Double Blinded Prospective Pilot Study to Determine the Safety and Effectiveness of a Connective Tissue Allograft (ActiveMatrix) vs. Standard of Care in Adhesive Capsulitis of the Shoulder
Phase: PHASE4
Conditions: Adhesive Capsulitis
Sponsor: The University of Texas Health Science Center, Houston

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Double Blinded Prospective Pilot Study to Determine the Safety and Effectiveness of a 
Connective Tissue Allograft (Active Matrix) vs. 
Standard of Care in Adhesive Capsulitis of the Shoulder 
 
NCT 05844930 
 
Version Date: 02/02/2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Study of Active Matrix in Adhesive Capsulitis of the Shoulder 
 
 
 
02/02/2023 
 
 
 
Double Blinded Prospective Pilot Study to Determine the Safety and 
Effectiveness of a Connective Tissue Allograft (Active Matrix) vs. 
Standard of Care in Adhesive Capsulitis of the Shoulder 
 
 
Short Title: Study of Active Matrix in Adhesive Capsulitis of the Shoulder 
 
 
 
Investigators: 
Eric Berkman, MD 
Principal Investigator 
 
 
Philip Noble, PhD 
Co-Investigator 
 
 
Dean W. Smith, MD 
Co-Investigator 
 
 
Robert K. Fullick, MD 
Co-Investigator 
 
 
James M. Gregory, MD 
Co-Investigator 
 
 
 
 
Study Site: 
Department of Orthopaedic Surgery 
University of Texas Health Science Center at Houston 
McGovern Medical School 
 
 
Sponsor: 
Skye Biologics Holdings, LLC 
 
 
 
 
Version Number: v.2.0 
02 February 2023 

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Table of Contents 
STATEMENT OF COMPLIANCE .................................................................................................................. 1 
1 
INTRODUCTION ............................................................................................................................... 1 
1.1 
Background .............................................................................................................................. 1 
1.2 
Risk/Benefit Assessment ......................................................................................................... 2 
1.2.1 
Known Potential Risks ........................................................................................... 2 
1.2.2 
Known Potential Benefits ....................................................................................... 2 
2 
Hypothesis ......................................................................................................................................... 3 
3 
STUDY DESIGN ................................................................................................................................ 3 
3.1 
Overall Design ......................................................................................................................... 3 
4 
STUDY POPULATION ...................................................................................................................... 3 
4.1 
Inclusion Criteria ...................................................................................................................... 3 
4.2 
Exclusion Criteria ..................................................................................................................... 3 
4.3 
Screen Failures ........................................................................................................................ 4 
4.4 
Blinded Group Assignment ...................................................................................................... 4 
5 
STUDY INTERVENTION ................................................................................................................... 4 
5.1 
Study Intervention(s) Administration ........................................................................................ 4 
5.1.1 
Study Intervention Description ............................................................................... 4 
5.1.2 
Treatment Group 1 ................................................................................................. 4 
5.1.3 
Treatment Group 2 ................................................................................................. 5 
5.2 
Preparation/Handling/Storage/Accountability .......................................................................... 5 
5.2.1 
Acquisition and accountability ................................................................................ 5 
5.2.2 
Formulation, Appearance, Packaging, and Labeling ............................................. 5 
5.2.3 
Product Storage and Stability ................................................................................ 6 
5.2.4 
Preparation ............................................................................................................. 6 
5.3 
Concomitant Therapy ............................................................................................................... 7 
6 
STUDY PARTICIPANT DISCONTINUATION/WITHDRAWAL ......................................................... 7 
6.1 
Participant Discontinuation/Withdrawal from the Study ........................................................... 7 
6.2 
Lost to Follow-Up ..................................................................................................................... 7 
7 
Outcome Measures ........................................................................................................................... 8 
7.1 
Data collected .......................................................................................................................... 8 
7.2 
Adverse Events and Serious Adverse Events ......................................................................... 8 
7.2.1 
Definition of Adverse Events (AE) .......................................................................... 8 
7.2.2 
Definition of Serious Adverse Events (SAE) .......................................................... 8 
7.2.3 
Classification of an Adverse Event ........................................................................ 9 
7.2.4 
Time Period and Frequency for Event Assessment and Follow-Up ...................... 9 
7.2.5 
Adverse Event Reporting ..................................................................................... 10 
7.2.6 
Serious Adverse Event Reporting ........................................................................ 10 
7.3 
Unanticipated Problems ......................................................................................................... 10 
7.3.1 
Definition of Unanticipated Problems (UP) .......................................................... 10 
7.3.2 
Unanticipated Problem Reporting ........................................................................ 11 
8 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................... 11 
8.1 
Regulatory, Ethical, and Study Oversight Considerations ..................................................... 11 
8.1.1 
Informed Consent Process .................................................................................. 11 
8.1.2 
Study Discontinuation and Closure ...................................................................... 11 
8.1.3 
Confidentiality and Privacy ................................................................................... 12 
8.1.4 
Quality Assurance and Quality Control ................................................................ 12 

Study of Active Matrix in Adhesive Capsulitis of the Shoulder 
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8.1.5 
Data Handling and Record Keeping .................................................................... 13 
8.1.6 
Protocol Deviations .............................................................................................. 13 
9 
REFERENCES ................................................................................................................................ 14 

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  STATEMENT  OF COMPLIANCE 
 
The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP). The protocol, informed consent form(s), and all participant materials will be submitted 
to the Advarra Institutional Review Board (IRB) for review and approval. Approval of both the protocol 
and the consent form must be obtained before any participant is enrolled. Any amendment to the 
protocol will require review and approval by the IRB before the changes are implemented to the study. In 
addition, all changes to the consent form will be IRB-approved; a determination will be made regarding 
whether a new consent needs to be obtained from participants who provided consent, using a previously 
approved consent form. 
 
Introduction 
Patients often present with pain and progressive limitation of active and passive shoulder motion due a 
variety of intrinsic and extrinsic pathologies, including adhesive capsulitis1. The term “frozen shoulder”, as 
first used by Codman2, is often used to refer to a painful stiff shoulder though this diagnosis does not 
denote a specific pathology. Rather, it encompasses what Codman described as “many conditions which 
cause spasm of the short rotators or adhesions about the joint or bursae.” To quote Nevaiser and 
Nevaiser1,” Adhesive capsulitis is a specific pathologic entity in which chronic inflammation of the capsule 
sub synovial layer produces capsular thickening, fibrosis, and adherence of the capsule to itself and to the 
anatomic neck of the humerus3 The contracted, adherent capsule causes pain, especially when it is 
stretched suddenly, and produces a mechanical restraint to motion. The natural history of adhesive 
capsulitis is a matter of controversy. Some have suggested that adhesive capsulitis is self-limiting and need 
not be treated. Management of true capsular restriction of motion (ie, true adhesive capsulitis) begins 
with gentle, progressive stretching exercises. Most patients improve with nonsurgical treatment. 
Uncertainty regarding the ultimate progression of adhesive capsulitis hampers efforts to measure the 
effectiveness of new treatments. Given the prolonged disability these patients face, interventions should 
be focused on hastening recovery of motion and diminishing pain.” 
There are many extracellular matrix (ECM) products currently being used for regenerative purposes in the 
repair of musculoskeletal injuries3. Placental-tissue derived matrices have recently become an area of 
increasing interest due to source tissue availability and the abundance of bioactive molecules in the 
tissue4. These bioactive molecules are known to promote tissue repair by regulating the inflammatory 
response and recruiting cells to the site of injury5. Past studies have shown that placental-based ECMs 
have helped treat other orthopedic connective tissue injuries, suggesting that such a matrix may have 
novel utility as a therapeutic for adhesive capsulitis 6-10. 
 
ActiveMatrix® 
ActiveMatrix® (AM) is a human placental allograft currently regulated by the FDA as a human cell, tissue, 
or cellular or tissue-based product (HCT/P) under Section 361 of the Public Health Service Act and 
regulations in 21 CFR Part 1271. AM is sterile with a primary function to supplement injured connective 
tissue where applied. 
 
Safety: There is low risk associated with the sterile AM graft other than injection site pain or discomfort, 
however, the patient will be under general anesthesia at the time of application. AM and other Skye grafts 
have been implanted in over 250,000 applications to date. Donors are screened and tissues are tested 
extensively per 21 CFR Part 1271 to ensure there is no risk of disease transmission. 
1.1 
BACKGROUND 
INTRODUCTION 
1 

Study of Active Matrix in Adhesive Capsulitis of the Shoulder 
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AM is a natural allograft derived from human placenta confirmed to contain high levels of various growth 
factors and structural proteins: PDGF-AA/-BB, bFGF, EGF, KGF, PIGF, IL-4, TGF-β3, TIMP-1/-2, hyaluronic 
acid, and collagen.4 Additional growth factors found in placental tissue are likely to be similarly preserved 
in AM as well, but remain to be differentially tested.4 
 
 
There is low risk associated with the sterile AM graft other than injection site pain or discomfort. AM is a 
commercially available, human placenta-derived tissue graft that is regulated by the FDA as a human cell, 
tissue, or cellular or tissue-based product (HCT/P) under Section 361 of the Public Health Service Act and 
regulations in 21 CFR Part 1271; AM and other Skye grafts have been implanted in over 250,000 
applications to date. Donors are screened and tissues are tested extensively per federal guidelines to 
ensure there is minimal risk of disease transmission. 
 
 
Numerous medical treatments through commercial use and scientific studies have investigated the role 
of placental grafts in the repair of soft tissue defects and shown numerous benefits/ enhancements; 
however, the exact mechanism of action of AM in response to injury, and regulation of physiologic and 
regenerative processes are unknown. The potential benefit from participating in this study is that the 
participants may achieve reduced pain and increased function of the effected shoulder. 
 
  2 
HYPOTHESIS 
 
 
In patients with adhesive capsulitis, shoulder function at 4 weeks, 12 weeks, and 6 months after 
administration of ActiveMatrix connective tissue allograft will be equivalent to treatment with 
corticosteroid injections. 
 
This prospective randomized control trial will include two intervention groups, each allocated an equal 
number of patients. We will not include a ‘control’ group of patients due to ethical considerations of 
withholding treatment. One intervention group will receive an intra-articular corticosteroid injection 
(Group 1) and the other will receive a human placental connective tissue derived allograft injection (Group 
2; ActiveMatrix, Skye Biologics, Inc.). Assuming an attrition rate of 20%, the number of patients required 
for the study was calculated to be 25 in each group. The intervention period will be over a period of 
months until we reach this target sample size of 50. Patients will be assessed at 4 weeks, 12 weeks, and 6 
months after administration of therapy. The patients will be recruited from the city of Houston and 
neighboring municipalities by referral from UT Houston orthopedic surgeons. 
 
In order to be eligible to participate in this study, an individual must meet all the following criteria: 
1. Provision of signed and dated informed consent form 
2. Stated willingness to comply with all study procedures and availability for the duration of the 
1.2.1 KNOWN POTENTIAL RISKS 
1.2 
RISK/BENEFIT ASSESSMENT 
1.2.2 KNOWN POTENTIAL BENEFITS 
3.1 
OVERALL DESIGN 
3 
STUDY DESIGN 
4.1 
INCLUSION CRITERIA 
4 
STUDY POPULATION 

Study of Active Matrix in Adhesive Capsulitis of the Shoulder 
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study 
3. Male or female, ≥ 18 years of age to ≤ 75 years of age 
4. Have a clinical diagnosis of adhesive capsulitis, defined as: 
i. pain along the C5 dermatome 
ii. limitations of passive range of motion of more than 20 degrees in at least one or more of 
the PROM measurements compared to the contralateral side. The planes of motion 
measured are abduction internal rotation, abduction external rotation, forward elevation, 
abduction, neutral external rotation, neutral internal rotation.  
5. Have no contraindications or allergies to the treatment administered 
6. Have experienced shoulder pain for more than 6 weeks and less than 1 year (to ensure the 
patient is in the “freezing” stage of adhesive capsulitis). 
7. Have current imaging studies (plain radiographs and MRI exams) of the shoulder to rule out other 
etiologic diagnoses. 
8. Negative pregnancy test for patients who are of childbearing age 
i. Female patients who are postmenopausal do not need a pregnancy test 
ii. Female patients who are surgically sterile do not need a pregnancy test 
 
  4.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Any prior treatment for this episode of shoulder pain, such as prior intra-articular injection  
2. Evidence, based on MRI or plain radiographs, of any pathology within the shoulder other than 
adhesive capsulitis (e.g. glenohumeral osteoarthritis, full thickness tears of the labrum or rotator 
cuff, , calcific tendonitis) 
3. A history of significant trauma to the shoulder 
4. Poorly controlled diabetes mellitus, as defined by HbA1c > 8 mmol/L and glucose > 200 mg/dL. 
For diabetic participants HbA1c and glucose levels will be measured prior to intervention and 
documented for later analysis. For non-diabetic participants, previous labs will be utilized. All 
other medical diseases will be documented for later analysis. 
5. History of Cardiovascular Accident (CVA) such as stroke or Transient Ischemic Attack (TIA) 
6. Blood dyscrasias 
7. Prior shoulder surgery 
8. Any one of child-bearing age who has a positive pregnancy test 
 
There is no intended distribution or restriction of subjects by racial and ethnic origin. No vulnerable 
subjects are included in this protocol. 
 
  4.3 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants, to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a systemic 
or local infection may be rescreened. Rescreened participants should be assigned the same participant 
number as for the initial screening. 
 
  4.4 
BLINDED GROUP ASSIGNMENT 
 
Eligible patients who consented to the study will be randomly assigned to one of two treatment groups 
according to a serial number on a closed envelope. Investigators and patients will be “blinded” to each 
5 
STUDY INTERVENTION 

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patients group assignment for the duration of the trial. 
 
 
 
5.1 
STUDY INTERVENTION(S) ADMINISTRATION 
5.1.1 
STUDY INTERVENTION 
DESCRIPTION 
Both the corticosteroid and the AM treatment will be administered via intra-articular injections. This 
procedure will be performed by an interventional radiologist via a posterior approach using ultrasound 
guidance. (Prior studies indicate that injection performed without fluoroscopic guidance are inaccurate in 
as many as 60% of cases11.) The same interventional radiologist will complete all of the injections for the 
trial to eliminate any bias. 
 
 
Patients in Group 1 will receive a corticosteroid injection consisting of Triamcinolone 20 mg (1cc) with 
Lidocaine 10 mg/ml (5 cc). 
 
 
 
Patients in Group 2 will receive an injection consisting of ActiveMatrix (1cc; Skye Biologics, Inc.) with 
Lidocaine 10 mg/ml (5cc). ActiveMatrix is a human tissue derived allograft intended for homologous use 
to supplement or replace inadequate connective tissue (Skye Biologics, Inc). The allograft has been 
registered with the U.S. FDA and commercially available since 2014 as a human cell, tissue, or cellular or 
tissue-based product (HCT/P; Skye Biologics, Inc). All participants will begin physical therapy 1-week 
post-injection. In total, 8-12 sessions of physical therapy. 
 
Distribution of AM for this study will be handled by Skye Biologics. The product will be shipped to the 
study site and received by the investigator. Recipient records must be maintained for the purpose of 
tracking tissue post-transplant per The Joint Commission and FDA requirements. Supplemental labels, 
which indicate the Tissue ID number, are contained in the package to aid in the tracking process. The 
allograft ID number must be recorded in the operative record. The Allograft Tracking Record must be 
completed and returned to Skye Biologics, Inc. 
 
Donor eligibility determined & tissues processed by: Human Regenerative Technologies, LLC 
Distributed by: Skye Biologics, Inc. 
 
 
 
Tissue Origin: Tissue is obtained aseptically at Cesarean birth delivery, which is performed by a licensed 
OB/GYN physician in a hospital operating room environment. 
 
Processing: The HCT/Ps are processed in a controlled environment using methods designed to prevent 
contamination of the tissues. Tissues are exposed to antibiotics at an initial processing step and 
subsequently subjected to multiple rinse steps using sterile saline. Final products are sized and packaged 
according to approved specifications and procedures and are terminally sterilized by E-Beam irradiation 
technology in accordance with ANSI/AAMI/ISO11137. 
 
5.1.3 TREATMENT GROUP 2 
5.1.2 TREATMENT GROUP 1 
5.2.1 ACQUISITION AND ACCOUNTABILITY 
5.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
5.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 

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Donor/Tissue Screening: The donor of the Donated Human Tissue has been deemed free from risk factors 
for, and clinical evidence of, infection due to relevant communicable diseases and other exclusionary 
disease conditions through the review of the donor’s medical records, including medical/behavior risk 
assessment and a recent physical examination. The donor is deemed eligible for tissue donation by the 
tissue bank’s Medical Director and the enclosed Donated Human Tissue has been determined to be 
acceptable for transplantation use through a stringent quality assurance review process. Additionally, 
testing of a qualified blood sample indicates that the donor is negative or nonreactive for the following 
communicable disease markers: 
• 
Human Immunodeficiency Virus (HIV) 
o HIV-1/2 Antibodies 
o Nucleic Acid Test for HIV-1 RNA 
• 
Hepatitis B Virus (HBV) 
o HBV Surface Antigen 
o HBV Core Antibody (Total) 
o Nucleic Acid Test for HBV DNA 
• 
Hepatitis C Virus (HCV) 
o HCV Antibody 
o Nucleic Acid Test for HCV RNA 
• 
Human T Cell Lymphotrophic Virus I/II 
o HTLV-I/II Antibody 
• 
Syphilis 
o Rapid Plasma Reagin Screen*, or 
o Treponemal Specific Test 
• 
West Nile Virus (WNV) 
o Nucleic Acid Test for WNV RNA** 
* A donor whose blood specimen is unsuitable for the nontreponemal screening assay, such as the RPR 
test, or with a reactive result from the non-treponemal screening assay, is deemed eligible for tissue 
donation only when the result from the treponemal-specific (confirmatory) assay is nonreactive. 
 
** Starting June 2017, blood samples from donors acquired during the seasonal time period (from June 1 
- October 31 every year), will be tested with the WNV NAT assay. 
 
The non-required screening test for exposure to the virus listed below may have been performed on the 
donor. A negative / nonreactive result is not required for this test; however, all donors are evaluated on 
a case-by-case basis by the Medical Director. 
• 
Cytomegalovirus (CMV) 
o CMV Antibody (Total) 
 
All laboratories performing these tests are registered with FDA and certified to perform testing on human 
specimens in accordance with the Clinical Laboratory Improvement Amendments of 1988 (CLIA) and 42 
CFR part 493, or equivalent requirements. Test kits used are approved and cleared (for screening blood 
specimens collected from living donors) by the FDA. A copy of the medical records can be obtained upon 
request. 
 
Adverse Reactions: No adverse clinical reactions to this tissue product have been reported. Adverse 
reactions or outcomes that potentially involve the use of this tissue product must be reported 
immediately to Skye Biologics, Inc. 
 
The product can be stored at ambient temperature (50-86°F / 10-30°C) until use. The product is for single 
5.2.3 PRODUCT STORAGE AND STABILITY 

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patient, one time use only. Once opened, the AM must be used immediately or disposed of appropriately. 
Do not re-sterilize. Dispose of any unused product. Do not use if the integrity of the packaging has been 
violated, opened or damaged, or if mishandling has caused possible damage or contamination. Do not use 
if the seal has been broken or compromised. 
 
The tissue in its vial packaging is terminally sterilized via irradiation and may be placed directly onto the 
sterile field. 
1. Open product package & remove the peel-pack containing the vial. 
2. Using aseptic technique, peel open pouch and present vial into sterile field. 
3. Shake the vial to mix completely. 
4. Open vial and draw into a syringe containing the predetermined amount of saline using an 18G 
needle. 
5. Mix thoroughly in the syringe. 
6. Replace 18G needle with a 21G needle prior to injection. 
 
  5.3 
CONCOMITANT THERAPY 
 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications to be reported in the Case Report Form (CRF) are 
concomitant prescription medications, over-the-counter medications and supplements. 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
• 
Pregnancy 
• 
Significant study intervention non-compliance 
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (CRF). Subjects who sign the informed consent form and are randomized but do not receive 
the study intervention may be replaced. Subjects who sign the informed consent form, and are 
randomized and receive the study intervention, and subsequently withdraw, or are withdrawn or 
discontinued from the study, will not be replaced. 
 
  6.2 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for 2 scheduled visits and is 
unable to be contacted by the study site staff. 
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within 5 days of 
the missed visit and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
5.2.4 PREPARATION 
6.1 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
6 
STUDY PARTICIPANT DISCONTINUATION/WITHDRAWAL 

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These contact attempts should be documented in the participant’s medical record or study file. 
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
  7       OUTCOME MEASURES 
 
The primary outcome measure for this study will be the Shoulder Pain and Disability Index (SPADI). SPADI 
is a self-administered questionnaire that measures a combination of pain and functional disability. SPADI 
is scored from 0 to 100 with a high score representing more pain and disability. SPADI score will be 
recorded at inclusion and at 4 weeks, 12 weeks, and 6 months following injection. 
 
We will use SPADI as the primary outcome measure. The minimal clinically important difference (MCID) 
for SPADI in the literature has been primarily cited as between 8 and 13, however values as high 23 have 
been cited12-16. Prior trials have considered a change of 14 to be clinically significant1,17. For our MCID 
we will use a value of 13. In previous studies where SPADI was the primary outcome measure, the variance 
in SPADI was 15. Given  
= 0.05, a sample size of 21 per group is required to provide 80% power in 
detecting a 13 point difference in mean SPADI score of the 2 treatment groups. Assuming an attrition rate 
of 20%, the number of patients required for the study was calculated to be 25 in each group. 
 
The Visual Analogue Scale (VAS), The American Shoulder and Elbow Surgeons Shoulder Score (ASES), and 
Passive range of motion (PROM) will be secondary outcome measures. VAS is a questionnaire scored on 
a 100mm horizontal scale that represents the patients pain intensity. A higher score corresponds to 
increased pain intensity. ASES is a standardized shoulder assessment form and is offered as a baseline 
measure of shoulder function. Score ranges from 0 to 100, with a score of 0 indicating a worse shoulder 
condition and a score of 100 indicating a better shoulder condition. A goniometer will be the measuring 
instrument for PROM. In addition, photographs will be taken to document each joint position. PROM will 
be measured in the following planes: abduction internal rotation, abduction external rotation, forward 
elevation, abduction, extension and neutral internal rotation. PROM will be measured on both sides and 
compared at inclusion and at each follow-up visit. The endpoint for PROM is when the patient either 
cannot move their arm any further or the pain becomes unbearable.1 PROM will be measured by 
UTHealth MD shoulder specialists who are “blinded” to which group the patient was randomized to. 
 
  7.1 
DATA COLLECTED 
 
Demographics (DOB/age, sex, involved shoulder, race, PMedHx, PSurgHx, Allergies, smoking Hx, 
medications), PROM measurements (abduction internal rotation, abduction external rotation, forward 
elevation, abduction, extension and neutral internal rotation), vascular/neuro status of the involved limb, 
pain levels (VAS), and SPADI index. Patient will be assessed at the time of initial injection as well as 4 
weeks, 12 weeks, and 6 months after administration of therapy. Adverse and Serious Adverse Events will 
be collected and reported as defined below. 
 
 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An 
adverse event (AE) can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (see the ICH 
Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting). 
 
Any untoward medical occurrence that at any dose: 
7.2 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
7.2.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
7.2.1 DEFINITION OF ADVERSE EVENTS (AE) 

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• 
results in death, 
• 
is life-threatening, 
• 
requires inpatient hospitalization or prolongation of existing hospitalization, 
• 
results in persistent or significant disability/incapacity, 
or 
• 
is a congenital anomaly/birth defect 
 
For adverse events (AEs), the following guidelines will be used by the investigator to describe severity: 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities. 
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating. Of note, the term “severe” does not necessarily equate to “serious”. 
 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. The 
degree of certainty about causality will be graded using the categories below. In a clinical trial, the study 
product must always be suspect. 
• 
Related – The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
 
The investigator will be responsible for determining whether an adverse event (AE) is expected or 
unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the study intervention. 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of onset, 
clinician’s assessment of severity, relationship to study product (assessed only by those with the training 
and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs occurring 
while on study must be documented appropriately regardless of relationship. All AEs will be followed to 
adequate resolution. 
7.2.3
CLASSIFICATION OF AN ADVERSE EVENT 
7.2.3.1
SEVERITY OF EVENT 
7.2.3.2 RELATIONSHIP TO STUDY INTERVENTION 
7.2.3.3 EXPECTEDNESS 
7.2.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW -UP 

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Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any time 
during the study, it will be recorded as an AE. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The investigator will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study 
participation. At each study visit, the investigator will inquire about the occurrence of AE/SAEs since the 
last visit. Events will be followed for outcome information until resolution or stabilization. 
 
The investigator must record nonserious adverse events and report them to the sponsor within 30 days. 
 
The study clinician will immediately report to the sponsor any serious adverse event, whether or not 
considered study intervention related, including those listed in the protocol or investigator brochure and 
must include an assessment of whether there is a reasonable possibility that the study intervention caused 
the event. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be reported in 
accordance with the protocol unless there is evidence suggesting a causal relationship between the study 
intervention and the event (e.g., death from anaphylaxis). In that case, the investigator must immediately 
report the event to the sponsor. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site investigator 
deems the event to be chronic or the participant is stable. Other supporting documentation of the event 
may be requested by the study sponsor and should be provided as soon as possible. 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)- 
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
7.2.5 ADVERSE EVENT REPORTING 
7.2.6 SERIOUS ADVERSE EVENT REPORTING 
7.3.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
7.3 
UNANTICIPATED PROBLEMS 

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The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the Sponsor within 24 hours. The UP report will include the following information: 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome; 
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP; 
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
8 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
8.1 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
8.1.1 INFORMED CONSENT PROCESS 
8.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention. 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study 
and continues throughout the individual’s study participation. Consent forms will be Institutional Review 
Board (IRB)-approved and the participant will be asked to read and review the document. The investigator 
will explain the research study to the participant and answer any questions that may arise. A verbal 
explanation will be provided in terms suited to the participant’s comprehension of the purposes, 
procedures, and potential risks of the study and of their rights as research participants. Participants will 
have the opportunity to carefully review the written consent form and ask questions prior to signing. The 
participants should have the opportunity to discuss the study with their family or surrogates or think about 
it prior to agreeing to participate. The participant will sign the informed consent document prior to any 
procedures being done specifically for the study. Participants must be informed that participation is 
voluntary and that they may withdraw from the study at any time, without prejudice. A copy of the 
informed consent document will be given to the participants for their records. The informed consent 
process will be conducted and documented in the source document (including the date), and the form 
signed, before the participant undergoes any study-specific procedures. The rights and welfare of the 
participants will be protected by emphasizing to them that the quality of their medical care will not be 
adversely affected if they decline to participate in this study. 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party. If the study is prematurely terminated or suspended, the Principal 
Investigator (PI) will promptly inform study participants, the Institutional Review Board (IRB), and sponsor 
and will provide the reason(s) for the termination or suspension. Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule.
7.3.2 
UNANTICIPATED PROBLEM REPORTING 
8.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
8.1.2 STUDY DISCONTINUATION AND CLOSURE 

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Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and 
satisfy the sponsor and IRB. 
 
Participant confidentiality and privacy is strictly held in trust by the investigator, their staff, and the 
sponsor and their interventions. This confidentiality is extended to cover testing of biological samples in 
addition to the clinical information relating to participants. Therefore, the study protocol, documentation, 
data, and all other information generated will be held in strict confidence. No information concerning the 
study or the data will be released to any unauthorized third party without prior written approval of the 
sponsor. 
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), regulatory agencies or pharmaceutical company supplying study product may inspect 
all documents and records required to be maintained by the investigator, including but not limited to, 
medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at the clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored by the sponsor. This will not include the participant’s contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique study 
identification number. The study data entry and study management systems used by clinical sites and by 
sponsor research staff will be secured and password protected. At the end of the study, all study databases 
will be de-identified and archived at the sponsor facility. 
 
8.1.4 QUALITY ASSURANCE AND QUALITY CONTROL 
The clinical site will perform internal quality management of study conduct, data and biological specimen 
collection, documentation and completion. 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
clarified/resolved. 
8.1.3 CONFIDENTIALITY AND PRIVACY 

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The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory 
authorities. 
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. All source documents should be completed in a neat, legible manner to 
ensure accurate interpretation of data. 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study. Data recorded in the electronic case report form 
(eCRF) derived from source documents should be consistent with the data recorded on the source 
documents. 
 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP). The noncompliance may be either on the part of the 
participant, the investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly. 
 
 
8.1.5
DATA HANDLING AND RECORD KEEPING 
8.1.5.1
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
8.1.6 PROTOCOL DEVIATIONS 

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  9 
REFERENCES 
 
 
 
1. Neviaser AS, Neviaser RJ. Adhesive capsulitis of the shoulder. JAAOS-Journal of the American 
Academy of Orthopaedic Surgeons. 2011 Sep 1;19(9):536-42. 
 
2. Sharma SP, Bærheim A, Moe-Nilssen R, Kvåle A. Adhesive capsulitis of the shoulder, treatment with 
corticosteroid, corticosteroid with distension or treatment-as-usual; a randomised controlled trial in 
primary care. BMC Musculoskelet Disord. 2016;17(1):232. doi:10.1186/s12891-016-1081-0 
 
3. 
Badylak SF. The extracellular matrix as a scaffold for tissue reconstruction. Semin Cell Dev Biol. 
2002;13(5):377-383. doi:10.1016/s1084952102000940 
 
4. 
Irvin J, Danchik C, Rall J, et al. Bioactivity and composition of a preserved connective tissue 
matrix derived from human placental tissue. J Biomed Mater Res B Appl Biomater. 2018;106(8):2731- 
2740. doi:10.1002/jbm.b.34054 
 
5. 
Diegelmann R F. Wound healing: an overview of acute, fibrotic and delayed healing. Front Biosci. 
2004;9(1-3):283. doi:10.2741/1184 
6. 
Werber B, Martin E. A Prospective Study of 20 Foot and Ankle Wounds Treated with 
Cryopreserved Amniotic Membrane and Fluid Allograft. J Foot Ankle Surg. 2013;52(5):615-621. 
doi:10.1053/j.jfas.2013.03.024 
 
7. 
Zelen CM, Poka A, Andrews J. Prospective, randomized, blinded, comparative study of injectable 
micronized dehydrated amniotic/chorionic membrane allograft for plantar fasciitis--a feasibility study. 
Foot Ankle Int. 2013;34(10):1332-1339. doi:10.1177/1071100713502179 
 
8. 
Lullove E. A Flowable Placental Tissue Matrix Allograft in Lower Extremity Injuries: A Pilot Study. 
Cureus. 7(6). doi:10.7759/cureus.275 
 
9. 
Huddleston HP, Cohn MR, Haunschild ED, Wong SE, Farr J, Yanke AB. Amniotic Product 
Treatments: Clinical and Basic Science Evidence. Curr Rev Musculoskelet Med. 2020;13(2):148-154. 
doi:10.1007/s12178-020-09614-2 
 
10. 
McIntyre JA, Jones IA, Danilkovich A, Vangsness CT. The Placenta: Applications in Orthopaedic 
Sports Medicine. Am J Sports Med. 2018;46(1):234-247. doi:10.1177/0363546517697682 
 
11. 
Carette S, Moffet H, Tardif J, et al. Intraarticular corticosteroids, supervised physiotherapy, or a 
combination of the two in the treatment of adhesive capsulitis of the shoulder: A placebo-controlled 
trial. Arthritis Rheum. 2003;48(3):829-838. doi:10.1002/art.10954 

Study of Active Matrix in Adhesive Capsulitis of the Shoulder 
02/02/2023 
14 
 
 
 
 
12. 
Schmitt JS, Di Fabio RP. Reliable change and minimum important difference (MID) proportions 
facilitated group responsiveness comparisons using individual threshold criteria. J Clin Epidemiol. 
2004;57(10):1008-1018. doi:10.1016/j.jclinepi.2004.02.007 
 
13. 
Roy J-S, MacDermid JC, Woodhouse LJ. Measuring shoulder function: A systematic review of 
four questionnaires. Arthritis Care Res. 2009;61(5):623-632. doi:10.1002/art.24396 
14. 
Laslett M, Steele M, Hing W, McNair P, Cadogan A. Shoulder pain patients in primary care--part 
1: Clinical outcomes over 12 months following standardized diagnostic workup, corticosteroid injections, 
and community-based care. J Rehabil Med. 2014;46(9):898-907. doi:10.2340/16501977-1860 
15. 
Starkey C, Brown SD. Examination of Orthopedic & Athletic Injuries. F.A. Davis; 2015. 
 
16. 
Graaf M, Scholten-Peeters G, Duijn E, et al. The Responsiveness and Interpretability of the 
Shoulder Pain and Disability Index. J Orthop Sports Phys Ther. 2017;47:1-21. 
doi:10.2519/jospt.2017.7079 
17. 
Paruthikunnan SM, Shastry PN, Kadavigere R, Pandey V, Karegowda LH. Intra-articular steroid 
for adhesive capsulitis: does hydrodilatation give any additional benefit? A randomized control trial. 
Skeletal Radiol. 2020;49(5):795-803. doi:10.1007/s00256-019-03316-8