Treatment for Mixed Urinary Incontinence: Mid-urethral Sling vs. Botox A
Phase: PHASE3
Conditions: Urinary Incontinence, Stress, Urinary Incontinence, Urge
Sponsor: NICHD Pelvic Floor Disorders Network

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
1 
Version 4.0 
01 22 2021 
 
 
CONFIDENTIAL 
 
 
Pelvic Floor Disorders Network 
 
Protocol 
Treatment for Mixed Urinary Incontinence: Mid-urethral Sling vs. Botox A (MUSA) 
 
Short title: Sling vs Botox for Mixed Incontinence 
 
 
 
 
Concept Proposal:  Approved by Steering Committee: January 27, 2017 
Mini Protocol:  Approved by Steering Committee: July 19, 2019 
Protocol: Approved by Steering Committee: December 16, 2019 
 
 
Revised:  
 
January 10, 2020 after DSMB review, Approved by DSMB: February 19, 2020 
May 11, 2020 revised, Approved by DSMB: May 18, 2020 
June 30, 2020 revised 
November 9, 2020 revised, Approved by DSMB: December 18. 2020 
January 22, 2021 revised, Approved by DSMB February 12, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 Project 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
2 
Version 4.0 
01 22 2021 
Protocol Chair: 
Heidi S. Harvie 
University of Pennsylvania 
Division of Urogynecology 
3400 Spruce Street, Dulles Building 5th Floor 
Philadelphia, PA 19104 
hharvie@pennmedicine.upenn.edu 
 
 
 
Protocol Committee: 
Brown/Women and Infants: Vivian Sung 
Duke University Medical Center: Cindy L. Amundsen 
University of Alabama at Birmingham: Holly E. Richter 
Kaiser Permanente-San Diego: Shawn Menefee 
University of Pennsylvania: Lily Arya (Co-Chair) 
University of Pittsburgh: Christopher Chermansky 
University of Texas Southwestern: David Rahn 
RTI DCC: Sonia Thomas 
NIH/NICHD: Donna Mazloomdoost 
 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
3 
Version 4.0 
01 22 2021 
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 
CIC 
Clean intermittent catheterization 
CST 
Cough stress test 
DCC 
Data Coordinating Center 
DO 
Detrusor overactivity 
DSMB 
Data and Safety Monitoring Board 
ESTEEM 
Effects of Surgical Treatment Enhanced with Exercise for Mixed Urinary 
Incontinence trial 
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-IR 
Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire  

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
4 
Version 4.0 
01 22 2021 
POPQ 
Pelvic Organ Prolapse Quantification system 
PRO 
Patient reported outcomes 
PVR 
Postvoid residual 
QoL 
Quality of life 
QUID 
Questionnaire for Urinary Incontinence Diagnosis  
RCT 
Randomized controlled trial 
ROSETTA 
Refractory Overactive Bladder: Sacral Neuromodulation v. Botulinum Toxin 
Assessment trial 
RUBI 
Refractory idiopathic urge incontinence and botulinum A injection trial 
SAE 
Serious adverse event 
SD 
Standard deviation 
SF-36 
Short Form 36 
SF-6D 
Short Form 6D 
SISTEr 
Stress Incontinence Surgical Treatment Efficacy Trial 
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 
Urgency urinary incontinence 
ValUE 
Value of Urodynamic Evaluation trial 
VPFMC 
Voluntary pelvic floor muscle contraction 
3IQ 
3 Incontinence Questions Assessment Tool 
 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
5 
Version 4.0 
01 22 2021 
TABLE OF CONTENTS  
 
 
1. 
STUDY AIMS ..................................................................................................................................... 9 
1.1. 
Primary Aim .............................................................................................................................. 9 
1.2.  Exploratory Aims .................................................................................................................... 10 
2. 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE .......................................... 10 
2.1 
Disease/Condition Background ............................................................................................... 10 
2.1.1 
Clinical Importance of Focusing on the Urgency Component of Mixed Urinary 
Incontinence .................................................................................................................................. 11 
2.2 
What is MUI: Current Definition and challenges .................................................................... 12 
2.2.1 
Pathophysiology of MUI: Shared Mechanisms for SUI and UUI ............................... 13 
2.3 
Rationale for Considering Surgical Treatment for MUI ......................................................... 14 
2.3.1 
Behavioral/Pelvic Floor Therapy (BPTx) ................................................................... 14 
2.3.2 
Anti-Cholinergic or Beta-Mimetic Medication ........................................................... 15 
2.4 
Rationale for Considering Botulinum Toxin A Injection for Treatment of MUI in Women .. 15 
2.4.1 
Rationale for Dose of Botox A Injection ..................................................................... 17 
2.4.2 
Rationale for Subsequent Botox A Injection ............................................................... 18 
2.5 
Rationale for Considering Mid-Urethral Slings for the Treatment of MUI in Women .......... 18 
2.6 
Limitations of Existing Trials for the MUI Population ........................................................... 20 
2.7 
MIMOSA Trial: First Network Trial Attempt Focused on MUI Population .......................... 20 
2.8 
Summary of Known and Potential Risks and Benefits of Study Treatment ........................... 21 
2.9 
Significance of Proposed Study ............................................................................................... 22 
2.10 Innovation ................................................................................................................................ 23 
3. 
STUDY DESIGN ............................................................................................................................... 23 
3.1 
Description of Study Design ................................................................................................... 23 
3.1.1 
MUSA Interventions ................................................................................................... 23 
3.1.2 
Rationale for Not Incorporating the Type of MUI as inclusion criteria ...................... 23 
3.1.3 
Management of Patient Who is Unwilling for Randomization or Requests Treatment Off-
Protocol 
24 
3.2 
Masking ................................................................................................................................... 24 
3.3 
Randomization and Stratification ............................................................................................ 24 
3.4 
Outcomes ................................................................................................................................. 25 
3.4.1 
Detailed Description of Primary Study Outcome ........................................................ 26 
3.4.2 
Secondary Outcomes ................................................................................................... 29 
3.4.3 
Other Outcomes ........................................................................................................... 31 
4. 
SELECTION OF PARTICIPANTS .................................................................................................. 33 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
6 
Version 4.0 
01 22 2021 
4.1 
Eligibility Criteria/Rationale for Inclusion/Exclusion ............................................................. 33 
4.1.1 
Defining the MUSA MUI Population ......................................................................... 33 
4.1.2 
Targeting a Population That is Distinct From ESTEEM ............................................. 35 
4.2 
Inclusion Criteria ..................................................................................................................... 35 
4.3 
Exclusion Criteria .................................................................................................................... 36 
4.4 
Screening for Eligibility .......................................................................................................... 37 
4.5 
Baseline Visit ........................................................................................................................... 37 
4.6 
Appointment Scheduling and Randomization ......................................................................... 37 
5. 
DESCRIPTION OF STUDY INTERVENTIONS ............................................................................ 38 
5.1 
Mid-urethral Sling Procedure .................................................................................................. 38 
5.1.1 
Surgeon Certification ................................................................................................... 38 
5.1.2 
Standardization of Mid-urethral Sling Procedures ...................................................... 38 
5.1.3 
Need for Postoperative Mid-urethral Sling Revision .................................................. 39 
5.2 
Botox Injection ........................................................................................................................ 39 
5.2.1 
Surgeon Certification ................................................................................................... 39 
5.2.2 
Standardization of Botox Injection Procedures ........................................................... 39 
5.2.3 
Criteria for Botox Reinjections ................................................................................... 40 
5.3 
Patient Management and Follow-Up ....................................................................................... 41 
5.3.1 
Baseline Procedures ..................................................................................................... 41 
5.3.2 
Postoperative Visits and Procedures ........................................................................... 41 
6. 
STATISTICAL CONSIDERATIONS ............................................................................................... 43 
6.1 
Sample size and Power ............................................................................................................ 43 
6.1.1 
Primary Aim ................................................................................................................ 43 
6.2 
Statistical Analysis Plan .......................................................................................................... 44 
6.2.1 
Analysis Populations and Management of Study Discontinuations Prior to Receiving 
Treatment 44 
6.2.2 
Primary Aim ................................................................................................................ 44 
6.2.3 
Exploratory Aims ........................................................................................................ 45 
6.3 
Interim Data Monitoring .......................................................................................................... 47 
7. 
ETHICAL CONCERNS/SAFETY .................................................................................................... 47 
7.1 
Ethical Concerns ...................................................................................................................... 47 
7.2 
Informed Consent .................................................................................................................... 48 
7.3 
Data Safety Monitoring Board ................................................................................................ 48 
7.4 
Reporting of Serious Adverse Events ...................................................................................... 48 
7.5 
Side Effects/Safety .................................................................................................................. 48 
7.5.1 
Mid-urethral Sling ....................................................................................................... 48 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
7 
Version 4.0 
01 22 2021 
7.5.2 
Botox A ....................................................................................................................... 48 
7.5.3 
Botox A Contraindications102 ...................................................................................... 49 
7.5.4 
Botox A Warnings and Precautions102 ........................................................................ 49 
7.5.5 
Adverse Reactions to Botox A102 ................................................................................ 53 
7.5.6 
Immunogenicity of Botox A102 .................................................................................... 55 
7.5.7 
Post-Marketing Experience of Botox A102 .................................................................. 56 
7.6 
Drug Interactions with Botox A102 .......................................................................................... 56 
7.6.1 
Aminoglycosides and Other Agents Interfering with Neuromuscular Transmission . 56 
7.6.2 
Anticholinergic Drugs ................................................................................................. 56 
7.6.3 
Other Botulinum Neurotoxin Products ........................................................................ 56 
7.6.4 
Muscle Relaxants ......................................................................................................... 56 
7.7 
Use of Botox A in Specific Populations102 .............................................................................. 57 
7.8 
Overdosage of Botox A102 ....................................................................................................... 58 
7.9 
Adverse Event Reporting ........................................................................................................ 59 
8. 
FEASIBILITY ................................................................................................................................... 59 
9. 
REFERENCES .................................................................................................................................. 59 
10. ADDENDUM - 12 Month Extension ................................................................................................ 66 
 
List of Figures 
Figure 1. Conceptual model of symptom bother in women with MUI ..................................................... 11 
Figure 2. MUSA Outcomes ....................................................................................................................... 25 
 
List of Tables 
Table 1: Summary of Studies of Botox A for the Treatment of UUI or Urge-Predominant MUI ............ 17 
Table 2: Randomized Trials Reporting Mid-Urethral Sling Outcomes in Women with MUI*† .............. 19 
Table 3: Rates of Urinary Tract Infection Following Botox A or Mid-Urethral Sling ............................. 21 
Table 4: Rates of Urinary Retention Following Botox A and Mid-Urethral Sling ................................... 22 
Table 5: Masking in MUSA ...................................................................................................................... 24 
Table 6: UDI MID ..................................................................................................................................... 27 
Table 7: ESTEEM outcomes at 6 and 12 months in the sling-only arm ................................................... 29 
Table 8: Resource Utilization Data Collection and Price Data Source by Utilization Category .............. 32 
Table 9: Timeline of Visits, Events, and Data Collection ......................................................................... 42 
Table 10: 6 Month Discontinuation Rates from ROSETTA and ESTEEM .............................................. 43 
Table 11: MUSA Power Calculation for N=146 (73 Per Treatment Arm) ............................................... 44 
Table 12: Number and Percent of Patients Experiencing at Least a 15% or 20% Decrease in FVC From 
Baseline at Week 2, 6, 12 Post-injection with BOTOX or Placebo................................................... 51 
Table 13: Proportion of Patients Catheterizing for Urinary Retention and Duration of Catheterization 
Following an Injection in Double-blind, Placebo-Controlled Clinical Trials in OAB ...................... 52 
Table 14: Proportion of Patients Experiencing Urinary Retention Following an Injection in Double-blind, 
Placebo-controlled Clinical Trials in OAB According to History of Diabetes Mellitus ................... 52 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
8 
Version 4.0 
01 22 2021 
Table 15: Proportion of Patients Not Using CIC at Baseline and then Catheterizing for Urinary Retention and 
Duration of Catheterization Following an Injection in Double-blind, Placebo-controlled Clinical Trials
 ............................................................................................................................................................ 53 
Table 16: Adverse Reactions Reported by ≥2% of BOTOX treated Patients and More Often than in Placebo-
treated Patients Within the First 12 Weeks after Intradetrusor Injection, in Double-blind, Placebo-
controlled Clinical Trials in Patients with OAB ................................................................................ 54 
Table 17: Proportion of Patients Experiencing Urinary Tract Infection following an Injection in Double-
blind, Placebo-controlled Clinical Trials in OAB according to history of Diabetes Mellitus ........... 54 
Table 18: Incidence of Urinary Tract Infection and Urinary Retention according to Age Group ............ 58 
 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
9 
Version 4.0 
01 22 2021 
 
 
ABSTRACT  
 
Mixed urinary incontinence (MUI), defined as the presence of both stress urinary incontinence and urgency 
urinary incontinence, is a challenging condition for which clinicians frequently use multiple sequential 
treatments that have undergone limited head to head comparison in rigorous clinical trials. Mid-urethral 
Sling vs. Botox A (MUSA) is a randomized 2-arm clinical trial for women who have at least moderate bother 
from both stress and urgency incontinence and who have failed one or more conservative treatments.  The 
primary objective is to estimate the effect of 100 units of intradetrusor injections of Botulinum toxin A 
(Botox A ®) compared to mid-urethral sling surgery for the treatment of MUI in 146 women. Participants in 
the Botox A arm may receive one additional injection of 100 units Botox A between 3 months and 6 months 
after the initial injection if they have persistent urgency incontinence symptoms and meet the safety criteria. 
The primary outcome for this trial is the change in severity of MUI symptoms which will be measured at 6 
months using the Urogenital Distress Inventory. Secondary objectives include identifying predictors of 
treatment failure and cost-effectiveness of treatments.  Safety and adverse events data will also be collected. 
At the completion of this study, we will better understand whether a surgical treatment that focuses on the 
urgency component (Botox A) is superior to a surgical treatment that focuses on the stress component (mid-
urethral sling).  The trial will provide clinically useful information for two treatments that are widely used to 
treat MUI but for which evidence-based data are not available. 
1. 
STUDY AIMS   
Mixed urinary incontinence (MUI), defined as the presence of both stress urinary incontinence (SUI) and 
urgency urinary incontinence (UUI), is a challenging condition for which clinicians frequently use multiple 
sequential treatments that have undergone limited evaluation in rigorous clinical trials. The Mixed Urinary 
Incontinence: Mid-urethral Sling vs. Botox A (MUSA) trial will estimate the effect of intradetrusor 
injections of Botulinum toxin A (Botox A ®) compared to mid-urethral sling for the treatment of MUI 
symptoms in 146 women. MUSA is a randomized 2-arm clinical trial. 
The purpose of MUSA is to: 
• compare treatment with either intradetrusor injections of Botulinum toxin A (Botox A ®) or mid-
urethral sling for women with MUI 
• characterize patient characteristics associated with treatment response  
The primary objective is to estimate the effect of intradetrusor injections Botulinum toxin A (Botox A ®) 
compared to mid-urethral sling for treatment of MUI in 146 women 6 months after treatment. The change in 
severity of MUI symptoms will be measured using the Urogenital Distress Inventory.1 
Secondary objectives include identifying predictors of treatment failure and cost-effectiveness of treatments 
in this MUI population.  
1.1. 
Primary Aim 
To compare the effectiveness of intradetrusor injection of 100 units of Botox A to mid-urethral sling for 
change in MUI symptoms 6 months following treatment. 
 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
10 
Version 4.0 
01 22 2021 
Primary Outcome: Change in severity of MUI symptoms 6 months post treatment measured using the 
Urogenital Distress Inventory (UDI)1 in patients randomized to either Botox A or mid-urethral sling.  
 
Secondary Outcomes: Change in severity of SUI and UUI symptoms 6 months post treatment measured 
using the stress and irritative subscales of the UDI and change in MUI symptoms 3 months post treatment 
measured using the UDI total score. 
 
Null Hypothesis: There is no difference in the change in MUI symptoms between women receiving Botox A 
versus mid-urethral sling 6 months following treatment. 
 
Alternative Hypothesis: Botox A is superior to mid-urethral sling for improving MUI symptoms 6 months 
following treatment. 
1.2.  
Exploratory Aims 
1. 
Secondary urinary outcomes: To compare treatment with Botox A to treatment with mid-urethral 
sling for improving the number of urinary incontinence episodes on bladder diary 6 months post-
treatment.  
2.  
Predictors of poor treatment response: To develop models to identify baseline predictors of 
change of MUI, OAB, and SUI outcomes measured using the UDI, between baseline and 6 months 
post-treatment.  
3. 
Quality of life and global impression: To compare quality of life outcomes and Patient Global 
Impression-Improvement (PGI-I), Patient Global Impression-Severity (PGI-S) between groups 
randomized to Botox A versus mid-urethral sling 6 months post-treatment. 
4. 
Safety and additional treatments: To describe rates of reoperation (sling revision) after mid-
urethral sling and intermittent catheterization due to voiding dysfunction/partial urinary retention 
after Botox A detrusor injection, to compare the proportion of women in each group with UTI and 
recurrent UTI, rates of other serious and non-serious adverse events, and to compare the proportion 
of women in each group initiating additional (off protocol) treatment other than Botox A and mid-
urethral sling for SUI and/or OAB.  
5. 
Cost-effectiveness analysis: To determine the cost effectiveness of Botox A injection versus mid-
urethral sling for the treatment of MUI symptoms on an intent-to-treat basis 6 months post-
treatment. 
6. 
UDI MID: To explore MIDs for UDI total score and stress and irritative subscores for this MUI 
population.  
2. 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
2.1 
Disease/Condition Background 
Up to 50% of women with urinary incontinence have mixed urinary incontinence (MUI), a combination of 
stress urinary incontinence (SUI) and urgency urinary incontinence (UUI).2-4 MUI is a frustrating problem 
for both patients and clinicians. Patients report that the urgency component is more bothersome than the 
stress component (Figure 1) and the combination of both is more bothersome than either UUI or SUI alone.5-
9 For clinicians, the treatment of MUI is challenging due to high failure rates that lead to multiple sequential 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
11 
Version 4.0 
01 22 2021 
treatments that have undergone limited evaluation in clinical trials. Despite this, most clinical trials have 
either excluded women with MUI or focused on treating one component of the MUI defined as either “stress-
predominant” or “urgency-predominant” urinary incontinence. 
Figure 1. Conceptual model of symptom bother in women with MUI 
 
 
2.1.1 
Clinical Importance of Focusing on the Urgency Component of Mixed Urinary Incontinence 
The recently completed ESTEEM trial has provided valuable insight for the treatment of MUI, however, a 
key gap in knowledge remains: what is the effect when the more bothersome UUI component is treated 
before the SUI component? 
The ESTEEM trial compared combined mid-urethral sling and behavioral treatment (sling-BPTx) to sling 
alone for the treatment of MUI in women. In ESTEEM, improvement in the total UDI score was greater in 
women in the combined sling-BPTx group (-128.2 points, 95% CI -146.51, -109.78) than the sling only 
group (-114.7, 95% CI -133.3, -96.2) but did not reach the pre-specified minimally important difference. 
Though authors concluded that combined sling-BPTx is not more effective than sling alone for the treatment 
of MUI, the study provided several additional findings that have important implications for the treatment of 
women with MUI. 
1. 
Combined sling-BPTx treatment compared to sling alone contributes to better UUI outcomes 
and better QOL in women with MUI. Women in the combined treatment group reported 
significantly better quality of life as measured by the Incontinence Impact Questionnaire than 
women in the sling only group ( -131.66 vs -102.01, p = .009). The number of SUI episodes was 
not significantly different between groups (-1.2 vs -0.96, p = 0.2), however, women in the 
combined group reported significantly fewer UUI episodes than the sling only group (-1.06 vs -0.38, 
p = 0.016). Women in the combined group also reported fewer additional treatment with OAB 
medications than the sling only group (8.5% vs 17.7%, adjusted odds ratio 0.47, 95% CI 0.26, 0.85). 
These findings suggest that improvement in UUI and OAB outcomes were important contributors 
to the better quality of life in the combined treatment group and that treatments that target UUI 
symptoms could potentially be highly effective for the treatment of MUI. However, clinical trials 
that have used highly effective treatments for UUI such as Botox A for the treatment of MUI are 
lacking.  
2. 
Sling alone provides satisfactory treatment of SUI component and does not worsen UUI 
component in women with MUI. Clinicians are frequently concerned that a mid-urethral sling in 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
12 
Version 4.0 
01 22 2021 
women with MUI could potentially worsen co-existing UUI. In ESTEEM, within the sling only 
group, UDI-total, UDI-irritative, and UDI-stress scores at 12 months improved and exceeded the 
corresponding MIDs of 35 points (SD 50.4), 15 points (SD 25.6) and 8 points (SD 21.5) 
respectively.10 These findings suggest that the mid-urethral sling  alone is a highly effective 
treatment for stress component of MUI and can actually improve the UUI component. However, it 
remains unknown the extent to which women with MUI would require additional treatment for SUI 
if the more bothersome UUI symptoms were treated first.  
3.     Predictors of treatment.   The ESTEEM trial showed that women with worse baseline OAB 
symptoms are more likely to be treatment failures at 12 months.  Specifically, DO on urodynamics 
and previous OAB medication use were predictors of treatment failure in both groups.  In addition, 
there was an interaction between baseline UDI-irritative score and treatment type with respect to 
predicting treatment failure. Women with higher baseline UDI Irritative scores randomized to sling 
only had higher odds of failure, compared to combined treatment. For each 10 point increase in 
UDI-irritative score, the adjusted odds of failure increased by 1.45 in the sling only group. This 
effect was not seen in the combined group.  
 
The MUSA trial builds on the findings of ESTEEM but has several important differences from ESTEEM. 
1. 
The primary hypothesis of MUSA is different from ESTEEM. The ESTEEM trial primarily 
treated the stress component of SUI using the mid-urethral sling and determined if behavioral 
treatment provided additional benefits. MUSA will determine if for women with MUI, an office-
based treatment directed at the more bothersome urgency component, Botox A, is more effective  
than a surgical treatment directed at the stress component, mid-urethral sling.  
2. 
The MUI population for MUSA will be different from ESTEEM. The ESTEEM study recruited 
women with MUI who desired surgical treatment for SUI symptoms. This may have allowed 
patients with more bother from stress symptoms to be included in the trial. The MUSA trial will 
recruit women with MUI who desire treatments of both the stress and urgency components. The 
ESTEEM trial showed that women with worse OAB are more likely to fail treatment with MUS.  
Therefore, in MUSA, we will recruit a patient population that will have a higher severity of 
urgency symptoms (objective UUI inclusion criteria of >4 UUIEs on a 3-day diary).  
2.2 
What is MUI: Current Definition and challenges 
The International Urogynecological Association (IUGA)/International Continence Society (ICS) joint 
terminology report defines MUI as “the complaint of involuntary leakage associated with urgency and also 
with exertion, effort, sneezing, or coughing”.11 This definition, based on subjectively reported symptoms, has 
several limitations including that: 1) many women with MUI do not report clear cut SUI or UUI but simply 
that “they leak” 2) the definition excludes women who may have significant urgency and/or frequency 
without UUI; and 3) it excludes women who have detrusor overactivity in the absence of sensory urgency.  
Attempts at developing more clinical meaningful definitions have not been successful. Brubaker et al of the 
Urinary Incontinence Treatment Network (UITN) tried to develop an operational definition of MUI based on 
a combination of subjective and objective criteria in a stress-predominant MUI population.12 These criteria 
included 1) the frequency of SUI and/or UUI as measured by the Medical, Epidemiologic and Social Aspects 
of Aging (MESA),13 2) the presence and degree of bother for SUI and UUI as measured by the Urogenital 
Distress Inventory (UDI), and 3) presence of urodynamic SUI and detrusor overactivity with or without 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
13 
Version 4.0 
01 22 2021 
associated leakage as measured by urodynamics. Despite testing 12 different definitions of MUI, the authors 
were unable to identify a definition that correlated with the clinical outcomes of the trial. Similar attempts to 
develop an operational definition for MUI in the urgency-predominant population of the UITN sponsored 
Behavior Enhances Drug Reduction of Incontinence (BE-DRI) trial also failed to identify criteria that 
predicted the clinical outcomes of the trial.14 
Based on the above findings, for the present trial, we will follow the recommendations of Brubaker et al that, 
until better definitions are developed, suggest that distinct descriptions of both urgency and stress 
subcomponents be used to characterize subjects with MUI.  
2.2.1 
Pathophysiology of MUI: Shared Mechanisms for SUI and UUI  
While some experts argue that SUI and UUI are separate and unrelated conditions,15 increasing evidence 
suggests that common pathophysiologic processes may explain co-existing SUI and UUI in women with 
MUI. It has long been known that anti-incontinence procedures of the bladder neck, such as colposuspension 
and bladder neck slings improve SUI but can worsen UUI.16 By contrast, in the recently completed ESTEEM 
study, mid-urethral sling procedures alone, even without additional behavioral treatment, resulted in 
improvement of both SUI and UUI components of MUI. Finally, in several Botox A clinical trials, the 
majority of which were performed in women with urgency-predominant MUI, subjects reported 
improvement not only of UUI episodes but also of overall UI episodes (see Table 1). Taken together, these 
studies suggest that a common pathophysiologic process may contribute to co-existing symptoms of SUI and 
UUI as well as response to treatment. 
Animal and human studies have implicated proximal urethral pathology in mechanisms of both SUI and UUI. 
Urethral afferent stimulation can trigger the micturition reflex in rats suggesting that in women with SUI, 
leakage of urine into the proximal urethra may stimulate urethral afferents and facilitate a detrusor 
contraction.17 Using urodynamics, Koonings et al demonstrated urethral relaxation in 39 women with mixed 
urinary incontinence.18 Combined urodynamics and ultrasound evaluations have demonstrated proximal 
urethral pathology, in the form of funneling and “urethral instability” (fluctuations of pressure in the 
proximal urethra), in women with SUI and UUI respectively.19,20 Other shared mechanisms between SUI and 
UUI include cough-associated detrusor overactivity (CADO) and low maximum urethral closure pressure. In 
a recent retrospective review of 7009 urodynamics studies, Sinha et al reported that the prevalence of CADO, 
defined as detrusor overactivity immediately following the cough pressure peak on urodynamics, was 2.2% 
with 70% cases occurring in women with MUI.21 The prevalence was higher (5%) in 100 women undergoing 
ambulatory urodynamics.22 Lower maximal urethral closure pressure, a well-known underlying mechanism 
of SUI, has also been associated with UUI. In 73 women with MUI undergoing mid-urethral sling surgery, 
Paick et al reported that lower maximal urethral pressure at baseline was associated with a greater risk of 
persistent OAB symptoms following mid-urethral sling surgery,23 suggesting that profound urethral 
dysfunction may contribute to OAB symptoms in women with MUI.  
Translational studies also support the idea of shared mechanisms for SUI and UUI. In the RUM study by the 
PFDN, a variety of inflammatory and connective tissue remodeling biomarkers were measured in the urine at 
baseline and at 6 months following treatment with either sacral neuromodulation or Botox A in women with 
predominant UUI.24 This study showed that response to Botox A was associated with significant decrease in 
levels of collagenase (p < .001) and increase in levels of matrix metalloprotease-9 (p <.001) and interleukin-
8 (p = .002). Additionally, higher baseline levels of CGRP and NGF were associated with less reduction in 
OAB symptom bother in the Botox A group. Similar changes in inflammatory and connective tissue 
remodeling biomarkers were observed in women with SUI undergoing stress incontinence surgery. Chai et al 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
14 
Version 4.0 
01 22 2021 
measured inflammatory and tissue remodeling biomarkers at baseline and one year following mid-urethral 
sling in 150 women with predominant SUI. In this study, interleukin 12p70 decreased (p = .04) and NGF 
increased (p =.03) one year following mid-urethral sling surgery.25 Furthermore, change in biomarker levels 
was neither associated with any clinical or demographic covariates nor surgical failure. 
The shared mechanisms for SUI and UUI suggest that treatments directed at one component of MUI, 
either UUI or SUI, have significant potential of affecting outcomes of the other component. In MUSA, 
outcomes for SUI, UUI and overall UI episodes will be measured separately using both patient reported 
outcome (PRO) questionnaires and bladder diary, thus providing valuable data on mechanisms that 
contribute to the pathophysiology of MUI. 
2.3 
Rationale for Considering Surgical Treatment for MUI 
MUSA will test the effectiveness of two surgical treatments for MUI: office-based Botox A injections versus 
mid-urethral sling. The rationale for choosing surgical treatment over non-surgical options for MUI such as 
behavioral/pelvic floor therapy (BPTx) and medications is discussed below. 
2.3.1 
Behavioral/Pelvic Floor Therapy (BPTx) 
BPTx includes teaching behavioral measures designed to encourage continence and pelvic floor muscle 
therapy designed to strengthen and improve coordination of the pelvic floor muscles. Several studies have 
been performed to investigate the efficacy of BPTx for the treatment of MUI. A recent Cochrane review 
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.26 Another recent systematic review concluded that BPTx, 
alone or in combination with other interventions, is generally more effective than pharmacologic therapies 
alone in treating both stress and urgency UI.27 These studies justify recommending BPTx as a first line 
treatment for MUI. 
Two large studies demonstrate limitations of BPTx for the treatment of more severe MUI. The UITN study 
BE-DRI (Burgio et al), evaluated whether combined anti-muscarinic therapy with BPTx would increase the 
number of women who could discontinue drug therapy (primary outcome) while sustaining a significant 
reduction in UUI.28 In a population of women with pure UUI or UUI-predominant MUI, BE-DRI found that 
although the combination of behavioral training and drug therapy yielded improved urinary outcomes 
compared to drug therapy alone, the addition of behavioral therapy did not improve drug therapy 
discontinuation. 
The recent ESTEEM trial conducted by the PFDN included 480 women with MUI who had “moderately or 
greatly bothersome” SUI and “moderately or greatly bothersome” UUI. In this study, women in the 
combined sling and BPTx group showed statistically significantly greater improvement in MUI symptoms 
reported on the UDI than women in the sling only group though these differences did not reach the pre-
specified minimally important differences. Women in the combined treatment group reported better quality 
of life, less urinary incontinence episodes, and fewer additional treatments. The authors concluded that 
although there may be secondary benefits to adding BPTx, combined BPTx and sling was not more effective 
than sling alone for the treatment of MUI. 
Intuitively, it makes sense to first offer non-surgical treatments such as BPTx to women with MUI. 
Therefore, in MUSA, women with MUI will be required to have tried and failed conservative therapy, which 
includes supervised behavioral therapy and/or physical therapy, before being included in the study.  

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
15 
Version 4.0 
01 22 2021 
2.3.2 
Anti-Cholinergic or Beta-Mimetic Medication 
Because medical therapy is considered conservative and can be initiated in primary care offices, anti-
cholinergic medications are frequently recommended before considering surgical management. However, 
improvement in MUI symptoms with anti-muscarinic medications over placebo is modest,9 side effects are 
common, and discontinuation rate is high, ranging from 43%-83% within the first 30 days of initial 
prescription and only 9% at one year.27,29 Finally, long-term anti-cholinergic use is potentially associated 
with potential irreversible cognitive changes.30 The efficacy of beta-mimetic medication such mirabegron is 
comparable to that of anticholinergics.31 A recent systematic review and meta-analysis of Botox A compared 
to medication concluded that Botox A 100 U was associated with higher odds of achieving a 100% and 
≥50% decrease in urinary incontinence episodes (UIE)/day than either anti-cholinergic medications or 
mirabegron.32 The combination of limited efficacy, poor compliance, and potentially serious side-effects 
make medication a limited treatment option for women with MUI.  
 
The modest success rate of BPTx in randomized clinical trials and poor adherence rate to medications 
point to the need to consider surgical treatment for MUI. These findings are supported by clinical 
practice where women with MUI commonly opt for surgical treatment as they become dissatisfied with 
failure of conservative treatment and/or the need to take a medication long-term. Furthermore, women with 
equally bothersome UUI and SUI components commonly choose surgery, with or without a trial of 
conservative treatment. Thus, the “traditional” empiric treatment paradigm for MUI is associated with high 
failure rates and we are now challenged to consider new paradigms for MUI.  
2.4 
Rationale for Considering Botulinum Toxin A Injection for Treatment of MUI in Women 
Onabotulinumtoxin A (Botox A ®, Allergan) has proved to be highly effective for the treatment of refractory 
UUI. Several studies on the efficacy of Botox A in improving symptoms of UUI as well as total UI episodes 
are summarized in Table 1 below. Major studies are discussed below. 
The ROSETTA study conducted by the PFDN was performed in women with refractory UUI and compared 
190 women who received Botox A 200 units to 174 women who received sacral neuromodulation (SNS).33 
Refractory UUI was defined as a minimum of 6 urgency UIE (UUIE) on a 3-day bladder diary and persistent 
symptoms in spite of at least one supervised behavioral or physical therapy intervention and use or failure to 
tolerate a minimum of 2 anti-cholinergic medications. The primary outcome was change from baseline in 
mean number of daily UUIE per day over 6 months measured by monthly 3-day bladder diaries. Secondary 
outcomes were change in OAB symptom bother Short Form and OAB treatment Satisfaction questionnaire. 
At baseline, mean UUIE episodes were 5.4 (SD 2.7) in the Botox A group and 5.2 (SD 2.7) in the SNS group. 
Women in the Botox A group had greater reduction in mean UUIE at 6 months than the sacral 
neuromodulation group (-3.9 vs -3.3 episodes per day; mean difference 0.63; 95% CI, 0.13 to 1.14; p = .01). 
Women in the Botox A group showed significantly greater improvement in the OAB symptom bother (-46.7 
vs -38.6. mean difference 8.1, p =.002) and OAB treatment satisfaction (67.7 vs 59.8, mean difference 7.8, p 
=.01) scores than the sacral neuromodulation group. At 24 months, no difference in mean UUIE was noted (-
3.88 vs -3.5; mean difference 0.38; 95% CI -0.14, 0.89, p =.15); however, the Botox A group maintained 
higher satisfaction with treatment (mean difference -9.15, 95% CI -14.38, -3.9, p <.001).34 These findings 
show that Botox A is highly effective for the treatment of UUI and that its beneficial effects are sustained to 
24 months. 
In ROSETTA, mean total UI episodes at baseline was higher than UUI episodes, being 6.0 (SD 3.0) vs 5.3 
(SD 2.6) in the Botox A group. In the intent to treat population, women in the Botox A group reported 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
16 
Version 4.0 
01 22 2021 
greater reduction in total UI episodes than UUI episodes, over 6 months (-4.02 vs -3.89 episodes per day). 
Similarly, in the clinical responder population, women in the Botox A group reported greater reduction in 
total UI episodes than UUI episodes, over 6 months (-4.6 vs –4.4 episodes per day). These findings suggest 
that the beneficial effects of Botox A may extend beyond UUIE to total UI episodes. To further explore this, 
we looked at ROSETTA data for a sub-group with MUI similar to what we would recruit for MUSA to 
provide some preliminary data of Botox A in this urgency-predominant MUI population. There were 32 
ROSETTA participants randomized to Botox A with at least moderate stress bother and moderate urge 
bother on the Urogenital Distress Inventory Short Form (UDI-SF) questions plus 3 or more SUIE on 3-day 
bladder diary (average of at least 1 per day) at baseline. UDI-SF scores at baseline were worse in the 
“MUSA-like” group than the rest of the ROSETTA population (75.2 vs 58.2). Similarly, average daily total 
UIE (8.0 vs 5.7), UUIE (6.0 vs 5.5) and SUIE (1.8 vs 0.2) were higher in the “MUSA-like” group than the 
rest of the ROSETTA population. This supports the conceptual framework that MUI is a more severe 
condition than UUI alone. At 6 months, the “MUSA-like” group had a reduction of -1.1 SUIE/day (58% 
improvement) and -4.0 UUIE/day (66% improvement) with Botox A; the rest of the ROSETTA population 
had reduction of  -3.4 UUIE/day (66% improvement). These findings suggest that the beneficial effects of 
Botox A may extend beyond UUIE to SUIE in women with MUI. 
The ABC trial also conducted by the PFDN was performed in women with idiopathic UUI and compared 
126 women who received Botox A 100 units to 121 women who received anticholinergic medication.35 UUI 
was defined as 5 or more episodes of UUI on a 3-day bladder diary. The primary outcome was the same as in 
the ROSETTA study i.e. change from baseline in the mean number of UUIE over the course of 6 months on 
a 3-day bladder diary. At baseline, number of UUIE episodes in the Botox A group was 4.8 (SD 2.7) and 5.2 
(SD 2.7) in the anticholinergic medication group. Total UI episodes were 5.8 (SD 3.1) in the Botox A group 
and 6.1 (SD 3.3) in the anticholinergic medication group. In this study, mean reduction in UUI episodes was 
similar in the Botox A and medication groups (-3.3 vs -3.4, p= 0.81). Women in the Botox A group were 
significantly more likely to report complete resolution of UUI (27% vs 13%, p =.003). Additionally, women 
in the Botox A group were significantly more likely to report complete resolution of all incontinence than the 
anticholinergic medication group (23% vs 11%, p =.003).  
Chapple et al compared 100 units of Botox A to placebo in women with idiopathic OAB.36 OAB was defined 
as ≥ 3 UUIE over 3 days and ≥ 8 micturitions per day and inadequately managed by anticholinergic 
medications. Co-primary outcomes were change from baseline in the number of UIE per day and proportion 
of patients reporting benefit on the treatment benefit scale (TBS) at week 12. At baseline, mean daily UUIE 
was 5.1 (SD 3.7) in the Botox A group and 5.3 (SD 3.7) in the placebo group. Baseline daily total UI 
episodes was 5.5 (SD 3.8) in Botox A group and 5.7 (SD 3.9) in the placebo group. Following treatment, at 
12 weeks change in UUI episodes was greater in the Botox A group than the placebo group (-2.8 vs -0.82, p 
< .001). Change in total UI was also greater in the Botox A group than the placebo (-2.95 vs -1.03, p < .001). 
Nitti 2016 analyzed the efficacy of Botox A 100 units for the treatment of refractory OAB by the number of 
injections received over 3.5 years.37 Patients requested Botox injections as needed to control symptoms. The 
co-primary outcomes were change from baseline in the number of UI episodes per day and proportion 
reporting benefit on the treatment benefit scale (TBS). Mean overall change in UI episodes per day ranged 
from -3.1 to -3.8. Median duration of effect was 7.6 months. Long-term treatment with Botox A consistently 
decreased UUI symptoms with 66% to 83% patients reporting improved QOL with 1 to 4 injections. 
In summary, the majority of studies investigating Botox A have been performed in subjects who have 
urgency-predominant MUI. These studies show that treatment with Botox A results in improvement of both 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
17 
Version 4.0 
01 22 2021 
UUIE as well as total UI episodes. Though existing studies show that Botox A can improve overall UI, data 
on the efficacy of Botox A in a MUI population that is not urgency predominant incontinence is lacking. 
Table 1: Summary of Studies of Botox A for the Treatment of UUI or Urge-Predominant MUI 
First Author 
No. Pts 
Inclusion 
Criteria 
Primary 
Objective 
Baseline 
UUI/UIE  
FU 
Change in 
UUI  
Change in  
Total UI 
Other 
Relevant 
Findings 
Dmochowski 
201038 
313 
Refractory 
UUI 
Dose ranging 
Botox 50u-
300u 
100u N=54 
200u N=53 
vs Placebo 
8 UUIE 
on a 7-day 
bladder 
diary 
12 weeks 
7-day diary 
UUIE 
reduction 
100u -20.7 
200u -23.0 
 
NA 
 
Nitti 
201339 
557 
UUI 
predom 
refractory 
Botox 100 
vs Placebo 
 
UI/day 5.5 
UUI/day 
4.8 
12 weeks 
UUI/day not 
reported  TBS 
60.8% 
UI/day -2.65 
 
Dry 22.9% 
>50% 57.5% 
IQOL impr 
21.9 points 
 
Nitti 
201637 
812 
Refractory 
UUI 
 Botox 100u 
(no. of 
injections) 
1 =812 
2 =597 
3 =372 
4 =264 
12 weeks 
from last tx 
UI 5.6 
3.5 years 
UUI/day not 
reported 
 
TBS 
(treatment 
benefit scale) 
1=74.0% 
2=81.3% 
3=82.1% 
4=78.3% 
UI/day  
1 inj UI -3.3 
2 inj UI -3.6 
3 inj UI -3.8 
4 inj UI -3.5 
IQOL improv 
1 inj 66% 
2 inj 83% 
3 inj 76% 
4 inj 72% 
 
Chapple 201336 
548 
UUI 
predom 
refractory  
Botox 100 
vs Placebo 
UI/day 5.5 
UUI/day 
5.1 
12 weeks 
UUI/day 
 -2.80 
UI/day -2.95 
Treatment 
benefit 62.8% 
Tincello 
201240 
122 
women 
Refractory 
OAB/DO 
Botox 200u 
vs Placebo 
UI 6.2 
6 months 
UUI/day not 
reported 
UI/day -4.3  
Dry = 31% 
IQOL improv 
27.84 points 
ROSETTA 
2016/201833,34 
381 
women 
Refractory 
UUI 
Botox 200u 
vs SNS 
UUI/day 
5.4 
UI/day 6 
6 months 
 
 
 
 
24 
months 
UUI/day -3.9 
 
 
 
 
UUI/day -3.88 
 
UI/day - 4.59 
Dry 23% 
≥ 75% 55% 
≥ 50% 74% 
 
Dry 5% 
>75% 22% 
>50% 43% 
Treatment 
satisfaction 
67.7 
 
 
ABC 
2012 35 
249 
women 
UUI 
predom 
(includes 
non-
refractory) 
Botox 100u 
/placebo med 
vs anti-
cholinrtgics/ 
placebo inj 
UUI 4.8 
UI 5.8 
6 months 
 UUI/day -3.3 
100% UUI 
resolution 27% 
>75% UUI 
54% 
Dry all UI 23% 
PGI-I 
3mth 55% 
6mth 54% 
 
PGSC (4-5) 
6mth 71% 
12mth 38% 
 
2.4.1 
Rationale for Dose of Botox A Injection 
Botox A is currently FDA approved for the treatment of idiopathic OAB at a dose of 100 units. The safety 
and efficacy of 100 units of Botox A for the treatment of UUI and urgency has been established through 
several large RCTs.36-39 Since MUSA will be the first study to investigate the efficacy of Botox A in a 
population of women with MUI with bothersome SUI and UUI, the protocol committee made the decision 
that the dose used for MUSA would be to 100 units of Botox A.  

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
18 
Version 4.0 
01 22 2021 
2.4.2 
Rationale for Subsequent Botox A Injection 
Botox A is a therapy requiring repeated injections. Based on product guidelines for OAB, patients should be 
considered for reinjection when the clinical effect of the previous injection has diminished but no sooner 
than 12 weeks from the prior bladder injection. MUSA will allow participants with persistent bothersome 
UUI to have a second Botox A injection of 100 units after 3 months, provided no contraindication to Botox 
A injection is present (See section 5.2.3). 
2.5 
Rationale for Considering Mid-Urethral Slings for the Treatment of MUI in Women 
“Traditional teaching” is that women with MUI should not undergo anti-incontinence surgery for SUI due to 
the potential risk of worsening OAB symptoms. However, these recommendations are based on expert 
opinion and secondary analysis and retrospective studies that included traditional bladder neck slings and 
colposuspensions.44-46 Most studies report that success rates of the treatment of the SUI component in a MUI 
population are as high as 80%.47,48 Increasing evidence also indicates that 1) the rate of de novo UUI after 
mid-urethral slings is low and that 2) mid-urethral slings improve UUI and OAB symptoms in women with 
MUI (Table 2).  
The recently completed ESTEEM trial was conducted in women with MUI who at baseline had 1) 
“moderately or severely bothersome” SUI and UUI; 2) at least one documented stress and urgency 
incontinence episode on the 3-day bladder diary and 3) desired surgical treatment of SUI.49 In ESTEEM, 480 
women with MUI were randomized to sling alone or sling combined with BPTx. Women in both groups had 
improvements in MUI symptoms as measured by the UDI-total score at 12 months (-128.15 vs -114.73, p 
=.03) but the difference (-13.42) did not reach the pre-specified MID of 35 points indicating that combined 
therapy was not more effective than MUS alone for treating MUI. However, both groups had mean within-
group changes in the UDI-total, UDI-irritative, and UDI-stress scores that exceeded the corresponding MIDs 
of 35 points (SD 50.4), 15 points (SD 25.6) and 8 points (SD 21.5) respectively.10 Women in both groups 
also reported reduction in total UI, UUI, and SUI episodes on bladder diary with significantly greater 
improvements in the total and urgency incontinence episodes in the combined treatment group. OAB-q 
symptom severity and satisfaction scores also improved in both groups and were not significantly different 
between groups. Finally, the rate of new or worsening urgency incontinence at or beyond the 3-month visit 
was 4.5% in the combined and 2% in the MUS only group. Taken together, these findings demonstrate that 
mid-urethral sling alone improves overall symptoms of MUI including both the stress and urgency 
components and is associated with a low overall rate of worsening of de novo UUI/OAB.  
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.48 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.50 However, other studies report that 
MUI is a risk factor for failure of both SUI and OAB outcomes51 or that mid-urethral sling 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.52 Whether there may be specific patient characteristics 
that are associated with resolution or exacerbation of OAB symptoms also remains unclear. 
Two prior large trails of mid-urethral slings have been conducted in women with stress-predominant MUI. 
The Trial of Mid-Urethral Slings (TOMUS) trial (Richter et al) performed by the UITN, randomized 597 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
19 
Version 4.0 
01 22 2021 
women with pure SUI or SUI-predominant MUI (based on MESA scores) to retropubic versus transobturator 
MUS.47 Barber et al performed a second trial also comparing retropubic versus transobturator MUS for 
SUI.51,53 In the Barber trial, although women with baseline detrusor overactivity were excluded, 71% had 
baseline UUI based on the UUI item on the PFDI-20 questionnaire.54 In both trials, the UDI-irritative 
subscales improved from baseline: in the TOMUS trial, the UDI-irritative subscale improved from a mean of 
41.2 (25.4) to 8.9 (15.1) at 12 months and in the Barber trial from a baseline of 3 points to 0 points at 12 
months (unpublished data). The rate of de novo UUI was low in both trials (.002% and 4% respectively). 
However, planned secondary analysis of both trials showed that pre-operative UUI worsened post-operative 
outcomes. In the TOMUS trial, higher baseline MESA urge scores increased the risk of overall (objective 
and subjective) sling failure.47 In the Barber trial, 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. 
  
In summary, the majority of clinical trials of mid-urethral sling in women with MUI have recruited women 
with stress-predominant MUI. While the ESTEEM trial recruited women with both bothersome SUI and UUI 
components, it tested a surgical intervention developed for the stress-component. These trials report high 
cure rate of the stress component and marked improvement and/or “cure” of OAB symptoms after mid-
urethral sling; however, to date there has not been a study that has tested an intervention that primarily treats 
the urgency component of MUI. 
Table 2: Randomized Trials Reporting Mid-Urethral 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 
2010, 
Richter 
201747,55,56 
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 
Barber51,53 
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 
Palva57 
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-
fattah58,59 
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 
4.3% UUI 
• 52% Cure 
urgency 
• 58% Cure 
UUI 
• 75% “cure” 
by PGI-I < 
2. 
 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
20 
Version 4.0 
01 22 2021 
UUI 
• ~25% worsened 
OAB taking 
anticholinergics 
ESTEEM 
Sung et al 
(unpublished 
data) 
480 
bothersome 
UUI and SUI, 
desiring 
surgical Rx for 
SUI 
MUS + 
BPTx vs 
MUS only 
100% 
1 year 
By UDI-irritative: 
Improved in both 
groups 
• 45.01 vs -38.88 
• New or 
worsening 
UUI 
4.5% vs 
2.1% 
• Additional 
treatment 
of LUTS 
8.5% vs. 
15.7% 
• OABq 
Symptom 
severity 
and OABq 
satisfaction 
score 
improved 
in both 
groups 
*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 Trials for the MUI Population 
With the exception of ESTEEM, existing 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. UUI-predominant for most Botox A trials and SUI-predominant for most mid-urethral 
sling 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 clinical trials focus 
on teasing out the effect of the intervention on urgency and stress components separately rather on improving 
UI as a whole. ESTEEM included women with MUI who had both bothersome SUI and UUI; however, the 
inclusion criteria of “desire for SUI surgery” may have resulted in the inclusion of more women with stress-
predominant symptoms. 
Most Botox A trials report outcomes for either UUIE or total UI episodes but not both, making it difficult to 
ascertain if Botox A consistently improves UIE. Similarly, many mid-urethral sling trials use a composite 
outcome to define failure (including response to cough stress test, negative pad test, any self-reported 
incontinence or incontinence on diary) and therefore it is difficult to tease out 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.60 MIMOSA was designed as a pragmatic clinical trial randomizing women to 
nonsurgical treatment (pharmacological therapy and behavioral therapy) versus surgical treatment (mid-
urethral sling 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.  
The MUSA trial differs from the MIMOSA trial in that it compares an office-based surgical intervention 
(Botox A) to an operating room based surgical intervention (mid-urethral sling). Interventions being 
compared in MUSA are comparable to that of ROSETTA where an office-based treatment (Botox A) was 
compared to an operating room-based procedure, sacral neuromodulation. Therefore, the MUSA has 
equipoise in the treatment interventions being tested. In addition, the MUSA protocol team has carefully 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
21 
Version 4.0 
01 22 2021 
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 
Botox A has been shown to be beneficial when used for the treatment of urgency-predominant MUI. Prior 
studies have documented a low rate of side-effects such as recurrent urinary tract infection and retention of 
urine even with a dose of 200 units of Botox A in an urge-predominant MUI population (Tables 3 and 4). 
For the MUSA population of women with MUI who receive Botox A, risks are expected to be no worse than 
previously reported for urgency-predominant MUI populations.  
Several prior studies have documented the benefit of slings in stress-predominant MUI. The recent large 
ESTEEM study has shown benefit of the mid-urethral slings for both SUI and UUI in women with MUI. 
However, there are women with MUI who report persistent or worse UUI/OAB symptoms after mid-urethral 
sling and this is one potential risk, but this was <5% in ESTEEM. Risks of UTI and retention of urine 
following mid-urethral sling are summarized in Tables 3 and 4. For the MUSA population of women with 
MUI who receive mid-urethral sling alone, risks are not expected to be different compared to previous 
studies including MUI or SUI-predominant MUI subjects.  
 
Table 3: Rates of Urinary Tract Infection Following Botox A or Mid-Urethral Sling 
 
Time Point 
How Defined 
UTI Rate 
SLING FOR MUI 
ESTEEM 
Urine dip at baseline AND 12 months. At 
additional visit if clinically indicated. 
Negative dip required prior to baseline 
bladder diary. If UTI suspected at baseline, 
UTI was treated before collecting baseline 
diary. For remaining visits: dip not required 
solely for the purpose of bladder diary 
unless clinically indicated.  
Urine dip: positive if RBC/WBC/nitrites 
greater than trace. Urine culture: performed 
only if clinically indicated. Positive if ≥ 10 3 
UTI diagnosis: based on symptoms or recent 
dipstick suspicious of UTI or in opinion of 
provider.  
UTI Symptoms include acute /recent changes 
such as burning with urination, acute 
worsening of urgency, frequency or 
incontinence, hesitancy of urination, blood 
(seen by them) in their urine, odor, lower 
abdominal discomfort. 
24% (sling only) vs 
22% (BPTx + sling) 
TOMUS47 
Not in paper 
Not in paper 
15.4% (TVT) vs. 
9% (TOT) 
Barber, 200853 
Not in paper 
Not in paper 
13.6% (TVT) vs 
13.4% (TOT) 
BOTOX A 
ROSETTA33 
Urine dip at baseline, every Injection visit, 
2 wk, 1m, 3m, 6m 
Same as above 
200u: 35% 
ABC35 
Urine dip at baseline 
Not described 
100u: 33% 
Dmochowski 
201038 
At each FU visit and as clinically indicated 
Not described 
100u: 36% 
200u: 48% 
Denys 201262 
At each FU visit and as clinically indicated 
Positive dip confirmed by culture 
100u: 4.8% 
150u: 9.1% 
Tincello 201257 
At each FU visit and as clinically indicated 
Not described 
200u: 30% 
Chapple 201336 
At each FU visit and as clinically indicated 
Urine microscopy >5/hpf + >103 cfu 
100u: 24% 
Nitti 201637 
At each FU visit and as clinically indicated 
Not described 
100u: 13-17% 
 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
22 
Version 4.0 
01 22 2021 
Table 4: Rates of Urinary Retention Following Botox A and Mid-Urethral Sling 
 
Botox 
Dose 
Time Point 
How Defined 
Retention Rate 
MID-URETHRAL SLING 
ESTEEM 
NA 
At baseline and 
2 weeks postop 
No specific PVR cutoff 
7% in both groups (sling vs sling ± BPTx) 
Catheter after 2 weeks: 2% in both groups 
TOMUS Richter, 
201047 
NA 
Baseline and 12 
months 
ISC after 6 weeks or surgery 
for obstructed voiding 
3.6% (TVT) vs. 0.6% (TOT) 
Barber, 200853 
N/A 
Baseline and 12 
months 
ISC after 6 weeks or surgery 
for obstructed voiding 
4.7% (TVT) vs. 2.6% (TOT) 
BOTOX A 
ROSETTA33 
200 u 
At baseline and 
every FU visit 
PVR>300 ml or PVR>200 
ml and symptoms of 
incomplete voiding 
ISC: 2wks (16%), 1 m (8%), 3m (4%), 6 m 
(2%), any visit (20%) 
ABC35 
100 u 
At baseline and 
every FU visit 
PVR>300 ml or PVR> 150 
ml and symptoms of 
incomplete voiding 
ISC: 2wks (9%), 1m (3%), 2m (5%), 4m 
(3%), 6m (1%) 
 
PVR > 150 ml: 2wks (30%), 1m (27%), 
2m (20%), 4m (15%), 6m (7%) 
Dmochowski 
201038 
100 u 
200 u 
At baseline and 
every FU visit 
> 200 ml 
100u: 14.5%, 200u: 28% 
ISC: 100u: 11%, 200u: 21% 
Denys 201262 
100 u 
150 u 
At baseline and 
every FU visit 
> 200 ml, need for ISC 
very low 
Tincello 201240 
200 u 
 Not specified 
Need for ISC 
ISC: 14-16% 
Chapple 201336 
100 u 
Not specified 
ISC at PVR > 200 ml  
6.9% 
Nitti 201637 
100 u 
Not specified 
Need for ISC 
ISC 4% 
 
2.9 
Significance of Proposed Study  
In summary, at least four gaps of knowledge contribute to clinical challenges of treating women with MUI.  
1. 
Though urgency urinary incontinence is the more bothersome component of MUI, most studies 
have focused on treating the stress incontinence-component, with or without additional treatment of 
the urgency component. The question that MUSA seeks to answer is: what happens to MUI 
symptoms if the urgency component is treated first?  
2. 
Surgeons and researchers have spent considerable time and energy on trying to tease out stress 
versus urgency components of MUI to decide which component should be treated first. MUSA will 
provide data that will help to answer the question: Does it matter whether the urgency or the stress 
component of MUI is treated first with surgery? 
3. 
Most clinical trials of Botox A have been performed in urgency-predominant MUI populations. 
MUSA will answer the question: What is the effect of Botox A in patients with MUI who have 
bothersome SUI and bothersome UUI?  
4. 
Little is known about risk factors that predict failure of procedural treatments of MUI. MUSA will 
provide data to determine which women with MUI would benefit from Botox A versus which 
women should get mid-urethral sling. 
Patients with MUI are often hopeful that their overall urinary condition will improve, but as surgeons when 
we offer a surgical treatment that focuses on treating the urgency component (Botox A), we cannot assure 
patients that it will improve their stress component. Similarly, we can provide only limited assurance that 
treating the SUI component with mid-urethral sling will improve their urgency component. MUSA will 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
23 
Version 4.0 
01 22 2021 
provide much needed information on how outcomes can be optimized in women seeking surgical treatment 
of their overall urinary incontinence. 
2.10 
Innovation  
This proposal is innovative for several reasons. First, the MUSA study is investigating a population of 
women who are often excluded from clinical intervention trials but are at high risk for treatment failure. 
Second, this trial will provide important information regarding baseline predictors of response such as 
whether urgency-predominance or stress-predominance have different optimal treatments. At the completion 
of this study, we will better understand whether a surgical treatment that focuses on the urgency component 
(Botox A) is superior to a surgical treatment that focuses on the stress component (mid-urethral sling) and 
will obtain 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  
MUSA is a multi-center randomized trial of 146 women with MUI who have elected to undergo surgical 
treatment for MUI. Participants will be randomized to Botox A versus mid-urethral sling.  
At 6 months, the effect of treatment with Botox A or mid-urethral sling will be evaluated within a classic 
RCT model. The analysis will determine the effect of treatment on the primary outcome, change in 
Urogenital Distress Inventory (UDI) score at 6 months. 
3.1.1 
MUSA Interventions  
In MUSA, two evidence-based interventions widely used for the treatment of MUI, Botox A and mid-
urethral sling, will be compared within a classic RCT setting.  
The results of the MUSA trial will ultimately inform future research studies and the development of a 
clinical approach, potentially tailored to individual patients with MUI based on important patient 
characteristics. 
3.1.2 
Rationale for Not Incorporating the Type of MUI as inclusion criteria  
The protocol committee spent considerable time debating whether the type of MUI, stress- or urgency- 
predominant should be an inclusion criterion. Based on expert opinion, many clinicians begin the treatment 
of MUI with segregating symptoms of MUI into the stress and urgency components and then focusing 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 “more 
bothersome”. Additionally, there is little evidence that determining stress-predominance or urgency-
predominance predicts response to treatment for women with MUI. The committee ultimately decided to not 
incorporate determining the type of MUI into the inclusion criteria as this would allow determination of 
whether the type of MUI is a predictor of treatment response.  

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
24 
Version 4.0 
01 22 2021 
3.1.3 
Management of Patient Who is Unwilling for Randomization or Requests Treatment Off-
Protocol 
We anticipate that the number of patients who are unwilling for randomization or request treatment off 
protocol will be low because 1) based on our eligibility criteria, subjects will already have tried and failed a 
variety of conservative treatments 2) every effort will be made to recruit subjects who understand the study 
design and are willing to undergo randomization and 3) 6 month duration of the study that would allow them 
to obtain the other treatment at the end of the study.  
Revision of sling (e.g. for voiding dysfunction or mesh exposure) and replacement of sling that is not 
effective will be allowed during the study. This number was low in ESTEEM (only one subject in each arm 
underwent sling revision and there were no sling replacements).  
Subjects who initiate additional treatment off-protocol will remain in their group assignment and primary 
and secondary outcome measures will be completed as scheduled. The type of additional treatment e.g. 
behavioral and/or pelvic floor therapy, continence pessary, medical therapy, other procedure-based 
treatments (posterior tibial nerve stimulation, Botox A off-protocol, mid-urethal sling off-protocol, sacral 
neuromodulation) will be recorded. 
3.2 
Masking 
It is not feasible to mask the patients or surgeons to the intervention due to the nature of the interventions. 
While a placebo for Botox A is possible through saline injection during mid-urethral sling surgery, sham 
sling surgery would require suprapubic and vaginal incisions that would expose patients to the risks of 
sedation/anesthesia for the Botox A group. 
Outcome assessors will be masked to treatment assignment. All post-randomization outcome measures will 
be assessed by masked outcome assessors. All patient-reported outcomes (PROs) will be administered prior 
to other clinical assessments or procedures. (Table 5) 
Table 5: Masking in MUSA 
Study Individual 
Masking 
Study participant 
No 
Study surgeon 
No 
Outcome assessors 
Yes 
 
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 and age group (≥ 65, < 65). 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
25 
Version 4.0 
01 22 2021 
Age is a well-known predictor for reduced response to treatment for both Botox A and sub-urethral sling.64-66 
In women with refractory UUI undergoing Botox A injection in the ROSETTA study, age ≥ 65 years was 
associated with 3.3 fold reduced odds of ≥ 75% resolution of UUI episodes on bladder dairy and 
significantly less improvement on the OABq-SF than women < 65 years of age.65  Increasing patient age was 
also associated with decreased odds of satisfaction after sling surgery for stress urinary incontinence.66 
Therefore, women will also be stratified by age < 65 years or ≥ 65 years. 
Prior studies suggest that preoperative severity of UUI can affect treatment outcomes for UI. The “severity” 
of UUI has been identified as a potential risk factor for treatment failure for mid-urethral sling.67,68 
Conversely, in the ROSETTA trial, greater number of pretreatment UUI episodes was associated with 
greater response to treatment with Botox A injection.64 In ESTEEM, subjects with MUI were stratified based 
on the number of UUI episodes.  Subjects in ESTEEM were not stratified based on the number of SUI 
episodes because both groups were receiving the same treatment for SUI (mid-urethral sling). Similarly, in 
TOMUS,47 there was no stratification on SUI severity because both groups were receiving a mid-urethral 
sling (retropubic mid-urethral sling versus transobturator mid-urethral sling).  
The protocol committee had extensive discussions on whether subjects in MUSA should also be stratified 
based on the severity of UI. The definition of severity of UI for the MUI population is complex. What is 
important: overall UI or separate UUI and SUI severity measures? How do the various measures of UI 
severity differentially affect treatment failure with Botox A versus mid-urethral sling? Is there interaction 
between the level of UUI and SUI severity? There is limited data to inform these questions. One possible 
approach would be to stratify based on both UUI and SUI severity; however, this would create significant 
complexity in the randomization process and analysis plan. Given that subjects in MUSA will have moderate 
to severe UUI and SUI symptoms, have failed conservative treatments, and will be able to receive highly 
successful treatments for both UUI (Botox A) and SUI (mid-urethral sling), the team agreed that women will 
not be stratified based on incontinence severity.  
3.4 
Outcomes  
Figure 2. MUSA Outcomes 
 
 
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 
 
 
 
 
 
 
 
 
 
Cost-effectiveness 
 
 
 
 
 
 
 
 
 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
26 
Version 4.0 
01 22 2021 
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 6 months after the 
intervention is administered (mid-urethral sling or Botox A). Outcomes at 6 months will assess the 
effectiveness of the study treatments. 
We have elected to use the total UDI as the primary outcome because it is a validated, condition-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 increasingly being used as primary outcomes 
and supported by federal agencies.69,70  
The long form of the UDI is a 19 item, validated UI symptom specific PRO measure with 3 subscales: stress, 
irritative, and obstructive symptoms.1 The UDI fulfills the minimum qualities needed for interpretation in a 
clinical trial including construct, criterion and discriminant validity. 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. Higher scores represent more severe disease or bother from the patient perspective. 
The UDI will be the primary outcome because it has all the characteristics that are important for a MUI 
population: 
1. 
It captures a meaningful outcome from the patient perspective, incorporating both the presence and 
bother of SUI and OAB symptoms.  
2. 
The overall UDI score includes both a stress and irritative subscale, allowing us to comprehensively 
capture both SUI and OAB symptom outcomes.  
3. 
It includes 3 UI items that are not necessarily specific to stress or urgency 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 
Another important advantage of using the UDI is a primary outcome measure is that its minimum important 
difference (MID) has been extensively studied. From the patient perspective, MID represents “the smallest 
difference in score in the domain of interest which patients perceive as beneficial...”28 Statistically, the 
minimum important difference (MID) of a measure is a score change that reflects 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 clinical trial perspective, the MID 
represents the magnitude of benefit for which trials should be powered to minimize type 1 and type 2 errors.  
Table 6 shows the MID of the UDI from three large clinical trials. Prior estimates of the MID for the UDI 
were obtained in urge-predominant and stress-predominant MUI populations by Dyer et al and Barber et al 
respectively. The most recent estimate of MID of the UDI is from the ESTEEM trial which recruited subjects 
that are most similar to the MUSA population: women with MUI who have bothersome stress and 
bothersome urgency incontinence. The baseline mean UDI score of ESTEEM is higher than that of the BE-

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
27 
Version 4.0 
01 22 2021 
DRI and ATLAS populations. Using the anchor-based method, ESTEEM recommends a MID of -26 for the 
UDI total, -10.2 for the UDI-irritative subscale, and -5.4 for the UDI-stress subscale.  
Table 6: UDI MID 
Trial / 
Author 
Population 
Endpoint / 
Intervention 
UDI 
Component 
Anchor-
Based 
MID 
Distribution-
Based MID 
(1/2 SD) 
Recommend 
MID 
SD 
ESTEEM 
MUI 
Baseline mean UDI 
Score: 178 ± 43,  
UDI-irritative 66 ± 20,  
UDI stress 86 ± 18 
Sling vs. Sling 
+ Behavioral at 
3, 6, 12 months 
UDI-total 
-26.1 
 
-26 
43 (at bl) 
55 (change) 
46 (chg model) 
UDI-
irritative 
-10.2 
 
-10 
20 (at bl) 
25(change) 
21 (chg model) 
UDI-stress 
-5.4 
 
-5.4 
18 (at bl) 
28 (change) 
23 (chg model) 
BE-DRI, 
Dyer 
2011 71 
Pure urge/Urge-
predominant MUI. 
 
Baseline mean UDI 
score 120 ± 49, UDI 
irritative 58 ± 22 
8 month 
Meds +/- BPTx 
UDI-total 
 
-45 to -
35 
-25 
-35 
50 
UDI-
irritative 
-20 to -
15 
-11 
-15 
26 
ATLAS, 
Barber 
2009 10 
Pure SUI/SUI 
predominant MUI 
 
Baseline mean UDI 
score 80 ± 40, UDI 
stress 47 ± 19 
3 month 
Pessary vs 
BPTx vs both 
UDI-total 
-22.6 to 
-6.4 
-21.9 to -18.8 
-11 
36 
UDI-stress 
-16.5 to 
-4.6 
-10.6 to -9.1 
-8 
21 
 
There are at least 3 different ways to analyze the UDI scores:  
#1. Compare postoperative mean UDI scores between groups at 3 and 6 months 
 
#2. Compare mean changes (delta) in UDI scores from baseline to 3 and 6 months between groups 
(preferred, see below) 
#3. Dichotomize “success” and “failure” as women who achieved a 26-point improvement versus those 
who did not (also known as “responder analysis”) 
For analysis, we plan to compare mean changes (delta) in UDI scores from baseline to 3 and 6 months 
between groups (option #2). We prefer this to comparing postoperative mean UDI scores between groups 
(option #1) because 1) it will account for baseline differences in UDI scores between groups, which will be 
important in the unlikely event that baseline scores between groups differ in spite of randomization and 2) 
UDI scores typically have a distribution that is highly skewed, but differences from baseline are more likely 
to be normally distributed. We have elected to not dichotomize patients into responders and non-responders 
based on MID because information such as “slightly improved” is typically lost when lumping subjects into 
groups and furthermore, patients may worsen significantly on one of the subscales and yet be classified as a 
“success”.  
3.4.1.a Advantages of the UDI Over Other Outcome Measures  
The team discussed using bladder diary, IIQ (Incontinence Impact Questionnaire), and global impression of 
severity or improvement. Arguments against each of these were based on the following rationale: 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
28 
Version 4.0 
01 22 2021 
1. 
Problems with using bladder diary as primary outcome:  
a. Diary does not capture a meaningful patient outcome- It is becoming increasingly clear that 
typical clinical trial endpoints such as reduction in the number of incontinence episodes (IEs), 
voided volumes, etc. do not capture what is meaningful to patients. For example, having 3 large 
urinary urgency 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. Diary 
IEs also have limited correlation with patient satisfaction.72 Finally, bladder diaries have been 
shown to be less reliable in women with MUI, particularly for the SUI component.73 
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. However, IEs on the 
bladder diary will be a secondary outcome because this outcome measure has been widely used in other 
urinary incontinence trials. 
2. Problems with using a quality of life measure as primary outcome 
 
The protocol committee had extensive discussion about using a quality of life measure, such as the 
Incontinence Impact Questionnaire (IIQ) as the primary outcome. The IIQ long form measures the 
impact of UI on the QOL and is therefore suitable for capturing the effect of treatment of either 
stress or urgency component on QOL.1 Ultimately, the team decided to not use the IIQ as a primary 
outcome because the IIQ does not allow measurement of the impact of the interventions 
individually on the stress and urgency components. Though there are some women with MUI who 
may not be able to clearly distinguish all UI episodes as stress- or urge- related, the team felt it 
would be important to capture the effect of the interventions individually on symptoms. Finally, the 
MID of the IIQ was determined in stress-predominant and urge-predominant populations and has 
less validity for a MUI population.10,71 
3. 
Problems with using global impression measure as primary outcome 
 
Several Botox A trials have used a patient’s overall global impression of improvement as a primary 
outcome measure (see table 1). Although this outcome is simple and captures a clinically 
meaningful outcome, for our trial it could potentially introduce bias. Because it is not feasible to 
mask subjects in MUSA to the intervention, a single, subjective global impression item would be 
subject to bias. For example, if subjects in the Botox A group were more likely to ask for additional 
treatment and report they were not “improved” because they knew there was another potential 
surgical treatment available that they did not receive, this would bias our study towards a higher 
failure rate in the Botox A group (making the mid-urethral sling seem more effective than it really 
is). The challenges of masking or designing a sham procedure for the control group for MUSA have 
already been noted above (Section on Masking 3.2).  

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
29 
Version 4.0 
01 22 2021 
3.4.1.b Rationale for Timing of Primary Outcome 
In framing this question, the protocol committee considered the time-point at which a difference in outcome 
would lead to recommendation of Botox A versus mid-urethral sling as treatment for MUI in clinical practice. 
While three month outcomes are common for Botox A studies (table 1), longer-term outcomes of 1 year or 
more are “standard” for surgical trials with mid-urethral sling (table 2). The choice of 6 months for the 
primary outcome has precedent in our patient population for both Botox A and mid-urethral sling. For Botox 
A, both the ABC35 and ROSETTA33 trials had 6 month primary outcomes.  For mid-urethral sling, while 
ESTEEM’s primary outcome was 12 months, results for UDI total score, UDI stress score, UDI-irritative 
score, total UIE/day, UUIE/day, and SUIE/day did not change from 6 to 12 months within the sling only 
group (Table 7). In MUSA, the 6 month outcome will capture the short-term effect of therapy with either 
Botox A or mid-urethral sling for MUI before additional treatments are allowed.  
The time of procedure (mid-urethral sling surgery or Botox A injection) will serve as time = 0. If a 
participant is randomized but procedure is never performed, then Time 0 will be the planned surgery date.  
Table 7: ESTEEM outcomes at 6 and 12 months in the sling-only arm 
 
 Measure (Sling arm) 
6 month mean change 
12 month mean change 
UDI total score 
-118 
-114 
UDI stress score 
-64 
-61 
UDI irritative score 
-40 
-39 
UUIE per day 
-0.57 
-0.38 
SUIE per day 
-0.96 
-0.95 
 
3.4.1.c 
Management of Subjects Who Request Other Non-Study Treatment for SUI and/or OAB 
After Botox A or Mid-Urethral Sling 
The overarching goal of MUSA is to evaluate the effect of Botox A or mid-urethral sling on improving both 
SUI and UUI outcomes in women with MUI. Therefore, other non-study treatment for urinary incontinence 
(either SUI or UUI) should not be offered during the 6 month study period. We anticipate that the number of 
patients who request treatments other than Botox A or mid-urethral sling will be low (See section 
Management of patient who are unwilling for randomization or request treatment off-protocol). Patients 
requesting other non-study treatment during the 6-month study period will be asked to take advantage of 
treatments offered per-protocol and defer other treatments until after 6 months. Any non-study treatment will 
be recorded as a protocol deviation.  
3.4.2 
Secondary Outcomes 
The UDI total score at 3 months is a secondary outcome. Because MUI includes both SUI and UUI, it is 
important to be able to report SUI, UUI and other OAB symptom outcomes separately. The UDI-stress 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
30 
Version 4.0 
01 22 2021 
subscale and UDI-irritative subscale will be important secondary outcomes for which MUSA will be 
powered to detect differences and each will have a priori analysis plans (see Section 6, Statistical 
Considerations). 
3.4.2.a Urgency Urinary Incontinence/Overactive Bladder Symptom Outcomes 
Unlike ESTEEM, “desire for surgical treatment of SUI” is not an inclusion criterion for MUSA and there is 
an objective UUI inclusion criteria of >4 UUIEs on a 3 day diary. Therefore, it is likely that the MUSA 
population may have more prominent UUI symptoms than ESTEEM. A potential important clinical problem 
in this population is the potential for persistent or worsening OAB symptoms after mid-urethral sling, it is 
highly important to capture and report on the cardinal symptoms of OAB (urgency, frequency, urgency 
urinary incontinence and nocturia) 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 MUSA, this comprehensive OAB 
measure will be important to understanding how mid-urethral sling may affect all OAB symptoms 
individually and as a whole.  
3.4.2.b Stress Urinary Incontinence Symptom Outcomes 
Botox A has been shown to reduce overall UIEs in a urge-predominant MUI population (see section 2.4). 
Additionally, the common presence of cough-induced DO suggest that Botox A could potentially improve 
SUI symptoms in patients with MUI. However, direct data on whether Botox A can improve SUI symptoms 
are lacking. Therefore, it is important that SUI outcomes are reported separately in MUSA.  
Prior studies have also reported higher failure rates for SUI in women with MUI. In ESTEEM, improvement 
in stress score of the UDI was greater in the combined sling-BPTx group than the sling only group though 
these differences were not statistically significant (-67.11 vs – 61.65, p =.08). The MUSA population is 
different from ESTEEM in that they will already have “failed” behavioral therapy. Therefore, they may be at 
higher risk for persistent SUI symptoms. Other studies have also reported higher failure rates for SUI for 
women with MUI undergoing sling surgery. 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.23 They 
also reported that low 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. 
In ESTEEM, baseline urodynamic evaluation (UDE) parameters that predicted failure included detrusor 
overactivity, lower volume at first urge, and Valsalva leak point pressure <60 cmH2O. A study by Gleason et 
al using data from the University of Alabama at Birmingham including 534 women with MUS found that a 
lower proportion of women with MUI had SUI success compared with the SUI only group (64% vs 84.5%, p 
<  0.001). 74 Therefore, as a secondary outcome, we will also compare SUI outcomes between women 
randomized to Botox A versus mid-urethral sling. SUI symptoms will be measured using the UDI-stress 
subscale.  

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
31 
Version 4.0 
01 22 2021 
3.4.3 
Other Outcomes 
3.4.3.a Other UUI/OAB Outcomes 
1. 
Bladder diary – Change in IE frequency and type, number of urgency incontinence episodes, 
urgency incontinence severity with voids, number of diurnal voids, and number of nocturnal voids 
will be assessed and compared between groups at 3 and 6 months. 
2. 
Overactive Bladder treatment satisfaction (OAB-SAT-q)75 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 treatment. We will 
compare OAB-SAT-q scores at 3 and 6 months between treatment groups. 
3. 
Overactive Bladder Questionnaire- subscales (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).76 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.77 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.78,79 We will compare change from baseline in 
OAB-q subscale scores at 3 and 6 months between treatment groups. 
3.4.3.b Quality of Life/Global Impression 
We will compare change from baseline score in the measures below at 3 and 6 months between treatment 
groups. 
1. 
Incontinence Impact Questionnaire Long Form (IIQ-LF)57 
2. 
Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-IR)80 
3. 
European Quality of Life-5 Dimensions (EQ-5D) 84   
4. 
Short Form 36 (SF-36)81 and Short Form 6D (SG-6D)82  
5. 
Patient Global Impression of Improvement (PGI-I) and Patient Global Impression of Severity (PGI-
S).83  Observed PGI-I at 3 and 6 months will be compared between groups. 
3.4.3.c 
Safety/Additional Treatment 
1. 
Additional re-treatments for SUI or UUI within 6 months of treatment, and type of re-treatment 
2. 
Return to OR for sling revision due to worsened OAB symptoms, urinary retention, mesh exposure, 
repeat sling  
3. 
Rate of urinary retention, UTIs and recurrent UTIs 
4. 
Rate of other serious and non-serious adverse events. 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
32 
Version 4.0 
01 22 2021 
3.4.3.d Cost-Effectiveness Outcomes   
The cost-effectiveness analysis will be conducted from the health care sector and societal perspectives 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 the follow up period. Direct and indirect costs of the treatment of urinary 
incontinence with Botox A compared to mid-urethral sling (MUS) 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. mid-
urethral sling surgery and Botox injections) 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 2 weeks 
and 6 months. Data from medical resource types (physician visits, 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 
national unit costs as indicated in the following Table 8.  
 
Table 8: Resource Utilization Data Collection and Price Data Source by Utilization Category 
Service  
Source Documentation 
Price Weight  
Surgery: mid-urethral sling 
Case Report Form 
Medicare reimbursement 
 Botox injection 
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 
CIC products 
Case Report Form 
Average national cost 
UI products 
Questionnaire 
Average national cost 
UI laundry / dry cleaning 
Questionnaire 
Average national cost 
Time 
Questionnaire 
Average national cost 
Lost Productivity 
Questionnaire 
Average national cost 
 
 
 
 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
33 
Version 4.0 
01 22 2021 
Rationale for Using the EQ-5D and SF-6D 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 score.84 This instrument will be 
collected at baseline and follow up study visits (3 months and 6 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 and used in women with urinary incontinence, including 
ESTEEM.41,42,62,63 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.  
The Short Form 6-Dimensions (SF-6D) is a single summary preference based or utility measure of health 
derived from 11 items of the SF36 and will also be used to calculate each subjects utility score.81,82 This 
instrument will be collected at baseline and follow up study visits (3 months and 6 months). The SF-6D has 6 
dimensions (physical functioning, role limitation, social functioning, pain, mental health, vitality); each 
dimension has 2 to 6 levels for 18,000 possible unique health states. The SF-6D scoring function is based on 
the standard gamble method. The SF-6D preference-based measure is a continuous outcome scored on a 0.29 
to 1.00 scale, with 1.00 indicating "full health. This instrument has been previously validated and used in 
women with urinary incontinence and pelvic organ prolapse.85-87 We are using both the SF-6D and the EQ-
5D to measure utility scores because though both the SF-6D and EQ-5D weigh health states on a scale of 0 
(dead) to 1 (optimal health) and the MID values for both instruments are similar, they are not directly 
comparable. Studies have demonstrated that the SF-6D does not appear to describe health states at the lower 
end of the scale as well as the EQ-5D but is better able to describe health states and detect improvements 
towards the top of the utility scale.88 
Further data is needed to determine which instrument performs better as a preference-based utility and 
general HRQOL measure for women with MUI or if both are acceptable.  
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 SISTEr,89 ValUE90 and 
ESTEEM49 studies, this instrument should take approximately 15 minutes for a subject to complete at 3 
months and 6 months. 
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 MUSA MUI Population 
The MUSA population consists of women with bothersome MUI. Women in MUSA must report 
subjectively bothersome SUI and UUI and must also objectively demonstrate SUI and UUI. In determining 
eligibility criteria, the protocol committee considered the ultimate goal of MUSA. The population of MUSA 
are women with MUI who would benefit from either Botox A or mid-urethral sling but it is unclear whether 
treatment should begin with Botox A or mid-urethral sling. Therefore, participants must have bothersome 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
34 
Version 4.0 
01 22 2021 
symptoms, however, criteria are not so strict that women on either the moderate or severe end of the 
spectrum are excluded or recruitment is hindered (as was in MIMOSA). 
A single instrument that provides objective documentation of both SUI and UUI does not exist. A bladder 
diary allows documentation of both conditions; however, women are frequently unable to clearly 
characterize a leakage episode as SUI or UUI. Similarly, more invasive UDE testing also allows objective 
documentation of SUI and detrusor overactivity (DO) but DO correlates poorly with OAB symptoms and 
UDE does not predict treatment outcomes of either SUI or UUI.90-93 Therefore, similar to ESTEEM, MUSA 
will use a variety of instruments to identify women with MUI who have both subjective and objective 
evidence of MUI. This includes subjective documentation of at least moderately bothersome SUI and UUI 
on a PRO (UDI), objective documentation of UUI on bladder diary, and objective documentation of SUI by 
CST or UDE.  
Rationale for Bladder diary criteria for MUSA 
In determining the number of episodes required on bladder diary for inclusion into MUSA, the protocol 
committee reviewed bladder diary criteria for existing SUI and UUI trials (see tables 1 and 2 on Botox and 
mid-urethral sling). SUI trials typically have not used a bladder diary inclusion criterion; objective criteria of 
SUI is met by CST or UDE. Most Botox A trials have specified the number of UUI episodes in their 
inclusion criteria. The ESTEEM trial has shown that worse OAB (DO on urodynamics, previous OAB 
medication use, and for the sling only group, higher baseline UDI irritative subscore) is a predictor of failure 
to treatment, based on combined subjective (not meeting MCID for UDI-total score) and objective (not 
achieving >70% improvement on mean IE/day or additional SUI / UUI treatment) criteria . The team decided 
that at least 4 UUI episodes on a 3-day diary would be appropriate for documenting objective UUI and allow 
recruitment of a MUI population with higher UUI bother than ESTEEM while not necessarily being UUI-
predominant. In ESTEEM, 70% of participants at baseline had at least 4 UUIE in 3 days (>1.3 UUIE/day on 
average); this population had a mean 3.7 UUIE/day, 2.5 SUIE/day, 6.6 total UIE/day, 70 UDI-irritative score, 
and 85 UDI-stress score and an overall 20% failure rate at 3 months. The number of UUI incontinence 
episodes has purposefully not been set as high as previous Botox trials (Table 1) because the MUSA 
population is not limited to a refractory UUI or UUI-predominant population and to allow recruitment of a 
broad spectrum of women with MUI. Additionally, MUSA’s primary outcome is not defined by diary 
improvement.  
Rationale for Urodynamic evaluation inclusion criteria for MUSA 
The protocol committee considered the utility of including UDE as a MUSA inclusion criteria.  Given that 
this is the first trial to compare treatment with Botox A versus mid-urethral sling in women with MUI, 
baseline UDE information was considered important. In addition, other studies in women with MUI 
undergoing mid-urethral sling surgery have reported association of baseline UDE parameters with treatment 
failure.  Paick et al reported that low maximal urethral pressure at baseline UDE was associated with a 
greater risk of persistent OAB after mid-urethral sling23. In ESTEEM, baseline UDE parameters that 
predicted failure included detrusor overactivity, lower volume at first urge, and Valsalva leak point pressure 
<60 cmH2O.  Thus, standardized UDE will be performed before study interventions.   
There are no specific UDE parameters that determine eligibility for this trial beyond diagnosis of SUI 
defined by a positive CST or UDE. Patients in MUSA will undergo UDE testing, primarily to allow 
evaluation of variables that may predict clinical outcome. If patients have already undergone UDE prior to 
enrollment, results performed within 18 months of enrollment will be allowed if studies meet MUSA 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
35 
Version 4.0 
01 22 2021 
standards.  MUSA will use UDE standards similar to ESTEEM.  For those women who have not had UDE in 
the past 18 months, UDE will be performed before randomization. 
4.1.2 
Targeting a Population That is Distinct From ESTEEM 
While several inclusion criteria of MUSA are similar to that of the recently completed ESTEEM study, there 
are also important differences.  First, inclusion criteria for the number of UUIE per day is higher in MUSA 
than ESTEEM, thus ensuring recruitment of a population with higher UUI bother (see above Defining the 
MUSA MUI Population). Second, unlike ESTEEM, desire for surgical treatment for SUI symptoms is not an 
inclusion criterion for MUSA. Removing this criterion ensures that participants are eligible for both Botox A 
and mid-urethral sling. Additionally, removing this criterion prevents unconscious bias of including a stress-
predominant MUI population in MUSA. 
Behavioral therapy is first line management for urinary incontinence, either stress or urgency UI. In MUSA, 
women must report persistent symptoms despite at least one or more conservative treatments, (e.g. 
supervised behavioral/physical therapy).  
After extensive discussion, the protocol committee ultimately decided that “failure” (inadequate response, 
intolerant of, or for whom they are contraindicated as determined by the physician) of medical therapy with 
anti-cholinergic and/or beta-mimetic medications would be an eligibility criterion per Botox label indications.  
Based on the above rationale, the MUSA inclusion/exclusion criteria are as follows: 
4.2 
Inclusion Criteria 
1. 
Reporting at least “moderate bother” from UUI item on UDI  
a. “Do you experience urine leakage associated with a feeling of urgency?”  
2. 
Reporting at least “moderate bother” from SUI item on UDI 
a. “Do you experience urine leakage related to physical activity, coughing, or sneezing” 
3. 
Diagnosis of SUI defined by a positive cough stress test (CST) or UDE within the past 18 months 
If participant does not demonstrate SUI during CMG they must demonstrate SUI through a cough 
stress test or other comparable valsalva maneuver to be eligible. 
 
4. 
Presence of UUI on bladder diary with > 4 Urgency IE/3-day diary 
5. 
Urinary symptoms >3 months 
6. 
Persistent symptoms despite at least one or more conservative treatments (e.g. supervised 
behavioral therapy, physical therapy) as determined adequate by the physician. 
7. 
Inadequate response to oral overactive bladder medications (including anti-cholinergic and/or beta-
mimetic medication) unless patient is  
a. intolerant of oral overactive bladder medications, or  
b. oral overactive bladder medications are contraindicated as determined by the treating provider. 
8.  
Urodynamics within past 18 months prior to enrollment or done after enrollment, prior to 
randomization. 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
36 
Version 4.0 
01 22 2021 
9. 
Demonstrates understanding (or have caregiver demonstrate  understanding) to perform clean 
intermittent self-catheterization. 
Provider and patient review CISC process and patient (and/or caregiver) demonstrates 
understanding to the satisfaction of the provider. 
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 
b. Women undergoing only rectocele repair or other repair unrelated to anterior or apical 
compartment 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 6 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 urinary incontinence 
Women with known Burch or Marshall-Marchetti-Krantz  (MMK) are excluded. 
 
11. Spinal cord injury or advanced/severe neurologic conditions including Multiple Sclerosis, 
Parkinsons, Myasthenia Gravis, Charcot-Marie-Tooth 
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 6 month follow-
up 
16. Diagnosis of and/or history of bladder pain or chronic pelvic pain 
17. Women who had intravesical Botox injection within the past 12 months 
18. Women who have undergone anterior or apical pelvic organ prolapse repair within the past 6 
months 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
37 
Version 4.0 
01 22 2021 
4.4 
Screening for Eligibility 
It is anticipated that participants will be recruited 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. Patients 
who are considered candidates for either Botox A injection or mid-urethral sling by their physician will be 
offered participation in MUSA.  
Subjects will be identified as MUSA candidates by their physician. Subjects will be approached by study 
personnel consistent with local IRB requirements. Enrollment will occur after written and/or verbal consent. 
If the participant accepts participation in MUSA, 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. 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 medication with the longest half-life 
currently on the market is Vesicare with a half-life of 45-68 hours. Therefore, by 1week 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 trial,35 ESTEEM,49 ROSETTA33). In addition, because we are highly interested in what 
happens to OAB outcomes, subjects will need to remain off overactive bladder medication for the 6 month 
duration of the study to allow accurate assessment of these symptoms following treatment (See statistical 
analysis plan for details). Subjects who take overactive bladder medication during the study period will be 
considered as having “additional treatment”. Every effort will be made to schedule the patient’s surgery 
within 2 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 examination – Body mass index, pelvic organ prolapse quantification (POPQ) 
• Questionnaires – self-administered 
4.6 
Appointment Scheduling and Randomization 
Once patients are enrolled and randomized, the intervention (either Botox A or mid-urethral sling) should be 
scheduled within 8 weeks from randomization. If a participant is randomized but does not undergo the 
intervention within 8 weeks, the patient can be retained in the study at the investigator’s discretion  until the 
planned intervention is scheduled, with the planned intervention date serving as Time 0 for calculating 
windows for follow up visits and phone calls. If surgery is rescheduled but does not occur, then the last 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
38 
Version 4.0 
01 22 2021 
planned date of intervention will be Time 0. If the participant decides against the intervention but later 
changes her mind, the date of the intervention that did occur will be Time 0. 
Postoperatively, all subjects will return and/or be contacted for visits at 2 weeks, 3 months, and 6 months. 
All subjects will return for a clinic visit at 2 weeks after Botox A or mid-urethral sling intervention to check 
PVR. PROs will be administered at baseline, 3 months, and 6 months post-intervention. (See Assessment 
Table 9).  
5. 
DESCRIPTION OF STUDY INTERVENTIONS 
5.1 
Mid-urethral Sling Procedure 
In MUSA, we plan to allow retropubic as well as transobturator full length slings. This is based on the 
findings of the TOMUS and Barber’s equivalence trials in which these approaches demonstrated equivalence 
for improving objective success of SUI.47,53 In these studies, both approaches also showed similar results for 
subjective success of SUI, persistent UUI or de novo UUI. A recent Cochrane review that evaluated data of 
12,113 women undergoing mid-urethral sling procedures in 81 clinical trials has demonstrated the safety and 
efficacy of mid-urethral slings from several different manufacturers.94 
“Mini-sling” and “single-incision” sling will not be allowed due to potential risk for higher failure rate.95  
Key aspects of the procedure will be standardized across surgeons and sites.  
5.1.1 
Surgeon Certification  
To address the issue of surgeon certification for mid-urethral slings and to ensure standardized training of all 
surgeons, all “certified surgeons” will have performed a minimum of 20 mid-urethral slings of any type, 
including 5 of the mid-urethral sling allowed in MUSA that the surgeon will be using in the study. The site 
PI must sign off that each participating surgeon has met the criteria. 
5.1.2 
Standardization of Mid-urethral 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.  

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
39 
Version 4.0 
01 22 2021 
5.1.3 
Need for Postoperative Mid-urethral 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” regardless of indication. The reason for sling revision will 
be documented. 
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 mid-urethral sling. In the ESTEEM trial, the rate of sling revision was low (only 
one subject in each arm underwent sling revision). Similarly, 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.  
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. 
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 following sling. 
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 
Botox Injection 
5.2.1 
Surgeon Certification  
To address the issue of surgeon certification for Botox intradetrusor injection and to ensure standardized 
training of all surgeons, all “certified surgeons” administering injections will be required to view a short 
instructional video demonstrating optimal techniques and detailing sites of drug injection in a standardized 
manner. In addition, “certified surgeons”  at each site must have previously performed a total of 10 
intradetrusor injection procedures. 
5.2.2 
Standardization of Botox Injection Procedures 
Detailed standardization of the surgical procedure will be developed and will include the following key 
points: 
1. The Coordinator will ensure that the subject has been instructed regarding the proper technique 
for clean intermittent self-catheterization (CISC) and will confirm that the subject or designated 
caretaker is able to perform the task. 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
40 
Version 4.0 
01 22 2021 
2. Within one week prior to injection, a confirming urine pregnancy test will be performed in all 
premenopausal women. A urine dip to rule out infection will also be performed. If the urine dip is 
positive the participant will be treated for a urinary tract infection and rescheduled within 4 weeks 
for Botox A® injection visit.  
3. The bladder will be catheterized and 50 ml of 2% lidocaine placed in the bladder and 10 ml of 2% 
lidocaine jelly in the urethra. The subject will be asked to lie on their left and right lateral 
decubitus for several minutes at a time to ensure diffuse anesthetic effect on the bladder. 
Cystoscopic surveillance of the bladder will be used to confirm normality.  
4. Cystoscopy will be performed with a 12 or 30-degree lens and rigid or flexible scope. A 22 gauge 
disposable needle, which is passed through the cystoscopic channel, will be used. Approximately 
100-200 ml of total fluid will be instilled during cystoscopy to allow adequate visualization of the 
entire bladder urothelium. Botulinum toxin A will be prepared by dissolving 100 units of 
botulinum toxin A into 10 ml of injectable saline. Indigo carmine or methylene blue 0.1 ml will 
be added to each syringe of botulinum toxin A. The treating physician will inject a total of 10 ml 
of the Botox A® into approximately 15 to 20 different detrusor muscle sites under direct 
visualization. Injections will be spread out to equally cover the posterior bladder wall and dome, 
but spare the bladder trigone and ureteral orifices. The anterior bladder dome will be not be 
injected secondary to technical difficulties associated with injecting this area cystoscopically. 
5. The Coordinator will record peri-procedural events and complications. The instilled fluid will be 
left in the bladder after the injections are complete. The subject will remain in a post-procedure 
area until a spontaneous void occurs. The patient must have a spontaneous void before going 
home. All subjects will receive a single dose of antibiotics orally per standard of care 
immediately after injection and subjects will take antibiotics orally once daily for 3 days post 
injection.  
5.2.3 
Criteria for Botox Reinjections 
Participants with persistent bothersome UUI at 3 months after their initial 100 unit Botox A injection may 
receive one additional injection of 100 units Botox A between 3 months and 6 months after initial injection. 
Eligibility for repeat Botox A injection are: 
1. Persistent bothersome UUI as determined by reporting at least “moderate bother” from UUI item 
on UDI: “Do you experience urine leakage associated with a feeling of urgency, that is a strong 
sensation of needing to go to the bathroom?”  
2. Continued UI bother based on the Patient Global Symptom Control (PGSC): “My current 
treatment is giving me adequate control of my urinary leakage”, score of ≤ 3 
3. Participant desires additional treatment with Botox A 
4. No UTI as determined by the health care provider on the day of the PGSC evaluation 
5. PVR < 200 ml, per Botox A guidelines for UUI 
6. No medical contraindication for the procedure as determined by the physician 
7. Continuing to meet study inclusion/exclusion criteria (except inclusion items 2, 3, 4 7 and 8 and 
exclusion item 7). 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
41 
Version 4.0 
01 22 2021 
A maximum of 1 additional 100 unit Botox A injection will be allowed between 3 and 6 months (total of 2 
injections of 100 units Botox A). No injections will be given at an interval less than 3 months and the 
participant will have a post injection visit at 2 weeks (+/- 1 week) following injection.   
 
5.3 
Patient Management and Follow-Up 
5.3.1 
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, and neurological examination will be done if indicated. POP-Q, post-void 
residual, urinary cough stress test will be documented. 
e. 
Standardized urodynamic evaluation (UDE) will be performed before study interventions – there 
are no specific UDE parameters that determine eligibility for this trial beyond diagnosis of SUI 
defined by a positive CST or UDE. Small retrospective studies suggest that UDE parameters may 
be helpful in predicting outcomes after surgery in women with MUI and were predictors of failure 
in ESTEEM.23,96 Therefore, patients in MUSA will undergo UDE testing, primarily to allow 
evaluation of variables that may predict clinical outcome. If patients have already undergone UDE 
prior to enrollment, results performed within 18 months of enrollment will be allowed if studies 
meet MUSA standards. For those women who have not, UDE will be performed at baseline. 
f. 
Patient-reported outcomes and questionnaires – includes UDI, IIQ, EQ5D, PGI-I, PGI-S, OAB-q, 
OAB-SAT-q, PISQ-IR, SF-36, PGSC. 
5.3.2 
Postoperative Visits and Procedures 
Patients will undergo clinical and PRO assessments at 2-weeks, 3 months, and 6 months postoperatively (See 
Table 9). The primary outcome will be at 6 months.  

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
42 
Version 4.0 
01 22 2021 
 
Table 9: Timeline of Visits, Events, and Data Collection 
 
† primary outcome visit 
* all subjects will undergo a post-op visit for PVR/urine dip 2 weeks after Botox A or sling procedure  
‡ standard of care visit 
** must be done in clinic 
 
 
Screening Baseline 
Procedure 
(Botox or 
Sling) ‡, ** 
1-2 Week 
 Visit *‡ 
Telephone 
 Call 
3 Month 
Visit 
Botox 
reinjection
‡, ** 
1-2 Week 
Visit *‡ 
Telephone 
 Call 
6 Month 
Visit† 
Window 
1-4 w 
1-4 w 
 
 
1w before 
3m visit 
2 w pre – 
4 w post 
 
 
1w before 
6m visit 
2 w pre –  
4 w post 
Consent 
X 
 
 
 
 
 
 
 
 
 
Coordinator visit 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
Hx/PE 
X 
X 
 
 
 
X 
 
 
 
X 
Urodynamics** 
 
X 
 
 
 
 
 
 
 
 
Medication and other 
treatment audit 
X 
X 
 
 
 
X 
 
 
 
X 
Preg test~** 
 
 
X 
 
 
 
X 
 
 
 
Urine dip~** 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
PVR 
X 
X 
 
X 
 
X 
 
X 
 
X 
Adverse Events 
 
 
X 
X 
 
X 
X 
X 
 
X 
PGSC 
 
 
 
 
 
X 
 
 
 
X 
UDI 
 
X 
 
 
 
X 
 
 
 
X 
Bladder diary 
 
X 
 
 
Diary 
reminder 
X 
 
 
Diary 
reminder 
X 
PRO/Questionnaires 
Varies by milestone. 
 
X 
 
X 
 
X 
 
X 
 
X 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
43 
Version 4.0 
01 22 2021 
6. 
STATISTICAL CONSIDERATIONS  
6.1 
Sample size and Power  
MUSA will randomize 146 women to treatment with Botox or Sling in a 1:1 ratio. The sample size was 
derived to provide sufficient power for the primary Aim (comparison of Botox versus sling after 6 months) 
assessed for the primary outcome (change in UDI total score).  
6.1.1 
Primary Aim 
Assumptions 
For the primary outcome (UDI total score change from baseline at 6 months), alpha was set at 0.05 and 
power was set at 90%.  
Sample size estimates were based on an evaluation of minimum important differences (MIDs) and 
corresponding standard deviation (SD) for the UDI total score from the ESTEEM study of MUI, with 
support from other published populations of women with urge and stress incontinence; however, the 
populations on which those MIDs were based might differ from the target population of mixed incontinence 
for MUSA. 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 6 months for the UDI MID determined from ESTEEM 
as that will be a clinically important difference in our population. Table 6 summarizes the published MIDs 
for ESTEEM, BE-DRI, and ATLAS. To use the most accurate standard deviation applicable to MUSA, we 
calculated the SD based on a mixed effects repeated measures model with adjustment for baseline UDI score 
and clinical site rather than the SD of the observed data in order to account for improvements in variance 
estimation from the covariate adjustment planned for MUSA. To most closely match MUSA, this analysis 
model included all 3-month and 6-month ESTEEM data points after any retreatments and excludes patients 
with <4 Urge IEs/3 days.  The MID for ESTEEM UDI-Total is 26, and the SD=46.5 from the analysis model, 
resulting in an effect size = 0.56.  
Total number of randomized patients required to meet planned power estimates were adjusted for the 
assumed patient discontinuation rate at 6 months. ROSETTA and ESTEEM discontinuation rates are 
displayed in Table 10. Based on average estimates from ROSETTA and ESTEEM, we plan for 5% 
discontinuation rate by 6 months. 
 
 
Table 10: 6 Month Discontinuation Rates from ROSETTA and ESTEEM 
Study 
Population 
6-Month 
Discontinuation 
Rate 
ROSETTA 
UUI 
10/386=2.6% 
ESTEEM sling arm 
MUI  
16/235 = 6.8% 
Plan for MUSA 
MUI 
5% 
 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
44 
Version 4.0 
01 22 2021 
Sample Size and Power Calculation 
Sample size estimates were generated using nQuery Advisor under the assumptions outlined above.  The 
evaluable sample size required at 6 months for 90% power for the primary total UDI outcome is 69 per arm. 
Because data from ROSETTA and ESTEEM suggests that follow-up at 6 months should be about 95%, a 
total sample size of 73 randomized per treatment arm is selected (69/0.95 =73), for a total sample size of 146 
randomized participants. These calculations are provided in Table 11.  
Table 11: MUSA Power Calculation for N=146 (73 Per Treatment Arm) 
UDI component 
Primary or 
Secondary Outcome 
MID  
SD a 
Effect 
Size 
Alpha 
Power at 
6 months 
 
Randomized 
Sample Size per 
Group b  
UDI-Total 
Primary 
26 (ESTEEM) 
46.5 
0.56 
0.05 
90% 
73 
UDI-Total 
Primary 
26 (ESTEEM) 
46.5 
0.56 
0.05 
85% 
62 
UDI-Total 
Primary 
26 (ESTEEM) 
46.5 
0.56 
0.05 
80% 
55 
 
 
 
 
 
 
 
 
UDI-Total 
Primary 
23 
46.5 
0.50 
0.05 
82% 
73 
a SD: standard deviation is estimated from ESTEEM participants with at least 4 Urge IEs/3 days using a repeated measures linear 
model for change from baseline to 3 and 6 months with adjustment for baseline value and clinical site. 
b Assumes 5% of randomized participants discontinue by 6 months estimated by average of ROSETTA and ESTEEM 
Sensitivity to MID Assumptions for the Primary Outcome 
With the sample size of 146 subjects and the planned standard deviation, our study will have 82% power to 
detect a statistically significant difference in UDI-total score at p<0.05 if the true difference is as small as 23 
points (0.50 effect size) between groups at 6 months (Table 11). Thus, the planned sample size may allow 
for analyses to assess whether the true MID in this population is smaller than 26.  
 
6.2 
Statistical Analysis Plan 
6.2.1 
Analysis Populations and Management of Study Discontinuations Prior to Receiving Treatment 
It is possible that some women in both groups may cancel their surgical procedure due to personal or other 
reasons. Consistent with analyses for prior PFDN protocols (SUPeR, ASPIRe, ROSETTA), non-treated 
patients will be removed from evaluation of efficacy in a modified intent-to-treat population.  
6.2.2 
Primary Aim 
Primary Outcome 
The mean change from baseline in UDI total score will be compared between groups at 6 months at the 
p<0.05 statistical significance level using a mixed effects analysis of covariance model for repeated measures 
(MMRM)with adjustment for baseline UDI score, and randomization stratification factors site and age group. 
The model will include fixed effect categorical factors for treatment group, visit (3 and 6 months), and 
treatment × visit interaction with a heterogeneous Toeplitz covariance pattern for the within-subject repeated 
measures. Estimates, p-values and 95% confidence intervals will be presented for treatment group 
comparisons at 6 moths (primary) and 3 months (secondary).   

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
45 
Version 4.0 
01 22 2021 
This model assumes missing data due to a missed visit or early study discontinuation is missing at random. If 
more than 10% of participants are missing their 6-month score, then a sensitivity analysis will be performed 
using multiple imputation under a variety of missing data patterns to be specified in the statistical analysis 
plan in order to assess the robustness of the primary results to missing data. . 
We will report whether change in total UDI score from baseline to 6 months is statistically significantly 
different between groups. If the difference is statistically significant, the potential clinical significance of the 
difference will be discussed. We recognize that our sample size may allow us to find a difference between 
groups that is statistically significant yet smaller than published MID 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 MUSA, and an exploratory aim of MUSA is to explore whether the MID 
in this population differs from previously published values.  
Secondary Outcomes 
There are two secondary outcomes for the primary aim. The mean change from baseline in UDI-stress and 
UDI-irritative subscores will be compared between groups at 6 months.  Each of these outcomes will be 
evaluated using an alpha level of 0.05, with no adjustment for multiple comparisons. The statistical analysis 
of the two secondary outcomes will be identical to the analysis described above for the UDI total score. 
6.2.3 
Exploratory Aims 
All statistical evaluations of the exploratory aims are for descriptive purposes and p-values resulting from 
these analyses will not be evaluated for statistical significance. 
1. 
Secondary urinary outcomes: To compare treatment with Botox A to treatment with mid-urethral 
sling for improving the number of urinary incontinence episodes on bladder diary after 6 months. 
 
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 6 months. 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 at 6 months 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 site and age 
group.  
2. 
Predictors of poor treatment response: To develop models to identify baseline predictors of 
change of MUI, OAB, and SUI outcomes measured using the UDI between baseline and 6 months 
post-treatment 
Regression models will be created to identify predictors of change from baseline to 6 months for UDI total 
score and stress and irritative subscale scores. Potential predictors will include age, diary parameters such as 
number of UUI episodes/3 days, functional bladder capacity, stress and irritative bother severity at baseline, 
type of urinary incontinence (stress-predominant or urgency-predominant: see definition below), and co-
existing anterior vaginal wall prolapse. The relationship between potential predictors and outcomes will be 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
46 
Version 4.0 
01 22 2021 
explored in models that include one predictor plus stratification factors (site and age 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. 
The definition of the type of urinary incontinence, stress- or urgency predominant will be based on 2 
questions of the Urogenital Distress Inventory,  
1. 
“Do you experience urine leakage associated with a feeling of urgency?”  
2. 
“Do you experience urine leakage related to physical activity, coughing, or sneezing?” 
 
Based on our inclusion criteria, patients must report at least “moderate” bother on both questions.  
If the subject reports greater bother on the stress question, she will be classified as stress-predominant MUI. 
If the subject reports greater bother on the urgency question, she will be classified as urgency-predominant 
MUI. If the subject reports equal bother on both questions, she will be classified as “balanced” MUI.  
3. 
Quality of life and global impression: To compare quality of life outcomes and Patient Global 
Impression-Improvement (PGI-I), Patient Global Impression-Severity (PGI-S) between groups 
randomized to Botox versus sling after 6 months. 
 
Changes from baseline in all quality of life PRO instruments and global impression will be 
calculated and analyzed using the methods described for the analysis of the primary outcome 
4. 
Safety and additional treatments: To describe rates of reoperation (sling revision) after mid-
urethral sling and intermittent catheterization due to voiding dysfunction/partial urinary retention 
after Botox injection, to compare the proportion of women in each group with UTI and recurrent 
UTI, rates of other serious and non-serious adverse events, and to compare the proportion of 
women in each group initiating additional (off protocol) treatment other than Botox and mid-
urethral sling for SUI and/or OAB, and the types of additional treatment (behavioral therapy, 
medications, other).  
 
Groups will be summarized with n and percent, and rates will be compared with chi-square tests.  
5. 
Cost-effectiveness analysis: To determine the cost effectiveness of Botox A injection versus mid-
urethral sling for the treatment of MUI symptoms at 6 months. 
 
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 stratification factors of study site and age group, 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.97 
 
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 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
47 
Version 4.0 
01 22 2021 
resampling technique will be used to derive the 95% confidence interval for the ICER.98 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.  
 
We plan to conduct supplemental analyses using alternative outcome measures, such as incremental 
cost per reduction in UIE/day.  
 
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. 
6. 
UDI MID: To explore 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 
the PGSC, global impression of change, and incontinence episodes from the bladder diary.  
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.  
Since we expect to enroll MUSA within 7 months, and since the primary outcome is attained at 6 months 
following surgery, no formal interim analyses of efficacy outcomes will be performed. At each meeting, the 
DSMB will be presented with information about enrollment, participant adverse events, 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, urgency, 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 will have already 
been offered more conservative therapies. We will be assured that women will have previously tried 
behavioral and/or pelvic floor therapy because it is an inclusion criterion. The potential benefits of the Botox 
A intervention are improvement of UUI and MUI symptoms while the risks are minimal. The benefit of mid-
urethral sling for patients with SUI is well documented and several studies, including ESTEEM, have also 
documented an improvement in OAB and MUI symptoms following sling.  

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
48 
Version 4.0 
01 22 2021 
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 mid-urethral and willing to undergo sling surgery and Botox A treatment for 
MUI will 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. Documented 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 study 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 3 times per 
year, 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 and efficacy data will be assessed in a 
descriptive manner at each DSMB meeting without formal statistical tests.  
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. The DSMB reviews all SAEs. 
7.5 
Side Effects/Safety 
7.5.1 
Mid-urethral Sling 
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. 
7.5.2 
Botox A  
Botox A detrusor injection is a commonly performed procedure for the treatment of UUI and MUI. Like all 
surgical interventions it has the risk of bleeding, infection, and injury to surrounding structures.  
A recent comprehensive review identified 44 original research studies that reported on 16 different 
conditions treated with multiple treatments with Botox A ®. The conditions treated with Botox A ® were 
varied and included such disorders such as achalasia, blepharospasm, cervical dystonia, cerebral palsy, 
esophageal spasm, hemifacial spasm, laryngeal dystonia, oromandibular dystonia, strabismus in addition to 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
49 
Version 4.0 
01 22 2021 
detrusor overactivity. Botox A® has been FDA approved since 1989 for only some of the conditions it is 
currently been used for. According to the American Society of Plastic Surgery, 7.4 million cosmetic 
botulinum toxin A injections were administered in 2018. This figure was up from 787,000 in 2000. 
http://www.plasticsurgery.org.  
7.5.3 
Botox A Contraindications102  
BOTOX is contraindicated in patients who are hypersensitive to any botulinum toxin product or to any of the 
components in the formulation. In the presence of infection at the proposed injection site(s). For intradetrusor 
injection in patients with a urinary tract infection; or in patients with urinary retention or post-void residual 
(PVR) urine volume >200 mL who are not routinely performing clean intermittent self-catheterization (CIC). 
7.5.4 
Botox A Warnings and Precautions102 
Lack of Interchangeability Between Botulinum Toxin Products  
The potency Units of BOTOX are specific to the preparation and assay method utilized. They are not 
interchangeable with other preparations of botulinum toxin products and, therefore, units of biological 
activity of BOTOX cannot be compared to nor converted into units of any other botulinum toxin products 
assessed with any other specific assay method [see Description].   
Spread of Toxin Effect 
Post-marketing safety data from BOTOX and other approved botulinum toxins suggest that botulinum toxin 
effects may, in some cases, be observed beyond the site of local injection. The symptoms are consistent with 
the mechanism of action of botulinum toxin and may include asthenia, generalized muscle weakness, 
diplopia, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties. These 
symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be 
life threatening and there have been reports of death related to spread of toxin effects. The risk of symptoms 
is probably greatest in children treated for spasticity but symptoms can also occur in adults treated for 
spasticity and other conditions, and particularly in those patients who have an underlying condition that 
would predispose them to these symptoms. In unapproved uses and in approved indications, symptoms 
consistent with spread of toxin effect have been reported at doses comparable to or lower than doses used to 
treat cervical dystonia and spasticity. Patients or caregivers should be advised to seek immediate medical 
care if swallowing, speech or respiratory disorders occur.  
No definitive serious adverse event reports of distant spread of toxin effect associated with BOTOX for 
blepharospasm at the recommended dose (30 Units and below), severe primary axillary hyperhidrosis at the 
recommended dose (100 Units), strabismus, or for chronic migraine at the labeled doses have been reported. 
Serious Adverse Reactions with Unapproved Use  
Serious adverse reactions, including excessive weakness, dysphagia, and aspiration pneumonia, with some 
adverse reactions associated with fatal outcomes, have been reported in patients who received BOTOX 
injections for unapproved uses. In these cases, the adverse reactions were not necessarily related to distant 
spread of toxin, but may have resulted from the administration of BOTOX to the site of injection and/or 
adjacent structures. In several of the cases, patients had pre-existing dysphagia or other significant 
disabilities. There is insufficient information to identify factors associated with an increased risk for adverse 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
50 
Version 4.0 
01 22 2021 
reactions associated with the unapproved uses of BOTOX. The safety and effectiveness of BOTOX for 
unapproved uses have not been established.  
Hypersensitivity Reactions  
Serious and/or immediate hypersensitivity reactions have been reported. These reactions include anaphylaxis, 
serum sickness, urticaria, soft tissue edema, and dyspnea. If such a reaction occurs, further injection of 
BOTOX should be discontinued and appropriate medical therapy immediately instituted. One fatal case of 
anaphylaxis has been reported in which lidocaine was used as the diluent, and consequently the causal agent 
cannot be reliably determined.  
Increased Risk of Clinically Significant Effects with Pre-Existing Neuromuscular Disorders  
Individuals with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis or neuromuscular 
junction disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) should be monitored when given 
botulinum toxin. Patients with known or unrecognized neuromuscular disorders or neuromuscular junction 
disorders may be at increased risk of clinically significant effects including generalized muscle weakness, 
diplopia, ptosis, dysphonia, dysarthria, severe dysphagia and respiratory compromise from therapeutic doses 
of BOTOX [see Warnings and Precautions]. 
Dysphagia and Breathing Difficulties  
Treatment with BOTOX and other botulinum toxin products can result in swallowing or breathing 
difficulties. Patients with pre-existing swallowing or breathing difficulties may be more susceptible to these 
complications. In most cases, this is a consequence of weakening of muscles in the area of injection that are 
involved in breathing or oropharyngeal muscles that control swallowing or breathing [see Warnings and 
Precautions]. 
Deaths as a complication of severe dysphagia have been reported after treatment with botulinum toxin. 
Dysphagia may persist for several months, and require use of a feeding tube to maintain adequate nutrition 
and hydration. Aspiration may result from severe dysphagia and is a particular risk when treating patients in 
whom swallowing or respiratory function is already compromised.  
Treatment with botulinum toxins may weaken neck muscles that serve as accessory muscles of ventilation. 
This may result in a critical loss of breathing capacity in patients with respiratory disorders who may have 
become dependent upon these accessory muscles. There have been post-marketing reports of serious 
breathing difficulties, including respiratory failure.  
Patients with smaller neck muscle mass and patients who require bilateral injections into the 
sternocleidomastoid muscle for the treatment of cervical dystonia have been reported to be at greater risk for 
dysphagia. Limiting the dose injected into the sternocleidomastoid muscle may reduce the occurrence of 
dysphagia. Injections into the levator scapulae may be associated with an increased risk of upper respiratory 
infection and dysphagia.  
Patients treated with botulinum toxin may require immediate medical attention should they develop problems 
with swallowing, speech or respiratory disorders. These reactions can occur within hours to weeks after 
injection with botulinum toxin [see Warnings and Precautions]. 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
51 
Version 4.0 
01 22 2021 
Pulmonary Effects of Botox in Patients with Compromised Respiratory Status Treated for Detrusor 
Overactivity Associated with a Neurologic Condition  
In a double-blind, placebo-controlled, parallel group study in adult patients with detrusor overactivity 
associated with a neurologic condition and restrictive lung disease of neuromuscular etiology [defined as 
FVC 50-80% of predicted value in patients with spinal cord injury between C5 and C8, or MS] the event rate 
in change of Forced Vital Capacity ≥15% or ≥20% was generally greater in patients treated with BOTOX 
than in patients treated with placebo (see Table 12). 
Table 12: Number and Percent of Patients Experiencing at Least a 15% or 20% Decrease in FVC 
From Baseline at Week 2, 6, 12 Post-injection with BOTOX or Placebo 
BOTOX 
200 Units 
Placebo 
 
>15% 
>20% 
>15% 
>20% 
Week 2  
0/15 (0%) 
0/15 (0%) 
1/11 (9%) 
0/11 (0%) 
Week 6  
2/13 (15%) 
1/13 (8%) 
0/12 (0%) 
0/12 (0%) 
Week 12  
0/12(0%) 
0/12 (0%) 
0/7 (0%) 
0/7 (0%) 
 
Autonomic Dysreflexia in Patients Treated for Detrusor Overactivity Associated with a Neurologic 
Condition  
Autonomic dysreflexia associated with intradetrusor injections of BOTOX could occur in patients treated for 
detrusor overactivity associated with a neurologic condition and may require prompt medical therapy. In 
clinical trials, the incidence of autonomic dysreflexia was greater in patients treated with BOTOX 200 Units 
compared with placebo (1.5% versus 0.4%, respectively). 
Urinary Tract Infections in Patients with Overactive Bladder  
BOTOX increases the incidence of urinary tract infection [see Adverse Reactions]. Clinical trials for 
overactive bladder excluded patients with more than 2 UTIs in the past 6 months and those taking antibiotics 
chronically due to recurrent UTIs. Use of BOTOX for the treatment of overactive bladder in such patients 
and in patients with multiple recurrent UTIs during treatment should only be considered when the benefit is 
likely to outweigh the potential risk.  
Urinary Retention in Patients Treated for Bladder Dysfunction  
Due to the risk of urinary retention, treat only patients who are willing and able to initiate catheterization 
post-treatment, if required, for urinary retention.  
In patients who are not catheterizing, post-void residual (PVR) urine volume should be assessed within 2 
weeks post-treatment and periodically as medically appropriate up to 12 weeks, particularly in patients with 
multiple sclerosis or diabetes mellitus. Depending on patient symptoms, institute catheterization if PVR urine 
volume exceeds 200 mL and continue until PVR falls below 200 mL. Instruct patients to contact their 
physician if they experience difficulty in voiding as catheterization may be required.  

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
52 
Version 4.0 
01 22 2021 
The incidence and duration of urinary retention is described below for patients with overactive bladder and 
detrusor overactivity associated with a neurologic condition who received BOTOX or placebo injections.  
 
Overactive Bladder  
In double-blind, placebo-controlled trials in patients with OAB, the proportion of subjects who initiated 
clean intermittent catheterization (CIC) for urinary retention following treatment with BOTOX or placebo is 
shown in Table 13. The duration of post-injection catheterization for those who developed urinary retention 
is also shown. 
Table 13: Proportion of Patients Catheterizing for Urinary Retention and Duration of Catheterization 
Following an Injection in Double-blind, Placebo-Controlled Clinical Trials in OAB 
Timepoint 
BOTOX 100 Units 
(N=552) 
Placebo 
(N=542) 
Proportion of Patients Catheterizing for Urinary Retention  
At any time during complete treatment cycle  
6.5% (n=36)  
0.4% (n=2)  
Duration of Catheterization for Urinary Retention (Days)  
Median  
63  
11  
Min, Max  
1, 214  
3, 18  
 
 
Patients with diabetes mellitus treated with BOTOX were more likely to develop urinary retention than those 
without diabetes, as shown in Table 14. 
Table 14: Proportion of Patients Experiencing Urinary Retention Following an Injection in Double-
blind, Placebo-controlled Clinical Trials in OAB According to History of Diabetes Mellitus 
 
Patients with Diabetes 
Patients without Diabetes 
BOTOX 100 Units  
(N=81) 
Placebo 
(N=69) 
BOTOX 100 Units 
(N=526) 
Placebo 
(N=516) 
Urinary retention  
12.3% (n=10)  
  0  
6.3% (n=33)  
0.6% (n=3)  
 
 
Detrusor Overactivity Associated with a Neurologic Condition  
In two double-blind, placebo-controlled trials in patients with detrusor overactivity associated with a 
neurologic condition (NDO-1 and NDO-2), the proportion of subjects who were not using clean intermittent 
catheterization (CIC) prior to injection and who subsequently required catheterization for urinary retention 
following treatment with BOTOX 200 Units or placebo is shown in Table 15. The duration of post-injection 
catheterization for those who developed urinary retention is also shown. 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
53 
Version 4.0 
01 22 2021 
Table 15: Proportion of Patients Not Using CIC at Baseline and then Catheterizing for Urinary 
Retention and Duration of Catheterization Following an Injection in Double-blind, Placebo-controlled 
Clinical Trials 
Timepoint  
BOTOX 200 Units 
(N=108) 
Placebo 
(N=104) 
Proportion of Patients Catheterizing for Urinary Retention  
At any time during complete treatment cycle  
30.6% (n=33)  
6.7% (n=7)  
Duration of Catheterization for Urinary Retention (Days)  
Median  
289  
358  
Min, Max  
1, 530  
2, 379  
 
Human Albumin and Transmission of Viral Diseases  
This product contains albumin, a derivative of human blood. Based on effective donor screening and product 
manufacturing processes, it carries an extremely remote risk for transmission of viral diseases and variant 
Creutzfeldt-Jakob disease (vCJD). There is a theoretical risk for transmission of Creutzfeldt-Jakob disease 
(CJD), but if that risk actually exists, the risk of transmission would also be considered extremely remote. No 
cases of transmission of viral diseases, CJD or vCJD have ever been identified for licensed albumin or 
albumin contained in other licensed products. 
7.5.5 
Adverse Reactions to Botox A102  
The following adverse reactions to BOTOX (onabotulinumtoxinA) for injection are discussed in greater 
detail in other sections of the labeling:  
• Spread of Toxin Effects  
• Serious Adverse Reactions with Unapproved Use  
• Hypersensitivity Reactions  
• Increased Risk of Clinically Significant Effects with Pre-Existing Neuromuscular Disorders  
• Dysphagia and Breathing Difficulties   
• Pulmonary Effects of BOTOX in Patients with Compromised Respiratory Status Treated for 
Spasticity or for Detrusor Overactivity associated with a Neurologic Condition  
• Corneal Exposure and Ulceration in Patients Treated with BOTOX for Blepharospasm  
• Retrobulbar Hemorrhages in Patients Treated with BOTOX for Strabismus 
• Bronchitis and Upper Respiratory Tract Infections in Patients Treated for Spasticity  
• Autonomic Dysreflexia in Patients Treated for Detrusor Overactivity associated with a Neurologic 
Condition 
• Urinary Tract Infections in Patients with Overactive Bladder 
• Urinary Retention in Patients Treated for Bladder Dysfunction 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
54 
Version 4.0 
01 22 2021 
Botox A Clinical Trials Experience  
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in 
the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may 
not reflect the rates observed in clinical practice.  
BOTOX and BOTOX Cosmetic contain the same active ingredient in the same formulation, but with 
different labeled Indications and Usage. Therefore, adverse reactions observed with the use of BOTOX 
Cosmetic also have the potential to be observed with the use of BOTOX.  
In general, adverse reactions occur within the first week following injection of BOTOX and, while generally 
transient, may have a duration of several months or longer. Localized pain, infection, inflammation, 
tenderness, swelling, erythema, and/or bleeding/bruising may be associated with the injection. Symptoms 
associated with flu-like symptoms (e.g., nausea, fever, myalgia) have been reported after treatment. Needle-
related pain and/or anxiety may result in vasovagal responses (including syncope, hypotension), which may 
require appropriate medical therapy.  
Local weakness of the injected muscle(s) represents the expected pharmacological action of botulinum toxin. 
However, weakness of nearby muscles may also occur due to spread of toxin  
Overactive Bladder  
Table 16 presents the most frequently reported adverse reactions in double-blind, placebo-controlled clinical 
trials for overactive bladder occurring within 12 weeks of the first BOTOX treatment. 
Table 16: Adverse Reactions Reported by ≥2% of BOTOX treated Patients and More Often than in 
Placebo-treated Patients Within the First 12 Weeks after Intradetrusor Injection, in Double-blind, 
Placebo-controlled Clinical Trials in Patients with OAB 
Adverse Reactions  
BOTOX 100 Units 
(N=552) 
% 
Placebo 
(N=542) 
% 
Urinary tract infection  
Dysuria  
Urinary retention  
Bacteriuria  
Residual urine volume*  
18  
9  
6  
4  
3  
6  
7  
0  
2  
0  
*Elevated PVR not requiring catheterization. Catheterization was required for PVR >350 mL regardless of symptoms, and for 
PVR >200 mL to <350 mL with symptoms (e.g., voiding difficulty). 
A higher incidence of urinary tract infection was observed in patients with diabetes mellitus treated with 
BOTOX 100 Units and placebo than in patients without diabetes, as shown in Table 17. 
Table 17: Proportion of Patients Experiencing Urinary Tract Infection following an Injection in 
Double-blind, Placebo-controlled Clinical Trials in OAB according to history of Diabetes Mellitus 
 
Patients with Diabetes 
Patients without Diabetes 
BOTOX 100 Units 
(N=81) % 
Placebo 
(N=69) % 
BOTOX 100 Units 
(N=526) % 
Placebo 
(N=516) % 
Urinary tract infection (UTI)  
31  
12  
26  
10  

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
55 
Version 4.0 
01 22 2021 
 
The incidence of UTI increased in patients who experienced a maximum post-void residual (PVR) urine 
volume >200 mL following BOTOX injection compared to those with a maximum PVR <200 mL following 
BOTOX injection, 44% versus 23%, respectively. No change was observed in the overall safety profile with 
repeat dosing during an open-label, uncontrolled extension trial.  
7.5.6 
Immunogenicity of Botox A102 
As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation 
is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of 
antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors 
including assay methodology, sample handling, timing of sample collection, concomitant medications, and 
underlying disease. For these reasons, comparison of the incidence of antibodies to onabotulinumtoxinA in 
the studies described below with the incidence of antibodies in other studies or to other products may be 
misleading.  
In a long term, open-label study evaluating 326 cervical dystonia patients treated for an average of 9 
treatment sessions with the current formulation of BOTOX, 4 (1.2%) patients had positive antibody tests. All 
4 of these patients responded to BOTOX therapy at the time of the positive antibody test. However, 3 of 
these patients developed clinical resistance after subsequent treatment, while the fourth patient continued to 
respond to BOTOX therapy for the remainder of the study.  
One patient among the 445 hyperhidrosis patients (0.2%), two patients among the 380 adult upper limb 
spasticity patients (0.5%), and no patients among 406 migraine patients with analyzed specimens developed 
the presence of neutralizing antibodies.  
In overactive bladder patients with analyzed specimens from the two phase 3 studies and the open-label 
extension study, neutralizing antibodies developed in 0 of 954 patients (0.0%) while receiving BOTOX 100 
Unit doses and 3 of 260 patients (1.2%) after subsequently receiving at least one 150 Unit dose. Response to 
subsequent BOTOX treatment was not different following seroconversion in these three patients. 
In detrusor overactivity associated with neurologic condition patients with analyzed specimens in the drug 
development program (including the open-label extension study), neutralizing antibodies developed in 3 of 
300 patients (1.0%) after receiving only BOTOX 200 Unit doses and 5 of 258 patients (1.9%) after receiving 
at least one 300 Unit dose. Following development of neutralizing antibodies in these 8 patients, 4 continued 
to experience clinical benefit, 2 did not experience clinical benefit, and the effect on the response to BOTOX 
in the remaining 2 patients is not known.  
The data reflect the patients whose test results were considered positive for neutralizing activity to BOTOX 
in a mouse protection assay or negative based on a screening ELISA assay or mouse protection assay.  
Formation of neutralizing antibodies to botulinum toxin type A may reduce the effectiveness of BOTOX 
treatment by inactivating the biological activity of the toxin. The critical factors for neutralizing antibody 
formation have not been well characterized. The results from some studies suggest that BOTOX injections at 
more frequent intervals or at higher doses may lead to greater incidence of antibody formation. The potential 
for antibody 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
56 
Version 4.0 
01 22 2021 
7.5.7 
Post-Marketing Experience of Botox A102 
The following adverse reactions have been identified during post-approval use of BOTOX. Because these 
reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably 
estimate their frequency or establish a causal relationship to drug exposure. These reactions include: 
abdominal pain; alopecia, including madarosis; anorexia; brachial plexopathy; denervation/muscle atrophy; 
diarrhea; dry eye; hyperhidrosis; hypoacusis; hypoaesthesia; localized muscle twitching; malaise; paresthesia; 
peripheral neuropathy; radiculopathy; erythema multiforme, dermatitis psoriasiform, and psoriasiform 
eruption; strabismus; tinnitus; and visual disturbances.  
There have been spontaneous reports of death, sometimes associated with dysphagia, pneumonia, and/or 
other significant debility or anaphylaxis, after treatment with botulinum toxin. 
There have also been reports of adverse events involving the cardiovascular system, including arrhythmia 
and myocardial infarction, some with fatal outcomes. Some of these patients had risk factors including 
cardiovascular disease. The exact relationship of these events to the botulinum toxin injection has not been 
established.  
New onset or recurrent seizures have also been reported, typically in patients who are predisposed to 
experiencing these events. The exact relationship of these events to the botulinum toxin injection has not 
been established. 
7.6 
Drug Interactions with Botox A102 
7.6.1 
Aminoglycosides and Other Agents Interfering with Neuromuscular Transmission  
Co-administration of BOTOX and aminoglycosides or other agents interfering with neuromuscular 
transmission (e.g., curare-like compounds) should only be performed with caution as the effect of the toxin 
may be potentiated.  
7.6.2 
Anticholinergic Drugs  
Use of anticholinergic drugs after administration of BOTOX may potentiate systemic anticholinergic effects.  
7.6.3 
Other Botulinum Neurotoxin Products  
The effect of administering different botulinum neurotoxin products at the same time or within several 
months of each other is unknown. Excessive neuromuscular weakness may be exacerbated by administration 
of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin.  
7.6.4 
Muscle Relaxants  
Excessive weakness may also be exaggerated by administration of a muscle relaxant before or after 
administration of BOTOX. 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
57 
Version 4.0 
01 22 2021 
7.7 
Use of Botox A in Specific Populations102  
7.7.1 
Pregnancy  
Risk Summary  
There are no studies or adequate data from postmarketing surveillance on the developmental risk associated 
with use of BOTOX in pregnant women. In animal studies, administration of BOTOX during pregnancy 
resulted in adverse effects on fetal growth (decreased fetal weight and skeletal ossification) at clinically 
relevant doses, which were associated with maternal toxicity. In the U.S. general population, the estimated 
background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2-4% and 15-
20%, respectively. The background risk of major birth defects and miscarriage for the indicated populations 
is unknown. 
Animal Data  
When BOTOX (4, 8, or 16 Units/kg) was administered intramuscularly to pregnant mice or rats two times 
during the period of organogenesis (on gestation days 5 and 13), reductions in fetal body weight and 
decreased fetal skeletal ossification were observed at the two highest doses. The no-effect dose for 
developmental toxicity in these studies (4 Units/kg) is approximately equal to the human dose of 400 Units, 
on a body weight basis (Units/kg).  
When BOTOX was administered intramuscularly to pregnant rats (0.125, 0.25, 0.5, 1, 4, or 8 Units/kg) or 
rabbits (0.063, 0.125, 0.25, or 0.5 Units/kg) daily during the period of organogenesis (total of 12 doses in rats, 
13 doses in rabbits), reduced fetal body weights and decreased fetal skeletal ossification were observed at the 
two highest doses in rats and at the highest dose in rabbits. These doses were also associated with significant 
maternal toxicity, including abortions, early deliveries, and maternal death. The developmental no-effect 
doses in these studies of 1 Unit/kg in rats and 0.25 Units/kg in rabbits are less than the human dose of 400 
Units, based on Units/kg.  
When pregnant rats received single intramuscular injections (1, 4, or 16 Units/kg) at three different periods 
of development (prior to implantation, implantation, or organogenesis), no adverse effects on fetal 
development were observed. The developmental no-effect level for a single maternal dose in rats (16 
Units/kg) is approximately 2 times the human dose of 400 Units, based on Units/kg. 
7.7.2 
Lactation  
Risk Summary  
There are no data on the presence of BOTOX in human or animal milk, the effects on the breastfed infant, or 
the effects on milk production. The developmental and health benefits of breastfeeding should be considered 
along with the mother’s clinical need for BOTOX and any potential adverse effects on the breastfed infant 
from BOTOX or from the underlying maternal conditions. 
7.7.3 
Geriatric Use  
Of the 2145 adult patients in placebo-controlled clinical studies of BOTOX for the treatment of spasticity, 
33.5% were 65 or older, and 7.7% were 75 years of age or older. No overall differences in safety were 
observed between elderly patients and adult patients younger than 65 years of age.  

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
58 
Version 4.0 
01 22 2021 
In clinical studies of BOTOX across other indications, no overall differences in safety were observed 
between elderly patients and younger adult patients, with the exception of Overactive Bladder (see below). 
Other reported clinical experience has not identified differences in responses between the elderly and 
younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.  
7.7.4 
Overactive Bladder  
Of 1242 overactive bladder patients in placebo-controlled clinical studies of BOTOX, 41.4% were 65 years 
of age or older, and 14.7% were 75 years of age or older. Adverse reactions of UTI and urinary retention 
were more common in patients 65 years of age or older in both placebo and BOTOX groups compared to 
younger patients (see Table 18). Otherwise, there were no overall differences in the safety profile following 
BOTOX treatment between patients aged 65 years and older compared to adult patients younger than 65 
years of age in these studies. 
 
Table 18: Incidence of Urinary Tract Infection and Urinary Retention according to Age Group 
 
<65 Years 
65 to 74 Years 
≥75 Years 
Adverse Reactions  
BOTOX 
100 Units 
(N=344) 
% 
Placebo 
(N=348) 
% 
BOTOX 
100 Units 
(N=169) 
% 
Placebo 
(N=151) 
% 
BOTOX 
100 Units 
(N=94) 
% 
Placebo 
(N=86) 
% 
Urinary tract infection  
21  
7  
30  
13  
38  
19  
 
Observed effectiveness was comparable between these age groups in placebo-controlled clinical studies. 
7.8 
Overdosage of Botox A102  
Excessive doses of BOTOX (onabotulinumtoxinA) for injection may be expected to produce neuromuscular 
weakness with a variety of symptoms.  
Symptoms of overdose are likely not to be present immediately following injection. Should accidental 
injection or oral ingestion occur or overdose be suspected, the person should be medically supervised for 
several weeks for signs and symptoms of systemic muscular weakness which could be local, or distant from 
the site of injection [see Boxed Warning and Warnings and Precautions (5.2, 5.6)]. These patients should be 
considered for further medical evaluation and appropriate medical therapy immediately instituted, which 
may include hospitalization.  
If the musculature of the oropharynx and esophagus are affected, aspiration may occur which may lead to 
development of aspiration pneumonia. If the respiratory muscles become paralyzed or sufficiently weakened, 
intubation and assisted respiration may be necessary until recovery takes place. Supportive care could 
involve the need for a tracheostomy and/or prolonged mechanical ventilation, in addition to other general 
supportive care.  
In the event of overdose, antitoxin raised against botulinum toxin is available from the Centers for Disease 
Control and Prevention (CDC) in Atlanta, GA. However, the antitoxin will not reverse any botulinum toxin-
induced effects already apparent by the time of antitoxin administration. In the event of suspected or actual 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
59 
Version 4.0 
01 22 2021 
cases of botulinum toxin poisoning, please contact your local or state Health Department to process a request 
for antitoxin through the CDC. If you do not receive a response within 30 minutes, please contact the CDC 
directly at 1-770-488-7100. More information can be obtained at 
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5232a8.htm. 
7.9 
Adverse Event Reporting 
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.  
Adverse events will be reported in a manner consistent with the requirements outlined in the NICHD Clinical 
Research Policy Guidance Document. That document specifies which adverse events be reported to the 
Office for Human Research Protections (OHRP), and to the FDA, if FDA-regulated products such as a 
device, drug, or biologic are used. Consistent with that policy, adverse events will be reported in a manner 
consistent with OHRP and FDA regulations.  
8. 
FEASIBILITY 
The proposed MUI study population has already failed conservative management and are interested in more 
effective therapies. We have taken care to have highly effective treatments for both UUI (Botox A) and SUI 
(mid-urethral sling) available if needed in both arms, in a clinical efficacy trial design with inclusion criteria 
that are not overly strict. In addition, a population similar to this population has been previously recruited 
within the PFDN for ESTEEM; therefore, we do not anticipate particular difficulty in recruitment of MUI 
patients as encountered in MIMOSA.60 
9. 
REFERENCES 
1. 
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. Quality of life research : 
an international journal of quality of life aspects of treatment, care and rehabilitation 1994;3:291-306. 
2. 
Melville JL, Katon W, Delaney K, Newton K. Urinary incontinence in US women: a population-
based study. Archives of internal medicine 2005;165:537-42. 
3. 
Karram MM, Bhatia NN. Management of coexistent stress and urge urinary incontinence. Obstetrics 
and gynecology 1989;73:4-7. 
4. 
Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the 
United States. World journal of urology 2003;20:327-36. 
5. 
Agarwal A, Eryuzlu LN, Cartwright R, et al. What is the most bothersome lower urinary tract 
symptom? Individual- and population-level perspectives for both men and women. European urology 
2014;65:1211-7. 
6. 
Monz B, Chartier-Kastler E, Hampel C, et al. Patient characteristics associated with quality of life in 
European women seeking treatment for urinary incontinence: results from PURE. European urology 
2007;51:1073-81; discussion 81-2. 
7. 
Dooley Y, Lowenstein L, Kenton K, FitzGerald M, Brubaker L. Mixed incontinence is more 
bothersome than pure incontinence subtypes. International urogynecology journal and pelvic floor 
dysfunction 2008;19:1359-62. 
8. 
Coyne KS, Zhou Z, Thompson C, Versi E. The impact on health-related quality of life of stress, urge 
and mixed urinary incontinence. BJU international 2003;92:731-5. 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
60 
Version 4.0 
01 22 2021 
9. 
Minassian VA, Devore E, Hagan K, Grodstein F. Severity of urinary incontinence and effect on 
quality of life in women by incontinence type. Obstetrics and gynecology 2013;121:1083-90. 
10. 
Barber MD, Spino C, Janz NK, et al. The minimum important differences for the urinary scales of the 
Pelvic Floor Distress Inventory and Pelvic Floor Impact Questionnaire. American journal of 
obstetrics and gynecology 2009;200:580.e1-7. 
11. 
Haylen BT, de Ridder D, Freeman RM, et al. An International Urogynecological Association 
(IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic 
floor dysfunction. Neurourology and urodynamics 2010;29:4-20. 
12. 
Brubaker L, Stoddard A, Richter H, et al. Mixed incontinence: comparing definitions in women 
having stress incontinence surgery. Neurourology and urodynamics 2009;28:268-73. 
13. 
Herzog AR, Diokno AC, Brown MB, Normolle DP, Brock BM. Two-year incidence, remission, and 
change patterns of urinary incontinence in noninstitutionalized older adults. Journal of gerontology 
1990;45:M67-74. 
14. 
Brubaker L, Lukacz ES, Burgio K, et al. Mixed incontinence: comparing definitions in non-surgical 
patients. Neurourology and urodynamics 2011;30:47-51. 
15. 
Petros PE. Mixed urinary incontinence--time to uncouple urgency from stress? International 
urogynecology journal 2011;22:919-21. 
16. 
Langer R, Lipshitz Y, Halperin R, Pansky M, Bukovsky I, Sherman D. Long-Term (10-15 years) 
follow-up after Burch colposuspension for urinary stress incontinence. International urogynecology 
journal and pelvic floor dysfunction 2001;12:323-6; discussion 6-7. 
17. 
Jung SY, Fraser MO, Ozawa H, et al. Urethral afferent nerve activity affects the micturition reflex; 
implication for the relationship between stress incontinence and detrusor instability. The Journal of 
urology 1999;162:204-12. 
18. 
Koonings P, Bergman A, Ballard CA. Combined detrusor instability and stress urinary incontinence: 
where is the primary pathology? Gynecologic and obstetric investigation 1988;26:250-6. 
19. 
Dekhtiar YM, Kostyev FI, Zacheslavsky OM, Kuznietsov DO. Urodynamic characteristics of lower 
urinary tract of patients with idiopathic overactive bladder. Urology annals 2019;11:83-6. 
20. 
Dietz HP, Clarke B. The urethral pressure profile and ultrasound imaging of the lower urinary tract. 
International urogynecology journal and pelvic floor dysfunction 2001;12:38-41. 
21. 
Sinha S, Lakhani D, Singh VP. Cough associated detrusor overactivity in women with urinary 
incontinence. Neurourology and urodynamics 2019;38:920-6. 
22. 
Kulseng-Hanssen S, Moe K, Schiotz HA. How often does detrusor overactivity cause urinary leakage 
during a stress test in women with mixed urinary incontinence? International urogynecology journal 
2013;24:1537-41. 
23. 
Paick JS, Ku JH, Kim SW, Oh SJ, Son H, Shin JW. Tension-free vaginal tape procedure for the 
treatment of mixed urinary incontinence: significance of maximal urethral closure pressure. The 
Journal of urology 2004;172:1001-5. 
24. 
Richter HE, Moalli P, Amundsen CL, et al. Urinary Biomarkers in Women with Refractory Urgency 
Urinary Incontinence Randomized to Sacral Neuromodulation versus OnabotulinumtoxinA 
Compared to Controls. The Journal of urology 2017;197:1487-95. 
25. 
Chai TC, Richter HE, Moalli P, et al. Inflammatory and tissue remodeling urinary biomarkers before 
and after mid urethral sling surgery for stress urinary incontinence. The Journal of urology 
2014;191:703-9. 
26. 
Dumoulin C, Cacciari LP, Hay-Smith EJC. Pelvic floor muscle training versus no treatment, or 
inactive control treatments, for urinary incontinence in women. The Cochrane database of systematic 
reviews 2018;10:Cd005654. 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
61 
Version 4.0 
01 22 2021 
27. 
Balk EM, Rofeberg VN, Adam GP, Kimmel HJ, Trikalinos TA, Jeppson PC. Pharmacologic and 
Nonpharmacologic Treatments for Urinary Incontinence in Women: A Systematic Review and 
Network Meta-analysis of Clinical Outcomes. Annals of internal medicine 2019. 
28. 
Burgio KL, Kraus SR, Menefee S, et al. Behavioral therapy to enable women with urge incontinence 
to discontinue drug treatment: a randomized trial. Annals of internal medicine 2008;149:161-9. 
29. 
Sexton CC, Notte SM, Maroulis C, et al. Persistence and adherence in the treatment of overactive 
bladder syndrome with anticholinergic therapy: a systematic review of the literature. International 
journal of clinical practice 2011;65:567-85. 
30. 
Gray SL, Anderson ML, Dublin S, et al. Cumulative use of strong anticholinergics and incident 
dementia: a prospective cohort study. JAMA internal medicine 2015;175:401-7. 
31. 
Kelleher C, Hakimi Z, Zur R, et al. Efficacy and Tolerability of Mirabegron Compared with 
Antimuscarinic Monotherapy or Combination Therapies for Overactive Bladder: A Systematic 
Review and Network Meta-analysis. European urology 2018;74:324-33. 
32. 
Drake MJ, Nitti VW, Ginsberg DA, et al. Comparative assessment of the efficacy of 
onabotulinumtoxinA and oral therapies (anticholinergics and mirabegron) for overactive bladder: a 
systematic review and network meta-analysis. BJU international 2017;120:611-22. 
33. 
Amundsen CL, Richter HE, Menefee SA, et al. OnabotulinumtoxinA vs Sacral Neuromodulation on 
Refractory Urgency Urinary Incontinence in Women: A Randomized Clinical Trial. Jama 
2016;316:1366-74. 
34. 
Amundsen CL, Komesu YM, Chermansky C, et al. Two-Year Outcomes of Sacral Neuromodulation 
Versus OnabotulinumtoxinA for Refractory Urgency Urinary Incontinence: A Randomized Trial. 
European urology 2018;74:66-73. 
35. 
Visco AG, Brubaker L, Richter HE, et al. Anticholinergic therapy vs. onabotulinumtoxina for 
urgency urinary incontinence. The New England journal of medicine 2012;367:1803-13. 
36. 
Chapple C, Sievert KD, MacDiarmid S, et al. OnabotulinumtoxinA 100 U significantly improves all 
idiopathic overactive bladder symptoms and quality of life in patients with overactive bladder and 
urinary incontinence: a randomised, double-blind, placebo-controlled trial. European urology 
2013;64:249-56. 
37. 
Nitti VW, Ginsberg D, Sievert KD, et al. Durable Efficacy and Safety of Long-Term 
OnabotulinumtoxinA Treatment in Patients with Overactive Bladder Syndrome: Final Results of a 
3.5-Year Study. The Journal of urology 2016;196:791-800. 
38. 
Dmochowski R, Chapple C, Nitti VW, et al. Efficacy and safety of onabotulinumtoxinA for 
idiopathic overactive bladder: a double-blind, placebo controlled, randomized, dose ranging trial. The 
Journal of urology 2010;184:2416-22. 
39. 
Nitti VW, Dmochowski R, Herschorn S, et al. OnabotulinumtoxinA for the treatment of patients with 
overactive bladder and urinary incontinence: results of a phase 3, randomized, placebo controlled trial. 
The Journal of urology 2013;189:2186-93. 
40. 
Tincello DG, Kenyon S, Abrams KR, et al. Botulinum toxin a versus placebo for refractory detrusor 
overactivity in women: a randomised blinded placebo-controlled trial of 240 women (the RELAX 
study). European urology 2012;62:507-14. 
41. 
Sahai A, Khan MS, Dasgupta P. Efficacy of botulinum toxin-A for treating idiopathic detrusor 
overactivity: results from a single center, randomized, double-blind, placebo controlled trial. The 
Journal of urology 2007;177:2231-6. 
42. 
Brubaker L, Richter HE, Visco A, et al. Refractory idiopathic urge urinary incontinence and 
botulinum A injection. The Journal of urology 2008;180:217-22. 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
62 
Version 4.0 
01 22 2021 
43. 
Flynn MK, Amundsen CL, Perevich M, Liu F, Webster GD. Outcome of a randomized, double-blind, 
placebo controlled trial of botulinum A toxin for refractory overactive bladder. The Journal of 
urology 2009;181:2608-15. 
44. 
Kobashi KC, Albo ME, Dmochowski RR, et al. Surgical Treatment of Female Stress Urinary 
Incontinence: AUA/SUFU Guideline. The Journal of urology 2017;198:875-83. 
45. 
Abrams P, Andersson KE, Birder L, et al. Fourth International Consultation on Incontinence 
Recommendations of the International Scientific Committee: Evaluation and treatment of urinary 
incontinence, pelvic organ prolapse, and fecal incontinence. Neurourology and urodynamics 
2010;29:213-40. 
46. 
Welk B, Baverstock RJ. The management of mixed urinary incontinence in women. Canadian 
Urological Association journal = Journal de l'Association des urologues du Canada 2017;11:S121-s4. 
47. 
Richter HE, Albo ME, Zyczynski HM, et al. Retropubic versus transobturator midurethral slings for 
stress incontinence. The New England journal of medicine 2010;362:2066-76. 
48. 
Jain P, Jirschele K, Botros SM, Latthe PM. Effectiveness of midurethral slings in mixed urinary 
incontinence: a systematic review and meta-analysis. International urogynecology journal 
2011;22:923-32. 
49. 
Sung VW, Borello-France D, Dunivan G, et al. Methods for a multicenter randomized trial for mixed 
urinary incontinence: rationale and patient-centeredness of the ESTEEM trial. International 
urogynecology journal 2016;27:1479-90. 
50. 
Tahseen S, Reid P. Effect of transobturator tape on overactive bladder symptoms and urge urinary 
incontinence in women with mixed urinary incontinence. Obstetrics and gynecology 2009;113:617-
23. 
51. 
Barber MD, Kleeman S, Karram MM, et al. Risk factors associated with failure 1 year after 
retropubic or transobturator midurethral slings. American journal of obstetrics and gynecology 
2008;199:666.e1-7. 
52. 
Houwert RM, Venema PL, Aquarius AE, Bruinse HW, Roovers JP, Vervest HA. Risk factors for 
failure of retropubic and transobturator midurethral slings. American journal of obstetrics and 
gynecology 2009;201:202.e1-8. 
53. 
Barber MD, Kleeman S, Karram MM, et al. Transobturator tape compared with tension-free vaginal 
tape for the treatment of stress urinary incontinence: a randomized controlled trial. Obstetrics and 
gynecology 2008;111:611-21. 
54. 
Barber MD, Walters MD, Bump RC. Short forms of two condition-specific quality-of-life 
questionnaires for women with pelvic floor disorders (PFDI-20 and PFIQ-7). American journal of 
obstetrics and gynecology 2005;193:103-13. 
55. 
Richter HE, Litman HJ, Lukacz ES, et al. Demographic and clinical predictors of treatment failure 
one year after midurethral sling surgery. Obstetrics and gynecology 2011;117:913-21. 
56. 
Nager CW, Sirls L, Litman HJ, et al. Baseline urodynamic predictors of treatment failure 1 year after 
mid urethral sling surgery. The Journal of urology 2011;186:597-603..  
57.  
Shumaker SA, Wyman JF, Uebersax JS, McClish D, Fantl JA (1994) 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 
3:291–306 
58. 
Abdel-fattah M, Ramsay I, Pringle S, Hardwick C, Ali H. Evaluation of transobturator tapes (E-TOT) 
study: randomised prospective single-blinded study comparing inside-out vs. outside-in 
transobturator tapes in management of urodynamic stress incontinence: short term outcomes. 
European journal of obstetrics, gynecology, and reproductive biology 2010;149:106-11. 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
63 
Version 4.0 
01 22 2021 
59. 
Abdel-Fattah M, Ramsay I, Pringle S, et al. Evaluation of transobturator tension-free vaginal tapes in 
management of women with recurrent stress urinary incontinence. Urology 2011;77:1070-5. 
60. 
Brubaker L, Moalli P, Richter HE, et al. Challenges in designing a pragmatic clinical trial: the mixed 
incontinence -- medical or surgical approach (MIMOSA) trial experience. Clinical trials (London, 
England) 2009;6:355-64. 
61. 
Miotla P, Futyma K, Cartwright R, et al. Effectiveness of botulinum toxin injection in the treatment 
of de novo OAB symptoms following midurethral sling surgery. International urogynecology journal 
2016;27:393-8. 
62. 
Denys P, Le Normand L, Ghout I, et al. Efficacy and safety of low doses of onabotulinumtoxinA for 
the treatment of refractory idiopathic overactive bladder: a multicentre, double-blind, randomised, 
placebo-controlled dose-ranging study. European urology 2012;61:520-9. 
64. 
Richter HE, Amundsen CL, Erickson SW, et al. Characteristics Associated with Treatment Response 
and Satisfaction in Women Undergoing OnabotulinumtoxinA and Sacral Neuromodulation for 
Refractory Urgency Urinary Incontinence. The Journal of urology 2017;198:890-6. 
65. 
Komesu YM, Amundsen CL, Richter HE, et al. Refractory urgency urinary incontinence treatment in 
women: impact of age on outcomes and complications. American journal of obstetrics and 
gynecology 2018;218:111.e1-.e9. 
66. 
Trabuco EC, Klingele CJ, Weaver AL, McGree ME, Lightner DJ, Gebhart JB. Preoperative and 
postoperative predictors of satisfaction after surgical treatment of stress urinary incontinence. 
American journal of obstetrics and gynecology 2011;204:444.e1-6. 
67. 
Maldonado PA, Kogutt BK, Wai CY. Patient satisfaction following midurethral sling surgeries. 
Current opinion in obstetrics & gynecology 2014;26:404-8. 
68. 
Aydin S, Arioglu Aydin C, Ersan F. Prediction of Mid-Urethral Sling Failure with Clinical Findings 
and Urodynamics. Lower urinary tract symptoms 2017;9:89-93. 
69. 
Guidance for Industry Patient-Reported Outcome Measures: Use in Medical Product Development to 
Support Labeling Claims. 2009. (Accessed June 16, 2009, at 
https://www.fda.gov/media/77832/download.) 
70. 
Nager CW, Brubaker L, Litman HJ, et al. A randomized trial of urodynamic testing before stress-
incontinence surgery. The New England journal of medicine 2012;366:1987-97. 
71. 
Dyer KY, Xu Y, Brubaker L, et al. Minimum important difference for validated instruments in 
women with urge incontinence. Neurourology and urodynamics 2011;30:1319-24. 
72. 
Goode PS, Burgio KL, Kraus SR, Kenton K, Litman HJ, Richter HE. Correlates and predictors of 
patient satisfaction with drug therapy and combined drug therapy and behavioral training for urgency 
urinary incontinence in women. International urogynecology journal 2011;22:327-34. 
73. 
Lowenstein L, Kenton K, FitzGerald MP, Brubaker L. Clinically useful measures in women with 
mixed urinary incontinence. American journal of obstetrics and gynecology 2008;198:664.e1-3; 
discussion .e3-4. 
74. 
Gleason JL, Parden AM, Jauk V, Ballard A, Sung V, Richter HE. Outcomes of midurethral sling 
procedures in women with mixed urinary incontinence. International urogynecology journal 
2015;26:715-20. 
75. 
Margolis MK, Fox KM, Cerulli A, Ariely R, Kahler KH, Coyne KS. Psychometric validation of the 
overactive bladder satisfaction with treatment questionnaire (OAB-SAT-q). Neurourology and 
urodynamics 2009;28:416-22. 
76. 
Coyne KS, Matza LS, Thompson CL. The responsiveness of the Overactive Bladder Questionnaire 
(OAB-q). Quality of life research : an international journal of quality of life aspects of treatment, care 
and rehabilitation 2005;14:849-55. 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
64 
Version 4.0 
01 22 2021 
77. 
Avery KN, Bosch JL, Gotoh M, et al. Questionnaires to assess urinary and anal incontinence: review 
and recommendations. The Journal of urology 2007;177:39-49. 
78. 
Coyne KS, Matza LS, Thompson CL, Kopp ZS, Khullar V. Determining the importance of change in 
the overactive bladder questionnaire. The Journal of urology 2006;176:627-32; discussion 32. 
79. 
Coyne KS, Matza LS, Thompson C, Jumadilova Z, Bavendam T. The responsiveness of the OAB-q 
among OAB patient subgroups. Neurourology and urodynamics 2007;26:196-203. 
80. 
Rogers RG, Coates KW, Kammerer-Doak D, Khalsa S, Qualls C. A short form of the Pelvic Organ 
Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12). International urogynecology journal 
and pelvic floor dysfunction 2003;14:164-8; discussion 8. 
81. 
Ware JE, Jr., Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual 
framework and item selection. Medical care 1992;30:473-83. 
82. 
Brazier J, Roberts J, Deverill M. The estimation of a preference-based measure of health from the SF-
36. Journal of health economics 2002;21:271-92. 
83. 
Yalcin I, Bump RC. Validation of two global impression questionnaires for incontinence. American 
journal of obstetrics and gynecology 2003;189:98-101. 
84. 
Brooks R. EuroQol: the current state of play. Health policy (Amsterdam, Netherlands) 1996;37:53-72. 
85. 
Harvie HS, Lee DD, Andy UU, Shea JA, Arya LA. Validity of utility measures for women with 
pelvic organ prolapse. American journal of obstetrics and gynecology 2018;218:119.e1-.e8. 
86. 
Harvie HS, Shea JA, Andy UU, Propert K, Schwartz JS, Arya LA. Validity of utility measures for 
women with urge, stress, and mixed urinary incontinence. American journal of obstetrics and 
gynecology 2014;210:85.e1-6. 
87. 
Harvie HS, Honeycutt AA, Neuwahl SJ, et al. Responsiveness and minimally important difference of 
SF-6D and EQ-5D utility scores for the treatment of pelvic organ prolapse. American journal of 
obstetrics and gynecology 2019;220:265.e1-.e11. 
88. 
Longworth L, Bryan S. An empirical comparison of EQ-5D and SF-6D in liver transplant patients. 
Health economics 2003;12:1061-7. 
89. 
Albo ME, Richter HE, Brubaker L, et al. Burch colposuspension versus fascial sling to reduce urinary 
stress incontinence. The New England journal of medicine 2007;356:2143-55. 
90. 
Nager CW, Brubaker L, Daneshgari F, et al. Design of the Value of Urodynamic Evaluation (ValUE) 
trial: A non-inferiority randomized trial of preoperative urodynamic investigations. Contemporary 
clinical trials 2009;30:531-9. 
91. 
Bosch JL, Cardozo L, Hashim H, Hilton P, Oelke M, Robinson D. Constructing trials to show 
whether urodynamic studies are necessary in lower urinary tract dysfunction. Neurourology and 
urodynamics 2011;30:735-40. 
92. 
Nager CW, Kraus SR, Kenton K, et al. Urodynamics, the supine empty bladder stress test, and 
incontinence severity. Neurourology and urodynamics 2010;29:1306-11. 
93. 
Rovner ES, Goudelocke CM. Urodynamics in the evaluation of overactive bladder. Current urology 
reports 2010;11:343-7. 
94. 
Ford AA, Rogerson L, Cody JD, Aluko P, Ogah JA. Mid-urethral sling operations for stress urinary 
incontinence in women. The Cochrane database of systematic reviews 2017;7:Cd006375. 
95. 
Nambiar A, Cody JD, Jeffery ST, Aluko P. Single-incision sling operations for urinary incontinence 
in women. The Cochrane database of systematic reviews 2017;7:Cd008709. 
96. 
Paick JS, Ku JH, Shin JW, Son H, Oh SJ, Kim SW. Tension-free vaginal tape procedure for urinary 
incontinence with low Valsalva leak point pressure. The Journal of urology 2004;172:1370-3. 
97. 
McCulloch CE, Searle SR. Generalized, linear, and mixed models. New York: John Wiley & Sons; 
2001. 
98. 
Efron B, Tibshirani R. An introduction to the bootstrap. New York: Chapman & Hall; 1994. 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
65 
Version 4.0 
01 22 2021 
102 
OnabotulinumtoxinA [package insert]. Madison, NJ: Allergan, Inc. (2019). 
 
 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
66 
Version 4.0 
01 22 2021 
10. 
ADDENDUM - 12 Month Extension 
Amendment: Extension of the Treatment for Mixed Urinary Incontinence: Mid-urethral Sling vs. 
Botox A (MUSA) study for follow-up to 12 months 
Background 
The primary purpose of the MUSA trial was to estimate the effect of intradetrusor injections of Botulinum 
toxin A (Botox A ®) compared to mid-urethral sling for the treatment of mixed urinary incontinence (MUI) 
symptoms in 146 women at 6 months. MUSA is a 1:1 randomized 2-arm clinical trial: intradetrusor injection 
of 100 units of Botox A, with a second dose after 3 months if needed, versus mid-urethral sling. The 
primary aim was to compare the effectiveness of intradetrusor injection of 100 units of Botox A to mid-
urethral sling for change in MUI symptoms 6 months following treatment. The primary Outcome was 
change in severity of MUI symptoms 6 months post treatment measured using the Urogenital Distress 
Inventory (UDI) in patients randomized to either Botox A or mid-urethral sling. The secondary outcomes 
were 1) change in severity of stress urinary incontinence (SUI) and urgency urinary incontinence (UUI) 
symptoms 6 months post treatment measured using the stress and irritative subscales of the UDI and 2) 
change in MUI symptoms 3 months post treatment measured using the UDI total score. 
 
Exploratory Aims included: 
1. 
Secondary urinary outcomes: To compare treatment with Botox A to treatment with mid-urethral 
sling for improving the number of urinary incontinence episodes on bladder diary 6 months post-
treatment.  
2.  
Predictors of poor treatment response: To develop models to identify baseline predictors of 
change of MUI, OAB, and SUI outcomes measured using the UDI, between baseline and 6 months 
post-treatment.  
3. 
Quality of life and global impression: To compare quality of life outcomes and Patient Global 
Impression-Improvement (PGI-I), Patient Global Impression-Severity (PGI-S) between groups 
randomized to Botox A versus mid-urethral sling 6 months post-treatment. 
4. 
Safety and additional treatments: To describe rates of reoperation (sling revision) after mid-
urethral sling and intermittent catheterization due to voiding dysfunction/partial urinary retention 
after Botox A detrusor injection, to compare the proportion of women in each group with UTI and 
recurrent UTI, rates of other serious and non-serious adverse events, and to compare the proportion 
of women in each group initiating additional (off protocol) treatment other than Botox A and mid-
urethral sling for SUI and/or OAB.  
5. 
Cost-effectiveness analysis: To determine the cost effectiveness of Botox A injection versus mid-
urethral sling for the treatment of MUI symptoms on an intent-to-treat basis 6 months post-
treatment.  
6. 
UDI MID: To explore MIDs for UDI total score and stress and irritative subscores for this MUI 
population.  
 
The MUSA study was initially designed as a 12 month study, however due to constraints related to funding 
and completing the study within the current PFDN cycle, the study was revised to a 6 month outcome. The 
DSMB recommended a 12 month follow up. 12 month outcomes are common in midurethral sling surgical 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
67 
Version 4.0 
01 22 2021 
trials and a similar outcome to the ESTEEM study. The PFND bridge year funding now allows us the 
opportunity to extend the MUSA trial to 12 month outcomes.  
 
MUSA recruitment began in July 2020 and was estimated to be completed by May 2021, by the end of the 
current PFDN cycle. The bridge year would extend until June 2022 and allow completion of the 12 month 
MUSA outcome within the bridge year. The first MUSA subject 9-month and 12-month windows would 
open Apr 2021and August 2021, respectively. The current cycle ends in June 2021, if the MUSA 12 month 
follow-up needs to be discontinued due to time or financial reasons, there would be a potential of 9, 9-month 
calls and no 12-month calls completed before June 2021. 
 
Proposed Extension of Study 
 
This amendment proposes to continue to follow all the MUSA subjects from 6 to 12 months. The 6-12 
month extension would be observational. Participants would be allowed to pursue other clinical treatments 
after 6 months, including the alternative arm treatment. The primary MUSA study outcome remains at 6 
months. The 12-month aims, outcomes, outcome measures, and analysis are similar to the existing 
MUSA study at 6 months. 
12-month aim:  To compare the effectiveness of intradetrusor injection of 100 units of Botox A to mid-
urethral sling for change in MUI symptoms 12 months following treatment.  
Primary Outcome: Change in severity of MUI symptoms 12 months post treatment measured using the 
UDI 
Secondary Outcomes: Change in severity of SUI and UUI symptoms 12 months post treatment measured 
using the stress and irritative subscales of the UDI 
Additional study visits for the 12-month extension include a 9-month call and a 12-month call. The first 
MUSA subject will reach the 9-month call window in April 2021. The table below represents the outcome 
measures that will be collected at each MUSA call or visit.  The existing MUSA outcome measures and data 
collection forms remain the same for the 9-month call (excluding the bladder diary, PVR, and urine dip) and 
12-month call (excluding the PVR, and urine dip). 
Table 1: MUSA Visit Schedule and Data Collection Forms 
 
MUSA Study Visit 
3 M 
Visit 
6 M 
Visit 
9 M 
Call 
12 M 
Call 
MUSA Data Collection Forms 
UDI 
X 
X 
X 
X 
Bladder Diary 
X 
X 
X 
PVR – Clinic Visit 
X 
X 
Urine Dip  
X 
X 
Medical History – follow up  
X 
X 
X 
X 
Overactive Bladder Questionnaire-Symptom subscale 
(OAB-q) 
X 
X 
X 
X 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
68 
Version 4.0 
01 22 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sample Size Estimate 
 
For the MUSA study, sample size estimates were based on an evaluation of minimum important differences 
(MIDs) and corresponding standard deviation (SD) for the UDI total score from the ESTEEM study, with 
support from other published populations of women with urge and stress incontinence. For the primary 
outcome (UDI total score change from baseline at 6 months), alpha was set at 0.05 and power was set at 90%.  
We assumed a discontinuation rate of 5% at 6 months based on ROSETTA and ESTEEM, for a total sample 
size of 146 (Table 2).  Assuming an additional 5% discontinuation rate between 6 and 12 month, we would 
still have 88% power for the 12 month UDI total score outcome. 
Table 2: MUSA Power Calculation for N=146 (73 Per Treatment Arm) 
UDI 
component 
Primary or 
Secondary 
Outcome 
MID  
SD a 
Effect 
Size 
Alpha 
Power at 
6 months 
 
Randomized 
Sample Size 
per Group b  
UDI-Total 
Primary 
26 (ESTEEM) 
46.5 
0.56 
0.05 
90% 
73 
UDI-Total 
Primary 
26 (ESTEEM) 
46.5 
0.56 
0.05 
85% 
62 
UDI-Total 
Primary 
26 (ESTEEM) 
46.5 
0.56 
0.05 
80% 
55 
a SD: standard deviation is estimated from ESTEEM participants with at least 4 Urge IEs/3 days using a 
repeated measures linear model for change from baseline to 3 and 6 months with adjustment for baseline 
value and clinical site. 
b Assumes 5% of randomized participants discontinue by 6 months estimated by average of ROSETTA and 
ESTEEM 
 
Statistical Analysis and Feasibility 
 
The analysis at 12 months will be similar to planned 6 month analysis. The primary MUSA study outcome 
remains at 6 months. 
The discontinuation rate of ESTEEM and ROSETTA were 12% and 9%, respectively at 12 months.  An 
additional participant incentive of $75 will be given at the 12 month call.  Given that MUSA participants are 
allowed to pursue other clinical treatments after 6 months, including the alternative arm treatment, retention 
Incontinence Impact Questionnaire (IIQ) 
X 
X 
X 
X 
Pelvic Organ Prolapse/Urinary Incontinence Sexual 
Questionnaire (PISQ) 
X 
X 
X 
X 
European Quality of Life-5 Dimensions (EQ-5D) 
X 
X 
X 
X 
Short Form 36 (SF-36)/ Short Form 6D (SG-6D) 
X 
X 
X 
X 
Patient Global Impression of Severity (PGI-S). 
X 
X 
X 
X 
Lost Productivity / Costs 
X 
X 
X 
X 
Overactive Bladder treatment satisfaction (OAB-SAT-q) 
X 
X 
X 
X 
Patient Global Impression of Improvement (PGI-I) 
X 
X 
X 
X 
PGSC 
X 
X 
X 
X 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
69 
Version 4.0 
01 22 2021 
from 6 to 12 months should not exceed 10%.  The 9 and 12 month calls will be halted if we determine that it 
is not feasible to collect sufficient data due to time or budget constraints 
Statistical Analysis Plan 
Primary outcome: The mean change from baseline in UDI total score will be compared between groups at 
12 months at the p<0.05 statistical significance level using a mixed effects analysis of covariance model for 
repeated measures (MMRM)with adjustment for baseline UDI score, and randomization stratification factors 
site and age group. The model will include fixed effect categorical factors for treatment group, visit and 
treatment × visit interaction with a heterogeneous Toeplitz covariance pattern for the within-subject repeated 
measures. Estimates, p-values and 95% confidence intervals will be presented for treatment group 
comparisons at 12 months.  
This model assumes missing data due to a missed visit or early study discontinuation is missing at random. If 
more than 10% of participants are missing their 12-month score, then a sensitivity analysis will be performed 
using multiple imputation under a variety of missing data patterns to be specified in the statistical analysis 
plan in order to assess the robustness of the primary results to missing data. 
We will report whether change in total UDI score from baseline to 12 months is statistically significantly 
different between groups. If the difference is statistically significant, the potential clinical significance of the 
difference will be discussed. We recognize that our sample size may allow us to find a difference between 
groups that is statistically significant yet smaller than published MID 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 MUSA, and an exploratory aim of MUSA is to explore whether the MID 
in this population differs from previously published values.  
Secondary outcomes: There are two secondary outcomes for the primary aim. The mean change from 
baseline in UDI-stress and UDI-irritative subscores will be compared between groups at 12 months.  Each of 
these outcomes will be evaluated using an alpha level of 0.05, with no adjustment for multiple comparisons. 
The statistical analysis of the two secondary outcomes will be identical to the analysis described above for 
the UDI total score. 
Exploratory aims: All statistical evaluations of the exploratory aims are for descriptive purposes and p-
values resulting from these analyses will not be evaluated for statistical significance. 
1. 
Secondary urinary outcomes: To compare treatment with Botox A to treatment with mid-urethral 
sling for improving the number of urinary incontinence episodes on bladder diary after 12 months. 
 
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 6 months. 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 at 6 months 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 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
70 
Version 4.0 
01 22 2021 
analyzed using logistic regression, controlling for the design effects of stratification by site and age 
group.  
2. 
Predictors of poor treatment response: To develop models to identify baseline predictors of 
change of MUI, OAB, and SUI outcomes measured using the UDI between baseline and 12 months 
post-treatment 
Regression models will be created to identify predictors of change from baseline to 12 months for UDI total 
score and stress and irritative subscale scores. Potential predictors will include age, diary parameters such as 
number of UUI episodes/3 days, functional bladder capacity, stress and irritative bother severity at baseline, 
type of urinary incontinence (stress-predominant or urgency-predominant: see definition below), and co-
existing anterior vaginal wall prolapse. The relationship between potential predictors and outcomes will be 
explored in models that include one predictor plus stratification factors (site and age 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. 
The definition of the type of urinary incontinence, stress- or urgency predominant will be based on 2 
questions of the Urogenital Distress Inventory,  
1. 
“Do you experience urine leakage associated with a feeling of urgency?”  
2. 
“Do you experience urine leakage related to physical activity, coughing, or sneezing?” 
 
Based on our inclusion criteria, patients must report at least “moderate” bother on both questions.  
If the subject reports greater bother on the stress question, she will be classified as stress-predominant MUI. 
If the subject reports greater bother on the urgency question, she will be classified as urgency-predominant 
MUI. If the subject reports equal bother on both questions, she will be classified as “balanced” MUI.  
3. 
Quality of life and global impression: To compare quality of life outcomes and Patient Global 
Impression-Improvement (PGI-I), Patient Global Impression-Severity (PGI-S) between groups 
randomized to Botox versus sling after 12 months. 
 
Changes from baseline in all quality of life PRO instruments and global impression will be 
calculated and analyzed using the methods described for the analysis of the primary outcome 
4. 
Safety and additional treatments: To describe rates of reoperation (sling revision) after mid-
urethral sling and intermittent catheterization due to voiding dysfunction/partial urinary retention 
after Botox injection, to compare the proportion of women in each group with UTI and recurrent 
UTI, rates of other serious and non-serious adverse events, and to compare the proportion of 
women in each group initiating additional (off protocol) treatment for SUI and/or OAB, and the 
types of additional treatment (off protocol Botox or mid-urethral sling, behavioral therapy, 
medications, other).  
 
Groups will be summarized with n and percent, and rates will be compared with chi-square tests.  
5. 
Cost-effectiveness analysis: To determine the cost effectiveness of Botox A injection versus mid-
urethral sling for the treatment of MUI symptoms at 12 months. 
 
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 

PFDN Protocol 
 
 
 
MUSA 
Confidential 
01-10-2020, revised May 11, 2020, June 30, 2020, November 9, 2020, January 22, 2021 
 
71 
Version 4.0 
01 22 2021 
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 stratification factors of study site and age group, 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.  
 
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. 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.  
 
We plan to conduct supplemental analyses using alternative outcome measures, such as incremental 
cost per reduction in UIE/day.  
 
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. 
6. 
UDI MID: To explore 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 
the PGSC, global impression of change, and incontinence episodes from the bladder diary.