A Prospective Double Blinded Randomized Controlled Trial Examining the Effectiveness of a Connective Tissue Matrix Implant in Reducing Post-operative Pain and Narcotic Use in Patients Under 55yo After Outpatient Arthroscopic Shoulder Surgery
Phase: NA
Conditions: Arthroscopic Shoulder Surgery, Pain, Postoperative
Sponsor: Brian Badman

 
 
Clinical Trial Research Study Protocol  
 
 
Date: October 23, 2020 
 
 
Official Protocol Title: 
 
 
A Prospective Double Blinded Randomized Controlled Trial Examining the 
Effectiveness of a Connective Tissue Matrix Implant in Reducing Post-
operative Pain and Narcotic Use in Patients Under 55yo After Outpatient 
Rotator Cuff Surgery 
 
 
 
Principal Investigator, Research Team, and Study Site: 
 
 
Principal investigator:  Brian Badman, MD 
 
 
Study site address: 
American Health Network 
 8607 E US Hwy 36, Avon, IN 46123 
Phone: 
 
 
 (317)208-3866 
 
 
 
 
 
 

 
 
Table of Contents: 
Introduction 
3 
Background Information and Scientific Rationale 
3 
Study Objectives 
3 
Primary Aims & Objective 
4 
Secondary Aims & Objectives 
4 
Study Design 
5 
The study design is a randomized double-blind randomized controlled trial. 
5 
Research Design 
5 
Study Agent, Device, and/or Intervention Description 
6 
Sample Size 
6 
Subject Selection 
6 
Inclusion Criteria 
6 
Patients who meet the following conditions will be excluded from participation: 
7 
Exclusion Criteria 
7 
Study Outcome Measures (Endpoints) 
7 
Study Procedures 
7 
Subject Recruitment and Screening 
7 
Study Visits/ Study Duration 
8 
Specimen Collection, Preparation, Handling and Shipping 
9 
Statistical Analysis Plan 
10 
Potential Risks and Benefits 
10 
Potential Risks 
10 
Potential Benefits 
11 
Adverse Event Reporting: 
11 
Adverse Events 
11 
Recording of Adverse Events 
11 
Notification of Adverse Events 
11 
Ethical Considerations 
11 
Funding Source 
11 
Subject Stipends or Payments 
11 
Publication Plan 
12 
References 
12 
 
 
 

 
 
Introduction 
 
This document is a protocol for a human research study. This study is to be conducted according 
to United States standards of Good Clinical Practice in accordance with applicable Federal 
regulations and institutional research policies and procedures.  
 
Extracellular matrix grafts have been used to help with postoperative inflammation 
 
Background Information and Scientific Rationale 
 
Shoulder surgery has evolved over the past decade with many procedures now done on an 
outpatient basis.  Multimodal pain management strategies and regional anesthesia have greatly 
contributed to this transition and newer strategies continue to evolve.  Uncontrolled pain can 
often lead to readmissions, prolonged hospital or ambulatory stays and an overall negative 
patient experience.  Despite improvements in regional anesthetic technique and newer longer 
acting medicines such as liposomal bupivacaine, the duration of pain relief is often only over the 
course of 72 hours postoperatively.  Post-operative pain beyond 72 hours is largely inflammatory 
in nature. As such, biologic approaches to reduce surgical tissue damage-induced inflammation 
is an attractive therapeutic addition to surgical procedures. These approaches are especially 
relevant in light of the current opioid epidemic plaguing the United States.   
 
Flowable, placental-derived connective tissue matrix (pECM) is a potential option to supplement 
damaged tissue prone to inflammation as it introduces nascent, hydrated components of the 
inflammatory phase, including structural proteins and growth factors, which allow for efficient 
repair. Derived from relatively immune-privileged tissue, placental-derived pECM elicits little or 
no immune response in recipients. They have been shown to greatly reduce inflammatory cell 
influx and inflammatory cytokines present in dermal and mucosal surgical sites post-operatively. 
Moreover, placental-derived pECM reduces expression of prostaglandin E2, a potent pain 
mediator, in vitro. In the orthopedic space, ECM has been used effectively to reduce pain 
following spinal fusion and for treatment of knee arthritis.   Taken together, biologic therapies 
directed at modulating inflammation and associated pain is an increasing area of interest with far 
reaching implications. 
 
The purpose of the current study is to prospectively analyze two groups of patients treated for 
rotator cuff repair with and without a flowable pECM to determine if a significant reduction in 
pain and opioid consumption as measured in morphine equivalent units is demonstrated within 
the first 6 weeks of surgery. Furthermore, patients will be compared in regard to early range of 
motion and patient reported outcomes to determine if a difference is present when the ECM is 
utilized within the first 6 months of surgery. This is the first double blinded prospective series in 
the shoulder literature to date looking at a pECM graft for pain reduction and improved range of 
motion perioperatively. 
 
 
Study Objectives 
 

 
 
Utilizing a prospective randomized controlled trial, the aim of this study is to assess modulation 
of post-operative pain and narcotic use when a placental-derived extracellular matrix is injected 
into the bed of the repair following outpatient rotator cuff repair surgery. Furthermore, this study 
aims to determine if the addition of pECM influences patient reported outcomes and influences 
early postoperative range of motion. 
 
 
Primary Aims & Objective 
 
 
Aim 1a: To assess post-operative narcotic consumption (measured in morphine equivalent units) 
between patients treated with flowable placental-derived pECM compared to those patients 
undergoing rotator cuff surgery. 
 
Hypothesis: Narcotic consumption (measured in morphine equivalent units) will be reduced in 
patients treated with an extracullar matrix graft as compared to those patients undergoing rotator 
cuff surgery without. 
 
Objective: Utilizing a prospective randomized controlled trial, narcotic use will be measured for 
12-hour increments for a total of 7 post-operative days (PODs) then once on POD 14, 21, 28, and 
42. . Consumption will be measured by the number of tablets ingested and converted to 
morphine equivalent units and compared between the two treatment groups.  
 
Aim 1b: To determine if flowable placental-derived pECM decreases patient-reported post-
operative VAS pain in patients undergoing outpatient rotator cuff surgery 
 
Hypothesis: There will be a decrease in VAS pain for up to 6 weeks post-operatively among 
participants who receive pECM, as compared to the control group (no pECM). 
 
Objective: Utilizing a prospective randomized controlled trial, post-operative patient-reported 
VAS pain (on a scale of 0-10) will be collected 2 times per day (every 12 hours) for 7 post-
operative days (PODs); then an average score collected on POD 14, POD 21, POD 28, and POD 
42.  Scores will be averaged and compared between the two treatment groups for the first 7 days, 
2 week, 3rd week, 4th week and 6th week postoperatively. 
 
 
 
Secondary Aims & Objectives 
 
Aim 2a: To assess patient-reported outcomes and early range of motion (measured in morphine 
equivalents) in patients treated with flowable placental-derived pECM compared to patients 
injected with saline control. 
 
Hypothesis: There will be improved patient reported outcomes and early range of motion 
measured at 6 weeks and 3 months and 6 months postoperatively in patients receiving and 
extracellular matrix injection following outpatient rotator cuff surgery. 

 
 
 
Objective: Utilizing a prospective randomized controlled trial, patient reported outcomes as 
measured by American Shoulder and Elbow Score, Simple Shoulder Test and SANE scores and 
range of motion (External rotation, internal rotation and forward flexion) will be collected 
preoperatively and at 2 weeks (external rotation),  6 weeks (all)) , 3 months (all) and 6 months 
(all) postoperatively.  Scores and range of motion measurements will be averaged and compared 
for differences between the two groups. 
 
 
 
Study Design 
 
The study design is a randomized double-blind randomized controlled trial.  
 
Research Design 
 
Patients will be randomly assigned to one of two treatment groups (see Intervention Description). 
Patients will randomly select one of 70 sealed envelopes the day of surgery.  Patients will be 
blinded to the medication utilized as well as the treating surgeon (PI). A consecutive series of 
patients will be enrolled to prevent selection bias. A single surgeon will be performing all 
procedures to minimize variability.  Upon completion of the surgery, a spinal needle will be 
loaded into the substance of the rotator cuff tendon under direct arthroscopic visualization.   The 
surgeon will then leave the room and the envelope will be opened by the circulating operating 
room nurse.  If the patient is in the treatment group, 2cc of an extracellular matrix graft be 
opened and then injected with a 22g spinal needle already placed into the bed of the repair by the 
physician assistant.  Those patients that are in the control group will have the needle removed 
and no injection administered.  The envelope will be then sealed with the patient’s name and 
treatment group to allow for data analysis upon completion of the study. 
 
Data Collection will occur post-operatively for 6 months. Data will be collected at 20 timepoints, 
in total for pain and opioid consumption.  For the first seven days, data will be collected at 12-
hour time intervals beginning the first evening of the surgery (POD0) at 8pm then at 12-hour 
intervals for the next 7 days (POD7).  Data will be collected using PatientIQ, an application that 
uses text message or email to collect information. The day of surgery (POD0) the first text will 
occur at 8pm.  Patients will then be notified by text alert 2 times per day (8am and 8pm) asking 
to rate their pain on a scale of 0-10 (VAS) beginning on POD 1 thru POD 7.  Patients will also 
respond to the number of pain pills taken in the slotted time span. All patients will be prescribed 
the same narcotic regimen (oxycodone IR) barring any allergies encountered.  Patients who fail 
to respond to the text alert will be notified by the data collection system and contacted via phone 
by study personnel. Patients lacking smartphone technology will all be notified via telephone and 
also asked to keep a personal log to capture the information needed. 
 
 
 
 
 

 
 
 
Data Management 
 
Patient IQ is password protected and HIPPA compliant data collection system. Patients upon 
enrollment will be assigned an ID to allow for data tracking within the application.  The 
application does not have access to other personal information on the patient’s electronic device. 
Primary data will be collected via the web-based system and stored electronically and encrypted 
under password protection. The principal investigator will only have access to the database. At 
the conclusion of the study, the data will be exported to a password-protected encrypted Excel 
file on a password-protected computer. Once the data have been checked for accuracy and prior 
to statistical analysis, patient identifiers will be removed from the data set. The de-identified 
password-protected Excel spreadsheet will be provided to a statistician who will import the file 
into SPSS for analysis. 
 
 
Study Agent, Device, and/or Intervention Description  
 
The pECM graft administered at completion of the surgery is the intervention in this study. Study 
participants will be randomized into one of two groups. The treatment groups are listed below:  
 
Group 1 (Control) 
Group 2 
Standard rotator cuff repair and 
no pECM injection 
Rotator cuff repair and 
2cc of pECM injection 
into perimeter of repair 
 
 
 
Sample Size 
 
For an analysis of variance (ANOVA) test, a sample size of 28 participants per group would be 
required, given an effect size of f=0.30 a power of 80%, and a two-tailed alpha level of 0.05. 
However, to account for 20% subject attrition, a total of 35 patients per group will be enrolled, 
yielding a total of 70 participants.  
 
 
Subject Selection 
 
Patients who meet the following criteria will be included in the study: 
 
Inclusion Criteria 
1. Age 18 and older 
2. Primary diagnosis of rotator cuff tear 
3. Able to provide informed consent 
4. Is willing and able to accept text messages 

 
 
 
Patients who meet the following conditions will be excluded from participation:  
 
Exclusion Criteria 
1. Older than 55 years old. 
2. Pregnancy. 
3. Known narcotic or alcohol abuse (< 3 months) 
4. Revision rotator cuff surgery 
5. Current narcotic regimen or contract with pain management specialist 
 
 
Study Outcome Measures (Endpoints) 
 
Primary Endpoint: Patient-reported post-operative VAS pain (on a scale of 0-10), measured post 
operatively, in 12-hour increments, for a total of 7 days postoperatively and then once per day on 
POD 14, 21, 28 and 42. 
Patients will be prompted via text message to provide VAS pain every 12 hours for the first 
7 days and then once per day at later timepoints. If a response text message is not received, 
a phone call will be made to obtain the information. Patients who do not have a smart 
phone will receive a phone call or keep a personal log of VAS pain.  
 
Secondary Endpoint: Patient-reported post-operative opioid use (converted to morphine 
equivalents), collected post operatively, in 12-hour increments for the first 7 days and then once 
per day on POD 14, 21, 28 and 42. 
 
Patients will be prompted via text message to provide the amount of narcotics (number of 
pills converted to morphine equivalents) taken over the course of the previous 12 hours. If 
a response text message is not received, a phone call will be made to obtain the 
information. Patients who do not have a smart phone will receive a phone call or keep a 
personal log of narcotic use.  
 
 
 
Study Procedures 
 
Subject Recruitment and Screening 
 
Participants will be recruited from the clinical practice of Dr. Brian Badman. Patients who 
present for an office visit and are diagnosed with a rotator cuff tear requiring outpatient surgical 
intervention will screened for eligibility for participation in the study. If a patient is eligible for 
the study, Dr. Badman will discuss the study with the patient and obtain informed consent during 
the routine office visit.  
 
 
Randomization 

 
 
 
This is a double-blinded study, thus, neither the surgeon nor the patient will know if a pECM 
injection is used. A total of 70 envelopes will be generated consisting of 35 with Group 1” (no 
pECM) and 35 with “Group 2” (pECM Injection).  Envelopes will be sealed and randomly 
chosen prior to surgery.  Once the envelope is opened to determine if pECM is to be injected, the 
name of the patient will be added to the envelope along with the treatment group, and the 
envelope will be sealed. The treatment group and name of patient will be kept confidential until 
completion of the study.  Envelopes will be opened at end of study for data collection and 
analysis purposes with patient information deidentified.  They will be stored in a locked 
container at the surgery center only accessible by the chief of staff.  Patients will be blinded to 
the treatment as well as the treating surgeon.  The physician assistant will not be blinded as she 
will administer the injection for the treatment group but will keep the information confidential. 
She will not participate in follow-up data collection of the patients in this study postoperatively. 
 
 
Study Visits/ Study Duration  
 
Participants enrolled in this study will be followed for a period of 6 months post-operatively. For 
the first week, twice per day (12-hour increments), patients will self-report VAS pain and 
indicate their narcotic use (number of tablets ingested). Data concerning pain and narcotic use 
will be collected via text message (or phone if patients fail to respond to text messages). 
 
Post-operative day (POD) 
Data Collection Time 
Data to be Collected 
 
POD 0 
 
8PM 
 
VAS; #pain pills used 
 
POD1 
 
8AM 
VAS; #pain pills used 
 
8PM 
VAS; #pain pills used 
 
POD2 
8AM 
VAS; # pain pills used 
8PM 
VAS; # pain pills used 
 
POD3 
8AM 
VAS; # pain pills used 
8PM 
VAS; # pain pills used 
 
POD4 
8AM 
VAS; # pain pills used 
8PM 
VAS; # pain pills used 
 
POD5 
8AM 
VAS; # pain pills used 
8PM 
VAS; # pain pills used 
 
POD6 
8AM 
VAS; # pain pills used 
8PM 
VAS; # pain pills used 

 
 
 
 
POD7 
 
8AM 
 
VAS; # pain pills used 
8PM 
VAS; # pain pills used 
 
 
 
POD14 (2 weeks) 
 
Office Exam 
 
 
 
8PM 
 
ER (neutral); ASES; SANE; 
SST 
 
 
VAS; # pain pills used 
 
POD21 (3 weeks) 
 
8PM 
 
VAS; # pain pills used 
 
POD28 (4 weeks) 
 
8PM 
 
VAS; # pain pills used 
 
 
 
POD42 (6 weeks) 
 
Office Exam 
 
 
 
 
8PM 
 
ER (neutral and scapular/IR-
scapular/FF; ASES; SANE; 
SST 
 
 
VAS; # pain pills used 
 
 
3 months 
 
 
Office Exam 
 
VAS; ER (neutral and 
scapular/IR-scapular/FF; 
ASES; SANE; SST 
 
 
6 months 
 
 
Office Exam 
 
VAS; ER (neutral and 
scapular/IR-scapular/FF; 
ASES; SANE; SST 
 
 
 
 
The enrollment period for study participation is anticipated to last for 12 months only for data 
analysis.  
 
Specimen Collection, Preparation, Handling and Shipping 
 
N/A 
 

 
 
Statistical Analysis Plan 
 
After data checking and validation are completed, the analysis of the data will begin with 
examination of the distribution of each of the study variables. In this process, outliers will be 
identified and evaluated for inclusion in the final study database. Appropriate summary statistics 
will be calculated. Means and standard deviations will be reported for normally distributed 
continuous variables, a median and range will be tabulated for continuous variable that are not 
normally distributed, and frequencies and percentages will be provided for categorical variables. 
The remainder of the analysis will correspond to the specific aims provided above. 
 
Specific Aims 1a-b:  
 
To determine if there is a difference in patient-reported post-operative narcotic use (measured in 
morphine equivalents) among two groups.  
If data are normally distributed, analysis of variance (ANOVA) with Tukey’s HSD pairwise 
comparisons will be used to compare narcotic use (converted to morphine equivalents) 
between the three groups at each PODs. Cumulative narcotic use during all PODs will also be 
compared between groups. If data are not normally distributed, then Kruskal-Wallis with 
Dunn’s multiple comparisons tests will be used. 
 
 
To determine if there is a difference in mean VAS pain between the control group and ECM 
group postoperatively. 
If data are normally distributed, analysis of variance (ANOVA) with Tukey’s HSD pairwise 
comparisons will be used to compare VAS pain between the two groups at each PODs 1-7, 
14, 21, 28 and 42. If data are not normally distributed, then Kruskal-Wallis with Dunn’s 
multiple comparisons tests will be used. 
 
Specific Aim 2:  
 
To determine if there is a difference in clinical and functional outcomes of patients with rotator 
cuff tears treated with the nanofiber scaffold compared to those treated without. 
 
If data are normally distributed, independent t-tests will be used to compare VAS 
Pain, SANE, V-12, ASES, and ROM measures between the control and 
intervention groups at each preoperative and postoperative timepoint. If data are 
not normally distributed, then Mann-Whitney U tests will be performed. 
 
 
Potential Risks and Benefits 
 
Potential Risks 
 
 
This research is collecting data on human tissue implants which are routinely used in surgical 
repair. They are all FDA registered. The following risks can be related to the procedure, study 
analysis, and medications given: 
 

 
 
1. Risk of extracellular matrix injection: Like any medical procedure, there are risks 
associated with the procedure itself. Theoretical risks associated with the extracellular 
matrix injection include infection, allergic reaction and injection site irritability.  These 
risks are inherently low risks associated with administration. 
2. Risk of text alerts:  A HIPPA compliant and password protected database called Patient 
IQ is the application that will help gather and collect the data.  Texting is not a secure 
form of communication and there is a risk of loss of privacy by entering the data.  
Measures to lessen these risks include using a password protected database and all 
personal information will be deidentified with your name removed.  In addition, the only 
information you will provide will be regarding pain level and number of pain pills taken.  
Your phone number will be kept confidential and not shared with any outside party. 
 
Potential Benefits 
 
An individual benefit from this study is that patients will be monitored closely via text messages 
two times per day; thus, if any side effects or complications occur related to the injection, the PI 
will be alerted. Additionally, knowledge gained from this study will allow investigators to 
determine the most effective treatment methods for minimizing post-operative pain and narcotic 
use in patients who undergo outpatient rotator cuff surgery. These findings will benefit future 
patients.  
 
 
Adverse Event Reporting: 
 
Adverse Events 
 
Recording of Adverse Events 
At each contact with the subject, the investigator will seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events 
should be recorded immediately.  All clearly related signs, symptoms, and abnormal diagnostic 
procedures results should recorded in the source document. 
 
Notification of Adverse Events 
All adverse events will be reported according to WIRB guidelines. 
 
Ethical Considerations 
N/A 
 
Funding Source 
N/A 
 
Subject Stipends or Payments 
N/A 

 
 
 
Publication Plan 
The paper will be submitted for publication in the Journal of Shoulder and Elbow Surgery or the 
Journal of Bone and Joint Surgery upon completion. 
 
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