3) no 
retreatment for SUI; 4) 
no UI on 3-day diary; 
4) no self-reported 
SUI; 5) no self-
reported retreatment of 
SUI 
Barber31  
Retropubic vs 
transobturator MUS 
No BD criteria 
SUI on UDE 
No DO 
Range of IE/d = (0-
16.3) 
Composite: 1) No UI of 
any type; 2) neg CST; 
3) no retreatment for 
SUI; 4) no postop 
retention 
SISTEr17 
Burch versus fascial 
sling 
No BD 
MESA stress> urge, 
+CST 
Mean IE/d = 3.1-3.3 
1) no self report UI; 
2)pad test; 3) no IE on 
diary; 4) neg CST; 5) 
no re-treatment for UI 
 
BD=bladder diary 
 
Based on the above rationale, the ESTEEM inclusion/exclusion criteria are as follows: 
4.2. Inclusion Criteria 
1) Presence of both SUI and UUI on bladder diary; and > 2 IEs/3 days 
a) > 1 Stress IE/3 day diary 
b) > 1 Urge IE/3 day diary 
2) Reporting at least “moderate bother” from UUI item on 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 UDE 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 (see 
Section 5.3 for Rationale) 
8) Urodynamics within past 18 months 
4.3. 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 

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a) Women undergoing only rectocele repair or other repair unrelated to anterior or apical compartment 
(ie: anal sphincter 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 within the past 6 months, 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 overactive bladder medication/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 
19) Women who have undergone anterior or apical pelvic organ prolapse repair within the past 6 months 
 
The team discussed the issue of whether bladder capacity should determine eligibility. Historically, some 
clinicians have used bladder capacity as a criteria for whether a woman with MUI is eligible for an anti-
incontinence procedure for SUI, often excluding women with capacities <150-200 cc to avoid exacerbation 
of OAB symptoms. Upon review of the literature, there is very little evidence to support excluding women 
with a “small” bladder capacity, or to guide what volume defines a “small” capacity bladder. Gamble et al 
performed a retrospective study to evaluate predictors of persistent postoperative detrusor overactivity after 
a variety of slings.79 They found that the mean maximum cystometric capacity was smaller in women with 
postoperative persistent DO compared to those with resolved DO. However, the mean capacity in women 
with persistent DO was 459 cc (SD 185) versus 539 cc (SD 176), which does not support the traditional 
teaching of avoiding slings in women with capacities less than 150-200 cc. Also, 37% of their study 
population included traditional bladder neck slings, which may be more obstructive than MUS.  Finally, the 
proportion of women reporting UUI symptoms in this study was not different between women who had 
resolved versus persistent DO, highlighting the limitation of using UDE parameters to predict symptoms.  
Numerous other studies have failed to demonstrate any specific bladder capacity cutoff that is associated 
with better or worse outcomes or poses a safety issue for MUS. 
 
Because there is a lack of evidence to support setting a minimum bladder capacity cutoff for this 
study, women determined to be eligible for a MUS based on their clinician’s judgment will be eligible for 
ESTEEM, regardless of bladder capacity. One advantage of the ESTEEM design is that only women who 
have been offered a MUS by their clinician will be eligible. Therefore, if the provider determines that the 
patient is not clinically a candidate for a MUS, she will not be eligible. In addition, we will be excluding 
women with a history of painful bladder or chronic pelvic pain syndromes who often have “small” capacity 
bladders. To further contribute to the literature about this issue, we will collect data on both maximum 
cystometric capacity on UDE and functional bladder capacity based on voiding diaries and evaluate these 
variables as potential predictors of worsening OAB symptoms in our exploratory analyses.  
 
4.4. Screening for Eligibility 
 
It is anticipated that participants will come from PFDN Clinical Site practices. Women with MUI will 
be offered the full range of treatment options consistent with routine practice including expectant 
management, pelvic floor muscle therapy, behavioral therapy, medication and possibly surgery. Those 

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patients who are offered surgery by their physician and who elect to undergo MUS for SUI will be offered 
participation in ESTEEM. Subjects will be identified as ESTEEM candidates by their physician. Because in 
ESTEEM, women must have elected to undergo MUS, it does not compete with the current ongoing PFDN 
trial, ROSETTA, in which women desiring a MUS are actually excluded from that trial. 
 
Subjects will be approached by study personnel consistent with local IRB requirements. Enrollment 
will occur after written and verbal consent. If the participant accepts participation in ESTEEM, the UDI will 
be administered to confirm at least moderate bother from both SUI and UUI and the coordinator will confirm 
documentation of SUI by either CST or UDE within the past 18 months, and UI symptoms for at least 3 
months. The coordinator will also document that the patient understands that behavioral/pelvic floor therapy 
is a treatment option for MUI outside of ESTEEM (See section 5.3, “What is the best control group”). She 
will be instructed on how to complete the voiding diary.  
 
To address the issue of overactive bladder medication use, these subjects will be required to have a 
washout of 3 weeks prior to completing the voiding diary.  The anticholinergic with the longest half-life 
currently on the market is Vesicare with a half life of 45-68 hours. Therefore, by 1 week there should be 
negligible amounts in the bloodstream and by 2 weeks the drug would be completely out of the system. 
Therefore, 3 weeks should be adequate time for washout and this time period is consistent with prior PFDN 
studies (ABC trial78). In addition, because we are highly interested in what happens to OAB outcomes after 
MUS, subjects will need to remain off of overactive bladder medication until 3 months postoperative to allow 
accurate assessment of these symptoms postoperatively (See statistical analysis plan for details on why 3 
months is adequate to allow analyses). Subjects who re-start overactive bladder medication  postoperatively 
will be considered as having “additional treatment”. Every effort will be made to schedule the patient’s 
surgery within 3 months from enrollment (see Section 4.6, Appointment scheduling below). 
 
4.5. Baseline Visit 
 
At the baseline visit, the voiding diary will be reviewed to ensure that entries are clear and 
interpretable. If the first baseline voiding diary is not acceptable, the subject will be allowed one more 
attempt. If the second baseline voiding diary is not acceptable, the subject will not be eligible for the trial. 
 
Once eligibility is confirmed, pre-treatment information will be obtained including: 
• 
Demographics – age, race/ethnicity, education level 
• 
Medical history – prior urinary incontinence procedures and treatments, prior pelvic 
surgeries, comorbidities, smoking, medications 
• 
Physical exam – Body mass index, pelvic organ prolapse quantification (POPQ), PFM 
strength (Peritron and Brink measures) 
• 
Questionnaires – self-administered 
 
4.6. Appointment scheduling and randomization 
 
Once patients are enrolled, surgery should be scheduled within 3 months from enrollment, and 
randomization should occur 7-35 days prior to the booked surgical date. This will allow enough time for 
those subjects randomized to the BPTx intervention to have their first preoperative visit scheduled, while 
minimizing withdrawal from the study due to unforeseen personal circumstances that may require a patient 
to cancel or change the date of their surgical procedure. Surgery should be performed 7-35 days after 
randomization and the surgery should be scheduled before randomization occurs. If a participant is 
randomized but does not undergo surgery, the planned surgery date will serve as Time 0 for calculating 
windows for follow up visits and phone calls. If surgery is rescheduled but does not occur, then the last 
planned date of surgery will be Time 0. If the participant decides against surgery but later changes her 
mind, the planned date of the surgery that did not occur will be Time 0, and the surgery that occurs after she 
changes her mind will be considered additional treatment. 
 
Postoperatively, all subjects will return for visits at 2 and 8 weeks and 3, 6, and 12 months. Subjects 
randomized to BPTx will undergo undergo BPTx intervention sessions at 2 weeks preoperatively, and then 
postoperatively at 2, 4, 6, 8 weeks and 6 months. All subjects (intervention and control) will have visits with 
a masked assessor for PFM Peritron measurements at baseline, and 2 weeks and 8 weeks, and 12 months 

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postoperative. (See Assessment Table 11). All subjects will receive calls from research staff to determine 
AEs and additional treatment 4 and 6 weeks postoperative. 
5. DESCRIPTION OF STUDY INTERVENTIONS 
5.1. Midurethral sling procedure (both groups) 
 
To address the potential issue that different sling or mesh types may result in different outcomes, 
MUS types will be standardized.  All women (both groups) will receive a MUS which 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). In the 
TOMUS trial and Barber’s equivalence trial, these approaches and devices demonstrated equivalence for 
improving objective success of SUI and were not significantly different for subjective success, persistent 
UUI or de novo UUI.24, 31 The Gynecare “laser-cut” slings will not be allowed in this trial due to data from 
Moalli et al showing that the laser-cut meshes are “stiffer” (less deformation under an applied load), which 
theoretically may increase risk of mesh complications.80 Although it is unclear how “laser-cut” meshes may 
affect clinical outcomes, these types of slings were not included in the TOMUS or Barber’s equivalence 
trials resulting in less published, long-term outcome data. “Mini-sling” or “single-incision” slings will not be 
allowed.  Key aspects of the procedure will be standardized across surgeons and sites.  
 
 
5.1.a. Surgeon Certification- To address the issue of surgeon certification and to ensure standardized 
training of all surgeons, all “certified surgeons” will have performed a minimum of 20 midurethral sings of 
any type, including 5 of the specific MUS allowed in ESTEEM that the surgeon will be using in the study. 
The site PI must sign off that each participating surgeon has met the criteria. 
 
5.1.b. Standardization of sling procedures: 
 
Detailed standardization of the surgical procedure will be developed and will include the following 
key points: 
 
1. The participating surgeon must be present and scrubbed for key portions of the procedure. 
Residents and fellows may participate in procedures as is standard for each Clinical Site 
 
2. All subjects will receive preoperative intravenous antibiotic prophylaxis. The choice of antibiotic 
will be determined by each surgeon. 
 
3. Deep vein thrombosis prophylaxis is required for all participants. The choice of prophylaxis will be 
determined by each surgeon. 
 
4. Any concomitant native tissue procedures must be declared prior to randomization. Per exclusion 
criteria, women clinically requiring anterior vaginal prolapse or apical repairs are ineligible. 
 
5. Tensioning of the sling will be performed in a fashion to ensure that it is a tension-free technique. 
This can include either by placing a blunt instrument between the sling and the urethra, or by folding a small 
knuckle of mesh in a Babcock clamp or similar method during tensioning.  
 
5.1.c. Need for postoperative sling revision: 
 
To address the issue of postoperative sling revision, the team developed a plan for several potential 
scenarios which may require the surgeon to revise the sling, detailed below. Women who undergo a sling 
revision will all be considered as having “additional treatment” in outcome analyses regardless of indication. 
Prior to sling revision, subjects will complete all outcome assessments including the primary outcome (UDI). 
 
1. Urinary retention / incomplete bladder emptying (abnormal PVR) – An abnormal post-void residual 
is defined as PVR > 150 cc in this protocol (consistent with exclusion criteria). This is a known complication 
after MUS, and there is no evidence to support that this would be higher in women with MUI. Based on 
Barber’s trial which included 70% women with MUI, the sling revision rate was 0-1%, which is also 
consistent with the TOMUS trial. For retention/incomplete emptying, the postoperative management and 
need for sling revision will be left up to the surgeon’s clinical judgment.  

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2. Worsening OAB/lower urinary tract symptoms with a normal PVR – it is possible that some 
women may experience worsening OAB symptoms immediately postoperatively. It is unclear from the 
literature in which women such symptoms may be transient and ultimately resolve once postoperative 
recovery is complete, or in which women it will persist and/or worsen over time (an aim of ESTEEM). 
Therefore, for women with a normal PVR complaining of worsening OAB symptoms, sling revision will be 
deferred until 3 months postoperatively. This will provide important information about the natural course of 
these symptoms in the immediate postoperative period, and whether BPTx is effective for improving these 
symptoms early on. If after 3 months the patient desires sling revision due to worsening OAB symptoms, the 
surgeon can perform the procedure based on his/her clinical judgment. There is no evidence to support any 
potential harm by delaying sling revision in a woman with OAB symptoms and a normal PVR. 
 
3. Persistent SUI symptoms – For women who have persistent SUI symptoms, sling 
revision/replacement can be performed after 3 months based on the surgeon’s clinical judgment.   
5.2. Background for BPTx intervention  
 
To develop the most evidence-based, reproducible, standardized, and logical BPTx intervention 
protocol, the team reviewed the evidence and determined that bladder training/urge suppression 
techniques, pelvic floor muscle therapy, and weight loss have high level of evidence for treatment of urinary 
incontinence. Therefore, weight loss will be discussed with all women, and bladder training/urge 
suppression and pelvic muscle exercises will be incorporated into the ESTEEM BPTx intervention.  
The summary of evidence for 5 key questions relevant to our intervention are summarized below: 
5.2.1. What is the evidence for behavioral/lifestyle modification?   
 
There are many components that can be defined as “behavioral” or “lifestyle” modification including 
caffeine intake, fluid intake, obesity, smoking, constipation and timed voiding. A summary of ICI evidence 
and recommendations is below: 
 
Table 9. Summary of ICI recommendations 
Modification 
Level of evidence 
Grade of 
recommendation 
Recommendation 
1. Caffeine intake 
2 
B 
Caffeine reduction may improve incontinence 
2. Fluid intake 
3 
B 
Minor decreases by 25% may be recommended 
provided baseline consumption is not less than 
one liter a day 
3. Weight loss 
1 
A 
Morbidly and moderately obese women should 
consider weight loss to reduce UI 
4. Smoking 
3 
None 
More research 
5. Constipation 
3 
None 
More research 
6. Timed voiding 
3 
C 
Two-hour voiding intervals in women with mild 
UI and infrequent voiding patterns 
7. Bladder training/urge 
suppression 
1 
A 
Recommended for UI reduction 
 
Caffeine:  Aside from the volume of fluid ingested with these beverages, caffeine has been shown to have a 
diuretic effect and may increase OAB symptoms by increasing bladder pressure and bladder muscle 
excitability.81-83  In addition, caffeine is a central nervous system stimulant and animal research has 
suggested that caffeine increases calcium release from smooth muscle leading to excitatory contraction of 
smooth muscle organs like the bladder.84  Few well designed studies have addressed the impact of caffeine 
on bladder symptoms and those that have produced conflicting results, but there are some small studies 
suggesting decreasing caffeine may improve continence.85 
 
Fluid intake:  Excessive fluid intake can certainly increase urinary frequency and exacerbate OAB 
symptoms.86  Interestingly, excessive restriction of fluid may also exacerbate symptoms due to poor 

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elimination of irritants from the bladder, decreasing the functional capacity of the bladder and increasing the 
risk of urinary tract infections.87  Appropriate fluid intake should be balanced against activity level, climate, 
and fluid content of ingested foods. For most older adults, fluid intake should be approximately six 8-oz 
glasses per day.88    
 
Weight loss:  Obesity, defined as a body mass index greater than or equal to 30 kg/m2, was traditionally 
considered a risk factor for SUI only but more recently has been appreciated as a risk factor for OAB and 
UUI as well.89, 90  Bump et al showed improvement in both SUI and UUI following surgical weight reduction 
in morbidly obese women.91  But, even moderate weight loss can improve bladder symptoms in overweight 
women. A large randomized trial demonstrated that a structured weight loss intervention group resulting in a 
loss of 8% of body weight was associated with a clinically relevant reduction of 70% or more in the 
frequency of all IEs (P<.001), SUI (P=.009), and urge IEs (P=.04) compared to a control group which only 
lost 1.6% of body weight.90, 92   
 
Smoking:  Smoking, particularly nicotine, has been implicated as a risk factor for OAB and incontinence.93, 94  
Potential etiologies are increased intra-abdominal pressure from chronic cough and increased nicotine 
induced detrusor overactivity (as shown in cats).95  Little clinical data is available assessing the impact of 
smoking cessation on bladder symptoms. 
 
Constipation:  Constipation is a common co-morbid complaint among patients with OAB and UI.96-98  
Although several studies in children document that constipation is linked to urinary tract symptoms including 
infection, enuresis, voiding problems and vesicoureteral reflux, the majority of studies in adults have 
identified an association but no clear causal link.  While patients often report an exacerbation of bladder 
symptoms during times of constipation, few clinical studies exists to suggest resolving constipation 
improves OAB symptoms.  Promotion of bowel regularity initially through natural methods including 
increasing dietary fiber, increasing water intake, physical activity and use of stool softeners is often 
recommended because it is low risk; however the evidence for its effect on improving OAB or UUI 
symptoms in the general adult population is limited.  
 
Timed Voiding: Timed voiding or prompted voiding is a mechanism to theoretically increase bladder 
awareness, although firm evidence for its effectiveness for UI does not exist.  Timed voiding involves a 
voiding schedule that starts with interval voiding on a fixed schedule regardless of the desire to go.99   It 
involves patient cooperation, adequate mobility, and intact cognitive function.  For some patients who delay 
urination, initially decreasing the voiding interval to every 30-90 minutes may be necessary to decrease 
incontinence episodes while urgency control strategies are being taught.100 The maintenance of the timed 
voiding schedule during nighttime hours is determined by the patient’s general sleep pattern (weather 
he/she awakens naturally to void), their motivation to stay dry (whether he/she sets an alarm to make sure 
to awaken), and the availability of help if needed.   
 
5.2.2. What is the evidence for bladder training/urge suppression? 
 Bladder training through urgency control and suppression techniques has been an effective means 
of decreasing the intensity of urgency and incontinence in well motivated patients.  Bladder training, 
sometimes referred to as bladder retraining, bladder reeducation or bladder drills, may be effective as the 
result of rewiring of complex circuitry between the bladder and the brain.101  The training consists of three 
important components, (1) education about bladder function, dysfunction and urgency control strategies; (2) 
a timed voiding regimen that evolves to gradually increase the interval between voids; and (3) positive 
feedback and reinforcement by caregivers.102, 103  Utilization of relaxation techniques including slow deep 
breathing and distraction techniques (mental concentration on other tasks) are most popular during urgency 
suppression.100  Additional strategies including rapid contractions of the pelvic floor, or quick flicks 
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popular.104  Furthermore, patients are instructed to avoid running or walking fast to the bathroom as this 
may increase intra-abdominal pressure and promote leakage.  Bladder training is used to slowly increase 
the interval between voids in attempts of reestablishing normal voiding intervals, break previously formed 
voiding habits, and diminishing urgency.  In general, the voiding interval is increased on a weekly basis by 
approximately 15 to 30 minutes until a voiding interval of every 3-4 hours is reached.104  A randomized 
controlled trial of 123 women with mixed urinary incontinence showed a 57% reduction in incontinence 
episodes and a 54% reduction in quantity of urine loss after implementation of a bladder training program.105  
The ICI rated the level of evidence a 1 (based on scant evidence) and the grade of recommendation 
an A for the impact of bladder training on reduction in urinary incontinence. 
 
5.2.3. What is the evidence for Pelvic Floor Muscle Training (PFMT)? 
 
A recent Cochrane review titled “Pelvic floor muscle training versus no treatment, or inactive control 
treatments, for urinary incontinence in women” reported on 12 PFMT trials.20 Of the 12 PFMT trials meeting 
their inclusion criteria, 3 provided no details of the PFMT method used. Per the review, most existing trials 
were at moderate to high risk of bias.  There was considerable heterogeneity in interventions used, study 
populations and outcome measures.  Women who did PFMT were more likely to report subjective 
improvement, cure and improvement in quality of life compared to those who did not.  Women who did 
PFMT also reported fewer incontinence episodes per day, and less leakage on short office based pad test 
compared to those that did not.  The authors concluded that PFMT should be considered first-line 
conservative treatment for SUI, UUI, or MUI. The effect seemed greatest in women with pure SUI and for 
programs that were at least 3 month in duration; however the authors recommend additional research to 
support these conclusions. 
 
5.2.4. What is the best approach to PFMT for treatment of urinary incontinence? 
 
The same Cochrane review20 above also attempted to separate trials by those that increase: 1) 
Strength 2) Endurance, and/or 3) Coordination (for urgency suppression).  Based on the descriptions of 
training, two trials had PFMT programs that clearly or predominantly targeted coordination106 or strength 
training107. Miller and colleagues described a short (one week) program to improve coordination between a 
voluntary pelvic floor muscle contraction (VPFMC) and a rise in intra-abdominal pressure.106 Bø et al 
recommended a program that comprised 8 to 12 high intensity (close to maximal) VPFMC, with six to eight 
second hold and three to four fast contractions added at the end of each hold, six second rest between 
contractions three times per day. Exercises were done in different body positions included lying, kneeling, 
sitting, standing; all with legs apart107.  
 
It was difficult to characterize the other PFMT programs, because they were either a mixed program 
(for example strength and endurance) or had not described a key training parameter (for example amount of 
voluntary effort per contraction). This Cochrane review highlighted some gaps and opportunities for future 
research in this field. Recommendations from the authors included research in which one arm would 
comprise a supervised PFMT program derived from sound exercise science, confirmation of a correct 
voluntary pelvic floor muscle contraction, and incorporate appropriate supervision and adherence measures 
to promote maintenance of knowledge acquisition. The choice of program would have to be set against the 
resource implications of intensively supervised individual programs and the opportunity cost this represents.  
The reporting of formal economic analysis would have to be added to the study.  Careful clinical judgment 
would be needed about what sort of program could actually be applied in everyday practice and in different 
countries with their different health care delivery systems while still delivering an effective intervention.  
 
A second relevant Cochrane review108 titled “Comparisons of approaches to pelvic floor muscle 
training for urinary incontinence in women” also attempted to compare different approaches and/or 
components. These included: 1) differences in training supervision (amount, individual versus group), 2) 
approach (one versus another, the effect of an additional component) and 3) exercise training (type of 
contraction, frequency of training). Overall, the review concluded that there was insufficient evidence 

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regarding the best approach to PFMT; however, more frequent visits resulted in improved subjective 
outcomes (women receiving “regular” supervision were more likely to report improvement compared to little 
or no supervision).  
 
5.3. What is the best “control” group for this study? 
 
The team discussed whether women randomized to the control arm should receive baseline 
educational materials about behavioral and/or pelvic floor therapy. Educational materials that are routinely 
provided to women with MUI considering treatment options (before deciding on surgery) from each site 
were collected. The majority of sites (7/8) currently provide routine written material to patients on 
Kegel’s/pelvic floor muscle exercises. The majority also routinely provide information on: 1) urge 
suppression/kegel (7/8 sites); caffeine (7/8 sites); other bladder irritants (5/8 sites), and excessive fluid 
intake (6/8 sites). All sites were in agreement that these are routinely offered to women prior to moving 
forward with surgical intervention, although not all women choose to use these behavioral strategies. 
 
The team considered the possibility of providing educational pamphlets to the control group; 
however, the ESTEEM population includes women who have already elected to proceed with surgery. In 
clinical practice, women who have decided on surgery have already been offered other conservative options 
and it is not routine practice to provide pamphlets again about other options at a preoperative visit. 
Therefore, this would not mirror what happens in the “real world”.  
 
Because of these reasons, the team agreed the control group in ESTEEM should be MUS only. 
However to balance this, as part of our inclusion criteria, women will be reminded that BPTx is a treatment 
option for MUI (even outside of the study) to ensure they have been offered behavioral therapy and/or 
physical therapy outside of ESTEEM. (See Inclusion Criteria, Section 4.2). Along these lines, women who 
previously tried other behavioral or pelvic therapy will not be excluded. If the patient meets eligibility for 
ESTEEM, she would still have bothersome MUI by inclusion criteria. If the patient was not aware that 
behavioral/physical therapy was an option, she would be offered a referral at that point for which she can 
either accept (and cancel her surgery), or decline (and still be eligible for ESTEEM). The research 
coordinator will ask this screening question using similar wording that has been used in previous PFDN 
protocols.  
 
Although routine educational pamphlets may be provided to subjects prior to their enrollment into 
ESTEEM per usual care at each site, once enrolled, no additional educational pamphlets may be provided 
to either control or intervention subjects outside of the protocol. The control group will complete bladder 
diaries and undergo PFM assessments at the same time intervals as the intervention group to control for 
any potential independent effects that bladder diary completion may have.  
 
Rationale for including women who have previously tried behavioral and/or physical therapy: 
 
There are many reasons to include women who have previously tried behavioral and/or pelvic floor 
physical therapy. First, women eligible for ESTEEM must have at least moderately bothersome MUI and 
desire surgery; therefore, even though these women have had treatments in the past, they did not improve 
enough to forego additional treatment. In addition, ESTEEM is evaluating the effect of combined surgical 
and BPTx treatment and not just BPTx alone. Therefore, women who have previously failed BPTx alone 
in the past may still significantly improve with combined surgical/BPTx treatment or surgery alone and there 
is no evidence to support their exclusion from this trial. This is the most important reason why these women 
should be included. Second, many women who have previously tried behavioral and/or physical therapy 
may have had a wide range of non-standardized interventions to varying degrees, durations, and with 
various components. Therefore, it is difficult to conclude that they may be at “higher risk” for failure, or that 
they will not benefit from the ESTEEM intervention. In ESTEEM, the BPTx protocol is based on existing 
evidence for specific BPTx components and the expertise of interventionists focused solely on improving 
MUI symptoms. This standardized protocol can potentially enhance the surgical effects for women with MUI. 
The protocol does provide the opportunity to identify risk factors for failure of a standardized BPTx 
intervention which will help build additional evidence for future trials. 

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5.4. Intervention - See Appendix A for the full BPTx Intervention Protocol 
As stated above, for the intervention the team focused on evidence-based BPTx strategies. When evidence 
was lacking, the team made decisions based on the most logical and pragmatic rationale with a focus on 
developing a reproducible and standardized protocol. 
 
 
For the purposes of this proposal “Behavioral training” (BPTx) will include: 
 
1. Pelvic floor muscle training 
 
2. Urge strategies defined in the field (included in intervention handout) 
 
3. Stress strategies defined in the field (included in intervention handout) 
 
4. Delayed voiding techniques (included in intervention handout) 
 
The intervention will include 1 preoperative BPTx intervention visit and 5 post-operative intervention visits at 
2, 4, 6, and 8 weeks and 6 months postoperative. Data from the ATLAS trial demonstrated that adherence 
with BPTx strategies decreased after 6 months, corresponding to a potential decrease in benefit.110 
Therefore, a 6 month BPTx intervention session is part of the intervention in ESTEEM. Participants 
randomized to intervention will receive BPTx implemented by an experienced registered nurse, nurse 
practitioner or physical therapist. Patients will be monitored using an adherence questionnaire. 
 
The intervention will be standardized through the following mechanisms: 
a. Certification of all interventionists through passing of e-learning modules and attendance and 
demonstration of hands-on skills at a 2-day, in-person interventionist training session 
b. There will be an interventionist checklist to ensure the same components have been performed 
across subjects 
c. There is a detailed protocol for the PFM exercise progression 
d. There is a detailed protocol for “special circumstances” for when the standard PFM exercise 
progression protocol cannot be followed (ie: weak muscle) that the interventionist will be required to 
follow 
e. Subject handouts will be developed for the 4 components (PFME, Urge strategies, stress 
strategies, and delayed voiding techniques) and the interventionists will be required to refer only to 
the handouts during the education component 
f. All intervention sessions will be audiotaped and a subset will be audited by behavioral therapy 
experts to ensure adherence to protocol. Any protocol deviations will be addressed as necessary. 
g. Phone calls between interventionists and behavioral experts will take place as needed to ensure 
adherence to protocol and address any issues and deviations. 
 
 
Preliminary data from the OPTIMAL trial suggest that perioperative BPTx was not effective for 
improving urinary, prolapse, or colorectal symptoms at 6 months (unpublished data); however, the study 
population in OPTIMAL is significantly different from ESTEEM. Regarding baseline urinary symptoms, 
subjects in OPTIMAL were required to have an affirmative response to one SUI item only on the UDI 
whereas subjects in ESTEEM will be required to have an affirmative response to both the SUI and UUI 
items on the UDI and these symptoms must be at least moderately bothersome. Only 40% of women in the 
OPTIMAL trial reported mixed UI. In addition, all women in OPTIMAL had at least stage 2 symptomatic 
pelvic organ prolapse and all underwent apical prolapse suspension procedures as part of the intervention. 
Existing data support that urgency and urge incontinence symptoms may be associated with severe 
prolapse and surgical correction of prolapse may improve OAB symptoms.111 In addition, there is solid 
evidence supporting that MUS is an effective treatment for SUI and therefore it is plausible that BPTx may 
not provide any additional effect in the OPTIMAL study population. However, there is minimal high-quality 
data regarding outcomes in MUI and there is evidence supporting that MUI is a risk factor for MUS failure. 
Finally, the BPTx component in OPTIMAL was developed as a prophylactic  intervention, whereas the 
combined effect of MUS and BPTx is designed as a treatment intervention in ESTEEM. For all of these 

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reasons, we believe that the early findings from OPTIMAL do not directly address the aims proposed in 
ESTEEM and are not applicable to a MUI population.      
 
The intervention in ESTEEM has been designed to focus on SUI and UUI symptoms and includes 
only components that address these 2 symptom constellations. Differences between the ATLAS, OPTIMAL 
and ESTEEM interventions are presented in Table 10. 
 
 
Table 10. ATLAS and OPTIMAL behavioral therapy interventions and control compared to ESTEEM 
Study 
ATLAS 
OPTIMAL 
ESTEEM 
Study design 
Pessary vs BPTx vs both 
Periop BPTx vs control + 
vaginal suspension 
Combined periop BPTx+MUS 
vs control 
Study population 
-SUI or SUI predominant 
desiring non-surgical 
treatment 
-Stage 2-4 prolapse with 
presence of SUI 
-All women underwent 
vaginal vault suspension 
-SUI defined as 
affirmative response to 
SUI item on UDI and 
objective confirmation 
-No significant prolapse 
-No vaginal vault repair 
allowed 
-Bothersome mixed UI 
desiring midurethral sling 
(defined as at least moderate 
bother for both SUI and UUI 
items on UDI and 
confirmation on bladder diary) 
Primary outcome definition 
PGI-I and PFDI < 
somewhat bother for SUI 
items 
UDI (urinary outcome) 
 
-Urinary outcome 
powered to detect 11 
point diff in UDI 
UDI(total)-long form 
 
-Powered to detect 35 point 
diff in UDI(total), 15 point in 
UDI(irrit), and 8 points 
UDI(stress) scales. 
Primary outcome time point 
3 months 
-Urinary-short term 6 
months for urinary sxs 
-Prolapse-long term 2 
years 
12 months 
# visits 
4 
5 
6 
Duration of active treatment 
6 weeks 
2 weeks preop to 
3 months postop 
2 weeks preop to  
6 months postop 
Interval between visits 
Q2-3 weeks 
Postop: (Q2-4 wks) 
2, 4, 8 wks 
3 months 
Postop: 
2, 4, 6, 8 weeks 
6 months 
Intervention components 
  1. Bladder diary review 
2. PFMT, technique eval 
3. Standardized protocol for 
PFMT exercise progression 
3. PFMT standardized 
“special circumstances” 
3. SUI strategies 
4. UUI strategies 
5. Dysfx void strategies 
6. Colorectal Sx strategies 
7. Verbal/written home 
PFME Px 
8. PFMT Adherence 
9. Addressing other PFD 
Sx 
10. Other written 
educational materials 
Yes 
Yes 
No 
 
No 
 
Yes 
Yes 
No 
No 
Yes 
 
Yes 
No 
 
SUI, UUI, PFME, Diary 
No 
Yes 
No 
 
No 
 
Yes 
Yes 
Yes 
Yes 
Yes 
 
Yes 
Yes 
 
SUI, UUI, PFME, Postop 
instructions, lifting, 
healthy bladder, healthy 
bowel 
Yes 
Yes 
Yes 
 
Yes 
 
Yes 
Yes 
Yes 
No 
Yes 
 
Yes 
No 
 
SUI, UUI, PFME, Diary 

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Control group 
 
-Completed diaries same 
as intervention 
-“Usual care” – routine 
periop teaching and 
standardized postop 
handouts 
-No diaries 
-Will complete diaries at 
same time intervals as 
intervention group 
-Will have PFM measures 
same as intervention 
 
 
 
 
Methods to standardize 
intervention 
 
 
1. Interventionist checklist 
2. Protocol for exercise 
progression 
3. Interventionist protocol for 
“Special Circumstances” 
4. Subject handouts that 
interventionist will review 
during education 
Findings 
-BPTx superior for SUI 
symptoms: 33% vs 49% for 
pessary vs BPTx (P=.006) 
-No difference in PGI-I 
-Higher satisfaction in 
BPTx: 63% vs 75% pessary 
vs BPTx (P=.02) 
-Combination better than 
pessary alone, but not 
BPTx 
Preliminary: 
6 months no diff in UDI 
score between groups 
N/A 
 
5.5. Patient management and follow-up 
5.5.1. Baseline Procedures 
 
In addition to information collected to determine eligibility and standardized questionnaires, the 
following information will be obtained for all randomized patients by chart review or patient report: 
a. Demographic information: age, race, ethnicity, insurance status, education 
b. Medical history: vaginal parity, comorbidities, height, weight, prior pelvic surgeries, medications, estrogen 
status, previous treatments for pelvic floor disorders 
c. Social history: tobacco use 
d. Pelvic, rectal exam, neurological examination, POP-Q, PFM strength (collectively will include Brink and 
Peritron measurement), post-void residual, urinary stress test  
e. Standardized urodynamic evaluation (UDE) will be performed preoperatively – There continues to be 
controversy regarding the usefulness of UDE for preoperative evaluation of SUI. However, it is often 
recommended in women who have a “mixed” UI picture and there are no definitive studies to determine if 
UDE parameters may be helpful in predicting outcomes after surgery in women with MUI. Therefore, the 
protocol team agreed that patients in ESTEEM should undergo UDE testing, primarily to allow evaluation of 
variables that may predict clinical outcome. Because eligibility includes women electing surgery, and 
because this is a complex population, many patients may already have UDE results prior to enrollment. For 
those women who have not, they will undergo testing preoperatively, although there are no specific UDE 
parameters that determine eligibility for this trial. Urodynamic tests performed within the past 18 months will 
be allowed. 
f. Patient-reported outcomes and questionnaires – includes UDI, IIQ, EQ5D, Adaptation questionnaire, PGI-
I, PGI-S, OAB-q, OAB-sat-q, PISQ,  
 
 
 

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5.5.2. Postoperative visits and procedures 
 
Patients will undergo clinical and PRO assessments at 3 months, 6 months, and 12 months 
postoperatively. (See Table 11 above). The primary outcome will be at 12 months. Additional treatment for 
patients with persistent OAB symptoms should not be offered in the first 3 months, given this time period 
may still represent recovery from acute events related to surgery. Patients requesting additional treatment in 
the first 12 months will be considered treatment failures, and will complete PRO assessments at the time of 
initiation of additional treatment. Any additional long term follow up beyond 12 months, consideration would 
need to be given to the natural history of progression and remission of OAB.112, 113 
 
 

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Table 11. Timeline of visits, events, and data collection 
 
Baseline 
Random-
ization visit 
(T1-5 wks 
preop) 
Preop 
BTPx visit 
(range 1-5 
wks preop) 
Surg 
MUS 
(T0) 
Call 
 (2-4d 
post-
op) 
2 wk 
post-
Clinic 
4 & 6 wks 
post  
8 wk 
post- 
3 mo post- 
Clinic and 
QoL 
6 mo post- 
Clinic and 
QoL 
12 mo post- 
Clinic and 
QoL 
Estimated duration of 
clinic and/or BPTx visit 
for each group 
 
Both: 1.5-
2hr 
Control: 
N/A 
 
Contr: 
N/A 
Control: 
1.5hr 
Control: N/A 
Control: 
1hr  
Both: 1.5hr 
Control: 
1.5hr 
Both: 1.5-
2hr 
Interv: 
1.5hr 
Interv: 
15 min 
Interv: 
2.5hr 
Interv: 1hr 
Interv: 
2hr 
Interv: 
 2.5 hr 
All subjects 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
Coordinator visit 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
Masked clinical staff 
visit (for PFM measures) 
 
X 
 
 
 
X 
 
X 
 
 
X 
Hx/PE (update) 
 
 
 
 
 
X 
 
X 
X 
X 
X 
Medication audit 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
UDE 
X 
 
 
 
 
 
 
 
 
 
 
UDI (inclusion and 
primary outcome) 
X 
 
 
 
 
 
 
 
X 
X 
X 
Other PRO 
questionnaires 
 
X 
 
 
 
 
 
 
X 
X 
X 
Voiding diary  
X* 
 
 
 
 
X* 
X 
X* 
 
X* 
X* 
PFM measures 
 
X 
 
 
 
X 
 
X 
 
 
X 
Additional treatment** 
 
 
 
 
 
X 
X 
(both groups 
by phone) 
X 
X 
X 
X 
Adverse events 
 
 
 
X 
 
X 
X 
(both groups 
by phone) 
X 
X 
X 
X 
Voiding function (PVR) 
X 
 
 
 
 
X 
 
 
 
 
 
Subjects randomized to intervention only 
BPTx visit 
 
 
X 
 
 
X 
X 
X 
 
X 
 
BPTx self-efficacy 
questionnaire 
 
X 
 
 
 
 
 
 
 
X 
X 
 BPTx Adherence / 
Barrier questionnaire 
 
 
 
 
 
X 
X 
X 
 
X 
X 
* Data will be keyed into iMedidata 
**For subjects who request/initiate additional treatment, all outcome measures will be completed prior to initiation of additional treatment. 

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6. Statistical considerations 
6.1. Sample size estimates 
6.1.1. Primary aim and secondary aims: 
This study is designed to compare the efficacy of MUS+BPTx versus MUS alone on improving MUI 
symptom outcomes. Because OAB and SUI symptoms are highly important secondary outcomes as stated 
previously, we felt strongly that our sample size should provide adequate power to detect differences for the 
separate UDI-irritative and UDI-stress subscales in addition to the UDI total score. Our initial sample size 
estimates were based on published MIDs for the UDI total score and subscales; however, we recognize that 
the populations on which those MIDs were based might differ from the target population for ESTEEM. A 
secondary aim of ESTEEM is to estimate the MIDs for UDI scores in this study population, and it is possible 
that the MIDs in this population could be smaller than values previously published, particularly for the UDI 
total score. Thus, our goal was to power the study to detect a statistically significant difference between 
groups in change from baseline in UDI total score at 1 year that was smaller than the published MID but still 
in a range of what we think may be a clinically important difference in our population.  
Sample size estimates are based on simulations using analysis methods accounting for both the 
rate of additional treatment in the two groups as well as UDI total score or subscore values over the 12 
month follow up period (refer to the statistical analysis plan for details). We assumed that 30% of women in 
the MUS only group and 20% of women in the MUS+BPTx group would request additional treatment. In 
TOMUS, 10-12% of women who had baseline MUI had persistent UUI postoperatively based on MESA 
responses and/or initiation of anticholinergic treatment.24 In Barber’s TVT vs TOT equivalence trial, 70% 
reported baseline MUI and postoperatively, 30% of all women reported bothersome UUI with 16% of 
subjects on anticholinergic treatment postoperatively.31 In Abdel-Fattah’s transobturator MUS trial, 25% 
reported worsening OAB and almost all of these women were on anticholinergic treatment postoperatively.34 
In Palva’s TVT vs TVT-O trial, 174 women reported preoperative UUI and of these, 7 women (4%) had tried 
anticholinergics postoperatively after 3 years. Therefore, based on existing MUS trials, the rate of additional 
treatment for OAB ranges from 4-25%, supporting our conservative assumption that 30% of women will 
request additional treatment in the MUS only group. 
 
i. Primary outcome: MUI symptoms = UDI-total score 
 
 The MID for the UDI-total score published by Dyer et al is estimated to be 35 points.50 Assuming a 
two-sided alpha of .05, SD of 50.4, and true difference in mean change from baseline in UDI-total scores at 
1 year between treatment groups of 35, 75 women per group would provide 90% power to detect a 
statistically significant difference between groups. 
 
ii. Secondary outcome: OAB symptoms= UDI-irritative subscale: For the UDI-irritative subscale, the 
published MID estimate is 15 points.50 Assuming a two-sided alpha of 0.05, SD of 25.6, and true difference 
in mean change from baseline in UDI-irritative scores at 1 year between treatment groups of 15, 92 women 
per group would provide 90% power. 
iii. Secondary outcome: SUI symptoms = UDI-stress subscale: For the UDI-stress subscale, the 
published MID is 8 points.51 Assuming a two-sided alpha of 0.05, SD of 21.5, and true difference in mean 
change from baseline in UDI-stress scores at 1 year between treatment groups of 8, 200 women per group 
would provide 90% power to detect a statistically significant difference between groups.  
 
Using 200 per group as our base estimate and adjusting for 15% dropout post-operatively results in 
a total sample size of 472 randomized to treatment.  
Additionally, this sample size will provide approximately 90% power to detect a difference as small 
as 19 between treatment groups for the UDI-total score, and a difference as small as 16.5 points with 80% 
power. 

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6.1.2. Potential limitations of the UDI and primary outcome: 
 
One potential limitation of using change from baseline score as the primary outcome is that point 
estimates of the difference in means between 2 groups may mask important changes for individual patients 
that are meaningful. However, this would also be the case if we dichotomized the outcome into “success” 
versus “failure”.  In addition, the published MID used for our primary outcome is derived from the BE-DRI 
population, an urge-predominant MUI population and MID estimates can vary depending on the study 
population. The published estimate for UDI-total MID for the BE-DRI urge-predominant population is 35 
points based on Dyer et al50 whereas Barber et al found the MID for pure stress/stress-predominant 
population to be 11 points in the ATLAS population.51 One advantage of the BE-DRI population is that 96% 
had MUI, which is more similar to the anticipated ESTEEM population. It is possible that women with UUI 
require larger improvements compared to pure/SUI predominant women to be meaningful. This is 
consistent with many previous studies showing that women with UUI experience worse impact and bother 
than SUI patients and that the UUI component drives patient perception of severity and satisfaction after 
treatment.  
 
Although we do not definitively know whether 35 is an accurate MID for determining success or 
failure in this study population, we consider this MID estimate from BE-DRI to be the published MID that is 
most applicable to our target population. In addition, because our total sample size is 400 subjects (before 
adjustment for drop out), our study will have 90% power to detect a statistically significant difference in UDI-
total scores if the true difference is as small as 19 points between groups and 80% power to detect a 
difference if the true difference is as small as 16.5 points. This difference is smaller than the conservative, 
distribution-based MID estimate of -24.8 based on the BE-DRI population. Thus, the planned sample size 
will allow for analyses to assess whether the true MID in this population is smaller than 35.  
 
Finally, the UDI total score includes 3 subscales: stress, irritative and obstructive. Therefore, our 
primary outcome will include a total score combining all 3 of these subscales. We believe the inclusion of 
the obstructive subscale is appropriate for the following reasons: 
 
1. Although obstructive symptoms related to prolapse are not a focus of ESTEEM, some items in 
this subscale may still be relevant to the MUI population (ie: “general urine leakage not related to urge or 
activity”; symptoms of “difficulty emptying”; and “incomplete emptying”).  
 
2. Because women with symptomatic prolapse will be excluded in both groups, it is unlikely that the 
inclusion of this subscale in the primary outcome will lead to bias.  
 
3. The published MID for the UDI in the BE-DRI population also includes all 3 subscales for an urge-
predominant MUI population.50 
 
6.1.3. Management of women who drop out prior to receiving MUS 
 
It is possible that some women in both groups may cancel their surgical MUS procedure due to 
personal reasons, or other. It is also possible that women randomized to BPTx may cancel their surgical 
procedure if they receive preoperative BPTx treatment and experience improvement. These women will still 
be included from an ITT perspective.  
6.2. Statistical analysis plan 
 
6.2.1. Primary aim 
The mean change from baseline in UDI scores will be compared between groups at 1 year. As 
explained previously, participants will be permitted to seek additional treatment for SUI and/or OAB after 3 
months following MUS. Because such treatment is expected to impact the participant’s UDI score at 1 year, 
we will use an analysis method that accounts for the impact of additional treatment. Specifically, a general 
linear mixed model will be constructed to model change from baseline in UDI scores using scores recorded 

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at time points up to 1 year following MUS. For participants who request additional treatment, only UDI 
measurements up to the time of additional treatment will be included in the model, and measurements taken 
between additional treatment and 1 year will be considered missing for the purpose of the primary analysis. 
The model will include fixed effects for treatment group, time, request for additional treatment, and 
interactions between those variables. It will also be adjusted for the design effects of stratification by center 
and by baseline urge IE group. Thus, the models will allow for different trajectories of change for women 
who are or are not randomized to BPTx and for those who do or do not request additional treatment. A 
statistical test based on the model will be conducted to assess whether mean changes from baseline in UDI 
scores at 1 year are significantly different between the two treatment groups, accounting for the percent of 
women in each group who request additional treatment. Sensitivity analysis will be conducted to test the 
robustness of test results to model specifications.  
We will report whether change in total UDI score between baseline and one year is significantly 
different in the two groups. If the difference is statistically significant, the potential clinical significance of the 
difference will be discussed. We recognize that our sample size would allow us to find a difference between 
groups that is statistically significant yet smaller than published MIDs for total UDI score for women with 
MUI. However, published MIDs were calculated based on populations that may be somewhat different from 
the one targeted for enrollment in ESTEEM, and a secondary aim of ESTEEM is to explore whether the true 
MID in this population differs from previously published values.  
 
6.2.2. Secondary aims 
 
The mean change from baseline in UDI-irritative and UDI-stress scores at 1 year will be compared 
between groups using the same analysis methods described for the primary outcome. If the difference is 
statistically significant, the potential clinical significance of the difference will be discussed. Additional 
analyses will be conducted to determine whether the MIDs in this MUI population differ from previously 
published MIDs. 
 
6.2.3. Exploratory aims 
a.  Other UUI/OAB outcomes  
Bladder diary 
 
We will compare change in number of urge IEs and urgency-episodes and nocturia episodes 
between groups from baseline to 6 and 12 months. Of note, not all four symptoms of OAB (frequency, 
urgency, nocturia, and UUI) are required to be present at baseline for eligibility into this trial (only UUI 
required).  Changes from baseline in bladder diary outcomes will be calculated and analyzed using the 
methods described for the analysis of the primary outcome. 
 
For urinary frequency, women reporting on average >8 voids/24 hours at baseline will be considered 
symptomatic, and normalization of voiding frequency will be defined as < 8 voids/24 hours at 1 year. A 50% 
improvement will be defined as a reduction by half in the number of voids that patients had at baseline.  The 
number of women who had normalization of voiding frequency and 50% improvement will be compared 
between groups separately and collectively. We will also assess the proportion of women who had 
worsening of urinary frequency (includes women who developed de novo frequency and those who 
worsened). These dichotomous outcomes will be analyzed using logistic regression, controlling for the 
design effects of stratification by center and by baseline urge IE group. To assess the impact of additional 
treatment prior to 1 year, sensitivity analyses will be conducted in which women who request additional 
treatment will be assigned the less-favorable outcome. 
 
OAB-SAT-q and OAB-q 
 
For these scales and associated subscales, differences from baseline will be calculated for the OAB-
q, and methods described for analysis of the primary outcome will be used to test for differences between 
treatment groups at 12 months. For the OAB-SAT-q, differences in post-treatment scores will be compared 
between groups. 

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b. Differences in time to failure between groups  
 
Although our primary outcome is at 12 months, the team was interested in whether perioperative 
BPTx may be associated with a delayed time to failure compared to Control. In other words, is BPTx 
associated with a significant effect, but the effect is not sustained at the 12 month time point?  For example, 
if BPTx could delay the need for anti-muscarinics for up to 9 months, this would be relevant information for 
counseling women and perhaps clinically recommending perioperative BPTx. As described previously, 
failure will be defined as initiation of any additional treatment for either SUI or UUI/OAB symptoms. 
 
A class of survival model which can account for interval censoring (outcomes measured at pre-
planned time points as opposed to continuously over time) will be used to determine if combined 
MUS+BPTx is associated with a decrease time to failure compared to MUS alone between 3-12 months. 
Depending on the distribution of the observed data, an accelerated failure time frailty model or a Bayesian 
survival model may be used. The model will be adjusted for the design effects of stratification by center and 
by baseline urge IE group. 
 
c. Predictors of treatment success and failure  
 
Regression models will be created to identify predictors of change from baseline to 1 year for UDI 
total score and stress and irritative subscale scores. Participants who request additional treatment prior to 1 
year will not be included in the predictive models. Potential predictors will include age, diary parameters 
such as number of UUI episodes/3 days, functional bladder capacity, bother severity at baseline. The 
relationship between potential predictors and outcomes will be explored in models that include one predictor 
plus stratification factors (center and baseline urge IE group). Predictive models will be constructed using 
backward selection of predictors. The impact of collinearity between predictors will be assessed and the 
final model modified as necessary. 
   
d. Quality of life/global impression 
For these scales and associated subscales, differences from baseline will be calculated and 
methods described for analysis of the primary outcome will be used to test for differences between 
treatment groups from baseline and 6 and 12 months.  
 
e. To describe safety and initiation of additional treatment for worsening OAB and/or persistent SUI 
 
We will describe rates of sling revision due to worsening OAB symptoms and rates of additional 
treatment. 
 
f. To determine MIDs and clinically meaningful MUI definitions that predict clinical outcomes.  
  
                We will explore potential MIDs for UDI total score and stress and irritative subscores for this MUI 
population. MIDs will be calculated using anchor- and distribution-based approaches. Potential anchors 
include global impression of change, incontinence episodes from the bladder diary, and request for 
additional treatment.  
We will attempt to create threshold definitions, based on baseline measures of the UDI, IIQ, OAB-q, 
UDE, and baseline bladder diary parameters in isolation and in combination, that are predictive of clinical 
success at 1 year. Definitions of success will be based on a change from baseline in total UDI score, UDI-
irritative score or UDI-stress score at least as large as the MID for this MUI population. 
 
g. To compare pelvic floor muscle strength changes between women randomized to combined MUS+BPTx 
versus MUS alone, to estimate associations between pelvic floor muscle strength improvement and UI 
symptoms, and to identify predictors of unsuccessful pelvic floor muscle strengthening and urge 
suppression and their effects on urinary outcomes in women randomized to BPTx 
 
As mentioned above, all women will undergo PFM strength measurements using the Peritron device 
by masked coordinators at baseline, postoperative at 2 weeks, 8 weeks (end of intervention), and 12 
months (primary endpoint). The difference in the maximum pelvic floor muscle contraction pressure 
(maximum amplitude) will be compared between the BPTx and the control groups. A table of comparative 

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studies using the Peritron device to measure PFM strength changes with PFM therapy is provided in Table 
12 below. 
Based on the existing comparative studies using the Peritron, continent women have a maximum 
amplitude PFM contraction between 36-45 cm H2O. Incontinent women have significantly lower maximum 
contractions, ranging from 15.5 to 26.5 cm H2O, with most studies showing a maximum contraction of 25 
cm H2O. In these studies, incontinent women can improve their maximum contraction pressure up to 34-41 
cm H2O with PFM training, which is comparable to continent women. In addition, these studies report 
women experience significant improvement in UI symptoms, although there is limited information on the 
direct specific relationship between PFM strength changes and UI symptom changes. 
Assuming that women in ESTEEM will have a mean baseline PFM maximum contraction amplitude 
of 25 cm H2O, and that women randomized to control will not demonstrate significant improvement 
postoperatively (no change from mean maximum amplitude of 25 cm H2O (SD 13), and that  women 
randomized to BPTx will demonstrate improvement to 35 (SD 13) to 40 (SD 16) cm H2O at 6-12 months, 
the power to detect a difference between the groups with the current ESTEEM sample size of 400 women 
would be greater than 0.99.  Also, the difference from 25 (SD 13) that we could detect with 80% power is 
3.66 cm H2O between groups and with 90% power we could detect a difference as small as 4.23 cm H2O.  
 
For analyses, we will compare the mean change from baseline in PFM maximum contraction 
strength between the BPTx and control groups at 8 weeks and at 12 months. General linear mixed 
modeling will be used, controlling for stratification factors and time (8 weeks and 12 months). We will test 
whether there is significant interaction between treatment group and time. Because additional treatment is 
not expected to impact this outcome, it will be ignored for the purpose of this analysis. We will estimate the 
correlation between PFM strength and UI symptoms at baseline and at 12 months. Using regression 
models, we will also explore potential predictors of unsuccessful pelvic floor muscle strengthening and urge 
suppression and their effects on urinary outcomes. We will assess the effect of self-efficacy114, 115, 
adherence, and barriers to performing pelvic muscle contractions and behavioral therapy. 
 
 
Table 12. Comparative studies using Peritron measurement of pelvic floor muscle strength 
 
Author 
Pop 
Study details 
Baseline PFM 
strength (SD)* 
Post-
treatment 
PFM strength 
(SD) 
P-value 
Notes 
Rett 
2007116 
SUI 
N=26 
Single cohort PFME 
with sEMG 
biofeedback 
Max amp= 24.5 (16) 
After 12 
sessions: 
40.0 (17) 
<.0001 
No info on “subjective 
improvement” and PFM 
strength 
Overall cohort: 
Obj cure = 61.5% 
Subj cure = 23% 
Subj “almost 
cure”=65.4% 
 
Gameiro 
2010117  
Any UI 
N=103 
RCT 
G1 =vag cones 
G2 =APFMT 
Max amp: 
G1=24.4 (12.5) 
G2=20.0 (12.9) 
6 mos: 
G1=40.8 
(15.73) 
G2=35.16 
(11.05) 
 
12 mos: 
G1=34.98 
(13.2) 
G2=34.12 
(9.84) 
P<.05 for 
both 
*No specific correlation 
btwn subjective “cure” 
and PFM strength; 
however: 
a. Reduction of pads 
better for G1 
b. # micturitions, 
nocturia, UI episodes, 
urgency, pad test ND 
btwn grps 
Amaro 
2005118 
SUI 
N=101 
Comparative cohort 
G1 = SUI 
Max amp:  
G1=26.1 (1.15) 
G2=38.4 (1.33) 
 
P<.001 for 
all 3 
baseline 
 

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G2=controls 
 
Mean amp: 
G1=15.4 (.62) 
G2=28.1 (1.22) 
 
Duration (s) 
G1=8.9 (.17) 
G2=11.8 (.96) 
comparisons 
Gilling 
2009119 
SUI 
N=70 
RCT 
G1=Estim 
G2=Sham 
Max amp: 
G1=17.3 (1.8) 
G2=15.5 (1.9) 
8 wks: 
G1=19.2 (2) 
G2=15.1 (1.9) 
ND 
Subgroup findings: 
“Patients with poor 
initial PFM ctx by 
perinometer 
randomized to Estim 
had better UI outcomes 
than sham” but cannot 
tease out their PFM 
scores 
Hung 
2011120 
Any UI 
 
N=23 PMT 
Prospective cohort, 
pre- post- PFM 
program 
65% SUI 
35% MUI 
39% UUI 
Max amp: 
27 (15.0) 
4 mos: 
41 (24.9) 
<.001 
 
Gamerio121 
SUI vs UUI 
N=51 
Cross-sectional 
G1=SUI (N=22) 
G2=UUI (N=29) 
Max amp: 
G1=26.5 (3) 
G2=21.7 (.79) 
 
Mean peak 
G1=16.56 (1.19) 
G2=13.72 (0.56) 
 
Duration: 
G1=9.54 (0.18) 
G2=8.43 (.42) 
 
P<.001 for 
all 3 
baseline 
comparisons 
Unclear clinical 
meaning 
 
h. To determine the cost effectiveness of combined midurethral sling (MUS) and peri-operative 
behavioral/pelvic floor therapy (BPTx) compared to MUS alone on successful treatment of MUI symptoms 
 
Differential mean costs and differential mean QALYs between the two treatment groups will be 
estimated using multiple regression analysis. Specifically, a generalized linear model with appropriate link 
function (e.g., log-link) and response probability distribution (e.g., gamma distribution) will be used to 
analyze costs due to the potential skewness and heteroscedasticity of medical expenditure data, while an 
ordinary least squares regression will be used for analyzing QALY data. The models will account for 
treatment group, study site and stratification factors, as well as other characteristics of the subjects that are 
found to differ significantly between the groups. When estimating QALYs, we will also adjust for subjects’ 
baseline utility scores to account for potential imbalance in baseline utility between the two treatment 
groups.122 
We will calculate the incremental cost-effectiveness ratio (ICER), which is the differential mean costs 
divided by the differential mean QALYs between the two groups, to assess the additional costs associated 
with each additional QALY gained. Our base case analysis will be conducted based on subjects with 
complete data. Sensitivity analysis will be conducted to include subjects with incomplete data using the 
multiple imputation method.  Non-parametric bootstrapping resampling technique will be used to derive the 
95% confidence interval for the ICER.118, 123 In addition, cost-effectiveness acceptability curve (CEAC) will 
be generated to illustrate the likelihood that one treatment is more cost-effective than the other with various 
ceiling cost-effectiveness ratios.  
In the case that a statistically significant difference in changes in utilities (as measured by EQ-5D) 
between the treatment groups is not detected, we plan to conduct supplemental analyses using alternative 

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outcome measures, such as incremental cost per treatment success, incremental cost per  HRQOL, or 
incremental cost per satisfaction.  
The cost-effectiveness evaluations will be conducted as within-trial comparisons. A decision analytic 
model will also be developed from trial data to evaluate the trajectory of the cost-effectiveness ratio over a 
lifetime; assuming an average life expectancy, given the average age of participants at the time of the 
intervention. 
 
6.3. Interim data monitoring 
 
Safety outcomes will be assessed at each DSMB meeting. This will include the need for sling 
revision due to worsening OAB symptoms. Rates of sling revision and other safety outcomes will be 
compared between treatment groups using Fisher’s exact tests and provided to the DSMB. There is no 
established guidance regarding what sling revision rate is “appropriate” for worsening OAB symptoms in this 
population: this is one of the exploratory aims of this study.  
Since we expect to enroll ESTEEM within 2 years, and since the primary outcome is attained at 12 
months following surgery, we propose that no interim analyses of outcomes will be performed. Thus, reports 
to the DSMB will not include outcome data until primary outcomes have been attained for all participants. At 
each meeting, the DSMB will be presented with information about enrollment and outcome data attainment 
(for example, the percent of expected clinic visits that have been completed) to allow them to determine that 
the study is making reasonable progress. 
 
7. Ethical Concerns/Safety 
7.1. Ethical Concerns 
 
As discussed in the background section, current clinical practice varies with respect to treatment of MUI and 
likely reflects training and experiential bias.  Although treatment with behavioral modifications and Kegel 
exercises have been described as effective first line treatments for mild stress, urge, and mixed urinary 
incontinence, many patients go on to request further therapy for their condition.  For moderate symptoms of 
SUI or UUI additional therapeutic options are generally offered based on treatment paradigms geared 
toward each of these conditions.  When patients have MUI, clinicians must decide which component (the 
SUI or the UUI) should be addressed first.  There is very little evidence to support a defined treatment 
strategy in this patient population and most recommendations are based on expert opinion.  The only way to 
test the superiority of one approach over another is in the setting of a randomized clinical trial.  We have 
carefully designed this trial to balance the risks and benefits to subjects. All patients in this study have 
elected to undergo surgery for SUI.  Therefore, they will have already been offered more conservative 
therapies. We will be assured that women will have either previously tried behavioral or pelvic floor therapy 
or at least have been offered this treatment because it is an inclusion criteria. In addition all patients will be 
treated with a midurethral sling and half the patients will be randomized to perioperative supervised BPTx. 
The potential benefits of the BPTx intervention are improvement of MUI symptoms while the risks are very 
small.  The benefits of BPTx in SUI and UUI alone and MUI have been documented as has the benefit of 
MUS for patients with SUI.  Several studies have also documented an improvement in OAB and MUI 
symptoms following sling.  The added benefit of a combined approach of sling plus BPTx in patients with 
MUI has not been defined and is the subject of this RCT.  Any subject can request additional treatment after 
3 months postoperative. 
 
7.2. Informed Consent 
Subjects will be clinically examined as part of screening and to ensure eligibility for the study.  Those 
subjects who are candidates for and agree to undergo sling surgery and behavioral treatment for MUI will 

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be approached for enrollment into the trial.  Clinical and research staff will describe the study in detail and 
answer any questions the subject may have. Written informed consent for trial participation will be obtained 
at that time.  A common template for the research informed consent form will be used by all of the clinical 
sites, modifying the content or format as necessary to meet the requirements of their respective institutional 
human subjects committees.  This protocol must be approved by the IRBs at the clinical sites and DCC 
before study implementation. 
 
7.3. Data Safety Monitoring Board 
The National Institutes of Health has set up a Data Safety Monitoring Board (DSMB) to oversee all PFDN 
studies, including this study.  Members of the DSMB are independent of the study investigators and 
represent Urology, Urogynecology and Biostatistics, as well as having a lay member. The DSMB meets 
every 3 months, or more frequently if requested by the Chair, either in person or by teleconference.  This 
protocol has been approved by the DSMB prior to implementation. Safety outcomes will be assessed in a 
descriptive manner at each DSMB meeting without formal statistical tests. This will include the need for 
sling revision due to worsening OAB symptoms. There is no established stopping rule to guide what sling 
revision rate is “appropriate” for worsening OAB symptoms in this population. 
 
7.4. Reporting of serious adverse events 
Each clinical investigator is responsible for reporting serious adverse events (SAEs) to the IRB per their IRB 
guidelines at their institution, and to the DCC. The DCC Safety Specialist reviews and summarizes the SAE 
per DCC SAE reporting procedures for the PFDN.  
7.5. Adverse events 
Adverse events are defined as untoward medical events that are temporally-related to participation 
in a clinical study, regardless of whether they are causally-related to the study. Adverse events will be 
collected during the course of this study and reported to the DSMB as described above.  
Sling surgery is a commonly performed operation for the treatment of SUI and MUI.  Like all surgical 
interventions it has the risk of bleeding, infection, and injury to surrounding structures.  In addition, the sling 
procedure utilizes polypropylene mesh which can introduce additional risk of mesh complication.  These 
include vaginal mesh extrusion, mesh infection, and bladder or urethral mesh erosion.  Complications 
specific to sling placement include bladder perforation, retropubic hematoma, obturator nerve or vessel 
injury, groin pain, worsening incontinence, and worsening OAB.  The FDA has recently issued guidelines on 
the use of surgical mesh and has recommended it only be used by trained surgeons.  All surgeons 
participating in this study will be specifically trained to use surgical mesh. 
 
8. Feasibility 
 
The proposed study population has already chosen to undergo surgical treatment and the BPTx 
intervention is low risk. We have taken care to have comparable arms in a clinical efficacy trial design with 
inclusion criteria that are not overly-strict; therefore, we do not anticipate particular difficulty in recruitment of 
MUI patients as encountered in MIMOSA.37 If needed in the postoperative period, medical therapy will not 
be withheld after 3 months postoperative. Women reporting bothersome OAB symptoms for which they 
desire additional treatment will be presented their options (additional BPTx and/or FDA approved OAB 
pharmacologic therapy, or other procedures or surgeries), and additional treatment will be offered. Request 
for additional treatment for either OAB or SUI postoperatively will be driven by patient preference and 
clinician judgment in both groups. 

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9. References 
 
1. 
Katsumi HK, Rutman MP. Can we predict if overactive bladder symptoms will resolve after sling 
surgery in women with mixed urinary incontinence? Curr Urol Rep;11:328-37. 
2. 
Shumaker SA, Wyman JF, Uebersax JS, McClish D, Fantl JA. Health-related quality of life measures 
for women with urinary incontinence: the Incontinence Impact Questionnaire and the Urogenital Distress 
Inventory. Continence Program in Women (CPW) Research Group. Qual Life Res 1994;3:291-306. 
3. 
Yalcin I, Bump RC. Validation of two global impression questionnaires for incontinence. Am J Obstet 
Gynecol 2003;189:98-101. 
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10. ESTEEM Ancillary Study: Goals among women with mixed urinary incontinence undergoing 
midurethral sling surgery randomized to behavioral therapy or no behavioral therapy (GloW) 
 
Patient reported outcome (PRO) measures are of critical importance in the evaluation of functional 
disorders because anatomical and physiologic tests do not precisely correlate with patient experience. 
Symptom severity and quality of life questionnaires partly fill this gap. The Urinary Distress Inventory (UDI), 
a measure of pelvic floor symptoms, the Pelvic Floor Impact Questionnaire (PFIQ) and the Pelvic Organ 
Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ), measures of health related quality of life, are 
commonly used symptom and quality of life questionnaires. Within the PFDN, these questionnaires are 
used in conjunction with physical exam and physiologic testing to measure disease burden and to assess 
cure. While these questionnaires characterize the severity of symptoms and their impact on quality of life, 
they do not rank symptom importance nor do they provide an individualized blueprint of what women hope 
to achieve with treatment. More recently, goal attainment scaling (GAS) has emerged as an established 
methodology of determining individual women’s goals and whether or not they meet personalized goals 
following treatment.  
 
In goal attainment scaling, patients are asked to list goals and rank their importance; following treatment, 
women rate whether or not the goal was achieved. Patient-identified goals have been described as the 
“fourth dimension” of pelvic floor disorder assessment, after physical findings, symptoms, and quality of life. 
(Lowenstein, 2008) Individualized goals are not adequately captured by traditional symptom severity or 
quality of life measures. For example, among a group of 200 women seeking care for pelvic floor 
dysfunction, continence goals were ranked more highly than resolution of bulge symptoms, despite the 
presence of advanced (Stage 3) prolapse on exam and bother reported on the PFDI.(Elkardy, 2013) In a 
UITN randomized trial with standardized video consent (SIStr), women undergoing SUI surgery had high 
expectations for treatment of not only SUI symptoms, but also for treatment of their urgency and frequency, 
despite being told in that study that the midurethral sling (MUS) was not designed to resolve their urgency 
symptoms, documentation of stress incontinence on urodynamics and bother and quality of life changes 
consistent with SUI reported on the PFDI and PFIQ.(Mallett, 2008) Among women with a variety of pelvic 
floor disorders, patient goals and expectations vary and are linked to treatment satisfaction. (Elkardy, 2003; 
Hullfish 2004; Komesu 2008) Conversely, unmet goals are closely associated with patient dissatisfaction 
after treatment. (Elkardy, 2003; Hullfish 2004; Komesu 2008) Despite the importance of individualized goal 
setting, prior goal attainment scaling studies in urogynecology are limited by inclusion of small numbers of 
women with an array of pelvic floor dysfunction, lack of assessment of the difference between short and 
long term goals, and have not consistently followed women after treatment to determine whether their goals 
are achieved. A key gap in our understanding of mixed urinary incontinence and women’s 
expectations following treatment is accurate goal characterization and determination of whether or 
not goals are attained in the short and long term following treatment. ESTEEM provides an ideal study 
setting in which to answer this question. 
 
ESTEEM will compare the effect of peri-operative behavioral/pelvic floor therapy (BPTx) plus MUS to 
MUS alone on MUI treatment in 472 women. This trial provides an ideal setting in which to describe 
individualized goals for MUI treatment as well as the importance of goal attainment on women’s impression 
of cure. This, in turn, will enable providers to ultimately negotiate expectations so that providers and patients 
have better communication regarding the benefits and limitations of various treatments for mixed urinary 
incontinence. The long-term goal of this supplementary study to ESTEEM is to better understand patient 
expectations following treatment for MUI in order to provide patients and providers an informed platform 
for discussion of treatment options and realistic outcome expectations. The objectives of this proposal 
are to describe patient centered goals among a group of women with MUI undergoing midurethral sling 
surgery with and without BPTx as well as determine whether or not these goals were met following 
treatment using the validated Self-Assessment Goal Achievement (SAGA) questionnaire. Our expectation 
is that a better understanding of individualized patient goals will improve patient-provider communication, 

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and provide a unique aspect of patient reported outcomes not currently measured with standard 
symptom severity and quality of life measures.  
Aim 1: To describe patient reported goals and goal ranking among women consenting to ESTEEM. We 
hypothesize that women’s goals vary and are not currently captured by standard symptom severity and 
QOL measures. 
Aim 2: To determine whether or not women achieve self-reported goals following treatment for MUI and 
to compare those who achieve their goals to those who do not in both the intermediate (6 months) and 
longer term (12 months). We hypothesize that women who report and rank continence related goals are 
more likely to achieve those goals than goals related to general health and specific activities and that goal 
achievement is related to patient’s PGI-I scores.  
Significance: PROs are critical to the assessment of pelvic floor dysfunction, yet standardized measures of 
symptom severity and quality of life may not capture an individual women’s motivation and expectations for 
seeking treatment. Goal attainment scaling is an established methodology of describing and ranking 
individual goals and has been used in a variety of fields including treatment of pelvic floor 
dysfunction.(Khuller, 2013) Goal attainment scaling offers unique insight into individual concerns regarding 
common disorders, such as MUI. While it is known that the impact of pelvic floor dysfunction varies between 
individuals with similar physiologic measures of disease, the underpinnings of what explains the differences 
in bother and impact on quality of life are less well characterized. In addition, patient expectations are likely 
to drive care seeking as well as adherence to treatment regimens and are, in turn, correlated with 
satisfaction with those treatment outcomes. MUI is a common disorder with lack of consensus regarding 
treatment; ESTEEM will test whether or not BPTx is beneficial prior to and following sling surgery. A key 
aspect of understanding women’s satisfaction with these treatment options is determining the importance of 
various lower urinary tract symptoms to individuals and what individualized goals women have for 
treatment.  
 
Innovation: Mixed urinary incontinence is bothersome to women and often presents a treatment 
conundrum to providers. The symptom of urinary leakage is what concerns the patient most, yet the etiology 
of the UUI and SUI are thought to be different and the treatments for one may lead to exacerbation of the 
other. While ESTEEM will measure symptom severity and quality of life for both SUI and UUI symptoms, 
currently the protocol does not contain a measure of the importance of alleviating specific symptoms to 
individual women. In addition, women participating in the trial likely have unique goals and concerns not 
currently captured with standard symptom severity and quality of life measures presently included in this 
study. Inclusion of the SAGA questionnaire at baseline, six months and one year after MUS with or without 
BPTx will offer the PFDN the opportunity to characterize treatment goals in a large number of women with 
MUI undergoing MUS surgery and assess whether or not those goals are achieved. While goal attainment 
scaling is an established method of assessing individual goals, until recently, a standardized and valid 
measure of assessing goals was not available. The SAGA questionnaire has been validated among women 
with lower urinary tract symptoms and fills that void.(Brubaker, 2013) SAGA consists of nine standardized 
goals regarding urinary symptoms, and asks women to rate the importance of these standardized goals on 
a scale from 0 (not applicable) to 5 (very important goal). In addition to these common goals, women are 
asked to record up to five of their individualized goals and rank them in a similar fashion. At follow-up 
following treatment, women are asked to rate whether or not they achieved their goals on a scale from 1 
(did not achieve goal) to 5 (greatly exceeded goal). Importantly, the common goal list of 9 items was 
generated from patient and expert interviews, and has undergone validation both within the US and abroad. 
Adequate face, concurrent, known-groups, and convergent validity and item distribution validity have been 
determined in a pilot study of 104 subjects and re-evaluated on an international basis in an additional 29 
subjects. Reliability and internal consistency testing was not performed because goals were assumed to 
vary between individuals. This proposal is innovative, in our opinion, because it will assess goal setting 
using a newly validated questionnaire in a large group of women with MUI, a common condition which is 
difficult for patients to understand and for providers to explain, and will determine whether goal attainment is 
linked to patient global impression of improvement both in the short and long term.  Finally, this innovative 
proposal offers the PFDN the opportunity to add an translational aim to ESTEEM by linking the clinical 

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science of a comparative effectiveness trial to individual patients seeking care.  This ultimately may inform 
community dwelling women’s decisions to pursue or not to pursue care. 
 
Approach:  
Aim 1: To describe patient reported goals and ranking of goals among women consenting for ESTEEM. We 
hypothesize that women’s goals vary and are not currently captured by standard symptom severity and 
QOL measures. 
 
Introduction: Assessment of individualized patient goals offers a unique perspective of expectations and 
goals with treatment that current PROs do not capture. The objective of this aim is to administer the SAGA 
questionnaire at women’s baseline visit in ESTEEM and to describe their ranking of the nine standardized 
questions in SAGA. In addition, women will be asked to list up to five individualized goals for treatment and 
also rank their importance. Our working hypothesis is that the importance of the 9 common goals will vary 
between individuals. In addition we hypothesize that women will list a variety of individual goals which are 
not presently represented by symptom severity and quality of life measures. We will achieve this aim by 
administering the SAGA questionnaire at baseline in women recruited to ESTEEM. Our expectation is that 
the description of baseline goals of women recruited to ESTEEM will offer insight into what women are 
seeking with treatment for their MUI. 
 
Methods: Women will be administered the baseline set of nine pre-specified goals as well as be asked to 
list up to 5 individual goals for their therapy. Goals will be ranked on a 6 point scale from 0-Not applicable to 
5 – very important goal. In the original validation study of the SAGA, women randomly completed either the 
pre-specified or self-specified goals first.  No order effects were noted in the numbers of goals listed or 
ranking of nine pre-specified goals. For this study, women  
will complete the nine pre-specified goals  
followed by listing their individual goals. 
Individualized goals will be transcribed and 
entered into the patient database; these goals 
will then be presented to the patient in follow-
up assessment of goal achievement in Aim #2. 
Table 1 is the SAGA questionnaire. 
 
Aim #1 is descriptive in nature therefore the 
analyses are qualitative versus quantitative. 
For self-selected goals, goals will be classified 
by the study working group into categories.  
The working group will review the goals in 
order to generate categories; goals will be 
categorized and then compared across 
individual categorization.  Development of 
categories and categorization will be by 
consensus. For the analysis of ranking, each 
subject’s goal ‘selection’ will be ranked with #1 
for their 1st choice, #2 for their 2nd choice and #3 for their 3rd choice. We will rank goals on a preferential 
ballot which will be ultimately based on the number of goal categories identified by qualitative expert review 
for individualized goals and for nine categories in the pre-specified goals.   
 
A preferential ballot allows for comparison of goal rankings between individuals and assigns a value to each 
goal subdomain listed per individual, and a standard value to any goal subdomain identified in the entire 
population but not listed for a particular individual. A preferential ballot is used in political elections, but can 
also be used to prioritize preferences across individuals and is referred to as a “Borda count”. Originally 
designed for political elections when there were multiple candidates on a ballot, Borda counts determine the 
Table 1: Self-Assessment Goal Achievement 
Q
ti
i

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“winner” of a ballot by giving each candidate on the ballot points corresponding to the position in which the 
candidate is ranked by each voter. Once all votes have been counted, the candidate with the most points is 
the winner. In our analysis, a modified Borda preferential ballot consists of candidates (here, the list of goal 
subdomains) and a ballot for each participant, in which a rank of 1 is assigned for the participant’s highest 
ranked goal, a rank of 2 for their second highest ranked goal, and so on. If a participant doesn’t rank all of 
the candidates (goal subdomains), then the mid-rank of the un-used ranks are assigned – this assures each 
ballot receives equal weight in the ballot count. The derivation of mid-rank was calculated by summing the 
remainder of the ranks divided by number of left over ranks. The first winner is based in lowest average 
rank across all ballots, the second winner is based in second lowest average rank, and so on. The analysis 
of ballots can be done simply by computing the average rank for each goal category across all ballots.  
 
Since this aim is qualitative in nature a formal power analysis was not computed; given the number of 
women who will be recruited to ESTEEM, we should have more than enough subjects to reach saturation 
on goal categories and to evaluated even small difference between goal rankings. 
 
Potential Problems and Solutions: It may be that women have difficulty in generating individualized goals, 
although prior research has documented that women, on average, do not have difficulty generating up to 4 
goals in prior studies.  If women have difficulty generating goals, they will be prompted by the coordinators 
to list what they wish to achieve with their treatment; this will be done without prompting for specific goals to 
avoid bias. 
 
Aim 2: To determine whether or not women achieve self-reported goals following treatment for MUI. We 
hypothesize that women who report and rank specific continence related goals are more likely to achieve 
those goals than goals related to general health and specific activities and that achievement of these goals 
will be related to patient’s PGI-I scores. In addition, we hypothesize that women whose goals are achieved 
will report better global improvement in continence and quality of life than women who do not achieve their 
goals. 
 
 
 Introduction: Achievement of patient goals offers a unique perspective of patient’s assessment of 
outcome of treatment. The objective of this aim is to administer the SAGA follow-up goal achievement 
questionnaire at women’s follow-up visits in ESTEEM at 6 and 2 months.  We will describe women’s goal 
achievement and compare which goal categories are more likely to be achieved.  In addition, we will 
correlate goal achievement with PGI-I scores to further evaluate which goals are best correlated with 
patient’s global impression of improvement. Finally, we will observe whether goal achievement is stable 
between 6 and 12 months by comparing goals achievement at the two timepoints. Our working hypothesis 
is that goal achievement varies between individuals and that women who rank continence goals will be 
more likely to achieve those goals than goals not related to continence.  In addition we hypothesize that 
goal achievement changes over time and that more women will achieve goals at 6 months than do at one 
year. Finally, we hypothesize that goal achievement will be significantly correlated with PGI-I scores.  We 
will achieve this aim by administering the SAGA follow-up questionnaire at 6 months and one year in 
women recruited to ESTEEM. Our expectation is that goal achievement varies over time and between 
individuals based on baseline goal setting and treatment efficacy. 
 
Methods: Women will be administered the follow-up SAGA questionnaire at 6 months and one year follow-
up in the ESTEEM trial.  The follow-up questionnaire is similar to the baseline questionnaire in that it still 
contains the 9 pre-specified goals and a list of the patient’s self-determined goals established at baseline.  
The response categories for follow-up are 1 (did not achieve goal) to 5 (greatly exceeded goal).  The 
number of goals for each patient will vary as women may report less that 5 self-determined goals, and they 
may have ranked some of the nine pre-specified goals as “not-applicable” at baseline.   
 
Again a Borda count system will be used to rank in this cohort goals and goal categories that were most 
likely to be achieved and we will describe the goals that were more likely to be achieved in this cohort at 6 

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months and one year.  In the original validation study, a cut off T score of > 50 was determined to indicate 
women who achieved their goals, versus women who scored </= 50 who did not achieve goals according to 
the formula provided by Kiresuk and Sherman (T-scores with mean = 50 and SD = 10). (Kiresuk, 1968) 
Weights will be applied to women’s individualized goal achievement ratings. We will compare women who 
achieve goals to those who do not at 6 and 12 months to determine both if there are baseline differences 
between those women who achieve goals and do not, and if there is a different pattern of goal attainment at 
short term (6 months) and longer term (12 month) follow up.  
 
Potential problems and Strategies to overcome them:It is possible that women will rank goal attainment 
highly for all listed goals and that there will not be differences noted between continence goals and self 
stated goals.  In this instance the data generated are still valuable because the negative findings are 
informative to the counseling of patients. 
 
References: 
 
Adams S, Dramitinos P, Shapiro A et al.  Do patient goals vary with stage of prolapse? Am J Obstet 
Gynecol 2013; 205:502.e1-6 
 
Brubaker L, Piault EC, Tully SE et al.  Validation study of the self-assessment goal achievement (SAGA) 
questionnaire for lower urinary tract symptoms. Int J Clin Pract 2013; 67(4): 342–350.  
 
Brubaker L, Khullar V, Piault E et al.  Goal attainment scaling in patients with lower urinary tract symptoms: 
development and pilot testing of the Self-Assessment Goal Achievement questionnaire. Int Urogynecol J 
(2011) 22:937–946 
 
Elkadry EA, Kenton KS, FitzGerald MP, Shott S, Brubaker L. Patient-selected goals: a new perspective on 
surgical outcome. Am J Obstet Gynecol. 2003 Dec;189(6):1551-7; discussion 1557-8. 
 
Hullfish KL, Bovbjerg VE, Steers WD. Patient-centered goals for pelvic floor dysfunction surgery: long-term 
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Khuller V, Espuna-Pons M, Marschall-Kehrel D et al.  Clinical value of a patient-related goal attainment 
measure: The global development of Self-Assessment Global Achievement (SAGA) Questionnaire for 
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Khullar V, Marschall-Kehrel D, Espuna-Pons M et al.  European content validation of the Self-Assessment 
Goal Achievement (SAGA) questionnaire in patients with overactive bladder.  Int Urogynecol J 2013; DOI 
10.1007/s00192-012-2039-x 
 
Kiresuk T, Sherman R. Goal attainment scaling: a general method of evaluating comprehensive community 
mental health programs. Community Ment Health J 1968; 4: 443–53. 
 
Komesu YM, Rogers RG, Rode MA, Craig EC, Schrader RM, Gallegos KA, Villareal B. Patient-selected 
goal attainment for pessary wearers: what is the clinical relevance? Am J Obstet Gynecol. 2008 
May;198(5):577.e1-5. 
 
Lowenstein L, Fitzgerald MP, Kenton K, et al. Patient-selected goals: the fourth dimension in 
assessment of pelvic floor disorders. Int Urogynecol J Pelvic Floor Dysfunct 2008;19:81-4. 
 
Mallet V, Brubaker L, Stoddard AM et al. The expectations of patients who undergo surgery for stress 
incontinence.  Am J Obstet Gynecol 2008;198:308.e1-308.e6.