A Double-blind, Randomized, Controlled Trial Comparing the Safety and Efficacy of AMDC-USR With Placebo in Female Subjects With Stress Urinary Incontinence
Phase: PHASE3
Conditions: Stress Urinary Incontinence
Sponsor: Cook MyoSite

Cook MyoSite, Incorporated 
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AMDC-USR for Female SUI IND Clinical Trial 
 
COMPANY CONFIDENTIAL 
CIP 13-003-05, Version Date 18 February 2016 
CLINICAL INVESTIGATION PLAN 
 
 
A Double-blind, Randomized, Controlled Trial Comparing the Safety and Efficacy of 
AMDC-USR with Placebo in Female Subjects with Stress Urinary Incontinence 
 
 
Global Clinical Number 13-003 
 
Sponsor: 
 
 
Cook MyoSite, Incorporated 
  
 
105 Delta Drive 
Pittsburgh, PA 15238 USA  
 
 
 
Summary of Changes  
 
Version 
Description  
Date 
13-003-01 
Original version 
01 May 2013  
13-003-02 
13-003-03 
13-003-04 
Amendment 
Amendment 
Amendment 
03 June 2014 
02 November 2015 
14 January 2016 
13-003-05 
Amendment 
18 February 2016 
 
 
 

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COMPANY CONFIDENTIAL 
CIP 13-003-05, Version Date 18 February 2016 
 
CLINICAL INVESTIGATION PLAN SIGNATURE PAGE, 
CONTINUED 
 
 
 
Principal Clinical Investigator: 
 
I hereby confirm that I approve of this Clinical Investigation Plan and agree to comply 
with its terms as laid out in this document. 
 
 
X 
 
 
 
 Signature 
 
 Date (DD Month YYYY) 
 
 
 
 
 
 Printed Name 
 
 Title 
 
 
 
 Clinical Site Name 
 
 

Cook MyoSite, Incorporated 
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AMDC-USR for Female SUI IND Clinical Trial 
 
COMPANY CONFIDENTIAL 
CIP 13-003-05, Version Date 18 February 2016 
 
 
 
CONFIDENTIALITY STATEMENT 
 
 
 
This document shall be treated as a confidential document  
for the sole information and use of the  
clinical study team and the institution’s 
 Institutional Review Board (IRB). 
 
 
 

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COMPANY CONFIDENTIAL 
CIP 13-003-05, Version Date 18 February 2016 
Table of Contents 
1.0 
Clinical Investigation Plan Overview ......................................................................9 
2.0 
Objectives of the Clinical Study ............................................................................11 
2.1 
Primary Objective .......................................................................................11 
2.2 
Secondary Objectives .................................................................................12 
3.0 
Product Description and Intended Use ..................................................................12 
3.1 
General Product Description ......................................................................12 
3.1.1 Dose Justification ............................................................................13 
3.2 
Indication for Use .......................................................................................14 
3.3 
Product Identification and Tracking ...........................................................14 
3.4 
Instructions for Use ....................................................................................14 
4.0 
Summary of Preliminary Studies ...........................................................................16 
5.0 
Risk Analysis and Risk Assessment ......................................................................16 
5.1 
Risks and Foreseeable Adverse Events and Adverse Product Effects .......16 
5.2 
Methods to Minimize Risks ........................................................................17 
6.0 
Design of the Clinical Study ..................................................................................17 
6.1 
Type/Design of Study .................................................................................17 
6.2 
Inclusion and Exclusion Criteria ................................................................18 
6.3 
Endpoints ....................................................................................................22 
6.3.1 Primary Efficacy Endpoint .............................................................22 
6.3.2 Secondary Efficacy Endpoint Measures .........................................22 
6.3.3 Additional Efficacy Endpoints ........................................................22 
6.3.4 Safety Endpoints .............................................................................23 
6.3.5 Rationale for Endpoints ..................................................................23 
6.4 
Variables to be Measured to Demonstrate Achievement of Endpoints ......23 
6.5 
Measures to be Taken to Avoid or Minimize Bias .....................................25 
7.0 
Methods..................................................................................................................25 
7.1 
Initial Patient Assessment and Pre-screening .............................................26 
7.2 
Patient Consent ...........................................................................................26 
7.3 
Pre-enrollment – Screening ........................................................................26 
7.4 
Point of Enrollment ....................................................................................27 
7.5 
Medications ................................................................................................27 
7.6 
Biopsy and Randomization .........................................................................27 

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7.6.1   Post-Biopsy Follow-up .......................................................................... 28 
7.7 
Procedure – Treatment Day 0 .....................................................................28 
7.8 
Follow-up....................................................................................................29 
7.8.1 Post-Treatment Follow-up – Treatment Day 1-2 ............................29 
7.8.2  Follow-up Visit – Treatment Month 1 (± 1 week) ..........................29 
7.8.3 Follow-up Visit – Treatment Month 3 (± 4 weeks) ........................30 
7.8.4 Follow-up Visit – Treatment Month 6 (± 4 weeks) ........................30 
7.8.5 Follow-up Visit – Treatment Month 12 (± 4 weeks) ......................30 
7.8.6 Unblinded Treatment – Day 0.........................................................31 
7.8.6.1 Unblinded Follow-up - Treatment Day 1-2………………….. 31 
7.8.6.2 Unblinded Follow-up - Treatment Month 1 (± 1 week)…. 31 
7.8.6.3 Unblinded Follow-up - Treatment Month 3 (± 4 weeks)... 31 
7.8.7 Follow-up Visit – Treatment Year 2 (± 4 weeks) ...........................32 
7.9 
Duration of Study and Patient Participation ...............................................34 
7.10 
Criteria and Procedures for Withdrawal .....................................................34 
7.11 
Participation Endpoints of the Study ..........................................................34 
8.0  
Statistical Considerations .......................................................................................35 
8.1 
Hypothesis to be Tested ..............................................................................35 
8.2 
Sample Size ................................................................................................37 
8.3 
Futility Analysis .........................................................................................37 
8.4 
Randomization ............................................................................................38 
8.5 
Missing Data ...............................................................................................38 
8.6 
Site-level Poolability ..................................................................................39 
8.7 
Limitations of the Study .............................................................................40 
9.0 
Deviations from Clinical Investigation Plan ..........................................................40 
10.0 
Data Collection and Reporting...............................................................................42 
10.1 
Electronic Case Report Forms (eCRF system) ...........................................42 
10.2 
Data Reporting ............................................................................................42 
11.0 
Data Management and Quality Assurance .............................................................42 
11.1 
Data Entry and Quality Assurance .............................................................42 
11.2 
Data Monitoring Arrangements ..................................................................43 
12.0 
Safety Monitoring and Procedures for Reporting Adverse Events ........................43 
12.1 
Safety Monitoring .......................................................................................43 
12.2 
Adverse Event Reporting ............................................................................44 

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COMPANY CONFIDENTIAL 
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13.0 
Early Termination or Suspension of the Study ......................................................44 
14.0 
Ethical Considerations ...........................................................................................44 
15.0 
Publication Policy ..................................................................................................45 
16.0 
Clinical Study Administration and Investigators ...................................................45 
16.1 
Approvals and Agreements ........................................................................45 
16.2 
Investigators................................................................................................45 
16.3 
Insurance .....................................................................................................46 
17.0 
Bibliography ..........................................................................................................46 
 
Appendices  
A 
Contact Information 
B 
Written Procedures for Monitoring Studies 
C 
Definitions 
D 
Bladder “Cough” Stress Test  
E 
24-hour Pad Test 
F 
Q-tip Test 
 
 
 

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COMPANY CONFIDENTIAL 
CIP 13-003-05, Version Date 18 February 2016 
1.0 
Clinical Investigation Plan Overview 
This randomized, double-blind, placebo-controlled, multicenter, confirmatory study will 
evaluate the efficacy and safety of Cook MyoSite Incorporated Autologous Muscle 
Derived Cells for Urinary Sphincter Repair (AMDC-USR) compared to a placebo 
(vehicle) control dose in the treatment of stress urinary incontinence (SUI) in adult 
female patients. 
 
Patients will be stratified for randomization according to the number of stress 
incontinence episodes at screening (≤ 10 stress incontinence episodes, > 10 stress 
incontinence episodes) and if the patients have had previous surgery for treatment of SUI. 
Previous surgery includes but is not limited to midurethral sling, retropubic suspension, 
or bladder neck sling. For each stratum, patients will be randomly assigned to one of the 
two treatment groups (150 x 106 AMDC-USR or placebo control). The allocation ratio 
within each dose will be 2:1 (AMDC-USR: placebo control). Randomization will occur 
after enrollment, but prior to treatment. The study will enroll 267 patients (178 enrolled 
with 150 x 106 AMDC-USR and 89 enrolled with placebo control) at up to 35 clinical 
sites. Enrollment is expected to be completed within 4 years of initiating the study. 
Patients will be followed for 2 years. In addition, up to 12 roll-in patients may be treated 
at each investigative site, prior to enrolling patients in the main study arms. Therefore, up 
to 687 patients may be treated as part of this study protocol. Up to 3 initial injection 
procedures for each investigator may be proctored according to the study injection 
procedure guidelines, to ensure that investigators are familiar with the injection 
procedure. 
 
Placebo-injected patients will be given the opportunity to receive the 150 x 106 cell dose 
following the 12-month evaluation. Patients randomized to placebo control who opt to 
receive AMDC-USR treatment will be followed for up to 2 years following their initial 
placebo injection. 
 
The primary efficacy measure will be evaluated at 12 months post-treatment (initial) and 
will be based on the reduction in stress incontinence episodes, as recorded in a diary. The 
safety measures will be the incidence of study product-related serious adverse events 
(SAEs) and the incidence of study product-related, injection procedure-related, and 
biopsy procedure-related adverse events.  

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COMPANY CONFIDENTIAL 
CIP 13-003-05, Version Date 18 February 2016 
 
Analysis will also include evaluation of efficacy as measured by patient quality of life as 
reported by multiple surveys. Additionally, treatment durability at 2 years will be 
determined for patients randomized to AMDC-USR treatment. 
 
Female patients at least 18 years of age with primary symptoms of SUI as confirmed by 
patient medical history and clinical symptoms, including a focused incontinence 
evaluation, will be eligible for participation. All eligible patients consenting to study 
participation will have skeletal muscle tissue harvested via needle biopsy during an initial 
outpatient procedure. The harvested muscle tissue will be 
 
transported to Cook MyoSite, Incorporated for processing in their cell 
processing facility in Pittsburgh, Pennsylvania, USA. The muscle derived cells will be 
isolated and expanded in culture over several weeks to the final dose of 150 x 106 cells 
for the AMDC-USR-treated patients. 
 
After reaching the desired concentration, the isolated and expanded AMDC-USR will be 
frozen and shipped back to the investigating physician. 
 
 
 The resulting 
suspension will be injected into the patient’s urethral sphincter in a brief outpatient 
procedure. Patients will be assessed for improvement in urinary incontinence symptoms 
at 1 month, 3 months, 6 months, 12 months, and 2 years following treatment. Adverse 
events will be assessed and reported at each visit and during follow-up telephone calls. 
The study overview is depicted in Figure 1.1. 
 
 

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COMPANY CONFIDENTIAL 
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Informed consent is obtained 
 
 
 
 
 
 
 
 
Screening exams, assessments, and tests to confirm eligibility 
 
 
 
 
 
 
 
 
Patient meets inclusion/exclusion criteria 
 
 
 
 
 
 
 
 
Patient undergoes biopsy (formal enrollment and randomization, n = 267) and 7-day telephone follow-up 
 
 
 
 
 
 
Injection treatment with AMDC-USR 
(n = 178) 
 
 
Injection treatment with placebo 
control  
(n = 89) 
 
 
 
 
 
 
 
 
 
 
 
 
1-2 day telephone follow-up 
 
 
1-2 day telephone follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
1-month follow-up 
 
 
1-month follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
3-month follow-up 
 
 
3-month follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
6-month follow-up 
 
 
6-month follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-month follow-up 
(Primary outcome measures) 
 
 
12-month follow-up 
(Primary outcome measures) 
 
 
 
 
 
 
 
 
 
 
 
 
2-year follow-up 
 
 
2-year follow-up 
 
 
 
 
 
 
 
 
 
Placebo control patients offered AMDC-USR injection treatment 
Figure 1.1. Study flow diagram 
 
2.0 
Objectives of the Clinical Study 
2.1 
Primary Objective  
The primary objective of this study is to evaluate the efficacy and safety of the Cook 
MyoSite Incorporated Autologous Muscle Derived Cells for Urinary Sphincter Repair 
(AMDC-USR) in the treatment of SUI in female patients at 12 months post-treatment. 
The primary efficacy measure will be the frequency of stress incontinence episodes, 
while safety will be determined by the frequency and severity of adverse events related to 

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COMPANY CONFIDENTIAL 
CIP 13-003-05, Version Date 18 February 2016 
study procedures and study product. 
2.2 
Secondary Objectives 
The secondary objectives of the study are to evaluate additional measures of efficacy and 
safety of AMDC-USR in the treatment of SUI in female patients at 12 months and 2 
years.  
3.0 
Product Description and Intended Use 
3.1 
General Product Description 
Please reference the manufacturer’s Instructions for Use (IFU) or the Investigator’s 
Brochure (IB) for a description of the product and dose to be used in the clinical study. 
 
 
 
For the purpose of this study, the 
product will be referred to as AMDC-USR. 
 
Cook MyoSite, Incorporated will perform cell processing and preparation of cell 
suspensions for study use in their cell processing facility in Pittsburgh, Pennsylvania 
(USA). 
 
 
 
 Cell 
processing will follow current Good Manufacturing Practice (cGMP) methodologies to 
prevent contamination and to preserve tissue function and integrity. These practices will 
include defined procedures for tissue and cell handling, processing, and identification. 
 
Each AMDC-USR study agent vial supplied to the clinical site will contain cryogenically 
preserved autologous muscle derived cells, 
 
 
 
 
 
 

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COMPANY CONFIDENTIAL 
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assessed in the previous studies, the dose of 150 x 106 AMDC-USR was chosen for the 
study.  
3.2 
Indication for Use  
 
The AMDC-USR treatment is intended for treatment of SUI in female patients. It is 
indicated for use to reduce symptoms of SUI in women who experience an average of at 
least one leak episode per day. 
3.3 
Product Identification and Tracking  
Each product is manufactured individually and labeled with a unique product code 
containing enrollment number, patient initials, and six assigned digits for identification 
and traceability. To maintain blinding, this unique product code will not indicate the dose 
of AMDC-USR or whether the product is a placebo control. All cell preparations and 
placebo controls will be transported in identical vials with the same volume of transport 
medium and reconstituted to the same final volume prior to injection to maintain study 
blinding. Additional procedures have also been established to ensure blinding. 
 
Products under investigation will be tracked by the clinical site throughout the course of 
the study through the use of a product log, which includes information such as lot 
numbers, quantity, and disposition of products. Additionally, information such as the 
quantity and lot number(s) of products used in patients will be recorded on Case Report 
Forms (CRFs). 
3.4 
Instructions for Use  
The study Procedure Guidelines, which will be provided to physicians and appropriate 
study staff at the time of training, must be followed for step-by-step instructions for 
performing the following: 
 
• Obtaining the muscle biopsy 
• Packaging and shipping the muscle biopsy 
• Storing and handling requirements 
• Resuspending the final product (AMDC-USR or placebo control) 
• Performing the injection procedure 
 

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COMPANY CONFIDENTIAL 
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Muscle Biopsy 
 
The biopsy procedure will involve minor surgery to collect 
 
 Prior to the biopsy, patients who 
are currently taking any form of anticoagulant medication must stop using the medication 
as per standard of care for outpatient surgery procedures. Antianxiety medication, 
analgesia, or minimal sedation may be provided according to each site’s standard of care. 
Muscle biopsies are obtained approximately halfway from the patella to the hip, from the 
middle region of the vastus lateralis, and slightly beyond the fascia using a percutaneous 
needle biopsy technique.  
 
 
 
 
 
 
  
 
Using aseptic technique, the biopsy tissue will be transferred to the Biopsy Medium Vial. 
The Biopsy Medium Vial will be closed and packaged for shipment to the Manufacturer. 
 
Dilution and Preparation for Injection 
 
 
 
 
The entire vial contents are used for injection.  
 
Transurethral Cell Injection 
 
The study product (AMDC-USR or vehicle placebo) is injected into the urethral sphincter 
using a transurethral approach under local anesthesia (or in accordance with site standard 
of care regarding anesthesia). 
 
 
 The injections should be made into the muscle 

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of the urethral sphincter. Materials contacting the urethral tissue will include the patient’s 
own AMDC-USR, the cryogenic medium in which the cells are suspended and shipped, 
and the physiologic saline used to dilute the mixture for injection. Prior to the injection, 
patients who are currently taking any form of anticoagulant medication must stop using 
the medication as per standard of care for outpatient surgery procedures. Antianxiety 
medication, analgesia, or minimal sedation may be provided according to each site’s 
standard of care or physician’s discretion. 
 
 
 
 
 
 
 
 
 
 
After the injection is completed, cystoscopy is used to ensure the injection did not cause 
any excessive bleeding and/or excessive trauma. A post-void ultrasound/bladder scan is 
performed to determine post-void residual (PVR) urine volume.  
4.0 
Summary of Preliminary Studies 
Please refer to the Investigator’s Brochure for a summary of non-clinical testing and a 
summary of previous clinical experiences with this product or similar products. 
5.0 
Risk Analysis and Risk Assessment 
5.1 
Risks and Foreseeable Adverse Events and Adverse Product Effects 
Please refer to the Investigator’s Brochure for a list of specific risks of study procedures 
and study products.   
 

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5.2 
Methods to Minimize Risks  
This product will be administered only by trained healthcare professionals who are 
experienced with cystoscopy, urethral injection, and use of urethral bulking agents. 
Patients will be selected according to the indication and in accordance with 
inclusion/exclusion criteria outlined in this document. Adherence to and training on the 
research Clinical Investigation Plan (CIP) are necessary to reduce material- and 
procedure-related risk. Routine catheterization and venipuncture will be performed by 
qualified personnel. 
 
The product design, non-clinical testing, clinical study design, and guidelines are 
intended to minimize the risks associated with the use of this product. The risks of the 
study have been minimized and the potential benefits outweigh the risks. 
6.0 
Design of the Clinical Study 
6.1 
Type/Design of Study 
This randomized, double-blind, placebo-controlled, multicenter, confirmatory study will 
evaluate the efficacy and safety of Cook MyoSite Incorporated AMDC-USR compared to 
a placebo control dose for the treatment of SUI in adult female patients. 
 
The study will enroll 267 patients (178 enrolled with 150 x 106 AMDC-USR and 89 
enrolled with placebo control) at up to 35 clinical sites. Enrollment is expected to be 
completed within 4 years of initiating the study. Patients will be followed for 2 years.  
 
The sponsor may evaluate up to 12 initial patients (roll-in patients) at each investigative 
site.  Up to 3 initial injection procedures for each investigator may be proctored 
according to the study injection procedure guidelines, to ensure that investigators are 
familiar with the injection procedure. The roll-in patients will be followed according to 
the protocol-specified schedule but the data from these patients will not be used for 
primary efficacy analysis. Data from roll-in patients will be included in the safety 
analyses. Screening stress incontinence episodes from the roll-in patients will be 
collected and examined by an independent CRO (separate from the primary CRO being 
used for this study). Since the collection of stress incontinence episode data contributes to 
the primary efficacy endpoint, it is important to provide an early assessment of the 

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homogeneity of these data. 
6.2 
Inclusion and Exclusion Criteria 
Patient eligibility for enrollment shall be based on known information at the time of the 
screening. Information obtained at a later date may contradict previous information, but 
this will not be considered a violation of the CIP. 
 
Inclusion Criteria  
 
A patient is deemed suitable for inclusion in the study if the patient meets the following 
criteria: 
 
1. Adult female (≥ 18 years of age) with primary and moderate-to-severe symptoms 
of SUI (1 ≤ daily stress incontinence episodes per diary ≤ 15), as confirmed by 
patient medical history and clinical symptoms, including a focused incontinence 
evaluation and have a history of inefficient, insufficient, or refused pelvic floor 
muscle training (PFMT). 
2. Must complain of involuntary leakage on effort or exertion or on sneezing or 
coughing and must produce a leak during the bladder “cough” stress test. 
3. Must have bladder capacity of ≥200 mL and a PVR value of ≤ 150 mL after 
repeated testing (i.e., the patient has been asked to revoid to ensure complete 
emptying of the bladder and the PVR urine volume is ≤ 150 mL). 
4. Must have low hypermobility of the urethra with Valsalva Q-tip ≤30º. 
5. Must be willing and able to comply with the study procedures, be mentally 
competent and able to understand all study requirements, must agree to read and 
sign the informed consent form prior to any study-related procedures.1 
6. Must be able to void spontaneously. 
7. Must have a negative urine test (dipstick) at time of treatment. 
8. Must be willing to use acceptable methods of contraception (birth control pills, 
barriers, or abstinence) if of childbearing potential. 
  
 
                                                 
 
1 Patients must demonstrate proficiency and willingness to complete 3-day diaries. Patients who enter data 
for less than 80% of the time intervals for their screening 3-day diary must be excluded from the study. 

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Exclusion Criteria 
 
Patients are excluded from enrollment in the study if any of the following are true: 
 
Patient History-based Criteria 
 
1. Simultaneously participating in another investigational drug or device study or has 
completed the follow-up phase for the primary endpoint of any previous study less 
than 30 days prior to the first evaluation in this study. 
2. Has been treated with an investigational device, drug, or procedure for urinary 
incontinence within the last 6 months. 
3. Has had surgical intervention in the pelvic area (e.g. surgery for SUI, mesh 
removal, prolapse surgery) within the last 6 months prior to the first evaluation in 
the study. 
4. Has ever been treated with a cell therapy for SUI. 
5. An average of fewer than 1 stress incontinent episodes per day, or fewer than 
3 discrete episodes of stress incontinence during the screening 3-day diary (not 
continuously leaking, rather leakage of urine that is associated with activities such 
as lifting, coughing, sneezing, or exercise with periods free of leakage between 
episodes). An incontinent episode is a leakage of urine that would wet a pad, 
diaper, or other containment garment, or article of clothing. 
6. An average of greater than 15 stress incontinent episodes per day, or greater than 
45 discrete episodes of stress incontinence during the screening 3-day diary (not 
continuously leaking, rather leakage of urine that is associated with activities such 
as lifting, coughing, sneezing, or exercise with periods free of leakage between 
episodes). 
7. Symptoms of only urge incontinence as confirmed by basic evaluation of etiology 
from a patient medical history, including a focused incontinence history. 
8. Symptoms of mixed urinary incontinence where urge incontinence is the 
predominant factor. 
9. Stress urinary incontinence symptoms for less than 6 months prior to signing the 
informed consent. 
10. No previously attempted conservative treatment prior to signing the informed 
consent. (Examples of conservative treatment include behavior modifications, 
bladder exercises, biofeedback.) 

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11. Has experienced significant worsening or improvement in SUI symptoms within 
the last 1 month prior to signing the informed consent (i.e., symptoms have not 
been stable). 
12. Routinely has more than 2 episodes of awakening to void during normal sleeping 
hours. 
13. Urinary incontinence of neurogenic etiology. 
14. Indwelling urinary catheter or requires intermittent catheterization for bladder 
emptying. 
15. Systemic neuromuscular disorder (e.g., muscular dystrophy, multiple sclerosis, 
fibromyalgia). 
16. Uncorrected congenital abnormality leading to urinary incontinence. 
17. Morbidly obese (BMI ≥ 35). 
18. Uncontrolled diabetes. 
19. Adult nocturnal enuresis. 
20. Severe constipation (history of impaction). 
21. Compromised immune system due to disease state, chronic corticosteroid use, or 
other immunosuppressive therapy. 
22. History of radiation treatment to the urethra or adjacent (or nearby) structures. 
23. Medical condition or disorder that may limit life expectancy or that may cause CIP 
deviations (e.g., unable to perform self-evaluations and/or accurately report 
medical history, urinary symptoms, and/or data). 
24. History of bleeding diathesis, uncorrectable coagulopathy, or would refuse a blood 
transfusion. 
25. Has known allergy or hypersensitivity to bovine proteins or allergens, gentamicin 
sulfate, or ampicillin that medically warrants exclusion as determined by the 
physician. 
26. History of cancer in pelvic organs, ureters, or kidneys. 
27. Any cancer that has undergone treatment within the past 12 months.  
28. History of adult vesicoureteral reflux. 
 
Patient Physical Examination or Testing-based Criteria 
 
1. Does not have a viable mucosal lining along the urethra and bladder. 
2. Pelvic organ prolapse extending to or out of the vaginal opening, including but 
not limited to vaginal vault prolapse, uterine prolapse, cystocele, urethrocele, 
rectocele, and/or enterocele. 

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3. Fistula involving the urethra, uterus, bladder, vagina, and/or rectum. 
4. Urethral stricture, bladder neck contracture, or bladder stones.   
5. Fails to produce a leak during the bladder “cough” stress test (see Appendix D for 
a description of the test). 
6. Ambulatory 24-hour pad test, where the increased pad weight is < 3 grams (see 
Appendix E for a description of the test).  
7. Moderate or severe urethral fibrosis at likely injection site. 
8. Voiding difficulty (complains of difficulty emptying the bladder).  
9. Residual urine volume > 150 mL after repeated testing (i.e., the patient has been 
asked to revoid to ensure complete emptying of the bladder and the PVR urine 
volume is still > 150 mL). 
10. Urethral hypermobility as judged by a Q-tip angle > 30 degrees (see Appendix F 
for a description of the test). 
11. Bladder capacity < 200 mL.  
12. Tests positive for Hepatitis B (required tests: Hepatitis B Surface Antigen 
[HBsAg] and Anti-Hepatitis B Core Antibody [Anti-HBc]), Hepatitis C (required 
test: Hepatitis C Antibody [Anti-HCV]), HIV (required tests: HIV Type 1 and 2 
Antibodies [Anti-HIV-1, 2]), and/or Syphilis. 
 
Patient’s Current Status-based Criteria 
 
1. Cannot be, or is not willing to be, maintained on a stable dose and/or frequency of 
medication known to affect lower urinary tract function, including but not limited 
to, anticholinergics, beta 3 adrenergic receptor agonists, tricyclic antidepressants, 
SNRI or SSRI antidepressants, diuretics, or alpha-adrenergic blockers, for at least 
2 weeks prior to screening assessments; or use of these medications is likely to 
change during the course of the study. 
2. Cannot, or is not willing to, maintain the current treatment regimen for existing 
conservative therapy (e.g., pelvic floor muscle training routine, incontinence 
medications). 
3. Requires prophylactic antibiotics for chronic urinary tract infections, cystitis, or 
urethritis, or has required 2 or more courses of antibiotics for lower urinary tract 
infections in the 2 months prior to signing the informed consent. 
4. Pregnant, lactating, or plans to become pregnant during the course of the study. 
5. Any condition that could lead to significant post-operative complications, 
including current infection.  

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6. Unresolved pain or complication from prior intervention for incontinence or 
pelvic organ prolapse. 
7. Current or acute conditions involving cystitis or urethritis. 
8. Refuses to provide written informed consent. 
9. Not at least 18 years of age.  
10. Not available for or willing to comply with the screening, baseline, and follow-up 
evaluations as required by the CIP.  
6.3 
Endpoints 
6.3.1 Primary Efficacy Endpoint 
The number of diary-reported stress incontinence episodes will be used as the primary 
efficacy measure to assess the treatment effect of AMDC-USR for SUI symptoms at 
12 months. The primary efficacy endpoint is defined as the percentage of patients who 
have at least 50% (≥ 50%) reduction in stress incontinence episodes at 12 months using 
the ITT population, which is defined as non-roll-in patients who are randomized to either 
AMDC-USR or placebo control treatment group.  
6.3.2 Secondary Efficacy Endpoint Measures 
• Percentage of patients with at least 75% reduction in stress incontinence episodes 
from baseline at 12 months; 
• Percentage of patients with 0 or 1 stress incontinence episodes at 12 months; and 
• Improvement (reduction) in frequency of stress incontinence episodes from 
baseline at 12 months. 
6.3.3  Additional Efficacy Endpoints 
• Quality of life at 12 months as determined by Incontinence Quality of Life 
(IQOL) Assessment, Incontinence Impact Questionnaire – Short Form (IIQ – 7), 
Urogenital Distress Inventory – Short Form (UDI – 6), and Global Quality of Life 
Assessment (GQOL);  
• Association of quality of life improvement with stress incontinence episode 
reduction at 12 months;  

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• Incontinence severity as determined by Sandvik Incontinence Severity Index (ISI) 
at 12 months; and 
• Treatment durability at 2 years. 
6.3.4 Safety Endpoints 
• Study product-related serious adverse events; 
• Biopsy procedure-related, injection procedure-related, and study product-related 
adverse events; and 
• Post-void residual urine volume. 
 
6.3.5 Rationale for Endpoints 
 
The 3-day leak diary is a commonly used measurement for evaluating changes in a 
patient’s SUI symptoms. The selected quality of life instruments are recommended by the 
International Continence Society for studying the impact of treatments on patients. 
  
The safety endpoints have been chosen as part of the overall assessment of the safety of 
the biopsy and injection procedures as well as the safety of the product being 
investigated. The assessment will include descriptive evaluations of the types and 
frequency of adverse events observed with a comparison to the placebo control group. 
6.4 
Variables to be Measured to Demonstrate Achievement of Endpoints 
The primary efficacy measure for evaluating the treatment effect will be the number of 
stress incontinence episodes as reported in patient 3-day diaries. The primary efficacy 
endpoint for the study is the percentage of patients with treatment success where 
treatment success is defined as: 
 
• At least 50% (≥ 50%) reduction from baseline in the number of stress 
incontinence episodes over 3 consecutive days as recorded in a diary at 12 months 
after treatment. 
 
 
Secondary efficacy endpoints will be measured as follows: 
 

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• Percentage of patients with at least 75% reduction in stress incontinence episodes 
from baseline at 12 months; 
• Percentage of patients with 0 or 1 stress incontinence episodes at 12 months; and 
• Improvement (reduction) in frequency of stress incontinence episodes from 
baseline at 12 months. 
 
Additional efficacy endpoints will be measured as follows: 
• Change from baseline in disease-specific quality of life (QOL) measurements will 
be measured by Incontinence Quality of Life (IQOL)2 score and subscores, 
Urogenital Distress Inventory – Short Form (UDI – 6),3 and Incontinence Impact 
Questionnaire – Short Form (IIQ – 7)2 at 12 months.  
• Global Quality of Life Assessment (GQOL)4 at 12 months. 
• Association of quality of life improvement with stress incontinence episode 
reduction at 12 months. 
• Change from baseline in patient perceived symptom severity measured by the 
Sandvik Incontinence Severity Index (ISI)5 at 12 months.  
• Treatment durability defined as the percentage of patients who have at least (≥) 
50% reduction in stress incontinence episodes at 12 months and 2 years. 
Safety endpoints will be measured as follows: 
• Study product-related serious adverse events and study product-related, biopsy 
procedure-related, and injection procedure-related adverse events where adverse 
events are reported on eCRFs by the clinical site study staff; and 
                                                 
 
2 Wagner TH, Patrick DL, Bavendam TG, et al. Quality of life with urinary incontinence: development of a 
new measure. Urology 1996;47(1):67-72. 
3 Uebersax JS, Wyman JF, Shumaker SA, et al. Short forms to assess life quality and symptom distress for 
urinary incontinence in women: The incontinence impact questionnaire and the urogenital distress 
inventory. Neurourol Urodyn 1995;14:131-139. 
4 The global quality of life assessment is taken from the International Prostate Symptom Score (IPSS) 
Assessment. The IPSS Assessment includes the same seven questions as the American Urological 
Association (AUA) Symptom index plus an additional quality of life (QOL) question. The question referred 
to here as the GQOL is the QOL question from the IPSS Assessment. Ref: AUA Practice Guidelines 
Committee. AUA guideline on management of benign prostatic hyperplasia. Chapter 1: Diagnosis and 
treatment recommendations. J Urol 170(2 Pt 1):530-547. 
5 Sandvik H, Hundskaar S, et al. Validation of a severity index in female urinary incontinence and its 
implementation in an epidemiological survey. J Epidemiol Community Health 1993;47:497-499. Sandvik 
H, Selm A, et al. A severity index for epidemiological surveys of female urinary incontinence comparison 
with 48 hours pad-weighing tests. Neurolurol Urodyn 2000;19:137-145.   

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• Ultrasound/bladder scan determination of PVR on the day of injection and at 1, 3, 
6 and 12 months. 
 
The clinical data will be collected on eCRFs, which may serve as source documents.  
6.5 
Measures to be Taken to Avoid or Minimize Bias 
This study is designed as a double-blind, prospective, randomized controlled trial to 
minimize bias in both assigning patients to treatments and in analyzing the results. To 
maintain a double-blind study, it is necessary for all patients to receive a biopsy and an 
injection. This assures that both the patient and doctor are blinded to the study treatments, 
even when patients receive the placebo control. After the biopsy is completed, a 
computer-generated randomization scheme will be used off-site to eliminate site 
participation in the randomization and to maintain blinding. Additionally, only the 
persons directly involved in manufacturing the product will handle the AMDC-USR and 
correctly dispense the proper dose into a nondescript vial (all vials will appear the same 
and have an anonymous identifier). Thus, persons from the sponsor (Cook MyoSite) and 
the CRO (Cook Research Incorporated) who interact with physicians or clinical staff at 
the clinical site can remain blinded whenever possible. In the event of an emergency, site 
personnel are able to rapidly unblind a patient for her safety if deemed necessary. In such 
event the data coordinating center (Cook Research Incorporated) must be contacted 
immediately. 
7.0 
Methods 
If a patient has had a hysterectomy and/or is post-menopausal (i.e., the patient does not 
have a uterus and/or is no longer menstruating), then the patient is not required to 
complete the pregnancy tests as outlined in the visit schedule. (Note: tubal ligation is not 
an acceptable reason for not doing the test, as it is not guaranteed to be permanent.) For 
visual representation of methods specific to patient visits, refer to Table 7.1. For an 
illustrated overview of the study, refer to Figure 1.1. 

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7.1 
Initial Patient Assessment and Pre-screening 
Female patients who present with SUI symptoms may be considered for participation in 
this study. If available, clinical site study staff should review patient symptoms against 
the inclusion/exclusion criteria before consenting patients. 
7.2 
Patient Consent 
Patients who appear to meet the inclusion criteria and none of the exclusion criteria will 
be invited to participate in this study. All patients eligible for entry into the study will 
have the study explained to them, as well as potential risks and benefits of their 
participation in the study. Each patient who agrees to participate will be required to sign 
and date an informed consent document prior to any study-specific testing and the 
procedure.  
7.3 
Pre-enrollment – Screening 
Screening tests may be completed in up to 3 screening visits to accommodate site-
specific scheduling.  It is recommended that screening tests conducted in Visit 1 be 
completed within the 8 weeks preceding the biopsy visit. Bloodborne pathogen testing 
must be completed within 30 days before the biopsy procedure. If more than one visit is 
required, adverse events that occur during the screening time period shall be recorded 
during subsequent visits. 
 
After providing informed consent, the patient will have her medical history recorded 
(including a urinary incontinence-focused history), a physical examination performed 
(including assessment of vital signs), and a medication log completed. A clinical 
assessment will be performed. Urine samples will be collected to test for pregnancy, 
nitrites, and leukocyte esterase. If the urine test is positive for nitrites or leukocyte 
esterase, then it is recommended a urine culture be performed. The patient will undergo a 
bladder “cough” stress test 
 
 and a Q-tip test 
 
. A PVR urine volume will be measured with ultrasound. 
If, after multiple void attempts, the residual urine volume is > 150 mL, the patient must 
be excluded from the study.  
 
The patient will be given a diary in which to record liquid intake, incontinence episodes, 

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and normal voids for 3 consecutive days. Instructions for the diaries will be explained in 
detail to the patient during this visit. The patient will also be provided with sufficient pre-
weighed pads with which to complete a 24-hour ambulatory pad test that corresponds 
with 1 day of the 3-day diary. The patient will be instructed on how to perform the 24-
hour pad test 
 
. During the study visit, a study team member will give the patient clear 
instructions for completing the diary and pad test. Patients will also receive written 
instructions for the diary to take home as reference. The patient will complete the IIQ – 7, 
UDI – 6, and GQOL questionnaires (collectively QOL assessment), the IQOL 
assessment, and the Incontinence Severity Index (ISI) assessment. Blood samples will be 
collected to assess for bloodborne pathogens, hematocrit, hemoglobin, WBC count, blood 
urea nitrogen (BUN) or urea, and creatinine. Patients will also undergo cystoscopy for 
evaluation of the appearance of urethral and bladder tissue.  An existing cystoscopy 
evaluation can be used if performed within 6 months prior to the time of consent. It is 
recommended that screening tests be performed from the least invasive test to the most 
invasive. 
7.4 
Point of Enrollment 
Patients are considered enrolled in the study at the time of the biopsy procedure. 
7.5 
Medications 
Patients may be given medication (including for pain or anxiety) according to the 
institution’s standard of care or at the physician’s discretion. Additionally, patients 
should be maintained on a stable dose and/or frequency of medication known to affect 
lower urinary tract function, including but not limited to, anticholinergics, beta 3 
adrenergic receptor agonists, tricyclic antidepressants, diuretics, or alpha-adrenergic 
blockers, for at least 2 weeks prior to screening assessments and throughout the study. 
7.6 
Biopsy and Randomization 
After patient eligibility is confirmed, patients will return to the clinic for an outpatient 
procedure in which muscle tissue is obtained using a needle biopsy technique. 
 
 
 
 

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 If the biopsy procedure is scheduled for more than 30 days after the most 
recently completed bloodborne pathogen tests, the bloodborne pathogen tests (i.e. 
Hepatitis B, Hepatitis C, HIV, and Syphilis) must be repeated before the biopsy 
procedure to confirm the patient’s continued eligibility for study participation. If 
appropriate, the patient will also have a urine sample collected prior to the biopsy 
procedure for pregnancy testing, which would be repeated at any additional biopsy visits 
if more than one biopsy is required. If the patient has a positive pregnancy test at this 
visit, the biopsy will not be performed, and the patient will be excluded from the study 
for safety. Additionally, the medication log will be updated if necessary. Any adverse 
events occurring since the last visit or before, during, or after the biopsy procedure will 
be recorded and reported as appropriate.  
 
Patients will be randomized to a treatment arm after AMDC-USR product is made; 
patients randomized to placebo arm will not receive the product.  
7.6.1 Post-Biopsy Follow-up  
Within 7 business days after the biopsy procedure, patients will be contacted by phone to 
determine whether any adverse events have occurred and whether any updates to the 
medication log are necessary. 
7.7 
Procedure – Treatment Day 0 
Within 45 days preceding the scheduled injection, patients will be given a 3-day diary to 
complete. Patients will complete the QOL assessments, the IQOL assessment, and the ISI 
assessment. The questionnaires and 3-day diary data collected preceding the injection 
visit will be used as the baseline data. 
 
 after the muscle biopsy, patients will return to the clinic for 
a brief outpatient injection procedure. Prior to injection, patients will have a urine sample 
collected for a pregnancy test (if necessary), nitrites, and leukocyte esterase. If the urine 
test is positive for nitrites or leukocyte esterase, a urine culture must be performed and 
the injection will be delayed pending completion of an appropriate culture and course of 
antibiotic therapy. If the patient has a positive pregnancy test at this visit, the injection 

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will not be performed, and the patient will be excluded from the study for safety.  
The product will be injected using a transurethral injection technique. Cystoscopic 
evaluation of the urethra will be performed after the injection to evaluate the appearance 
of urethral tissue. Prior to discharge, patients should demonstrate a normal void and have 
their PVR urine volume determined by ultrasound. If, after multiple void attempts, the 
residual urine volume is > 150 mL, additional evaluation for obstruction is recommended 
at the discretion of the investigator. The medication log will be updated if necessary. Any 
adverse events occurring since the last visit or before, during, or after the procedure will 
be recorded and reported as appropriate.  
7.8 
Follow-up 
Follow-up windows are intended as recommendations only. They are not absolute and are 
not intended to limit data collection due to scheduling conflicts. If a patient has a positive 
pregnancy test at any given follow-up visit, no further study procedures will be 
conducted, but the patient will be followed for safety. 
7.8.1 Post-Treatment Follow-up – Treatment Day 1-2 
Within 2 business days after treatment, patients will be contacted by phone to determine 
if any adverse events have occurred and if the patient has any updates for the medication 
log.  
7.8.2  Follow-up Visit – Treatment Month 1 (± 1 week) 
Patients will have urine samples collected for a pregnancy test (if necessary), nitrites, and 
leukocyte esterase. If the urine test is positive for nitrites or leukocyte esterase, it is 
recommended a urine culture be performed. Blood samples will be collected to assess for 
hematocrit, hemoglobin, WBC count, BUN or urea, and creatinine. Patients will also 
undergo ultrasound for determination of PVR urine volume. If, after multiple void 
attempts, the PVR volume is > 150 mL, additional evaluation for obstruction is 
recommended at the discretion of the investigator. During the visit, patients will complete 
the QOL assessments, the IQOL assessment, and the ISI assessment. Patients will be 
given a 3-day diary to complete. The medication log will be updated if necessary. A 
clinical assessment shall be performed. Patients will have height and weight assessed. 
Any adverse events occurring since the last visit will be recorded and reported as 
appropriate. 

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7.8.3 Follow-up Visit – Treatment Month 3 (± 4 weeks) 
Patients will have urine samples collected for a pregnancy test (if necessary), nitrites, and 
leukocyte esterase. If the urine test is positive for nitrites or leukocyte esterase, then it is 
recommended a urine culture be performed. Patients will also undergo ultrasound for 
determination of PVR urine volume. If, after multiple void attempts, the PVR volume is 
> 150 mL, additional evaluation for obstruction is recommended at the discretion of the 
investigator. During the visit, patients will complete the QOL assessments, the IQOL 
assessment, and the ISI assessment. Patients will be given a 3-day diary to complete. The 
medication log will be updated if necessary. A clinical assessment shall be performed. 
Patients will have height and weight assessed. Any adverse events occurring since the last 
visit will be recorded and reported as appropriate. 
7.8.4 Follow-up Visit – Treatment Month 6 (± 4 weeks) 
Patients will have urine samples collected for a pregnancy test (if necessary), nitrites, and 
leukocyte esterase. If the urine test is positive for nitrites or leukocyte esterase, then it is 
recommended a urine culture be performed. Patients will undergo ultrasound for 
determination of PVR urine volume. If, after multiple void attempts, the PVR volume is 
> 150 mL, additional evaluation for obstruction is recommended at the discretion of the 
investigator. During the visit patients will complete the QOL assessments, the IQOL 
assessment, and the ISI assessment. Patients will be given a 3-day diary to complete. The 
medication log will be updated if necessary. A clinical assessment will be performed. 
Patients will have height and weight assessed. Any adverse events occurring since the last 
visit will be recorded and reported as appropriate.  
7.8.5 Follow-up Visit – Treatment Month 12 (± 4 weeks) 
Patients will have urine samples collected for a pregnancy test (if necessary), nitrites, and 
leukocyte esterase. If the urine test is positive for nitrites or leukocyte esterase, then it is 
recommended that a urine culture be performed. Blood samples will be collected to 
assess for hematocrit, hemoglobin, WBC count, BUN or urea, and creatinine. Patients 
will undergo ultrasound for determination of PVR urine volume. If, after multiple void 
attempts, the PVR volume is > 150 mL, additional evaluation for obstruction is 
recommended at the discretion of the investigator. Patients will also undergo cystoscopy 
for evaluation of the appearance of urethral tissue. During the visit, patients will complete 
the QOL assessments, the IQOL assessment, and the ISI assessment. Patients will be 

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given a 3-day diary to complete. The medication log will be updated if necessary. A 
clinical assessment will be performed. Patients will have height and weight assessed. Any 
adverse events occurring since the last visit will be recorded and reported as appropriate.  
7.8.6 Unblinded Treatment – Day 0 
Following completion of product manufacturing, placebo control patients who agree to 
receive the unblinded treatment will return to the clinic for a brief outpatient procedure. 
Prior to injection, patients will have a urine sample collected for a pregnancy test (if 
necessary), nitrites, and leukocyte esterase. If the urine test is positive for nitrites or 
leukocyte esterase, a urine culture must be performed and the injection will be delayed 
pending completion of an appropriate culture and course of antibiotic therapy. Cells will 
be injected using a transurethral injection technique. Cystoscopic evaluation of the 
urethra will be performed after the injection to evaluate the appearance of urethral tissue. 
Prior to discharge, patients should demonstrate a normal void and will have their residual 
urine volume determined by ultrasound. If, after multiple void attempts, the residual urine 
volume is > 150 mL, additional evaluation for obstruction is recommended at the 
discretion of the investigator. The medication log will be updated if necessary. Any 
adverse events occurring since the last visit or before, during, or after the procedure will 
be recorded and reported as appropriate. 
 
Patients receiving an unblinded treatment shall be contacted for post-treatment follow-up 
according to the schedule specified in Sections 7.8.6.1 through 7.8.6.3. 
 
7.8.6.1  Unblinded Follow-up – Treatment Day 1-2 
 
Within 2 business days after treatment, patients will be contacted by phone to determine 
if any adverse events have occurred and if the patient has any updates for the medication 
log.  
 
7.8.6.2  Unblinded Follow-up – Treatment Month 1 (± 1 week) 
 
Patients will be contacted by phone to determine if any adverse events have occurred and 
if the patient has any updates for the medication log. 
 
7.8.6.3  Unblinded Follow-up – Treatment Month 3 (± 4 weeks) 

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Patients will be contacted by phone to determine if any adverse events have occurred and 
if the patient has any updates for the medication log. 
7.8.7 Follow-up Visit – Treatment Year 2 (± 4 weeks) 
During the visit, patients will complete the ISI quality of life assessment. Patients will be 
given a 3-day diary to complete. A urine sample will be collected to test for pregnancy. 
The medication log will be updated if necessary. A clinical assessment will be performed. 
Patients will have height and weight assessed. Any adverse events occurring since the last 
visit will be recorded and reported as appropriate. Patients randomized to the placebo 
control group who chose to receive AMDC-USR treatment at 12 months will also 
undergo cystoscopy to evaluate the appearance of urethral tissue. 
 
The schedule for assessments is summarized in Table 7.1. 

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7.9 
Duration of Study and Patient Participation 
Patients are expected to participate in this study for 2 years after the initial procedure. If 
placebo control patients elect not to receive cells after 12 months, their participation is 
concluded. 
7.10 
Criteria and Procedures for Withdrawal 
A patient may decide to withdraw from the study at any time either before or after 
undergoing study procedures without prejudice or loss of care. The patient shall notify 
the investigator of her desire to withdraw. The investigator will notify the sponsor. The 
investigator may also decide to withdraw a patient from the study at any time based on 
medical judgment. In all instances of withdrawal, the appropriate study visit and study 
termination data shall be submitted to the data coordinating center, and shall include the 
reason why the patient has been withdrawn from the study. Prior to formal withdrawal, 
patients will be asked to complete a final follow-up visit to collect data on adverse events, 
current medications, clinical assessment, 3-day diary and questionnaires and allow access 
to their medical records for 30 days after the date of withdrawal. Any data collected on 
the patient up to the point of withdrawal plus 30 days may be used in the study. 
 
In the event a patient is lost to follow-up or cannot be contacted for post-treatment 
assessments, at least three attempts will be made to locate the patient, and these efforts 
will be documented. If the patient cannot be located, a lost to follow-up entry will be 
submitted. 
7.11 
Participation Endpoints of the Study 
A patient’s participation in the study will end after any of the following: 
 
• Patient completes all scheduled clinical and imaging evaluations to 2 years; 
• Patient underwent study procedures, but fails to receive treatment (such patients 
will be followed for 30 days after the last study procedure); 
• Patient withdrawal or lost to follow-up; 
• Patient receives treatment for SUI other than the study treatment (e.g., receives an 
injection of a bulking agent, or completes a surgery for a sling); 

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• Closure of the study; or 
• Patient death. 
8.0  
Statistical Considerations 
8.1 
Hypothesis to be Tested 
The primary hypothesis for efficacy is that patients treated with AMDC-USR will have a 
superior treatment efficacy success rate (π, as defined in Section 6.3.1) at 12 months, 
compared to the placebo control. The null (H0) and alternative (HA) primary efficacy 
hypotheses are expressed as follows: 
 
 
𝐻𝑜  ∶ 𝜋𝐴𝐴𝐴𝐴−𝑈𝑈𝑈  ≤ 𝜋𝑝𝑝𝑝𝑝𝑝𝑝𝑝  
              𝐻𝐴  ∶ 𝜋𝐴𝐴𝐴𝐴−𝑈𝑈𝑈  > 𝜋𝑝𝑝𝑝𝑝𝑝𝑝𝑝  
 
where πAMDC-USR is the treatment success rate for the AMDC-USR group and πplacebo is 
the treatment success rate for the placebo control group. 
 
The following secondary efficacy endpoints will be tested using the Holm procedure to 
control the type I error at the significance level of 0.025 for multiple testing.  
• Percentage of patients with at least 75% reduction in stress incontinence episodes 
from baseline at 12 months; 
• Percentage of patients with 0 or 1 stress incontinence episodes at 12 months; 
• Improvement (reduction) in frequency of stress incontinence episodes from 
baseline at 12 months; 
 
The hypothesis testing for each of the secondary endpoints is as follows: 
• Percentage of Patients with at Least 75% (≥ 75%) Reduction in Stress 
Incontinence Episodes from Baseline at 12 Months 
The treatment success based on an endpoint that considers stress incontinence episodes is 
defined as a ≥ 75% reduction in the stress incontinence episodes based on the 3-day diary 
at 12-month follow-up. The null and alternative hypotheses for the endpoint are: 
 
𝐻𝑜  ∶ 𝐶𝐴𝐴𝐴𝐴−𝑈𝑈𝑈 ≤ 𝐶𝑝𝑝𝑝𝑝𝑝𝑝𝑝  

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              𝐻𝐴  ∶ 𝐶𝐴𝐴𝐴𝐴−𝑈𝑈𝑈 > 𝐶𝑝𝑝𝑝𝑝𝑝𝑝𝑝  
where  𝐶𝐴𝐴𝐴𝐴−𝑈𝑈𝑈  is the percentage of patients in the AMDC-USR group with treatment 
success at 12 months based on the endpoint definition and 𝐶𝑝𝑝𝑝𝑝𝑝𝑝𝑝  is the percentage of 
patients in the placebo control group with treatment success at 12 months based on the 
endpoint definition. 
• Percentage of Patients with Zero (0) or One (1) Stress Incontinence Episodes 
Based on the 3-Day Diary Data at 12 Months 
Patients who have 0 or 1 stress incontinence episodes (stress incontinence episodes = 0 or 
1) based on the 3-day diary at the 12-month visit will be defined as a treatment success 
for this endpoint. Patients who have stress incontinence episodes (> 1) at 12 months will 
be denoted as a treatment failure for this endpoint.  
 
The null and alternative hypotheses for the endpoint are: 
 
𝐻𝑜  ∶ 𝜏𝐴𝐴𝐴𝐴−𝑈𝑈𝑈  ≤ 𝜏𝑝𝑝𝑝𝑝𝑝𝑝  
              𝐻𝐴  ∶ 𝜏𝐴𝐴𝐴𝐴−𝑈𝑈𝑈  > 𝜏𝑝𝑝𝑝𝑝𝑝𝑝  
where  𝜏𝐴𝐴𝐴𝐴−𝑈𝑈𝑈  is the percentage of patients in the AMDC-USR group with treatment 
success at 12 months and 𝜏𝑝𝑝𝑝𝑝𝑝𝑝  is the percentage of patients in the placebo control 
group with treatment success at 12 months. 
• Improvement (Reduction) in Frequency of Stress Incontinence Episodes from 
Baseline at 12 Months 
The improvement (reduction) in the frequency of stress incontinence episodes from 
baseline at 12 months is defined as the change in the number of diary-reported stress 
incontinence episodes from baseline to 12 months. It is calculated as (improvement in the 
frequency of stress incontinence episodes) = (# of diary-reported stress incontinence 
episodes at 12 months) – (# of diary-reported stress incontinence episodes at baseline).  
 
The null and alternative hypotheses for the endpoint are: 
              𝐻𝑜  ∶ 𝜇𝐴𝐴𝐴𝐴−𝑈𝑈𝑈  ≥ 𝜇𝑝𝑝𝑝𝑝𝑝𝑝𝑝  
              𝐻𝐴  ∶ 𝜇𝐴𝐴𝐴𝐴−𝑈𝑈𝑈  < 𝜇𝑝𝑝𝑝𝑝𝑝𝑝𝑝  
where 𝜇𝐴𝐴𝐴𝐴−𝑈𝑈𝑈  is the change in the frequency of stress incontinence episodes for the 
AMDC-USR group at 12 months and 𝜇𝑝𝑝𝑝𝑝𝑝𝑝𝑝 is the change in the frequency of stress 
incontinence episodes for the placebo control group at 12 months. 

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Additional efficacy endpoints and safety measures will be analyzed to evaluate the 
treatment effect of AMDC-USR. A separate statistical analysis plan will detail the 
additional endpoints of interest and the statistical analysis methods.  
8.2 
Sample Size 
The study will enroll 267 patients (178 enrolled with 150 x 106 AMDC-USR and 89 
enrolled with placebo control) at up to 35 clinical sites to ensure that no less than 213 
patients will be injected with product (AMDC-USR or placebo control). The number of 
patients enrolled at each site shall not exceed 15% of the total enrollment.  
 
The sample size for the study was calculated based on the following assumptions: 
•  The treatment success (defined in Section 6.3.1) rate for patients who receive 
150 x 106 AMDC-USR will be 50% (conservatively estimated for the purposes 
of sample size calculations); 
•  The treatment success rate for the placebo control patients will be 30%; 
•  A 2:1 AMDC-USR to placebo control randomization will occur; and 
•  A one-sided z-test with type I error of 0.025, and a power of 0.8 will be used. 
 
Based on the assumptions above, a total sample size of 213 patients will be required to 
assess the primary hypotheses with sufficient power, with 142 patients assigned to 
AMDC-USR group and 71 patients assigned to the placebo control group. Cook MyoSite 
intends to enroll 267 patients (178 enrolled with 150 x 106 AMDC-USR and 89 enrolled 
with placebo control) to account for 20% early withdraw or lost to follow-up. 
 
Sample size calculations were performed using Proc Power in SAS 9.3. 
8.3 
Futility Analysis 
There is one interim look planned in this study that will evaluate futility of the primary 
efficacy endpoint. The look will occur when approximately 110 of the 267 non-roll-in 
patients have completed 12-month visits for the collection of primary efficacy data. 
 
Looking at the primary efficacy comparison of patients receiving 150×106 AMDC-USR 
versus placebo control patients the sample size is calculated under the following 

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conditions. Assume the efficacy success rate is 50% in the patients receiving 150×106 
AMDC-USR, and 30% in placebo control patients, the O’Brien-Fleming boundary under 
futility analysis,  a one-sided z-test with a 2:1 AMDC-USR to placebo randomization, 
type I error of 0.05, and a power of 0.8. A sample size of 207 patients is required.  
 
The study will be stopped early for futility if the p-value is ≥ 0.249 at the interim look. 
Under H0, the study has a 75% chance of stopping early at the look; under Ha, the study 
has a 9% chance of stopping early at the look. The independent DSMB will review these 
calculations in a blinded manner to determine if the study should be stopped for futility of 
efficacy. 
8.4 
Randomization 
Patients will be stratified for randomization based on the severity of urinary incontinence 
at screening and whether patients have undergone prior surgery for treatment of SUI. 
Each of these two strata have two levels: less than or equal to 10 (≤ 10) stress 
incontinence episodes over 3 days at screening or greater than 10 (> 10) stress 
incontinence episodes over 3 days at screening; and if the patient has undergone a prior 
surgery, or if the patient has not received prior surgery. At each study site, patients will 
be stratified based on these criteria, then randomized to one of the treatments in a 2:1 
ratio (AMDC-USR: placebo control).  
 
Assignment of patients to a treatment group will also be block randomized by site. Sites 
will not be informed of the block size. 
8.5 
Missing Data 
The total study enrollment is augmented to achieve sufficient power to test the 
hypotheses in the presence of missing outcome data due to lost to follow-up or withdrawn 
patients.  
 
Missing data will be addressed using three primary strategies: 1) multiple imputation, 
2) complete case analysis, and 3) tipping point analysis. Multiple imputation will be the 
primary strategy to address missing data. Specifically, the multiple imputation method 
will sample from the empirical distribution of complete data, by treatment group and 
strata used for randomization. This method will be used to predict missing endpoint or 

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covariate data. It may be that the primary study endpoint depends upon certain covariates; 
therefore, it may be possible to model study endpoints, given a series of related 
covariates. This model-based imputation exercise may provide approximations of the 
missing data that can be utilized to estimate event rates and confidence bounds. 
 
Both complete case and tipping point analyses may also be used to explore the impact of 
missing data on the primary study endpoint. 
 
The pattern of missingness will also be evaluated to assess if missing data are related to 
product treatment or other relevant patient or study factors. Based on this exploratory 
analysis, additional imputation methods will be considered, if appropriate. 
 
Patients who undergo biopsy, but are not randomized, will be included in the assessment 
of biopsy-related safety. For each patient who is biopsied, but not randomized, an 
additional patient will be enrolled and randomized to fulfill the required sample size.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.6 
Site-level Poolability 
At the final analysis, poolability of data from multiple sites will be verified by examining 
the primary endpoint among sites. Site-level poolability will be considered appropriate 
provided that the endpoint is similar among sites. 

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It is recognized that patient baseline characteristics may differ among sites, with some 
sites routinely treating patients with more severe disease progression. It is anticipated that 
the primary endpoint measure may be related to covariates that reflect this disease 
progression, which are in turn related to outcome. Thus, observed primary endpoint site-
specific differences will be checked for confounding with other measured covariates 
(e.g., age). This can be accomplished using regression models (linear and logistic where 
appropriate) that include site and other measured covariates as independent variables. 
 
If one or more sites is found to differ significantly from the rest, then subsequent analyses 
may include the discriminating covariate or a covariate to distinguish between the 
unusual site(s) and those sites that are considered poolable. 
 
8.7 
Limitations of the Study 
The primary outcome measure for defining treatment efficacy success based on the 
reduction from baseline in average daily number of stress incontinence episodes is not 
able to address all potential improvements in SUI symptoms that a patient may 
experience. No individual subjective or objective measure of SUI improvement has been 
reliably established among the urologic or regulatory communities. As such, the 
individual measure selected may not directly correlate for all patients, potentially causing 
difficulty in correctly analyzing study results.  
 
The control group for the study will be injected with a vehicle control. This mechanism 
of control may create some difficulty in identifying peri- or post-injection adverse events 
or responses as procedure- or product-related. Additionally, the placebo control arm will 
be carried out to 12 months, while AMDC-USR treated patients will be evaluated for up 
to 2 years. This may result in challenges interpreting safety data and reduces the 
confidence in collected efficacy data during this time window. 
9.0 
Deviations from Clinical Investigation Plan 
Investigators are not allowed to deviate from this CIP without prior authorization by the 
sponsor except under emergency situations when necessary to preserve the rights, safety, 
and well-being of study patients. 

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Deviations (failures to follow requirements of the CIP and guidelines) and non-
compliances (failures to follow applicable regulations) will be recorded together with an 
explanation. Deviations or non-compliances that impact the rights, welfare, or safety of 
patients shall be reported to the sponsor and IRB as required and as soon as possible. 
 
If appropriate, corrective and preventive actions will be discussed by the sponsor, 
investigator, and/or the IRB to determine a suitable course of action.  
 
 

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10.0 
Data Collection and Reporting 
10.1 
Electronic Case Report Forms (eCRF system) 
Patient data will be collected and entered by trained personnel at the clinical site into 
electronic Case Report Forms (eCRFs) through an Electronic Data Capturing (EDC) 
system. This is a secure, web-based system, allowing those with permission to access 
data from any location at any time. Source data are to be retained for data entered into the 
eCRF system. Worksheets created from the eCRF are available to each site and may 
serve as source documentation. Site personnel are required to undergo data entry training 
and will have unique login names and passwords in order to enter patient data. In 
accordance with 21 CFR Part 11, the eCRF system creates a secure, computer-generated, 
time-stamped audit trail to record the date and time of operator entries and actions that 
create, modify, or delete electronic records. 
 
Patient questionnaire and diary information will be collected as source data on an 
electronic, hand-held device directly from the patient. The information collected on this 
device is considered source documentation and is stored in an EDC system. 
10.2 
Data Reporting 
Progress reports and a final report at the conclusion of the clinical study will be submitted 
by the investigators and sponsor to the regulatory bodies and IRB as required by local 
regulations. 
11.0 
Data Management and Quality Assurance 
11.1 
Data Entry and Quality Assurance 
Each principal investigator or appropriately trained designee shall enter the clinical data 
into the EDC system on standardized eCRFs. Investigators will provide all applicable 
clinical data and documentation to the sponsor. Patient data and documents pertaining to 
the study will be kept and archived by the sponsor. Data will be reviewed for missing 
data, data consistency, and reasonableness of responses. Discrepancies will be resolved 
through a formal query process involving direct contact with investigators or research 
coordinators. The data coordinating center is responsible for database management, data 

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verification, data archiving, and data retention. 
 
As needed to assist the sponsor in its research (e.g., during evaluation of an adverse 
event), data will be accessible to the sponsor, the participating investigators, the 
manufacturer, and companies or individuals the sponsor authorizes. 
 
Cook Research Incorporated (previously called MED Institute, Inc.), the data 
coordinating center, maintains a Safe Harbor Privacy Policy that describes the privacy 
principles followed with respect to the transfer of personal information from member 
states in Europe to the United States. 
11.2 
Data Monitoring Arrangements 
The conduct of the clinical study will be supervised through a process of remote and on-
site monitoring. The data coordinating center will remotely monitor the study for data 
completeness and for adverse events. On-site monitoring will be implemented as 
necessary throughout the course of the study. The investigator/institution will provide 
direct access to source data/documents for study-related monitoring, audits, IRB review, 
and regulatory inspection. Written procedures for monitoring the study are maintained by 
the data coordinating center 
 
12.0 
Safety Monitoring and Procedures for Reporting Adverse Events 
12.1 
Safety Monitoring 
A Data Safety Monitoring Board (DSMB) consisting of independent physicians and 
statisticians who are not investigators in the study and who do not have a perceived 
conflict of interest with the conduct and administration of the study will be convened on a 
regular basis to evaluate the clinical study progress and review adverse events.  
 
An independent Clinical Events Committee (CEC) consisting of physicians who are not 
investigators in the study and who do not have a perceived conflict of interest with the 
conduct and administration of the study will be established to adjudicate clinical events 
reported during the study, as needed. This adjudication will be performed to assess 
whether the events were due to a pre-existing or unrelated condition, or were biopsy 
procedure-related, injection procedure-related, and/or study product-related. 

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Regularly scheduled review/monitoring of all patient data will be conducted at the data 
coordinating center, in part, for identification of adverse events and assurance that they 
are correctly reported to the DSMB and CEC.  
12.2 
Adverse Event Reporting 
Adverse events are to be reported to the data coordinating center using the appropriate 
eCRF. In cases of adverse drug reactions or SAEs, completed forms shall be submitted to 
the data coordinating center as soon as possible upon knowledge of the event. 
 
The data coordinating center will review the information submitted for possible reporting 
to the sponsor. Adverse events will be assessed by the investigator in terms of 
relationship to the biopsy procedure, relationship to the injection procedure, relationship 
to the AMDC-USR product, severity of the event, subsequent treatment/intervention 
required, and resolution status.  
 
The sponsor shall, if required according to applicable regulations, report the event to the 
appropriate regulatory authority in accordance with 21 CFR 312.32. The principal 
investigator or designee will notify their IRB of applicable events according to 
institutional guidelines. Investigators and clinical sites will be notified by the sponsor, as 
appropriate. 
13.0 
Early Termination or Suspension of the Study 
Any decision to suspend enrollment or terminate the study, either completely or at one or 
more sites, will be made by the sponsor and, if appropriate, the local IRB. If a decision is 
made to terminate the study, all patients who have undergone 1 or more study procedures 
(i.e., biopsy or injection) will be followed for 30 days following the most recent 
procedure. 
14.0 
Ethical Considerations 
This clinical study will be conducted in accordance with the ethical principles that have 
their origin in the Declaration of Helsinki and in accordance with global regulations 
including 21 CFR 312 and ICH GCP. 

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The investigator is responsible for obtaining approval of this clinical study from the 
relevant IRB at the associated institution. The study will not begin until a favorable 
opinion of the IRB has been obtained. The investigator is responsible for complying with 
requirements imposed by the IRB and/or regulatory authority. Furthermore, the 
investigator will ensure that local regulations concerning data protection are followed. 
 
The use of a placebo control injection is necessary to evaluate the efficacy of the AMDC-
USR in the treatment of SUI. To maintain double-blinding, all patients must undergo the 
biopsy procedure, even if they are randomized to the placebo control group. For ethical 
considerations, all patients will be required to sign a consent indicating their willingness 
to participate, that they have been fully informed of the risks and benefits of participation, 
and that they may receive a placebo control treatment. 
15.0 
Publication Policy 
Publication policy, rights, and obligations for this study have been negotiated, detailed, 
and defined in the study’s contractual documents with the clinical site and investigators. 
16.0 
Clinical Study Administration and Investigators 
16.1 
Approvals and Agreements 
The sponsor, global principal investigator, and the principal clinical investigators for each 
clinical site shall agree to this document and any modifications. A justification for any 
modifications will be documented. Approval and agreement will be indicated by signing 
the signature page provided with this document. 
16.2 
Investigators 
To see a complete list of the sponsor, manufacturer, monitor, and data coordinating center 
along with their contact information, please refer to Appendix A. A complete list of the 
global clinical investigator, principal clinical investigators, and coordinating clinical 
investigators, along with their qualifications and contact information, will be maintained 
by the data coordinating center. A complete list of names and addresses of each 
reviewing IRB will also be maintained by the data coordinating center. 

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16.3 
Insurance 
Insurance for the study will be obtained by the sponsor prior to patient enrollment.  
17.0 
Bibliography 
Please refer to the Investigator’s Brochure for a complete literature review and 
evaluation. 
 
 
 

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APPENDIX B 
Written Procedures for Monitoring Studies 
 

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APPENDIX C 
Definitions 
 
Definitions for the following terms are not provided in this CIP, but can be found in the 
applicable regulations: 
 
Adverse Events 
Adverse Drug Reaction 
Serious Adverse Events  
Serious Adverse Drug Reaction 
Suspected Unexpected Serious Adverse Reaction (SUSAR)  
 
 

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APPENDIX D 
Bladder “Cough” Stress Test 
 
As part of the exclusion criteria for the study, each patient must have a bladder stress test. 

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APPENDIX E 
24-hour Pad Test 
 
All patients should have a 24-hour weighted pad test as part of the screening procedures. 
The 24-hour pad test must be completed during 1 day of the 3-day diary. 

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APPENDIX F 
Q-tip Test