Conditions: Mixed Urinary Incontinence Stress Urinary Incontinence Urgency Incontinence
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 100
Healthy volunteers: no

Brief summary:
This double-blind randomized controlled trial seeks to find a better treatment for women with mixed urinary incontinence (both stress and urgency incontinence). The primary aim is to determine whether midurethral sling surgery combined with injections of onabotulinumtoxinA (Botox®) into the detrusor muscle of the bladder improves symptoms of mixed urinary incontinence better than sling surgery alone.

Detailed description:

Arms:
arm 1: 100 units of OnabotulinumtoxinA (Botox®) injected into the detrusor (large muscle of the bladder) at the time of sling surgery. arm 2: 100 units of saline injected into the detrusor (large muscle of the bladder) at the time of sling surgery.

Interventions: intervention 1: OnabotulinumtoxinA (Botox ®) Injections intervention 2: Saline Injections
Intervention descriptions: intervention 1: OnabotulinumtoxinA (Botox ®) is a neurotoxin, which inhibits acetylcholine release and temporarily relaxes the bladder muscle to inhibit urgency incontinence. intervention 2: Saline will be injected into the bladder so that investigators are masked to subject randomization.

Protocol document:
ICF_002.pdf: 
Cover Page for Protocol 
Sponsor name: 
Northwestern University
NCT number 
NCT02678377
Sponsor trial ID: 
STU00201249
Official title of study: 
The SLIM Study: Sling and Botox® Injection for Mixed 
Urinary Incontinence
Document date: 
06 May 2019


PROTOCOL TITLE: The SLIM Study: Sling and Botox® Injection for Mixed Urinary 
Incontinence
Page 1 of 14
Version Date: August 12, 2016
PROTOCOL TITLE:
The SLIM Study: Sling and Botox® Injection for Mixed Urinary Incontinence
PRINCIPAL INVESTIGATOR:
Kimberly Kenton, MD, MS
Professor of Obstetrics & Gynecology and Urology
Department of Obstetrics and Gynecology
Division of Female Pelvic Medicine and Reconstructive Surgery
Email: aleaderc@nm.org 
Phone: 312-472-3874
Address: 250 E. Superior St.
  Suite 05-2370
  Chicago, IL 60611
VERSION NUMBER:
Version 3
VERSION DATE:
8/12/2016
IRB #: STU00201249 Approved by NU IRB for use on or after 3/11/2021 through 3/10/2022.


PROTOCOL TITLE: The SLIM Study: Sling and Botox® Injection for Mixed Urinary 
Incontinence
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Table of Contents
1.0
Objectives .................................................................................................................3
2.0
Background...............................................................................................................3
3.0
Inclusion and Exclusion Criteria ..............................................................................6
4.0
Study Timelines........................................................................................................7
5.0
Study Endpoints........................................................................................................7
6.0
Procedures Involved .................................................................................................8
7.0
Data and Specimen Banking.....................................................................................9
8.0
Data and Specimen Management .............................................................................9
9.0
Provisions to Monitor the Data to Ensure the Safety of Subjects...........................10
10.0
Withdrawal of Subjects*.........................................................................................10
11.0
Risks to Subjects*...................................................................................................10
12.0
Potential Benefits to Subjects .................................................................................11
13.0
Sharing of Results with Subjects ............................................................................11
14.0
Setting.....................................................................................................................11
15.0
Resources Available ...............................................................................................12
16.0
Recruitment Methods..............................................................................................13
17.0
Local Number of Subjects ......................................................................................13
18.0
Provisions to Protect the Privacy Interests of Subjects ..........................................13
19.0
Compensation for Research-Related Injury............................................................13
20.0
Economic Burden to Subjects.................................................................................14
21.0
Consent Process......................................................................................................14
22.0
Process to Document Consent in Writing...............................................................14
23.0
Drugs or Devices ....................................................................................................14
IRB #: STU00201249 Approved by NU IRB for use on or after 3/11/2021 through 3/10/2022.


PROTOCOL TITLE: The SLIM Study: Sling and Botox® Injection for Mixed Urinary 
Incontinence
Page 3 of 14
Version Date: August 12, 2016
1.0
Objectives
 Primary Aim:  To determine whether synthetic retropubic midurethral sling 
(MUS) combined with concomitant detrusor injections of onabotulinumtoxinA is 
more effective than midurethral sling alone in improving mixed urinary 
incontinence (MUI) symptoms.
Secondary Aims:
a. To compare incontinence episode frequency on a 3-day diary in women
who undergo midurethral sling plus onabotulinumtoxinA to those who
undergo midurethral sling alone.
b. To compare urinary incontinence symptoms and quality of life in women
who undergo midurethral sling plus onabotulinumtoxinA to those who
undergo midurethral sling alone.
c. To identify baseline factors associated with persistent urgency
incontinence in women after midurethral sling alone and midurethral sling
plus onabotulinumtoxinA.
 Hypotheses:
1. By using a double-blind randomized controlled trial, we will be
able to show that retropubic midurethral sling surgery with detrusor
muscle onabotulinumtoxinA injection will be more effective at
controlling mixed urinary incontinence symptoms than sling surgery
alone.
2. Patients who receive both midurethral sling and
onabotulinumtoxinA injection will have objectively have fewer
incontinence episodes than those who receive midurethral sling
alone
3. Patients who receive both treatments will have better quality of
life as it relates to urinary symptoms than those who receive
midurethral sling alone
4. Patients who have persistent urgency urinary incontinence after
either midurethral sling alone or both midurethral sling and
onabotulinumtoxinA injection alone will have significantly different
baseline urine microbial content than those who do not have
persistent urgency symptoms after treatment
2.0
Background
Project Abstract:
This double-blind randomized controlled trial looks to find a better treatment for 
women with mixed urinary incontinence.  The primary aim of this study is to 
determine whether midurethral sling, the predominant incontinence surgery 
performed worldwide, combined with injections of onabotulinumtoxinA 
(Botox®) into the large muscle of the bladder improves symptoms of mixed 
urinary incontinence better than sling surgery alone.  Secondary aims are to 
IRB #: STU00201249 Approved by NU IRB for use on or after 3/11/2021 through 3/10/2022.


PROTOCOL TITLE: The SLIM Study: Sling and Botox® Injection for Mixed Urinary 
Incontinence
Page 4 of 14
Version Date: August 12, 2016
compare objectively the frequency of incontinence episodes in patients who 
receive onabotulinumtoxinA injection versus those who do not. We will also 
compare urinary incontinence symptoms and quality of life measures in patients 
who receive the injections versus those who do not. Lastly, we plan to try to 
identify baseline factors associated with persistent urgency urinary incontinence 
in women after sling surgery alone and sling surgery plus injection.
We plan to enroll women who have mixed urinary incontinence and 
randomize them into either treatment with sling surgery alone or sling surgery 
with bladder onabotulinumtoxinA injection at the time of surgery. Patients will 
then be followed with scheduled, in-person follow-up with a physician at 2-
weeks,  3-months and at 1 year.  During these visits and prior to surgery, the 
patients will complete standardized surveys on urinary symptoms, quality of life, 
pelvic floor function, and sexual health.  A urine sample will also be collected 
from each patient for a detailed analysis of the microbial content that is beyond 
the scope of a normal hospital laboratory.
After this study, we hope to have developed a new and better treatment for 
mixed urinary incontinence that can be provided to women suffering with this 
malady both nationally and internationally.  There is currently no standard of care 
for treatment of mixed urinary incontinence and we aim to provide this to the 
urogynecologic community.  Additionally, differentiating those patients who will 
have persistent or worsening urgency urinary incontinence after sling surgery 
from those who have improvement in symptoms has been difficult.  By examining 
the detailed microbial content of participants’ urine, we hope to better understand 
this phenomenon.
Project Background:
Mixed urinary incontinence (MUI) is a clinical conundrum for providers and 
patients alike. The International Continence Society defined MUI as “involuntary 
loss of urine associated with urgency or urgency incontinence AND urine loss 
associated with physical exertion, sneezing or coughing or stress incontinence”. 
While some women ONLY experience one type of incontinence (stress OR 
urgency), many experience leakage with both, and it is unclear if these MUI 
symptoms are one disease with a continuum of symptoms or two separate diseases 
making treatment algorithms challenging. Despite our lack of understanding 
regarding the disease process or optimal treatment, MUI accounts for up to 50% 
of incontinence in women. The annual burden of MUI on the national economy is 
significant and growing. 
More importantly, women with MUI are more bothered and suffer more dramatic 
quality of life impact.  Yet, optimal treatments for MUI lag behind.  Definitive 
treatments for stress incontinence are typically surgical, while those for urgency 
incontinence are behavioral or medical. As early as the 1980s, investigators 
sought to determine if surgical or non-surgical treatments should be used first for 
MUI.  In one small trial, women with MUI were randomized to medical treatment 
(e.g. anticholinergic medications designed to relax the bladder muscle) for 
urgency incontinence or surgery for stress incontinence.  Forty-three percent of 
women in the medicine group continued to have incontinence symptoms, while 
IRB #: STU00201249 Approved by NU IRB for use on or after 3/11/2021 through 3/10/2022.


PROTOCOL TITLE: The SLIM Study: Sling and Botox® Injection for Mixed Urinary 
Incontinence 
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only 12-13% of the surgical patients had persistent incontinence symptoms.  
Further complicating treatment decisions, continence procedures designed to treat 
stress incontinence have historically worsened urgency incontinence in some 
women. 
There is no high-quality evidence or consensus amongst specialists on how to 
approach treatment for women with MUI.  The optimal treatment strategy for 
women with MUI is unclear.  Historically, health care providers tried to identify 
which type of incontinence, stress or urgency, was most bothersome to the patient 
and treated the bothersome subtype first.  Those with stress predominant 
incontinence underwent surgery, while those with urgency predominant 
incontinence received medications and behavioral/physical therapy.
Currently, the primary surgical treatment of stress incontinence is midurethral 
slings. Greater than 66% of women undergoing midurethral sling surgery for 
stress incontinence also report baseline urgency incontinence. Investigators report 
improvement in urgency incontinence in some women with MUI undergoing 
midurethral sling, however, subjective outcomes are worse in women with MUI 
compared to pure stress incontinence and the lower cure rates are associated with 
persistent urgency incontinence. Studies also demonstrated that urgency 
incontinence is the major cause of patient dissatisfaction of surgery for stress 
incontinence and prolapse. Reduced satisfaction and treatment failure after 
midurethral sling surgery is associated with higher baseline urgency and urgency 
incontinence.  Additionally, one study showed that 33% of women who did not 
have urgency incontinence symptoms prior to midurethral sling developed 
urgency symptoms after surgery. This study further complicates the issue, as it is 
possible that midurethral sling may cause urgency symptoms in some patients. 
Overall, studies have shown a wide range in improvement of urgency 
incontinence symptoms after midurethral sling placement between 46-74%.  The 
wide range of anticipated improvement coupled with the not insignificant rate of 
de novo in urgency incontinence symptoms after midurethral sling, make 
counseling women with MUI contemplating surgery challenging.  Essentially, 
surgeons can counsel women with MUI that although their stress incontinence 
symptoms are likely to improve after midurethral sling (90% satisfaction), their 
urgency incontinence may get better, stay the same, or get worse.
Other strategies for treating MUI have also been proposed including treatment 
with anticholinergic medication in addition to traditional sling surgery. In an 
AHRQ funded study, anticholinergic medical therapy had minimal to moderate 
efficacy for treatment of urgency incontinence symptoms. Furthermore, many 
women taking anticholinergic medications suffer bothersome side effects, such as 
dry mouth and constipation, and over 50% stop taking the medication during their 
treatment course.  In our prior work, we found that women treated with 
anticholinergic medications prior to traditional continence surgery were more 
likely to have urgency symptoms post-operatively, suggesting poorer outcomes in 
women with MUI. Understandably, patients with persistent urgency symptoms 
post-operatively are significantly less satisfied with their symptoms and surgical 
outcomes than patients who have complete resolution of their symptoms.
IRB #: STU00201249 Approved by NU IRB for use on or after 3/11/2021 through 3/10/2022.


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Incontinence 
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Given the known treatment shortcomings of anticholinergic medications for 
treatment of urgency incontinences, clinician-investigators began injecting 
onabotulinumtoxinA into the bladder in an attempt reduce urgency incontinence 
while minimizing side effects.  OnabotulinumtoxinA is a neurotoxin, which 
inhibits acetylcholine release and temporarily relaxes the bladder muscle to inhibit 
urgency incontinence.   A large NIH funded multicenter double-blind randomized 
controlled trial investigated the role of detrusor injections with 100 units of 
onabotulinumtoxinA compared to anticholinergic medications for the treatment of 
urgency incontinence.  More women in the onabotulinumtoxinA group were 
completely dry (no incontinence episodes) without having the bothersome side 
effects of the anticholinergic medications.  Women in the onabotulinumtoxinA 
group also had higher rates of transient urinary retention requiring self-
catheterization and urinary tract infection; however, these rates were significantly 
lower than earlier studies using higher doses of onabotulinumtoxinA.  Several 
studies suggest the optimal dose of onabotulinumtoxinA, which maximized 
resolution of urinary incontinence while minimizing complications, is 100 units 
per injection.  As a result, onabotulinumtoxinA injections are a standard treatment 
for urgency incontinence.
Given the superior efficacy and side effect profile of onabotulinumtoxinA and the 
high rates of persistent urgency incontinence and dissatisfaction after sling 
surgery in women with MUI, we hypothesize that a combined treatment approach 
for women with MUI is superior to simply treating the stress incontinence alone.  
Specifically, women with MUI undergoing sling plus intradetrusor 
onabotulinumtoxinA will have fewer bothersome incontinence symptoms than 
women undergoing sling alone.  The aim of this double-blind randomized 
comparative efficacy trial is to determine if women with MUI planning sling 
surgery sustain greater improvement in their urinary symptoms with the addition 
of onabotulinumtoxinA injection at the time of sling.  
A secondary aim is to identify subsets of women who may be prone to 
persistent urinary symptoms after treatment.  Although classic teaching is that the 
urine is ‘sterile’, recent studies identified that urine of normal asymptomatic 
women contain bacteria; in other words, similar to all other organ systems in the 
body (gastrointestinal tract, skin, etc) urine is NOT sterile rather it has a 
microbiome.  Recent data suggests that patients with urgency symptoms have a 
different bladder microbiome (different bacteria) than those who do not suffer 
from this ailment.  Our unit recently found that the microbiome of women with 
urgency and bladder pain differs from age-matched controls.
3.0
Inclusion and Exclusion Criteria
All women with MUI planning surgical intervention with midurethral sling will 
be approached for study participation.  MUI will be defined as an answer of 
“moderately’ or “quite a bit” bothered to Urinary Distress Inventory (UDI) items 
(2) “urine leakage with a feeling of urgency” AND (3) “urine leakage related to 
coughing, sneezing, or laughing”.
IRB #: STU00201249 Approved by NU IRB for use on or after 3/11/2021 through 3/10/2022.


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Incontinence 
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Enrolled participants must meet all the following criteria:

Undergoing mid-urethral sling surgery

Have symptoms of both stress and urgency urinary incontinence 

Able to consent, fill out study documents, and complete all study 
procedures and follow-up visits

At least 18 years of age

English speaking

Be able and willing to learn clean intermittent self catheterization 
technique
Women will be excluded for any of the following reasons:

History of recurrent UTI (defined as three culture proven UTIs within last 
12 months)

Systemic neuromuscular disease known to affect the lower urinary tract

Undergoing concomitant prolapse surgery

Previous incontinence surgery

Treatment with anticholinergic medication in the last 2 months

Darifenacin/Enablex

Oxybutynin IR/Ditropan

Oxybutynin ER/Ditropan XL

Oxybutynin Patch/Oxytrol

Oxybutynin Gel/Gelnique

Solifenacin/Vesicare

Tolterodine IR/Detrol

Tolterodine ER/Detrol LA

Trospium IR/Sanctura

Trospium ER/Sanctura XR

Fesoterodine/Toviaz

Mirabegron/Myrbetriq

Previous bladder injection with onabotulinumtoxinA

Prisoner status

Pregnancy

Patients on SGLT2 Inhibitors 

(canagliflozin, dapagliflozin, and empagliflozin)
4.0
Study Timelines
Individuals will participate and remain enrolled in the study for 
approximately 1 year or until they have completed their one year post-
operative visit.
We estimate that it will take two years to enroll the total number of 
subjects required to complete this study.
We expect to be able to complete primary analyses of this study 3 years 
from the date of IRB approval.
5.0
Study Endpoints
IRB #: STU00201249 Approved by NU IRB for use on or after 3/11/2021 through 3/10/2022.


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Incontinence 
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Primary endpoint will occur at 3 months.  Secondary endpoint is at 1 year, or 
when the subject completes her 1 year post-operative visit.
6.0
Procedures Involved
Women with MUI undergoing midurethral sling for bothersome SUI will 
be randomized to 100 units onabotulinumtoxinA or placebo (saline) injections in 
the detrusor at the time of sling surgery.  Specifically, the retropubic midurethral 
slings used will be either the Gynecare TVT Exact Continence System by Ethicon 
or the Boston Scientific Advantage Fit Transvaginal Mid-Urethral Sling System 
based on surgeon preference. Surgeons and participants will be masked to study 
assignment.  Primary outcome will be the Patient Global Assessment of 
Improvement (PGI-I), a global, patient oriented measure that assesses symptoms 
of SUI and UUI at 3-months.  The primary outcome, PGI-I asks subjects to best 
describe how their urinary tract condition is now, compared to how it was before 
treatment for urinary leakage. Response choices are: (1) ‘very much better’, (2) 
‘much better’, (3) ‘a little better’, (4) ‘no change’, (5) ‘a little worse’, (6) ‘much 
worse’, and (7) ‘very much worse’. Construct validity of the PGI-I was 
demonstrated in incontinence trials.32  
We selected a subjective, patient oriented outcome as our primary 
outcome measure secondary to the complex nature of MUI, and the association 
between dissatisfaction after incontinence surgery and persistent or new onset 
urgency.  We felt the patient’s overall impression of their continence status 
represented a more clinically meaningful outcome than traditional objective 
measures.  In addition, we will compare subjective and objective urinary 
symptoms and quality of life amongst treatment groups 3-months and 1-year after 
surgery.
All women with MUI planning surgical intervention with midurethral 
sling will be approached for study participation.  MUI will be defined as an 
answer of “moderately’ or “quite a bit” bothered to Urinary Distress Inventory 
(UDI) items (2) “urine leakage with a feeling of urgency” AND (3) “urine leakage 
related to coughing, sneezing, or laughing”.
Women will undergo standardized urologic evaluation at baseline 
including assessment of urinary symptoms and quality of life using short forms of 
the Urinary Distress Inventory (UDI-6) and Incontinence Impact Questionnaire 
(IIQ-7); assessment of overall severity of their incontinence symptoms with the 
Patient Global Impression of Severity (PGI-S);32 post void residual urine volume; 
urine analysis and culture; multichannel urodynamic testing; and pelvic exam 
with prolapse quantification using pelvic organ prolapse quantification system 
(POP-Q)33.  All patients will also complete a 3-day urinary diary at baseline 
quantifying the number of incontinence episodes (stress and urge).   Three months 
and 1-year after surgery, patients will again complete all baseline measures, 
including UDI, IIQ, PGI-I, PGI-S, and 3-day diary to report symptom and 
objective urinary symptoms after treatment.  A sample of urine will be obtained 
for microbiome analysis at each visit.
Scheduled in-person follow-up visits will occur at baseline, 2 and 6-weeks, 
3-months, and 1-year after surgery. At the baseline, 3-month, and 1-year visits, 
IRB #: STU00201249 Approved by NU IRB for use on or after 3/11/2021 through 3/10/2022.


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research staff will collect the 3-day diary information and record any adverse 
events that have occurred during the post-operative period. Subjects will also 
complete the general and condition specific symptom and QOL questionnaires.  In 
addition, an update of current medication and assessment as to whether any 
evaluation or treatment for pelvic floor disorders or adverse outcomes from 
surgery have occurred since the previous evaluation will be assessed by clinical 
staff at the in-person visits. All patient and survey data will be recorded in 
RedCAP.
7.0
Data and Specimen Banking
Data will be collected at Northwestern Medicine. All study data will be 
recorded on Case Report Forms by research coordinator and securely 
maintained in a locked cabinet. CRFs will be derived from source 
documentation and/or participant self-report. Data will be entered by the 
research coordinator at Northwestern into a REDCap database that will be 
stored on a secure sever at the Data Coordinating Center. All collected 
data must be entered into REDCap within 5 business days. Any queries to 
data entered into REDCap will be addressed by site staff within 5 business 
days. It is each site’s responsibility to regularly check REDCap for data 
queries. 
Both data and specimens will be banked for further use. Patient specimens 
will not have any directly identifiable patient information on them, but 
will remain coded for future studies if the specimen is unused in this 
study.  Argonne National Laboratories will have no access to any patient 
identifying information.  All patient identifiers will be removed prior to 
transferring microbiome samples to Argonne National Laboratories for 
processing.
8.0
Data and Specimen Management
All analyses will be conducted using SPSS version 20 (Chicago, IL).  Histograms 
will be used to determine distribution of data and appropriate non-parametric or 
parametric tests will be selected.  Primary outcome will be analyzed 
dichotomously with responses of “very much better” and “much better” 
considered an optimal outcome.  A chi-square test of association will be used to 
compare primary outcome (PGI-I) between treatment groups.  Questionnaire data 
will be compared between sling alone and sling plus onabotulinumtoxinA groups 
using Mann Whitney test. All test results will be considered significant with a p-
value of less than or equal to 0.05.
In a study of women with MUI undergoing retropubic midurethral sling, 66% of 
patients reported a PGI-I of “very much better’ or ‘much better’ at 3-months.23  
Similarly, in a randomized trial of intravesical onabotulinumtoxinA 55% of 
participants had PGI-I scores of “very much better’ or ‘much better’.  Therefore, 
assuming “optimal outcomes’ (PGI-I scores of “very much better’ or ‘much 
better) in 66% of women undergoing sling alone and 93% in those undergoing 
sling plus onabotulinumtoxinA, we will need to recruit 34 patients in each group 
IRB #: STU00201249 Approved by NU IRB for use on or after 3/11/2021 through 3/10/2022.


PROTOCOL TITLE: The SLIM Study: Sling and Botox® Injection for Mixed Urinary 
Incontinence 
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to show a significant difference with 80% power at a 0.5 significance level.  
Assuming a significant attrition rate, we will recruit approximately 100 women 
(50 in each arm).
Data will be collected at Northwestern Medicine. All study data will be recorded 
on Case Report Forms by research coordinator and securely maintained in a 
locked cabinet that only the study coordinator has access to. CRFs will be derived 
from source documentation and/or participant self-report. Data will be entered by 
the research coordinator at Northwestern into a REDCap database that will be 
stored on a secure sever. Only study staff will have passwords to access the 
project data on REDCap. 
The data that is banked locally will be entered into an electronic data capture 
website. All users of REDCap need an institutional username and password to log 
in and to enter data. Research personnel, including study staff as well as study 
doctors will be able to collect and have access to subject data.
All specimen collected will be stored locally in the clinic storage facility until 
patient de-identification and subsequent transfer to Argonne National Laboratory 
for analysis can be completed.  Any specimens that are not used for this study will 
be stored for future study use.  Only the study coordinator and physicians 
participating in the study directly will have access to the storage facility for the 
purposes of adding specimens and sending them out only.  Specimens will be 
batch-shipped to Argonne National Laboratories when enough have accumulated 
to do so.
9.0
Provisions to Monitor the Data to Ensure the Safety of Subjects
Adverse events associated with midurethral sling surgery in conjunction with 
onabotulinumtoxinA injection will be recorded, but only include events such as 
post-operative urinary retention requiring catheterization, post-operative urinary 
tract infection, and persistent urinary urgency. Adverse events will be recorded at 
each follow up visit on Case Report Forms and subsequently will be added in to 
REDCap electronic data capture system. The PI will be notified of any adverse 
events, which will be resolved with the patient.
10.0
Withdrawal of Subjects*
Subjects will be withdrawn from the research without their consent if they do not 
return for the scheduled 3 month post-operative visit.  In this case, subjects will be 
notified that they can no longer participate and their insurance billed for the cost 
of the onabotulinumtoxinA used during the procedure, with the subject covering 
any cost not covered by insurance.
11.0
Risks to Subjects*
Risks associated with the project are minimal.  Patients participating in the project 
will already be undergoing a retropubic midurethral sling for bothersome stress 
IRB #: STU00201249 Approved by NU IRB for use on or after 3/11/2021 through 3/10/2022.


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Incontinence 
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urinary incontinence, and will already have been counseled on and have 
understood the risks associated with that surgical procedure.  None of the risks 
associated with that surgical procedure will change (increase or decrease) by 
participating in this study.
This additional risks associated with the procedure are for the patients in the 
onabotulinumtoxinA arm.  Intravesical injection incurs a 5% increased risk of 
urinary retention requiring clean intermittent self catheterization.  All patients will 
be taught this technique prior to the procedure regardless of study arm.  Those 
with urinary retention have an increased risk of urinary tract infection.  This is 
time-limited and last for less than 2 months on average.  All patients will be 
informed of these risks as part of the consent process.
Another risk to subjects is that we will be collecting their personal health 
information in a database. All of the data will be kept confidential and will be 
stored on password protected, secure servers, or in locked cabinet files that only 
study staff on the project have access to. Personal health information will be 
stored on files that are separate from the subject’s name, all health information 
will be coded. Coded list will be kept on secure, password protected file.
12.0
Potential Benefits to Subjects
Given the superior efficacy and side effect profile of onabotulinumtoxinA and the 
high rates of persistent urgency incontinence and dissatisfaction after sling 
surgery in women with MUI, we hypothesize that a combined treatment approach 
for women with MUI is superior to simply treating the stress incontinence alone.  
Specifically, women with MUI undergoing sling plus intradetrusor 
onabotulinumtoxinA will have fewer bothersome incontinence symptoms than 
women undergoing sling alone.  It is possible that subjects will have significant 
improvement in quality of life due to the improvement in urinary symptoms that 
they would not have been offered without this study.
13.0
Sharing of Results with Subjects
Results will not be directly shared with subjects
14.0
Setting
Research will be conducted in Northwestern Medical Group’s outpatient clinic, 
the Integrated Pelvic Health Program (IPHP). Potential subjects will be identified 
and recruited by physicians within the practice. Once potential subjects are 
identified, the study coordinator will provide the patient with information about 
the study. If the patient is interested in joining the study, the study coordinator 
will consent the patient in the IPHP clinic. The patients will complete 
questionnaires per the study either at home or in the clinic in a private room. 
Demographic and medical and surgical data will be collected from the patient’s 
medical record and recorded on the RedCAP secure server.
IRB #: STU00201249 Approved by NU IRB for use on or after 3/11/2021 through 3/10/2022.


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Incontinence 
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After consenting to the study, the surgical procedure that subjects are undergoing 
as part of their standard of care will be performed at an NMHC facility. The 
onabotulinumtoxinA injections will be performed in the operating room by one of 
the study physicians. Randomization will be performed via RedCAP on a secure 
online server through a hospital computer.
The subjects post-operative visits will take place in the Integrated Pelvic Health 
program, and NMHC outpatient clinic, as part of standard of care. Additional 
questionnaires will be completed at these visits and data will be collected from 
these visits as well.
15.0
Resources Available
The staff that will be involved in this research are highly qualified. The Principle 
Investigator, Dr. Kimberly Kenton, is the chief of Female Pelvic Medicine and 
Reconstructive Surgery and is nationally and internationally recognized for 
research in pelvic floor disorders and has served as primary investigator on many 
studies funded by the National Institute of Health. She has authored or co-
authored 150 scientific papers and currently serves on the editorial board of 
Obstetrics & Gynecology and the Journal of Female Pelvic Medicine & 
Reconstructive Surgery. The other study physicians assisting in recruiting efforts 
have completed their fellowships in Female Pelvic Medicine & Reconstructive 
surgery and are both involved in numerous research studies and serve as 
reviewers for several scientific journals. The nurse practitioner on staff at the 
IPHP has worked on several other protocols during her time at Northwestern. The 
study coordinator on staff has over 3 years of research experience and 1 year of 
experience working in clinical trials and consenting patients.
Due to the high volume of patients that present with mixed urinary incontinence 
in our clinic, it is feasible that the required number of suitable subjects will be 
recruited within the estimated window of time. Also, since study participants are 
undergoing surgery as part of standard of care, they will be more likely to return 
for their follow-up visits since these are part of their standard post-operative care. 
Our center will begin enrolling participants once we have IRB approval, 
tentatively July 2015. With the time required recruit 100 patients (approximately 
two years), collect outcomes data on the enrolled subjects for a year, and analyze 
data, this study will be active until June 2018.
The Integrated Pelvic Health Program, affiliated with Northwestern Memorial 
Hospital, helps individuals with pelvic floor disorders. It is the only program in 
the Chicago area that brings together a multispecialty approach to pelvic floor 
disorders in one location. Our dedicated team of physicians, nurses, and physical 
therapists are committed to restoring the quality of life for people with such 
disorders. Both the physicians and the facilities offer state-of-the-art resources to 
ensure the highest quality evaluation, medical and surgical care to women with 
incontinence and prolapsed. Our physicians are national leaders in minimally 
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Incontinence 
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invasive pelvic reconstructive surgery and sacral nerve stimulation for urinary and 
fecal incontinence.
All study staff members are in possession of the protocol and the protocol has 
been reviewed by all of the study members during a research conference. 
Research procedures have been made clear and were outlined by the study 
coordinator and Principle Investigator.
16.0
Recruitment Methods
Subjects with mixed urinary incontinence already undergoing retropubic 
midurethral sling for bothersome stress urinary incontinence will be identified at 
the Integrated Pelvic Health Program, and Northwestern Medicine. Once potential 
subjects are identified, the study coordinator will provide the patient with 
information about the study.
The source of the subjects will be those women meeting criteria for mixed urinary 
incontinence who are already undergoing a retropubic midurethral sling for 
bothersome stress urinary incontinence with one of the providers at the Integrated 
Pelvic Health Program affiliated with Northwestern Medicine.
17.0
Local Number of Subjects
This is a single center study at Northwestern Medicine.  We will require up to 100 
participants to meet power requirements for this study while appropriately 
accounting for attrition rate.
18.0
Provisions to Protect the Privacy Interests of Subjects
To protect privacy interests, the personal health information collected for research 
purposes will be collected from the subject’s electronic medical record to limit the 
amount of people they interact with and provide personal information to.
All interviews will be conducted in a private office or examination room to ensure 
confidentiality. Phone conversations will be conducted from private offices. Any 
study correspondence with patients will not indicate disease status or focus on the 
envelope. All physical exams will be conducted in a private examination room. 
Subjects will be allowed to skip any question on a questionnaire that makes them 
feel uncomfortable.
The study staff, including investigators and the study coordinator, will have 
access to the subject’s medical record and study documents. All study documents 
will be kept in a locked cabinet and only those with password required access to 
EPIC will be able to access the subject’s electronic medical record.
19.0
Compensation for Research-Related Injury
Subjects in need of medical follow-up will be referred to their provider. There 
will be no compensation for research-related injury.
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20.0
Economic Burden to Subjects
Because these patients will already be undergoing retropubic midurethral sling as 
an inclusion criterion for participation in this study, each participant would 
already be incurring the costs of visits, parking, all pre-operative and post-
operative testing, and operating room fees.  There are no additional tests or visits 
required as part of this study.  All onabotulinumtoxinA used and placebo saline in 
addition to syringes and needles will be covered in the study budget and not 
incurred by the patient or the patient’s insurance.
21.0
Consent Process
Consent will be obtained from the patient by research staff, either by the study 
coordinator or by one of the investigators. The informed consent process is 
expected to take up to 30 minutes. The person obtaining consent will verbally go 
through the form and also allow time for the subject to read the form in its 
entirety. The subject will be allowed to consult with family. The person obtaining 
consent will ensure the subject understands the purpose and procedures of the 
study. After all the subject’s questions have been answered, the subject will be 
given time to make a decision about enrollment. The original signed written 
consent form will be kept separately from research data at Northwestern, and a 
signed copy will be given to the patient. We will not be enrolling Non-English 
speaking subjects. Decisionally-impaired subjects will not be enrolled in our 
study.  
22.0
Process to Document Consent in Writing
We will be following “SOP: Written Documentation of Consent (HRP-091)” and 
will be documenting process of consent in writing.
23.0
Drugs or Devices
OnabotulinumtoxinA and placebo saline will be stored in the IPHP clinic in a 
locked cabinet (as is currently done). Once the patient is randomized, the study 
coordinator will inform the clinic RN who will sterilely prepare the medication 
and deliver it to the operating room with the patient’s study number on the 
medication, so both the patient and the physician remain masked.  Lot number 
and expiration date will be recorded for each study patient.
IRB #: STU00201249 Approved by NU IRB for use on or after 3/11/2021 through 3/10/2022.

Prot_000.pdf: 
Cover Page for Protocol 
Sponsor name: 
Northwestern University
NCT number 
NCT02678377
Sponsor trial ID: 
STU00201249
Official title of study: 
The SLIM Study: Sling and Botox® Injection for Mixed 
Urinary Incontinence
Document Date:
11 March 2021 


PROTOCOL TITLE: The SLIM Study: Sling and Botox® Injection for Mixed Urinary 
Incontinence
Page 1 of 14
Version Date: August 12, 2016
PROTOCOL TITLE:
The SLIM Study: Sling and Botox® Injection for Mixed Urinary Incontinence
PRINCIPAL INVESTIGATOR:
Kimberly Kenton, MD, MS
Professor of Obstetrics & Gynecology and Urology
Department of Obstetrics and Gynecology
Division of Female Pelvic Medicine and Reconstructive Surgery
Email: aleaderc@nm.org 
Phone: 312-472-3874
Address: 250 E. Superior St.
  Suite 05-2370
  Chicago, IL 60611
VERSION NUMBER:
Version 3
VERSION DATE:
8/12/2016
IRB #: STU00201249 Approved by NU IRB for use on or after 3/11/2021 through 3/10/2022.


PROTOCOL TITLE: The SLIM Study: Sling and Botox® Injection for Mixed Urinary 
Incontinence
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Table of Contents
1.0
Objectives .................................................................................................................3
2.0
Background...............................................................................................................3
3.0
Inclusion and Exclusion Criteria ..............................................................................6
4.0
Study Timelines........................................................................................................7
5.0
Study Endpoints........................................................................................................7
6.0
Procedures Involved .................................................................................................8
7.0
Data and Specimen Banking.....................................................................................9
8.0
Data and Specimen Management .............................................................................9
9.0
Provisions to Monitor the Data to Ensure the Safety of Subjects...........................10
10.0
Withdrawal of Subjects*.........................................................................................10
11.0
Risks to Subjects*...................................................................................................10
12.0
Potential Benefits to Subjects .................................................................................11
13.0
Sharing of Results with Subjects ............................................................................11
14.0
Setting.....................................................................................................................11
15.0
Resources Available ...............................................................................................12
16.0
Recruitment Methods..............................................................................................13
17.0
Local Number of Subjects ......................................................................................13
18.0
Provisions to Protect the Privacy Interests of Subjects ..........................................13
19.0
Compensation for Research-Related Injury............................................................13
20.0
Economic Burden to Subjects.................................................................................14
21.0
Consent Process......................................................................................................14
22.0
Process to Document Consent in Writing...............................................................14
23.0
Drugs or Devices ....................................................................................................14
IRB #: STU00201249 Approved by NU IRB for use on or after 3/11/2021 through 3/10/2022.


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1.0
Objectives
 Primary Aim:  To determine whether synthetic retropubic midurethral sling 
(MUS) combined with concomitant detrusor injections of onabotulinumtoxinA is 
more effective than midurethral sling alone in improving mixed urinary 
incontinence (MUI) symptoms.
Secondary Aims:
a. To compare incontinence episode frequency on a 3-day diary in women
who undergo midurethral sling plus onabotulinumtoxinA to those who
undergo midurethral sling alone.
b. To compare urinary incontinence symptoms and quality of life in women
who undergo midurethral sling plus onabotulinumtoxinA to those who
undergo midurethral sling alone.
c. To identify baseline factors associated with persistent urgency
incontinence in women after midurethral sling alone and midurethral sling
plus onabotulinumtoxinA.
 Hypotheses:
1. By using a double-blind randomized controlled trial, we will be
able to show that retropubic midurethral sling surgery with detrusor
muscle onabotulinumtoxinA injection will be more effective at
controlling mixed urinary incontinence symptoms than sling surgery
alone.
2. Patients who receive both midurethral sling and
onabotulinumtoxinA injection will have objectively have fewer
incontinence episodes than those who receive midurethral sling
alone
3. Patients who receive both treatments will have better quality of
life as it relates to urinary symptoms than those who receive
midurethral sling alone
4. Patients who have persistent urgency urinary incontinence after
either midurethral sling alone or both midurethral sling and
onabotulinumtoxinA injection alone will have significantly different
baseline urine microbial content than those who do not have
persistent urgency symptoms after treatment
2.0
Background
Project Abstract:
This double-blind randomized controlled trial looks to find a better treatment for 
women with mixed urinary incontinence.  The primary aim of this study is to 
determine whether midurethral sling, the predominant incontinence surgery 
performed worldwide, combined with injections of onabotulinumtoxinA 
(Botox®) into the large muscle of the bladder improves symptoms of mixed 
urinary incontinence better than sling surgery alone.  Secondary aims are to 
IRB #: STU00201249 Approved by NU IRB for use on or after 3/11/2021 through 3/10/2022.


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compare objectively the frequency of incontinence episodes in patients who 
receive onabotulinumtoxinA injection versus those who do not. We will also 
compare urinary incontinence symptoms and quality of life measures in patients 
who receive the injections versus those who do not. Lastly, we plan to try to 
identify baseline factors associated with persistent urgency urinary incontinence 
in women after sling surgery alone and sling surgery plus injection.
We plan to enroll women who have mixed urinary incontinence and 
randomize them into either treatment with sling surgery alone or sling surgery 
with bladder onabotulinumtoxinA injection at the time of surgery. Patients will 
then be followed with scheduled, in-person follow-up with a physician at 2-
weeks,  3-months and at 1 year.  During these visits and prior to surgery, the 
patients will complete standardized surveys on urinary symptoms, quality of life, 
pelvic floor function, and sexual health.  A urine sample will also be collected 
from each patient for a detailed analysis of the microbial content that is beyond 
the scope of a normal hospital laboratory.
After this study, we hope to have developed a new and better treatment for 
mixed urinary incontinence that can be provided to women suffering with this 
malady both nationally and internationally.  There is currently no standard of care 
for treatment of mixed urinary incontinence and we aim to provide this to the 
urogynecologic community.  Additionally, differentiating those patients who will 
have persistent or worsening urgency urinary incontinence after sling surgery 
from those who have improvement in symptoms has been difficult.  By examining 
the detailed microbial content of participants’ urine, we hope to better understand 
this phenomenon.
Project Background:
Mixed urinary incontinence (MUI) is a clinical conundrum for providers and 
patients alike. The International Continence Society defined MUI as “involuntary 
loss of urine associated with urgency or urgency incontinence AND urine loss 
associated with physical exertion, sneezing or coughing or stress incontinence”. 
While some women ONLY experience one type of incontinence (stress OR 
urgency), many experience leakage with both, and it is unclear if these MUI 
symptoms are one disease with a continuum of symptoms or two separate diseases 
making treatment algorithms challenging. Despite our lack of understanding 
regarding the disease process or optimal treatment, MUI accounts for up to 50% 
of incontinence in women. The annual burden of MUI on the national economy is 
significant and growing. 
More importantly, women with MUI are more bothered and suffer more dramatic 
quality of life impact.  Yet, optimal treatments for MUI lag behind.  Definitive 
treatments for stress incontinence are typically surgical, while those for urgency 
incontinence are behavioral or medical. As early as the 1980s, investigators 
sought to determine if surgical or non-surgical treatments should be used first for 
MUI.  In one small trial, women with MUI were randomized to medical treatment 
(e.g. anticholinergic medications designed to relax the bladder muscle) for 
urgency incontinence or surgery for stress incontinence.  Forty-three percent of 
women in the medicine group continued to have incontinence symptoms, while 
IRB #: STU00201249 Approved by NU IRB for use on or after 3/11/2021 through 3/10/2022.


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only 12-13% of the surgical patients had persistent incontinence symptoms.  
Further complicating treatment decisions, continence procedures designed to treat 
stress incontinence have historically worsened urgency incontinence in some 
women. 
There is no high-quality evidence or consensus amongst specialists on how to 
approach treatment for women with MUI.  The optimal treatment strategy for 
women with MUI is unclear.  Historically, health care providers tried to identify 
which type of incontinence, stress or urgency, was most bothersome to the patient 
and treated the bothersome subtype first.  Those with stress predominant 
incontinence underwent surgery, while those with urgency predominant 
incontinence received medications and behavioral/physical therapy.
Currently, the primary surgical treatment of stress incontinence is midurethral 
slings. Greater than 66% of women undergoing midurethral sling surgery for 
stress incontinence also report baseline urgency incontinence. Investigators report 
improvement in urgency incontinence in some women with MUI undergoing 
midurethral sling, however, subjective outcomes are worse in women with MUI 
compared to pure stress incontinence and the lower cure rates are associated with 
persistent urgency incontinence. Studies also demonstrated that urgency 
incontinence is the major cause of patient dissatisfaction of surgery for stress 
incontinence and prolapse. Reduced satisfaction and treatment failure after 
midurethral sling surgery is associated with higher baseline urgency and urgency 
incontinence.  Additionally, one study showed that 33% of women who did not 
have urgency incontinence symptoms prior to midurethral sling developed 
urgency symptoms after surgery. This study further complicates the issue, as it is 
possible that midurethral sling may cause urgency symptoms in some patients. 
Overall, studies have shown a wide range in improvement of urgency 
incontinence symptoms after midurethral sling placement between 46-74%.  The 
wide range of anticipated improvement coupled with the not insignificant rate of 
de novo in urgency incontinence symptoms after midurethral sling, make 
counseling women with MUI contemplating surgery challenging.  Essentially, 
surgeons can counsel women with MUI that although their stress incontinence 
symptoms are likely to improve after midurethral sling (90% satisfaction), their 
urgency incontinence may get better, stay the same, or get worse.
Other strategies for treating MUI have also been proposed including treatment 
with anticholinergic medication in addition to traditional sling surgery. In an 
AHRQ funded study, anticholinergic medical therapy had minimal to moderate 
efficacy for treatment of urgency incontinence symptoms. Furthermore, many 
women taking anticholinergic medications suffer bothersome side effects, such as 
dry mouth and constipation, and over 50% stop taking the medication during their 
treatment course.  In our prior work, we found that women treated with 
anticholinergic medications prior to traditional continence surgery were more 
likely to have urgency symptoms post-operatively, suggesting poorer outcomes in 
women with MUI. Understandably, patients with persistent urgency symptoms 
post-operatively are significantly less satisfied with their symptoms and surgical 
outcomes than patients who have complete resolution of their symptoms.
IRB #: STU00201249 Approved by NU IRB for use on or after 3/11/2021 through 3/10/2022.


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Given the known treatment shortcomings of anticholinergic medications for 
treatment of urgency incontinences, clinician-investigators began injecting 
onabotulinumtoxinA into the bladder in an attempt reduce urgency incontinence 
while minimizing side effects.  OnabotulinumtoxinA is a neurotoxin, which 
inhibits acetylcholine release and temporarily relaxes the bladder muscle to inhibit 
urgency incontinence.   A large NIH funded multicenter double-blind randomized 
controlled trial investigated the role of detrusor injections with 100 units of 
onabotulinumtoxinA compared to anticholinergic medications for the treatment of 
urgency incontinence.  More women in the onabotulinumtoxinA group were 
completely dry (no incontinence episodes) without having the bothersome side 
effects of the anticholinergic medications.  Women in the onabotulinumtoxinA 
group also had higher rates of transient urinary retention requiring self-
catheterization and urinary tract infection; however, these rates were significantly 
lower than earlier studies using higher doses of onabotulinumtoxinA.  Several 
studies suggest the optimal dose of onabotulinumtoxinA, which maximized 
resolution of urinary incontinence while minimizing complications, is 100 units 
per injection.  As a result, onabotulinumtoxinA injections are a standard treatment 
for urgency incontinence.
Given the superior efficacy and side effect profile of onabotulinumtoxinA and the 
high rates of persistent urgency incontinence and dissatisfaction after sling 
surgery in women with MUI, we hypothesize that a combined treatment approach 
for women with MUI is superior to simply treating the stress incontinence alone.  
Specifically, women with MUI undergoing sling plus intradetrusor 
onabotulinumtoxinA will have fewer bothersome incontinence symptoms than 
women undergoing sling alone.  The aim of this double-blind randomized 
comparative efficacy trial is to determine if women with MUI planning sling 
surgery sustain greater improvement in their urinary symptoms with the addition 
of onabotulinumtoxinA injection at the time of sling.  
A secondary aim is to identify subsets of women who may be prone to 
persistent urinary symptoms after treatment.  Although classic teaching is that the 
urine is ‘sterile’, recent studies identified that urine of normal asymptomatic 
women contain bacteria; in other words, similar to all other organ systems in the 
body (gastrointestinal tract, skin, etc) urine is NOT sterile rather it has a 
microbiome.  Recent data suggests that patients with urgency symptoms have a 
different bladder microbiome (different bacteria) than those who do not suffer 
from this ailment.  Our unit recently found that the microbiome of women with 
urgency and bladder pain differs from age-matched controls.
3.0
Inclusion and Exclusion Criteria
All women with MUI planning surgical intervention with midurethral sling will 
be approached for study participation.  MUI will be defined as an answer of 
“moderately’ or “quite a bit” bothered to Urinary Distress Inventory (UDI) items 
(2) “urine leakage with a feeling of urgency” AND (3) “urine leakage related to 
coughing, sneezing, or laughing”.
IRB #: STU00201249 Approved by NU IRB for use on or after 3/11/2021 through 3/10/2022.


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Enrolled participants must meet all the following criteria:

Undergoing mid-urethral sling surgery

Have symptoms of both stress and urgency urinary incontinence 

Able to consent, fill out study documents, and complete all study 
procedures and follow-up visits

At least 18 years of age

English speaking

Be able and willing to learn clean intermittent self catheterization 
technique
Women will be excluded for any of the following reasons:

History of recurrent UTI (defined as three culture proven UTIs within last 
12 months)

Systemic neuromuscular disease known to affect the lower urinary tract

Undergoing concomitant prolapse surgery

Previous incontinence surgery

Treatment with anticholinergic medication in the last 2 months

Darifenacin/Enablex

Oxybutynin IR/Ditropan

Oxybutynin ER/Ditropan XL

Oxybutynin Patch/Oxytrol

Oxybutynin Gel/Gelnique

Solifenacin/Vesicare

Tolterodine IR/Detrol

Tolterodine ER/Detrol LA

Trospium IR/Sanctura

Trospium ER/Sanctura XR

Fesoterodine/Toviaz

Mirabegron/Myrbetriq

Previous bladder injection with onabotulinumtoxinA

Prisoner status

Pregnancy

Patients on SGLT2 Inhibitors 

(canagliflozin, dapagliflozin, and empagliflozin)
4.0
Study Timelines
Individuals will participate and remain enrolled in the study for 
approximately 1 year or until they have completed their one year post-
operative visit.
We estimate that it will take two years to enroll the total number of 
subjects required to complete this study.
We expect to be able to complete primary analyses of this study 3 years 
from the date of IRB approval.
5.0
Study Endpoints
IRB #: STU00201249 Approved by NU IRB for use on or after 3/11/2021 through 3/10/2022.


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Primary endpoint will occur at 3 months.  Secondary endpoint is at 1 year, or 
when the subject completes her 1 year post-operative visit.
6.0
Procedures Involved
Women with MUI undergoing midurethral sling for bothersome SUI will 
be randomized to 100 units onabotulinumtoxinA or placebo (saline) injections in 
the detrusor at the time of sling surgery.  Specifically, the retropubic midurethral 
slings used will be either the Gynecare TVT Exact Continence System by Ethicon 
or the Boston Scientific Advantage Fit Transvaginal Mid-Urethral Sling System 
based on surgeon preference. Surgeons and participants will be masked to study 
assignment.  Primary outcome will be the Patient Global Assessment of 
Improvement (PGI-I), a global, patient oriented measure that assesses symptoms 
of SUI and UUI at 3-months.  The primary outcome, PGI-I asks subjects to best 
describe how their urinary tract condition is now, compared to how it was before 
treatment for urinary leakage. Response choices are: (1) ‘very much better’, (2) 
‘much better’, (3) ‘a little better’, (4) ‘no change’, (5) ‘a little worse’, (6) ‘much 
worse’, and (7) ‘very much worse’. Construct validity of the PGI-I was 
demonstrated in incontinence trials.32  
We selected a subjective, patient oriented outcome as our primary 
outcome measure secondary to the complex nature of MUI, and the association 
between dissatisfaction after incontinence surgery and persistent or new onset 
urgency.  We felt the patient’s overall impression of their continence status 
represented a more clinically meaningful outcome than traditional objective 
measures.  In addition, we will compare subjective and objective urinary 
symptoms and quality of life amongst treatment groups 3-months and 1-year after 
surgery.
All women with MUI planning surgical intervention with midurethral 
sling will be approached for study participation.  MUI will be defined as an 
answer of “moderately’ or “quite a bit” bothered to Urinary Distress Inventory 
(UDI) items (2) “urine leakage with a feeling of urgency” AND (3) “urine leakage 
related to coughing, sneezing, or laughing”.
Women will undergo standardized urologic evaluation at baseline 
including assessment of urinary symptoms and quality of life using short forms of 
the Urinary Distress Inventory (UDI-6) and Incontinence Impact Questionnaire 
(IIQ-7); assessment of overall severity of their incontinence symptoms with the 
Patient Global Impression of Severity (PGI-S);32 post void residual urine volume; 
urine analysis and culture; multichannel urodynamic testing; and pelvic exam 
with prolapse quantification using pelvic organ prolapse quantification system 
(POP-Q)33.  All patients will also complete a 3-day urinary diary at baseline 
quantifying the number of incontinence episodes (stress and urge).   Three months 
and 1-year after surgery, patients will again complete all baseline measures, 
including UDI, IIQ, PGI-I, PGI-S, and 3-day diary to report symptom and 
objective urinary symptoms after treatment.  A sample of urine will be obtained 
for microbiome analysis at each visit.
Scheduled in-person follow-up visits will occur at baseline, 2 and 6-weeks, 
3-months, and 1-year after surgery. At the baseline, 3-month, and 1-year visits, 
IRB #: STU00201249 Approved by NU IRB for use on or after 3/11/2021 through 3/10/2022.


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research staff will collect the 3-day diary information and record any adverse 
events that have occurred during the post-operative period. Subjects will also 
complete the general and condition specific symptom and QOL questionnaires.  In 
addition, an update of current medication and assessment as to whether any 
evaluation or treatment for pelvic floor disorders or adverse outcomes from 
surgery have occurred since the previous evaluation will be assessed by clinical 
staff at the in-person visits. All patient and survey data will be recorded in 
RedCAP.
7.0
Data and Specimen Banking
Data will be collected at Northwestern Medicine. All study data will be 
recorded on Case Report Forms by research coordinator and securely 
maintained in a locked cabinet. CRFs will be derived from source 
documentation and/or participant self-report. Data will be entered by the 
research coordinator at Northwestern into a REDCap database that will be 
stored on a secure sever at the Data Coordinating Center. All collected 
data must be entered into REDCap within 5 business days. Any queries to 
data entered into REDCap will be addressed by site staff within 5 business 
days. It is each site’s responsibility to regularly check REDCap for data 
queries. 
Both data and specimens will be banked for further use. Patient specimens 
will not have any directly identifiable patient information on them, but 
will remain coded for future studies if the specimen is unused in this 
study.  Argonne National Laboratories will have no access to any patient 
identifying information.  All patient identifiers will be removed prior to 
transferring microbiome samples to Argonne National Laboratories for 
processing.
8.0
Data and Specimen Management
All analyses will be conducted using SPSS version 20 (Chicago, IL).  Histograms 
will be used to determine distribution of data and appropriate non-parametric or 
parametric tests will be selected.  Primary outcome will be analyzed 
dichotomously with responses of “very much better” and “much better” 
considered an optimal outcome.  A chi-square test of association will be used to 
compare primary outcome (PGI-I) between treatment groups.  Questionnaire data 
will be compared between sling alone and sling plus onabotulinumtoxinA groups 
using Mann Whitney test. All test results will be considered significant with a p-
value of less than or equal to 0.05.
In a study of women with MUI undergoing retropubic midurethral sling, 66% of 
patients reported a PGI-I of “very much better’ or ‘much better’ at 3-months.23  
Similarly, in a randomized trial of intravesical onabotulinumtoxinA 55% of 
participants had PGI-I scores of “very much better’ or ‘much better’.  Therefore, 
assuming “optimal outcomes’ (PGI-I scores of “very much better’ or ‘much 
better) in 66% of women undergoing sling alone and 93% in those undergoing 
sling plus onabotulinumtoxinA, we will need to recruit 34 patients in each group 
IRB #: STU00201249 Approved by NU IRB for use on or after 3/11/2021 through 3/10/2022.


PROTOCOL TITLE: The SLIM Study: Sling and Botox® Injection for Mixed Urinary 
Incontinence 
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to show a significant difference with 80% power at a 0.5 significance level.  
Assuming a significant attrition rate, we will recruit approximately 100 women 
(50 in each arm).
Data will be collected at Northwestern Medicine. All study data will be recorded 
on Case Report Forms by research coordinator and securely maintained in a 
locked cabinet that only the study coordinator has access to. CRFs will be derived 
from source documentation and/or participant self-report. Data will be entered by 
the research coordinator at Northwestern into a REDCap database that will be 
stored on a secure sever. Only study staff will have passwords to access the 
project data on REDCap. 
The data that is banked locally will be entered into an electronic data capture 
website. All users of REDCap need an institutional username and password to log 
in and to enter data. Research personnel, including study staff as well as study 
doctors will be able to collect and have access to subject data.
All specimen collected will be stored locally in the clinic storage facility until 
patient de-identification and subsequent transfer to Argonne National Laboratory 
for analysis can be completed.  Any specimens that are not used for this study will 
be stored for future study use.  Only the study coordinator and physicians 
participating in the study directly will have access to the storage facility for the 
purposes of adding specimens and sending them out only.  Specimens will be 
batch-shipped to Argonne National Laboratories when enough have accumulated 
to do so.
9.0
Provisions to Monitor the Data to Ensure the Safety of Subjects
Adverse events associated with midurethral sling surgery in conjunction with 
onabotulinumtoxinA injection will be recorded, but only include events such as 
post-operative urinary retention requiring catheterization, post-operative urinary 
tract infection, and persistent urinary urgency. Adverse events will be recorded at 
each follow up visit on Case Report Forms and subsequently will be added in to 
REDCap electronic data capture system. The PI will be notified of any adverse 
events, which will be resolved with the patient.
10.0
Withdrawal of Subjects*
Subjects will be withdrawn from the research without their consent if they do not 
return for the scheduled 3 month post-operative visit.  In this case, subjects will be 
notified that they can no longer participate and their insurance billed for the cost 
of the onabotulinumtoxinA used during the procedure, with the subject covering 
any cost not covered by insurance.
11.0
Risks to Subjects*
Risks associated with the project are minimal.  Patients participating in the project 
will already be undergoing a retropubic midurethral sling for bothersome stress 
IRB #: STU00201249 Approved by NU IRB for use on or after 3/11/2021 through 3/10/2022.


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Incontinence 
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urinary incontinence, and will already have been counseled on and have 
understood the risks associated with that surgical procedure.  None of the risks 
associated with that surgical procedure will change (increase or decrease) by 
participating in this study.
This additional risks associated with the procedure are for the patients in the 
onabotulinumtoxinA arm.  Intravesical injection incurs a 5% increased risk of 
urinary retention requiring clean intermittent self catheterization.  All patients will 
be taught this technique prior to the procedure regardless of study arm.  Those 
with urinary retention have an increased risk of urinary tract infection.  This is 
time-limited and last for less than 2 months on average.  All patients will be 
informed of these risks as part of the consent process.
Another risk to subjects is that we will be collecting their personal health 
information in a database. All of the data will be kept confidential and will be 
stored on password protected, secure servers, or in locked cabinet files that only 
study staff on the project have access to. Personal health information will be 
stored on files that are separate from the subject’s name, all health information 
will be coded. Coded list will be kept on secure, password protected file.
12.0
Potential Benefits to Subjects
Given the superior efficacy and side effect profile of onabotulinumtoxinA and the 
high rates of persistent urgency incontinence and dissatisfaction after sling 
surgery in women with MUI, we hypothesize that a combined treatment approach 
for women with MUI is superior to simply treating the stress incontinence alone.  
Specifically, women with MUI undergoing sling plus intradetrusor 
onabotulinumtoxinA will have fewer bothersome incontinence symptoms than 
women undergoing sling alone.  It is possible that subjects will have significant 
improvement in quality of life due to the improvement in urinary symptoms that 
they would not have been offered without this study.
13.0
Sharing of Results with Subjects
Results will not be directly shared with subjects
14.0
Setting
Research will be conducted in Northwestern Medical Group’s outpatient clinic, 
the Integrated Pelvic Health Program (IPHP). Potential subjects will be identified 
and recruited by physicians within the practice. Once potential subjects are 
identified, the study coordinator will provide the patient with information about 
the study. If the patient is interested in joining the study, the study coordinator 
will consent the patient in the IPHP clinic. The patients will complete 
questionnaires per the study either at home or in the clinic in a private room. 
Demographic and medical and surgical data will be collected from the patient’s 
medical record and recorded on the RedCAP secure server.
IRB #: STU00201249 Approved by NU IRB for use on or after 3/11/2021 through 3/10/2022.


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Incontinence 
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After consenting to the study, the surgical procedure that subjects are undergoing 
as part of their standard of care will be performed at an NMHC facility. The 
onabotulinumtoxinA injections will be performed in the operating room by one of 
the study physicians. Randomization will be performed via RedCAP on a secure 
online server through a hospital computer.
The subjects post-operative visits will take place in the Integrated Pelvic Health 
program, and NMHC outpatient clinic, as part of standard of care. Additional 
questionnaires will be completed at these visits and data will be collected from 
these visits as well.
15.0
Resources Available
The staff that will be involved in this research are highly qualified. The Principle 
Investigator, Dr. Kimberly Kenton, is the chief of Female Pelvic Medicine and 
Reconstructive Surgery and is nationally and internationally recognized for 
research in pelvic floor disorders and has served as primary investigator on many 
studies funded by the National Institute of Health. She has authored or co-
authored 150 scientific papers and currently serves on the editorial board of 
Obstetrics & Gynecology and the Journal of Female Pelvic Medicine & 
Reconstructive Surgery. The other study physicians assisting in recruiting efforts 
have completed their fellowships in Female Pelvic Medicine & Reconstructive 
surgery and are both involved in numerous research studies and serve as 
reviewers for several scientific journals. The nurse practitioner on staff at the 
IPHP has worked on several other protocols during her time at Northwestern. The 
study coordinator on staff has over 3 years of research experience and 1 year of 
experience working in clinical trials and consenting patients.
Due to the high volume of patients that present with mixed urinary incontinence 
in our clinic, it is feasible that the required number of suitable subjects will be 
recruited within the estimated window of time. Also, since study participants are 
undergoing surgery as part of standard of care, they will be more likely to return 
for their follow-up visits since these are part of their standard post-operative care. 
Our center will begin enrolling participants once we have IRB approval, 
tentatively July 2015. With the time required recruit 100 patients (approximately 
two years), collect outcomes data on the enrolled subjects for a year, and analyze 
data, this study will be active until June 2018.
The Integrated Pelvic Health Program, affiliated with Northwestern Memorial 
Hospital, helps individuals with pelvic floor disorders. It is the only program in 
the Chicago area that brings together a multispecialty approach to pelvic floor 
disorders in one location. Our dedicated team of physicians, nurses, and physical 
therapists are committed to restoring the quality of life for people with such 
disorders. Both the physicians and the facilities offer state-of-the-art resources to 
ensure the highest quality evaluation, medical and surgical care to women with 
incontinence and prolapsed. Our physicians are national leaders in minimally 
IRB #: STU00201249 Approved by NU IRB for use on or after 3/11/2021 through 3/10/2022.


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Incontinence 
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invasive pelvic reconstructive surgery and sacral nerve stimulation for urinary and 
fecal incontinence.
All study staff members are in possession of the protocol and the protocol has 
been reviewed by all of the study members during a research conference. 
Research procedures have been made clear and were outlined by the study 
coordinator and Principle Investigator.
16.0
Recruitment Methods
Subjects with mixed urinary incontinence already undergoing retropubic 
midurethral sling for bothersome stress urinary incontinence will be identified at 
the Integrated Pelvic Health Program, and Northwestern Medicine. Once potential 
subjects are identified, the study coordinator will provide the patient with 
information about the study.
The source of the subjects will be those women meeting criteria for mixed urinary 
incontinence who are already undergoing a retropubic midurethral sling for 
bothersome stress urinary incontinence with one of the providers at the Integrated 
Pelvic Health Program affiliated with Northwestern Medicine.
17.0
Local Number of Subjects
This is a single center study at Northwestern Medicine.  We will require up to 100 
participants to meet power requirements for this study while appropriately 
accounting for attrition rate.
18.0
Provisions to Protect the Privacy Interests of Subjects
To protect privacy interests, the personal health information collected for research 
purposes will be collected from the subject’s electronic medical record to limit the 
amount of people they interact with and provide personal information to.
All interviews will be conducted in a private office or examination room to ensure 
confidentiality. Phone conversations will be conducted from private offices. Any 
study correspondence with patients will not indicate disease status or focus on the 
envelope. All physical exams will be conducted in a private examination room. 
Subjects will be allowed to skip any question on a questionnaire that makes them 
feel uncomfortable.
The study staff, including investigators and the study coordinator, will have 
access to the subject’s medical record and study documents. All study documents 
will be kept in a locked cabinet and only those with password required access to 
EPIC will be able to access the subject’s electronic medical record.
19.0
Compensation for Research-Related Injury
Subjects in need of medical follow-up will be referred to their provider. There 
will be no compensation for research-related injury.
IRB #: STU00201249 Approved by NU IRB for use on or after 3/11/2021 through 3/10/2022.


PROTOCOL TITLE: The SLIM Study: Sling and Botox® Injection for Mixed Urinary 
Incontinence 
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20.0
Economic Burden to Subjects
Because these patients will already be undergoing retropubic midurethral sling as 
an inclusion criterion for participation in this study, each participant would 
already be incurring the costs of visits, parking, all pre-operative and post-
operative testing, and operating room fees.  There are no additional tests or visits 
required as part of this study.  All onabotulinumtoxinA used and placebo saline in 
addition to syringes and needles will be covered in the study budget and not 
incurred by the patient or the patient’s insurance.
21.0
Consent Process
Consent will be obtained from the patient by research staff, either by the study 
coordinator or by one of the investigators. The informed consent process is 
expected to take up to 30 minutes. The person obtaining consent will verbally go 
through the form and also allow time for the subject to read the form in its 
entirety. The subject will be allowed to consult with family. The person obtaining 
consent will ensure the subject understands the purpose and procedures of the 
study. After all the subject’s questions have been answered, the subject will be 
given time to make a decision about enrollment. The original signed written 
consent form will be kept separately from research data at Northwestern, and a 
signed copy will be given to the patient. We will not be enrolling Non-English 
speaking subjects. Decisionally-impaired subjects will not be enrolled in our 
study.  
22.0
Process to Document Consent in Writing
We will be following “SOP: Written Documentation of Consent (HRP-091)” and 
will be documenting process of consent in writing.
23.0
Drugs or Devices
OnabotulinumtoxinA and placebo saline will be stored in the IPHP clinic in a 
locked cabinet (as is currently done). Once the patient is randomized, the study 
coordinator will inform the clinic RN who will sterilely prepare the medication 
and deliver it to the operating room with the patient’s study number on the 
medication, so both the patient and the physician remain masked.  Lot number 
and expiration date will be recorded for each study patient.
IRB #: STU00201249 Approved by NU IRB for use on or after 3/11/2021 through 3/10/2022.

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan  
Sponsor name: 
Northwestern University
NCT number 
NCT02678377
Sponsor trial ID: 
STU00201249
Official title of study: 
The SLIM Study: Sling and Botox® Injection for Mixed 
Urinary Incontinence
Document date: 
21 October 2022 


Statistical Analysis Plan 
We based the sample size estimation off of previous studies assessing treatment of slings for mixed 
urinary incontinence and onabotulinumtoxinA injections for overactive bladder. A PGI-I response at 3 
months postoperatively of “very much better” or “much better” was designated “improved.” Assuming 
66% of women in the placebo group and 93% in the onabotulinumtoxinA group were “improved” based 
on overall PGI-I scores, 68 women (34 in each arm) were needed to show a significant difference with 
80% power at 0.05 significance level. If we assumed a 15% dropout rate, we aimed to recruit 78 
participants (39 in each arm). R 3.6.3 was used for statistical analysis of the deidentified data. 
Independent samples t test, Mann-Whitney, x2, Wilcoxon signed rank sum statistical 
tests were used as appropriate. 
21 October 2022