Autologous Muscle Derived Cells for Underactive Bladder
Phase: PHASE1
Conditions: Urinary Retention, Urinary Incontinence
Sponsor: Jason Gilleran

TITLE:  
Autologous Muscle Derived Cells for Underactive Bladder  
 
NCT 02463448 
 
Approval date: 04/18/2019 

Autologous Muscle Derived Cells for Underactive Bladder 
 
 
CLINICAL INVESTIGATIONAL PLAN 
 
 
 
Autologous Muscle Derived Cells for Underactive Bladder  
 
 
 
 
INVESTIGATIONAL NEW DRUG (IND) NUMBER: 16108 
 
 
 
 
 
 
 
 
PRINCIPAL INVESTIGATOR:  
Jason Gilleran, MD 
Beaumont Health System 
3535 W. 13 Mile Road, Suite 438 
Royal Oak, MI 48073 
 
 
 
Protocol Version: March 22, 2019  
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TABLE OF CONTENTS  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cover Page …………………………………………….. 
1 
Table of Contents……………………………………... 
2 
Study Overview………………………………………… 
3 
Objectives and/or Endpoints ……………………….. 
4 
Methodology……………………………………………. 
5 
Risks and Benefits…………………………………….. 
16 
Eligibility Criteria………………………………………. 
20 
Data Analysis…………………………………………... 
22 
Data Safety Monitoring Plan………………………… 
25 
Summary of Existing Study Data…………………… 
25 
References……………………………………………… 
36 
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STUDY OVERVIEW 
Rationale or Background 
This proposal evaluates the safety of Autologous Muscle Derived Cells (AMDC) in the 
treatment of chronic Underactive Bladder (UAB). 
 
UAB is caused by deteriorating bladder functioning with incomplete bladder emptying. In 
addition to incomplete bladder emptying, symptoms of UAB may include urine 
frequency, urgency, hesitancy (a weak urine stream), difficulty starting and/or stopping 
voiding, incontinence, nocturia (night time voiding), straining to void and recurrent 
urinary infections.  
 
UAB is common and no effective pharmacotherapy or cellular therapies are available. 
Currently, no medications or therapies have proven effective in the long-term treatment 
of UAB and no known cure exists. Consequently, patients who suffer from UAB are 
usually managed with clean intermittent self catheterization or indwelling catheters or 
riskier surgical procedures such as suprapubic catheter or urinary diversion with 
urostomy and/or must wear adult diapers. 22, 27 
 
Diokno and associates reported that 22% of men over 60 and 11% of women over 60 
reported difficulty emptying.25 The physical and psychological impact of underactive 
bladder can be devastating. Since the bladder does not fully empty upon urination, it 
can quickly fill with urine again and unbeknownst to the individual, can cause overflow 
and leakage.  
 
The long-term effects of UAB can lead to other conditions as well. For example, urine 
left behind in the bladder can lead to urinary tract infections which can be extraordinarily 
painful and, if they become chronic, can lead to kidney damage. Sediments can also 
accumulate in the bladder, forming bladder stones and blood in the urine. In severe 
cases, urine left behind in the bladder can build up to a level that causes reflux up the 
ureters, the tubes that join the kidneys to the bladder, and may cause kidney damage.  
 
UAB patients using catheters to ensure the emptying of their bladders also face long-
term medical difficulties, including inflammation and discomfort, the potential for injury, 
and an increased risk of bacterial infection. Urinary tract infections can lead to kidney 
damage and blood infections. In addition, for many individuals, the use of catheters is a 
cause for embarrassment and can negatively impact their work and home life.  
 
For many patients with UAB, the emotional effects of the disease can feel just as 
devastating as the physical effects. For older patients, it can have a major impact on 
quality of life. In fact, loss of bladder control is the second most common reason for 
nursing home placement of the elderly. Finding a way to reduce these bladder issues 
would allow millions more older adults to remain independent and experience life 
without the worry and embarrassment associated with bladder control dysfunction. 
 
AMDC are currently under investigation and have been tested in women with SUI (BB-
IND 11618; Sponsor: Cook MyoSite Incorporated). William Beaumont Hospital was the 
primary study site evaluating 4 doses of AMDC (NCT00847535). AMDC have not been 
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associated with any serious adverse effects (SAEs). Preliminary results indicate that the 
majority of women reported ≥ 50% improvement in stress leaks after receiving treatment 
with AMDC29. 
 
With the approval from the Food and Drug Administration (FDA) we will use AMDC for 
the treatment of chronic UAB in patients who have deteriorated bladder functioning with 
incomplete emptying. 
 
OBJECTIVES AND ENDPOINTS 
a. Primary Objective and Endpoints 
The primary objective of this study is to evaluate the safety of AMDC in the treatment of 
underactive bladder at 6 months post initial injection. 
 
Primary safety endpoints will be assessed by the following safety measures at these 
specified timepoints:  
 Vital signs at each study visit 
 Physical examination at baseline and at 6 months post initial injection 
 Urinalysis at each study visit 
 Hematology and clinical chemistry assessments at baseline and at 6 
months post initial injection 
 Post-injection cystoscopy immediately post initial injection and at 6 
months post initial injection 
 
Of special interest are adverse events related to the study product or procedures, 
specifically: 
 AMDC  
 Biopsy procedure 
 Injection procedure 
Systemic Safety: Will be monitored by a) measuring vital signs (blood pressure, heart 
rate) at each study visit, and b) performing standard laboratory studies (blood and 
urine). 
 
Localized Safety: Any local adverse effects (hematuria, micturition pain, urinary tract 
infection) that may occur after AMDC injection will be properly recorded and managed. 
Urinalysis will be evaluated for the possibility of urinary tract infection (UTI) at each visit. 
If the subject develops a UTI, antibiotics will be prescribed by the study physician to 
treat the infection. Signs and symptoms of wound infection will be described to the 
subject at the biopsy visit. If the subject suspects an infection he/she will be evaluated 
by study staff and a treatment plan will be created, as necessary. Initial cystoscopy will 
be performed immediately after AMDC injection and again at 6 months post injection. 
Cystoscopy will be performed to visualize the bladder and urethra in order to identify 
changes in appearance as well as abnormalities. Cystoscopic pictures will be obtained 
to assess changes over the duration of the study.  
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Allergic reactions to the study medications and AMDC may present locally or 
systemically. Signs of infection including flu symptoms (body aches, nausea, fatigue), 
itching, and rash. An allergic response or reaction may be initially identified during the 
study visit; therefore study staff will observe the subject in the research office for 30 
minutes after AMDC injection. Signs and symptoms of allergic reaction will also be 
discussed with the subject and the subject will be instructed to contact the research staff 
immediately if they suspect an allergic reaction. 
 
b. Secondary Objectives 
The secondary objective of the study is to evaluate the safety and efficacy of AMDC in 
the treatment of underactive bladder at 12 months post initial injection.  
 
Secondary efficacy endpoint measures include: 
 Changes in Quality of Life (QOL) determined by responses on symptom 
questionnaires  
o Patient Global Impression of Improvement (PGI-I) 
o Global Response Assessment (GRA) 
o Underactive Bladder Questionnaire (UAB-Q) 
o Incontinence Questionnaire Lower Urinary Tract Symptoms Long Form 
Female (ICIQ-FLUTS Long Form) 
Male (ICIQ-MLUTS Long Form) 
 Changes in voiding habits (i.e. frequency, urgency, urine volume voided 
independently, urine volume voided via catheterization) as recorded on the 3-day 
bladder diary  
 
METHODOLOGY 
a. Study Design 
This is a prospective, open-label, Phase I, single center study evaluating the safety and 
efficacy of AMDC as a treatment for chronic UAB.  
 
A maximum of 20 subjects, who satisfy all eligibility criteria, will be enrolled and treated 
with AMDC. Potential study subjects will be identified by referring physicians from within 
Beaumont Health System.  
 
Initial screening of available existing records provided by the patient will take place to 
screen for inclusion criteria (presence of chronic UAB symptoms). Informed consent will 
be obtained prior to any research activity taking place (first study visit). The study 
coordinator will obtain informed consent and will explain the study in full including, but 
not limited to, what is involved, the possible risks, and the possible benefits. The 
explanation will occur at a level of understanding appropriate for the potential 
participant. Once the potential subject has had ample time to consider the study, review 
the consent form and ask questions, he/she will be asked to sign the written consent 
form in the presence of the consent provider. The subject will receive a copy of the 
consent form for his/her records.  
 
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b. Proposed Intervention 
Prior to beginning AMDC therapy, the study physician (Principal Investigator (PI) or 
Sub-Investigator (Sub-I) will assess the subject for lower urinary tract abnormalities with 
a cystoscopic examination. Cystoscopy will also be used to document bladder 
appearance at baseline. Routine venipuncture will be required for blood and serum 
assessment including serum chemistry, hematology and blood borne viruses. Serum 
chemistry includes tests for white blood cell count, red blood cell count, platelet count, 
hemoglobin, hematocrit, creatinine, urea, and partial thromboplastin time (PTT).  Blood 
borne viruses will also be tested; Human Immunodeficiency Virus (HIV), Hepatitis B, 
Hepatitis C, and Syphilis. If the biopsy procedure is scheduled more than 30 days after 
the most recent blood borne pathogen tests were completed, the blood borne pathogen 
tests must be repeated before the biopsy procedure to confirm the patient’s continued 
eligibility for study participation.  
 
Urine will be collected and evaluated with a dipstick test for blood, glucose, ketones, 
leukocytes, nitrates and protein. Urinalysis, urine culture, patient symptom report, and/or 
cystoscopy will be used to identify urinary tract infections, as outlined in Appendix A. If 
the patient is positive for urinary tract infection at the time of screening, the patient will 
be excluded from the study and eligible for re-screening after the infection has been 
treated, UTI status has been re-evaluated (as outlined in Appendix A), and the patient is 
negative for UTI. Residual urine volume or post void residual (PVR) will be assessed via 
ultrasound or straight catheterization. Assessment of PVR will be performed in the least 
invasive manner (via bladder scan) whenever possible. If the bladder scan indicates a 
high urine residual volume (>150 mL), catheterization may be performed. Since 
catheterization is a more accurate measurement of residual urine volume, the urine 
volume collected via catheterization will be recorded, rather than the volume detected 
via bladder scan (if results differ). Since insertion of a urinary catheter is required for the 
instillation of the numbing medication pre-injection, PVR will be assessed via 
catheterization at this visit. A urine pregnancy test will also be conducted for women of 
childbearing potential. If the urine pregnancy test is positive at any time during the 
study, the patient will be withdrawn from the study and the event will be reported to the 
local Investigational Review Board (IRB) and the FDA. 
  
A separate consent will be obtained in order to collect urine for the evaluation of 
biomarkers. If the participant consents to this part of the study, part(s) of the urine 
samples will be retained in a repository (storage area for safety and preservation) for 
future research. The type of testing that may be done on the samples could be useful in 
understanding underactive bladder. The urine samples will be kept indefinitely and will 
be labeled with a unique code to protect the participant’s identity. A subject may 
withdraw their sample at any time upon request to study staff. The study participant will 
not be informed of any results of the analysis of their urine sample. The results will not 
be placed in the participant’s medical record. If/when the results are disseminated to the 
public via presentations and/or publications, the findings may be available to 
participants upon request to study staff and/or via internet search. Beaumont’s Urology 
Bench Laboratory will store the urine samples, as well as the data collected from the 
analysis. 
 
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Bladder diaries and questionnaires will be used to evaluate UAB symptoms. Bladder 
function will be assessed with cystometrogram and uroflow studies. Concomitant 
medication information (dosage, route, frequency, start and stop dates, and indication), 
therapies, and minor procedures done during the course of treatment will be assessed 
at each visit.  
 
Compassionate use of AMDC to treat UAB was previously approved by the FDA for use 
in a single patient (IND 15417). The subject received a single treatment of 250 million 
cells in approximately 30 sites (0.5 ml/injection) to enhance bladder detrusor 
contractility. To date, there have been no adverse events (AEs) related to the treatment 
or the cell dose. Therefore, the investigators have determined that a total dose of 250 
million cells may be safe.  
 
In this study, all enrolled subjects will receive an initial injection of 125 x 106 AMDC. If 
after the 6 month visit the study investigator determines that the subject may benefit 
from undergoing a second treatment, the patient will have the option of receiving 
another injection of 125 x 106 AMDC. Therefore the total cell dose delivered over the 
course of the study will not exceed 250 x 106. 
 
The AMDC injection is performed via cystoscope. Visualization of the bladder will occur 
before the procedure to assess appearance and identify abnormalities, during the 
procedure, and after the injection is completed. The post-injection cystoscopy will 
ensure that the injection did not cause excessive bleeding and/or excessive bladder 
trauma.  
 
The biopsy and culture technique allows AMDC to be produced for multiple injections 
from a single biopsy procedure. Therefore patients will not have to undergo a second 
biopsy procedure prior to receiving the second injection.   
 
In order to evaluate the long-term safety profile and clinical outcomes associated with 
AMDC, all subjects that have not been withdrawn from the study or discontinued study 
participation will be evaluated for 1 year post initial injection. 
 
Muscle Biopsy Procedure 
The biopsy procedure will involve minor surgery, as an outpatient procedure, to collect 
approximately 50-250 mg of the quadriceps femoris muscle using a sampling needle. 
Muscle biopsies are obtained approximately 15 cm above the patella from the middle 
region of the vastus lateralis, and approximately 2 cm away from the fascia using a 
percutaneous needle biopsy technique. The skin is prepared by shaving a small area at 
the site of the muscle biopsy and cleaning with an antimicrobial skin wash. The biopsy 
site is anesthetized with a local injection of 1% lidocaine. A small incision of 
approximately 5 mm is made in the skin to allow the sterile needle to enter and remove 
between 50 and 250 mg of muscle tissue.  
 
The Medinvents Spirotome 8 gauge needle will be used for this biopsy procedure. This 
needle type has been used clinically to safely and successfully procure skeletal muscle 
tissue and is used according to the manufacturer’s instructions. Several passes of the 
biopsy needle may be required to obtain a satisfactory sample of muscle tissue. The 
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tissue harvested from the patient’s quadriceps femoris is immersed in hypothermic 
medium within a coded vial and is transported to the cell processing facility in 
Pittsburgh, PA. The AMDC will be isolated and expanded in culture over several weeks 
to a final concentration of 125 million ±20% (see Appendix 2 for additional process 
information). 
 
If the first biopsy does not produce an adequate sample for product isolation, it may be 
necessary for the patient to return for another biopsy procedure. The risk that the 
patient will be requested to undergo a re-biopsy procedure is less than 10%. The 
maximum permissible number of biopsy needle passes and total number of biopsies is 
contingent upon patient tolerance and the satisfactory procurement of muscle tissue. 
After the biopsy, the incision is closed and dressed appropriately in accordance with 
standard physician’s care. Non-prescription analgesics may be used to manage post-
biopsy pain.  
 
Cell Processing Procedure 
Cell processing will begin with isolation of cells from the subject’s tissue. The cells will 
then be grown in culture and expanded in number. The culture process will 
preferentially expand desirable AMDC, producing a final cell culture that is highly 
enriched in myogenic cell content. Cell culture will be performed in medium consisting of 
physiological saline solutions with cell nutrients. Cell processing will follow current Good 
Manufacturing Practices (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. 
 
The expanded AMDC will be supplied to the physician frozen in a cryogenic medium 
containing Human Serum Albumin (HSA), and then thawed and diluted with 
physiological saline for injection into the subject. Materials contacting subject’s 
periurethral tissue will include the subject’s own MDC, the cryogenic medium in which it 
is suspended and shipped, and the physiological saline used to dilute the mixture for 
injection. 
 
Isolation and Expansion of the Study Agent  
After receipt at the cell processing center, desirable AMDC will be isolated from the 
tissue biopsy. The isolated AMDC will be expanded in medium consisting of 
physiological saline solutions with cell nutrients that contain bovine serum. The bovine 
product used in the culture medium is sourced from countries considered free of bovine 
spongiform encephalopathy (BSE), and is derived from animals not born, raised, 
shipped through, or slaughtered in countries where BSE is known to exist. This assures 
to as great a degree as is possible that the products are BSE-free.  
 
Once the desired cell number has been achieved, quality tests following cGTP 
guidelines (FDA, 21 CFR Parts 16, 1270, and 1271, Current Good Tissue Practice for 
Human Cell, Tissue, and Cellular and Tissue-Based Product Establishments) assure 
the cells meet acceptance criteria for sterility, contaminants, cell viability, and functional 
integrity. The cells are then suspended in a cryogenic medium containing HSA, sealed 
in a glass vial, frozen, and shipped to the physician for injection. 
 
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Quality control testing samples consists of AMDC Final Product cells in 
cryopreservation medium.  The sample is collected during packaging and prior to 
cryopreservation. Lot-release tests are performed to determine the identity, purity, and 
safety of the AMDC Final Product, and include: sterility, mycoplasma, endotoxin, 
myogenic content, and myogenic differentiation. 
 
All lot-release test results are available prior to final product release.  A quality review of 
the Product Batch Record, by a Quality Representative, includes a review of all lot-
release test results prior to product release.  A copy of the signed Certificate of Analysis 
is included in the shipping container along with the final product.  This form indicates the 
product approval status along with the test completion date, test criteria, pass/fail status, 
and internal sample batch number of each lot-release test performed. Individual 
samples for all lot-release testing are removed from a single common sample. This 
sample of the AMDC Final Product cell suspension is withdrawn during fill.  Excess 
sample used for lot-release testing is retained, cryopreserved, and may be used for 
repeat testing in cases in which invalid test results are obtained (if applicable). 
 
Transportation and Storage of the Study Agent  
The cells must remain frozen and undiluted until ready for use. Specialized packaging 
for transport from the processing center is certified to maintain appropriate temperature 
for up to 72 hours. If the cells cannot be injected within that period, the cells should be 
stored at least -60 °C to –80 °C until the subject is available for injection. The cells are 
intended for a single use, should be thawed immediately prior to the injection, and 
should be used within the immediate procedure. Any unused portion shall be discarded. 
 
Injection Procedure 
The injection procedure consists of injections of 125 million AMDC in approximately 30 
sites (0.5 ml/injection) throughout the bladder to enhance the bladder detrusor 
contractility. This procedure was utilized in the previous UAB AMDC single subject 
study and is similar to other bladder injection protocols. The procedure requires local 
lidocaine anesthesia only.  
 
The materials contacting the bladder wall will include the subject’s own AMDC, the 
cryogenic medium in which it is suspended and shipped, and the physiological saline 
used to dilute the mixture for injection.  
 
Subjects will receive appropriate antibiotic prior to the injection procedure.  After a 
negative urine analysis, 30 ml of 1% liquid lidocaine will first be instilled, via catheter, 
into subject’s bladder and left for 15 minutes.  The lidocaine will then be emptied and 
the bladder rinsed with 30 ml of sterile saline.  The saline and catheter will then be 
removed.  
 
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Dose:  
Single treatment with 
an optional second 
treatment; 125 million 
cells/2 ml frozen cell 
suspension will be 
reconstituted per 
manufacturer’s 
instructions with 13 
ml physiological 
sterile injectable 
saline without 
preservative (15 ml 
total) and injected 2 
mm deep 
intradetrusor into 30 
sites (0.5 ml/site) 
throughout the 
bladder.  Any unused 
solution will be 
discarded. The subject will be monitored in the urology research area for a minimum of 
30 minutes after injection. 
 
Planned Duration: AMDC will be injected during one visit (Visit 3) and possibly Visit 7 
(approximately 8 months post initial injection). The study requires seven to eight visits to 
the research office and at least 2 phone contacts for treatment and follow-up over 
approximately 30 months as outlined below and located in Appendix 3. 
 
 
c. Description of Research Activities 
 
1. Schedule of Intervention/Activities 
The following questionnaires will be completed by the subject during the study: 
 3-Day Bladder Diary 
 Incontinence Questionnaire Lower Urinary Tract Symptoms Long Form Module -
Female (ICIQ-FLUTS Long Form), Male (ICIQ-MLUTS Long Form)  
 Underactive Bladder Questionnaire (UAB-Q) 
 Patient Global Impression of Improvement (PGI-I) Scale 
 Global Response Assessment (GRA) 
 
Visit 1: Screening 
Obtain written informed consent 
Demographics (birth date, gender, etc.) 
Review medical and surgical history 
Review of concomitant medications  
Vital signs: blood pressure, heart rate 
Baseline testing: 
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 Blood collection and analysis; CBC, blood chemistry, PTT, blood borne viruses: 
(Human Immunodeficiency Virus (HIV), Hepatitis B, Hepatitis C, and Syphilis) 
 Urinalysis (dipstick), and culture (if required) 
 Urine pregnancy test (if required) 
Urine collection for evaluation of biomarkers (presence of inflammatory and neuronal 
innervation proteins in the urine) 
Physical examination 
Assessment of post void residual (PVR): measured by bladder scan or catheter 
Questionnaire completion (ICIQ, UAB-Q) 
Antibiotic (a medicine to prevent infection) given, by mouth, to prevent urinary tract 
infection 
Pressure flow studies 
Determination of study enrollment, review inclusion/exclusion criteria 
Assess for side effects 
 
Visit 2: Muscle Biopsy 
Review of concomitant medications  
Vital signs: blood pressure, heart rate 
Urine pregnancy test (if required) 
Muscle biopsy - After the biopsy surgical glue will be used to adhere steri-strips 
(surgical tape) to the biopsy site. A gauze pad containing Bacitracin Zinc Ointment, to 
prevent infection, will then be applied. Finally an ACE bandage will be wrapped firmly 
around your leg as a protective covering and to reduce possible bruising.Assess for 
adverse events 
Dispense 3-day bladder diary to be completed prior to visit 3; instruct/reinforce 
maintaining bladder diary  
 
Visit 3: Injection (approximately 10 weeks from visit 2) 
Review bladder diary 
Assess concomitant medications 
Vital signs: blood pressure, heart rate 
Urinalysis (dipstick), and culture (if required) 
Urine pregnancy test (if required) 
Assessment of post void residual (PVR): measured by bladder scan or catheter 
Antibiotic (a medicine to prevent infection) given, by mouth, to prevent urinary tract 
infection  
Flexible cystoscopy 
AMDC bladder injection 
Assess for adverse events 
Dispense 3-day bladder diary to be completed prior to visit 4; instruct/reinforce 
maintaining bladder diary  
 
24-48 Hours Post-Injection Phone Call 
Assess concomitant medications 
Assess for adverse events 
Review diary completion dates 
 
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Visits 4: 1 Month Post-Injection Follow-up (+/- 7 days) 
Review bladder diary 
Assess concomitant medications 
Questionnaire completion (PGI-I, GRA, UAB-Q, ICIQ) 
Vital signs: blood pressure, heart rate 
Urinalysis (dipstick), and culture (if required) 
Urine pregnancy test (if required) 
Assessment of post void residual (PVR): measured by bladder scan or catheter 
Assess for adverse events 
Dispense 3-day bladder diary for completion prior to visit 5; instruct/reinforce 
maintaining bladder diary  
 
Visit 5: 3 Months Post-Injection Follow-up (+/- 7 days) 
Review bladder diary 
Assess concomitant medications 
Questionnaire completion (PGI-I, GRA, UAB-Q, ICIQ) 
Vital signs: blood pressure, heart rate 
Urinalysis (dipstick), and culture (if required) 
Urine pregnancy test (if required) 
Urine collection for evaluation of biomarkers (presence of inflammatory and neuronal 
innervation proteins in the urine) 
Assessment of post void residual (PVR): measured by bladder scan or catheter 
Assess for adverse events 
Dispense 3-day bladder diary to be completed prior to visit 6; instruct/reinforce 
maintaining bladder diary  
 
* While an in-person study visit is preferable, this visit may be completed as a phone 
call visit, if the participant is otherwise unable or unavailable. The diary, questionnaires 
and urine will be collected via mail. 
 
In the event the study visit is not conducted in-person, the visit may be conducted by 
phone and/or mail. Research staff will: 
Send the 3- month questionnaires to the participant for completion 
Send the 6-month diary to the participant for completion prior to their next visit 
Review the diary and questionnaires and completion dates 
Request and verify the completed diary and questionnaires have been returned to the 
research office 
Send a Urine Specimen Collection Kit and instructions to the participant. The kit will be 
utilized to collect urine to perform urinalysis and for the evaluation of biomarkers. 
Verify the kit has been returned to the research office. 
Assess concomitant medication changes 
Assess for adverse events 
 
Visit 6: 6 Months Post-Injection Follow-up (+/- 7 days) 
Review bladder diary 
Assess concomitant medications 
Questionnaire completion (PGI-I, GRA, UAB-Q, ICIQ) 
Vital signs: blood pressure, heart rate 
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Urinalysis (dipstick), and culture (if required) 
Urine pregnancy test (if required) 
Urine collection for evaluation of biomarkers (presence of inflammatory and neuronal 
innervation proteins in the urine) 
Physical examination 
Assessment of post void residual (PVR): measured by bladder scan or catheter 
Pressure flow studies 
Flexible cystoscopy 
Antibiotic (a medicine to prevent infection) given, by mouth, to prevent urinary tract 
infection 
Blood collection and analysis; CBC, blood chemistry 
Assess for adverse events 
 
If the study physician determines that a second AMDC injection may be beneficial 
to the subject and the subject agrees to undergo a repeat treatment, the following 
visits will occur: 
 
Visit 7: Injection #2 (approximately 10 weeks from visit 6) 
Assess concomitant medications 
Vital signs: blood pressure, heart rate 
Urinalysis (dipstick), and culture (if required) 
Urine pregnancy test (if required) 
Assessment of post void residual (PVR): measured by bladder scan or catheter 
Antibiotic (a medicine to prevent infection) given, by mouth, to prevent urinary tract 
infection  
Flexible cystoscopy 
AMDC bladder injection 
Assess for adverse events 
Dispense: 
 Two 3-day bladder diaries; instruct/reinforce maintaining bladder diary  
 One set of questionnaires: PGI-I, GRA, UAB-Q, ICIQ (1 of each) 
 One postage paid envelope 
The Research Nurse Clinician (RNC) will provide completion and study document return 
instructions. Completion and mailing dates will be provided by the RNC. Diaries and the 
questionnaires will be completed and returned via U.S. mail at the 1 month post second 
injection date. A diary will also be completed and returned in person at the 12 months 
post initial injection visit.  
 
24-48 Hours Post-Injection #2 Phone Call 
Assess concomitant medications 
Assess for adverse events 
Review diary and questionnaire completion dates 
 
1 Month Post Injection #2 Phone Call (+/- 3 days) 
Verify completed diary and questionnaires have been returned to research office via 
U.S. mail 
Assess concomitant medications 
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Assess for adverse events 
Review diary and questionnaire completion dates 
 
The following visits will be conducted for all subjects: 
 
Visit 7 (single injection subjects)/Visit 8 (double injection subjects):  
12 Months Post Initial Injection Follow-up (+/- 14 days) 
Review bladder diary 
Assess concomitant medications 
Questionnaire completion (PGI-I, GRA, UAB-Q, ICIQ) 
Vital signs: blood pressure, heart rate 
Urinalysis (dipstick), and culture (if required) 
Urine pregnancy test (if required) 
Urine collection for evaluation of biomarkers (presence of inflammatory and neuronal 
innervation proteins in the urine) 
Assessment of post void residual (PVR): measured by bladder scan or catheter 
Antibiotic (a medicine to prevent infection) given, by mouth, to prevent urinary tract 
infection 
Pressure flow studies 
Flexible cystoscopy 
Blood collection and analysis; CBC, blood chemistry 
Assess for adverse events
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Schedule of Events
ALL SUBJECTS 
SUBJECTS OPTING FOR 2ND 
INJECTION (OPTIONAL)  
ALL 
SUBJECTS 
Event 
Visit 1 
Screening 
Visit 2 
Muscle 
Biopsy 
Visit 3 
Injection 
Phone 
Call  
Post- Inj 
Visit 4 
1 Month 
Post-Inj 
Visit 5 
3 Months 
Post-Inj 
Visit 6  
6 Months 
Post-Inj 
Visit 7  
2nd 
Injection 
Phone 
Call 
Post-Inj 
#2 
Phone 
Call 
1 Month 
Post-Inj 
#2 
Visit 7/8 
12 Months 
Post-Initial 
Inj 
Visit window  
 
 
Approx  
10 wks 
from Visit 2 
24-48 
Hrs 
+/- 
7 days 
+/- 
7 days 
+/- 
7 days 
Approx  
10 wks 
from Visit 6 
24-48 
Hrs 
+/- 
3 days 
+/- 
7 days 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical and 
surgical history 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
 
X 
X 
X 
X 
 
 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
examination 
X 
 
 
 
 
 
X 
 
 
 
 
Residual urine 
volume 
X 
 
X 
 
X 
X 
X 
X 
 
 
X 
Pressure flow 
studies 
X 
 
 
 
 
 
X 
 
 
 
X 
Cystoscopy 
 
 
X 
 
 
 
X 
X 
 
 
X 
Muscle Biopsy 
 
X 
 
 
 
 
 
 
 
 
 
AMDC injection 
 
 
X 
 
 
 
 
X 
 
 
 
Antibiotic 
X 
 
X 
 
 
 
X 
X 
 
 
X 
CBC / blood 
chemistry 
X 
 
 
 
 
 
X 
 
 
 
X 
PTT 
X 
 
 
 
 
 
 
 
 
 
 
Blood borne 
virus4  
X 
 
 
 
 
 
 
 
 
 
 
Urinalysis1 
X 
 
X 
 
X 
X 
X 
X 
 
 
X 
Urine culture2 
X 
 
X 
 
X 
X 
X 
X 
 
 
X 
Urine pregnancy3 
X 
X 
X 
 
X 
X 
X 
X 
 
 
X 
Urine biomarker 
collection 
X 
 
 
 
 
X 
X 
 
 
 
X 
IRB NUMBER: 2015-134
IRB APPROVAL DATE: 04/18/2019

Autologous Muscle Derived Cells for Underactive Bladder 
 
 
1  Urine will be evaluated with a dipstick test for blood, glucose, ketones, leukocytes, nitrates, and protein.  If the initial test is positive for 
leukocytes, further quantitative and diagnostic testing will be performed. 
2  Urine culture will be performed only if qualitative urinalysis is positive for leukocytes (> +2). 
3  If the subject has had a hysterectomy, is post -menopausal, or male, this test is not required. 
4 If the biopsy procedure is scheduled more than 30 days after the most recent blood borne pathogen tests were 
completed, 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.
ALL SUBJECTS 
SUBJECTS OPTING FOR 2ND 
INJECTION (OPTIONAL) 
ALL 
SUBJECTS 
Event 
Visit 1 
Screening 
Visit 2 
Muscle 
Biopsy 
Visit 3 
Injection 
Phone 
Call  
Post- Inj 
Visit 4 
1 Month 
Post-Inj 
Visit 5 
3 Months 
Post-Inj 
Visit 6 
6 Months 
Post-Inj 
Visit 7  
2nd 
Injection 
Phone 
Call 
Post-Inj 
#2 
Phone 
Call 
1 Month 
Post-Inj 
#2 
Visit 7/8 
12 Months 
Post-Initial 
Inj 
Visit window  
 
 
Approx  
10 wks 
from Visit 2 
24-48 
Hrs 
+/- 
7 days 
+/- 
7 days 
+/- 
7 days 
Approx  
10 wks 
from Visit 6 
24-48 
Hrs 
+/- 
3 days 
+/- 
7 days 
3 day bladder 
diary 
 
 
X 
 
X 
X 
X 
 
 
X 
X 
ICIQ 
X 
 
 
 
X 
X 
X 
 
 
X 
X 
PGI-I, GRA 
 
 
 
 
X 
X 
X 
 
 
X 
X 
UAB-Q 
X 
 
 
 
X 
X 
X 
 
 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IRB NUMBER: 2015-134
IRB APPROVAL DATE: 04/18/2019

Autologous Muscle Derived Cells for Underactive Bladder 
 
 
2. Facilities 
All study visits, including biopsy and injection, will occur in the William Beaumont 
Hospital Urology Research Suite on the Royal Oak campus. The clinical research office 
is approximately 3,000 square feet of office space consisting of two examination rooms, 
a consenting/consultation room and a laboratory. Each examination room is equipped 
with an examination table and appropriate equipment to support clinical trials and 
provide care including cystoscopy. The laboratory space is capable of conducting 
urinalysis, urine pregnancy tests, and other minor laboratory procedures. This space 
includes secure storage for study supplies and records.  
 
Blood collection and analysis will be conducted by the William Beaumont Hospital 
Outpatient Laboratory. Lab results will be recorded and available in the electronic 
medical record (EMR). 
 
 
3. Investigational Product Storage and Accountability 
Once the AMDC are ready for injection, they will be shipped frozen and undiluted from 
the laboratory in Pittsburgh PA to the study site. The research pharmacist will receive 
the AMDC and evaluate the integrity of the shipment and packaging. Specialized 
packaging for transport from the processing center is certified to maintain appropriate 
temperature for up to 72 hours. The cells must remain frozen and undiluted until ready 
for use. If the cells cannot be injected within that period, the cells should be stored at 
least -60 °C to –80 °C until the subject is available for injection. AMDC will be 
appropriately stored in the Investigation Drug Services (IDS) Office in Pharmaceutical 
Services per policy until the injection visit.  
 
The cells are intended for a single use, should be thawed immediately prior to the 
injection, and should be used for the immediate procedure. Any unused portion shall be 
discarded. The IDS will follow a drug accountability plan that includes processes for 
receiving, storing, dispensing, and final disposition of the investigational product (IP).  
 
 
4. Criteria for Subject Discontinuation or Withdrawal 
The subject may be withdrawn or be discontinued from the study for any of the following 
reasons: 
1. The subject voluntarily withdraws consent. 
2. The subject refuses to complete any of the study-related activities. 
3. The subject is lost to follow-up. 
4. Based on clinical judgment, the investigator may discontinue the subject from 
participation at any time during the study for any reason (i.e. subject non-
compliance). However, if AMDC injection has occurred, the subject will be 
followed for at least 6 months post-injection.  
 
The subject may also be discontinued from the study, if unable to tolerate treatment. If 
the biopsy cannot be tolerated, then the procedure will be stopped immediately and the 
study will be terminated. The subject will be contacted by phone within 24-48 hours for 
follow-up evaluation. A clinic visit may also be conducted if necessary.  
 
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If the injection cannot be tolerated, then the procedure will be stopped immediately. If 
any of the study product was injected into the bladder, follow up will occur for at least 6 
months post-injection. 
 
In order to protect subject safety, enrollment may be suspended or the study may be 
terminated. Decision to suspend enrollment or terminate the study will be made by the 
principal investigator with guidance and recommendation from the Medical Safety 
Monitor. The FDA and IRB will be promptly notified of these actions. If a decision is 
made to terminate the study, all patients already treated will be followed for 6 months 
following the injection procedure. 
 
RISKS AND BENEFITS  
a. Potential Benefits 
This is a prospective, open-label, Phase I, single center study. The treatments 
described in this protocol are investigational and involve greater than minimal risk to the 
subject.  
 
The benefits to participating in this study include receiving a treatment that is not 
currently available to persons suffering with UAB. It is hypothesized that injection of 
AMDC will reduce UAB symptoms, improve quality of life, and delay or eliminate the 
need for invasive, surgical treatments in the future. Since this has not been proven, 
patients may receive no direct benefit from inclusion in this study. Knowledge gained in 
this study may benefit future patients with chronic UAB. 
 
b. Potential Risks 
The study involves procedures that may cause pain and discomfort. Additionally, it is 
possible, that the subject may experience some side effects. Should any side effects 
occur, or should the subject experience discomfort or pain, the subject should contact 
the study doctor and their personal doctor immediately. 
 
Muscle Biopsy Procedure  
Most Frequent (occurring more than 10% of the time): 
 Bleeding 
 Pain  
 Muscle spasms and tightness 
 Weight-bearing difficulty (experience pain/discomfort when applying 
weight to the leg) 
Less Frequent (occurring more than 1% but less than 10% of the time): 
 Wound infection 
 Hematoma (bruise) 
 Need for re-biopsy due to inability to grow cells from the muscle biopsy 
tissue  
Rare (occurring less than 1% of the time): 
 Dizziness and related responses (sweating, anxiety) from the procedure 
 Numbing and tingling  
 Scarring 
 Allergic reaction to numbing medicine  
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Urinary Catheterization  
Less Frequent (occurring more than 1% but less than 10% of the time): 
 Temporary inability to urinate 
 Bleeding 
 Discomfort or pain during catheter insertion 
 Mild cramping 
 Urinary tract infections 
 
Cystoscopy Procedure 
Less Frequent (occurring more than 1% but less than 10% of the time): 
 Discomfort or pain 
 Mild cramping 
 Infection 
 
 Painful or difficult urination 
Rare (occurring less than 1% of the time): 
 Bleeding (blood in urine) 
 Urinary tract infection 
 Inability to pass urine after the procedure 
 Puncture of the bladder 
 Trauma 
 Temporary swelling or injury to the urethra 
 Overstretching of the bladder 
 A change in urinary frequency 
 Urgency in urination, including urgency resulting in episodes of urge 
incontinence 
 Feeling of tiredness 
 Back pain 
 For men, testicular pain and/or temporary swelling of the testes or 
epididymis 
 
Injection Procedure 
 
Most Frequent (occurring more than 10% of the time) 
 Temporary urinary passage (urethral) pain or discomfort   
 Temporary bladder pain or discomfort  
 Blood in urine 
 
 
Rare (occurring less than 1% of the time): 
 Temporary bleeding at injection site(s) resulting in blood clot(s) in the 
bladder tissue 
 Infection 
 Accidental bladder wall puncture resulting in inadvertently injecting AMDC 
into the lower abdominal area 
 Urinary urgency 
 Changes in urine frequency 
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Investigational Product (AMDC) 
 
Rare (occurring less than 1% of the time): 
 Flu like symptoms (nausea, fatigue, body aches) 
 Allergic response (cells or components of the final product including: 
bovine (cow) proteins (used in the process to grow your cells), ampicillin 
and gentamicin sulfate (antibiotic medications) 
o Risk of allergic response to the cells is expected to be minimal due 
to the use of your own cells. Risks of allergic response to bovine 
proteins, ampicillin, and gentamicin sulfate used in AMDC 
production should be minimal since only trace amounts are 
expected to be in the final product. 
o Signs/symptoms of an allergic response may include, but are not 
limited to: swelling, itching, hives, shortness of breath, and nausea 
 
Lidocaine (Numbing Medicine)  
1) Used in liquid form pre-biopsy, injected into the skin at the biopsy site,  
2) Used in liquid form pre-injection, instilled in the bladder with a catheter 
3) Used in gel form pre-cystoscopy, injected into the urethra (urinary passage) 
 
Rare (occurring less than 1% of the time): 
 Lightheadedness, dizziness, confusion 
 Lowered blood pressure, slowed heart rate 
 Swelling or local irritation  
 Allergic reaction 
 
Antibiotic (Medicine to Prevent Infection) 
Less Frequent (occurring more than 1% but less than 10% of the time): 
 Diarrhea 
 Nausea and vomiting 
 Cramping 
 
 Rare (occurring less than 1% of the time): 
 Headache 
 Itching  
 Rash 
 Allergic reaction 
 
 
 
Risks of Blood Drawing Procedure 
Most Frequent (occurring more than 10% of the time): 
 Pain  
 Discomfort 
 Bleeding 
 Bruising at the needle puncture site 
 
Rare (occurring less than 1% of the time): 
 Blood clot 
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 Infection at the needle puncture site 
 Feeling lightheaded 
 Fainting 
 
There is a rare risk of breach of confidentiality (release of information which personally 
identifies the participant). Multiple processes are in place to reduce this risk.  
 
Cell Therapy 
All cell therapies are thought to involve the possible risk of tumor formation (a nodule or 
mass-like structure). The true risk of tumor formation is unknown in cell therapy. With 
the type of cells used in this study, the risks are considered to be extremely low. Testing 
was carried out on the type of cells used in this study to determine the risk and no 
evidence of tumor formation was found. 
 
Breach of Privacy and Confidentiality 
There is a rare risk of breach of privacy and data confidentiality (release of information 
which personally identifies the participant). Confidentiality procedures will be strictly adhered 
to when transferring, managing, and analyzing study data. The subject will be assigned a 
unique study identification number, research information will be stored in a locked, 
secure cabinet with access limited to authorized research personnel, and all visits will 
be conducted in a private area of the clinic.  
 
Unforeseen Risks 
Not all possible effects are known. With any therapy, unusual, unexpected or previously 
unreported side effects may occur. This study includes experimental procedures, 
therefore not all risks and outcomes can be foreseen. 
 
Methods to Minimize Risk 
Only qualified physicians trained in cystoscopy, cystoscopic injection and the use of 
bladder injection agents will perform the injection procedure. The PI and sub-
Investigators have had this experience in private practice utilizing botulinum toxin for 
bladder injections using a similar approach and needle. Adherence to the treatment 
protocol is necessary to reduce material- and procedure-related risk. Routine 
venipuncture will be performed by qualified personnel. Local anesthetic will be used to 
minimize discomfort. Injection of AMDC will occur under direct vision. After injection, 
cystoscopy will be used to ascertain the presence of bleeding or puncture. A 
prophylactic antibiotic will be given to reduce the risk of infection. The patient will be 
monitored for a minimum of 30 minutes after injection. The risks of incontinence, urinary 
tract infection, urinary retention, and allergic reaction to the injected reagents will be 
assessed through follow-up clinical visits and review of the 3-day bladder diary.  
 
ELIGIBILITY CRITERIA 
Inclusion 
a. Males and females, at least 18 years of age 
b. History of UAB for at least 6 months documented in the medical record 
c. Recurring UAB symptoms 
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d. Subjects unresponsive to relief symptoms of UAB with previous use of 
medications and/or other treatments 
e. Voiding difficulty (complains of difficulty emptying the bladder) 
f. Post void residual > 150 mL 
g. Total UAB Questionnaire Score > 3 or 100% reliant on intermittent self-
catheterization to empty bladder 
h. Females of child-bearing potential agree to use a reliable form of birth control for 
the entire study duration 
i. Willing and capable of understanding and complying with all requirements of the 
protocol, including proper completion of the voiding diaries and self-administered 
questionnaires 
 
   Exclusion 
a. Pregnant, plans to become pregnant or lactating 
b. History of bleeding diathesis, uncorrectable coagulopathy, or would refuse a 
blood transfusion 
c. Currently on anticoagulant therapy 
d. Obvious neurological impairment 
e. Known allergy or hypersensitivity to bovine proteins or allergens, gentamicin 
sulfate, ampicillin, and/or lidocaine that medically warrants exclusion as 
determined by the physician 
f. Simultaneously participating in another investigational drug or device study or 
use of any investigational drug(s) or therapeutic device(s) within 3 months 
preceding enrollment 
g. Has been treated with an investigational device, drug, or procedure for UAB 
within the last 6 months. 
h. Medical condition or disorder that may limit life expectancy or that may cause 
protocol deviations (e.g. unable to perform self-evaluations and/or accurately 
report medical history, urinary symptoms, and/or data) 
i. History of cancer in pelvic organs, ureters, or kidneys or any cancer that has 
undergone treatment within the past 12 months 
j. Compromised immune system due to disease state, chronic corticosteroid use, 
or other immunosuppressive therapy 
k. History of radiation therapy to the bladder 
l. Tests positive for Hepatitis B (Hepatitis B Surface Antigen [HBsAg] and Anti-
Hepatitis B Core Total Antibody [Anti-HBc])), Hepatitis C (Hepatitis C Antibody 
[Anti-HCV]), HIV (HIV Type 1 and 2 Antibodies [Anti-HIV-1, 2]), and/or Syphilis. 
m. Abnormal renal function 
n. An active urinary tract infection, determined by an investigator, as evidenced by 
urinalysis, urine culture, patient symptom report, and/or cystoscopy (see 
appendix A for details) 
o. Taking medication(s) that affect urination (e.g. medically necessary, stable 
drugs) such as prescription drugs, over-the-counter drugs, or dietary 
supplements, including herbal supplements and those taken with teas  
p. Requires concomitant use of or treatment with immunosuppressive agents 
q. Pelvic organ prolapse beyond the introitus (e.g., cystocele, rectocele) 
r. Abnormal bladder capacity (i.e., less than 100 mL) 
IRB NUMBER: 2015-134
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ADEQUACY OF PROTECTION FOR HUMAN SUBJECTS 
Investigational Review Board (IRB) 
The Institutional Review Board (IRB) must provide written approval of the study protocol 
and informed consent prior to the initiation of any study related procedures.  The PI will 
supply the required documentation to the IRB for the annual renewal of the protocol, 
and any approvals of revisions to the informed consent document or amendments to the 
protocol.  The PI will be responsible for providing to the IRB, prompt notification of any 
new information that may adversely affect the safety of subjects or the conduct of the 
trial. 
 
Informed Consent 
The study coordinator will obtain informed consent and will explain the study in full 
including, but not limited to, what is involved, the possible risks, and the possible 
benefits. The explanation will occur at a level of understanding appropriate for the 
potential participant. Once the potential subject has had ample time to consider the 
study, review the consent form and ask questions, he/she will be asked to sign the 
written consent form in the presence of the consent provider and a witness (a Beaumont 
employee). The subject will receive a copy of the consent form for his/her records.  
 
SUBJECT CONFIDENTIALITY  
A report of the results of this study may be published but participants’ names will not be 
disclosed in these documents. The participants’ identities may be disclosed to the 
governing health authorities or the FDA if they inspect the study records. Appropriate 
precautions will be taken to maintain confidentiality of medical records and personal 
information.  
 
DATA ANALYSIS AND REPORTING 
Descriptive statistics will be reported on clinical and demographic characteristics of 
patients, as well as for the frequency of AEs and SAEs (both overall and for specific 
ones of interest). Continuous variables will be summarized using means and standard 
deviations or median and range, as appropriate. Categorical variables will be 
summarized with counts and percentages. Assumptions needed for all inference 
procedures will be checked. Blyth-Still-Casella confidence intervals may be calculated 
for the proportions of AEs and SAEs. Frequency tables will be presented for the 12 
month results on Patient Global Impression of Improvement and the Global Response 
Assessment. For assessments involving other questionnaires and voiding habits, the 
pre-treatment assessments will be used as a control for each subject. Analysis may be 
based on  the changes; nonparametric tests (Friedman tests, Wilcoxon signed rank 
tests) or parametric alternatives may be used. Repeated measures analysis may be 
used if appropriate.  
 
The primary assessment of safety outcomes will use 6 month outcomes; 
secondary analyses will use 12 month data. The primary assessments of efficacy 
will be made at 12 months post initial AMDC injection,  
 
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A description of this study will be available on http://www.ClincalTrials.gov. This site will 
not include any subject identifiers. After study completion, the posting will include a 
summary of the results.  
 
Results may also be disseminated in poster or platform presentations at various 
local, national, and/or international scientific meetings, as well as published in 
peer-reviewed journals.  
 
DATA SAFETY MONITORING PLAN 
Overall, ongoing, safety monitoring will be performed by the study site staff including the 
principal investigator and sub-investigators. A Medical Safety Monitor will be assigned 
by the PI.  The Medical Safety Monitor (MSM) will be a physician who is not involved in 
the study and who has no conflict of interest. The MSM will review for SAEs and will 
determine expectedness of the event. In the event that an AE is unreported and cannot 
be determined within reportable timeliness, the causality will be determined by the 
MSM. The MSM may suggest protocol modifications to prevent the occurrence of 
particular AEs (e.g., modifying the protocol to require frequent measurement of 
laboratory values predictive of the event or to improve expeditious identification of SAE). 
In the event that the MSM is unavailable for an extended period of time (i.e. extended 
vacation, illness, etc.) a back-up MSM will be nominated by the study PI. Safety issues 
will also be addressed in the annual reports to the IRB and the FDA.  
 
Additional data safety monitoring procedures include: 
 Research Administration’s Clinical Research Quality and Process Improvement 
Program (CRQIP) will perform in-house monitoring of the first subject enrolled 
after the completion of visit 1 
 Monitoring of the study will be conducted by the Beaumont Research 
Coordinating Center (BRCC) 
 Safety data review at study team meetings 
 
Adverse Event Reporting  
An AE is any untoward medical occurrence in a subject participating in a clinical 
investigation and which does not necessarily have a causal relationship with treatment. 
An AE can therefore by any unfavorable and unintended sign (included an abnormal 
laboratory finding), symptom, or disease temporarily associated with the use of an 
investigational product (AMDC) or study-related procedure, whether or not related to the 
product or procedure.  
 
Study subjects will be instructed to report any changes in baseline health from the time 
the subject enters the study through the end of the study regardless if the event is listed 
as a risk on the informed consent form. Study staff will also inquire about AEs at each 
visit. All AEs should be recorded on the case report form (CRF) and submitted to the 
electronic data capture (EDC) system within 10 days of knowledge of the event. The 
investigator is responsible for reporting AEs to the IRB in accordance with institutional 
policy.  
 
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All SAEs are to be reported to the Principal Investigator within 24 hours of knowledge of 
the event. A SAE is defined to include any adverse experience that results in the 
following:  
 Death;  
 Life threatening;  
 Hospitalization;  
 Persistent or significant disability or incapacity; 
 Require intervention to prevent death or a life threatening condition.  
 
All such reported SAEs will be investigated by the Medical Safety Monitor in 
collaboration with the investigator involved as well as with the principal investigator. The 
principal investigator, as the IND holder, shall, if required according to applicable 
regulations, report the event to the appropriate regulatory authority in accordance with 
21 CFR 312.32. Fatal or life-threatening AEs will be reported to the FDA by telephone 
or fax within seven days. Unexpected SAEs will be reported to the FDA in writing within 
15 days. The principal investigator or designee will notify the IRB of applicable events 
according to institutional guidelines. AEs identified prior to the end of study will be 
followed for one month after the last study visit is conducted. 
 
Pre-Existing Conditions 
Any chronic or acute sign, symptom, illness, or condition that the subject has at the time 
of enrollment of this trial that is unrelated to the treatment is considered a pre-existing 
condition (e.g., asthma, diabetes etc.). Information on pre-existing medical conditions 
will be obtained at the screening visit. This information will be utilized to assist with 
identifying changes in health conditions and increase the accuracy of AE reporting. A 
pre-existing condition should be reported as an AE only if its frequency, intensity or 
character worsens during the study period. 
 
Determination of Event Causality 
Definitely related events are those that the site PI/Sub-I determines are definitely 
related to the intervention, and for which the PI/Sub-I believes no alternative etiology 
exists.  
Probably related events are those that the site PI/Sub-I believes there is a reasonable 
likelihood the AE may have been caused by the intervention involved in the research.  
Probably not related events are those that the site PI/Sub-I believes there is a 
reasonable likelihood the AE may have been caused by other factors and not caused by 
the intervention involved in the research.  
Unrelated events are those that the site PI/Sub-I determines are not related to the 
intervention.  
 
Grading of Adverse Events 
The severity of each AE will be categorized using the following criteria: 
Grade I (Mild): Transient or mild discomfort; no medical intervention/therapy required 
Grade II (Moderate): Mild to moderate limitation in activity – some assistance may be 
needed; no or minimal medical intervention/therapy required 
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Grade III (Severe): Marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalizations possible 
Grade IV (Life-Threatening): Extreme limitation in activity, significant assistance 
required; significant intervention/therapy required, hospitalization or hospice car 
probable 
Grade V (Death) 
 
Protocol Deviations  
The RNC will utilize Beaumont Hospitals, policy 229, “Protocol Deviations” as guidance 
for IRB reporting.  Each event will be reviewed by the PI or his designee (a Sub-I). All 
reportable and un-reportable deviations will be recorded on a protocol deviation log. The 
log will aide with identifying trends and recurring issues to be addressed by study staff. 
The data will be routinely reviewed by the study team, including the PI. 
 
PLAN FOR DATA MANAGEMENT AND MONITORING 
Study data will be transcribed by study personnel from the source documents onto the 
eCRF.  Worksheets will be provided for the capture of data for easier transfer to the 
eCRF.  Electronic data capture process for the proposed study will require connecting to 
the data website via the Microsoft Internet Server. To ensure accuracy and integrity, 
data entered for each variable will be validated by an electronic audit procedure, which 
entails a three-step process. The validation rules are to insure that no data is missing, 
entries are logical, skip patterns are followed, and that non-numerical data entries are 
appropriate.  
 
The study will be reviewed in accordance with written standard operating procedures 
consistent with 21CFR812. The BRCC will be assigned to review completed case report 
forms and/or electronic data entry, data base review, IRB decisions, and investigator 
and clinical site records at regular intervals throughout the study.  Additionally, patient 
charts, and clinical records will be reviewed to assure protocol adherence. Source 
documentation may also be verified. Reports from the BRCC will include enrollment 
data, eCRF completion and delinquencies, query resolutions and delinquencies, 
protocol deviations, and frequency of unanticipated problems/adverse events. In order 
to identify, evaluate and prevent adverse events, the total number of events will be 
reviewed, as well as the details of each event, for example visit number and severity. 
Data will be reviewed to identify trends and possible concerns. Enrollment data will 
direct recruitment efforts and assist in study planning. See BRCC monitoring plan for 
more details. 
 
 
SUMMARY OF EXISTING STUDY DATA 
a. Animal Pharmacology and Toxicology  
Nonclinical testing of muscle derived cell (MDC) injection into the lower urinary tract has  
been conducted in a number of animal studies. The studies summarized here include: 
1) a preliminary evaluation of MDC persistence and differentiation after injection in the 
bladder wall of a mouse model; 2) an assessment of injected MDC persistence as 
compared to injected bovine collagen in an autologous rat model; and 3) assessment of 
periurethral injected allogeneic MDCs in rat bladder wall.  
 
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Feasibility Testing in an Allogeneic Mouse Model 
The feasibility of MDC injection was evaluated in a preliminary assessment of MDC 
persistence and differentiation into myotubes and myofibers in the bladder wall.9 In this 
study, primary MDCs isolated from normal mice were transduced to express the β-
galactosidase reporter gene. Twelve adult immunodeficient mice received injections of 
1-1.5 x 106 MDCs into the right and left lateral bladder walls. The tissue was harvested 
after 5, 35, and 70 days, and stained for fast myosin heavy chain to assess the 
formation of muscle fibers, and β-galactosidase to mark the injected cells. 
 
A large number of cells expressing β-galactosidase were observed in the bladder wall at 
each time point. Many myotubes and myofibers expressing β-galactosidase and 
positively stained for fast myosin heavy chain were also seen in the bladder wall at 35 
and 70 days after injection, demonstrating feasibility and persistence of injected MDC 
cells through 70 days. 
 
Persistence of MDCs vs. Bovine Collagen in an Autologous Rat Model 
The persistence of MDCs as compared to bovine collagen was assessed after injection 
into the bladder or urethral wall in an autologous rat model.10 In this study, 12 female 
Sprague-Dawley rats received injections into the bladder or urethra. Six animals 
received autologous MDC injection and six received collagen injection. Three animals 
from each group were sacrificed at three days and at 30 days after injection, and tissues 
were prepared for histopathological examination. Slides were evaluated for the 
presence of MDCs by staining for fast myosin heavy chain and β-galactosidase, for the 
presence of collagen by Tri-chrome staining, and for evidence of inflammation or tissue 
damage by microscopic examination. 
 
At the three and 30-day time points, a large number of cells expressing β-galactosidase 
were observed in the bladder and urethral wall of the MDC-injected animals. Moreover, 
injected MDCs comprised a mass that protruded toward the lumen of the bladder and 
urethra. The persistence of injected MDCs and collagen was similar at three days. 
However, at 30 days only scant bovine collagen was detectable at the injection site in 
the collagen-injected animals while there was significant MDC persistence at the 
injection site in the MDC-injected animals. Measurement by cell mediated reporter gene 
expression indicated approximately 88% MDC survival at 30 days. 
 
At three and 30 days post-injection, the measured diameters of nodules created by 
injection averaged 1.0 ± 0.05 mm and 0.84 ± 0.08 mm for MDC, respectively. The 
diameter of nodules by collagen injection was 0.78 ± 0.07 mm at three days post-
injection, and decreased to 0.15 ± 0.05 mm at 30 days post injection. The three day 
post-injection sizes were not significantly different between MDC and collagen injection; 
however, at 30 days post-injection, the mean size of remaining collagen nodules was 
significantly smaller than for MDCs (P<.05). 
Histopathological examination revealed no evidence of inflammation (platelets, 
macrophages, and monocytes) or tissue damage at the injected site. Importantly, no 
MDCs (as evidenced by fast myosin heavy chain staining) were observed in the area 
outside the injection. 
 
Testing in an Allogeneic Rat Incontinence Model 
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Testing was performed in a rat incontinence model in which the sciatic nerve on each 
side was transected distal to its origin from the vertebral column and proximal to the 
pudendal nerve branch. Animals were evaluated for the effect of periurethral injected 
allogeneic MDCs on leak point pressure, local histopathology, and the potential for 
immune response.11 
 
In this study, cells for injection were isolated from skeletal muscle of normal female rats 
and purified in MDC content using the pre-plate technique. Fifteen six-week old normal 
female rats were evenly divided into three experimental groups: a control group had a 
sham operation without injections, a denervated group had periurethral saline injections, 
and a denervated group had periurethral MDC injections. Leak point pressure (LPP) 
was measured at one and four weeks following injection. Following the final LPP 
measurement, the injection sites were harvested and processed for histopathological 
assessment. 
 
The potential for immune response was evaluated in four additional animals; two 
received bladder wall injections of normal satellite cells, and two received bladder wall 
injections of MDCs. Two weeks after injection the injection sites were harvested and 
processed for immunohistochemical evaluation of the presence of CD8 lymphocytes. 
 
Results of testing provided evidence of the effectiveness of MDC injection. At one week, 
the measured LPP was not significantly different between control and saline injection 
groups, but was significantly greater in the MDC group as compared to control (P=.001). 
At four weeks, the LPP was significantly decreased in the saline injected group vs. 
control (P=.01), while the LPP was significantly increased in the MDC injected group vs. 
control (P=.001). These results are summarized in the table below. 
 
LPP MDCs vs. Control 
Group 
1-week LPP 
(cm·H2O) 
4-week LPP 
(cm·H2O) 
Difference 
(cm·H2O) 
Control 
25.2 ± 1.9 
25.8 ± 2.5 
0.6 
Saline injection 
28.6 ± 0.8 
18.6 ± 5.2 
-10.0 
MDC injection 
36.7 ± 2.3 
44.1 ± 6.6 
7.4 
 
Results of histopathological assessment showed both smooth and skeletal muscle 
contained in the urethral sphincter of control animals, with the smooth muscle cells in 
tightly packed bundles. As expected, sections from the saline injected denervated rats 
showed cell atrophy, while the samples from the MDC animals showed increased 
dorsolateral skeletal muscle classes with variable fiber orientation at the injection sites. 
 
Immunohistochemical evaluation detected CD8 lymphocytes throughout the injection 
site in sections from animals injected with normal satellite cells; however, no CD8 
lymphocytes were observed in the MDC-injected bladders, demonstrating that MDC 
injected cells did not trigger an immune response, despite their allogeneic nature. 
 
In a more recent study, MDC doses of 1 x 105, 1 x 106 and 1 x 107 were injected into the 
urethral wall in the rat incontinence model.12 No adverse events related to treatment 
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were noted in any of the animals in the MDC injected group. Animals injected with 1 x 
106 and 1 x 107 doses showed significant increase in LPP over sham operated animals. 
 
 
Testing in Rat model of 
Underactive Bladder 
We have demonstrated that 
MDC transplantation 
increased muscle contractility 
in the cryoinjured bladder 
detrusor model 26, 28. We have 
(1) demonstrated the feasibility 
and survival of MDC injection 
into the bladder wall; (2) 
established improved detrusor 
contractility with MDC injection 
in a bladder injury model; (3) 
revealed the maturity of the b-
galactosidase expressing 
myofibers in the injured 
bladder by demonstrating the 
presence of neuromuscular 
junctions based on the 
accumulation of acetylcholine 
receptors (AChRs) in small 
segments of their membrane; 
and (4) demonstrated the 
possiblity of MDC differentiating into a smooth muscle lineage when injected into the 
bladder wall (Figures 1-3). Our preclinical data support that autologous MDC injections 
can be used as a nonallergenic agent to improve bladder contractility. Thus, 
transplantation of AMDCs from skeletal muscle might be a promising treatment strategy 
for patients with UAB. 
 
Figure 1: Physiological improvement of the injured bladder via muscle-derived cell 
implantation. Schematic representation of the cryoinjury model and location of the 
bladder strips (a). A representative contractile curve of bladder strips evoked by 
electrical stimulation (20 Hz 80 shocks) of control (b)and 30-s cryoinjured (c) rat 
bladders. Cryoinjured rat bladders with immediate saline and pp6 injection both resulted 
in a significant (∗P <0.05)decrease of contractile responses to electricalfield stimulation 
when compared with the control bladder (d). However, the pp6 injected at 1 week 
aftercryoinjury in the rat bladder displayed a significant improvement in bladder 
contractility versus cryo+saline (1 week) injection (+P<0.05) for up to 80% of the normal 
baseline level, which was not significantly different from the control group.  (e). The 
cryoinjured mouse bladder injected with mc13 at 1 week after injury significantly 
improved bladder contractility (+P 0.05) in contrast to that observed with pp1/pp2 (f). 
Compared with control; +compared with cryo+saline. 
 
Figure 1
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Figure 2: Expression of -SMA in the injected muscle cells at the injected site. Bladders 
at 8 weeks (pp6) and 2 weeks (mc13) after injection were stained forb-galactosidase 
(a, b) and SMA (c, d). Although some of the cells expressing b-galactosidase did not 
colocalize with SMA (arrowheads e, f), many of the injected MDC expressed both 
markers (arrows e, f) showing their differentiation into the smooth muscle lineage. 
Magnification a–f,×200 
 
b
d
a
Figure 2
c
f
e
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Figure 3: The muscle-derived cells 
differentiated into myotubes and 
myofibers with neuromuscular 
junctions in the injected bladders. 
Myotubes and myofibers expressing 
fast myosin heavy chain (a, c) were 
also found to express AChR clustered 
in their membranes at 15 days after 
injection with pp6 (b) and mc13 (d) 
suggesting that the myofibers became 
innervated (arrows). However, it has 
also been observed that in many 
myotubes and myofibers, the AChR 
expression was diffused throughout  
 
the myofibers, which is suggestive of  
the lack of innervation of these myofibers (stars, d). Magnification a–d,×400. 
 
The Dose-Effect Relationship Between Cell Dose and Resultant Myofibers 
Praud and colleagues demonstrated that the number of myofibers formed from muscle 
cell transplantation reaches a plateau. Once the plateau is reached, additional cells do 
not efficiently increase the number of myofibers formed.13 In fact, these additional cells 
may adversely impact overall survival of the implanted cells by overwhelming the 
available local nutrient supply leading to cell death and increased local inflammation. 
This principal has been demonstrated in encapsulated myoblast delivery devices and in 
studies of cardiomyocyte transplantation.14, 15 Thus, the over-delivery of cells may be 
counterproductive to regeneration due to the possibility of disruption and demise of cells 
that might otherwise survive. Based on these observations, it is postulated that 
transplants with lower initial cell counts might improve overall cell survival, and increase 
the number of viable myofibers formed from the transplanted cells.   
 
Summary 
Non-clinical testing has demonstrated MDC persistence and differentiation into 
myotubes and myofibers after injection in the bladder wall of a mouse model. Testing in 
an autologous rat model has demonstrated improved cell persistence and bulking as 
compared to injected bovine collagen, and an absence of cell migration. Testing in a rat 
incontinence model has demonstrated significant improvement in LPP, increased 
muscle mass, and no evidence of an immune response as determined by the absence 
of CD8 lymphocytes. Testing in model of underactive bladder demonstrated improved 
detrusor contractility.  
 
Additional testing (unpublished) has demonstrated significant autologous MDC survival 
at six months after injection into the bladder wall in an immunodeficient mouse model, 
and evidence of increased LPP in an immunodeficient rat incontinence model after 
Figure 3
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injection of human MDCs. Higher doses of MDCs have not been associated with 
adverse events. However, there may be a plateau beyond which additional cells do not 
improve myofiber content. In fact, lower initial cell doses may improve overall cell 
survival and improved myofiber content. 
 
b. Experience in Humans 
Indication: Underactive Bladder 
Compassionate use of AMDC to treat UAB was previously approved by the FDA for use 
in a single patient by Dr. Ananias Diokno, William Beaumont Hospital (IND 15417). The 
subject received a single treatment of 250 million cells in approximately 30 sites (0.5 
ml/injection) to enhance bladder detrusor contractility in September 2013. He has 
completed the 6 month post-injection follow-up visit. There were no changes in any of 
the specified safety measures from baseline to 6 months post AMDC injection. Specific 
safety measures evaluated include: vital signs, residual urine volume, and urinalysis. No 
study-related adverse events have been reported by the subject. At each study visit the 
subject denied experiencing any problems related to urinary functioning including gross 
hematuria, urgency, frequency and signs/symptoms of infection (i.e. odor, cloudiness, or 
dysuria). Additionally there have not been any significant changes in laboratory results 
post AMDC injection. Therefore, the injection of AMDC into the bladder appears to be 
safe.  
 
Indication: Stress Urinary Incontinence in Women 
AMDC has been evaluated in patients in clinical trials for urinary sphincter repair (USR) 
in female patients with stress urinary incontinence, for anal sphincter repair (ASR) in 
patients with fecal incontinence, and cardiac tissue repair (CTR) in patients following 
myocardial infarction (sub-acute), and chronic ischemic heart failure. AMDC products 
have been used safely in over 300 patients to date in clinical studies approved by FDA 
and Health Canada. The clinical pharmacology of AMDC is currently under investigation 
with clinical experience above and below the dose of 150 ± 20% x 106. AMDC-USR is 
expected to improve continence in female patients with stress urinary incontinence. 
Clinical data collected are suggestive of a safe toxicity profile with injections into the 
urethral sphincter up to 200 x 106 cells. Additionally, in two separate studies, a Phase II 
dose escalation and a Phase III confirmatory study have been conducted where 
patients have received a second treatment dose approximately 3-6 months after their 
initial treatment with AMDC ranging from 1-150 x 106 cells per treatment. The Phase III 
study is ongoing and data is still being collected, but data from the phase II study has 
been collected, analysed, and reported. No SAEs have been reported from the Phase III 
confirmatory study to date that have been attributed to the AMDC product (150 x 106 
cells at 1 or 2 treatments). 
 
Study Code: MCMT- Feasibility Study 
In an initial clinical feasibility study in Canada, 8 subjects have been treated with doses 
of 18-22 x 106 AMDC. All subjects have completed the study without experiencing any 
serious, related adverse events associated with the use of AMDC. [Reference Health 
Canada File #9427-C2135-21C, Control# 087205 (Original CTA), Control# 089071 
(CTA-A), Control# 095823 (CTA-A) and Control# 101701 (CTA-A)] 
 
 
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Study Code: MCDR- Dose Effect Study 
A multicenter dose escalating study demonstrating feasibility of this treatment is 
completed. A summary of results from the dose escalating clinical study in Canada is 
presented below. [Reference Health Canada File #9427-C2135-21C, Control# 103555 
(Original CTA), Control# 116233 (CTA-A), Control# 117540 (CTA-A)] 
In the study, 38 female subjects with SUI, who demonstrated no improvement with 
standard therapy for at least 12 months, were enrolled in the three parts of this study. 
20 subjects were stratified between two sites. Ten subjects in each site were 
randomized to five arms to receive, in a double-blind fashion, an injection of one of five 
doses from 1, 2, 4, 8 to 16 x 106 cells of autologous MDC obtained from skeletal muscle 
biopsies. The second part of the study enrolled nine subjects, three in each arm, who 
were randomized to receive one of three stepped doses of 32, 64 or 128 x 106 cells. In 
the third part of the study, a second group of 9 subjects (3 at each dose level) received 
one of 3 doses of 16, 32 or 64 x 106 cells. The injections of these additional subjects 
were performed using ultrasound guidance to assure placement in the muscle of the 
urethral sphincter mechanism. All subjects were followed for one year after their last 
treatment and monitored closely for any adverse events.  For the analysis, doses of 1-
16 x 106 cells were grouped and analyzed as the “low dose” group while doses of 32, 64 
or 128 x 106 cells were grouped and analyzed as the “high dose” group. 
The first patient was enrolled in the study on September 6, 2006; the last patient 
completed follow-up on April 29, 2010.  Mean patient age was 50 years (range 30-73). 
A total of 38 patients were enrolled; 32 (84.2%) elected to receive a second AMDC 
treatment following their initial 3-month follow-up.  Thirty-three patients (4 with 
1 treatment; 29 with 2 treatments) completed the study; 4 patients withdrew and 1 
patient was lost to follow-up.  From discussions with physicians, it appears that all 
patients received periurethral injection of AMDC.  There have been no serious, related 
adverse events associated with the use of AMDC.  Minor events occurred at similar 
rates among all treatment groups and included pain and bruising at the muscle biopsy 
site, pain at the injection site, mild self-limiting urinary retention, and urinary tract 
infection.   
Treatment affected the amount of leakage during a 1-hour pad test and frequency of 
diary-reported stress incontinence episodes.  Of patients with ≥1 g baseline pad weight 
who received 2 AMDC treatments, 61.5% (8/13) of low dose patients and 88.9% (8/9) of 
high dose patients had ≥50% reduction in pad weight with ~30% of both dose groups 
dry (i.e., <1 g pad weight) at 18 months.   Similarly, 53.3% (8/15) of low dose patients 
and 77.8% (7/9) of high dose patients who received 2 AMDC treatments and who had at 
least 1 baseline stress leak reported ≥50% fewer stress leaks at 18 months.  Quality of 
life was also affected with ≥50% improvement in IIQ-7 and UDI-6 scores reported at 
18-month follow-up for 26.3% (5/19) of low dose patients and 50.0% (5/10) of high dose 
patients who received 2 AMDC treatments.  Improvement may be related to cell dose 
since a higher proportion of high dose patients than low dose patients experienced 
≥50% reduction in pad weight (88.9% vs. 61.5%), ≥50% reduction in diary-reported 
stress leaks (77.8% vs. 53.3%), 0-1 leaks (88.9% vs. 33.3%), and ≥50% improvement in 
IIQ-7 and UDI-6 scores (50.0% vs. 26.3%) at 18 months. Valsalva LPP improved for 
25.9% (7/27) of 2 treatment patients and an additional 14.8% (4/27) of this patient 
subset no longer experienced detectable valsalva or cough-induced leakage at 3 
months following the second AMDC treatment.  However, a standardized method to 
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assess valsalva LPP was not provided in the protocol and variability in methods 
between sites and operators may have affected the measurements.  Since limited data 
are available for single treatment patients, the effect of a single dose of AMDC on SUI 
symptoms cannot be determined. 
 
Study Code: IND1- Dose Effect Study 
This prospective, multi-center, multi-country dose escalation trial was initially designed 
to evaluate the 12-month safety and potential efficacy of 3 different doses (10, 50, 100 x 
106) of AMDC for treatment of SUI in adult females. In a multicenter, multi-country study 
[Reference Health Canada File #9427-C2135-21C, Control# 126664 (Original CTA), 
Control#140159 (CTA-A)]; FDA File #BB-IND-11618 (Original IND)], a fourth dosing 
group (200 x 106) was added (to FDA approved portion only). 
Sixty-four women received intrasphincteric injection of AMDC in this study; 16 received 
10 million cells, 16 received 50 million cells, 24 received 100 million cells, and 8 
received 200 million cells. Fifty-nine patients completed 12-month follow-up; 4 patients 
withdrew from the study and 1 patient was lost to follow-up.  
To assess potential efficacy of AMDC treatment, patients served as their own controls 
with quantitative and qualitative measures of incontinence assessed before treatment 
and compared to the same measures at various times after treatment.  Diary-reported 
stress leaks over 3 days and 24-hour pad weight tests were used as quantitative 
measures of incontinence, while Stamey score and scores from validated quality of life 
questionnaires (i.e., UDI-6, IIQ-7, GQOL, PGI-S, and PGI-I) served as qualitative 
measures of incontinence.  Potential efficacy was evaluated for all patients, patients 
with ≥3 stress leaks and ≥3 g pad weight at baseline, and patients maintained on no or 
stable doses of medications known to affect LUTS.  Similar trends for efficacy outcomes 
were observed for each group. 
Twelve months following AMDC treatment, median stress leaks reported over 3 days 
were significantly lower for all dose groups compared to baseline.  Additionally, the 
percentage of patients who experienced ≥50% reduction in stress leaks increased with 
increasing AMDC dose and ranged from 53% (8/15) in the 10 x 106 dose group to 88% 
(7/8) in the 200 x 106 dose group at 12-month follow-up.  Of patients with ≥3 stress 
leaks and ≥3 g pad weight at baseline who were treated with 200 x 106 AMDC, 100% 
(6/6) had ≥50% reduction in stress leaks and 50% (3/6) were dry (i.e., zero stress leaks 
over 3 days) at 12-month follow-up. 
Similarly, the percentage of patients with ≥50% reduction in pad weight increased with 
increasing AMDC dose at 12-month follow-up.  While only 20% (3/15) of patients in the 
10 x 106 dose group met this end point, 75% (6/8) of patients in the 200 x 106 dose 
group had ≥50% reduction in pad weight.  
The 200 x 106 dose group also had the highest percentage of patients with negative pad 
tests (i.e., <1.3 g pad weight) at 12-month follow-up with 63% (5/8) of patients meeting 
this endpoint.  When only patients with ≥3 stress leaks and ≥3 g pad weight at baseline 
were considered, 83% (5/6) of patients in the 200 x 106 dose group had ≥50% reduction 
in pad weight and 67% (4/6) of these patients had negative pad tests at 12-month 
follow-up.  In contrast, 0% (0/13) of patients in the 10 x 106 dose group, 30% (3/10) of 
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patients in the 50 x 106 dose group, and 28% (5/18) of patients in the 100 x 106 dose 
group had negative pad tests at 12-month follow-up. 
 
Study Code: CTHM- Dose Effect Study 
This multicenter, nonrandomized, Canadian study (Reference Health Canada File 
#9427-C2135-21C, Control# 134363 [Original CTA], Control#136972 [CTA-A], 
Control#144277 [CTA-A]) examined the safety and potential efficacy of a single dose of 
200 million AMDC in 16 women with stress urinary incontinence. Subjects received 
intrasphincteric injection of AMDC via the transurethral route and were followed for one 
year after treatment. 
Sixteen patients were treated, and 1 patient withdrew from the study prior to 12-month 
follow-up.  No serious treatment or procedure-related adverse events were reported.  
To assess potential efficacy of AMDC treatment, patients served as their own controls 
with measures of incontinence assessed before treatment and compared to the same 
measures at various times after treatment. Diary-reported stress leaks over 3 days and 
24-hour pad weight tests were used as quantitative measures of incontinence. Diary 
and pad test data were available for 14 of the 16 treated patients at 12-month follow-up. 
The frequency of stress urinary incontinence episodes and 24-hour pad weight 
decreased following AMDC treatment. From baseline to 12-month follow-up, the median 
number of stress leaks reported over 3 days decreased from 12 leaks to 4 leaks 
(p=0.02), while the mean 24-hour pad weight decreased from 116 g to 52 g (p=0.06). 
Additionally, at 12-month follow-up, 71% (10/14) of patients had ≥50% reduction in 
stress leak frequency and 29% (4/14) of patients reported no stress leaks over 3 days. 
Although only 2 patients (14%) had negative pad tests (i.e., <1.3 g pad weight) at 12-
month follow-up, 57% (8/14) of patients had ≥50% reduction in pad weight. 
 
Study Code: UIAD- Dose Effect Study 
The study is a randomized, double-blind, placebo-controlled, multicenter study to 
determine the effectiveness and safety of AMDC in the treatment of SUI in female 
patients.  The study will randomize patients to receive one of two doses (placebo and 
150 x 106 cells) and either one or two treatments. Allocation ratio within dose will be 2:1 
(cells: placebo), while one and two treatments are equally allocated (1:1).  The study will 
treat a total of 246 patients (164 treated with 150×106 AMDC and 82 treated with 
placebo).  This is a multicenter, confirmatory Canadian study [Reference Health Canada 
File #9427-C2135-21C, Control# 144379 (Original CTA), Control#147259 (CTA-A)].  
 
The study will evaluate the injection of AMDC compared to a placebo dose, with the 
hypothesis that one or two treatments of AMDC are statistically superior to placebo at 
12 months following the initial treatment.  The primary effectiveness measure will be 
based on reduction in the number or size of leaks due to stress incontinence episodes, 
as recorded in a diary and pad test, respectively.  The primary safety measure will be 
the incidence of treatment-related serious adverse events (SAEs) and the incidence of 
protocol-defined treatment or procedure-related adverse events. Placebo injected 
patients will be given the opportunity to receive the 150 x 106 cell dose following the 12 
month evaluation.  
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At the time of this report, 63/246 patients have been treated and follow up is ongoing. 
There have been no serious, related adverse events associated with the use of AMDC. 
Efficacy data has not yet been tabulated. 
 
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IRB NUMBER: 2015-134
IRB APPROVAL DATE: 04/18/2019

Autologous Muscle Derived Cells for Underactive Bladder 
IRB NUMBER: 2015-134
IRB APPROVAL DATE: 04/18/2019