Extracellular Matrix Scaffold Graft Augmentation in Rotator Cuff Repair: a Prospective, Randomized, Controlled Trial
Phase: PHASE4
Conditions: Rotator Cuff Tear
Sponsor: Gregory Gilot

Cover Page 
Study Protocol and Statistical Analysis Plan 
 
Official Title: Extracellular matrix scaffold graft augmentation in rotator cuff repair: a 
prospective, randomized, controlled trial 
 
NCT Number: NCT03551509 
 
Document Date: 28 February 2023 
 
 
 

 
v.7 28 February 2023 
Page 1 of 17 
 
 
Title: Extracellular matrix scaffold graft augmentation in rotator cuff repair: a 
prospective, randomized, controlled trial  
 
Protocol No:  
 
FLA 18-008 
 
Principal Investigator:  
Gregory Gilot, MD        
Co-Investigator:      
Streubel Philipp, MD 
 
Organization:  
 
Cleveland Clinic Florida 
 
 
Levitetz Department of Orthopedic Surgery 
2950 Cleveland Clinic Blvd.  
Weston, FL 33331 
 
 
Summary of Changes from Previous Version: 
 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
1; 5 
Increase to 70 patients 
Increased due to large drop-out rates 
1; 2A 
Including 2.5-5 cm tears 
Large screen failure rate due to tear size 
specifications 
1; inclusion 
criteria; 2B 
Clarifying imaging needed for diagnosis 
Imaging is only needed for diagnostic 
purposes, not all is needed 
2D 
Removal of Dr. Vani Sabesan 
No longer a surgeon at Cleveland Clinic 
3C 
Added in time points for ultrasounds  
IRB approved previously – updating 
protocol to reflect this 
3C 
Updated the US physician 
All sports medicine physicians at 
Cleveland Clinic can perform the US 
10 
Included verbiage for adding/removing 
study personnel 
Was not in the original protocol and 
needed guidance 
 
 
 
 

 
v.7 28 February 2023 
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Contact Information 
 
Role 
Name 
Number and Email 
Research 
Director: 
Carlos Higuera, MD 
higuerc@ccf.org 
(216) 401-1385  
Principal 
Investigator:  
 
Co-Investigator: 
Gregory Gilot, MD 
 
 
Philipp Streubel, MD 
 gilotg@ccf.org 
(954) 659-5430 
 
streubp@ccf.org 
(954) 659-5000   
Research 
Manager: 
Alison Klika                               klikaa@ccf.org  
(216) 444-4954 
Research 
Coordinator(s): 
Ashley Valdes                            valdesa4@ccf.org 
(561) 923-5830 
 
 
 
 
 

 
v.7 28 February 2023 
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Synopsis 
 
Title: 
Extracellular matrix scaffold graft augmentation in rotator cuff 
repair: a prospective, randomized, controlled trial 
Study Description: 
This is a prospective, randomized, controlled, multi-center clinical 
trial to evaluate the effectiveness of an ECM scaffold graft to 
augment repair of a large/massive rotator cuff tear. The study will 
involve 70 patients. 35 patients will be randomly assigned to each 
arm of the study.   
A-FLEX graft will be used in those patients randomly assigned to 
the treatment group who are undergoing an arthroscopic large 
(defined as 2.5-5 cm) or massive (defined as >5 cm) rotator cuff 
repair. Patients randomly assigned into the control group will 
undergo open or arthroscopic rotator cuff repair using the 
surgeon’s standard technique. 
 
Objectives: 
The purpose of this study is to evaluate the efficacy of using the 
Arthroflex (A-FLEX) graft to augment large to massive 
arthroscopic rotator cuff repairs in vivo and decrease repair 
failures in a prospective, randomized, controlled trial.  By 
undergoing serial US examinations at follow-ups, we also intend 
to evaluate when during the postoperative period the failure of the 
repair occurs. 
 
Indication/Target: 
The population target is all subjects 18 years or older undergoing 
primary arthroscopic rotator cuff surgery (please see 
Inclusion/Exclusion criteria). 
Endpoints: 
The primary clinical outcomes to be measured and 
subsequently evaluated will be the following:  
a. 
Success as defined by tendon healing after rotator cuff 
repair, as indicated based on MRI at 1year.   
b. Comparison of tendon healing will be assessed using US 
imaging modalities versus MRI at 1 year time point.   
c. 
Progress of tendon healing based on US will be used as 
predictive data for 1 year success (based on primary 
outcome). 
 
The secondary clinical outcomes to be measured and 
subsequently evaluated will be the patient satisfaction, 
quality of life, and shoulder function, to be determined 
with the following outcome measures: 
a. 
The Veterans Rand 12-item Health Survey (VR-12). 
b. The American Shoulder and Elbow Surgeons Shoulder 
(ASES) 
c. 
The Western Ontario Rotator Cuff Index (WORC). 
d. Shoulder activity level as per Brophy et al. [15]. 

 
v.7 28 February 2023 
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e. 
Subjective Shoulder Value (SSV) 
f. 
Constant Shoulder Score (Constant) 
Study Population: 
Approximately 70 subjects is needed to assess the primary 
outcome, measured as the percentage of repairs that heal and 
remain intact after 1 year. 
All statistical comparisons will be made using the Statistical 
Package for Social Science (SPSS) version 16.0 software. 
 
Inclusion Criteria:  
 
1. Patients with a large (2.5-5 cm) to massive (>5 cm) 
rotator cuff tear who will be undergoing open or 
arthroscopic repair. The cuff tear size will be determined 
on either pre-operative magnetic resonance imaging 
(MRI), or ultrasound (US), or intra-operative 
measurements, or computerized tomography (CT). 
2. Patients who are willing and able to provide written 
informed consent for their involvement in the study.  
3. Patients who meet criteria for RCR surgery.  
4. Patients older than 18 years of age. 
 
Exclusion criteria: 
 
1. Those with a known sensitivity to materials of porcine 
origin. 
2. Patients with addiction to illegal drugs, solvents or 
alcohol who are actively using or have previously 
attempted and failed a treatment program.  
3. Patients with bacteremia, a systemic infection, or 
infection of the surgical site. 
4. All those who are prisoners.  
5. Patients who are pregnant or nursing.   
6. All those with a condition that may limit a patient’s 
ability to finalize the study or that may cause an undue 
risk to the patient’s health and well-being.  
Description of Site/Facilities 
Enrolling Participants: 
Levitetz Department of Orthopedic Surgery 
Department of Anesthesiology 
 
Locations: 
Cleveland Clinic Florida – Weston 
2950 Cleveland Clinic Blvd 
Weston, FL 33331 
 
Cleveland Clinic Florida – Coral Springs 
5701 N University Dr 
Coral Springs, FL 33067 
Study Duration: 
Subjects will be followed for 1 year. 
Data Collection: 
Electronic (REDCap and EPIC) database (please see Data 
Handling and Record Keeping). 

 
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Statistical Reporting: 
Statistical analysis will be performed by a biostatistician at 
Cleveland Clinic. 
 
 
Schedule of Activities (SoA) 
 
Time and Events Schedule: Summary Table 
 
 
 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 6 
Visit 5 
Assessment 
Screening 
(Pre-Op) 
6 weeks 
Post-op 
3 mo. 
Post-op 
6 mo. 
Post-op 
9 mo. 
Post-op 
1 year 
Post-op 
Eligibility 
X 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
Medical History and Physical 
Exam 
X 
 
 
 
 
 
MRI 
 
 
 
 
 
X 
US 
 
X 
X 
X 
X 
X 
Shoulder Outcome Surveys 
X 
X 
X 
X 
X 
X 

 
v.7 28 February 2023 
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Introduction 
Despite advances in surgical technology, repairs of large (3-5 cm) and massive (>5 cm) 
rotator cuff tears (RCT) fail from 20-90% [1].  Due to their size and increased structural 
involvement, large or massive RCT present a substantial challenge to orthopaedic 
surgeons. [16] The repairs tend to fail at the suture-tendon junction, which is due to 
several factors, including tension at the repair and quality of the tendon [1-2,5].  Full 
thickness tears are uncommon in younger patients, especially those less than forty years 
old and are usually traumatic in etiology.  Younger patients also typically fair better 
following arthroscopic rotator cuff repair with fewer failures and more successful return 
to pre-injury level of function [16].  One strategy to augment repair of large to massive 
rotator cuff tears has been the development of biological scaffold materials, which are 
composed of extracellular matrix (ECM).  The ECM composing the scaffolds are made 
from a number of tissues, including, but not limited to, small intestinal submucosa (SIS), 
dermis, and pericardium [3].  Studies to date include both prospective and retrospective 
in animal and human models, and include Restore, a porcine-derived SIS by DePuy 
Orthopaedics, GraftJacket, a human-derived, non-cross-linked dermis graft by Wright 
Medical Technology, and Zimmer Collagen Repair, a cross-linked porcine derived 
dermal graft made by Zimmer.  Restore studies have shown no benefit and some even an 
increase in repair failure with recommendations not to use to augment repair [1, 4-8].  
GraftJacket studies have shown a reduction in graft failure [1, 9-11]; however, several of 
the Restore and GraftJacket studies are limited by a lack of a control cohort.  The Zimmer 
graft studies have conflicting results with both an improvement and no improvement in 
failure rates of repair [1,12,13].  The prior studies listed are all in vivo; however, the 
majority are not randomized trials and thus do not have a control with which to compare 
data.  In addition, some trials include open repairs.  A lack of prospective, randomized, 
controlled, in vivo trials exist that evaluate the ability of the ECM scaffold graft 
augmentation in large to massive arthroscopic rotator cuff repairs to decrease the failure 
rate.   
 
The purpose of this study is to evaluate the efficacy of using the Arthroflex (A-FLEX) 
graft to augment large to massive arthroscopic rotator cuff repairs in vivo and decrease 
repair failures in a prospective, randomized, controlled trial.  By undergoing serial US 
examinations at follow-ups, we also intend to evaluate when during the postoperative 
period the failure of the repair occurs. 
 
1. Study Design 
Methods 
This is a prospective, randomized, controlled, multi-center clinical trial to evaluate 
the effectiveness of an ECM scaffold graft to augment repair of a large/massive 
rotator cuff tear. The study will involve 70 patients. 35 patients will be randomly 
assigned to each arm of the study.   

 
v.7 28 February 2023 
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A-FLEX graft will be used in those patients randomly assigned to the treatment group 
who are undergoing an arthroscopic large (defined as 2.5-5 cm) or massive (defined 
as >5 cm) rotator cuff repair. Patients randomly assigned into the control group will 
undergo open or arthroscopic rotator cuff repair using the surgeon’s standard 
technique. 
      A. Inclusion Criteria 
The following patients will be found eligible for inclusion into the study sample: 
1. Patients with a large (2.5-5 cm) to massive (>5 cm) rotator cuff tear who 
will be undergoing open or arthroscopic repair. The cuff tear size will be 
determined on either pre-operative magnetic resonance imaging (MRI), or 
ultrasound (US), or intra-operative measurements, or computerized 
tomography (CT). 
2. Patients who are willing and able to provide written informed consent for 
their involvement in the study.  
3. Patients who meet criteria for RCR surgery.  
4. Patients older than 18 years of age. 
 
B. Exclusion Criteria 
The following patients will not be found eligible for inclusion into the study 
sample. 
1. Those with a known sensitivity to materials of porcine origin. 
2. Patients with addiction to illegal drugs, solvents or alcohol who are 
actively using or have previously attempted and failed a treatment 
program.  
3. Patients with bacteremia, a systemic infection, or infection of the surgical 
site. 
4. All those who are prisoners.  
5. Patients who are pregnant or nursing.   
6. All those with a condition that may limit a patient’s ability to finalize the 
study or that may cause an undue risk to the patient’s health and well-
being.  
 
2. Research Procedures 
Treatment Plan 
A.  Preoperative Screening 

 
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Patients scheduled for an open or arthroscopic repair of a rotator cuff tear ≥ 2.5 
cm will be identified during clinical visits or through EPIC. If the patient meets 
the eligibility inclusion/exclusion criteria for the study, he or she will be asked to 
participate in the study the following way: 
During a patient’s pre-operative clinical visit, the researcher will describe in detail 
the study at hand including, but not limited to, study benefits, potential risks, and 
alternative treatment modalities. He/she will hand a copy of the Informed Consent 
to the patient for review. If the patient agrees to participate in the study, the 
written informed consent will be completed and filed.  The patient will be told 
explicitly that if he or she declines participation, his or her care will not be 
affected.   
 
If patient is unavailable during pre-operative clinical visit, patient will be 
contacted via phone call. Any information regarding the study including IRB 
approved consent and brochure will be emailed and/or mailed to the patient for 
review. There will be documentation in the patient’s chart when this patient was 
contacted via phone. Patient will be consented in-person on same-day as surgery, 
only if the above is completed and documented. 
 
 
B. Enrolled Patients 
After enrollment, all indicated preoperative assessments will be performed and 
recorded.   
C. Randomization 
All patients that meet the criteria will be randomized the day the informed 
consent is signed.  If the patient is randomized into the control group, the surgery 
will continue as planned with no ECM scaffold graft to augment the repair. 
However, if the patient falls within the treatment group, an FDA-approved ECM 
scaffold graft will be used to augment the repair.  The post-operative care will be 
as per standard care following a rotator cuff repair.  There is no expectation that 
the patient should require a longer hospital stay.   
 
D. Surgical Treatment 
All surgical procedures will be performed by Board Certified and Fellowship 
trained Orthopedic Surgeons from Cleveland Clinic, Dr. Gregory Gilot or as 
appointed by the PI. A standardized surgical repair technique will be used by the 
participating surgeon.  
 1.  Control Treatment Group 

 
v.7 28 February 2023 
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Patients randomly assigned into the control group will undergo open or 
arthroscopic rotator cuff repair using the surgeon’s standard practice. No 
ECM graft will be used.   
2. Treatment Group 
Patients randomly assigned into the treatment group will undergo open or 
arthroscopic rotator cuff repair with A-FLEX graft to augment the repair. 
ECM scaffold grafts are indicated for the reinforcement of soft tissues 
repaired by sutures or suture anchors during tendon repair surgery, including 
rotator cuff.   
3. Alternative Treatment Group 
Patients who meet pre-op inclusion criteria where a repair cannot be 
accomplished due to intraoperative findings will remain in the study. This 
group will be analyzed separately and still follow study procedures. 
  
E.  Surgical Methods 
Prior to repair 
Tendon qualities and measurements will quantified and recorded: 
• Tear size, retraction, quality of tissue 
Arthroscopic Primary Rotator Cuff Repair  
All patients will undergo arthroscopic primary repair using a suture bridge 
technique. An acromioplasty, distal clavicle excision and biceps tenodesis or 
tenotomy may be performed by routine techniques as clinically indicated. The 
tendon tear will be identified and mobilized, as indicated, such that the tendon can 
be approximated over the greater tuberosity.  Standard double row suture bridge 
fixation technique will be used for all repairs 
Mini-open/ Arthroscopic Graft Augmentation  
In patients receiving a graft, thru mini open technique the lateral portal incision 
will be extended vertically approximately 5-6 cm. A standard, deltoid-splitting, 
mini-open approach will then be performed, leaving the deltoid attachment to the 
acromion intact. For arthroscopic technique same method of fixation will be used 
below. The dermis graft will be sized and cut so as to cover the entire repair site 
in both medial-lateral and anterior-posterior dimensions. The medial sutures 
previously placed in the tendon at the time of arthroscopic repair will then be 
passed in a mattress technique through the medial side of the graft. At least two 

 
v.7 28 February 2023 
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mattress sutures will be used, bringing the graft medial to the medial sutures used 
for the primary tendon repair. The graft will then be tensioned and secured in the 
anterior-posterior direction using at least two sutures on each side, passed through 
intact rotator cuff tissue. The suture limbs retained from the laterally placed suture 
bridge repair anchors will be placed as mattress sutures into the graft, and the 
graft will be tensioned to a position distal to the repair footprint. 
Data for RCR will be recorded: 
• Number of anchors 
• Quality of repair 
• Footprint coverage 
 
3. Assessments 
 
Eligible patients will be evaluated according to the pre-, intra- and post- operative 
assessment plans, delineated below, as well as the time and events schedule. All 
clinical results will be assessed during the period of hospital stay.  
A. Preoperative Assessments 
The following assessments/tests will be taken prior to patient operative treatment. 
• Eligibility criteria, including informed consent. 
• Age, gender, height, weight, BMI 
• Primary diagnosis 
• Medical History 
• Physical Exam 
• Current medications 
• American Society of Anesthesiologists (ASA) risk 
• Smoking status 
• Imaging of shoulder 
• Shoulder outcome surveys (SSV, ASES, Constant, VR12, WORC) 
 
B. Operative Assessments 
 
The following medical information will be collected from the Operative and 
Anesthesia records. 
• Tear size, retraction, quality of tissue 
• Length of surgery  
• Possible intraoperative arthroscopic photographs 

 
v.7 28 February 2023 
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• Implants used 
• Quality of repair 
C. Postoperative Assessments 
 
The following information will be collected after surgery: standard clinical 
follow-up PE and history, medications and serial US exams at 6 weeks, 3 months, 
6 months, 9 months and 1 year postop, and MRI exam at 1 year postop. All US 
examinations will be performed by one Board Certified and Fellowship trained 
Sports Medicine physician in the office and coordinated with scheduled follow-up 
appointments. Shoulder outcome forms will also be collected at each follow up 
visit (listed below): 
4. Data Collection and Analysis 
The primary clinical outcomes to be measured and subsequently evaluated will be the 
following:  
d. Success as defined by tendon healing after rotator cuff repair, as indicated based 
on MRI at 1year.   
e. Comparison of tendon healing will be assessed using US imaging modalities 
versus MRI at 1 year time point.   
f. Progress of tendon healing based on US will be used as predictive data for 1 year 
success (based on primary outcome). 
The secondary clinical outcomes to be measured and subsequently evaluated will be 
the patient satisfaction, quality of life, and shoulder function, to be determined with 
the following outcome measures: 
 
g. The Veterans Rand 12-item Health Survey (VR-12). 
h. The American Shoulder and Elbow Surgeons Shoulder (ASES) 
i. The Western Ontario Rotator Cuff Index (WORC). 
j. Shoulder activity level as per Brophy et al. [15]. 
k. Subjective Shoulder Value (SSV) 
l. Constant Shoulder Score (Constant) 
 
5. Sample Size Justification and Statistical Analysis 
 
Approximately 70 subjects are needed to assess the primary outcome, measured as the 
percentage of repairs that heal and remain intact after 1 year.  A re-tear rate of 40% is 
expected in patients who have undergone rotator cuff repair for large and massive rotator 
cuff tears, based on the current literature (reference ted below). We anticipate that in this 
study, the percentage of re-tears in the augmented group will be reduced by 

 
v.7 28 February 2023 
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approximately half (~20%), while the control group would experience rates of re-tear 
comparable to what is reported in the current literature (~40%). Reducing this rate by half 
would be clinically meaningful. An SD of 15% within groups was allowed. Power 
analysis indicated that 20 patients in each group would provide sufficient power to 
identify statistical significance in healing rates between the control and augmented 
groups. With the assumption that the control group will have a failure rate of 
approximately 40% and the augmented group will have a failure rate of approximately 
20%, at least 34 should be randomized in the control group and 26 in the augmented 
group.  It is estimated that an overall fewer percentage of subjects initially randomized to 
the control group will complete the trial as augmentation may be required due to tear 
severity and other procedure variables. Those patients randomized to the control arm and 
withdrawn for repair by augmentation may be followed for safety.   
A power analysis was also considered for shoulder function, a secondary clinical 
outcome.  It demonstrated that at least thirty-four cases must complete the study 
(seventeen cases in each arm- augmented and control) in order to assess the difference 
between each group.  This sample size was statistically derived by an ASES score power 
analysis, using a power of 0.8, an effect size d of 0.9, an alpha error probability of 0.05, 
and an allocation ratio of 1.  This is assuming an ASES score of 84 at 12 months 
postsurgical repair in the augmented group (standard deviation of 16) and 72 (standard 
deviation of 12) for the control group. The ASES data used was derived from a recently 
completed ArthroFlex rotator cuff repair study for which data is on file at LifeNet Health. 
Again, with the assumption that the control group will have a failure rate of 
approximately 40% and the augmented group will have a failure rate of approximately 
20%, at least 30 should be randomized in the control group and 22 in the augmented 
group to assess a difference in shoulder function.  
Once data is acquired for 15 subjects in each group, a post-hoc power analysis will be 
conducted to confirm that alpha and beta error probabilities are still under the accepted 
limits. 
The primary analysis will be conducted on both the intent to treat and the per protocol 
populations.  The intent to treat population will be comprised of all subjects that have 
completed rotator cuff repair surgery.  The per protocol population will be comprised of 
all subjects that have completed all study visits and did not have any major protocol 
violations (e.g., missed visits, noncompliance with postsurgical instructions, etc.). Standard 
adjustments to analyses for pre-specified or baseline-suggested clinical covariates will be 
made; these covariate-adjusted analyses will be considered secondary analyses.  Primary 
analysis results will be declared statistically significant if the two-sided p-value is less than 
0.05.   
Safety analyses will be performed on the intent to treat population and will include the 
incidence of treatment-emergent AEs and clinically significant changes in vital signs and 

 
v.7 28 February 2023 
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physical examinations.  Impact of treatment on infection rate, treatment emergent AEs, and 
changes in vital signs and physical examination will all be assessed. 
Safety data will be summarized with descriptive statistics by treatment group and also by 
visit, where applicable. AE data will be listed individually and summarized by system 
organ class and preferred terms within a system organ class for each treatment group. 
All statistical comparisons will be made using the Statistical Package for Social Science 
(SPSS) version 16.0 software.  Results will be reported as an aggregate.  
Statistical analysis will be performed by the orthopaedic research fellows in conjunction 
with Cleveland Clinic-Main biostatistician.  
 
6. Study Product Description 
 
ArthroFlex (A-FLEX) is not considered investigational and is currently 
available.  The material is classified as a human and cellular tissue product under Food 
and Drug Administration (FDA) regulations and thus is not subject to any clinical 
evaluations before use.  LifeNet Health uses several steps to ensure that allograft tissue is 
safe for use with patients.  Extensive donor screening is performed to prevent risk of 
disease transmissions.  There is a medical and social history taken from every donor, and 
questionable donors are refused.  Blood is drawn from each donor for testing to rule out 
diseases such as HIV, hepatitis, and syphilis.  Each section of recovered tissue is tested 
for any bacteria.  In addition, tissue used to make A-FLEX is treated with antibiotic to 
inactivate bacteria.  The tissue is also cleaned thoroughly with detergent, enzymes, and 
solvent to remove cells from tissue.  This MATRACELL™ technology also effectively 
removes donor DNA from the ADM ensuring a biocompatible scaffold to facilitate 
repair.  All these screenings, tests, and treatments are designed to eliminate the risk of 
disease transmission.  The remaining intact acellular framework contains native growth 
factors, proteoglycans, hyaluronic acid, collagen, fibronectin, and elastin, therefore 
promoting wound healing.  
A-FLEX is terminally sterilized with low dose gamma irradiation to provide a medical-
device grade Sterility Assurance Level (SAL) of 10-6. 
 
Labeling 
Since this will be an open-label study, study product will be identified.  The 
Instructions for Use for A-FLEX will be provided in the site study binders.   
 
Storage and Handling of Investigational Product 
A-FLEX is provided in a sealed and sterile pouch and is stored at room 
temperature (between 15ºC and 30ºC).  A-FLEX should not be frozen or 
refrigerated.  It should be stored in its original cardboard sleeve.  There should be 
minimal excessive exposure to light and A-FLEX should be protected from 
excessive heat.  The product should not be used past the expiration date indicated 

 
v.7 28 February 2023 
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on the label. A-FLEX should not be used if it is damaged, if the packaging 
integrity is compromised, if the color of the product is other than white, or if the 
temperature dot on the package is not present.  Rinsing is not required prior to 
application; however, it may improve handling.   
 
Accountability Procedures for the Study Products 
Investigation product records must include the following: 
− Receipt, date and quantity, and batch or lot number  
− Disposition dates and quantity administered to each subject 
− Inventory records 
− All correspondence related to the study product 
 
All product records should be stored in the study binder with product instructions 
for use. 
7. Confidentiality of Data 
 
The only patient identifying information to be used will be the medical record number in 
order to facilitate collection and organization of data and ensure that serial US and 
shoulder surveys are attributed to the same patient. All data will be recorded in a 
password-protected REDCap database. The principal investigator, orthopaedic research 
fellows, research coordinators, and the study’s preceptors will be the only individuals 
allowed access to this information. 
 
8. Adverse Events and Data Monitoring Committee 
 
All adverse events (AE) will be recorded.  Details to be documented include the nature, 
onset, duration, severity, relationship to the device, relationship to the operative 
procedure and outcome of each event.  
Most likely adverse events: 
• Infection 
• Injury to nerves and blood vessels 
• Chronic pain or Complex regional pain syndrome 
Note: The above-mentioned AE are not related to the use of ECM scaffold graft. They are 
potential complications associated with rotator cuff repair.  
Potential serious adverse events related to ECM scaffold graft use: 
• Anaphylactoid or anaphylactic reaction to ECM allograft.  
If an unanticipated (in nature, severity or frequency) or serious (fatal, life-threatening or 
permanently disabling) adverse event arises, the study will be halted and the IRB 

 
v.7 28 February 2023 
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notified. The situation will be discussed among surgical faculty, and if there is a prudent 
solution, it will be presented to the IRB for approval. If there are no effective solutions, 
the investigators will have no choice but to discontinue the study.  
Data will be reviewed by the PI and physicians conducting the study.  The ECM scaffold 
grafts have not been linked to potentially serious or life-threatening complications. Our 
research will limit the potential for complications even further by screening and 
excluding patients with a known allergy to materials of porcine origin. Lastly, the ECM 
grafts are FDA-approved scaffold material that is indicated for reinforcement or 
augmentation of soft tissue repairs.  In view of this, we will not be deviating from the 
standard of care by using the ECM allograft and the investigators do not anticipate having 
to discontinue the study or having to alter the protocol based on interim results. For these 
reasons, an independent data monitoring committee will not be needed or used. 
9. Consent 
In a private, outpatient setting, the PI or one of the research coordinators involved in the 
study will describe in detail the characteristics of the research study. Understandable 
language will be used. The process of pre-operative assessment, randomization, 
treatment, data collection and analysis along with the potential risks/benefits of the study 
are to be described in detail.  Furthermore, the methods of maintaining data security and 
confidentiality will be outlined. The patient is to be explicitly told that he or she does not 
have to participate in the study and that regardless of his/her decision, will receive the 
best care this hospital can provide.  
The informed consent process will take place during the patient’s pre-operative clinical 
visit. The original consent form will be kept with study records by the principal 
investigator in a secure location, and a copy of the consent will be given to the subject.  
The subject’s decision to participate will be documented in his or hers electronic record. 
A copy of the consent may be placed in the hospital record. 
10. Principal Investigators 
Principal Investigators (PIs) and Co-Investigators (Co-Is) and any other study personnel 
will added and removed through Cleveland Clinic’s IRB. Any changes to this will be 
communicated with the sponsor via e-mail, and the regulatory binder will be updated 
accordingly. It is not necessary to amend this protocol with the changes of PIs, Co-Is, and 
other study personnel.  
Adding and removing PIs will also be updated in regards to the legal agreements. 
 
 
References 
1. Derwin KA, Badylak SF, Steinmann SP, Ianotti JP.  Extracellular matrix scaffold 
devices for rotator cuff repair. J Shoulder Elbow Surg 2010;19:467-476. 

 
v.7 28 February 2023 
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2. Schlegel TF, Hawkins RJ, Lewis CW, Motta T, Turner AS. The effects of 
augmentation with swine small intestine submucosa on tendon healing under 
tension:  histologic and mechanical evaluations in sheep.  Am J Sports Med 
2006;34:275-280. 
3. Badylak SF, Freytes DO, Gilbert TW. Extracellular matrix as a biological scaffold 
material:  Structure and function.  Acta Biomaterialia 2009;1:1-13. 
4. Metcalf MH, Savioe FH, Kellum B. Surgical technique for xenograft (SIS) 
augmentation of rotator-cuff repair.  Oper Tech Orthop 2002;12:204-8. 
5. Sclamberg SG, Tibone JE, Itamura JM, Kasraeian S.  Six-month magnetic 
resonance imaging follow-up of large and massive rotator cuff repairs reinforced 
with porcine small intestinal submucosa.  J Shoulder Elbow Surg 2004;13:538-41. 
6. Ianotti JP, Codsi MJ, Kwon YW, Derwin K, Ciccone J, Brems JJ.  Porcine small 
intestine submucosa augmentation of surgical repair of chronic two-tendon rotator 
cuff tears.  A randomized, controlled trial.  J Bone Joint Surg Am 2006;88:1238-
44. 
7. Walton JR, Bowman NK, Khatib Y, Linklater J, Murrell GA.  Restore 
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