Clinical trial NCT04171531
Conditions: Urinary Incontinence, Stress Urinary Incontinence, Urge
Keywords: urinary incontinence midurethral sling Botulinum toxin A (Botox A ®)
Sponsor: NICHD Pelvic Floor Disorders Network
Start date: 2020-06-08; Completion date: 2024-02-12
Enrollment: 150 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary aim is to compare the effectiveness of intradetrusor injection of 100 unit injection of Botulinum toxin A to mid-urethral sling for change in MUI symptoms 6 months following treatment.

Detailed description:
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 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 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.

Secondary outcomes include:

• Urogenital Distress Inventory Stress and Irritative subscales

Other outcomes include:

* Urogenital Distress Inventory Obstructive subscale
* Patient bladder diary metrics including numbers of daily incontinence episodes and voids and voiding frequency
* Other patient reported outcomes/validated instruments and associated scales and subscales: EQ-5D, IIQ-LF, OABq-LF, OAB-SATq, PISQ-IR, PGI-I, PGI-S, PGSC, and SF-36
* Physical measures of effectiveness: Postvoid Residual Volume

The study will continue with an additional 6 month observational period until 12 months post treatment.

A supplemental study will characterize baseline putative proteins/protein pathways in women with MUI associated with change in UDI after treatment with MUS or onabotulinum toxin A. Those results are not reported with this record.

Arms: arm 1: A dose of 100 units of Botulinum toxin A will be injected into the bladder. Follow up visits at 2 weeks, 3 and 6 months post intervention to collect clinical and patient-reported outcomes. arm 2: Mid-urethral Sling Procedure includes retropubic as well as transobturator full length slings. Follow up visits at 2 weeks, 3 and 6 months post intervention to collect clinical and patient-reported outcomes.
Interventions: intervention 1: Botox® injection intervention 2: Mid-urethral sling
Intervention descriptions: intervention 1: 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. intervention 2: Mid-urethral Sling Procedure includes retropubic as well as transobturator full length slings. "Mini-sling" and "single-incision" sling will not be allowed due to potential risk for higher failure rate.

Protocol documents:
ICF_002.pdf: 
University of Pennsylvania 
Institutional Review Board 
3600 Civic Center Blvd., 9th Floor 
Philadelphia, PA 19104 
Ph: 215-573-2540 
(Federalwide Assurance # 00004028)  
15-Mar-2022 
Dr. Heidi Harvie 
HHarvie@pennmedicine.upenn.edu 
Attn: Lorraine Flick 
Lorraine.Flick@pennmedicine.upenn.edu 
  
PRINCIPAL INVESTIGATOR 
: Dr. Heidi S Harvie 
TITLE 
: Treatment for Mixed Urinary Incontinence: Mid-urethral Sling vs. Botox A 
SPONSORING AGENCY 
: National Institute of Child Health and Human Development/NIH/DHHS 
PROTOCOL # 
: 842657 
REVIEW BOARD 
: IRB #4 
 
Dear Dr. Heidi Harvie: 
 
The above referenced protocol, and any applicable consent form(s), HIPAA authorization, recruitment materials and supporting 
documents were reviewed and re-approved by the above Institutional Review Board on 15-Mar-2022. 
 
Approval by the IRB does not necessarily constitute authorization to initiate the conduct of a human subject research 
study. You are responsible for obtaining any relevant committee approvals. 
 
This approval is for the period 15-Mar-2022 to 14-Mar-2023. 
 
The following documents were included in this review: 
 
- HSERA Continuing Review, confirmation code: dfficcae, submitted 02/09/2022 
- This Cover Letter dated 2.07.22 
- Continuing Review Request Form, uploaded 2.07.22 
- Adverse Event Report, uploaded 2.07.22,  
- Protocol Deviation Report, uploaded 2.07.22 
- Protocol V 3.0 dated 11.9.20, uploaded 2.07.22 
- Informed Consent Form approved 5.27.20, uploaded 2.07.22 
- DSMB Recommendation Letters 5.17.21 and 9.13.21, uploaded 2.24.21 
- Investigator’s Brochure/product labelling (botoxapkginsert.pdf) uploaded 2.07.22 
 
When enrolling subjects at a site covered by the University of Pennsylvania's IRB, a copy of the IRB approved informed consent 
form with the IRB approved from/to stamp must be used unless a waiver of written documentation of consent has been granted. 
 
If you have any questions about the information in this letter, please contact the IRB administrative staff. Contact information is 
available at our website: http://www.upenn.edu/IRB/directory. 
 
Thank you for your cooperation. 
 
Sincerely, 
 
 
 
 
IRB Administrator  
Patrick J 
Landis, Esq.
Reason: I have 
reviewed this 
document 
Date: 2022.03.15 
15:40:09 -04'00'
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You will be given a copy of this Research Subject HIPAA Authorization describing your 
confidentiality and privacy rights for this study.  
 
By signing this document, you are permitting University of Pennsylvania to use and 
disclose personal health information collected about you for research purposes as 
described above. 
 
Who can I call with questions, complaints or if I’m concerned about 
my rights as a research subject? 
If you have questions, concerns or complaints regarding your participation in this 
research study or if you have any questions about your rights as a research subject, you 
should speak with the Principal Investigator listed on page one of this form. If a member 
of the research team cannot be reached or you want to talk to someone other than 
those working on the study, you may contact the IRB at the number on page one of this 
form.  
 
CONTACT FOR FUTURE RESEARCH  
There may be studies in the future that may be of interest to you. May we have your 
permission to contact you in the future to discuss other research projects? The person 
contacting you would be your physician or a member of this research team. Please 
initial below to indicate your permission regarding contact for future research. 
 
_____ Yes, you may contact me in the future regarding research projects. 
 
_____ No, you may not contact me in the future regarding research projects. 
 
 
When you sign this form, you are agreeing to take part in this research study. This 
means that you have read the consent form, your questions have been answered, 
and you have decided to volunteer.  Your signature also means that you are 
permitting the University of Pennsylvania to use your personal health information 
collected about you for research purposes within our institution. You are also allowing 
the University of Pennsylvania to disclose that personal health information to outside 
organizations or people involved with the operations of this study. 
 
A copy of this consent form will be given to you.  
 
 
________________________       ____________________________________ 
Name of Subject (Please Print)  Signature of Subject  
 
           Date 
 
 
________________________ 
_____________________________________ 
Name of Person Obtaining  
Signature of Person Obtaining 
 
Date 
Consent (Please Print) 
 
Consent 
 
 
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x to evaluate and manage research functions.   
 
Who may use and share information about me?   
The following individuals may use or share your information for this research study: 
 
x The investigator for the study and the study team  
x Other authorized personnel at the University of Pennsylvaniaincluding offices that 
support research operations 
x Other research personnel with access to the databases for research and/or study 
coordination and as otherwise approved by the IRB 
x Greenphire employees who will administer/process Clincards and payments for 
study participation 
x The study Data Coordinating Center, Research Triangle Institute (RTI) 
x The sponsor of the study, the NICHD Pelvic Floor Disorders Network (PFDN) 
 
Oversight organizations 
x The U. S. Office of Human Research Protections (OHRP) 
x The study Data and Safety Monitoring Board 
 
Once your personal health information is disclosed to others outside the School of 
Medicine, it may no longer be covered by federal privacy protection regulations.   
 
The Principal Investigator or study staff will inform you if there are any additions to the 
list above during your active participation in the trial. Any additions will be subject to 
University of Pennsylvania procedures developed to protect your privacy. 
 
How long may my personal health information be used?   
Your authorization for use of your personal health information for this specific study 
does not expire.  
 
Your information may be held in a research database.  However, the University of 
Pennsylvania may not re-use or re-disclose information collected in this study for a 
purpose other than this study unless: 
x You have given written authorization  
x The University of Pennsylvania Institutional Review Board grants permission 
x As permitted by law  
 
Can I change my mind about giving permission for use of my 
information? 
Yes. You may withdraw or take away your permission to use and disclose your health 
information at any time.  You do this by sending written notice to the investigator for the 
study.  If you withdraw your permission, you will not be able to stay in this study. 
 
What if I decide not to give permission to use and give out my health 
information? 
Then you will not be able to be in this research study. 
 
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RESEARCH SUBJECT 
INFORMED CONSENT  
AND HIPAA AUTHORIZATION FORM 
 
Protocol Title:   
Therapy for Mixed Urinary Incontinence: Mid-urethral Sling 
vs. Botox A (MUSA) 
Principal 
Investigator: 
Heidi Harvie, MD  
 University of Pennsylvania Division of Urogynecology          
3400 Spruce St. Dulles 5 
 Philadelphia, PA 19104 
Emergency 
Contact: 
 Doctor on Call 
 215-662-6747 
Sponsor 
NICHD Pelvic Floor Disorders Network 
  
Research Study Summary for Potential Subjects 
 
You are being invited to participate in a research study.  Your participation is voluntary, 
and you should only participate if you completely understand what the study requires 
and what the risks of participation are.  You should ask the study team any questions 
you have related to participating before agreeing to join the study.  If you have any 
questions about your rights as a human research participant at any time before, during 
or after participation, please contact the Institutional Review Board (IRB) at 215-573-
2540 for assistance. 
 
The research study is being conducted to find the best way to treat women who have 
urinary incontinence due to BOTH stress urinary incontinence (SUI) and urgency urinary 
incontinence (UUI), also known as mixed urinary incontinence (MUI). Stress urinary 
incontinence is when you leak urine with sneezing, coughing and/or physical activity. 
Urgency urinary incontinence (also called overactive bladder) is when you feel a 
sudden, strong desire to pass urine that results in leakage before reaching the toilet.  
 
In this study we are trying to find out which treatment is best to use for women with MUI.  
Usually, BOTOX ® injections in the bladder are used for treating the urgency part of 
MUI and a mid-urethral sling (sling) surgery is used for treating the stress part of MUI, 
but recent studies show that maybe both types of leakage improve in women with MUI 
after either BOTOX or sling. Both of these procedures are standard of care for your 
condition and are not experimental. What we are studying is which one works better for 
women who have MUI. 
 
The study involves several research visits in addition to standard medical care 
treatments for your condition outlined below.  If you agree to join the study, you will first 
undergo an assessment by your doctor and study personnel to determine if you are 
eligible for the study. If you are eligible, you will be asked to complete surveys about 
your health and quality of life.  You will be asked to stop any current treatment (such as 
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medications or a pessary) for your MUI and keep a bladder diary for 3 days.  After this, 
you will come in for a visit and if you are eligible for the study, you will be assigned by 
chance (like the flip of a coin) to receive either 100 units of BOTOX through an injection 
in the bladder or a mid-urethral mesh sling performed surgically. You will be followed 
after the procedure, including a follow up visit 1 to 4 weeks after the procedure to check 
for infection or trouble with urinating. For the research study you will then be asked to 
complete a 3-day bladder diary at 3 months, 6 months and 12-months; come in at 3 
months and 6 months; and complete a phone call at 9 months and 12 months after the 
treatment to assess your symptoms.  Each visit will take about 1 hour. The research 
staff will call you at 9 months and 12 months to assess your symptoms, these phone 
calls will take about 30 minutes. If you received BOTOX, after 3 months you may be 
eligible for a second injection of 100 units of BOTOX if needed. After 6 months you may 
receive other treatments for your MUI if needed, including the alternative treatment 
(BOTOX or mid-urethral sling). Your participation will last for up to 15 months.  
 
Participation in the study may or may not benefit you directly and may result in new 
knowledge that may help others. Possible risks of participation are loss of 
confidentiality, boredom and fatigue from completing questionnaires and burden of 
doing the bladder diaries. The mid-urethral sling procedure and BOTOX injections are 
standard of care treatments and risks associated with these procedures may be 
experienced whether you receive these treatments as a part of the study, or outside of 
the study.   
 
The risks of BOTOX include discomfort from the injections, urinary tract infection, and 
difficulty emptying your bladder requiring you to use a catheter to empty your bladder. 
Other rare risks include worsening or unexpected difficulty swallowing or talking, trouble 
breathing or muscle weakness.  There may be unknown side effects or problems that 
could result in serious illness or even death.  
 
The risks of sling surgery include retention requiring a catheter, urinary tract infection, 
additional surgery, or exposure of mesh material, and pain.  Additional rare risks related 
to the mid-urethral sling surgery include bleeding requiring a blood transfusion, surgical 
infection, injury to surrounding organs and medical complications from anesthesia 
including death.  
 
Your doctor will discuss in more detail the procedures you are assigned to in a separate 
procedure consent.  
 
Alternatives to this study can include receiving BOTOX or a mid-urethral sling surgery 
outside the research study. There are also other treatments for urgency incontinence 
including medications, tibial nerve stimulation and sacral neuromodulation.  The other 
options for stress urinary incontinence include lifestyle modifications, weight loss, pelvic 
exercises, use of a pessary or support device, or a surgical procedure that does not 
involve mesh (pubovaginal sling, urethral colpopexy, or urethral bulking injection 
material).  You also may elect not to have any treatment.  Additional, detailed 
information about this research is provided below. Please ask any questions you have 
before signing this consent. 
 
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A clinical trial management system (CTMS) is used to register your information as a 
participant in a study and to allow for your research data to be entered/stored for the 
purposes of data analysis and any other required activity for the purpose of the conduct 
of the research.  
 
If you are receiving care or have received care within the University of Pennsylvania 
(outpatient or inpatient) and are participating in a University of Pennsylvania research 
study, information related to your participation in the research (i.e. laboratory tests, 
imaging studies and clinical procedures) may be placed in your existing EMR 
maintained by the University of Pennsylvania.  Information related to your participation 
in clinical research will also be contained in the CTMS. 
 
If you have never received care within the University of Pennsylvania and are 
participating in a University of Pennsylvania research study that uses University of 
Pennsylvania services, an EMR will be created for you for the purpose of maintaining 
any information produced from your participation in this research study.  The creation of 
this EMR is required for your participation in this study. In order to create your EMR, the 
study team will need to obtain basic information about you that would be similar to the 
information you would provide the first time you visit a hospital or medical facility (i.e. 
your name, the name of your primary doctor, the type of insurance you have). 
Information related to your participation in the study (i.e. laboratory tests, imaging 
studies and clinical procedures) may be placed in this EMR.  
 
Once placed in your EMR or in the CTMS, your information may be accessible to 
appropriate University of Pennsylvania workforce members that are not part of the 
research team.  Information within your EMR may also be shared with others who are 
determined by the University of Pennsylvania to be appropriate to have access to your 
EMR (e.g. Health Insurance Company, disability provider, etc.). 
 
What information about me may be collected, used or shared with 
others?   
x Name 
x Contact information: address, email address, telephone number 
x Date of birth 
x Medical history 
x Social Security Number 
x Medical Record Number 
x Information from your study visits and procedures, including all test results 
x Information from your medical records pertaining to any illnesses or medical 
complications you may have during your participation in the study. 
 
Why is my information being used? 
Your information is used by the research team to contact you during the study. Your 
information and results of tests and procedures are used to: 
x do the research 
x oversee the research 
x to see if the research was done right 
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If an insurer or employer learns about your participation, and obtains your consent to 
receive research information, then we may not use the Certificate of Confidentiality to 
withhold this information. This means that you and your family must also actively protect 
your own privacy.  
 
You should understand that we will in all cases, take the necessary action, including 
reporting to authorities, to prevent serious harm to yourself or others (ie: in the case of 
elder abuse or neglect). 
 
 
Will information about this study be available to the public? 
A description of this clinical trial will be available on www.ClinicalTrials.gov, as required 
by U.S. Law. This website will not include information that can identify you.  
 
 
What may happen to my information collected on this study? 
Your information will be de-identified. De-identified means that all identifiers have been 
removed. The information could be stored and shared for future research in this de-
identified fashion. This reduces the risk that future researchers would be able to identify 
you as we would not share any identifiable information about you with future 
researchers. This can be done without seeking your consent again in the future, as 
permitted by law. The future use of your information only applies to the information 
collected on this study. 
 
Eunice Kennedy Shriver National Institute of Child Health and Human Development 
(NICHD) Pelvic Floor Disorders Network (PFDN) plans to make data generated by 
PFDN studies available to external researchers in accordance with NIH data sharing 
policies. Data to be shared include clinical datasets of variables collected via the clinical 
trial management system, and analysis datasets containing derived variables that would 
enable a researcher to reproduce published study results. The data will be de-identified 
to protect study participant confidentiality. PFDN Data Coordinating Center (DCC) 
statisticians will implement a series of steps to de-identify study datasets in order to 
minimize the risk of researchers identifying any individuals in the data. This process will 
be consistent with Health Insurance Portability and Accountability Act (HIPAA), Health 
and Human Services (HHS) policies for protection of human research subjects, and 
related requirements for protecting participant confidentiality.  
 
 
Electronic Medical Records and Research Results  
 
What is an Electronic Medical Record and/or a Clinical Trial Management 
System?  
An Electronic Medical Record (EMR) is an electronic version of the record of your care 
within a health system. An EMR is simply a computerized version of a paper medical 
record.  
 
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Please note that there are other factors to consider before agreeing to participate such 
as additional procedures, use of your personal information, costs, and other possible 
individual concerns. If you are interested in participating, a member of the study team 
will review the full information with you. You are free to decline or stop participation at 
any time during or after the initial consenting process. 
 
Why am I being asked to volunteer? 
 
You are being invited to participate in a research study because you have mixed urinary 
incontinence (MUI). Your doctor is an investigator in this research study. You do not 
have to participate in any research study offered by your doctor. If you choose not to 
participate, you will not lose benefits to which you are otherwise entitled. You may also 
decide to discuss the study with your family, friends, or family doctor before deciding 
whether to participate. Being in a research study is different from being a patient. As an 
investigator, your doctor is interested both in your clinical welfare and in the conduct of 
this study.  If you decide to participate, you will be asked to sign this consent form.  
 
What is the purpose of this research study? 
The purpose of this study is to determine the best way to treat women with MUI. 
Because MUI includes both types of incontinence (stress and urgency), it is difficult to 
treat. Treatments that might help one type of incontinence may not help the other type. 
Right now, we do not know the best treatment for women who have not been successful 
in controlling their leakage with behavioral therapy, physical therapy, pessary and/or 
medications. In this study, you will receive treatment for your leakage with either 
BOTOX ® injections in the bladder or mid-urethral sling surgery. 
 
BOTOX® helps to treat UUI by preventing bladder spasms that cause leakage.  The 
use of BOTOX is currently approved by the FDA to treat conditions like overactive 
bladder including UUI.  It is FDA approved to treat UUI at 2 doses: 100 units for those 
who have UUI without an associated neurological condition and 200 units for those 
people with UUI and an associated neurological condition like spinal cord injury or 
multiple sclerosis. In this study, you will receive 100 units of BOTOX®.  For the 
treatment of UUI, BOTOX® is injected into the bladder wall through a cystoscope (a thin 
telescope passed into the bladder through the urethra or urinary tube).  The urethra is 
the small tube-shaped organ that carries urine from the bladder to the outside. The 
injection is performed under local anesthesia in the clinic, hospital or surgical center. 
Repeat injections are usually necessary when the therapy wears off (usually 6 to 12 
months).  BOTOX® is an effective treatment for UUI, but we do not know if it also helps 
improve SUI. 
 
A surgical treatment for MUI is a mid-urethral sling (MUS), where a small piece of 
permanent mesh is placed under the urethra. Mid-urethral slings are generally placed in 
the operating room under general anesthesia or deep sedation. They are primarily used 
for treating SUI, but they might also help UUI in women who have MUI.  Because it is 
hard to treat both SUI and UUI at the same time, we need treatments that can help both 
conditions in women who have MUI. This study is evaluating whether BOTOX® or a 
sling works better for treating MUI. 
 
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How long will I be in the study?  
 
Including the time required for screening and to schedule your procedures, you will be in 
the study for up to 15 months. You will be followed in the study for 12 months after your 
first procedure (BOTOX® or sling).  In total, we expect it will take 16 months to enroll all 
participants and complete the study. 
 
What am I being asked to do? 
 
Baseline / Screening visit – (Research visit - approximately 1 hour). 
 
If you decide you want to be in the study, you will have the following procedures to find 
out if you qualify to be in this study: 
x The study will be explained in detail and you will be asked to read and sign this 
consent form when you are comfortable. 
x You will be asked about any bladder medications you are taking and any previous 
surgeries for urinary incontinence. 
x You will empty your bladder and the coordinator or doctor will check to see if there is 
any urine remaining in your bladder by ultrasound or by inserting a catheter (thin 
tube) through the urethra into the bladder. 
x Your urine will be checked for infection. If you have a urinary tract infection (UTI), you 
will be treated by your physician and then re-tested at a follow-up visit to confirm that 
your UTI has resolved and that you are eligible to continue participation in the study. 
x You will be asked to complete health-related questionnaires about your medical and 
surgical history, urinary incontinence, general health and quality of life. 
x If you qualify so far, you will receive a 3-day bladder diary with verbal and written 
detailed instructions on how to complete the diary. You will record the times that you 
urinate, leak urine, and what you were doing when any urine leakage occurred. You 
will return the completed diary by mail or you will bring the diary with you to the 
Randomization visit. 
x If you are currently taking a bladder medication for overactive bladder, you will be 
asked to stop the medication for 3 weeks before completing the bladder diary and 
you will be asked to remain off medications during the 9 months of the study. 
x If you currently have a pessary or other devices for incontinence, you will be asked to 
remove the pessary before completing the bladder diary. 
 
Randomization visit (Research visit - approximately 1 hour) 
Randomization & Treatment:  
 After you have completed your bladder diary, you will return to the office. At this visit 
the following will take place: 
x Your completed bladder diary will be reviewed by study staff. 
x You will complete some questionnaires about how much your urinary incontinence 
bothers you and how your incontinence has affected your activities and quality of life. 
x Your urine will be checked for infection. If you have a urinary tract infection (UTI), you 
will be treated by your physician and then re-tested at a follow-up visit to confirm that 
your UTI has resolved and that you are eligible to continue participation in the study. 
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any time by your physician, the study Sponsor, or the Food and Drug Administration 
(FDA) without your consent because: 
x 
The Primary Investigator feels it is necessary for your health or safety.  Such an 
action would not require your consent, but you will be informed if such a decision is 
made and the reason for this decision. 
x 
You have not followed study instructions.  
x 
The Sponsor, the study Principal Investigator, or the FDA has decided to stop the 
study. 
If you decide to participate, you are free to leave the study at any time.  Withdrawal will 
not interfere with your future care.   
 
How will my personal information be protected during the study?   
We will do our best to make sure that the personal information obtained during the 
course of this research study will be kept private.  However, we cannot guarantee total 
privacy.  Your personal information may be given out if required by law. If information 
from this study is published or presented at scientific meetings, your name and other 
personal information will not be used. The Institutional Review Board (IRB) at the 
University of Pennsylvania will have access to your records. If this study is being 
overseen by the Food and Drug Administration (FDA), they may review your research 
records.   
 
Information you have provided will be kept in a research record and stored in a locked 
facility and on a secure, password-protected computer. Research information will not be 
made a part of your regular medical record. There is no personal information (name, 
social security number, etc.) about you that is associated with your research data; a study 
number will indicate your identity on the research records. 
 
Information relating to this study, including your name, medical record number, date of 
birth and social security number, may be shared with the billing offices of the University 
of Pennsylvania so that the costs for clinical services can be appropriately paid for by 
either the study account or by your insurance.  
 
 
Certificate of Confidentiality 
This research has a Certificate of Confidentiality from the Eunice Kennedy Shriver 
National Institute of Child Health and Human Development that protects your privacy. 
 
With this Certificate, we cannot be forced (for example by court order or subpoena) to 
disclose information that may identify you in any federal, state, local, civil, criminal, 
legislative, administrative, or other proceedings. The researchers will use the Certificate 
to resist any demands for information that would identify you, except to prevent serious 
harm to you or others, and as explained below. 
 
You should understand that a Certificate of Confidentiality does not prevent you, or a 
member of your family, from voluntarily releasing information about yourself, or your 
involvement in this study. 
 
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manage any side effects, unless you are told that certain tests are supplied at no cost. 
Before you decide to be in the study, you should check with your health plan/insurance 
company to find out exactly what they will pay for.  
 
You are still responsible for any deductibles or applicable co-pays for routine office 
visits, scans and blood work.  Examples of routine procedures and drugs that may be 
billed to you or your insurance company include the following: urine analysis, urine 
culture, Botox injection procedures, mid-urethral sling procedures, medications and 
catheterizations.  If your bladder symptoms get worse after surgery, or if other 
complications after surgery occur, all costs associated with the treatment of these 
complications are considered part of your standard clinical care and will be billed to you 
or your insurance company. Please talk to your doctor and study team about putting you 
in touch with a financial counselor to determine exactly what the deductible and co-pay 
will be for you; this depends on your insurance. 
 
Will I receive the results of research testing? 
 
As part of this study, the study team may ask you to have certain tests. Bladder testing 
or a cough stress test are part of your regular care. He/she will use these test results 
both to treat you and to complete this research.  These test results will be recorded in 
your medical record and will be reported to the Pelvic Floor Disorders Network (PFDN) 
Data Coordinating Center (DCC). Results of tests and studies done solely for this 
research study and not as part of your regular care will not be included in your medical 
record. They will only be kept in your research record. You are permitted access to 
information (including information resulting from your participation in this research 
study) contained within your medical records. 
 
What happens if I am injured from being in the study?  
 
We will offer you the care needed to treat injuries directly resulting from taking part in 
this research.  We may bill your insurance company or other third parties, if appropriate, 
for the costs of the care you get for the injury, but you may also be responsible for some 
of them. 
 
There are no plans for the University of Pennsylvania to pay you or give you other 
compensation for the injury.  If you feel this injury was caused by medical error on the 
part of the study doctors or others involved in the study, you have the legal right to seek 
payment, even though you are in a study. You do not give up your legal rights by 
signing this form.   
 
If you think you have been injured as a result of taking part in this research study, tell 
the person in charge of the research study as soon as possible.  The researcher’s name 
and phone number are listed in the consent form. 
 
 
When is the Study over?  Can I leave the Study before it ends? 
This study is expected to end after all participants have completed all visits, and all 
information has been collected.  Your participation in this study may also be stopped at 
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x If you are still eligible and willing to participate, you will be taught how to pass a thin 
tube (catheter) through the urinary tube into your bladder. 
x If the study staff confirms that you qualify and you still want to participate in the study, 
you will be assigned by chance (like the flip of a coin) to receive initial treatment with: 
 
BOTOX® injection procedure with 100 units 
OR 
Mid-urethral sling surgery 
 
x You will have an equal chance of receiving either the BOTOX® or sling. Neither you 
nor the researcher(s) can choose the group to which you will be assigned. 
x You will be told which treatment you are assigned. Some of the study staff will not 
know which treatment you are receiving. 
 
Procedure visit (Standard of care - 1 to 3 hours) 
You will undergo mid-urethral sling surgery or BOTOX injection per standard of care 
according to the group you are assigned to. 
x You will come to the clinic, hospital or surgical center for your BOTOX® injection or 
mid-urethral sling surgery with your surgeon according to standard of care. 
x Both BOTOX® 100 units and sling surgery are standard of care treatments for 
women with MUI and are not considered experimental.  The procedures will be 
performed according to standard practice and billed to you or your insurance 
whether you participate in this research study or not.  Because we currently do not 
know which procedure might be better for treating MUI, we are studying both 
treatments.  
o A sling surgery is performed under anesthesia in the operating room.  You 
will receive preoperative intravenous antibiotic to help prevent infection. A 
mesh sling will be placed under the midportion of your urethra (the tube 
through which the urine comes out of the bladder) through an 
approximately one 1-inch incision in the vagina and two ¼-inch incisions 
either above your pubic bone or in your groin.  
o A BOTOX injection is performed in the office under local anesthesia.  First 
a catheter will be placed in your bladder and an anesthetic solution will be 
instilled in order to provide numbing of the bladder. A camera (cystoscope) 
with an attached needle will be used to inject 15 to 20 different sites with  
BOTOX into your bladder. You will take an antibiotic pill before you leave 
to help prevent a UTI and you will take an antibiotic for three days after 
your injection. 
 
2 weeks after-procedure visit (Standard of care - approximately 30 minutes) 
Two weeks after your procedure, you will return to the clinic for a routine post-operative 
check with your surgeon. This visit is considered routine care. You will also see the 
research staff: 
x You will be asked if you have had any changes in your health and medications. 
x You will empty your bladder and the coordinator or doctor will check to see if there 
is any urine remaining in your bladder by ultrasound or by inserting a catheter (thin 
tube) through the urethra into the bladder. 
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x Your urine will be checked for infection. If you have a urinary tract infection (UTI), 
you will be treated by your physician. 
x You will be given a bladder diary to complete for the 3-month visit 
 
3 and 6 months after-procedure visits (Research visit - approximately 1 hour) 
At 3 and 6 months after surgery, you will return for a visit with the research staff. At this 
visit: 
x You will be asked if you have had any changes in your health and medications. 
x You will complete some questionnaires asking you about your bladder symptoms 
and quality of life. 
x Your completed bladder diary will be collected. 
x You will empty your bladder and the coordinator or doctor will check to see if there 
is any urine remaining in your bladder by ultrasound or by inserting a catheter (thin 
tube) through the urethra into the bladder. 
x Your urine will be checked for infection. If you have a urinary tract infection (UTI), 
you will be treated by your physician. 
x The research staff or doctor will answer any questions you might have. 
x If you received BOTOX and the injection is not giving you adequate control of your 
urinary leakage, after 3 months you may be eligible to receive additional 100 units 
of Botox®.   
 
9 and 12 months after-procedure call (Research call- approximately 30 minutes) 
At 9 and 12 months after surgery, you will have a call with the research staff. At this call: 
x You will be asked if you have had any changes in your health and medications. 
x You will complete some questionnaires asking you about your bladder symptoms 
and quality of life. 
x The research staff or doctor will answer any questions you might have. 
x After 6 months you may receive other treatments for your MUI if needed, including 
additional BOTOX or the alternative treatment (BOTOX or mid-urethral sling). 
x  
Botox Procedure visit (Standard of care - 1 to 3 hours)  
x You will come to the clinic, hospital or surgical center for your BOTOX® injection 
with your surgeon according to standard of care. 
x BOTOX® 100 units is a standard of care treatment for women with MUI and is not 
considered experimental.  The procedure will be performed according to standard 
practice and billed to you or your insurance whether you participate in this research 
study or not.   
o A BOTOX injection is performed in the clinic, hospital or surgical center  
under local anesthesia.  First a catheter will be placed in your bladder and 
an anesthetic solution will be instilled in order to provide numbing of the 
bladder. A camera (cystoscope) with an attached needle will be used to 
inject 15 to 20 different sites with  BOTOX into your bladder. You will take 
an antibiotic pill before you leave to help prevent a UTI and you will take 
an antibiotic for three days after your injection. 
  
 
2 weeks after-procedure visit (Standard of care - approximately 30 minutes) 
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injections and sling surgery have the potential to improve urine leakage and we hope 
the information learned from this study will benefit other women with your condition in 
the future. 
 
What other choices do I have if I do not participate?  
Alternatives to this study can include receiving BOTOX or a mid-urethral sling surgery 
outside the research study. There are also other treatments for urgency urinary 
incontinence (medications, tibial nerve stimulation and sacral neuromodulation).  The 
other options for stress urinary incontinence include use of a pessary or support device, 
or a surgical procedure that does not involve mesh (pubovaginal sling, retropubic 
colpopexy, or urethral bulking injection material). You also may elect to not have any 
treatment. Ask your doctor to talk with you about the other options. 
 
Will I be paid for being in this study? 
To compensate you for your time and travel, you will receive up $275 for participating in 
this research.  The amount will depend on the number of visits you attend in the study: 
  
x $75 after completion of the procedure  
x $50 after completion of the 3- month visit 
x $75 after completion of the 6- month visit 
x $75 after completion of the final 12- month call 
 
Payment will be made in the form of a debit card called a Clincard. Reimbursement 
payments will be loaded on your Clincard after completion of the above study contacts.  
 
Please note: In order to be compensated for your participation in this study, you must 
provide your Social Security Number. Additionally, please note that the we are required 
to report to the IRS any cumulative payments for participation in research studies that 
exceed a total of $600 in a calendar year. 
 
Will I have to pay for anything? 
 
The sling surgery and Botox ® injection procedures and physician visits are considered 
part of standard clinical care and will be billed to your insurance in the usual manner. As 
usual for any medical procedure, if there are portions of the cost that your insurance 
does not cover, you will be billed in the usual manner for any surgery you may choose 
to have. You are advised to consult your insurance company before having any 
operation.  
 
Those tests (e.g., pregnancy, urine dip, bladder emptying) and visits which are only for 
research will be paid for by the study.  In order to make sure that tests and studies done 
solely for research purposes are charged correctly, we will carefully monitor your 
procedure and clinic charges as long as you are participating in this study. Please ask 
your provider if you would like to know more about which tests and studies are being 
done solely for research purposes.  
 
You and/or your health plan/insurance company will need to pay for the costs of your 
condition while in this study, including the cost of tests, procedures, or medicines to 
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anesthesia (all <1% for major problems). Some women experience urinary problems 
after the procedure, including difficulty urinating or urgency symptoms, these can be 
temporary or persistent (about 10-15%). Although recent research suggests that women 
with MUI have improvement in incontinence, up to 15% of women may need additional 
treatment for urinary incontinence after a sling. Recent research suggests that 1-6% of 
women may need to return to the operating room to remove or revise the sling because 
of a mesh exposure or problems urinating.  
 
 
Risks of stopping your bladder medication or pessary treatment: To be eligible for 
MUSA, if you are taking bladder medication for overactive bladder or using a pessary or 
other device for stress incontinence, you will need to stop the treatment for 3 weeks 
before you can fill out the bladder diary. If you are eligible for the study and you choose 
to enroll in the study, you will be asked to stay off of your bladder medication and all 
other treatments (as mentioned above) for incontinence during the study, until 6 months 
after surgery. During this time, you may notice that your incontinence symptoms return. 
Please feel free to discuss any concerns you have about stopping your medical or 
pessary treatment with your doctor.  
 
Risks of questionnaires: The quality of life questionnaires contain items that are of a 
personal nature and may make you uncomfortable or embarrassed. For example, some 
questions will ask about your sexual activity. You may refuse to answer any question 
that you do not want to answer. 
 
Reproductive risks: The effects of the treatment procedures may pose some 
unforeseeable risks on the reproductive system (eggs) or to the developing fetus. For 
this reason, participants in this study should not become pregnant. We require that all 
participants who are able to become pregnant agree to either abstain from sexual 
intercourse or use a reliable, effective contraception for this period, such as hormonal 
contraceptive, intrauterine device (IUD), diaphragm with spermicide, contraceptive 
sponge or use of condom by the partner. 
 
After you have been enrolled in this study, pregnancy testing will be performed before 
you undergo a procedure (either sling or BOTOX). If you have a positive pregnancy test, 
your doctor may withdraw you from the study. If you become pregnant or if there is any 
chance of pregnancy (e.g., late menstrual period), please contact the study personnel 
immediately so that we may provide medical assistance and counseling. 
 
What if new information becomes available about the study? 
During the course of this study, we may find more information that could be important to 
you.  This includes information that, once learned, might cause you to change your mind 
about being in the study.  We will notify you as soon as possible if such information 
becomes available. 
 
What are the possible benefits of the study?  
Participation in the study may or may not benefit you directly. This study may help the 
investigator(s) learn more about the best options for treating MUI.  You may or may not 
have a decrease in the amount of urinary leakage you are experiencing. Both Botox® 
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If you received additional injections of BOTOX, you will return for a routine post-
operative check with your surgeon 2 weeks after the injection. This visit is considered 
routine care. You will also see the research staff:  
x You will be asked if you have had any changes in your health and medications. 
x You will empty your bladder and the coordinator or doctor will check to see if there 
is any urine remaining in your bladder by ultrasound or by inserting a catheter (thin 
tube) through the urethra into the bladder. 
x Your urine will be checked for infection. If you have a urinary tract infection (UTI), 
you will be treated by your physician as part of your routine clinical care. 
 
 
What are the possible risks or discomforts?  
 
Participation in this study may involve some risks or discomforts. Because this is a 
research study, there may be some unknown risks that are currently unforeseeable.  
 
It is possible that the study procedures you receive may not be effective in treating your 
UUI or SUI symptoms or could make them worse.  Additionally, below is a list of risks 
related to specific study procedures and medications. 
 
Risks of randomization: You will be assigned to a study group at random (by chance). 
Your assignment is based on chance rather than a medical decision made by the 
researchers. The study group you are assigned to might not be the group you would 
prefer to be in. Your assigned study group might also prove to be less effective or have 
more side effects than the other study group, or other treatments available for your 
condition. 
 
Risks of Botox® injection:  Your surgeon will talk to you about the risks involved with 
your BOTOX injection. The risks of the procedure are the same whether or not you 
choose to participate in the study. This procedure is considered to be an accepted 
procedure for UUI and the procedure itself is not experimental. The risk of urinary tract 
infection is about 25-30%, and all women will be given an antibiotic to reduce the 
chance that a urinary tract infection will develop. Research suggests that up to 20% of 
women may have temporary difficulty emptying the bladder completely and need to 
insert a small tube into the bladder (catheterizing) several times per day to drain it. Rare 
risks of BOTOX® (1 in 1000) include: nausea, vomiting, dry mouth, trouble swallowing, 
weakness of muscles resulting in difficulty breathing, and paralysis.  While some of 
these side effects are very serious and could cause death, they have never been 
described in patients receiving BOTOX® treatment for urinary problems.  
 
Risks of mid-urethral sling surgery: Your surgeon will talk to you about the risks 
involved with your mid-urethral sling surgery. The risks of the mid-urethral sling surgery 
are the same whether or not you choose to participate in the study. This procedure is 
considered to be an accepted surgical procedure for SUI and the surgery itself is not 
experimental.  The risk of urinary tract infection is about 5-10% and risk of wound 
infection is about 1%; all women will be given an antibiotic to reduce the chance that an 
infection will develop.  Other risks of mid-urethral sling surgery include injury to the 
bladder, bowel, blood vessels, or nerves, bleeding, and problems related to the 
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Prot_000.pdf: 
PFDN Protocol 
 
 
 
MUSA 
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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 
 
 
 
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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 
 
 
 
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ABBREVIATIONS 
 
 
ABC 
Anticholinergic versus Botox Comparison trial 
ATLAS 
Ambulatory Treatments for Leakage Associated with Stress Incontinence trial 
BBUSQ 
Birmingham Bowel Urinary Symptom Questionnaire 
BD 
Bladder diary 
BE- DRI 
Behavior Enhances Drug Reduction of Incontinence trial 
BPTx 
Behavioral/pelvic floor therapy 
CDF 
Cumulative distribution function 
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  


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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 
 
 
 
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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 


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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 


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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 
 
 
 
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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 
 


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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. 
 


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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 


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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 


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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 


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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 


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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.  


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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 


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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 


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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.  


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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 


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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. 
 


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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 


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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 
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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 


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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.  


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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). 


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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 
 
 
 
 
 
 
 
 
 


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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-


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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: 


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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).  


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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 


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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.  


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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. 


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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 
 
 
 
 


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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 


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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 


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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. 


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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 
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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 


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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 
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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. 


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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). 


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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.  


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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 


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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% 
 


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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).   


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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 


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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 


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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.  


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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 


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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 


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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]. 


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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.  


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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. 


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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 


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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  


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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 


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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. 


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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.  


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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 


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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. 
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urodynamics 2009;28:416-22. 
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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. 


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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; 
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Efron B, Tibshirani R. An introduction to the bootstrap. New York: Chapman & Hall; 1994. 


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OnabotulinumtoxinA [package insert]. Madison, NJ: Allergan, Inc. (2019). 
 
 


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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 


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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 


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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 


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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 


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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 


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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. 
 

SAP_001.pdf: 
Pelvic Floor Disorders Network 
MUSA Statistical Analysis Plan 
 
 
 
 
   
Version 1.0 February 8, 2024 Page 1   
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Treatment for Mixed Urinary Incontinence: Mid-urethral Sling vs. Botox A (MUSA) 
 
Short title: Sling vs Botox for Mixed Incontinence 
 
SAP VERSION: 
Version 1.0 
 
SAP DATE: 
February 8, 2024 
 
PREVIOUS VERSIONS: N/A 
 
SPONSOR: 
NICHD  
 
PREPARED BY: 
RTI International. 
 
 
3040 Cornwallis Rd 
 
 
Research Triangle Park, NC 27709-2104 
 
AUTHOR (S): 
Lindsey Barden 
 
 
Evan Rhodes  
Ben Carper  
Sonia Thomas 
 
 
 
 


Pelvic Floor Disorders Network 
MUSA Statistical Analysis Plan 
 
 
 
 
   
Version 1.0 February 8, 2024 Page 2   
 
Contents 
1 
BACKGROUND AND PROTOCOL HISTORY 
6 
2 
PURPOSE OF THE ANALYSES 
6 
3 
STUDY AIMS AND OUTCOMES 
6 
3.1 
STUDY AIMS 
6 
3.1.1 
Primary Aims 
7 
3.1.2 
Exploratory Aims 
7 
3.2 
OUTCOMES 
7 
3.2.1 
Primary Outcomes 
7 
3.2.2 
Secondary Outcomes 
7 
3.2.3 
Exploratory Outcomes 
8 
3.2.4 
Safety Outcomes 
8 
4 
STUDY METHODS 
8 
4.1 
OVERALL STUDY DESIGN AND PLAN 
8 
4.2 
STUDY POPULATION 
9 
4.3 
STUDY ARM ASSIGNMENT AND RANDOMIZATION 
10 
4.4 
CRITERIA FOR BOTOX RE-INJECTIONS 
10 
4.5 
MASKING AND DATA LOCK 
11 
4.5.1 
General Masking Procedures 
11 
4.5.2 
Database Lock 
11 
4.6 
STUDY FLOW CHART OF ASSESSMENTS AND EVALUATIONS 
12 
5 
ANALYSIS POPULATIONS 
14 
5.1 
MODIFIED INTENTION-TO-TREAT (MITT) POPULATION 
14 
5.2 
PER-PROTOCOL (PP) POPULATION AND ANALYSIS 
14 
5.3 
SAFETY (SAF) POPULATION 
14 
6 
SAMPLE SIZE DETERMINATION 
14 
7 
STATISTICAL AND ANALYTICAL ISSUES 
15 
7.1 
GENERAL RULES 
15 
7.2 
ADJUSTMENTS FOR COVARIATES 
15 
7.3 
HANDLING OF DROPOUTS AND MISSING DATA 
16 
7.4 
HANDLING OF CROSS-OVERS AND OFF-STUDY TREATMENT 
16 
7.5 
INTERIM ANALYSES AND DATA MONITORING 
16 
7.6 
MASKED DATA REVIEW 
17 
7.7 
MULTICENTER STUDIES 
17 
7.8 
MULTIPLE COMPARISONS AND MULTIPLICITY 
17 
7.9 
EXAMINATION OF SUBGROUPS 
17 


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7.10 
ASSESSMENT WINDOWS 
17 
8 
STUDY SUBJECT CHARACTERIZATION 
17 
8.1 
SUBJECT DISPOSITION 
17 
8.2 
PROTOCOL DEVIATIONS 
17 
8.3 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
18 
9 
EFFICACY ANALYSES 
18 
9.1 
OVERVIEW OF EFFICACY ANALYSES METHODS 
18 
9.2 
VARIABLE DEFINITIONS 
19 
9.3 
ANALYSIS METHODS FOR THE PRIMARY OUTCOME 
48 
9.4 
ANALYSIS METHODS FOR SECONDARY AND EXPLORATORY OUTCOMES 
49 
9.5 
OTHER ANALYSIS METHODS 
49 
9.5.1 
Predictors of  Treatment Response 
49 
9.5.2 
Cost-effectiveness analysis 
50 
9.5.3 
UDI MID 
51 
10 
SAFETY ANALYSES 
52 
10.1 
OVERVIEW OF SAFETY ANALYSIS METHODS 
52 
10.2 
ADVERSE EVENTS/COMPLICATIONS/ADVERSE SYMPTOMS 
52 
10.3 
DEATHS AND SERIOUS ADVERSE EVENTS 
54 
11 
ANALYSIS OF OTHER OUTCOMES 
54 
12 
REPORTING CONVENTIONS 
54 
13 
CHANGES TO THE ANALYSIS PLANNED IN THE PROTOCOL 
55 
14 
REFERENCES 
55 
15 
LIST OF POTENTIAL DISPLAYS 
55 
 
 
 


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LIST OF ABBREVIATIONS 
BD 
Bladder diary 
BPTx 
Behavioral/pelvic floor therapy 
CISC 
Clean intermittent self-catheterization 
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 
IE 
Incontinence episode 
IIQ 
Incontinence Impact Questionnaire 
ITT 
Intention-to-treat 
MID 
Minimum important difference 
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 
PFDN 
Pelvic Floor Disorders Network 
PGI-I 
Patient Global Impression- Improvement 
PGI-S 
Patient Global Impression-Severity 
PGSC 
Patient Global Symptom Control 
PISQ-IR 
Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire  
POPQ 
Pelvic Organ Prolapse Quantification system 
PRO 
Patient reported outcomes 
PVR 
Postvoid residual 
QoL 
Quality of life 
RCT 
Randomized controlled trial 
ROSETTA 
Refractory Overactive Bladder: Sacral Neuromodulation v. Botulinum Toxin 
Assessment trial 
SAE 
Serious adverse event 
SD 
Standard deviation 
SF-36 
Short Form 36 
SF-6D 
Short Form 6D 
SUI 
Stress urinary incontinence 


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UDE 
Urodynamic evaluation 
UDI 
Urogenital Distress Inventory 
UI 
Urinary incontinence 
UIE 
Urinary incontinence episode  
UUI 
Urgency urinary incontinence 
 
 
 


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Version 1.0 February 8, 2024 Page 6   
 
1 
BACKGROUND AND PROTOCOL HISTORY 
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. 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. MUSA will randomize 146 women to treatment 
with Botox or Sling in a 1:1 ratio. 
  
MUSA was originally designed as a 6-month trial and began enrolling participants in June 2020. 
Protocol amendment 4.0 approved by the DSMB in February 2021 added an observational 6-month 
follow-up period, with phone assessments at 9 and 12 months. At the time of transitioning to protocol 
version 4.0, 2 participants had already completed the study at 6 months and did not give consent to 
participate in the follow-up period.  
 
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. 
2 
PURPOSE OF THE ANALYSES 
This statistical analysis plan (SAP) contains detailed information about statistical analyses to be 
performed to address the primary aim and selected exploratory aims of MUSA, including both the 6-
month treatment period and the observational period to 12 months. All analyses that will be included 
in the primary manuscript are described. Additional exploratory analyses may be performed to 
support further manuscript development.  These analyses will not require an update to the SAP.   
Since the 6-month observational period was added to the protocol as an addendum, all design and 
analysis components for the observational period are described in the protocol addendum. In this 
SAP, the follow-up observational period design, aims, outcomes and analyses are fully integrated 
with the treatment period within each section.   
Detailed methods for exploratory aim 2 (predictors of outcome) and exploratory aim 5 (cost 
effectiveness) will be described in separate analysis plans, as they will be covered in separate 
secondary manuscripts. 
3 
STUDY AIMS AND OUTCOMES 
3.1 
Study Aims 
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 and characterize patient 
characteristics associated with treatment response.  


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3.1.1 
Primary Aims  
The primary aim of this study is 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. 
3.1.2 
Exploratory Aims 
Exploratory aims of this study (consolidated from the main protocol and the 12-month 
  
addendum) are the following: 
1. 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  
2. 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 and 12 months post-treatment.  
3. 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 and 12 months post-treatment.  
4. 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 and 12 months post-
treatment. 
5. 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.  
6. 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 
and 12 months post-treatment.  
7. UDI MID: To explore MIDs for UDI total score and stress and irritative subscores for 
this MUI population.  
3.2 
Outcomes     
3.2.1 
Primary Outcomes 
The primary outcome for this study is the change from baseline in UDI-total score at 6 
months post-treatment. 
3.2.2 
Secondary Outcomes 
The three secondary outcomes for this study are: 
• 
the change from baseline in the UDI-stress and UDI-irritative subscales at 6 months 
post-treatment and  
• 
change from baseline in UDI-total score at 3 months post-treatment. 


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3.2.3 
Exploratory Outcomes 
Exploratory efficacy outcomes for this study include: 
• 
Change from baseline in UDI-total score, UDI-stress and UDI-irritative subscales at 
other collected timepoints (3, 9, 12 months) 
• 
Change from baseline in number of urinary incontinence episodes on bladder diary 
at 3-, 6-, and 12-months post-treatment (not measured at 9 months),  
• 
Change from baseline in overactive bladder symptoms and satisfaction scores and 
subscales (OAB-q, OAB-SAT-q) at 3-, 6-, 9- and 12-months post-treatment, 
• 
Change from baseline in quality of life outcomes (IIQ, PISQ-IR) and global 
impression scales (PGI-I, PGI-S, PGSC) at 3, 6, 9, and 12 months post-treatment, 
• 
Additional treatment for SUI and/or OAB (both rates and types) within 6 months of 
treatment and during the 6-month follow-up,  
• 
a Cost-effectiveness analysis to compare the direct & indirect costs of urinary 
incontinence treatment by Botox A and mid-urethral sling.  Effectiveness outcomes 
are: SF-6D, and EQ-5D 
3.2.4 
Safety Outcomes 
• 
Rates of reoperation or sling revision due to worsening OAB after MUS 
• 
Rates of urinary retention / intermittent catheterization after Botox injection,  
• 
Proportion of women in each group with UTI and recurrent UTI, 
• 
Rates of other serious and non-serious adverse events, 
 
Safety outcomes will be assessed in a descriptive manner at each DSMB meeting without 
formal statistical tests. There is no established stopping rule to guide what sling revision rate 
is “appropriate” for worsening OAB symptoms in this population.  
4 
STUDY METHODS 
4.1 
Overall Study Design and Plan 
The study is a multi-center randomized trial of 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. Participants are followed for an additional 6-month observational period. The 
analysis will determine the effect of treatment on the primary outcome, change in Urogenital 
Distress Inventory (UDI) score at 6 months. A study schematic is shown below:  


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4.2 
Study Population 
 
 
Inclusion and exclusion criteria for the MUSA trial are as follows: 
 
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. 
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 
 
Exclusion Criteria: 
1. Anterior or apical compartment prolapse at or beyond the hymen (>0 on POPQ), 
regardless if patient is symptomatic  
MUI; elected to undergo 
surgical treatment 
Randomization (N=146)  
Botox A 
Mid-urethral sling surgery 


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a. Women with anterior or apical prolapse above the hymen (<0) who do not report 
vaginal bulge symptoms will be eligible 
2. Planned concomitant surgery for anterior vaginal wall or apical prolapse > 0 
a. Women undergoing only rectocele repair 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   
4.3 
Study Arm Assignment and Randomization 
The participant will be randomized to one of the two treatment arms (Botox A or MUS) using a 
web-based data management system. Randomization (1:1 to the two treatment arms) will be 
performed using permuted blocks, with a block size that is known only to the DCC and will be 
stratified by site and age group (≥ 65, < 65). Once patients are enrolled and randomized, the 
intervention (either Botox A or mid-urethral sling) should be scheduled within 8 weeks from 
randomization. If treatment is not completed within 91 days of the baseline UDI, the baseline 
assessments are to be repeated. 
 
4.4 
Criteria for Botox re-injections 
 
Participants in the Botox arm 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: 


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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 ≤ 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). 
 
 
4.5 
Masking and Data Lock 
4.5.1 
General Masking Procedures 
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. 
 
Study Individual 
Masking 
Study participant 
No 
Study surgeon 
No 
Outcome assessors 
Yes 
 
The senior statistician who reviewed and approved the SAP (SMT) also remained fully 
masked until database lock, and all study PIs were masked to cumulative results. 
4.5.2 
Database Lock 
Database lock and unmasking will occur when data collection has been completed and all 
data queries are resolved, and prior to the final data analysis. Prior to database lock a masked 
data review with the study PI (HH) will evaluate key data including study populations, 
protocol violations and completeness of key efficacy and safety data. 


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4.6 
Study Flow Chart of Assessments and Evaluations 
 
MUSA Study 
Visit 
Screen/ 
Consent 
Baseline/ 
Eligibility 
Repeat 
Baseline* 
Rando
mizati
on 
Operation 
/ 
Procedure 
2 wk 
3 mo 
Botox-
Reinj 
(Botox 
only) 
Botox 
Reinj 
2wk 
FU 
6 mo 
9 mo 
12 mo 
Close
- 
out 
Add’
nl 
/As 
nec. 
MUSA Data 
Collection 
Forms 
Durat. 
1-4 w 
Duration 
1-4 w 
Prior Tx 
>91 d 
after UDI 
w/in  
8 wks 
pre Tx 
Time 0 
14 ± 
7 d 
91 ± 
30 d 
 
14 ± 7 
d 
183 ± 
30 d 
274  
± 30 d 
365  
± 30 d 
 
 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
§ UDI 
X 
 
X 
 
 
 
X 
 
 
X 
X 
X 
 
 
Bladder Diary 
 
X 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History / 
Medications 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
† Urodynamics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
† POPQ 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
† PVR – Clinic 
Visit 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
† Urine Dip  
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
† Pregnancy 
Test 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
† Surgeon 
report/ 
Complications 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
Medical – 
follow up  
 
 
 
 
 
X 
X 
 
X 
X 
X 
X 
 
 


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§ OAB-q 
 
X 
X 
 
 
 
X 
 
 
X 
X 
X 
 
 
§ IIQ 
 
X 
X 
 
 
 
X 
 
 
X 
X 
X 
 
 
§ PISQ 
 
X 
X 
 
 
 
X 
 
 
X 
X 
X 
 
 
§ EQ-5D 
 
X 
X 
 
 
X 
X 
 
X 
X 
X 
X 
 
 
§ SF-36/ SF-
6D 
 
X 
X 
 
 
X 
X 
 
X 
X 
X 
X 
 
 
§ PGI-S 
 
X 
X 
 
 
 
X 
 
 
X 
X 
X 
 
 
§ Lost 
Productivity / 
Costs 
 
 
 
 
 
X 
X 
 
X 
X 
X 
X 
 
 
§ OAB-SAT-q 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
 
 
§ PGI-I 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
 
 
§ PGSC 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
 
 
Final Status 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Adverse Events 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serious AE 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Protocol Viol. 
/Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
CISC/PVR – 
Patient 
Reported 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Additional 
Therapies  
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Additional 
Office Visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
*Repeat baseline if not randomized and treatment not initiated within 90 days of the date UDI completed as part of the initial baseline visit. 
† Performed in clinic only.  MUS procedure urine dip collected per usual clinical practice. 
§ Patient Reported Outcomes 
Note; extended follow-up begins after the 6m visit.  


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5 
ANALYSIS POPULATIONS 
5.1 
Modified Intention-to-Treat (mITT) Population 
It is possible that some women in both groups may cancel their surgical procedure due to personal 
or other reasons.  It is also possible that a treated participant might discontinue from the study 
after treatment while providing no efficacy data to be included in the analysis. The mITT 
population is defined as all randomized subjects, regardless of their final study status, that 
received any study treatment, and have some post-baseline efficacy data.  
Unless otherwise specified, the mITT population will be used to analyze all efficacy outcomes. 
Subjects will be summarized according to the arm to which they were randomized, irrespective of 
the received treatment. 
5.2 
Per-Protocol (PP) Population and Analysis 
The per-protocol population will be used in supportive sensitivity analyses of the primary and 3 
secondary outcomes.  
The Per-Protocol population is defined as a subset of the mITT population who received the 
intervention to which they were randomized, and had no major protocol violations, defined as any 
major inclusion or exclusion violations. 
Receipt of any additional treatment for urinary incontinence before the 6-month visit assessments, 
including cross-over to the non-randomized study treatment or any other non-study UI treatment 
(other than a second Botox injection allowed by the protocol for the Botox arm) is also a major 
protocol violation.  Thus, the per-protocol analysis will exclude (set value to missing) any data 
points at 3 or 6 months that are collected after a cross-over treatment or additional therapy. All 
data prior to the violation will be included in the analysis.  
Note that if a second Botox injection is performed in the Botox arm before 6 months without 
meeting the protocol-specified criteria for a second injection, data after this second injection will 
not be excluded from the per-protocol analysis specifically due to this protocol deviation. In 
addition, since cross-over and additional UI treatments after the 6 month assessment were 
allowed by protocol, no values will be excluded from the 9 and 12 month data points for the per-
protocol analysis.   
 
5.3 
Safety (SAF) Population  
The safety population will comprise all subjects who were randomized and treated, grouped by 
the treatment to which they actually received (for any situations in which a participant was not 
initially treated with their randomized treatment assignment). If all patients received their 
randomized treatment and have some post-baseline efficacy data, then the safety population 
would be the same as the mITT.  
6 
SAMPLE SIZE DETERMINATION 
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).  
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%.  


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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. 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. Based on average estimates from ROSETTA and 
ESTEEM, we plan for 5% discontinuation rate by 6 months. 
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.  
With the sample size of 146 subjects and the planned standard deviation of 46.5, 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. Thus, the planned 
sample size may allow for analyses to assess whether the true MID in this population is smaller than 
26. 
Assuming an additional 5% discontinuation rate between 6 and 12 month, the study will have 
88% power for the 12 month UDI total score outcome based on the MID of 26, and the SD of 
46.5. 
 
7 
STATISTICAL AND ANALYTICAL ISSUES 
7.1 
General Rules 
All statistical computations will be performed and data summaries will be created using SAS 9.4 
or higher. If additional statistical packages are required, these will be discussed in the study 
report. For summaries of study data, categorical measures will be summarized in tables listing the 
frequency and the percentage of subjects in each study arm; continuous data will be summarized 
by presenting mean, standard deviation, and where appropriate, minimum, and maximum values. 
Non-normal continuous data will be summarized by only presenting median and interquartile 
range (25th and 7th percentile). 
7.2 
Adjustments for Covariates  
Indicator variables for the study stratification factors of site and age group (≥ 65, < 65) will be 
included as covariates in most efficacy analyses performed for this study (details in section 9). 
The baseline value of the outcome variable will also be a covariate in models of change from 
baseline.  


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Additionally, demographic and baseline characteristics will be compared between study arms 
using a t-test for continuous measures, Mantel-Haenszel mean score test using standardized 
midrank scores for ordinal measures, and Cochran Mantel-Haenszel chi-square tests for general 
association for categorical measures. If these analyses suggest that a substantial difference exists 
among arms for an important characteristic, supportive exploratory analyses of the primary 
efficacy outcome adjusting for the characteristic may be explored.  
7.3 
Handling of Dropouts and Missing Data 
The repeated measures analysis for the primary outcome for the MITT population (see Section 
9.3) assumes missing data due to a missed visit or early study discontinuation is missing at 
random. The impact of missing data on the primary efficacy MITT analysis results will be 
explored through multiple imputation sensitivity analyses using control-based imputation if more 
than 10% of participants in the mITT population are missing their 6-month UDI score and a 
treatment group difference is identified, in order to assess the robustness of the primary results to 
missing data. (See Section 9.3). Sensitivity analyses are not planned for secondary or other 
outcomes.  
7.4 
Handling of Cross-over and off-study treatment 
It is a protocol deviation for participants to receive any other UI treatments during the first 6 
months after treatment. After 6 months, participants may cross-over to receive their non-
randomized treatment and may also receive additional off-study UI treatments. 
For all primary mITT analyses, data for participants who cross-over and receive the other study 
treatment or receive an off-study treatment during the first 6 months will be included in all 
analyses in an intent-to-treat fashion.  
The mITT analysis is conservative as it may minimize differences between groups or bias results 
to make a treatment appear more efficacious due to inclusion of data after a participant has 
received the other study treatment or additional treatments. Therefore, a supportive per-protocol 
analysis of the primary and 3 secondary outcomes will be based on the per-protocol population 
with data excluded (value set to missing) for any data points at 3 or 6 months that are collected 
after a cross-over treatment or additional therapy.  Since crossing over and additional treatments 
were allowed after 6 months, data points after 6 months will not be excluded. See Section 9.3.  
The per-protocol analysis is expected to remove bias in outcome caused by the off-protocol 
additional therapies, in order to provide a more accurate estimate of the true difference in UDI 6 
months after the randomized treatment with no further interventions.  
The repeated measures analysis assumes that the values set to missing after cross-over treatment 
are missing at random. However, since additional treatment was sought, it's possible that the 
outcome scores with no extra treatment received, had they been available, would reflect poorer 
outcome scores than other recorded data, and thus not be missing at random. Therefore, a 
multiple imputation tipping point sensitivity analysis of the per-protocol analysis will be 
conducted. Tipping point analysis will consist of a set of multiple imputation analyses in which 
the imputed UDI change from baseline scores are increased (made worse) by successively fixed 
amounts, in order to identify at what amount would have a change in the interpretation of the per-
protocol analysis. See Section 9.3   
7.5 
Interim Analyses and Data Monitoring 
Safety outcomes will be assessed at each DSMB meeting. This will include the need for sling 
revision due to worsening OAB symptom.  
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 


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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. Interim efficacy data can 
be reviewed by the DSMB upon their request.  
7.6 
Masked Data Review 
A masked data review of the primary and secondary outcomes for this study will be performed by 
the protocol team. This review will occur prior to data lock analyses.  This will include evaluation 
of missing data, descriptive statistics (e.g. means, standard deviations, percentiles for continuous 
variables and counts and percentages of categorical variables) of key efficacy and safety 
outcomes, protocol violations and model predictor variables. In the masked review, any 
summaries will be aggregated over both treatment groups.  
7.7 
Multicenter Studies 
For this multicenter study, randomization of study participants was stratified within center and by 
age group (≥ 65, < 65).  Consequently, for all model-based primary and secondary analyses, 
center and age group will be included as fixed effects in the models. There were 8 enrolling sites, 
each with at least 10 treated participants, so sites will not be pooled. 
7.8 
Multiple Comparisons and Multiplicity 
The primary hypothesis will be tested at a nominal two-sided type I error of 0.05. The three 
secondary outcomes will also be tested at a nominal two-sided type 1 error of 0.05, with no 
adjustment for multiple comparisons, and thus p-values are descriptive.  All p-values for any 
baseline and demographic characteristics, exploratory outcomes, and safety parameters will also 
be for descriptive purposes only. 
7.9 Examination of Subgroups 
We will evaluate the primary outcome for one pre-planned subgroup of interest, which is the type 
of mixed urinary incontinence based on the baseline UDI: stress-predominant, urgency-
predominant, or balanced.   
7.10 Assessment Windows 
Baseline assessments were to be completed no longer than 3 months prior to intervention with 
assessments repeated if participant treatment is delayed for over 3 months.  All other visits were 
completed at 2 weeks with a ± 1 week window around the visit and 3-month intervals (3, 6, 9, 12 
months) with a ± 1 month window around the visit.  Coordinators attempted to complete all 
follow-up visits, even if they couldn’t be completed within window. For all analyses, all available 
data will be used regardless of if the assessment was completed within window or not. 
8 
STUDY SUBJECT CHARACTERIZATION 
8.1 
Subject Disposition 
Disposition of study participants will be described using a standard Consort diagram, including 
the number of subjects screened, consented, randomized, treated, receiving protocol specified 
botox at 3-6 months, and completing or discontinuing from the treatment period prior to 6 months 
and from the 6-month follow-up period. Reasons for study withdrawal will be presented.  
8.2 
Protocol Deviations 
Protocol deviations are identified via automated checks of the clinical database and reported by 
site study coordinators in the study data management system. For DSMB reports, protocol 
deviations will be listed by site with information such as type of deviation, time of occurrence, 
and reason, and incidence rate of protocol deviations will be summarized overall and for each 


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protocol deviation category. Incidence rate of protocol deviations will be calculated as: number of 
deviations divided by the number of subjects at the site.  
Key protocol deviations are violations of inclusion/exclusion criteria, receipt of any off-protocol 
treatments for UI prior to the 6 month assessment, including switching arms, re-treatment of 
botox before 3 months, and any non-study UI treatment. 
8.3 
Demographic and Baseline Characteristics 
Demographic and baseline clinical characteristics for the study participants will be summarized 
by study arm using the general analysis rules describe above.  Variables of interest include age 
(years), parity, gravidity, race and ethnicity, BMI, education level (classified as binary variable as 
having some education greater than high school), smoking status (current yes or no), menopausal 
status, and estrogen use.  Also included is time from baseline to treatment and percent of 
participants with > 91 days to treatment. 
Baseline levels of all OAB and QOL measures will be presented on efficacy tables. 
9 
EFFICACY ANALYSES 
9.1 
Overview of Efficacy Analyses Methods 
All efficacy analyses will be performed on the mITT population unless otherwise specified.  
All primary, secondary and exploratory efficacy variables were collected longitudinally across 
this study.  Consequently, all efficacy analyses will be conducted using appropriate models for 
these correlated data collected across time.  Specifically, continuous outcome variables will be 
analyzed using linear mixed models and binary outcome variables will be analyzed using 
generalized linear mixed models. Models will include terms for treatment and for the 
stratification variables included in the study design (site and age group (≥ 65, < 65)).  Additional 
details are provided in the specific sections below (See section 9.3).   
 


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9.2 
Variable Definitions  
Primary and secondary efficacy variables as well as exploratory and safety outcomes are described in the table below. 
 
Note that for any patient who had a repeat baseline, their repeat measures will be used in the definition of baseline (their updated baseline 
scores were entered into the repeat baseline CRF by the sites).  
 
Variable 
Type 
Definition 
Primary Outcomes 
type of urinary incontinence  
Categorical 
stress-predominant  
urgency-predominant 
balanced 
The definition of the type of urinary incontinence 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. 
Change from baseline in 
UDI Total Score at 6 months 
(and at 3, 9, and 12 months) 
 
6 months is primary,  
Continuous 
The Urogenital Distress Inventory-Total Score will be computed at baseline and 6 
months (and 3, 9, and 12 months) using the standard scoring algorithm. Specifically, the 
instructions are to sum the Stress, Irritative, and Obstructive subscales of the UDI (see 
below). If any subscale scores are missing, then the score will be calculated as the sum of 
the non-missing scales. The outcome will then be computed as the difference in Total 
score at 6 months (and 3, 9, and 12 months) and the Total score at baseline.  If data for an 
assessment time point are missing, the outcome variable will be coded as missing.  
 
 


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Variable 
Type 
Definition 
Secondary Outcomes  
Change from baseline in 
UDI Obstructive Score at 6 
months (and at 3, 9 and 12 
months) 
Continuous 
The Urogenital Distress Inventory-Obstructive Score will be computed as baseline and 6 
months (and 3, 9, and 12 months) using the standard scoring algorithm. Specifically, the 
instructions are to average responses across questions E, J, K, L, M, N, O, P, Q, R, and S 
and their respective sub-questions (0=No or Yes and Not at all; 1=Yes and Slightly; 
2=Yes and Moderately; 3=Yes and Greatly), and then multiply by 100/3. If any 
responses are missing, then the score will be calculated as the average of the non-missing 
responses. The outcome will be computed as the difference in score at 6 months (and 3, 
9, and 12 months) and the score at baseline. If data for an assessment time point are 
missing, the outcome variable will be coded as missing. 
Change from baseline in 
UDI Stress Score at 6 
months (and at 3, 9 and 12 
months) 
Continuous 
The Urogenital Distress Inventory-Stress Score will be computed at baseline and 6 
months (and 3, 9, and 12 months) using the standard scoring algorithm. Specifically, the 
instructions are to average responses across questions D and F and their respective sub-
questions (0=No or Yes and Not at all; 1=Yes and Slightly; 2=Yes and Moderately; 
3=Yes and Greatly), and then multiply by 100/3. If any responses are missing, then the 
score will be calculated as the average of the non-missing responses. The outcome will 
then be computed as the difference in score at 6 months (and 3, 9, and 12 months) and 
the score at baseline.  If data for an assessment time point are missing, the outcome 
variable will be coded as missing.  
Change from baseline in 
UDI Irritative Score at 6 
months (and at 3, 9 and 12 
months) 
Continuous 
The Urogenital Distress Inventory-Irritative Score will be computed at baseline and 6 
months (and 3, 9, and 12 months) using the standard scoring algorithm. Specifically, the 
instructions are to average responses across questions A, B, C, G, H, and I and their 
respective sub-questions (0=No or Yes and Not at all; 1=Yes and Slightly; 2=Yes and 
Moderately; 3=Yes and Greatly), and then multiply by 100/3. If any responses are 
missing, then the score will be calculated as the average of the non-missing responses. 
The outcome will then be computed as the difference in score at 6 months (and 3, 9, and 
12 months) and the score at baseline.  If data for an assessment time point are missing, 
the outcome variable will be coded as missing.  


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Variable 
Type 
Definition 
Exploratory Outcomes 
Normalization of Voiding 
Frequency at 6 (and at 3 and 
12 months) 
Dichotomous 
(Yes/No) 
The total number of daytime and nighttime voids will be taken from the bladder diary 
and summed and then divided by the number of diary days (<=3) to get a voiding 
frequency. The indicator for normalization at 6 months (and 3 and 12 months) will be 
defined for each subject as follows: 
If > 8 voids/24 hours at baseline: 
If > 8 voids/24 hours at time x: No 
If ≤ 8 voids/24 hours at time x: Yes 
If ≤ 8 voids/24 hours at baseline: Missing 
If data for the assessment time point are missing, the normalization indicator will be 
coded as missing. 
The variable is summarized as the percentage of participants with indicator equal to 
“Yes” among all non-missing indicators. 
Improvement of 50% or 
more in Voiding Frequency 
at 6 months (and at 3 and 12 
months) 
Dichotomous 
(Yes/No) 
The total number of daytime and nighttime voids will be taken from the bladder diary 
and summed and divided by the number of diary days (<=3) to get a voiding frequency.  
If there has been at least a 50% reduction in the voiding frequency between baseline and 
the time point, the improvement indicator at 6 months (and 3 and 12 months) will be set 
to “Yes”, otherwise it will be set to “No”.  If data for the assessment time point are 
missing, the improvement indicator will be coded as missing. 
The variable is summarized as the percentage of participants with indicator equal to 
“Yes” among all non-missing indicators. 
Worsening of Voiding 
Frequency at 6 months (and 
at 3 and 12 months) 
Dichotomous 
(Yes/No) 
The total number of daytime and nighttime voids will be taken from the bladder diary 
and summed and divided by the number of diary days (<=3) to get a voiding frequency.  
If there has been an increase of any amount between baseline and the time point, the 
worsening indicator at 6 months (and 3 and 12 months) will be set to “Yes”, otherwise it 
will be set to “No”.  If data for the assessment time point are missing, the improvement 
indicator will be coded as missing. 


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Variable 
Type 
Definition 
The variable is summarized as the percentage of participants with indicator equal to 
“Yes” among all non-missing indicators. 
Change from baseline in 
Urge Incontinence Episodes 
at 6 months (and at 3 and 12 
months) 
Continuous 
The daily frequency of urge incontinence episodes will be taken from the bladder diary. 
The outcome will then be computed as the difference in daily frequency of urge 
incontinence episodes at 6 months (and 3 and 12 months) and the daily frequency of urge 
incontinence episodes at baseline.  If data for the assessment time point are missing, the 
outcome variable will be coded as missing. 
Change from baseline in 
Stress Incontinence Episodes 
at 6 months (and at 3 and 12 
months) 
Continuous 
The daily frequency of stress incontinence episodes will be taken from the bladder diary. 
The outcome will then be computed as the difference in daily frequency of stress 
incontinence episodes at 6 months (and 3 and 12 months) and the daily frequency of 
stress incontinence episodes at baseline.  If data for the assessment time point are 
missing, the outcome variable will be coded as missing. 
Change from baseline in 
Mixed or Don’t Know 
Incontinence Episodes at 6 
months (and at 3 and 12 
months) 
Continuous 
The daily frequency of mixed urge and stress incontinence episodes will be taken from 
the bladder diary. The outcome will then be computed as the difference in daily 
frequency of mixed incontinence (noted on diary as “both stress/urge”) or “don’t know” 
episodes at 6 months (and 3 and 12 months) and the daily frequency of mixed 
incontinence episodes at baseline.  If data for the assessment time point are missing, the 
outcome variable will be coded as missing. 
Change from baseline in 
Total Incontinence Episodes 
at 6 months (and at 3 and 12 
months) 
Continuous 
The daily frequency of total incontinence episodes will be taken from the bladder diary. 
The outcome will then be computed as the difference in daily frequency of total 
incontinence episodes at 6 months (and 3 and 12 months) and the daily frequency of total 
incontinence episodes at baseline.  If data for the assessment time point are missing, the 
outcome variable will be coded as missing. 


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Variable 
Type 
Definition 
Change from baseline in 
Nocturnal voids at 6 months 
(and at 3 and 12 months)  
Continuous 
The daily frequency of total nighttime voids will be taken from the bladder diary. The 
outcome will then be computed as the difference in daily frequency of nighttime voids at 
6 months (and 3 and 12 months) and the daily frequency of nighttime voids at baseline.  
If data for the assessment time point are missing, the outcome variable will be coded as 
missing. 
Change from baseline in 
Diurnal voids at 6 months 
(and at 3 and 12 months) 
Continuous 
The daily frequency of total daytime voids will be taken from the bladder diary. The 
outcome will then be computed as the difference in daily frequency of daytime voids at 6 
months (and 3 and 12 months) and the daily frequency of daytime voids at baseline.  If 
data for the assessment time point are missing, the outcome variable will be coded as 
missing. 
Change from Baseline OAB-
q Symptom Severity Score at 
3, 6, 9, 12 Months 
Continuous 
The OAB-q Symptom Severity Score will be computed at baseline and 6 months (and 3, 
9, and 12 months) using the standard scoring algorithm. Specifically, instructions are to 
sum responses across questions 1 through 8 (1= Not at all, 2=A little bit, 3=Somewhat, 
4=Quite a bit, 5=A great deal, 6=A very great deal), then subtract the minimum possible 
score (8) and divide by the range of possible score (48-8=40), then multiply by 100. If 
less than half of the responses are missing, then the score will be calculated by 
substituting the missing responses with the average of the non-missing responses, 
otherwise no score is calculated. The outcome will then be computed as the difference in 
score at 6 months (and 3, 9, and 12 months) and the score at baseline.  If data for an 
assessment time point are missing, the outcome variable will be coded as missing. 
Change from Baseline OAB-
q HRQL Coping Score at 3, 
6, 9, 12 Months 
Continuous 
The OAB-q HRQL Coping Score will be computed at baseline and 6 months (and 3, 9, 
and 12 months) using the standard scoring algorithm. Specifically, instructions are to 
sum responses across questions 9, 11, 16, 21, 22, 26, 32, and 33 (1= None of the time, 
2=A little bit of the time, 3=Some of the time, 4=A good bit of the time, 5=Most of the 
time, 6=All of the time), then subtract from the maximum possible score (48) and divide 
by the range of possible score (48-8=40), then multiply by 100. If less than half of the 
responses are missing, then the score will be calculated by substituting the missing 
responses with the average of the non-missing responses, otherwise no score is 
calculated. The outcome will then be computed as the difference in score at 6 months 


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Variable 
Type 
Definition 
(and 3, 9, and 12 months) and the score at baseline. If data for an assessment time point 
are missing, the outcome variable will be coded as missing. 
Change from Baseline OAB-
q HRQL Concern Score at 3, 
6, 9, 12 Months 
Continuous 
The OAB-q HRQL Concern Score will be computed at baseline and 6 months (and 3, 9, 
and 12 months) using the standard scoring algorithm. Specifically, instructions are to 
sum responses across questions 12, 13, 14, 19, 23, 25, and 29 (1= None of the time, 2=A 
little bit of the time, 3=Some of the time, 4=A good bit of the time, 5=Most of the time, 
6=All of the time), then subtract from the maximum possible score (35) and divide by the 
range of possible score (42-7=35), then multiply by 100. If less than half of the responses 
are missing, then the score will be calculated by substituting the missing responses with 
the average of the non-missing responses, otherwise no score is calculated. The outcome 
will then be computed as the difference in score at 6 months (and 3, 9, and 12 months) 
and the score at baseline.  If data for an assessment time point are missing, the outcome 
variable will be coded as missing. 
Change from Baseline OAB-
q HRQL Sleep Score at 3, 6, 
9, 12 Months 
Continuous 
The OAB-q HRQL Sleep Score will be computed at baseline and 6 months (and 3, 9, and 
12 months) using the standard scoring algorithm. Specifically, instructions are to sum 
responses across questions 10, 15, 17, 24, and 30 (1= None of the time, 2=A little bit of 
the time, 3=Some of the time, 4=A good bit of the time, 5=Most of the time, 6=All of the 
time), then subtract from the maximum possible score (30) and divide by the range of 
possible score (30-5=25), then multiply by 100. If less than half of the responses are 
missing, then the score will be calculated by substituting the missing responses with the 
average of the non-missing responses, otherwise no score is calculated. The outcome will 
then be computed as the difference in score at 6 months (and 3, 9, and 12 months) and 
the score at baseline.  If data for an assessment time point are missing, the outcome 
variable will be coded as missing. 
Change from Baseline OAB-
q HRQL Social Score at 3, 6, 
9, 12 Months 
Continuous 
The OAB-q HRQL Social Score will be computed at baseline and 6 months (and 3, 9, 
and 12 months) using the standard scoring algorithm. Specifically, instructions are to 
sum responses across questions 18, 20, 27, 28, and 31 (1= None of the time, 2=A little bit 
of the time, 3=Some of the time, 4=A good bit of the time, 5=Most of the time, 6=All of 


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Variable 
Type 
Definition 
the time), then subtract from the maximum possible score (30) and divide by the range of 
possible score (30-5=25), then multiply by 100. If less than half of the responses are 
missing, then the score will be calculated by substituting the missing responses with the 
average of the non-missing responses, otherwise no score is calculated. The outcome will 
then be computed as the difference in score at 6 months (and 3, 9, and 12 months) and 
the score at baseline.  If data for an assessment time point are missing, the outcome 
variable will be coded as missing. 
Change from Baseline OAB-
q HRQL Total Score at 3, 6, 
9, 12 Months 
 
The OAB-q HRQL Total Score will be computed at baseline and 6 months (and 3, 9, and 
12 months) using the standard scoring algorithm. Specifically, instructions are to sum the 
OAB-q HRQL Coping, Concern, Sleep, and Social prior to subtracting from the 
respective maximum possible scores, then subtract from the maximum possible sum 
score (150) and divide by the range of possible scores ((18+42+30+10=150)-
(8+7+5+5=25)=125), then multiply by 100.  The outcome will then be computed as the 
difference in score at 6 months (and 3, 9, and 12 months) and the score at baseline. If any 
of the listed subscales are missing, the Total score will also be set to missing. If data for 
an assessment time point are missing, the outcome variable will be coded as missing. 
OAB-SAT-q Satisfaction 
Score at 3, 6, 9, 12 Months 
Continuous 
NOTE: The scoring manual for the OAB-SAT-q states that higher scores should 
correspond to better outcomes and details that final composite scores for each dimension 
should be obtained by subtracting raw scores from the highest possible score and 
dividing by range. However, based on the direction of score for individual responses, this 
derivation would result in lower scores corresponding with better outcomes. We have 
adjusted the scoring algorithm instead to be: 100*(raw score – lowest possible 
score)/score range. This calculation results in higher scores corresponding to better 
outcomes and an overall scale of 0-100. 
 
The OAB-SAT-q Satisfaction Score will be computed at 6 months (and 3, 9, and 12 
months) using the standard scoring algorithm. Specifically, instructions are to sum 
responses across questions 1, 2, and 3 (1=Extremely Dissatisfied, …, 6=Extremely 
Satisfied), then subtract the lowest possible score (3) from the raw score and divide by 
the range of possible scores (18-3=15), then multiply by 100.  If less than half of the 


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Variable 
Type 
Definition 
responses are missing, then the score will be calculated by substituting the missing 
responses with the average of the non-missing responses, otherwise no score is 
calculated.  If data for an assessment time point are missing, the outcome variable will be 
coded as missing. 
OAB-SAT-q Side Effects 
Score at 3, 6, 9, 12 Months 
Continuous 
NOTE: The scoring manual for the OAB-SAT-q states that higher scores should 
correspond to better outcomes and details that final composite scores for each dimension 
should be obtained by subtracting raw scores from the highest possible score and 
dividing by range. However, based on the direction of score for individual responses, this 
derivation would result in lower scores corresponding with better outcomes. We have 
adjusted the scoring algorithm instead to be: 100*(raw score – lowest possible 
score)/score range. This calculation results in higher scores corresponding to better 
outcomes and an overall scale of 0-100. 
 
The OAB-SAT-q Side Effects Score will be computed at 6 months (and 3, 9, and 12 
months) using the standard scoring algorithm. Specifically, if the response to question 5 
is Never then the score is 100, regardless of the responses to questions 6 and 7.  If the 
response to question 5 is not Never, then sum the responses across questions 5 (reverse 
coded: 1=All of the time, …, 5=A little of the time), 6 (1=Extremely bothersome, …, 
5=Not at all bothersome), and 7 (1=A great deal, …, 5=Not at all), then subtract the 
lowest possible score (3) from the raw score and divide by the range of possible scores 
(15-3=12), then multiply by 100.  If less than half of the responses are missing, then the 
score will be calculated by substituting the missing responses with the average of the 
non-missing responses, otherwise no score is calculated.  If data for an assessment time 
point are missing, the outcome variable will be coded as missing. 
OAB-SAQ-q Endorsement 
Score at 3, 6, 9, 12 Months 
Continuous 
NOTE: The scoring manual for the OAB-SAT-q states that higher scores should 
correspond to better outcomes and details that final composite scores for each dimension 
should be obtained by subtracting raw scores from the highest possible score and 
dividing by range. However, based on the direction of score for individual responses, this 
derivation would result in lower scores corresponding with better outcomes. We have 
adjusted the scoring algorithm instead to be: 100*(raw score – lowest possible 


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Variable 
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Definition 
score)/score range. This calculation results in higher scores corresponding to better 
outcomes and an overall scale of 0-100. 
 
The OAB-SAT-q Endorsement Score will be computed at 6 months (and 3, 9, and 12 
months) using the standard scoring algorithm. Specifically, instructions are to sum 
responses across questions 9 (1=Definitely would not use the same treatment again, …, 
4=Definitely would use the same treatment again), 10 (1=Definitely would not 
recommend, …, 4=Definitely would recommend), and 11 (1=Extremely Dissatisfied, …, 
6=Extremely Satisfied), then subtract the lowest possible score (3) and divide by the 
range of possible scores (14-3=11), then multiply by 100.  If less than half of the 
responses are missing, then the score will be calculated by substituting the missing 
responses with the average of the non-missing responses, otherwise no score is 
calculated.  If data for an assessment time point are missing, the outcome variable will be 
coded as missing. 
OAB-SAT-q Convenience 
Score at 3, 6, 9, 12 Months 
Continuous 
NOTE: The scoring manual for the OAB-SAT-q states that higher scores should 
correspond to better outcomes and details that final composite scores for each dimension 
should be obtained by subtracting raw scores from the highest possible score and 
dividing by range. However, based on the direction of score for individual responses, this 
derivation would result in lower scores corresponding with better outcomes. We have 
adjusted the scoring algorithm instead to be: 100*(raw score – lowest possible 
score)/score range. This calculation results in higher scores corresponding to better 
outcomes and an overall scale of 0-100. 
 
The OAB-SAT-q Convenience Score will be computed at 6 months (and 3, 9, and 12 
months) using the standard scoring algorithm. Specifically, instructions are to use the 
response to question 4 (1=Extremely Inconvenient, …, 6=Extremely Convenient), then 
subtract the lowest possible score (1) and divide by the range of possible scores (6-1=5), 
then multiply by 100.  If the response to question 4 is missing, then no score is 
calculated.  If data for an assessment time point are missing, the outcome variable will be 
coded as missing. 


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Variable 
Type 
Definition 
OAB-SAT-q Preference 
Indicator at 3, 6, 9, 12 
Months 
Continuous 
The OAB-SAT-q Preference Score will be computed at 6 months (and 3, 9, and 12 
months) using the standard scoring algorithm. Specifically, the indicator is set to 1 if the 
response to question 8 is either “Slight preference for the treatment I am receiving now” 
or “Definitely prefer the treatment I am receiving now”, otherwise it is set to 0.  If the 
response to question 8 is missing or the response is “Never been treated before for 
overactive bladder”, then the indicator is set to missing. If data for an assessment time 
point are missing, the outcome variable will be coded as missing. 
 
The score is calculated as the percentage of participants with Indicator=1 among all non-
missing Indicators. 
Change from Baseline IIQ 
Physical Activity Score at 3, 
6, 9, 12 Months 
Continuous 
The Incontinence Impact Questionnaire-Physical Activity Score will be computed at 
baseline and 6 months (and 3, 9, and 12 months) using the standard scoring algorithm. 
Specifically, instructions are to average responses across questions A, B, C, D, E, and U 
(0=Not at all, 1=Slightly, 2=Moderately, 3=Greatly), and then multiply by 100/3. If any 
responses are missing, then the score will be calculated as the average of the non-missing 
responses. The outcome will then be computed as the difference in score at 6 months 
(and 3, 9, and 12 months) and the score at baseline.  If data for an assessment time point 
are missing, the outcome variable will be coded as missing. 
Change from Baseline IIQ 
Travel Score at 3, 6, 9, 12 
Months 
Continuous 
The Incontinence Impact Questionnaire-Travel Score will be computed at baseline and 6 
months (and 3, 9, and 12 months) using the standard scoring algorithm. Specifically, 
instructions are to average responses across questions F, G, H, I, J, and M (0=Not at all, 
1=Slightly, 2=Moderately, 3=Greatly), and then multiply by 100/3. If any responses are 
missing, then the score will be calculated as the average of the non-missing responses. 
The outcome will then be computed as the difference in score at 6 months (and 3, 9, and 
12 months) and the score at baseline.  If data for an assessment time point are missing, 
the outcome variable will be coded as missing. 


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Variable 
Type 
Definition 
Change from Baseline IIQ 
Social Relationships Score at 
3, 6, 9, 12 Months 
Continuous 
The Incontinence Impact Questionnaire-Social Relationships Score will be computed at 
baseline and 6 months (and 3, 9, and 12 months) using the standard scoring algorithm. 
Specifically, instructions are to average responses across questions K, L, N, O, P, Q, R, 
S, W, and X (0=Not at all, 1=Slightly, 2=Moderately, 3=Greatly), and then multiply by 
100/3. If any responses are missing, then the score will be calculated as the average of 
the non-missing responses. The outcome will then be computed as the difference in score 
at 6 months (and 3, 9, and 12 months) and the score at baseline.  If data for an assessment 
time point are missing, the outcome variable will be coded as missing. 
Change from Baseline IIQ 
Emotional Health Score at 3, 
6, 9, 12 Months 
Continuous 
The Incontinence Impact Questionnaire-Emotional Health Score will be computed at 
baseline and 6 months (and 3, 9, and 12 months) using the standard scoring algorithm. 
Specifically, instructions are to average responses across questions T, V, Y, Z, AA, BB, 
CC, and DD, (0=Not at all, 1=Slightly, 2=Moderately, 3=Greatly), and then multiply by 
100/3. If any responses are missing, then the score will be calculated as the average of 
the non-missing responses. The outcome will then be computed as the difference in score 
at 6 months (and 3, 9, and 12 months) and the score at baseline.  If data for an assessment 
time point are missing, the outcome variable will be coded as missing. 
Change from Baseline IIQ 
Total Score at 3, 6, 9, 12 
Months 
Continuous 
The Incontinence Impact Questionnaire-Total Score will be computed at baseline and 6 
months (and 3, 9, and 12 months) using the standard scoring algorithm. Specifically, 
instructions are to sum the Physical Activity, Travel, Social Relationships, and Emotional 
Health subscale scores of the IIQ. If any subscale scores are missing, then no Total score 
will be calculated. The outcome will then be computed as the difference in Total score at 
6 months (and 3, 9, and 12 months) and the Total score at baseline.  If data for an 
assessment time point are missing, the outcome variable will be coded as missing. 
Change from Baseline PISQ-
IR not sexually active -
partner related subscale score 
at 3, 6, 9, 12 months 
Continuous 
The PISQ-IR not sexually active – partner related subscale score will be computed at 
baseline and 6 months (and 3, 9, and 12 months) using standard scoring algorithms.  
Specifically, instructions are to sum the scores for questions Q2a, Q2b using reverse 
scores (1=strongly agree, …, 4=strongly disagree). If there is more than 1 missing 
response then a total score is not calculated. To handle missing values, the final score is 
obtained by dividing the sum by the number of items answered. The outcome will then 


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Definition 
be computed as the difference in score at 6 months (and 3, 9, and 12 months) and the 
score at baseline. If data for a time point are missing, the outcome variable will be coded 
as missing. Scores should only be calculated for participants  not sexually active. 
Change from Baseline PISQ-
IR not sexually active – 
condition specific subscale 
score at 3, 6, 9, 12 months  
Continuous 
The PISQ-IR not sexually active – condition specific subscale score will be computed at 
baseline and 6 months (and 3, 9, and 12 months) using standard scoring algorithms.  
Specifically, instructions are to sum the scores for questions Q2c, Q2d, Q2e using reverse 
scores (1=strongly agree, …, 4=strongly disagree). If there is more than 1 missing 
response then a total score is not calculated. To handle missing values, the final score is 
obtained by dividing the sum by the number of items answered. The outcome will then 
be computed as the difference in score at 6 months (and 3, 9, and 12 months) and the 
score at baseline.  If data for a time point are missing, the outcome variable will be coded 
as missing. Scores should only be calculated for participants not sexually active. 
Change from Baseline PISQ-
IR not sexually active – 
global quality subscale score 
at 3, 6, 9, 12 months 
Continuous 
The PISQ-IR not sexually active – global quality subscale score will be computed at 
baseline and 6 months (and 3, 9, and 12 months) using standard scoring algorithms.  
Specifically, instructions are to sum the scores for questions Q4a, Q4b, Q5a, and Q6 
using reverse scores for only Q5a (Q4a and Q4b are Likert scales of 1 to 5; Q5a: 
1=strongly agree, …, 4=strongly disagree; Q6: 1=not at all, …, 4=a lot). If there are more 
than 2 missing responses then a total score is not calculated. To handle missing values, 
the final score is obtained by dividing the sum by the number of items answered. The 
outcome will then be computed as the difference in score at 6 months (and 3, 9, and 12 
months) and the score at baseline.  If data at an assessment time point are missing, the 
outcome variable will be coded as missing. Scores should only be calculated for 
participants that are not sexually active. 
Change from Baseline PISQ-
IR not sexually active – 
condition impact subscale 
score at 3, 6, 9, 12 months 
Continuous 
The PISQ-IR not sexually active – condition subscale score will be computed at baseline 
and 6 months (and 3, 9, and 12 months) using standard scoring algorithms.  Specifically, 
instructions are to sum the scores for questions Q3, Q5b, Q5c using reverse scores for 
Q5b and Q5c (Q3: 1=not at all, …, 4=a lot; Q5b, Q5c: 1=strongly agree, …, 4=strongly 
disagree). If there is more than 1 missing response then a total score is not calculated. To 
handle missing values, the final score is obtained by dividing the sum by the number of 


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Variable 
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Definition 
items answered. The outcome will then be computed as the difference in score at 6 
months (and 3, 9, and 12 months) and the score at baseline.  If data at an assessment time 
point are missing, the outcome variable will be coded as missing. Scores should only be 
calculated for participants that are not sexually active. 
Change from Baseline PISQ-
IR sexually active – arousal, 
orgasm subscale score 
change from baseline at 3, 6, 
9, 12 months 
Continuous 
The PISQ-IR sexually active – arousal, orgasm subscale score will be computed at 
baseline and 6 months (and 3, 9, and 12 months) using standard scoring algorithms.  
Specifically, instructions are to sum the scores for questions Q7, Q8a, Q10, and Q11 
using reverse scores for Q11 (Q7, Q8a, Q11: 1=never, …, 5=[almost] always; Q10: 
1=much less intense, …, 5=much more intense). If there are more than 2 missing 
responses then a total score is not calculated. To handle missing values, the final score is 
obtained by dividing the sum by the number of items answered. The outcome will then 
be computed as the difference in score at 6 months (and 3, 9, and 12 months) and the 
score at baseline.  If data at an assessment time point are missing, the outcome variable 
will be coded as missing. Scores should only be calculated for participants that are 
sexually active. 
Change from Baseline PISQ-
IR sexually active – 
condition specific subscale 
score at 3, 6, 9, 12 months 
Continuous 
The PISQ-IR sexually active – condition specific subscale score will be computed at 
baseline and 6 months (and 3, 9, and 12 months) using standard scoring algorithms.  
Specifically, instructions are to sum the scores for questions Q8b, Q8c, Q9 using reverse 
scores for all (Q8b, Q8c, Q9: 1=never, …, 5=[almost] always). If there is more than 1 
missing response then a total score is not calculated. To handle missing values, the final 
score is obtained by dividing the sum by the number of items answered. The outcome 
will then be computed as the difference in score at 6 months (and 3, 9, and 12 months) 
and the score at baseline.  If data at an assessment time point are missing, the outcome 
variable will be coded as missing. Scores should only be calculated for participants that 
are sexually active. 
Change from Baseline PISQ-
IR sexually active – partner 
related subscale score at 3, 6, 
9, 12 months 
Continuous 
The PISQ-IR sexually active – partner related subscale score will be computed at 
baseline and 6 months (and 3, 9, and 12 months) using standard scoring algorithms.  
Specifically, instructions are to sum the scores for questions Q13, Q14a, Q14b using 
reverse scores for Q14a and Q14b (Q13: 1=all of the time, …, 4=hardly ever/rarely; 


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Variable 
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Definition 
Q14a, Q14b: 1=very positive, …, 4=very negative). If there is more than 1 missing 
response then a total score is not calculated. To handle missing values, the final score is 
obtained by dividing the sum by the number of items answered. The outcome will then 
be computed as the difference in score at 6 months (and 3, 9, and 12 months) and the 
score at baseline.  If data at an assessment time point are missing, the outcome variable 
will be coded as missing. Scores should only be calculated for participants that are 
sexually active and have a sexual partner. 
Change from Baseline PISQ-
IR sexually active – desire 
subscale score at 3, 6, 9, 12 
months 
Continuous 
The PISQ-IR sexually active – desire subscale score will be computed at baseline and 6 
months (and 3, 9, and 12 months) using standard scoring algorithms.  Specifically, 
instructions are to sum the scores for questions Q15, Q16, Q17 using reverse scores for 
Q16 and Q17 (Q15: 1=never, …, 5=always; Q16: 1=daily, …,5=never; Q17: 1=very 
high, …, 5=very low or none at all). If there is more than 1 missing response then a total 
score is not calculated. To handle missing values, the final score is obtained by dividing 
the sum by the number of items answered. The outcome will then be computed as the 
difference in score at 6 months (and 3, 9, and 12 months) and the score at baseline.  If 
data at an assessment time point are missing, the outcome variable will be coded as 
missing. Scores should only be calculated for participants that are sexually active. 
Change from Baseline PISQ-
IR sexually active – 
condition impact subscale 
score at 3, 6, 9, 12 months 
Continuous 
The PISQ-IR sexually active – condition impact subscale score will be computed at 
baseline and 6 months (and 3, 9, and 12 months) using standard scoring algorithms.  
Specifically, instructions are to sum the scores for questions Q18, Q20b-d using reverse 
scores for Q18 (Q18: 1=not at all, …, 4=a lot; Q20b-d: 1=strongly agree, …, 4=strongly 
disagree). If there are more than 2 missing responses then a total score is not calculated. 
To handle missing values, the final score is obtained by dividing the sum by the number 
of items answered. The outcome will then be computed as the difference in score at 6 
months (and 3, 9, and 12 months) and the score at baseline.  If data at an assessment time 
point are missing, the outcome variable will be coded as missing. Scores should only be 
calculated for participants that are sexually active. 


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Variable 
Type 
Definition 
Change from Baseline PISQ-
IR sexually active – global 
quality rating subscale score 
at 3, 6, 9 12 months 
Continuous 
The PISQ-IR sexually active – global quality rating subscale score will be computed at 
baseline and 6 months (and 3, 9, and 12 months) using standard scoring algorithms.  
Specifically, instructions are to sum the scores for questions Q19a-Q19c, Q20a using 
reverse scores for Q19a-Q19c (Q19a: 1=satisfied, …, 5=dissatisfied; Q19b: 1=adequate, 
…, 5=inadequate; Q19c: 1=confident, …, 5=not confident; Q20a: 1=strongly agree, …, 
4=strongly disagree). If there are more than 2 missing responses then a total score is not 
calculated. To handle missing values, the final score is obtained by dividing the sum by 
the number of items answered. The outcome will then be computed as the difference in 
score at 6 months (and 3, 9, and 12 months) and the score at baseline.  If data at an 
assessment time point are missing, the outcome variable will be coded as missing. Scores 
should only be calculated for participants that are sexually active. 
Change from Baseline PISQ-
IR sexually active – average  
score at 3, 6, 9 12 months 
Continuous 
The PISQ-IR sexually active – average score will be computed at baseline and 6 months 
(and 3, 9, and 12 months) using standard scoring algorithms. For participants that have a 
sexual partner (Q12 = 1), instructions are to sum the scores for questions Q7, Q8a-8c, 
Q9, Q10, Q11, Q13, Q14a-b, Q15, Q16, Q17, Q18, Q19a-c, Q20a-d using reverse scores 
for Q8b-c, Q9, Q11, Q14a-b, Q16, Q17, Q18, Q19a-c. If there are more than 10 missing 
responses, then a total score is not calculated. To handle missing values, the final score is 
obtained by dividing the sum by the number of items answered. Scores should only be 
calculated for participants that are sexually active. 
 
For participants that do not have a sexual partner (Q12 = 2), instructions are to sum the 
scores for questions Q7, Q8a-8c, Q9, Q10, Q11, Q15, Q16, Q17, Q18, Q19a-c, Q20a-d 
using reverse scores for Q8b-c, Q9, Q11, Q16, Q17, Q18, Q19a-c. If there are more than 
9 missing responses, then a total score is not calculated. To handle missing values, the 
final score is obtained by dividing the sum by the number of items answered. Scores 
should only be calculated for participants that are sexually active. 
Change from Baseline EQ-
5D Total Score at 3, 6, 9,12 
Months 
Continuous 
The EQ-5D Total Score will be computed at baseline and 6 months (and 3, 9, and 12 
months) using the algorithm obtained from 
https://archive.ahrq.gov/professionals/clinicians-
providers/resources/rice/EQ5Dscore.html. The outcome will then be computed as the 


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Variable 
Type 
Definition 
difference in Total score at 6 months (and 3, 9, and 12 months) and the Total score at 
baseline. If data for an assessment time point are missing, the outcome variable will be 
coded as missing. 
Change from Baseline EQ-
5D Visual Analogue Scale 
(VAS) at 3, 6, 9, 12 Months 
Continuous 
The EQ-5D VAS is the response to a single question from the EQ-5D. The outcome will 
then be computed as the difference in EQ-5D VAS at 6 months (and 3, 9, and 12 months) 
and the EQ-5D VAS at baseline. If data for the assessment time point are missing, the 
outcome variable will be coded as missing. 
Change from Baseline SF-36 
Physical Component 
Summary at 3, 6, 9, 12 
Months 
Continuous 
The SF-36 Physical Component Summary score will be computed at baseline and 6 
months (and 3, 9, and 12 months) using the standard scoring algorithm. Specifically, 
instructions are to standardize the 8 SF-36 subscales scores using a set of means and 
standard deviations from Ware et al. 
(https://www.researchgate.net/publication/292390260_SF-
36_Physical_and_Mental_Health_Summary_Scales_a_User%27s_Manual), then 
multiply each subscale z-score by its respective physical/mental factor score coefficient, 
and sum the result from each subscale for the aggregate summary score.  
 
Taft et al. have conveniently created a table of reference values for scoring the SF-36 
Physical Component Summary 
(https://www.researchgate.net/publication/11595008_Do_SF-
36_Summary_Component_Scores_Accurately_Summarize_Subscale_Scores):  
 


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Variable 
Type 
Definition 
Change from Baseline SF-36 
Mental Component 
Summary at 3, 6, 9, 12 
Months 
Continuous 
The SF-36 Mental Component Summary score will be computed at baseline and 6 
months (and 3, 9, and 12 months) using the standard scoring algorithm. Specifically, 
instructions are to standardize the 8 SF-36 subscales scores using a set of means and 
standard deviations from Ware et al. 
(https://www.researchgate.net/publication/292390260_SF-
36_Physical_and_Mental_Health_Summary_Scales_a_User%27s_Manual), then 
multiply each subscale z-score by its respective physical/mental factor score coefficient, 
and sum the result from each subscale for the aggregate summary score.  
 
Taft et al. have conveniently created a table of reference values for scoring the SF-36 
Physical Component Summary 
(https://www.researchgate.net/publication/11595008_Do_SF-
36_Summary_Component_Scores_Accurately_Summarize_Subscale_Scores):  
 
Change from Baseline SF-36 
Physical Functioning 
subscale score at 3, 6, 9, 12 
Months 
 
 
Continuous 
The SF-36 Physical Functioning subscale score will be computed at baseline and 6 
months (and 3, 9, and 12 months) using the standard scoring algorithm. Specifically, 
instructions are to sum responses across questions 3 through 12 (1 = Yes, limited a lot, 
…, 3 = No, not limited at all), then subtract the minimum possible score (10) and divide 
by the range of possible score (30–10=20), then multiply by 100. If less than half of the 
responses are missing, then the score will be calculated by substituting the missing 
responses with the average of the non-missing responses, otherwise no score is 
calculated. The outcome will then be computed as the difference in score at 6 months 


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Variable 
Type 
Definition 
(and 3, 9, and 12 months) and the score at baseline. If data at an assessment time point 
are missing, the outcome variable will be coded as missing. 
Change from Baseline SF-36 
Role-Physical subscale score 
at 3, 6, 9, 12 Months 
Continuous  
The SF-36 Role-Physical subscale score will be computed at baseline and 6 months (and 
3, 9, and 12 months) using the standard scoring algorithm. Specifically, instructions are 
to sum responses across questions 13 through 16 (1 = Yes, 2 = No), then subtract the 
minimum possible score (4) and divide by the range of possible score (8–4=4), then 
multiply by 100. If less than half of the responses are missing, then the score will be 
calculated by substituting the missing responses with the average of the non-missing 
responses, otherwise no score is calculated. The outcome will then be computed as the 
difference in score at 6 months (and 3, 9, and 12 months) and the score at baseline. If 
data at an assessment time point are missing, the outcome variable will be coded as 
missing. 
Change from Baseline SF-36 
Bodily Pain subscale score at 
3, 6, 9, 12 Months 
Continuous 
The SF-36 Bodily Pain subscale score will be computed at baseline and 6 months (and 3, 
9, and 12 months) using the standard scoring algorithm. Specifically, instructions are to 
sum responses across questions 21 and 22 with specific recoded values (Q21: 1 = None, 
…, 6 = Very severe; Q22: 1 = Not at all, …, 5 = Extremely), then subtract the minimum 
possible score (2) and divide by the range of possible score (12-2=10), then multiply by 
100. If less than half of the responses are missing, then the score will be calculated by 
substituting the missing responses with the average of the non-missing responses, 
otherwise no score is calculated. The outcome will then be computed as the difference in 
score at 6 months (and 3, 9, and 12 months) and the score at baseline. If data at an 
assessment time point are missing, the outcome variable will be coded as missing. 
Change from Baseline SF-36 
General Health Perception 
subscale score at 3, 6, 9, 12 
Months 
Continuous 
The SF-36 General Health Perception subscale score will be computed at baseline and 6 
months (and 3, 9, and 12 months) using the standard scoring algorithm. Specifically, 
instructions are to sum responses across questions 1 and 33 through 36 with specific 
recode values for Q1 and using reverse scores for Q34 and Q36 (Q1: 1 = Excellent, …, 5 
= Poor; Q33 – Q36: 1 = Definitely True, …, 5 = Definitely False), then subtract the 
minimum possible score (5) and divide by the range of possible score (25-5=20), then 
multiply by 100. If less than half of the responses are missing, then the score will be 


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Variable 
Type 
Definition 
calculated by substituting the missing responses with the average of the non-missing 
responses, otherwise no score is calculated. The outcome will then be computed as the 
difference in score at 6 months (and 3, 9, and 12 months) and the score at baseline. If 
data at an assessment time point are missing, the outcome variable will be coded as 
missing. 
Change from Baseline SF-36 
Vitality subscale score at 3, 
6, 9, 12 Months 
Continuous 
The SF-36 Vitality subscale score will be computed at baseline and 6 months (and 3, 9, 
and 12 months) using the standard scoring algorithm. Specifically, instructions are to 
sum responses across questions 23, 27, 29, and 31 using reverse scores for Q23 and Q27 
(1 = All of the time, …, 6 = None of the time), then subtract the minimum possible score 
(4) and divide by the range of possible score (24-4=20), then multiply by 100. If less than 
half of the responses are missing, then the score will be calculated by substituting the 
missing responses with the average of the non-missing responses, otherwise no score is 
calculated. The outcome will then be computed as the difference in score at 6 months 
(and 3, 9, and 12 months) and the score at baseline. If data at an assessment time point 
are missing, the outcome variable will be coded as missing. 
Change from Baseline SF-36 
Social Functioning subscale 
score at 3, 6, 9, 12 Months 
Continuous 
The SF-36 Social Functioning subscale score will be computed at baseline and 6 months 
(and 3, 9, and 12 months) using the standard scoring algorithm. Specifically, instructions 
are to sum responses across questions 20 and 32 using reverse scores for Q20 (Q20: 1 = 
Not at all, …, 5 = Extremely; Q32: 1 = All of the time, …, 5 = None of the time), then 
subtract the minimum possible score (2) and divide by the range of possible score (10-
2=8), then multiply by 100. If less than half of the responses are missing, then the score 
will be calculated by substituting the missing responses with the average of the non-
missing responses, otherwise no score is calculated. The outcome will then be computed 
as the difference in score at 6 months (and 3, 9, and 12 months) and the score at baseline. 
If data at an assessment time point are missing, the outcome variable will be coded as 
missing. 
Change from Baseline SF-36 
Role-Emotional subscale 
score at 3, 6, 9, 12 Months 
Continuous 
The SF-36 Role-Emotional subscale score will be computed at baseline and 6 months 
(and 3, 9, and 12 months) using the standard scoring algorithm. Specifically, instructions 
are to sum responses across questions 17 through 19 (1 = Yes, 2 = No), then subtract the 


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Variable 
Type 
Definition 
minimum possible score (3) and divide by the range of possible score (6-3=3), then 
multiply by 100. If less than half of the responses are missing, then the score will be 
calculated by substituting the missing responses with the average of the non-missing 
responses, otherwise no score is calculated. The outcome will then be computed as the 
difference in score at 6 months (and 3, 9, and 12 months) and the score at baseline. If 
data at an assessment time point are missing, the outcome variable will be coded as 
missing. 
Change from Baseline SF-36 
Mental Health subscale score 
at 3, 6, 9, 12 Months 
Continuous 
The SF-36 Mental Health or Emotional Wellbeing subscale score will be computed at 
baseline and 6 months (and 3, 9, and 12 months) using the standard scoring algorithm. 
Specifically, instructions are to sum responses across questions 24 through 26, 28, and 30 
using reverse scores for Q26 and Q30 (1 = All of the time, …, 6 = None of the time), 
then subtract the minimum possible score (5) and divide by the range of possible score 
(30-5=25), then multiply by 100. If less than half of the responses are missing, then the 
score will be calculated by substituting the missing responses with the average of the 
non-missing responses, otherwise no score is calculated. The outcome will then be 
computed as the difference in score at 6 months (and 3, 9, and 12 months) and the score 
at baseline. If data at an assessment time point are missing, the outcome variable will be 
coded as missing. 
Change from Baseline SF-
6D at 3, 6, 9, 12 Months 
Continuous 
The SF-6D will be computed at baseline and 6 months (and 3, 9, and 12 months). The 
SF-6D is a classification for describing health derived from a selection of SF-36 items, 
composed of six multi-level dimensions. The instrument is managed by QualityMetric 
(https://www.qualitymetric.com/) where the licensed algorithm for the MUSA study was 
obtained. The algorithm comes with a set of preference weights obtained from a sample 
of the general population using the recognized valuation technique of standard gamble. 
The algorithm will generate 6 dimension scores (physical functioning, role limitations, 
social functioning, bodily pain, mental health, & vitality) and a utility value ranging from 
0 – 1 (0=”Dead”, 1=”Full Health”). 


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Variable 
Type 
Definition 
Patient Global Impression of 
Improvement at 3, 6, 9, 12 
months 
Dichotomous 
1 = Improved 
0 = No Improvement 
/Worsened 
The Patient Global Impression of Improvement score will be computed at 6 months (and 
3, 9, and 12 months). Improvement will be defined as a response of “Much better” or 
“Very much better”, any other response will be indicated as no improvement or 
worsened. If data at an assessment time point are missing, the outcome variable will be 
coded as missing. 
Patient Global Impression of 
Severity at 3, 6, 9, 12 months 
Dichotomous 
1 = Normal/Mild 
0 = Moderate/Severe 
 
The Patient Global Impression of Severity score will be computed at baseline and 6 
months (and 3, 9, and 12 months). For defining binary severity of urinary tract condition, 
a scale response of “Normal” or “Mild” will be set to “Normal/Mild”. Scale responses of 
“Moderate” or “Severe” will be set to “Moderate/Severe”. If data at an assessment time 
point are missing, the outcome variable will be coded as missing. 
Patient Global Symptom 
Control at 3, 6, 9, 12 months 
Dichotomous 
1=adequate leakage 
control  
0 = inadequate 
leakage control 
The Patient Global Symptom Control score will be computed at 6 months (and 3, 9, and 
12 months). The statement “My current treatment is giving me adequate control of my 
urine leakage” is scored on a scale from 1 (strongly disagree) to 5 (strongly agree). If the 
response is scored 1, 2, or 3, coded as “inadequate leakage control”. If the response is 
scored 4 or 5, coded as “adequate leakage control”.  
 
A score ≤ 3 is required to meet the criteria for additional Botox injection. 
Had protocol-specified 
additional Botox between 3-
6 months 
Dichotomous 
1=yes 
0=no 
 
 = yes for women who received Botox as the main study treatment and also received the 
additional 2nd allowed Botox treatment prior to 6 months,  
= no otherwise 
 
For participants who received MUS as their main study treatment, this indicator will be 
coded to missing. 
Additional treatment up to 6 
months, and  
 
Dichotomous 
1=yes 
0=no 
The types of additional treatment for SUI and/or OAB will be identified and categorized 
from the Additional Therapy form. 
 


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Variable 
Type 
Definition 
Additional treatment 
between 6 and 12 months 
 
An indicator of additional treatment will be calculated for each subject where subjects 
with additional treatments identified below will be assigned “Yes”, otherwise subjects 
are assigned “No”. The rate of receiving additional treatment is calculated as the 
percentage of participants with indicator =”Yes” among all non-missing indicators. 
 
This includes anyone who had a crossover treatment (MUS to Botox, or Botox to MUS), 
in addition to any other type of UI/OAB treatment or medication. 
 
If a participant is missing the visit required to derive additional treatment timing (6 
month or 12 month), the visit window close date (6 or 12 months from treatment + 30 
days) was used in place of the missing visit date. 
 
Indicators will be created for overall additional treatment and the following individual 
categories: 
 Up to 6 months (up to the day before the 6 months visit): 
      MUS for Botulinum toxin A arm 
      Botulinum toxin A for MUS arm 
 
OAB/UUI medication 
 
Behavioral Therapy 
 
Physical Therapy / Biofeedback 
 
PTNS 
 
Continence pessary / POISE Impressa 
 
Sacral neuromodulation 
       Bulking injections 
 
6-12 months (starting the day of the 6 months visit) 
      Mid-urethral Sling placement 


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Variable 
Type 
Definition 
 
Botulinum toxin A injection 
 
OAB/UUI medication 
 
Behavioral Therapy 
 
Physical Therapy / Biofeedback 
 
PTNS 
 
Continence pessary / POISE Impressa 
 
Sacral neuromodulation 
       Bulking injections 
Safety outcomes 
 
Adverse events are reported for a participant from the date they are randomized to the 
date that they exit the study. There were 9 adverse events that were collected after 
randomization but occurred before treatment. The majority of these were UTIs (n=8), 
with one “Fall” event that is important documentation leading into a subsequent serious 
adverse event. 
Sling Revision or removal at 
any time 
Dichotomous 
1=yes 
0=no 
 
An indicator of sling revision/removal will be calculated for each subject where those 
who have a sling revision/removal listed on the Additional Therapy form will be 
assigned a “Yes”, otherwise subjects are assigned “No”. 
 
At final database lock reviews, one “sling removal” was identified from the Additional 
Therapy form. Adverse events were further reviewed for implemented actions of 
“explant” or “surgical intervention” but yielded no further cases identified. An adverse 
event form was requested to be entered for the single reported removal. 
 
The rate of sling revision is calculated as the percentage of participants with indicator 
equal to “Yes” among all non-missing indicators. 


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Variable 
Type 
Definition 
Sling mesh exposure 
Dichotomous 
1=yes 
0=no 
 
An indicator of sling mesh exposure will be calculated for each subject (yes/no) using the 
MEDRA coded preferred term of reported adverse events. Subjects will be coded to 
“Yes” if they have any adverse event with a MEDRA preferred term of “Medical device 
site erosion”, or if the verbatim adverse event term includes text strings “Mesh”, “Mesh 
exposure”, or “MUS mesh exposure”.  
 
Two cases were identified from adverse event forms at final database lock review. 
Rate of Urinary Tract 
Infection (UTI) Events 
Dichotomous 
1=yes 
0=no 
 
The frequency of acute UTI events will be taken from all adverse event reporting forms 
submitted for a participant. The outcome variable will be coded with a value of “Yes” if 
the participant had any reported acute UTIs over their study duration, identified by 
MEDRA coding preferred term of “Urinary tract infection” and “recurrent” is NOT 
specified by verbatim adverse event term or comments. If no acute UTI events were 
reported for a participant, the outcome variable will be coded with a value of “No”.  
 
Final database lock review took efforts to query sites for participants with questionable 
urine test results and get PI confirmation that all necessary events had been reported.  
Rate of recurrent Urinary 
Tract Infection (UTI) Events 
Dichotomous 
1=yes 
0=no 
 
The frequency of recurrent UTI events will be taken from all adverse event reporting 
forms submitted for a participant. The outcome variable will be coded with a value of 
“Yes” if the participant had any reported recurrent UTIs over their study duration, 
identified by MEDRA coding preferred term of “Urinary tract infection” and “recurrent” 
is specified by verbatim adverse event term or comments. If no recurrent UTI events 
were reported for a participant, the outcome variable will be coded with a value of “No”. 
 
Final database lock review took efforts to query sites for participants with questionable 
urine test results and get PI confirmation that all necessary events had been reported.   
Rate of Urinary Retention 
Events 
 
Dichotomous 
1=yes 
0=no 
The frequency of urinary retention events will be taken from all adverse event reporting 
forms submitted for a participant. The outcome variable will be coded with a value of 
“Yes” if the participant had any reported urinary retention over their study duration, 


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Variable 
Type 
Definition 
 
identified by MEDRA coding preferred term of “Urinary retention”. If no urinary 
retention events were reported for a participant, the outcome variable will be coded with 
a value of “No”.  
 
Final database lock review took efforts to query sites for participants with reported self-
catheterization logs or questionable post void residual results (>200mL, aside from visits 
immediately post-surgery) and get PI confirmation that all necessary events had been 
reported.  
Rate of AE of “residual 
Urine Volume” 
 
Dichotomous 
1=yes 
0=no 
The frequency of residual urine volume events will be taken from all adverse event 
reporting forms submitted for a participant. The outcome variable will be coded with a 
value of “Yes” if the participant had any reported residual urine events over their study 
duration, identified by MEDRA coding preferred term of “Residual urine volume”. If no 
residual urine volume events were reported for a participant, the outcome variable will be 
coded with a value of “No”.  
 
Final database lock review took efforts to query existing adverse events with terms such 
as “incomplete bladder emptying”, “sensation of incomplete bladder emptying” for any 
post void residual assessments completed around the time of the event. Details from 
query responses helped with MEDRA coding the relevant level of severity (“Urinary 
Retention” vs. “Residual urine volume”) accurately.  
Complications after study 
intervention  
And  
Complication after cross-
over study intervention  
 
Bladder Injury 
Ureteral Injury 
Dichotomous 
1=yes 
0=no 
The frequency of complications after study intervention will be taken from Surgeon’s 
Report forms submitted for a participant, for both the main study treatment and allowed 
Botox reinjection if applicable. The outcome variable for each specific complication will 
be coded with a value of “Yes” if ever reported over their study duration, otherwise it 
will be coded with a value of “No”. If a participant experienced any complication after 
main study interventions, the composite indicator will be coded with a value of “Yes”, 
otherwise coded to “No”. 
The frequency of complications after cross-over study intervention will be taken from 
any Off Protocol Surgeon’s Report forms submitted for a participant The outcome 


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Variable 
Type 
Definition 
Urethral Injury 
Vaginotomy 
variable for each specific complication will be coded with a value of “Yes” if ever 
reported over their study duration, otherwise it will be coded with a value of “No”. If a 
participant experienced any complication after a crossover study intervention, the 
composite indicator will be coded with a value of “Yes”, otherwise coded to “No”. 
 
Note that all reported intervention complications are expected to have an accompanying 
adverse event form entered but may not be recorded as an adverse event to reduce 
database redundancy.  
Any catheter placement or 
intermittent self-
catheterization 2 or more 
weeks post-procedure 
 
 
Dichotomous 
1=yes 
0=no 
 
The frequency of catheter placement or intermittent self-catheterization will be identified 
from self-catheterization (CISC) logs submitted for a participant. Additionally, adverse 
events that occurred 2 or more weeks after procedure reported with a “Catheter 
placement” action or have any text detailing self-catheterization in the comments field 
will also identify these cases. The outcome variable will be coded with a value of “Yes” 
if the participant has any reported CISC log or adverse events detailing self-
catheterization, otherwise it will be coded with a value of “No”.  
 
Note that the Surgeon’s Report form completed at time of study intervention contains 
questions regarding self-catheterization, but this outcome is specifically limited to timing 
greater than 2 weeks from study procedure.  
 
Final database lock review took efforts to query sites for participants with reported self-
catheterization logs or questionable post void residual results (>200mL, aside from visits 
immediately post-surgery) and get PI confirmation of self-catheterization in relevant 
adverse event comments.  
Any AE that is unexpected 
and Related to intervention 
Dichotomous 
1=yes 
0=no 
Participants will be coded to “Yes” if any adverse event was reported over their study 
duration that had the following fields indicated on the form: 
Expected = “No” 
Relationship = “Related” 
Otherwise, the participant will be coded to “No”.  


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Variable 
Type 
Definition 
Any Hospital admission or 
return to OR related to 
intervention 
Dichotomous 
1=yes 
0=no 
The frequency of hospital readmissions / returns to the operating room related to study 
intervention will be identified by searching for applicable terms and comments submitted 
across all adverse events for a participant. If the participant has an event indicates 
hospital readmission or a return to the operating room and is reported as “Related”, this 
indicator will be coded to “Yes”, otherwise it will be coded to “No”. 
At final database lock review, there were no adverse events reported as “related” that 
indicated a hospital readmission or return to the operating room. 
Pelvic Pain 
 
Dichotomous 
1=yes 
0=no 
The frequency of pelvic pain events will be taken from all adverse event reporting forms 
submitted for a participant. The outcome variable will be coded with a value of “Yes” if 
the participant had any reported pelvic pain over their study duration, identified by 
MEDRA coding preferred term of “Pelvic pain”. If no pelvic pain events were reported 
for a participant, the outcome variable will be coded with a value of “No”.  
Dyspareunia 
Dichotomous 
1=yes 
0=no 
The frequency of dyspareunia events will be taken from all adverse event reporting forms 
submitted for a participant. The outcome variable will be coded with a value of “Yes” if 
the participant had any reported dyspareunia over their study duration, identified by 
MEDRA coding preferred term of “Dyspareunia”. If no dyspareunia events were 
reported for a participant, the outcome variable will be coded with a value of “No”. 
Levator Syndrome   
Dichotomous 
1=yes 
0=no 
The frequency of levator spasm events will be taken from all adverse event reporting 
forms submitted for a participant. The outcome variable will be coded with a value of 
“Yes” if the participant had any reported levator spasms over their study duration, 
identified by MEDRA coding preferred term of “Levator syndrome”. If no levator spasm 
events were reported for a participant, the outcome variable will be coded with a value of 
“No”. 
Self-report New/worsening 
abdominal/genital pain (UDI 
item N) 
Dichotomous 
1=yes 
0=no 
Self-report of new or worsening abdominal/genital pain is captured in the UDI form item 
N at baseline and 6 months (and 3, 9, and 12 months). The outcome variable will be 
coded with a value of “Yes” if any post-baseline UDI assessment reported a worse bother 
than at baseline (ordered categories are “No”, “Yes” with bother not specified / “Not at 
all”, “Yes” and “Slightly”, “Yes” and “Moderately, “Yes” and “Greatly”). For 


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Variable 
Type 
Definition 
participants that did not have any post-baseline visits, the outcome variable will be set to 
missing. 
 
UDI item N: 
Do you experience pain in the lower abdominal or genital area? 
 
 
 Yes 
 No (Skip to O.) 
 
If yes, how much does it bother you? 
 
 
 Not at all  
 Slightly 
 Moderately  
 Greatly 
Self-report New/worsening 
dyspareunia (PISQ item C5) 
Dichotomous 
1=yes 
0=no 
Self-report of new or worsening dyspareunia is captured on the PISQ-IR form item C5 at 
baseline and 6 months (and 3, 9, and 12 months). The outcome variable will be coded 
with a value of “Yes” if any post-baseline PISQ-IR assessment reported a worse 
frequency of pain than at baseline (ordered categories are “Never”, “Rarely”, 
“Sometimes”, “Usually”, “Always”). For participants that did not have any post-baseline 
visits or did not indicate they were sexually active at baseline, the outcome variable will 
be set to missing.  
 
PISQ item C5: (completed only for sexually active) 
How often do you feel pain during sexual intercourse? (If you don’t have intercourse 
check this box  and skip to the next item.)  
1    Never  
2    Rarely  
3    Sometimes  
4    Usually  
5    Always  


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Variable 
Type 
Definition 
Self-report New/worsening 
difficulty emptying bladder 
(UDI item J) 
Dichotomous 
1=yes 
0=no 
Self-report of new or worsening difficulty emptying bladder is captured on the UDI form 
item J at baseline and 6 months (and 3, 9, and 12 months). The outcome variable will be 
coded with a value of “Yes” if any post-baseline UDI assessment reported a worse bother 
than at baseline (ordered categories are “No”, “Yes” with bother not specified / “Not at 
all”, “Yes” and “Slightly”, “Yes” and “Moderately, “Yes” and “Greatly”). For 
participants that did not have any post-baseline visits, the outcome variable will be set to 
missing. 
 
UDI item J: 
Do you experience difficulty emptying your bladder? 
 
 
 Yes 
 No (Skip to K.) 
 
If yes, how much does it bother you? 
 
 Not at all 
 
 Slightly 
 Moderately 
 Greatly 
Other AEs or symptoms of 
interest 
Dichotomous 
1=yes 
0=no 
We will also look to see if there are any additional AEs to report on the AE table, covering 
the following:  These will be identified via evaluation of AE preferred terms, verbatim 
descriptions/comments and AE relationship at least possibly related. 
- 
Other MUS surgical wound healing problems >6 weeks 
- 
New/worsening vaginal infection 
- 
Other infection possibly related to intervention 
- 
New/worsening partner dyspareunia 
 
At final database lock review, 2 additional event terms of interest were identified: 
“pyelonephritis”, and “Gonococcal pelvic inflammatory disease”. Appropriate indicator 
variables will be created for each additional term of interest, coded to “Yes” if the 
participant has any reported events coded to the respective MEDRA preferred term. The 
outcome variable will be set to “No”, otherwise. 


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9.3 
Analysis Methods for the 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 6 months, 9, 12), and treatment × visit interaction with an unstructured 
covariance pattern for the within-subject repeated measures separately within the two treatment 
groups. Estimates, p-values and 95% confidence intervals will be presented for treatment group 
comparisons at 6 moths (primary) and 3 months (secondary), and 9 and 12 months (other 
efficacy). (SM Davis, 2014) 
 
Example code from SAS to produce this analysis is as follows: 
 
proc mixed covtest; 
 
class subject site trtgp VISIT; 
 
model DELTA_VAR = BL_VAR site trtgp VISIT trtgp*VISIT / ddfm=kenwardroger; 
 
repeated VISIT / subject=subject type=UN group=trtgrp R rcorr; 
 
title "Mixed model for change from baseline"; 
 
lsmeans trtgp*VISIT / cl pdiff=all; 
run; 
 
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 (see section 9.5.3). 
 
Sensitivity analysis: This model assumes missing data due to a missed visit or early study 
discontinuation is missing at random (MAR).  If more than 10% of participants are missing their 
6-month score and a statistical difference is seen between groups at 5 months, then a sensitivity 
analysis in order to assess the robustness of the primary results to missing data will be performed 
using multiple imputation under a  not -missing-at-random (NMAR) as follows: missing data 
from discontinuations in the arm found to be superior will be imputed based on data from the less 
superior arm (“control-based imputation”).  (Ratitich et al 2013, 2,14). This sensitivity analysis 
essentially takes the conservative assumption that missing data after discontinuation in the 
superior arm have outcome values as if they were in the non-superior arm. 
 
A supportive per-protocol analysis of the primary outcome will be based on the per-protocol 
population with data excluded (set value to missing) for any data points at 3 or 6 months that are 
collected after a cross-over treatment or additional therapy.  Since crossing over and additional 
treatments were allowed after 6 months, data points after 6 months are not planned to be excluded 
in any sensitivity analyses. 
Sensitivity of the per-protocol analysis: the data set to missing due to off-protocol treatments is 
assumed by the model to be missing at random. However, it is possible that if these measures 
were assessed without additional therapy, they might have reflected poor outcomes. To assess the 
impact of the results from the missing data, we will conduct a tipping point multiple imputation 


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analysis, in which the missing values are increased (worsened) by a fixed value, in successive 
intervals across successive analyses until a point at which statistical interpretation of the p-value 
at 6 months between treatment groups is changed.    (Ratitich et al 2013, 2,14). 
 
9.4 
Analysis Methods for secondary and exploratory outcomes 
There are three 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, and the UDI 
total will be compared at 3 months (see above). The statistical analysis of the three secondary 
outcomes will be identical to the primary analysis described above for the UDI total score.    
In addition, the per-protocol analysis will be repeated for the secondary outcomes.  
 
For all continuous exploratory measures, groups will be compared using the same model as the 
primary analysis described above for the UDI total score.  
 
For any dichotomous outcomes assessed across time, groups will be compared for the odds of the 
event, and an odds ratio will be estimated from a repeated measures logistic generalized linear 
regression model with adjustment for baseline value, site and baseline age category, and with 
treatment, visit and treatment by visit interaction with an unstructured covariance pattern 
separately within each treatment group for the within-subject repeated measures.  
 
For PGI-I and PGSC, the baseline PGI-S score will be the baseline covariate. 
 
Example code from SAS to produce this analysis is as follows: 
 
Proc glimmix; 
   class subjectID trtgrp VISIT site; 
   model dep_var = bbaseline_var trtgrp site visit trgrp*visit /  
         solution link=logit dist=binary oddsratio DDFM=KR; 
   random time / type=UN Group=trtgrp subject=subjectID RSIDE; 
   lsmeans trtgrp*time / ILINK CL; /*estimates event rates*/ 
   lsmeans trtgrp*time / oddsratio diff CL; /*estimates ORs*/ 
   estimate ‘trt a vs trt b at time 2’ trtgrp 1 -1 trtgrp*time 0 1 0 0 0  -10 0  / EXP CL; 
Run; 
 
Groups will be compared for receipt of additional treatment with chi-squared tests or Fisher’s 
exact test for small event rates. 
 
9.5 
Other Analysis Methods 
 
9.5.1 
Predictors of Treatment Response  
Predictors of response will be identified in a secondary manuscript, and methods for analysis 
will be documented in a separate SAP prior to beginning of the analysis.  Both traditional 
prediction model as well as machine learning methods will be used.  Methods specified in the 
protocol are as follows: 


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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, balanced), 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 (treatment group, 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. 
 
We will attempt to create threshold definitions, based on baseline measures of the UDI, IIQ, 
OAB-q, UDE, and baseline bladder diary parameters in isolation and in combination, that are 
predictive of clinical success at 6 months. Definitions of success will be based on a change 
from baseline in total UDI score, UDI-irritative score or UDI-stress score at least as large as 
the MID for this MUI population (see section 9.5.3). 
 
9.5.2 
Cost-effectiveness analysis  
  
The EQ-5D and the SF-6D will be used to calculate QALYs. Methods for cost-effectiveness 
analysis from the protocol are included here and will be expanded upon is a cost-
effectiveness analysis SAP that will be developed prior to analysis of the cost effectiveness 
data, which will be reported in a secondary manuscript.  
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. 
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. 


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9.5.3 
UDI MID 
We will explore potential minimally important differences (MIDs), the smallest change that 
can be regarded as clinically meaningful, 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, patient global impression of improvement (PGI-I), and incontinence 
episodes from the bladder diary. 
Anchor-based methods will examine the relationship between the UDI scores and 
independent external measure (or anchor) to elucidate the meaning of a particular change in 
the score. The anchor-based MID approach will evaluate the change from baseline at 6 
months in the UDI score and 2 subscores corresponding to a self-reported small, but 
important, change on the PGSC, PGI-I and number of incontinence episodes from the diary.  
• 
The PGSC “My current treatment is giving me adequate control of my urine leakage” 
is scored on a scale from 1 (strongly disagree) to 5 (strongly agree).  Responses of 1, 
2, or 3 are considered inadequate leakage control, responses of 4 or 5 are considered 
adequate leakage control. The MID will be defined as the difference between the 
mean change in UDI scores for patients whose PGSC rating at 6 months was “4” and 
the mean change in UDI scores for patients whose PGSC rating at 6 months was ”3.  
• 
The PGI-I “the one that best describes how your urinary tract condition is now, compared 
with how it was before treatment in this study” is scored on a scale from Very much better, 
Much better, A little better, No change, A little worse, Much worse, Very much 
worse. . The MID will be defined as the difference between the mean change in UDI 
scores for patients whose PGI-I rating at 6 months was “a little better” and the mean 
change in UDI scores for patients whose PGI-I rating at 6 months was ”no change”. 
• 
Change in average incontinence episodes per day from baseline to 6 months will be 
calculated from the 3-day diary.  “No change” in episodes will be defined for a 
person as a percent change in average episodes across the 3 days of from 0 to 25%. 
A “small improvement” in average episodes will range from 25% to 50%.  The MID 
will be defined as the difference between the mean change in UDI scores for patients 
with a small improvement and the mean change in UDI scores for patients with no 
change. 
Distribution-based MID calculations will focus on variability, using the baseline standard 
deviation of the UDI scores. The distribution-based MID will be defined as 0.5 × baseline SD 
(i.e., medium effect size) and 0.2 × baseline SD (i.e., small effect size). 
MID estimates of the anchor- and distribution-based approaches will be compared, and 
recommendations for the MID of the UDI and iterative and stress subscales will be made by 
consensus, consistent with the recommendations of Revicki et al.  For reference, ESTEEM 
used the anchor-based method and the PGI-I (selected as the most clinically relevant anchor), 
and recommends a MID of -26 for the UDI total, -10.2 for the UDI-irritative subscale, and -
5.4 for the UDI-stress subscale.(Sung et al) 
The change from baseline UDI total score and stress and irritative subscores for each 
participant will be compared to the MIDs estimated from the MUSA data, and the percentage 
of participants who meet or exceed the MID will be compared between treatment groups. 
 


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10 SAFETY ANALYSES 
10.1 
Overview of Safety Analysis Methods 
All safety analyses will be performed using the Safety population unless otherwise specified, 
consisting of all randomized and treated participants, summarized by the treatment actually 
received in the case of patients not receiving their randomized treatment. Descriptive p-values 
comparing the study arms will be provided on most safety table summaries and will be obtained 
using chi-square tests or Fisher’s exact tests (in the case of small numbers of events) for binary 
outcomes. 
10.2 
Adverse Events/Complications/Adverse Symptoms 
MUSA complications are divided into “adverse symptoms” and “adverse events”.  
Participants were asked to report any adverse events or adverse symptoms from randomization 
through 12 months follow-up. All adverse events were collected on an adverse event log and 
coded using MedDRA (V24.0). In addition, a few adverse symptoms are captured as part of the 
PRO questionnaires.  
 
Adverse symptoms will be captured using an active approach using validated questionnaires and 
an open-ended approach.  
a. Active capture for specific patient-reported adverse symptoms will be identified by 
responses on validated questionnaires These 3 adverse symptoms are patient report of 
new or worsening: 1) pelvic/vaginal pain, 2) sensation of incomplete bladder emptying 
(based on UDI responses) and 3) dyspareunia (based on PISQ-IR response). These are 
captured at 3, 6, 9, and 12 months. 
 
b. Open-ended capture for adverse symptoms will also be captured using the open-ended 
approach and recorded on the AE log. Symptoms of interest include: 1) New/worsening 
partner dyspareunia and 2) New/worsening constipation. Using the open-ended approach, 
symptoms are captured if reported by the participant and documented on the Adverse 
Event log.  
Adverse events will be captured using the standard AE open-ended capture approach using chart 
review, physician report, or patient report corroborated by medical documentation and recorded 
on the Adverse Event log. 
A table summarizing the Adverse Events and Adverse symptoms of interest is as follows (all 
variable definitions are included in Section 9.2): 
Postoperative complications 
 
Adverse symptom 
Definition 
*New/worsening abdominal/genital pain at or beyond 3 month 
visit 
UDI item N captured at 3, 6, 9, and 12 
months and per patient report, chart review, 
physician report 
*New/worsening dyspareunia at or beyond 3 month visit 
PISQ item C5 captured at 3, 6, 9, and 12 
months and per patient report, chart review, 
physician report 
*New/worsening report of difficulty emptying bladder at or 
beyond 3 months 
UDI item J captured at 3, 6, 9, and 12 months 
and per patient report, chart review, physician 
report 
New/worsening partner dyspareunia at or beyond 3 month visit 
Per patient report, chart review, physician 
report 


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Adverse Event 
 
 
Postop need for catheter and/or ISC at or beyond 2 weeks (sling 
or Botox) 
Captured by chart review, physician report, 
exam, or patient report corroborated by 
medical documentation 
Vaginal mesh exposure (sling only) 
Captured by chart review, physician report, 
exam, or patient report corroborated by 
medical documentation 
Vaginal mesh erosion into organ (sling only) 
Captured by chart review, physician report, 
exam or patient report corroborated by 
medical documentation 
Other wound healing problems >6 weeks (sling only) 
Captured by chart review, physician report, 
exam or patient report corroborated by 
medical documentation 
New/worsening vaginal infection (sling or Botox) 
Captured by chart review, physician report, 
exam, or patient report corroborated by 
medical documentation 
Urinary tract infection beyond 2 weeks (sling or Botox) 
UTI based on clinical judgment or 
confirmation of culture proven, also includes 
empiric antibiotic treatment for symptoms 
thought to be due to UTI, or patient report 
corroborated by medical documentation. 
If a culture is sent that turns out to be 
negative, this would not be classified as a 
UTI. 
Captured by chart review, physician report, or 
patient report corroborated by medical 
documentation 
Other infection possibly related to intervention (sling or Botox) 
Infection diagnosed using clinical or 
radiologic indicators – not including vaginal 
infection, UTI 
Captured by chart review, physician report, or 
patient report corroborated by medical 
documentation 
Non-study health care provider visit due to complication related 
to intervention (sling or Botox) 
Captured by chart review, physician report, or 
patient report corroborated by medical 
documentation 
Emergency room visit due to complication related to 
intervention (sling or Botox) 
Captured by chart review, physician report, or 
patient report corroborated by medical 
documentation 
Hospital readmission related to intervention (sling or Botox) 
Captured by chart review, physician report, or 
patient report corroborated by medical 
documentation 
Reoperation related to surgery (any return to OR for issue 
related to intervention (e.g. recurrent SUI, UUI/OAB) (sling 
only) 
Captured by chart review, physician report, or 
patient report corroborated by medical 
documentation 
An adverse event that is “unexpected” and “possibly, probably 
or definitely related” 
Captured by chart review, physician report, or 
patient report corroborated by medical 
documentation 
 


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AEs will be listed and summarized by system organ class and preferred event term. Summaries 
will be of the number of events and number of individuals experiencing events by treatment 
group and will be created for all AEs, and AEs by severity. If a complete onset date is unknown 
and it cannot be confirmed that the event occurred during this time period, then the event will be 
considered a treatment-emergent AE. 
 
Reported adverse events will be reviewed to identify terms meeting definitions for events or 
symptoms of interest The review will be conducted via keyword searches through reported event 
terms and comments for specific events (e.g. vaginal mesh exposure, ER visits, etc.) and by 
preferred term and system/organ class for more general complications (e.g. new/worsening 
vaginal infection, other infections, etc.).  
Worsening symptoms will be assessed by identifying worsening responses (compared to baseline) 
to the specific patient-questionnaire items identified at post-baseline collection times. 
Post-operative complications will be summarized by complication type. Summaries will be the 
number of individuals experiencing complications by treatment group. 
10.3 
Deaths and Serious Adverse Events 
A serious adverse event (SAE) is any event that is life threatening, results in death, causes or 
prolongs hospitalization, leads to a disability or birth defect, or requires an intervention to prevent 
a disability. Overall number percent of patients with an SAE will be presented, and SAEs will be 
summarized in the manner mentioned in Section 10.2 if there are enough events to summarize. 
Deaths will be listed. 
11 ANALYSIS OF OTHER OUTCOMES 
No analyses of outcomes other than efficacy and safety outcomes are planned. 
12 REPORTING CONVENTIONS 
Unless required otherwise by a journal, the following rules are standard:  
• 
Moment statistics including mean and standard deviation will be reported at 1 more 
significant digit than the precision of the data.  
• 
Order statistics including median, min and max will be reported to the same level of precision 
as the original observations.  If any values are calculated out to have more significant digits, 
then the value should be rounded so that it is the same level of precision as the original data. 
• 
Following SAS rules, the median will be reported as the average of the two middle numbers 
if the dataset contains even numbers. 
• 
Test statistics including t and z test statistics will be reported to two decimal places.  
• 
P-value will be reported to 3 decimal places if > 0.001.  If it is less than 0.001 then report 
‘<0.001’.  Report p-values as 0.05 rather than .05. 
• 
No preliminary rounding should be performed, rounding should only occur after analysis.  To 
round, consider digit to right of last significant digit:  if < 5 round down, if >=5 round up. 


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13 CHANGES TO THE ANALYSIS PLANNED IN THE PROTOCOL 
The primary repeated measures mixed model analysis planned in the protocol specified a 
heterogeneous Toeplitz covariance pattern for the within-subject repeated measures. The SAP 
updates this covariance pattern to instead be unstructured separately within each treatment arm. 
The unstructured pattern within group is preferable for the MUSA design since the Botox arm can 
receive a second treatment within the first 6 months but the sling arm does not, and additional 
treatments are allowed in either arm after 6 months. It is therefore best to specify the most general 
correlation structure possible.  
 
14 REFERENCES 
Davis, S., Chapter 5. Mixed models for repeated measures with categorical time effects (MMRM). in 
Clinical trials with missing data : a guide for practitioners, M. O'Kelly and B. Ratitch, 
Editors. 2014, John Wiley & Sons Inc.: Chichester, West Sussex. 
Ratitch, B., M. O'Kelly, and R. Tosiello, Missing data in clinical trials: from clinical assumptions to 
statistical analysis using pattern mixture models. Pharm Stat, 2013. 12(6): p. 337-47. 
Ratitch, B., Chapter 6: Multiple Imputation, in Clinical trials with missing data : a guide for 
practitioners, M. O'Kelly and B. Ratitch, Editors. 2014, John Wiley & Sons Inc.: Chichester, 
West Sussex. 
Revicki D, Hays RD, Cella D, Sloan J. Recommended methods for determining responsiveness and minimally important 
differences for patient-reported outcomes. J Clin Epidemiol 2008;61:102–9. 
Sung VW, et al. Effect of Behavioral and Pelvic Floor Muscle Therapy Combined with Surgery vs 
Surgery Alone on Incontinence Symptoms Among Women With Mixed Urinary 
Incontinence: The ESTEEM Randomized Clinical Trial. JAMA. 2019 Sep 17;322(11):1066-
1076. 
15 LIST OF POTENTIAL DISPLAYS  
Data displays may be added, deleted, rearranged or the structure may be modified after finalization of 
the SAP.  Such changes require no amendment to the SAP as long as the change does not contradict 
the text of the SAP.   
 
Tables 
Demographic and Baseline Characteristics 
Primary and secondary Efficacy Model Results 
Exploratory Efficacy and Quality of Life Outcomes Outcome Measures 
Additional Treatments received. 
MID estimates for UDI 
Adverse Events, Symptoms, and SAEs 
Figures 
Consort diagram of participant disposition 
Primary and secondary measures over time by treatment arm 
 
 


Pelvic Floor Disorders Network 
MUSA Statistical Analysis Plan 
 
 
 
 
   
Version 1.0 February 8, 2024 Page 56