Prospective Multi-center Study Comparing REGENETEN in Lieu of Standard Arthroscopic Repair of High-grade (>50%) Partial-thickness Tears
Phase: NA
Conditions: Arthroscopic Surgical Treatment of High-grade (>50%) Partialthickness
Sponsor: Smith & Nephew, Inc.

 
Prospective multi-center study comparing REGENETEN in lieu of standard 
arthroscopic repair of high-grade (>50%) partial-thickness tears
 
 
Protocol Number:  
 
REGEN.PUB.2018.09 
 
Protocol Date:  
 
10Sep2019 
Protocol Version: 
 
Version 3.0  
Study Product Name:  
REGENETEN Implant 
Sponsor:     
 
 
Smith & Nephew, Inc. 
7135 Goodlett Farms Parkway 
Cordova, TN 38016 
US    
 
 
 
 
 
 
  
                       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nondisclosure Statement 
This document contains information that is confidential and proprietary to Smith & Nephew PLC 
and Smith & Nephew, Inc. and is intended for use only by Smith & Nephew and its 
manufacturers.  It shall not be reproduced or copied in whole or in part, nor shall the contents be 
disclosed by any mean without prior written permission from Smith & Nephew, nor shall anyone 
make any use of it that is contrary to the expressed or implied wishes of Smith & Nephew.

Study Protocol
Device
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears
Number: 
REGEN.PUB.2018.09
Version: 3.0, 10SEP2019
Page: Page 2 of 105
CONFIDENTIAL AND PROPRIETARY
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew.
SIGNATURES
1.1
PROTOCOL SIGNATURE PAGE
This page will be returned to Smith & Nephew, Inc. and a copy retained at the investigational 
site.
I have read t
Prospective multi-center study comparing REGENETEN 
in lieu of standard arthroscopic repair of high-grade (>50%) partial-thickness tears
Version 3.0,
dated 10SEP2019, and agree to abide by all provisions set forth herein.
I agree to comply with the Investigator
Obligations stipulated in Section 21 of the protocol, 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the conduct of the described clinical investigation without the prior written 
consent of Smith & Nephew, Inc.
Role
Name
Signature
Date Signed
(DD-MMM-YYYY)
Principal Investigator

Study Protocol
Device
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears
Number: 
REGEN.PUB.2018.09
Version: 3.0, 10SEP2019
Page: Page 3 of 105
CONFIDENTIAL AND PROPRIETARY
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew.
1.2 SPONSOR APPROVAL
Job title
DocuSign Stamp
Head of Global 
Clinical Operations
Head of Global 
Clinical Strategy
Head of Global 
Biostatistics
Medical Affairs 
Representative
GRS Representative
President, Global Research Solutions
Signer Name: Mohit Bhandari
Date: 02-Oct-2019

Study Protocol
Device
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears
Number: 
REGEN.PUB.2018.09
Version: 3.0, 10SEP2019
Page: Page 4 of 105
CONFIDENTIAL AND PROPRIETARY
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew.
SYNOPSIS
Title of Study:
Prospective multi-center study comparing REGENETEN in lieu of 
standard arthroscopic repair of high-grade (>50%) partial-thickness 
tears
Study Design:
Non-blinded, multi-center
Study Type:
Prospective cohort study
Study Product: 
REGENETEN
Implant
Comparison Group:
Arthroscopic repair of the high-grade (>50%) partial-thickness tear 
using standard surgical techniques.
Study Purpose:
Demonstrate that REGENETEN is superior to standard repair 
techniques when surgically treating high-grade (>50%) partial-thickness 
tears because REGENETEN preserves more of the native tendon 
footprint resulting in less post-operative pain and faster recovery.
Primary Objective:
To determine if arthroscopic surgical treatment of high-grade (>50%) 
partial-thickness rotator cuff tears using REGENETEN yields 
statistically superior participant-rated shoulder function and reduced 
pain and disability at 3 months following index surgery compared to 
standard surgical repair techniques.
Secondary Objective:
To generate performance and health economic evidence supporting the 
use of REGENETEN in treating high-grade (>50%) partial-thickness 
rotator cuff tears.
Statistical Rationale: 
Superiority hypothesis for American Shoulder and Elbow Surgeons 
(ASES) score at 3 months following index surgery using a minimal 
clinically important difference (MCID) of 11.11 and a drop-out rate of 
15%.
Sample Size:
118 participants (59 per group)
Number of Study Sites:
Up to 12 clinical sites
Targeted Global 
Regions:
United States
Inclusion Criteria:
Patients will be considered qualified for enrollment if they meet the 
following criteria:

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 5 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
 
1. Male or female 18 years 
2. High-grade (>50% tendon thickness) partial-thickness tear 
3. Failed conservative medical management of the tendon tear defined 
as: 
a. Four (4) to six (6) weeks of formal physical therapy or guided 
home exercises 
b. Activity modification 
c. Shoulder injection at the discretion of the surgeon 
4. Able to comply with the post-operative physiotherapy and follow-up 
schedule 
5. Able to speak and read English  
6. Provide written informed consent 
Exclusion Criteria: 
Any one (1) of the following criteria will disqualify a patient from 
participation in the study: 
 
1. Prior shoulder surgery on index shoulder within 12 months of 
enrollment 
2. Failed primary rotator cuff surgery of the index shoulder 
3. Systemic steroid use (oral, IV) or locally injected at the surgical site 
within 1 month of enrollment 
4. Metastatic disease 
5. Concomitant surgeries for bone defects requiring bone implantation 
(Latarjet procedures) or for superior labral tear from anterior to 
posterior (SLAP) 
6. Concomitant biceps tenodesis 
7. Rheumatoid arthritis 
8. Advanced osteoarthritis 
9. Fatty infiltration of the index 
 
10. Chronic pain disorders (i.e., fibromyalgia) 
11. History of insulin dependent diabetes 
12. History of heavy smoking (> 1 pack per day) within 6 months of 
enrollment 
13. Currently involved in any injury litigation or workers compensation 
claims  
14. Hypersensitivity to bovine-derived materials 
15. Medical or physical condition that, in the opinion of the Investigator, 
would preclude safe participation in the study 
Study Duration: 
18 months enrollment (estimated), 24 month follow-up (primary 
endpoint assessed at 3 month follow-up) 
Primary endpoint: 
ASES (American Shoulder and Elbow Surgeons) score at 3 months 
following index surgery 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 6 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Secondary endpoint(s): Performance endpoints include: 
- 
ASES score over initial 3 months following index surgery 
- 
Single Assessment Numeric Value (SANE) score over initial 3 
months following index surgery 
- 
ASES Visual Analog Scale (VAS) pain score over initial 3 
months following index surgery 
- 
ASES score at 6, 12, 18 and 24 months following index surgery 
- 
SANE score at 6, 12, 18 and 24 months following index surgery 
- 
ASES VAS pain score at 6, 12, 18 and 24 months following 
index surgery 
- 
Constant-Murley score at 3, 6, 12 and 24 months following index 
surgery 
- 
Cumulative opioid use to treat the index shoulder over 3 months 
following index surgery 
- 
Cumulative non-opioid prescription medication use to treat the 
index should over 3 months following index surgery 
- 
Cumulative opioid use to treat the index shoulder over 12 
months following index surgery 
- 
Cumulative non-opioid prescription medication use to treat the 
index shoulder over 12 months following index surgery 
- 
Duration of shoulder immobilization following index surgery 
- 
Time to return to work by work type (sedentary; laborer) 
- 
Time to return to driving 
- 
Time to return to sports 
- 
Incidence of progression to full-thickness tear within 12 months 
following index surgery 
- 
Incidence of progression to full-thickness tear within 24 months 
following index surgery 
- 
MRI assessment of percent filling at 12 months following index 
surgery 
- 
MRI assessment of percent filling at 24 months following index 
surgery 
- 
Rotator cuff tendon thickness at 12 months following index 
surgery 
- 
Rotator cuff tendon thickness at 24 months following index 
surgery 
- 
Goutallier classification of rotator cuff at 12 months following 
index surgery 
- 
Goutallier classification of rotator cuff at 24 months following 
index surgery 
- 
Sugaya score of rotator cuff at 12 months following index 
surgery 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 7 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
- 
Sugaya score of rotator cuff at 24 months following index 
surgery 
- 
Incidence of revision surgery within 24 months following index 
surgery (index shoulder; all causes) 
 
Economic endpoints include: 
- 
Aggregate health care utilization costs over 12 months following 
index surgery 
- 
Operating room time (index surgery) 
- 
Number of steroid injections over 12 months following index 
surgery 
- 
Number of unscheduled clinic visits over 12 months following 
index surgery  
- 
Number of for-cause imaging procedures over 12 months 
following index surgery 
- 
Number of physiotherapy sessions over 12 months following 
index surgery 
 
Safety Data 
All Adverse Events over 24 months 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 8 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
 
STUDY SCHEMATIC 
 
Schedule of Events  
Pre-Op 
(days -60 
to -1) 
Surgery 
(day 0) 
3 Mo 
(±30 days) 
6 Mo 
(±30 days) 
12 Mo 
(±30 days) 
18 Mo 
(±60 days) 
24 Mo 
(±60 days)
Informed Consent 
 
 
 
 
 
 
 
Inclusion/Exclusion  
 
 
 
 
 
 
 
Demographics/ 
Medical History 
 
 
 
 
 
 
 
Operative Data 
 
 
 
 
 
 
 
ASES Score 
 
 
 
 
 
 
 
SANE 
 
 
 
 
 
 
 
Constant-Murley 
Score 
 
 
 
 
 
 
 
Participant Diary 
 
 
 
 
 
 
 
Adverse Events  
 
 
 
 
 
 
 
Heath Care 
Utilization 
 
 
 
 
 
 
 
Revision Surgery 
 
 
 
 
 
 
 
Upper Extremity MRI 
* 
 
 
 
 
 
 
Pre-Op indicates pre-operative; Mo, month(s); SANE, Single Assessment Numeric Evaluation; ASES, 
American Shoulder and Elbow Surgeons Score including VAS Pain  
The ASES score and SANE will be completed every week (i.e., every 7±3 days) though 3 month follow-up. 
Participant diaries will be used to document opioid and non-opioid prescription medication use, use of a 
sling, other related healthcare utilization (i.e. steroid injections, clinic visits, imaging, physiotherapy sessions, 
etc.) and return to work, driving, and sports. Participant diary will be updated weekly (7±3 days) through 3 
month follow-up and monthly (30±7 days) thereafter until 12 months post-surgery. 
*The pre-op MRI is the 
 and will not follow the study MRI Image 
Acquisition Protocol which is used for the 12 and 24 month MRIs. The pre-op MRI must occur within 6 
months of enrollment into this study. All MRIs will be submitted to the imaging vendor per the Image 
Transfer Protocol. 
 
 
 

Study Protocol
Device
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears
Number: 
REGEN.PUB.2018.09
Version: 3.0, 10SEP2019
Page: Page 9 of 105
CONFIDENTIAL AND PROPRIETARY
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew.
TABLE OF CONTENTS
Signatures..........................................................................................................................................2
1.1
Protocol Signature Page............................................................................................................2
1.2          Sponsor Approval.......................................................................................................................3
Synopsis ............................................................................................................................................4
Table of Contents ..............................................................................................................................9
List of Abbreviations................................................................................................................................11
Introduction ......................................................................................................................................13
4.1
Background..............................................................................................................................13
4.2
Study Purpose .........................................................................................................................14
Objectives ........................................................................................................................................14
5.1
Primary Objective ....................................................................................................................14
5.2
Secondary Objective(s) ...........................................................................................................14
Investigational Product(s) ................................................................................................................17
6.1
Identification.............................................................................................................................17
6.2
Product Use.............................................................................................................................19
6.3
Surgical procedure ..................................................................................................................20
Participant Enrollment and Withdrawal............................................................................................20
7.1
Participant Population..............................................................................................................20
7.2
Inclusion Criteria......................................................................................................................20
7.3 
Exclusion Criteria.....................................................................................................................21
7.3
Screening.................................................................................................................................21
7.4
Informed Consent ....................................................................................................................22
7.5
Enrollment................................................................................................................................22
7.6
Lost to Follow-Up.....................................................................................................................22
7.7
Withdrawal...............................................................................................................................23
Study Design ...................................................................................................................................24
8.1
Study Design ...........................................................................................................................24
8.2
Allocation and Blinding ............................................................................................................24
8.3
Study Endpoints ......................................................................................................................25
8.4
Methods Used to Minimize Bias and Maximize Validity ..........................................................26
Study Procedures ............................................................................................................................27
9.1
Visits and Examinations ..........................................................................................................27

Study Protocol
Device
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears
Number: 
REGEN.PUB.2018.09
Version: 3.0, 10SEP2019
Page: Page 10 of 105
CONFIDENTIAL AND PROPRIETARY
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew.
9.2
Study Endpoints ......................................................................................................................31
Statistical Design .............................................................................................................................35
10.1
General....................................................................................................................................35
10.2
Analysis Populations ...............................................................................................................35
10.3
Baseline Data ..........................................................................................................................36
10.4
Efficacy Analysis......................................................................................................................36
10.5
Safety Analyses.......................................................................................................................46
10.6
Interim Analyses ......................................................................................................................46
Sample Size Justification.................................................................................................................47
Adverse Events and Device Deficiencies........................................................................................47
12.1
Definitions................................................................................................................................47
12.2
AE Coding Dictionary ..............................................................................................................51
12.3
Reporting Procedures..............................................................................................................51
12.4
Follow-up of Participants with Adverse Events .......................................................................55
Investigator Obligations ...................................................................................................................55
Sponsor and Monitor Responsibilities .............................................................................................56
14.1
Contract Research Organization .............................................................................................56
Protocol Amendments .....................................................................................................................56
Confidentiality of the Study..............................................................................................................56
Statements of Compliance...............................................................................................................56
End of Study ....................................................................................................................................57
Publication Policy.............................................................................................................................57
19.1
Publication of Study Data ........................................................................................................57
19.2
Data Sharing............................................................................................................................57
References ......................................................................................................................................59
Appendices ......................................................................................................................................62
21.1
Protocol Amendment ...............................................................................................................62
21.2
Principal Investigator Obligations (ISO14155) ........................................................................97

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 11 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
AAROM 
Active Assisted Range of Motion 
ADE 
Adverse Device Effect(s) 
ADL 
Activities of Daily Living 
AE 
Adverse Event(s) 
AROM 
Active Range of Motion 
ASADE 
Anticipated Serious Adverse Device Effect 
ASES 
American Shoulder and Elbow Surgeons 
CRF 
Case Report Form(s) 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CTA 
Clinical Trial Agreement 
CV 
Curriculum Vitae 
DD 
Device Deficiency(ies) 
DDD 
Defined Daily Dosage 
EDC 
Electronic Data Capture 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation  
ICJME 
International Committee of Medical Journal Editors 
IFU 
Instructions for Use 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
MCID 
Minimal Clinically Important Difference 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 12 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Abbreviation 
Definition 
NSAE 
Non-Serious Adverse Event(s) 
PEEK 
Polyetheretherketone 
PI 
Principal Investigator 
PROM 
Passive Range of Motion 
PRP 
Platelet-rich Plasma 
SANE 
Single Assessment Numeric Evaluation 
S&N 
Smith & Nephew Inc. 
SADE 
Serious Adverse Device Effect(s) 
SAE 
Serious Adverse Event(s) 
SAP 
Statistical Analysis Plan 
SLAP 
Superior Labral Tear from Anterior to Posterior 
USADE 
Unanticipated Serious Adverse Device Effect(s) 
VAS 
Visual Analog Scale 
 

Study Protocol
Device
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears
Number: 
REGEN.PUB.2018.09
Version: 3.0, 10SEP2019
Page: Page 13 of 105
CONFIDENTIAL AND PROPRIETARY
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew.
INTRODUCTION
4.1
BACKGROUND 
Rotator cuff disease is a painful, progressive condition resulting from damage and/or injury to one 
or more of the tendons within the rotator cuff, often involving the upper-most (supraspinatus) 
tendon.2,3 Degenerative damage is predominantly the result of continual wear and tear, while 
acute injury may be caused by trauma such as sudden heavy lifting or a fall onto an outstretched 
arm.4 Patients with atraumatic rotator cuff disease usually report pain and weakness in the arm, 
leading to impaired function and mobility,5 and are typically recommended conservative 
treatments to manage symptoms in the first instance.6 However, such conservative treatments 
may be ineffective;7 surgical treatment may therefore be subsequently advised to remove 
damaged tissue or repair the rotator cuff.8,9,10  Tear progression may continue after conventional 
surgical intervention  with re-tear rates as 79% for massive tears.11,12,13
Overall, rotator cuff disease accounts for 4.5 million physician visits each year,14 a burden which 
will inevitably increase as the incidence of disease grows. The substantial burden of rotator cuff 
disease on healthcare resources is compounded by the additional indirect costs associated with 
reduced employment and income, missed workdays, and disability payments.  It is evident that 
the disability associated with rotator cuff disease comes at a high societal cost, which is expected 
to grow given the increasing prevalence of rotator cuff disease.14,15,16
The REGENETEN
Implant is a collagen implant that provides a layer of collagen over injured 
tendons. The induction of this layer of new tendinous tissue may reduce micro-strains within the 
tendon, resulting in an optimized mechanical environment for tendon healing.17 Use of 
REGENETEN in the treatment of high-grade partial-thickness tears in lieu of completion of tear 
and repair, which may accelerate patient recovery and shoulder mobility while reducing post-
operative pain.18

Study Protocol
Device
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears
Number: 
REGEN.PUB.2018.09
Version: 3.0, 10SEP2019
Page: Page 14 of 105
CONFIDENTIAL AND PROPRIETARY
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew.
The objective of this study is to demonstrate arthroscopic surgical treatment of high-grade (>50%) 
partial-thickness tears using REGENETEN yields statistically superior patient post-operative
recovery outcomes, faster return to activities of daily living, and less health care utilization versus 
standard surgical repair techniques.
4.2
STUDY PURPOSE
The purpose of this prospective, post-market, multi-center cohort study is to demonstrate 
REGENETEN is superior to standard arthroscopic repair techniques when surgically treating high-
grade (>50%) partial-thickness tears because REGENETEN preserves more of the native tendon 
footprint resulting in less post-operative pain and faster recovery.
OBJECTIVES
5.1
PRIMARY OBJECTIVE
The primary objective of this study is to determine if arthroscopic surgical treatment of high-grade 
(>50%) partial-thickness rotator cuff tears using REGENETEN yields statistically superior 
participant-rated shoulder function and reduced pain and disability at 3 months following index 
surgery compared to standard surgical repair techniques.
5.2
SECONDARY OBJECTIVE(S)
The secondary objectives of this study are to generate performance and health economic 
evidence supporting the use of REGENETEN in treating high-grade (>50%) partial-thickness 
rotator cuff tears. Specifically, these objectives will determine whether arthroscopic surgical 
treatment using REGENETEN versus standard surgical repair techniques for high-grade (>50%) 
partial-thickness rotator cuff tears results in:
1.
Early benefits related to a participant-reported composite of
daily
shoulder 
function/disability and pain (over initial 3 months following index surgery)
2.
Early benefits related to participant-reported average shoulder function as a percentage 
of normal (over initial 3 months following index surgery)

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 15 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
3. Early benefits related to participant-reported shoulder pain (over initial 3 months following 
index surgery) 
4. Improved participant-reported composite of daily shoulder function/disability and pain 
(over 24 months following index surgery) 
5. Improved participant-reported average shoulder function as a percentage of normal (over 
24 months following index surgery) 
6. Decreased participant-reported shoulder pain (over 24 months following index surgery) 
7. Improved participant-reported and examiner-assessed shoulder pain and function (over 
24 months following index surgery) 
8. Decreased opioid use to treat the index shoulder (over initial 3 months following index 
surgery) 
9. Decreased non-opioid prescription medication use to treat the index shoulder (over initial 
3 months following index surgery) 
10. Decreased opioid use to treat the index shoulder (over 12 months following index 
surgery) 
11. Decreased use of non-opioid prescription medication to treat the index shoulder (over 12 
months following index surgery)  
12. Decreased shoulder immobilization time following index surgery 
13. Earlier return to work by work type (sedentary; laborer) 
14. Earlier return to driving 
15. Earlier return to sports 
16. Lower incidence of progression to full-thickness tear (within 12 months following index 
surgery) 
17. Lower incidence of progression to full-thickness tear (within 24 months following index 
surgery) 
18. Increased percent filling of rotator cuff (at 12 months following index surgery) 
19. Increased percent filling of rotator cuff (at 24 months following index surgery) 
20. Improvements in rotator cuff tendon thickness (at 12 months following surgery) 
21. Improvements in rotator cuff tendon thickness (at 24 months following surgery) 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 16 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
22. Lower fatty infiltration of the rotator cuff (at 12 months following surgery) 
23. Lower fatty infiltration of the rotator cuff (at 24 months following surgery) 
24. Improved rotator cuff integrity (at 12 months following surgery)  
25. Improved rotator cuff integrity (at 24 months following surgery)  
26. Lower incidence of revision surgery (index shoulder; all causes) (within 24 months 
following index surgery) 
27. Lower aggregate health care utilization costs (over 12 months following index surgery) 
28. Decreased operating room time (index surgery) 
29. Fewer shoulder steroid injections (over 12 months following index surgery) 
30. Fewer unscheduled index shoulder-related clinic visits (over 12 months following index 
surgery)  
31. Fewer for-cause imaging procedures (over 12 months following index surgery) 
32. Fewer physiotherapy sessions (over 12 months following index surgery) 
 
 

Study Protocol
Device
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears
Number: 
REGEN.PUB.2018.09
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CONFIDENTIAL AND PROPRIETARY
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew.
INVESTIGATIONAL PRODUCT(S)
6.1
IDENTIFICATION 
The REGENETEN Implant system is biologic solution to a biomechanical problem and has been 
cleared by the Food and Drug Administration for commercial use in the United States. The 
REGENETEN Implant is a collagen implant that provides a layer of collagen over injured tendons. 
The induction of this layer of new tendinous tissue on the bursal side of the supraspinatus tendon 
may reduce micro-strains within the tendon. Reduction in these forces may in turn optimize the 
mechanical environment for tendon healing and inhibit, or arrest, tear propagation. Use of 
REGENETEN in the treatment of high-grade partial-thickness tears in lieu of converting the partial 
tear to a full-thickness tear and surgically reattaching the tendon to bone may accelerate patient 
recovery and shoulder mobility while reducing post-operative pain.
The REGENETEN Implant system (Figure 1) is comprised of disposable instruments, a 
resorbable collagen implant, and anchors to secure the scaffold to the underlying tendon and 
bone. The system is provided sterile, for single-use only, and in a dual sterile seal, tray-in-tray 
configuration. The REGENETEN Implant is indicated for the management and protection of 
rotator cuff tendon injuries in which there has been no substantial loss of tendon tissue.

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
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CONFIDENTIAL AND PROPRIETARY 
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intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Figure 1. Shown from left to right, tendon anchor, Implant and bone anchor 
 
The collagen implant consists of a resorbable type I collagen matrix derived from bovine Achilles 
tendon. It is contraindicated for use in patients with a history of hypersensitivity to bovine-derived 
materials. The device is designed to completely resorb within six to 12 months. 
 
The tendon anchors are made from poly(L-lactide-co-D,L-lactide) in a molar ratio of 70% L-lactide 
to 30% D,L-lactide. Polylactide materials have been used in a variety of medical devices, such as 
bone anchors, bone pins, screws, plates, and spinal fusion cages. The tendon anchors are 
intended for the fixation of prosthetic material to soft tissues and designed to completely absorb 
within approximately 12 months.  
 
The bone anchors are made from polyetheretherketone (PEEK), which is a common polymer 
used for bone anchors in orthopedic surgery. The bone anchors are intended for fixation of soft 
tissue grafts. The bone anchors are not resorbable. 
 
The device does not contain, nor does it deliver, any medicinal substance, phthalates or other 
hazardous substances. 
 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
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REGEN.PUB.2018.09 
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CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
The disposable instrument system (Figure 2) includes the arthroscopic implant delivery 
instrument, tendon anchor delivery instruments, and bone anchor delivery instruments. There is 
also an implant loading tool and tendon stabilizing guide. 
 
Figure 2 Disposable Instrument System 
 
 
 
 
 
A summary of known and potential risks and benefits to humans of the REGENETEN Implant 
system can be found in the Instructions for Use (IFU).  
6.2 
PRODUCT USE 
Surgical treatment of partial-thickness rotator cuff tears with the REGENETEN Implant system 
will be performed in accordance with its IFU. 

Study Protocol
Device
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears
Number: 
REGEN.PUB.2018.09
Version: 3.0, 10SEP2019
Page: Page 20 of 105
CONFIDENTIAL AND PROPRIETARY
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew.
6.3
SURGICAL PROCEDURE
All surgeries in both treatment cohorts will be performed arthroscopically unless the surgeon 
determines a mini-open procedure is required to protect participant health and well-being.  
Concomitant use of other biologics to augment the rotator cuff, including but not limited to stem 
cell therapy or platelet-rich plasma (PRP), are contraindicated.
PARTICIPANT ENROLLMENT AND WITHDRAWAL
7.1
PARTICIPANT POPULATION
One hundred eighteen (118) participants undergoing arthroscopic surgical treatment of a high-
grade (>50%) partial-thickness tear, meeting the eligibility criteria, will be recruited from up to 12
sites in the United States. Participants who meet the eligibility criteria will be enrolled from the 
population of patients routinely seen by the Investigator.
7.2
INCLUSION CRITERIA
Patients will be considered qualified for enrollment if they meet the following criteria:
1.
2.
High-grade (>50% tendon thickness) partial-thickness tear 
3.
Failed conservative medical management of the tendon tear defined as:
a.
Four (4) to six (6) weeks of formal physical therapy or guided home exercises
b.
Activity modification
c.
Shoulder injection at the discretion of the surgeon
4.
Able to comply with the post-operative physiotherapy and follow-up schedule
5.
Able to read and write English
6.
Provision of written informed consent

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
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CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
7.3  
EXCLUSION CRITERIA 
Any one (1) of the following criteria will disqualify a patient from enrollment in the study: 
1.
Prior shoulder surgery on index shoulder within 12 months of enrollment 
2.
Failed primary rotator cuff surgery of the index shoulder 
3.
Systemic steroid use (oral, IV) or locally injected at the surgical site within 1 month of 
enrollment 
4.
Metastatic disease 
5.
Concomitant surgeries for bone defects requiring bone implantation (Latarjet 
procedures) or for superior labral tear from anterior to posterior (SLAP) 
6.
Concomitant biceps tenodesis 
7.
Rheumatoid arthritis 
8.
Advanced osteoarthritis 
9.
 
10.
Chronic pain disorders (i.e., fibromyalgia) 
11.
History of insulin dependent diabetes 
12.
History of heavy smoking (> 1 pack per day) within 6 months of enrollment 
13.
Currently involved in any injury litigation or workers compensation claims  
14.
Hypersensitivity to bovine-derived materials 
15.
Medical or physical condition that, in the opinion of the Investigator, would preclude 
safe participation in the study 
7.3 
SCREENING  
All patients diagnosed with a high-grade (>50%) partial-thickness tear who are undergoing 
arthroscopic surgical treatment by the Investigator are to be screened for eligibility at their pre-
operative visit based on medical record review and discussions with the patient and Investigator.  
Participating clinical sites are required to document all screened patients. If a patient is excluded 
from the study, the reasons for exclusion will be documented in the 
 source documents 
and noted in the Screening Form.  

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
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partial-thickness tears 
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CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
7.4 
INFORMED CONSENT 
Before conducting any study procedures or examinations, informed consent shall be obtained 
from all participants according to ISO14155 guidelines. Patients must be informed as to the 
purpose of the study and the potential risks and benefits known or that can be reasonably 
predicted or expected as described in the written Informed Consent Form (ICF).  The patients 
shall have sufficient opportunity to consider participation in the study.  Patients will then be invited 
to read, sign and personally date the Institutional Review Board (IRB)-approved ICF, indicating 
their consent for enrollment.  Additionally, the individual who obtains consent from the participant 
will sign and date the ICF. A copy of the signed informed consent documentation will be provided 
to the participant, and the original filed in the investigator site file (ISF).  
7.5 
ENROLLMENT 
Enrollment in this study shall occur at the pre-operative visit after the investigator has confirmed 
eligibility and participant has completed the informed consent process.  At this time, the participant 
will be assigned a Subject ID via the REDCap Cloud Electronic Data Capture (EDC) system.  
7.6 
LOST TO FOLLOW-UP 
Once a participant is enrolled in the study, every reasonable effort will be made to follow the 
participant for the entire duration of the study period. A participant should not be deemed lost to 
follow-up until after he/she fails to complete the final 24 month visit and study personnel are 
unable to contact the participant.   
 
Study personnel must make a reasonable effort to contact the participant in accordance with the 
site's local policies. All attempts to reach the participant should be documented and retained with 
the participan
source documents. 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
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REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 23 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
7.7 
WITHDRAWAL 
Participants may be withdrawn from the study prior to 24 months post-surgery for the following 
reasons: 
 
Withdrawal of informed consent by the participant 
 
Determination of ineligibility by the Investigator during the index surgical procedure  
Study participation is voluntary and participants may withdraw at any point without giving their 
reason to do so.  Where participants withdraw consent, the Investigator should make a reasonable 
effort to ascertain the reason(s), while fully respecting the participan
privacy.  All reasonable 
efforts should be made to retain participants for the full 24 month follow-up period of this study. If 
a participant withdraws prior to completing the study, study personnel will document the reason 
for withdrawal and attempt to collect any available outcome data. In cases where the participant 
withdraws consent, the data collected up to the point of withdrawal may be used but no additional 
data for that participant may be collected.  
 
The Investigator may also withdraw a participant from the study if he/she determines during the 
index surgery that the rotator cuff tear does not meet the eligibility criteria based on direct 
arthroscopic visualization of the tear.   
 
Participants will not be withdrawn from the study due to lack of adherence to the requirements of 
the study protocol (e.g., lack of compliance with physiotherapy guidelines, missed follow-up 
visits). 
7.7.1 Replacement of Withdrawn Participants 
Participants who are withdrawn by the Investigator due to ineligibility identified during the index 
surgery will be replaced.  Any participants who withdraw their consent to participate prior to their 
index surgical procedure will also be replaced.  Participants who withdraw their consent at any 
time following their index surgical procedure will not be replaced.   

Study Protocol
Device
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears
Number: 
REGEN.PUB.2018.09
Version: 3.0, 10SEP2019
Page: Page 24 of 105
CONFIDENTIAL AND PROPRIETARY
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew.
STUDY DESIGN
8.1
STUDY DESIGN
This is a prospective, non-blinded, multi-center cohort study to collect relevant clinical data and 
compare the REGENETEN Implant in lieu of standard arthroscopic repair in 118 participants (59 
participants per group) with a high-grade (>50% tendon thickness) partial-thickness rotator cuff 
tear.
Up to 12 clinical sites in the United States will enroll and follow 118 participants who meet the 
study eligibility criteria.  Follow-up clinical assessments will be performed at 3 months (±30 days), 
6 months (±30 days), 12 months (±30 days), 18 months (±60 days), and 24 months (±60 days) 
post-operatively.
The total estimated study duration will be 42 months: 18 months enrollment (estimated) and up 
to 24 months follow-up (primary endpoint assessed at 3 month follow-up) post-operatively.
8.2
ALLOCATION AND BLINDING
This study is not randomized. Selection of the surgical approach (repair with REGENETEN versus 
standard repair techniques) will be at the discretion of the Investigator, in consultation with the 
participant, as appropriate.
Standard surgical repair techniques of the rotator cuff will be defined as either:
1.
Debridement and a transtendinous repair, or
2.
Complete takedown and repair.
To ensure an equal number of participants enrolled into each treatment group, the Sponsor and 
Contract Research Organization (CRO) will continuously monitor enrollment and will close 
enrollment into the faster enrolling cohort (REGENETEN cohort or standard repair technique

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
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REGEN.PUB.2018.09 
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CONFIDENTIAL AND PROPRIETARY 
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intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
cohort) once the targeted enrollment has been reached.  Enrollment into the slower enrolling 
cohort will continue until the study is fully enrolled. 
8.3 
STUDY ENDPOINTS 
8.3.1 Primary Endpoint 
The primary endpoint of this study is the American Shoulder and Elbow Surgeons (ASES) score 
at 3 months following index surgery. 
8.3.2 Secondary Endpoints  
The secondary endpoints of this study include performance endpoints and economic endpoints.   
The performance endpoints are:  
1. ASES score over initial 3 months following index surgery 
2. Single Assessment Numeric Evaluation (SANE) score over initial 3 months following index 
surgery 
3. ASES Visual Analog Scale (VAS) pain score over initial 3 months following index surgery 
4. ASES score at 6, 12, 18 and 24 months following index surgery 
5. SANE score at 6, 12, 18 and 24 months following index surgery 
6. ASES VAS pain score at 6, 12, 18 and 24 months following index surgery 
7. Constant-Murley score at 3, 6, 12 and 24 months following index surgery 
8. Cumulative opioid use to treat the index shoulder over 3 months following index surgery 
9. Cumulative non-opioid prescription medication use to treat the index shoulder over 3 
months following index surgery 
10. Cumulative opioid use to treat the index shoulder over 12 months following index surgery 
11. Cumulative non-opioid prescription medication use to treat the index shoulder over 12 
months following index surgery 
12. Duration of shoulder immobilization following index surgery 
13. Time to return to work by work type (sedentary; laborer) 
14. Time to return to driving 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
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CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
15. Time to return to sports 
16. Incidence of progression to full-thickness tear within 12 months following index surgery 
17. Incidence of progression to full-thickness tear within 24 months following index surgery 
18. MRI assessment of percent filling at 12 months following index surgery 
19. MRI assessment of percent filling at 24 months following index surgery 
20. Rotator cuff tendon thickness at 12 months following index surgery 
21. Rotator cuff tendon thickness at 24 months following index surgery 
22. Goutallier classification of rotator cuff at 12 months following index surgery 
23. Goutallier classification of rotator cuff at 24 months following index surgery 
24. Sugaya score of rotator cuff at 12 months following index surgery 
25. Sugaya score of rotator cuff at 24 months following index surgery 
26. Incidence of revision surgery within 24 months following index surgery (index shoulder; all 
causes 
The economic endpoints are:  
27. Aggregate related health care utilization costs over 12 months following index surgery 
28. Operating room time (index surgery) 
29. Number of steroid injections over 12 months following index surgery 
30. Number of unscheduled clinic visits over 12 months following index surgery  
31. Number of for-cause imaging procedures over 12 months following index surgery 
32. Number of physiotherapy sessions over 12 months following index surgery 
8.4 
METHODS USED TO MINIMIZE BIAS AND MAXIMIZE VALIDITY 
The study will be conducted at up to 12 clinical sites, reducing the risk of bias inherent in a single-
center study. To eliminate the potential for selection bias, Investigators will consecutively screen 
all patients over the age of 18 years who are candidates for arthroscopic surgical treatment of 
high-grade (>50%) partial-thickness rotator cuff tears.  

Study Protocol
Device
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears
Number: 
REGEN.PUB.2018.09
Version: 3.0, 10SEP2019
Page: Page 27 of 105
CONFIDENTIAL AND PROPRIETARY
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew.
STUDY PROCEDURES
9.1
VISITS AND EXAMINATIONS 
9.1.1
Summary
For a summary of the required procedures by visit, refer to Table 1: Study Procedures by Visit.
Table 1: Study Procedures by Visit
Schedule of Events 
Pre-Op
(days -60 to -1)
Surgery 
(day 0)
3 Mo
(±30 days)
6 Mo
(±30 days)
12 Mo
(±30 days)
18 Mo
(±60 days)
24 Mo
(±60 days)
Informed Consent
Inclusion/Exclusion
Demographics/ Medical 
History
Operative Data
ASES Score
SANE
Constant-Murley Score
Participant Diary
Adverse Events
Heath Care Utilization
Revision Surgery
Upper Extremity MRI
*
Pre-Op indicates pre-operative; Mo, month(s); SANE, Single Assessment Numeric Evaluation; ASES, 
American Shoulder and Elbow Surgeons Score including VAS Pain 
The ASES score and SANE will be completed every week (i.e., every 7±3 days) though 3 month follow-up.
Participant diaries will be used to document opioid and non-opioid prescription medication use, use of a sling, 
other related healthcare utilization (i.e. steroid injections, clinic visits, imaging, physiotherapy sessions, etc.) 
and return to work, driving, and sports. Participant diary will be updated weekly (7±3 days) through 3 month 
follow-up and monthly (30±7 days) thereafter until 12 months post-surgery.
*The pre-
Protocol which is used for the 12 and 24 month MRIs. The pre-op MRI must occur within 6 months of 
enrollment into this study. All MRIs will be submitted to the imaging vendor per the Image Transfer Protocol.

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
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Version: 3.0, 10SEP2019 
Page: Page 28 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
9.1.2 Pre-operative Visit (60 days to 1 day prior to surgery) 
1. Screen patient for protocol inclusion and exclusion criteria (based on medical record 
review and preliminary discussion of study with patient). 
2. Obtain written informed consent from the participant as detailed in Section 7.4 
----- Do not proceed until consent has been obtained ----- 
3. Enter screening data into REDCap Cloud EDC and obtain a Subject ID number.  
4. Obtain demographic information and medical history, including information on opioid 
and non-opioid prescription medications used during the past 30 days. 
5. Complete the ASES questionnaire, SANE questionnaire, and Constant-Murley 
assessment. 
6. Obtain copy of the standard of care MRI of index shoulder, if available. Pre-op MRI 
must have occurred within 6 months of enrollment into this study. 
7. Confirm date of surgery with participant. 
9.1.3 Index Surgery (Day 0)  
1. Confirm eligibility based on arthroscopic visualization of the tear. 
2. Complete surgical procedure. 
3. Record operative details as specified in Case Report Forms (CRFs) 
4. If any adverse events, adverse device effects, or device deficiencies are observed or 
reported, they must be recorded as instructed in Section 12  Adverse Events and 
Device Deficiencies. 
5. Instruct the participant on proper post-operative care/procedures, including any 
contraindicated treatments/medication(s). 
6. Instruct the participant on follow-up procedures, including completing the weekly 
ASES and SANE questionnaires, completing the weekly diary, and returning for 
clinical follow-up at 3 months. 
7. Provide participants with the cohort-specific Physiotherapy Guidelines. 
 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
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Page: Page 29 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
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intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
9.1.4 Weekly Diary (week 1 to week 12 (±3 days)) 
1. Participant will complete the ASES questionnaire and SANE questionnaire. 
2. Participant will document opioid and non-opioid prescription medication use, use of 
sling, other healthcare utilization related to the index shoulder (i.e. steroid injections, 
clinic visits, imaging, physiotherapy sessions, etc.) and return to work, driving, and 
sports in their diary. 
3. Study personnel will remind each study participant to complete the questionnaires and 
diary weekly via telephone, email, or text. 
4. Study personnel will remind participant of the importance of complying with the 
specified Physiotherapy Guidelines. 
9.1.5 3 Month Visit (±30 days), 6 Month Visit (±30 days), 12 Month Visit (±30 days), 18 
Month Visit (±60 days), and 24 Month Visit (±60 days) 
1. Complete the ASES questionnaire (all visits), SANE questionnaire (all visits), and 
Constant-Murley assessment (3, 6, 12 and 24 month visits only). 
2. Review diary entries for completeness with participant. 
3. Document any health care utilization involving the index shoulder not recorded in the 
participant diary (3, 6, and 12 month visits). 
4. Document any revision surgeries involving the index shoulder (all visits). 
5. If any adverse events, adverse device effects, or device deficiencies are observed or 
reported, they must be recorded as instructed in Section 12  Adverse Events and 
Device Deficiencies (all visits). 
6. MRI of index shoulder (12 month and 24 month visits). 
7. Instruct the participant on follow-up procedures, including returning for the next clinical 
follow-up (except for the 24 month exit visit). 
 

 
Study Protocol
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Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
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CONFIDENTIAL AND PROPRIETARY 
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intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
9.1.6 Post-Operative Physiotherapy Guidelines 
Participants in each cohort (i.e. REGENETEN and standard surgical repair) will be provided with 
cohort-specific Physiotherapy Guidelines.  Participants will be required to adhere strictly to the 
Physiotherapy Guidelines. Study personnel will remind participants of the importance of 
compliance, and the completion of physiotherapy sessions will be documented in the participant 
diary. Refer to the cohort-specific Physiotherapy Guidelines for details. 
9.1.7 Concomitant Medications 
Use of opioids, non-opioid prescription medications, and steroid injections to treat the index 
shoulder over 12 months following the index surgery will be documented in the participant diary 
medications associated with the treatment of SAEs or ADEs will also be recorded. 
9.1.8 MRI Submissions 
Upper extremity MRIs for study participants will be collected pre-operatively, at 12 months post-
surgery and at 24 months post-surgery. The pre-operative 
care MRI and will not follow the study MRI Image Acquisition Protocol. The pre-op MRI must occur 
within 6 months of enrollment into this study. 
Participants will receive an MRI of the index shoulder at 12 months and 24 months post-surgery 
per the Image Acquisition Protocol.  The standard of care pre-operative MRI and the 12 and 24 
month MRIs will be submitted to the imaging vendor per the Image Transfer Protocol. 3T MRIs 
are strongly preferred for submission, wherever available, but are not required. 
9.1.9 Discontinued Participants 
Discontinued participants are those who voluntarily discontinue participation or who are lost to 
follow-up after all reasonable attempts to contact them. Where possible, a final follow-up visit 
should be completed for all participants who discontinue the study early. Where consent is 
withdrawn, the date and any reason given for discontinuation should be captured, at a minimum 

 
Study Protocol
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Prospective multi-center study comparing REGENETEN in 
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partial-thickness tears 
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(Section 7.7). Finally, if appropriate, the Investigator will also advise the participant of subsequent 
therapy and/or procedures necessary for their medical condition. 
9.1.10 Pregnancy 
Women of child-bearing potential are not excluded from the study. Pregnancy is not reportable 
as an adverse event; however, complications related to the pregnancy may be reportable as 
determined on a case-by-case basis.  
9.2 
STUDY ENDPOINTS 
9.2.1 Performance Endpoints 
American Shoulder and Elbow Surgeons (ASES): The ASES instrument is composed of 2 
sections containing participant self-reported and clinician assessments.  The ASES score is a 0 
to 100-point rating based solely on participant responses and is a combination of the pa
 
shoulder pain rating (VAS Pain) and self-reported ability to perform 10 different activities of daily 
living (ADLs).19 ASES scores will be recorded pre-operatively, weekly from 1 week to 3 months 
post-surgery, and at 6,12,18 and 24 months post-surgery.  
 
Single Assessment Numeric Evaluation (SANE): The SANE is a simple, single-question, patient-
percentage of normal (0% 
simplicity and ability to be applied to a wide variety of clinical situations. It has not been validated 
and no minimal clinically important difference has been reported.20 SANE scores will be recorded 
pre-operatively, weekly from 1 week to 3 months post-surgery, and at 6,12,18 and 24 months 
post-surgery.  
 
Participant-reported Shoulder Pain
the VAS Pain rating from the ASES instrument. The VAS Pain rating will be recorded pre-

 
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partial-thickness tears 
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operatively, weekly from 1 week to 3 months post-surgery, and at 6, 12, 18, and 24 months post-
surgery.  
 
Constant-Murley Score: The Constant-Murley Score is a validated assessment of pain and 
shoulder functionality. The test is divided into four subscales: pain, activities of daily living, 
strength and range of motion (forward elevation, external rotation, abduction and internal rotation 
of the shoulder. At the end of the assessment, a score is obtained out of 100 points where higher 
scores indicate a higher quality of shoulder function.21 The score is obtained through a 
combination of participant-reported and objective (examiner-assessed) shoulder outcome 
measures.22  
 
Duration of Shoulder Immobilization: The duration of medically required shoulder immobilization 
following index surgery will be calculated based on the number of days in a sling, as reported in 
the participant diary. 
 
Cumulative opioid use: Cumulative opioid use to treat the index shoulder from index surgery to 
12 months will be calculated based on usage reported in the participant diary (name, dose, 
duration). 
 
Cumulative Non-opioid Prescription Medication Use: Cumulative non-opioid prescription 
medication use to treat the index shoulder from index surgery to 12 months will be calculated 
based on usage reported in the participant diary (name, dose, duration). 
 
Time to Return to Work, Driving, and Sports: Time from index surgery to return to ADLs will be 
calculated based on the date that participants report return to work (sedentary; laborer), return to 
driving, and return to sport as reported in the participant diary. 
 

 
Study Protocol
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Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
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Incidence of Progression to Full Thickness Tear:  An independent reviewer will assess MRIs for 
evidence of progression to a full-thickness tear within 12 months and 24 months of the index 
surgery. All MRI assessments are detailed in the Image Review Charter. 
 
Percent Filling of Rotator Cuff: An independent reviewer will assess MRIs for the percent filling of 
the rotator cuff at 12 months and 24 months post-surgery. All MRI assessments are detailed in 
the Image Review Charter. 
 
Rotator Cuff Tendon Thickness: An independent reviewer will assess MRIs for the rotator cuff 
tendon thickness at 12 and 24 months. All MRI assessments are detailed in the Image Review 
Charter. 
 
Goutallier Classification: The Goutallier classification will be used to classify the fatty infiltration of 
the rotator cuff. The Goutallier classification ranges from a grade of 0 indicating a completely 
normal muscles without any fatty streaks to a grade of 4 which indicates that more fat than muscle 
is present.23 An independent reviewer will assess MRIs for the fatty infiltration of the rotator cuff 
at 12 and 24 months post-surgery. All MRI assessments are detailed in the Image Review Charter. 
 
Sugaya Score: The Sugaya score will be used to measure the rotator cuff integrity. The Sugaya 
score ranges from Type I to Type V. Type I indicates a repaired cuff that had sufficient thickness 
with homogeneously low intensity on the MRI image while Type V indicates the presence of a 
major discontinuity on the MRI images suggesting a medium or large tear.24 An independent 
reviewer will use the MRI to assess rotator cuff integrity at 12 and 24 months post-surgery. All 
MRI assessments are detailed in the Image Review Charter. 
 
Incidence of Revision Surgery: All revision surgeries involving the index shoulder for any cause 
within 24 months of the index surgery will be documented. 

 
Study Protocol
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Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
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contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
9.2.2 Economic Endpoints 
Aggregate health care utilization costs: Related health care utilization costs over 12 months post-
surgery will be calculated based on health care utilization as reported in the participant diary 
and/or 
  
 
Operating Time (Index surgery): Operating time for the index surgery, defined as the time from 
first incision to wound closure (measured in minutes) as recorded in the operative procedure 
notes, will be recorded. 
 
Medication Use: Cumulative opioid and non-opioid prescription medication used to treat the index 
shoulder over 12 months following index surgery as reported in the participant diary and/or in the 
 
 
Number of Steroid Injections: The number of steroid injections administered to the index shoulder 
medical record, will be recorded. 
 
Number of Unscheduled Clinic Visits: The number of unscheduled clinic visits (defined as a return 
visit to a health care provider for examination/evaluation of the index shoulder) within 12 months 
, 
will be recorded. 
 
Number of For-Cause Imaging Procedures: The number of for cause imaging procedures (e.g. 
MRI or ultrasound) performed on the index shoulder within 12 months of the index surgery, as 
.  
 
Number of Physiotherapy Sessions: The number of physiotherapy sessions within 12 months of 
the index surgery, 
will be recorded. 

Study Protocol
Device
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears
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Version: 3.0, 10SEP2019
Page: Page 35 of 105
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contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew.
STATISTICAL DESIGN
A Statistical Analysis Plan (SAP) will be written and finalized prior to database lock. The following 
is a brief description of the analyses to be described in this plan. If there are any changes from 
the analysis described below it will be detailed in the SAP and the Clinical Study Report (CSR). 
Any changes/additions to the analysis described in the SAP will also be detailed in the CSR.
10.1
GENERAL
the economic analysis, which will be conducted by
For the primary outcome, the significance tests and hypothesis testing will be two-sided, 
performed at the 5% significance level. Resulting p-values will be quoted and 95% two-sided 
confidence intervals will be generated where appropriate. Unless otherwise stated, point 
estimates (mean differences or odds ratios) and 95% confidence intervals will be reported 
descriptively for secondary outcome as an exploratory assessment. Select secondary outcomes 
will undergo statistical testing as outlined in section 10.4.2.
Where data summaries are specified, categorical and ordinal variables will be summarized with 
frequencies and percentages. Continuous variables will be summarized with the following 
summary statistics: number of observations, means and standard deviations, or median and 
interquartile ranges.  All analyses will be performed using a statistical package such as SAS or 
SPSS.
10.2
ANALYSIS POPULATIONS
Due to the non-randomized nature of the study design, study participants will be analyzed as per 
the treatment they received.  Any safety analyses will include participants who received the 
investigational product (IP).

 
Study Protocol
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Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
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contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
10.3 
BASELINE DATA 
Patient demographics and baseline outcome variables will be summarized by treatment group 
using descriptive summary measures expressed as means with standard deviations or medians 
with interquartile ranges for continuous variables depending on the distribution and number 
(percent) for categorical and ordinal variables. 
10.4 
EFFICACY ANALYSIS 
10.4.1 Analysis of Primary Endpoint 
Multiple linear regression will be used to compare differences in the mean ASES scores between 
the REGENETEN cohort and the comparison cohort at 3 months post-treatment.  The significance 
tests and hypothesis testing will be two-sided, performed at the 5% significance level. Resulting 
p-values will be quoted and 95% two-sided confidence intervals will be generated where 
appropriate. The analysis will be adjusted for baseline ASES score and for differences in baseline 
characteristics between the two cohorts. 
 
The minimal clinically important difference (MCID) will be used to determine the clinical 
importance of the mean difference between treatment groups for the ASES score and all other 
patient-reported outcomes (i.e. SANE, Constant-Murley score). The MCID defines the change in 
the outcome score that results in the smallest, appreciable clinical improvement25. The MCID for 
the ASES is 11.1 points for patients undergoing rotator cuff repair1.The criteria for determining 
the clinical importance of the mean difference will be as follows:  
 If the confidence interval of the mean difference is completely above the MCID, the 
significant  
 If the confidence interval of the mean difference contains the MCID, the difference is 
significant  
 If the confidence interval of the mean difference is completely below the MCID, the 
significant 25 
 

 
Study Protocol
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partial-thickness tears 
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The assessment of clinical importance will be reported along with the confidence intervals for 
each outcome. 
10.4.2 Analysis of Secondary Endpoints 
Table 2 summarizes the secondary efficacy endpoint(s) and summary of planned analyses for 
select secondary outcomes. Unless otherwise stated, point estimates in the form of mean 
differences or odds ratios along with 95% confidence intervals will be reported descriptively for 
secondary outcomes. 
 
An exploratory assessment using the MCID will be done for select secondary outcomes. The 
MCID will be used to explore the clinical importance of the mean difference between treatment 
groups for all patient-reported outcomes (i.e. ASES, SANE, and Constant-Murley score). The 
MCID used for outcomes related to the ASES score, SANE score and Constant-Murley score will 
be 11.1 points1, 29.4 points1, and 5.5 points1, respectively. For outcomes involving the ASES-
VAS pain score, the MCID used will be 1.37 cm26. 

 
Study Protocol
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partial-thickness tears 
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Table 2: Analysis of Secondary Endpoints 
Item 
Objective 
Outcome 
Measure 
Statistical Test 
Secondary 
Objective #1 
To determine if there are early 
benefits (within 3 months of 
surgery) of arthroscopic surgical 
treatment of high-grade (>50%) 
partial-thickness rotator cuff tears 
using REGENETEN on 
participant-reported daily shoulder 
function/disability and pain 
compared to standard surgical 
repair techniques. 
American 
Shoulder and 
Elbow Surgeons 
(ASES) Score 
weekly through 3 
months post-index 
surgery. 
Generalized linear 
regression adjusting 
for baseline ASES 
score and differences 
in baseline 
characteristics. The 
mean ASES scores 
will be compared 
using an MCID of 11.1 
points. 
Secondary 
Objective #2 
To determine if there are early 
benefits (within 3 months of 
surgery) of arthroscopic surgical 
treatment of high-grade (>50%) 
partial-thickness rotator cuff tears 
using REGENETEN on 
participant-reported average 
shoulder function as a percentage 
of normal compared to standard 
surgical repair techniques. 
Simple 
Assessment 
Numeric 
Evaluation (SANE) 
Score weekly 
through 3 months 
post-index 
surgery. 
Generalized linear 
regression adjusting 
for baseline SANE 
score and differences 
in baseline 
characteristics. The 
mean SANE scores 
will be compared 
using an MCID of 29.4 
points. 
Secondary 
Objective #3 
 
To determine if there are early 
benefits (within 3 months of 
surgery) of arthroscopic surgical 
treatment of high-grade (>50%) 
partial-thickness rotator cuff tears 
using REGENETEN on 
participant-reported shoulder pain 
compared to standard surgical 
repair techniques. 
VAS pain score 
from the American 
Shoulder and 
Elbow Surgeons 
(ASES) Score 
weekly through 3 
months post-index 
surgery. 
 
Generalized linear 
regression adjusting 
for baseline VAS pain 
score and differences 
in baseline 
characteristics. The 
mean ASES-VAS pain 
score will be 
compared using an 
MCID of 1.37 cm. 
Secondary 
Objective #4 
To determine if arthroscopic 
surgical treatment of high-grade 
(>50%) partial-thickness rotator 
cuff tears using REGENETEN 
yields statistically improved 
participant-reported composite of 
daily shoulder function/disability 
and pain compared to standard 
surgical repair techniques over the 
American 
Shoulder and 
Elbow Surgeons 
(ASES) Score at 
6, 12, 18 and 24 
months. 
 
 
Generalized linear 
regression adjusting 
for baseline ASES 
score and differences 
in baseline 
characteristics. The 
mean ASES scores 
will be compared 
using an MCID of 11.1 
points. 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
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is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Item 
Objective 
Outcome 
Measure 
Statistical Test 
24 months from the index 
shoulder surgery. 
Secondary 
Objective #5 
To determine if arthroscopic 
surgical treatment of high-grade 
(>50%) partial-thickness rotator 
cuff tears using REGENETEN 
yields statistically improved  
participant-reported average 
shoulder function as a percentage 
of normal compared to standard 
surgical repair techniques over the 
24 months from index shoulder 
surgery. 
Simple 
Assessment 
Numeric 
Evaluation (SANE) 
Score at 6, 12, 18 
and 24 months. 
Generalized linear 
regression  
adjusting for baseline 
SANE score and 
differences in baseline 
characteristics. The 
mean SANE scores 
will be compared 
using an MCID of 29.4 
points. 
Secondary 
Objective #6 
To determine if arthroscopic 
surgical treatment of high-grade 
(>50%) partial-thickness rotator 
cuff tears using REGENETEN 
statistically decreases participant-
reported shoulder pain compared 
to standard surgical repair 
techniques over the 24 months 
from the index shoulder surgery. 
VAS Pain score 
from the American 
Shoulder and 
Elbow Surgeons 
(ASES) Score at 
6, 12, 18 and 24 
months. 
Generalized linear 
regression adjusting 
for baseline VAS pain 
score and differences 
in baseline 
characteristics. The 
mean ASES-VAS pain 
score will be 
compared using an 
MCID of 1.37 cm. 
Secondary 
Objective #7 
To determine if arthroscopic 
surgical treatment of high-grade 
(>50%) partial-thickness rotator 
cuff tears using REGENETEN 
statistically improved participant-
reported and examiner-assessed 
shoulder pain and function 
compared to standard surgical 
repair techniques over 24 months 
from the index shoulder surgery. 
Constant-Murley 
Score at 3, 6, 12 
and 24 months. 
Generalized linear 
regression adjusting 
for baseline Constant-
Murley score and 
differences in baseline 
characteristics. The 
mean Constant-
Murley score will be 
compared using an 
MCID of 5.5 points. 
Secondary 
Objective #8 
To determine if participants who 
undergo arthroscopic surgical 
treatment of high-grade (>50%) 
partial-thickness rotator cuff tears 
using REGENETEN use 
significantly less opioids to treat 
the index shoulder compared to 
standard surgical repair over the 
Dose/duration of 
opioid use from 
post-surgery to 3-
months post- 
surgery. Defined 
daily dose (DDD) 
will be used as the 
outcome measure. 
Generalized linear 
regression adjusting 
for baseline opioid use 
and differences in 
baseline 
characteristics. 

 
Study Protocol
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Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
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Item 
Objective 
Outcome 
Measure 
Statistical Test 
initial 3 months following index 
surgery. 
Secondary 
Objective #9 
To determine if participants who 
undergo arthroscopic surgical 
treatment of high-grade (>50%) 
partial-thickness rotator cuff tears 
using REGENETEN use 
significantly less non-opioid 
prescription medication to treat the 
index shoulder compared to 
standard surgical repair over the 
initial 3 months following index 
surgery. 
Dose/duration of 
non-opioid 
prescription pain 
medication use 
from post-surgery 
to 3-months post-
surgery. DDD will 
be used as the 
outcome measure. 
Generalized linear 
regression adjusting 
for baseline non-
opioid prescription 
pain medication use 
and differences in 
baseline 
characteristics. 
Secondary 
Objective 
#10 
To determine if participants who 
undergo arthroscopic surgical 
treatment of high-grade (>50%) 
partial-thickness rotator cuff tears 
using REGENETEN use 
significantly less opioids to treat 
the index shoulder compared to 
standard surgical repair over the 
12 months from the index 
shoulder surgery.  
Dose/duration of 
opioid use from 
post-surgery to 12-
months post-
surgery. DDD will 
be used as the 
outcome measure. 
 
 
Generalized linear 
regression adjusting 
for baseline opioid use 
and differences in 
baseline 
characteristics. 
Secondary 
Objective 
#11 
To determine if participants who 
undergo arthroscopic surgical 
treatment of high-grade (>50%) 
partial-thickness rotator cuff tears 
using REGENETEN use 
significantly less non-opioid 
prescription medication to treat the 
index shoulder compared to 
standard surgical repair over the 
12 months from the index 
shoulder surgery. 
Dose/duration of 
non-opioid 
prescription pain 
medication use 
from post-surgery 
to 12-months post-
surgery. DDD will 
be used as the 
outcome measure. 
 Generalized linear 
regression adjusting 
for baseline non-
opioid prescription 
pain medication use 
and differences in 
baseline 
characteristics. 
Secondary 
Objective 
#12 
To determine if participants who 
undergo arthroscopic surgical 
treatment of high-grade (>50%) 
partial-thickness rotator cuff tears 
using REGENETEN have a 
shorter shoulder immobilization 
Number of days in 
a sling 
 N/A 

 
Study Protocol
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Prospective multi-center study comparing REGENETEN in 
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partial-thickness tears 
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Item 
Objective 
Outcome 
Measure 
Statistical Test 
time compared to participants who 
had standard surgical repair. 
Secondary 
Objective 
#13 
To determine if participants who 
undergo arthroscopic surgical 
treatment of high-grade (>50%) 
partial-thickness rotator cuff tears 
using REGENETEN return to work 
earlier than participants who had 
standard surgical repair. 
Number of days to 
return to work 
estimated from 
date of surgery. 
Type of 
occupation is 
independent 
factor.    
Generalized linear 
regression, adjusting 
for type of occupation 
and for differences in 
baseline 
characteristics. 
Secondary 
Objective 
#14 
To determine if participants who 
undergo arthroscopic surgical 
treatment of high-grade (>50%) 
partial-thickness rotator cuff tears 
using REGENETEN return to 
driving earlier than participants 
who had standard surgical repair. 
Number days to 
return to driving. 
 N/A 
Secondary 
Objective 
#15 
To determine if participants who 
undergo arthroscopic surgical 
treatment of high-grade (>50%) 
partial-thickness rotator cuff tears 
using REGENETEN return to 
sports earlier than participants 
who had standard surgical repair. 
Number days to 
return to sports. 
Generalized linear 
regression, adjusting 
for baseline level of 
sporting activity and 
differences in baseline 
characteristics. 
Secondary 
Objective 
#16 
To determine if participants who 
undergo arthroscopic surgical 
treatment of high-grade (>50%) 
partial-thickness rotator cuff tears 
using REGENETEN have a lower 
incidence of progression to full-
thickness tears (diagnosed by 
MRI) compared to participants 
who had standard surgical repair 
at 12 months from the index 
shoulder surgery. 
Incidence of full-
thickness tears 
(diagnosed by 
MRI) within 12m 
from the index 
surgery. 
 N/A 
Secondary 
Objective 
#17 
To determine if participants who 
undergo arthroscopic surgical 
treatment of high-grade (>50%) 
partial-thickness rotator cuff tears 
using REGENETEN have a lower 
incidence of progression of full-
Incidence of full-
thickness tears 
(diagnosed by 
MRI) within 24m 
from the index 
surgery. 
 N/A  
 

 
Study Protocol
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Item 
Objective 
Outcome 
Measure 
Statistical Test 
thickness tears (diagnosed by 
MRI) compared to participants 
who had standard surgical repair 
at 24 months from the index 
shoulder surgery. 
Secondary 
Objective 
#18 
To determine if participants who 
undergo arthroscopic surgical 
treatment of high-grade (>50%) 
partial-thickness rotator cuff tears 
using REGENETEN have 
increased percent filling of the 
rotator cuff (based on MRI 
assessment) compared to 
participants who had standard 
surgical repair at 12 months from 
the index shoulder surgery. 
Percent filling 
(based on MRI 
assessment) at 
12-months post-
surgery 
N/A 
Secondary 
Objective 
#19 
To determine if participants who 
undergo arthroscopic surgical 
treatment of high-grade (>50%) 
partial-thickness rotator cuff tears 
using REGENETEN have 
increased percent filling of the 
rotator cuff (based on MRI 
assessment) compared to 
participants who had standard 
surgical repair at 24 months from 
the index shoulder surgery. 
Percent filling 
(based on MRI 
assessment) at 
24-months post-
surgery. 
N/A 
Secondary 
Objective 
#20 
To determine if participants who 
undergo arthroscopic surgical 
treatment of high-grade (>50%) 
partial-thickness rotator cuff tears 
using REGENETEN have 
improvements in rotator cuff 
tendon thickness (based on MRI 
assessment) compared to 
participants who had standard 
surgical repair at 12 months from 
the index shoulder surgery. 
Rotator cuff 
tendon thickness 
(based on MRI 
assessment) at 
12-months post-
surgery. 
Generalized linear 
regression  
adjusting for baseline 
tendon thickness and 
differences in baseline 
characteristics 
Secondary 
Objective 
#21 
To determine if participants who 
undergo arthroscopic surgical 
treatment of high-grade (>50%) 
Rotator cuff 
tendon thickness 
(based on MRI 
Generalized linear 
regression  

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
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CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Item 
Objective 
Outcome 
Measure 
Statistical Test 
partial-thickness rotator cuff tears 
using REGENETEN have 
improvements in rotator cuff 
tendon thickness (based on MRI 
assessment) compared to 
participants who had standard 
surgical repair at 24 months from 
the index shoulder surgery. 
assessment) at 
24-months post-
surgery. 
adjusting for baseline 
tendon thickness and 
differences in baseline 
characteristics. 
Secondary 
Objective 
#22 
To determine if participants who 
undergo arthroscopic surgical 
treatment of high-grade (>50%) 
partial-thickness rotator cuff tears 
using REGENETEN have a 
statistically lower fatty infiltration of 
the rotator cuff (based on MRI 
assessment) compared to 
participants who had standard 
surgical repair at 12 months from 
the index surgery. 
Goutallier 
classification of 
rotator cuff (based 
on MRI 
assessment) at 
12-months post-
surgery. 
N/A 
Secondary 
Objective 
#23 
To determine if participants who 
undergo arthroscopic surgical 
treatment of high-grade (>50%) 
partial-thickness rotator cuff tears 
using REGENETEN have a 
statistically lower fatty infiltration of 
the rotator cuff (based on MRI 
assessment) compared to 
participants who had standard 
surgical repair at 24 months from 
the index surgery. 
Goutallier 
classification of 
rotator cuff (based 
on MRI 
assessment) at 
24-months post-
surgery. 
N/A 
Secondary 
Objective 
#24 
To determine if participants who 
undergo arthroscopic surgical 
treatment of high-grade (>50%) 
partial-thickness rotator cuff tears 
using REGENETEN have 
statistically improved rotator cuff 
integrity (based on MRI 
assessment) compared to 
participants who had standard 
surgical repair techniques at 12 
months from the index surgery. 
Sugaya score 
(based on MRI 
assessment) at 
12-months post-
surgery. 
N/A 

 
Study Protocol
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Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
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intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Item 
Objective 
Outcome 
Measure 
Statistical Test 
Secondary 
Objective 
#25 
To determine if participants who 
undergo arthroscopic surgical 
treatment of high-grade (>50%) 
partial-thickness rotator cuff tears 
using REGENETEN have 
statistically improved rotator cuff 
integrity (based on MRI 
assessment) compared to 
participants who had standard 
surgical repair techniques at 24 
months from the index surgery. 
Sugaya score 
(based on MRI 
assessment) at 
24-months post-
surgery. 
N/A 
Secondary 
Objective 
#26 
To determine if participants who 
undergo arthroscopic surgical 
treatment of high-grade (>50%) 
partial-thickness rotator cuff tears 
using REGENETEN have a lower 
incidence of revision surgeries 
(index shoulder; all causes) 
compared to participants who had 
standard surgical repair over the 
24 months from the index 
shoulder surgery. 
 
 
Incidence of 
revision surgery 
(index shoulder; all 
cause) within 24m 
of the index 
surgery. 
Logistic regression 
analysis adjusting for 
differences in baseline 
characteristics.  
 
Secondary Economic Objectives/Outcomes 
Item 
Objective 
Outcome 
Measure 
Statistical Test 
Secondary 
Objective 
#27 
To determine if arthroscopic 
surgical treatment of high-grade 
(>50%) partial-thickness rotator 
cuff tears using REGENETEN 
results in lower aggregate heath 
care costs over 12 months post-
index surgery than standard 
surgical repair. 
Costs based on 
healthcare 
resource utilization 
as listed below. 
N/A 
Secondary 
Objective 
#28 
To determine if arthroscopic 
surgical treatment of high-grade 
(>50%) partial-thickness rotator 
cuff tears using REGENETEN 
requires less operating room time 
than standard surgical repair. 
Operating room 
time as measured 
from time of first 
incision to wound 
closure measured 
in minutes. 
Generalized linear 
regression, adjusting 
for differences in 
baseline 
characteristics. 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
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intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Item 
Objective 
Outcome 
Measure 
Statistical Test 
Secondary 
Objective 
#29 
To determine if participants who 
undergo arthroscopic surgical 
treatment of high-grade (>50%) 
partial-thickness rotator cuff tears 
using REGENETEN receive fewer 
shoulder steroid injections 
compared to standard surgical 
repair over the 12 months from the 
index shoulder surgery.  
Number of steroid 
injections in the 
shoulder from 
post-surgery to 12-
months post-
surgery. 
N/A 
Secondary 
Objective 
#30 
To determine if participants who 
undergo arthroscopic surgical 
treatment of high-grade (>50%) 
partial-thickness rotator cuff tears 
using REGENETEN have fewer 
index shoulder-related 
unscheduled clinic visits 
compared to standard surgical 
repair over the 12 months from the 
index shoulder surgery. 
Number of index 
shoulder-related 
unscheduled clinic 
visits within 12 
months of index 
surgery. 
N/A 
Secondary 
Objective 
#31 
To determine if participants who 
undergo arthroscopic surgical 
treatment of high-grade (>50%) 
partial-thickness rotator cuff tears 
using REGENETEN have fewer 
for-cause imaging procedures 
compared to standard surgical 
repair over the 12 months from the 
index shoulder surgery. 
Number of for 
cause imaging 
procedures (e.g. 
MRI, ultrasound) 
within 12 months 
of index surgery. 
N/A 
Secondary 
Objective 
#32 
To determine if participants who 
undergo arthroscopic surgical 
treatment of high-grade (>50%) 
partial-thickness rotator cuff tears 
using REGENETEN undergo less 
physiotherapy compared to 
standard surgical repair over the 
12 months from the index 
shoulder surgery. 
Number of 
physiotherapy 
sessions within the 
12 months of the 
index surgery 
N/A 
10.4.3 Analysis of Other Endpoint(s) 
Not applicable. 

 
Study Protocol
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Prospective multi-center study comparing REGENETEN in 
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intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
10.5 
SAFETY ANALYSES 
Frequency of the treatment-emergent AEs will be calculated for: each body system, by preferred 
terminology, and overall; by treatment cohort, for the number of participants and percentage of 
participants reporting the event. The seriousness, severity of the adverse events and the 
relationship to the investigational product will be summarized for: each body system, preferred 
terminology, and overall; by treatment group. Serious adverse events (SAE) (including deaths) 
will be listed for individual events. 
 
The Sponsor will prepare narratives for all deaths, non-fatal serious adverse events, and 
participants withdrawn due to adverse events 
 
The number and percentage of participants reporting treatment-emergent adverse events split by 
treatment separately by system organ class, and preferred term will be summarized by: 
1. Their relationship with the investigational device (not related or related).  If the 
relationship is missing, the adverse event will be assumed to be treatment-related and a 
footnote will be added to the table. If a participant experiences more than one preferred 
term within a system organ class, then the relationship at the system organ class level for 
that subject will be reported according to their most related relationship for each preferred 
term. 
2. The severity of the adverse event (mild, moderate or severe). 
3. Whether or not the adverse event is serious 
4. The adverse event outcome. 
5. Whether or not the adverse event is expected or unexpected. 
10.6 
INTERIM ANALYSES 
A data extract will be completed when the last enrolled participant has completed their three-
month follow-up visit. A report will not accompany this data extract but the findings may be 
presented as possible podium or conference activity.  

Study Protocol
Device
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears
Number: 
REGEN.PUB.2018.09
Version: 3.0, 10SEP2019
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CONFIDENTIAL AND PROPRIETARY
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew.
An interim analysis will be conducted when the last enrolled participant has completed their one-
year follow-up from index surgery. This analysis will include a simplified statistical report and a 
possible peer-reviewed publication. Further details will be provided in the SAP.
SAMPLE SIZE JUSTIFICATION
The sample size calculation was conducted for 80% power and an alpha of 0.05. The minimal 
clinically important difference (MCID) used as the difference to detect for was 11.1 points on the 
American Shoulder and Elbow Surgeons (ASES) score at 3 months following index surgery.1 An 
effect size of 0.56 was used to ensure that the difference in results represented a moderate 
27 The sample size calculations were completed in 
R statistical software (v3.5.0). Based on the calculation conducted, a sample size of 102 (51 per 
arm) was determined. To account for a dropout rate of 15%, the sample size was increased to 
118 (59 per arm).
ADVERSE EVENTS AND DEVICE DEFICIENCIES
12.1
DEFINITIONS
The categories of adverse events are shown in Table 3. The definitions for each of these 
categories are given in the subsequent sections.
Table 3: Categories of Adverse Event
NOT DEVICE-
RELATED
DEVICE- OR PROCEDURE-RELATED
NON-
SERIOUS
ADVERSE EVENT 
(AE)
ADVERSE DEVICE EFFECT 
(ADE)
SERIOUS
SERIOUS ADVERSE 
EVENT 
SERIOUS ADVERSE DEVICE EFFECT
(SADE) (SEE 12.1.3)

 
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partial-thickness tears 
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intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
(SAE)  
ANTICIPATED 
UNANTICIPATED 
ANTICIPATED SERIOUS 
ADVERSE DEVICE EFFECT  
(ASADE)  
UNANTICIPATED SERIOUS 
ADVERSE DEVICE EFFECT  
(USADE)  
 
12.1.1 Adverse Event 
An Adverse Event (AE) is any untoward medical occurrence, unintended disease of untoward 
clinical sign (including abnormal laboratory findings) in participants, users or other persons, 
whether or not causally related to the IP/Ancillary Product.   
 
Note 1: This definition includes events related to the IP, comparator or ancillary products.  
 
Note 2: This definition includes events related to the procedures involved.  
 
Note 3: For users or other persons, this definition is restricted to events related to the IP. 
 
AE is used both to refer to AE which do not meet the definitions of Adverse Device Effects or 
Serious Adverse Events and as an umbrella term referring to adverse events of all classifications. 
An AE can be any unfavorable and unintended sign (for example, an abnormal laboratory finding), 
symptom, or disease. For reporting purposes, emphasis is placed first and foremost on whether 
or not the event constitutes an untoward medical occurrence.    
12.1.2 Adverse Device Effect 
An Adverse Device Effect (ADE) is an adverse event that, in the opinion of the investigator, is 
related to the use of the IP.  
 
Note 1: This definition includes adverse events resulting from insufficient or inadequate 
instructions for use, deployment, implantation, installation or operation, or any malfunction of the 
investigational medical device.  

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
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Version: 3.0, 10SEP2019 
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intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
 
Note 2: This definition includes any event resulting from use error or from intentional misuse of 
the investigational medical device.  
 
Not Related -  An AE is considered to be not related to the use of an IP or the procedure when  
the effect is DEFINITELY UNRELATED or UNLIKELY to have any relationship to 
the use of the IP or the procedure; 
Related        An AE is considered to be related to the use of an IP or the procedure when there  
is a POSSIBLE, PROBABLE, or DEFINITE relationship between the AE and the 
use of the IP or the procedure. 
An ADE is further categorized depending on whether the criteria in section 12.1.3 and 12.1.4 are 
met. 
12.1.3 Serious Adverse Events and Serious Adverse Device Effects  
An AE or ADE is considered a Serious Adverse Event (SAE) or Serious Adverse Device Effects 
(SADE) if, in the view of either the Investigator or the Sponsor, it: 
 
a) led to death, 
 
b) led to serious deterioration in the health of the participant, that either resulted in 
 
1) a life-threatening illness or injury, or 
 
2) a permanent impairment of a body structure or a body function, or 
 
3) in-patient or prolonged hospitalization, or 
 
4) medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function, 
 
c) led to fetal distress, fetal death or a congenital abnormality or birth defect 
 
Note: Planned hospitalization for a pre-existing condition, or a procedure required by the study 
protocol, without serious deterioration in health, is not considered a serious adverse event. 
 

 
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Prospective multi-center study comparing REGENETEN in 
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intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious such as important medical events that might not be immediately life-
threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed in the definition above. Examples 
of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. 
12.1.4 Anticipated/Unanticipated Serious Adverse Device Effect 
An Unanticipated Serious Adverse Device Effect (USADE) is a serious ADE which by its nature, 
incidence, severity or outcome has not been identified in the current version of the risk analysis 
report.  
 
Note: Anticipated serious adverse device effect (ASADE) is an effect which by its nature, 
incidence, severity or outcome has been identified in the risk analysis report.  There are no 
ASADE in this study.  
12.1.5 Severity  
The severity of every AE will be assessed by the PI or medically qualified site staff to whom the 
responsibility has been delegated and documented on the delegation of authority log. AE should 
be classified as mild, moderate, or severe, regardless of whether or not the AE are considered to 
be serious or non-serious. The classification should be based on the following definitions: 
 
Mild -  
An event is mild if the participant is aware of, but can easily tolerate the  
sign or symptom; 
Moderate - 
An event is moderate if the sign or symptom results in discomfort significant  
enough to cause interference with the participant
 
Severe -   
An event is severe if the sign or symptom is incapacitating and results in the 
participant
 

 
Study Protocol
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Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
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intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
12.1.6 Device Deficiency 
A Device Deficiency (DD) is an inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety or performance. DD includes malfunctions, use errors and inadequate 
labeling.  
12.2 
AE CODING DICTIONARY 
Adverse events will be coded by the Sponsor for preferred terminologies, and grouped by system 
organ class, using Medical Dictionary for Regulatory Activities (MedDRA). 
12.3 
REPORTING PROCEDURES 
AE of any kind and DD will be recorded in the applicable CRF and source notes. The Investigator 
will evaluate all AE for relationship to the device and procedure, if applicable, seriousness, and 
severity. The following timescales should be followed for the AE/DD information to be 
submitted/entered into the CRF and reported to the Sponsor via the REDCap Cloud EDC system 
(see Figures 3 and 4): 
 
ADE and DD  without unreasonable delay 
 
SAE, SADE and DD with potential to cause SADE  immediately (i.e. within 24 hours of 
the Investigator being informed about the event) 
 
For ADE and DD, details of the product/procedure related to the event will be included and where 
applicable, pictures taken of the device. The deficient product should be retained for return to 
unless it is contaminated (e.g., used dressings must not be retained). Updates to submitted 
information will be recorded in the CRF according to the timescales above. 
 
All adverse events will be reviewed by a medically qualified person appointed by the Sponsor to 
determine which, if any, meet criteria for expedited reporting to the regulatory authorities.  
 
The investigator will inform the IRB of adverse events according to the IRB requirements.  

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
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Version: 3.0, 10SEP2019 
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intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Depending on the nature of the adverse event, S&N may request copies of the participant
medical records, imaging, operative notes, as well as results of any relevant laboratory tests 
performed or other documentation related to the AE. If the participant was hospitalized, a copy of 
the discharge summary may be requested by S&N and should be forwarded as soon as it 
becomes available. In certain cases, S&N also may request a letter from the Investigator that 
summarizes the events related to the case.  

Study Protocol
Device
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears
Number: 
REGEN.PUB.2018.09
Version: 3.0, 10SEP2019
Page: Page 53 of 105
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intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew.
Figure 3: Evaluation and Reporting of AE

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
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intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Figure 4: Evaluation and Reporting of DD 
 
 

Study Protocol
Device
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears
Number: 
REGEN.PUB.2018.09
Version: 3.0, 10SEP2019
Page: Page 55 of 105
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intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew.
12.4
FOLLOW-UP OF PARTICIPANTS WITH ADVERSE EVENTS
For participants who are experiencing ongoing unresolved AE at the time of their study completion 
or early discontinuation from the study, it is recommended that the Investigator schedule an 
appropriate follow-up visit to determine the outcome of the event. 
Any additional data must be documented and available to the Sponsor who will determine whether 
the data need to be documented within the CRF/Clinical Study Report.
12.4.1 Ongoing Adverse Events at Study Discontinuation
Adverse events which are related to a study procedure or REGENETEN Implant system and are 
ongoing at end of 
participation: The event should be followed until it is either resolved 
or until the event has become chronic and is not expected to further improve based on 
Investig
Adverse events which are not related to a study procedure or REGENETEN Implant system and 
are ongoing at end of 
participation should be followed for 30 days after 
discontinuation or if the AE is resolved, whichever is sooner.
At the time of data analysis (e.g. interim or final), an evaluation of ongoing events should take 
place and be listed as ongoing in the safety table.
INVESTIGATOR OBLIGATIONS
The Principal Investigator (PI) will comply with the commitments outlined in the Clinical Trial 
Agreement (CTA) and with Good Clinical Practice (GCP), as outlined in Appendix 21.2 of this 
protocol.

Study Protocol
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Prospective multi-center study comparing REGENETEN in 
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intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew.
SPONSOR AND MONITOR RESPONSIBILITIES
The CRO will designate a monitor to conduct the appropriate site visits at the appropriate intervals. 
The clinical investigation will be monitored to ensure that: the rights and wellbeing of the 
participants are protected; the reported data are accurate, complete, and verifiable from the 
source documents; and the study is conducted in compliance with the currently approved protocol 
and amendment(s), if applicable, and with GCP.
14.1
CONTRACT RESEARCH ORGANIZATION 
The Sponsor has engaged a Contract Research Organization (CRO) to assist in conducting this 
PROTOCOL AMENDMENTS
Amendments should be made only in exceptional cases once the study has started. Protocol 
amendments must be approved by the protocol signatories prior to submission to the IRB. 
Protocol amendments need to be approved by the IRB prior to implementation at the site.
CONFIDENTIALITY OF THE STUDY
The confidentiality of this study and associated documents is governed by the terms of the Clinical 
Trial Agreement (CTA).
STATEMENTS OF COMPLIANCE
This clinical study will be performed in compliance with the ethical principles of the Declaration of 
Helsinki; ISO 14155: Clinical investigation of medical devices
Good Clinical Practice; ICH-E6.
This clinical study will not commence until the required approval/favorable opinion from the IRB
has been obtained. Any additional requirements imposed by the IRB will be followed. 

Study Protocol
Device
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears
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intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew.
Public/Products Liability Insurance has been purchased by Smith & Nephew plc. Worldwide and 
incorporates coverage for personal injury in respect of clinical studies. 
END OF STUDY
The end of the study is defined as the date of the last patient, last visit.  No additional care for 
participants will be provided under the protocol once their participation in the study has ended. 
Should circumstances arise which require the termination of the entire study prior to its planned 
completion (e.g. safety concerns) or circumstances arise which mean the end of the participation 
of an individual site (e.g. departure of Investigator, non-compliance), then this will be undertaken 
according to the Standard Operating Procedures (SOPs) of the Sponsor and/or the CRO. 
PUBLICATION POLICY
19.1
PUBLICATION OF STUDY DATA
The preparation and submission for publication of manuscripts containing the study results shall 
be in accordance with a process determined by the CTAs between the study Sponsor and 
participating institutions. The publication or presentation of any study results shall comply with all 
applicable privacy laws, including, but not limited to the Health Insurance Portability and 
Accountability Act of 1996.
19.2
DATA SHARING
Smith & Nephew is committed to upholding the highest ethical and legal standards involved in 
conducting clinical trials. Smith & Nephew therefore supports the data sharing requirements of 
The International Committee of Medical Journal Editors (ICMJE) published on the 6th June 
2017.28 In accordance, Smith & Nephew will consider requests to share individual (deidentified) 
participant data that underlie the results of any interventional clinical trial, as presented from the 
1st July 2018 within an ICMJE associated journal. Requests made by researchers who provide a 
methodologically sound proposal will be considered. Requests may include data that underlie 

 
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results presented in text, tables, figures and appendices, together with data dictionaries. 
Availability of these data will begin 9 months and end 36 months after article publication. Data 
supplied may only be used by the researcher(s) named in the approved research proposal for the 
purposes of achieving the aims of the analyses specified therein. All proposals should be directed 
to datasharing.gcs@smith-nephew.com. To gain access, data requestors will need to sign a data 
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Study Protocol
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Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears
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Version: 3.0, 10SEP2019
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REFERENCES
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arthroscopic rotator cuff repair. J Shoulder Elbow Surg. 2019 May;28(5):939-948.
2 Armstron AD, Athwal GS. OrthoInfo: rotator cuff tears [Internet]. Rosemont (IL): American 
Academy of Orthopaedic Surgeons. 2017 Mar [cited 2018 Jun 17]. Available from: 
https://orthoinfo.aaos.org/en/diseases--conditions/rotator-cuff-tears/ 
3 Keener JD, Galatz LM, Teefey SA, et al. A prospective evaluation of survivorship of 
asymptomatic degenerative rotator cuff tears. J Bone Joint Surg Am. 2015;97(2):89-98.
4 Bupa UK. Rotator cuff injury [Internet]. London (UK): Bupa. [cited 17 May 18]. Available from: 
https://www.bupa.co.uk/health-information/directory/r/rotator-cuff-injury
5 Lin JC, Weintraub N, Aragaki DR. Nonsurgical treatment for rotator cuff injury in the elderly. J 
Am Med Dir Assoc. 2008;9(9):626-32.
6 Matthewson G, Beach CJ, Nelson AA, et al. Partial thickness rotator cuff tears: current concepts. 
Adv Orthop. 2015.
7 Yamanaka K, Matsumoto T. The joint side tear of the rotator cuff. A followup study by 
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9 Budoff JE, Nirschl RP, Guidi EJ. Debridement of partial-thickness tears of the rotator cuff without 
acromioplasty. Long-term follow-up and review of the literature. J Bone Joint Surg Am. 
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10 Strauss EJ, Salata MJ, Kercher J, et al. Multimedia article. The arthroscopic management of 
partial-thickness rotator cuff tears: a systematic review of the literature. Arthroscopy. 
2011;27(4):568-80.

 
Study Protocol
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Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 60 of 105 
 
 
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intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
11 Bishop J, Klepps S, Lo IK, et al. Cuff integrity after arthroscopic versus open rotator cuff repair: 
a prospective study. J Shoulder Elbow Surg. 2006;15(3):290-9. 
12 Henry P, Wasserstein D, Park S, et al. Arthroscopic repair for chronic massive rotator cuff tears: 
a systematic review. Arthroscopy. 2015;31(12):2472-80. 
13 Heuberer PR, Smolen D, Pauzenberger L, et al. Longitudinal Long-term Magnetic Resonance 
Imaging and Clinical Follow-up After Single-Row Arthroscopic Rotator Cuff Repair: Clinical 
Superiority of Structural Tendon Integrity. Am J Sports Med. 2017;45(6):1283-1288. 
14 McElvany MD, McGoldrick E, Gee AO, et al. Rotator cuff repair: published evidence on factors 
associated with repair integrity and clinical outcome. Am J Sports Med. 2015;43(2):491-500. 
15 Geary MB, Elfar JC. Rotator cuff tears in the elderly patients. Geriatr Orthop Surg Rehabil. 
2015;6(3):220-4. 
16 Van der Molen HF, Foresti C, Daams JG, et al. Work-related risk factors for specific shoulder 
disorders: a systematic review and meta-analysis. Occup Environ Med. 2017;74(10):745-755 
17 Chen Q. Two-dimensional finite element proof-of-concept modelling on rotator cuff tear scaffold 
efficacy. Technical Report from the Material and Structural Testing Core [Internet]. Rochester 
(MN): Mayo Clinic. [cited 25 Sep 17]. Available from: http://www.rotationmedical.com/wp-
content/uploads/2015/05/fea-white-paper-4-9-15.pdf  
18 Schlegel TF, Abrams JS, Bushnell BD, et al. Radiologic and clinical evaluation of a 
bioabsorbable collagen implant to treat partial-thickness tears: a prospective multicenter study. J 
Shoulder Elbow Surg. 2018;27(2):242-251. 
19 Richards RR, An KN, Bigliani LU, et al. A standardized method for the assessment of shoulder 
function. J Shoulder Elbow Surg. 1994 Nov;3(6):347-52. 
20 Williams GN, Gangel TJ, Arciero RA, et al. Comparison of the Single Assessment Numeric 
Evaluation method and two shoulder rating scales. Outcomes measures after shoulder surgery. 
Am J Sports Med. 1999 Mar-Apr;27(2):214-21. 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 61 of 105 
 
 
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intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
21 Physiopedia, Constant-Murley Shoulder Outcome Score [Internet]. Drochester (UK). 
Physiopedia. [cited 11Jun2019]. Available from: https://www.physio-pedia.com/Constant-
Murley_Shoulder_Outcome_Score 
22. Razmjou H, Bean A, MacDermid J, et al. Convergent Validity of the Constant-Murley Outcome 
Measure in Patients with Rotator Cuff Disease. Physiother Can. 2008 Apr; 60(1):72-79. 
23 Somerson JS, Hsu JE, Gorbaty JD, et al. Classifications in Brief : Goutallier Clasification of 
Fatty Infiltration of the Rotator Cuff Musculature. Clin Orthop Relat Res. 2016 May;474(5):1328-
1332. 
24 Yoshida M, Collin P, Josseaume T, et al. Post-operative rotator cuff integrity, based on 
 of the shoulder. Knee Surg Sports 
Traumatol Arthrosc. 2018 Jan;26(1):161-168. 
25 Jevsevar DS. Treatment of osteoarthritis of the knee: evidence-based guideline, 2nd edition. J 
Am Acad Orthop Surg. 2013 Sep;21(9):571-576. 
26 Tashjian RZ, Deloach J, Porucznik CA, et al. Minimal clinically important difference (MCID) ad 
patient acceptable symptomatic state (PASS) for visual analog scales (VAS) measuring pain in 
patients treated for rotator cuff disease. J Shoulder Elbow Surg. 2009 Nov;18(6):927-932. 
27 Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed. New York (United 
States): Routledge; 1988. 
28 Taichman DB, Sahni P, Pinborg A. Data Sharing Statements for Clinical Trials: A Requirement 
of the International Committee of Medical Journal Editors. Ann Intern Med. 2017 Jul 4;167(1):63-
55. 

Study Protocol
Device
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears
Number: 
REGEN.PUB.2018.09
Version: 3.0, 10SEP2019
Page: Page 62 of 105
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APPENDICES
21.1
PROTOCOL AMENDMENT
21.1.1 Amendment Overview
21.1.1.1
General Purpose
21.1.1.1.1Protocol Version 2.0
An additional participant-facing questionnaire has been added to assess shoulder stiffness among 
study participants during the first 12 months of the study. The protocol amendment incorporates 
the assessment of shoulder stiffness objectives and endpoints as appropriate.
21.1.1.1.2Protocol Version 3.0
The Constant-Murley score has been added to assess participant-reported and examiner 
assessed shoulder pain and function among study participants over 24 months following index 
surgery in the amended protocol (V3.0). The protocol amendment incorporates the use of the 
Constant-Murley score and the associated objectives and endpoints as appropriate.
The questionnaire used to assess shoulder stiffness among study participants during the first 12 
months of the study has been removed in the amended protocol (V3.0). The associated shoulder 
stiffness objectives and endpoints have also been removed.
Study objectives related to opioid medication use and non-opioid pain medication use over the 
initial 3 months of the study have been added. Protocol V3.0 also includes the addition of a variety 
of MRI-assessed objectives examining the percent filling, tendon thickness, Goutallier 
classification (to classify fatty infiltration) and Sugaya score (to classify rotator cuff integrity). The 
new objectives and their associated endpoints have been incorporated into the protocol as 
appropriate.

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
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Version: 3.0, 10SEP2019 
Page: Page 63 of 105 
 
 
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intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
In addition, V3.0 of the protocol, includes clarity and additional information regarding the steroid 
exclusion, window for weekly and monthly participant diary completion, clarification on the 
standard surgical repair procedure, the inclusion of the interim analysis and revisions to the type 
of analysis that will be conducted for some objectives. The abbreviated physiotherapy guidelines 
have been removed from the protocol and a reference was added to the separate cohort-specific 
guidelines. 
21.1.1.2 
Rationale 
21.1.1.2.1 Protocol Version 2.0 
The addition of new secondary study outcome aimed at assessing shoulder stiffness among study 
participants was added to determine whether the study product provides early benefits related to 
shoulder stiffness. 
21.1.1.2.2 Protocol Version 3.0 
The addition of a new secondary objective (Constant-Murley score) in V3.0 of the study protocol 
aimed at assessing participant-reported and examiner-assessed shoulder pain and function was 
added to determine whether the study products leads to improvements in shoulder pain and 
function both subjectively and objectively. 
 
The assessment of shoulder stiffness and its associated study objectives and endpoints were 
removed in V3.0 after the determination that it was no longer required following the addition of 
the Constant-Murley score. 
 
Additional study objectives related to opioid medication use and non-opioid pain medication use 
were added to determine whether there are early benefits to the use of the study product in the 
mentioned areas. The MRI-assessed objectives were added to determine if there were 
physiological benefits to the use of the study product in participants. 
 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 64 of 105 
 
 
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intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Some additional clarification was added in V3.0 of the protocol regarding the type of steroid use 
that is excluded from the study, the definition of standard surgical repair and participant diary 
completion windows. This will provide study sites with more clarity related to study-related 
processes. 
 
Protocol V3.0 includes a description of the interim analysis that will be completed when the final 
participant has completed their 1-year follow-up. In addition, statistical analysis for various study 
objectives have been revised in order to better analyze the study data. The abbreviated 
physiotherapy guidelines were deleted from the study protocol due to the creation of detailed 
cohort-specific guidelines. 
21.1.1.3 
Effect on Study Status 
21.1.1.3.1  Protocol Version 2.0 
At the time of amendment, there is one participant enrolled in the study. This participant will not 
complete a baseline assessment of shoulder stiffness. The participant will begin completing the 
assessment of shoulder stiffness question once approval is received for this amendment.  The 
impact on data collection is minimal. 
21.1.1.3.2 Protocol Version 3.0 
At the time of amendment to protocol V3.0, there are 27 participants treated in the study. These 
participants will not complete the Constant-Murley Assessment at completed study visits. These 
participants will begin completing the Constant-Murley Assessment once IRB approval is received 
for this amendment and the site has received training. The impact on data collection is not 
substantial. 
 
Removal of the shoulder stiffness questionnaire will have minimal impact on the study. Once IRB 
approval is received for this amendment and the site has received training, participants will no 
longer be required to complete the assessment of shoulder stiffness questionnaire. 
 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 65 of 105 
 
 
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contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Additional study objectives related to opioid medication use and non-opioid pain medication use 
will not impact participants in the study. The data required for the additional objectives was already 
being collected from study participants in previously approved case report forms.   
 
The new objectives based on the assessments of participant MRIs will not impact study 
participants. Study participants are already required to obtain a 12- and 24-month MRI as per the 
previous protocol. These MRIs will be assessed by an independent assessor to obtain data for 
these objectives.  
21.1.2 Amendment Summary 
21.1.2.1 
Revision History 
21.1.2.1.1  Protocol Version 2.0 
Version Date: 12-Dec-2018 
Version Number: 2.0 
21.1.2.1.2 Protocol Version 3.0 
Version Date: 10-Sep-2019 
Version Number: 3.0 
21.1.2.2 
Summary of Revisions 
21.1.2.2.1 Protocol Version 2.0 
The protocol changes encompass the inclusion of the assessment of shoulder stiffness which 
will be completed by participants weekly until 12 weeks post-surgery and then at the 6- and 12- 
month follow-up. The objectives associated with the assessment of shoulder stiffness have 
been added to the protocol in additional to the statistical analysis of this objective. 
 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
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Version: 3.0, 10SEP2019 
Page: Page 66 of 105 
 
 
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contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Section 
 
Current Text  
DD-MMM-YYYY Version # 
 
28-Sep-2018, V 1.0 
Revised Text  
DD-MMM-YYYY Version # 
 
12-Dec-2018, V 2.0 
2.0 
N/A 
stiffness over 12 months following 
Endpoints 
 
added to study schematic 
3.0 
N/A 
Table of Contents updated to 
reflect new sections/page numbers 
5.2 
N/A 
benefits related to 
participant-reported shoulder 
stiffness (over 12 months following 
objective 
8.3.2 
N/A 
Assessment of shoulder 
stiffness over 12 months following 
index sur
endpoint 
9.1.1 
N/A 
Shoulder 
procedures) 
9.1.2 
5. Complete the ASES 
questionnaires and SANE 
questionnaires. 
5. Complete the ASES 
questionnaire, SANE 
questionnaire, and assessment of 
shoulder stiffness. 
9.1.3 
6. Instruct the participant on 
follow-up procedures, including 
completing the weekly ASES 
and SANE questionnaires, 
completing the weekly diary 
and returning for clinical follow-
up at 3 months. 
6. Instruct the participant on follow-
up procedures, including 
completing the weekly ASES and 
SANE questionnaires, weekly 
assessment of shoulder stiffness, 
completing the weekly diary, and 
returning for clinical follow-up at 3 
months. 
9.1.4 
1. Participant will complete the 
ASES questionnaires and 
SANE questionnaires. 
1. Participant will complete the 
ASES questionnaire, SANE 
questionnaire, and assessment of 
shoulder stiffness. 

 
Study Protocol
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Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 67 of 105 
 
 
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intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Section 
 
Current Text  
DD-MMM-YYYY Version # 
 
28-Sep-2018, V 1.0 
Revised Text  
DD-MMM-YYYY Version # 
 
12-Dec-2018, V 2.0 
9.1.5 
1. Complete the ASES 
questionnaires and SANE 
questionnaires. 
1. Complete the ASES 
questionnaire (all visits), SANE 
questionnaire (all visits), and 
assessment of shoulder stiffness 
(3, 6 and 12 month visits only). 
9.2.1 
N/A 
Participant-reported 
Shoulder Stiffness: Stiffness in the 
assessed using the shoulder 
stiffness VAS. The VAS stiffness 
rating will be recorded pre-
operatively, weekly from 1 week to 
3 months post-surgery, and at 6 
and 12 months post-
list of Performance Endpoints 
10.4.2 
N/A 
Added Secondary Objective #7: 
(within 12 months of surgery) of 
arthroscopic treatment of high-
grade (>50%) partial-thickness 
rotator cuff tears using 
REGENETEN on participant-
reported shoulder stiffness 
compared to standard surgical 
 to Table 2 
(Analysis of Secondary Endpoints) 
 
Added Outcome Measure 
associated with secondary 
objective #7: 
shoulder stiffness over 12 months 
post-
 
 
Added Statistical Test associated 
with secondary objective #7: 
adjusting for baseline VAS 
stiffness rating and differences in 

 
Study Protocol
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Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
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Version: 3.0, 10SEP2019 
Page: Page 68 of 105 
 
 
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intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Section 
 
Current Text  
DD-MMM-YYYY Version # 
 
28-Sep-2018, V 1.0 
Revised Text  
DD-MMM-YYYY Version # 
 
12-Dec-2018, V 2.0 
2 
 
Revised numbering of objectives in 
table 2 as required 
 
21.1.2.2.2 Protocol Version 3.0 
Section 
 
Current Text  
DD-MMM-YYYY Version # 
 
12-Dec-2018, V 2.0 
Revised Text  
DD-MMM-YYYY Version # 
 
10-Sep-2019, V 3.0 
All 
N/A 
throughout protocol. 
 
2.0  Statistical 
Rationale 
Superiority hypothesis for 
American Shoulder and Elbow 
Surgeons (ASES) score at 3 
months following index surgery 
using a minimal clinically 
important difference (MCID) of 
121 and a drop-out rate of 
15%.  
Superiority hypothesis for 
American Shoulder and Elbow 
Surgeons (ASES) score at 3 
months following index surgery 
using a minimal clinically important 
difference (MCID) of 11.11 and a 
drop-out rate of 15%.  
2.0  Exclusion 
Criteria 
enroll
 
Systemic steroid use (oral, IV) or 
locally injected at the surgical site 
within 1 month of enrollment  
 
2.0  Secondary 
Endpoints 
N/A 
Added:  
 
-Murley score at 3, 6, 
12 and 24 months following 
 
 
the index shoulder over 3 
months 
 
 
-opioid 
prescription medication use to 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
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Version: 3.0, 10SEP2019 
Page: Page 69 of 105 
 
 
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contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Section 
 
Current Text  
DD-MMM-YYYY Version # 
 
12-Dec-2018, V 2.0 
Revised Text  
DD-MMM-YYYY Version # 
 
10-Sep-2019, V 3.0 
treat the index shoulder over 3 
 
 
MRI assessment of percent 
filling at 12 months following 
 
 
MRI assessment of percent 
filling at 24 months following 
 
 
at 12 months following index 
 
 
at 24 months following index 
 
 
rotator cuff at 12 months 
 
 
rotator cuff at 24 months 
 
 
12 months following index 
 
 
24 months following index 
 
 
Removed: 
 
Assessment of shoulder 
stiffness over 12 months 
following index surgery  
 
2.0  Secondary 
Endpoints 
- Time to return to activities of 
daily living (ADLs) 
 Return to work by work 
type (sedentary; 
laborer) 
 Return to driving 
 Return to 
- Time to return to work by work 
type (sedentary; laborer) 
 - Time to return to driving 
 - 
 

 
Study Protocol
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Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
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Version: 3.0, 10SEP2019 
Page: Page 70 of 105 
 
 
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contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Section 
 
Current Text  
DD-MMM-YYYY Version # 
 
12-Dec-2018, V 2.0 
Revised Text  
DD-MMM-YYYY Version # 
 
10-Sep-2019, V 3.0 
2.0  Study 
Schematic 
N/A 
-
study schematic. 
 
removed from study schematic. 
 
Clarification added to windows for 
participant diary completion: 
weekly (7±3 days) through 3 month 
follow-up and monthly (30±7 days) 
thereafter until 12 months post-
 
 
Collection of pre-op MRI added to 
study schematic. 
 
Additional information regarding 
-op 
care MRI and will not follow the 
study MRI Image Acquisition 
Protocol which is used for the 12 
and 24 month MRIs. The pre-op 
MRI must occur within 6 months of 
enrollment into this study. All MRIs 
will be submitted to the imaging 
vendor per the Image Transfer 
 
3.0 
N/A 
Table of Contents updated to 
reflect new sections/page numbers 
List of 
Abbreviations 
N/A 
 Defined Daily 
 
4.1 
Patients with rotator cuff 
disease usually report pain and 
weakness in the arm, leading 
to impaired function and 
mobility, and are typically 
recommended conservative 
Patients with atraumatic rotator 
cuff disease usually report pain 
and weakness in the arm, leading 
to impaired function and mobility, 
and are typically recommended 
conservative treatments to manage 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 71 of 105 
 
 
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intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Section 
 
Current Text  
DD-MMM-YYYY Version # 
 
12-Dec-2018, V 2.0 
Revised Text  
DD-MMM-YYYY Version # 
 
10-Sep-2019, V 3.0 
treatments to manage 
symptoms in the first instance. 
However, such conservative 
treatments are often ineffective; 
surgical treatment may 
therefore be subsequently 
advised to remove damaged 
tissue or repair the damage to 
the rotator cuff. However, 
further damage and 
progression may be seen even 
after conventional surgical 
treatments; re-tear rates within 
~4 years are reported to be as 
 
 
Bioinductive Implant is a 
bioabsorbable device that 
provides a layer of collagen 
over injured tendons. The 
induction of this layer of new 
tendinous tissue may reduce 
micro-strains within the tendon, 
resulting in an optimized 
mechanical environment for 
tendon healing. Use of 
REGENETEN in the treatment 
of high-grade partial-thickness 
tears in lieu of converting the 
partial tear to a full-thickness 
tear and surgically reattaching 
the tendon to bone may 
accelerate patient recovery and 
shoulder mobility while 
reducing post-operative pain.  
symptoms in the first instance. 
However, such conservative 
treatments may be ineffective; 
surgical treatment may therefore 
be subsequently advised to 
remove damaged tissue or repair 
the rotator cuff. Tear progression 
may continue after conventional 
surgical intervention with re-tear 
rates as 79% for massive tears.  
 
collagen implant that provides a 
layer of collagen over injured 
tendons. The induction of this layer 
of new tendinous tissue may 
reduce micro-strains within the 
tendon, resulting in an optimized 
mechanical environment for tendon 
healing. Use of REGENETEN in 
the treatment of high-grade partial-
thickness tears in lieu of 
completion of tear and repair, 
which may accelerate patient 
recovery and shoulder mobility 
while reducing post-operative 
pain.  
5.2 
N/A 
Added Secondary Objectives: 
 
-reported 
and examiner-assessed 

 
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Section 
 
Current Text  
DD-MMM-YYYY Version # 
 
12-Dec-2018, V 2.0 
Revised Text  
DD-MMM-YYYY Version # 
 
10-Sep-2019, V 3.0 
shoulder pain and function 
(over 24 months following index 
 
 
the index shoulder (over initial 3 
months following index 
 
 
-opioid 
prescription medication use to 
treat the index shoulder (over 
initial 3 months following index 
 
 
Increased percent filling of 
rotator cuff (at 12 months 
following index surgery)  
 
Increased percent filling of 
rotator cuff (at 24 months 
following index surgery)  
 
Improvements in rotator cuff 
tendon thickness (at 12 months 
following surgery)  
 
Improvements in rotator cuff 
tendon thickness (at 24 months 
following surgery)  
 
Lower fatty infiltration of the 
rotator cuff (at 12 months 
following surgery)  
 
Lower fatty infiltration of the 
rotator cuff (at 24 months 
following surgery)  
 
Improved rotator cuff integrity 
(at 12 months following 
surgery)   
 
Improved rotator cuff integrity 
(at 24 months following 
surgery)  
 
Removed secondary objective: 

 
Study Protocol
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Section 
 
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12-Dec-2018, V 2.0 
Revised Text  
DD-MMM-YYYY Version # 
 
10-Sep-2019, V 3.0 
 
reported shoulder stiffness 
(over 12 months following index 
 
 
 
5.2 
13. Earlier return to activities of 
daily living (ADLs) 
 Return to work by work 
type (sedentary; 
laborer) 
 Return to driving 
 Return to sports 
Separated sub-objectives related 
to return to activities of daily living 
(return to work, driving, and sports) 
into separate objectives to align 
with numbering of objectives and 
endpoints through-out protocol. 
 
13. Earlier return to work by work 
type (sedentary; laborer) 
14. Earlier return to driving 
15. Earlier return to sports 
6.1 
Bioinductive implant is a 
bioabsorbable implant device 
that provides a layer of 
 
 
Bioinductive Implant system 
(Figure 1) is comprised of 
disposable instruments, a 
bioabsorbable scaffold, and 
anchors to secure the scaffold 
to the underlying tendon and 
bone. 
 
The Bioinductive Implant  
consists of a resorbable type I 
collagen matrix derived from 
bovine Achilles tendon. It is 
contraindicated for use in 
patients with a history of 
hypersensitivity to bovine-
The REGENETEN Implant is a 
collagen implant that provides a 
layer of collagen over injured 
tendons  
 
 
The REGENETEN Implant system 
(Figure 1) is comprised of 
disposable instruments, a 
resorbable collagen implant,  and 
anchors to secure the scaffold to 
the underlying tendon and bone.  
 
 
 
resorbable type I collagen matrix 
derived from bovine Achilles 
tendon. It is contraindicated for use 
in patients with a history of 
hypersensitivity to bovine-derived 
materials. The device is designed 

 
Study Protocol
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derived materials. The device 
is designed to completely 
resorb  within six to 12 
months.  
 
 
The bone anchors are made 
from polyetheretherketone 
(PEEK), which is a common 
polymer used for bone anchors 
in orthopedic surgery. The 
bone anchors are intended for 
fixation of soft tissue grafts. 
The bone anchors are not 
bioabsorbable.  
to completely resorb within six to 
 
 
 
 
 
The bone anchors are made from 
polyetheretherketone (PEEK), 
which is a common polymer used 
for bone anchors in orthopedic 
surgery. The bone anchors are 
intended for fixation of soft tissue 
grafts. The bone anchors are not 
 
7.3 
 
Systemic steroid use (oral, IV) 
or locally injected at the surgical 
site within 1 month of enroll
 
8.2  
N/A 
Added clarification regarding 
standard surgical techniques: 
 
techniques of the rotator cuff will 
be defined as either: 
1. Debridement and a 
transtendinous repair, or 
2. Complete takedown and 
 
8.3.2 
N/A 
Added secondary endpoints: 
 
-Murley score at 3, 6, 
12 and 24 months following 
 
 
the index shoulder over 3 
months 
 
 
-opioid 
prescription medication use to 
treat the index shoulder over 3 
 

 
Study Protocol
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Section 
 
Current Text  
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Revised Text  
DD-MMM-YYYY Version # 
 
10-Sep-2019, V 3.0 
 
MRI assessment of percent 
filling at 12 months following 
index surgery  
 
MRI assessment of percent 
filling at 24 months following 
index surgery  
 
Rotator cuff tendon thickness 
at 12 months following index 
surgery  
 
Rotator cuff tendon thickness 
at 24 months following index 
surgery  
 
Goutallier classification of 
rotator cuff at 12 months 
following index surgery  
 
Goutallier classification of 
rotator cuff at 24 months 
following index surgery  
 
Sugaya score of rotator cuff at 
12 months following index 
surgery  
 
Sugaya score of rotator cuff at 
24 months following index 
surgery  
 
Removed secondary endpoint: 
 
stiffness over 12 months 
 
8.3.2 
of daily living (ADLs) 
 Return to work by work 
type (sedentary; 
laborer) 
 Return to driving 
 Return to sports
return to work by work 
type (sedentary; laborer) 
14. Time to return to driving 
 

 
Study Protocol
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Section 
 
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Revised Text  
DD-MMM-YYYY Version # 
 
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9.1.1  Table 1 
N/A 
-
Table 1 (Study procedures) 
 
(Study procedures) 
 
Collection of Pre-Op MRI added to 
Table 1.  
 
Clarification added to windows for 
Participant Diary completion: 
weekly (7±3 days) through 3 month 
follow-up and monthly (30±7 days) 
thereafter until 12 months post-
 
 
Additional information regarding 
-op 
care MRI and will not follow the 
study MRI Image Acquisition 
Protocol which is used for the 12 
and 24 month MRIs. The pre-op 
MRI must occur within 6 months of 
enrollment into this study. All MRIs 
will be submitted to the imaging 
vendor per the Image Transfer 
 
 
9.1.2 
5. Complete the ASES 
questionnaire, SANE 
questionnaire, and assessment 
of shoulder stiffness. 
5. Complete the ASES 
questionnaire, SANE 
questionnaire, and Constant-
Murley assessment. 
9.1.2 
N/A 
6. Obtain copy of standard of care 
MRI of index shoulder, if available. 
Pre-Op MRI must have occurred 

 
Study Protocol
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Section 
 
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Revised Text  
DD-MMM-YYYY Version # 
 
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within 6 months of enrollment into 
this study. 
 
Revised numbering as required 
9.1.3 
6. Instruct the participant on 
follow-up procedures, including 
completing the weekly ASES 
and SANE questionnaires, 
weekly assessment of shoulder 
stiffness, completing the 
weekly diary, and returning for 
clinical follow-up at 3 months. 
6. Instruct the participant on follow-
up procedures, including 
completing the weekly ASES and 
SANE questionnaires, completing 
the weekly diary, and returning for 
clinical follow-up at 3 months. 
9.1.4 
1. Participant will complete the 
ASES questionnaire, SANE 
questionnaire, and assessment 
of shoulder stiffness. 
1. Participant will complete the 
ASES questionnaire and SANE 
questionnaire. 
9.1.5 
1. Complete the ASES 
questionnaire (all visits), SANE 
questionnaire (all visits), and 
assessment of shoulder 
stiffness (3, 6 and 12 month 
visits only). 
Complete the ASES questionnaire 
(all visits), SANE questionnaire (all 
visits), and Constant-Murley 
assessment (3, 6, 12 and 24 
month visits only). 
9.1.6 
Participants in each cohort 
(i.e. REGENETEN and 
standard surgical repair) will be 
provided with cohort-specific 
Physiotherapy Guidelines.  
Participants will be required to 
adhere strictly to the 
Physiotherapy Guidelines. 
Study personnel will remind 
participants of the importance 
of compliance, and the 
completion of physiotherapy 
sessions will be documented in 
the participant diary. 
 
Participants in the standard 
surgical repair cohort will follow 
Participants in each cohort (i.e. 
REGENETEN and standard 
surgical repair) will be provided 
with cohort-specific Physiotherapy 
Guidelines.  Participants will be 
required to adhere strictly to the 
Physiotherapy Guidelines. Study 
personnel will remind participants 
of the importance of compliance, 
and the completion of 
physiotherapy sessions will be 
documented in the participant 
diary. Refer to the cohort-specific 
Physiotherapy Guidelines for 
details.  
 

 
Study Protocol
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Prospective multi-center study comparing REGENETEN in 
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partial-thickness tears 
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Section 
 
Current Text  
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Revised Text  
DD-MMM-YYYY Version # 
 
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standard of care physiotherapy 
guidelines as recommended by 
the surgeon to include the 
following: 
 shoulder immobilization up 
to 6 weeks; may be removed 
for therapy 
 passive range of motion 
(PROM) within the first 1-6 
weeks 
 active assisted range of 
motion (AAROM) beginning at 
4 weeks or later 
 transition to active range of 
motion (AROM) beginning at 8 
weeks or later 
 resistance/strengthening 
beginning at 12 weeks or later 
 return to sport at 12 weeks 
post-surgery and beyond 
 
Participants in the 
REGENETEN treatment cohort 
will follow physiotherapy 
guidelines that consist of the 
following: 
 shoulder immobilization for 
first 24-48 hours; may be 
removed for exercise 
 4-5 exercise sessions 
(pendulum, passive forward 
elevation, supine external 
rotation and shoulder shrugs) 
per day for first 5-7 days prior 
to physical therapy 
 frequent application of ice; 
20 minutes at a time, 4-5 times 
per day for 6 weeks post-
surgery 

 
Study Protocol
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partial-thickness tears 
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Section 
 
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DD-MMM-YYYY Version # 
 
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 start using index arm for 
activities of daily living between 
1-6 weeks post-surgery 
 PROM, AAROM, and 
AROM activities within 1-6 
weeks post-surgery 
 isometric and Isotonic 
exercises within 1-6 weeks 
post-surgery 
 active strengthening after 6 
weeks post-surgery 
 return to sport at 12 weeks 
post-surgery and beyond  
9.1.8 
N/A 
Added new section for further 
clarification regarding MRIs: 
 
 
 
Upper extremity MRIs for study 
participants will be collected pre-
operatively, at 12 months post-
surgery and at 24 months post-
surgery. The pre-operative MRI is 
MRI and will not follow the study 
MRI Image Acquisition Protocol. 
The pre-op MRI must occur within 
6 months of enrollment into this 
study. 
 
Participants will receive an MRI of 
the index shoulder at 12 months 
and 24 months post-surgery per 
the Image Acquisition Protocol.  
The standard of care pre-operative 
MRI and the 12 and 24 month 
MRIs will be submitted to the 
imaging vendor per the Image 
Transfer Protocol. 3T MRIs are 

 
Study Protocol
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Section 
 
Current Text  
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Revised Text  
DD-MMM-YYYY Version # 
 
10-Sep-2019, V 3.0 
strongly preferred for submission, 
wherever available, but are not 
 
9.2.1 
Incidence of Progression to 
Full Thickness Tear:  
Participants will receive a 
standard MRI per the Image 
Acquisition Protocol of the 
index shoulder at 12 months 
and 24 months post-surgery. 
The standard of care pre-
operative MRI and the 12 and 
24 month MRIs will be 
submitted to the imaging 
vendor per the Image Transfer 
Protocol. An independent 
reviewer will assess MRIs for 
evidence of progression to a 
full-thickness tear within 12 
months and 24 months of the 
index surgery.  
Revised 
to Full Thickness Tear:  An 
independent reviewer will assess 
MRIs for evidence of progression 
to a full-thickness tear within 12 
months and 24 months of the index 
surgery. All MRI assessments are 
detailed in the Image Review 
Charter.  
9.2.1 
N/A 
Participant reported 
Shoulder Stiffness  
 
Constant-Murley Score: 
The Constant-Murley Score is a 
validated assessment of the level 
of pain and shoulder functionality 
among participants. The test is 
divided into four subscales: pain, 
activities of daily living, strength 
and range of motion (forward 
elevation, external rotation, 
abduction and internal rotation of 
the shoulder. At the end of the 
assessment, a score is obtained 
out of 100 points where higher 
scores indicate a higher quality of 
shoulder function. The score is 

 
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Section 
 
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obtained through a combination of 
participant-reported and objective 
(examiner-assessed) shoulder 
 
 
Percent Filling of Rotator 
Cuff: An independent reviewer will 
assess MRIs for the percent filling 
of the rotator cuff at 12 months and 
24 months post-surgery. All MRI 
assessments are detailed in the 
Image Review Charter.  
 
Rotator Cuff Tendon 
Thickness: An independent 
reviewer will assess MRIs for the 
rotator cuff tendon thickness at 12 
and 24 months. All MRI 
assessments are detailed in the 
Image Review Charter.  
 
Goutallier Classification: 
The Goutallier classification will be 
used to classify the fatty infiltration 
of the rotator cuff. The Goutallier 
classification ranges from a grade 
of 0 indicating a completely normal 
muscles without any fatty streaks 
to a grade of 4 which indicates that 
more fat than muscle is present.23 
An independent reviewer will 
assess MRIs for the fatty infiltration 
of the rotator cuff at 12 and 24 
months post-surgery. All MRI 
assessments are detailed in the 
Image Review Charter.  
 
Sugaya Score: The 
Sugaya score will be used to 

 
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Section 
 
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12-Dec-2018, V 2.0 
Revised Text  
DD-MMM-YYYY Version # 
 
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measure the rotator cuff integrity. 
The Sugaya score ranges from 
Type I to Type V. Type I indicates 
a repaired cuff that had sufficient 
thickness with homogeneously low 
intensity on the MRI image while 
Type V indicates the presence of a 
major discontinuity on the MRI 
images suggesting a medium or 
large tear. An independent 
reviewer will use the MRI to assess 
rotator cuff integrity at 12 and 24 
months post-surgery. All MRI 
assessments are detailed in the 
Image Review Charter.  
10.1 
conduct the statistical analyses 
for this study, with the 
exception of the economic 
analysis, which will be 
conducted by Smith & 
group. Unless otherwise stated, 
all significance tests and 
hypothesis testing will be two-
sided, performed at the 5% 
significance level. Resulting p-
values will be quoted and 95% 
two-sided confidence intervals 
will be generated where 
appropriate. 
 
Where data summaries are 
specified, categorical and 
ordinal variables will be 
summarized with frequencies 
and percentages. Continuous 
variables will be summarized 
with the following summary 
conduct the statistical analyses for 
this study, with the exception of the 
economic analysis, which will be 
Global Biostatistics group. For the 
primary outcome, the significance 
tests and hypothesis testing will be 
two-sided, performed at the 5% 
significance level. Resulting p-
values will be quoted and 95% 
two-sided confidence intervals will 
be generated where appropriate. 
Unless otherwise stated, point 
estimates (mean differences or 
odds ratios) and 95% confidence 
intervals will be reported 
descriptively for secondary 
outcomes as an exploratory 
assessment.  Select secondary 
outcomes will undergo statistical 
testing as outlined in section 
10.4.2. 
 

 
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Section 
 
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statistics: number of 
observations, means and 
standard deviations, or median 
and interquartile ranges.  All 
analyses will be performed 
using a statistical package 
such as SAS or SPSS  
Where data summaries are 
specified, categorical and ordinal 
variables will be summarized with 
frequencies and percentages. 
Continuous variables will be 
summarized with the following 
summary statistics: number of 
observations, means and standard 
deviations, or median and 
interquartile ranges.  All analyses 
will be performed using a statistical 
package such as SAS or SPSS.  
10.3 
Patient demographics and 
baseline outcome variables will 
be summarized by treatment 
group using descriptive 
summary measures expressed 
as means with standard 
deviations or medians with 
interquartile ranges for 
continuous variables 
depending on the distribution 
and number (percent) for 
categorical and ordinal 
variables. Chi-squared tests 
and t-tests will be used to 
determine if there are 
significant differences in 
baseline characteristics 
between the two cohorts.  
Patient demographics and 
baseline outcome variables will be 
summarized by treatment group 
using descriptive summary 
measures expressed as means 
with standard deviations or 
medians with interquartile ranges 
for continuous variables depending 
on the distribution and number 
(percent) for categorical and 
ordinal variables  
10.4.1  
-way ANOVA will be 
used to compare differences in 
the mean ASES score between 
the REGENETEN cohort and 
the comparison cohort at 3 
months post-treatment. The 
analysis will be adjusted for 
baseline ASES score and for 
differences in baseline 
Multiple linear regression will be 
used to compare differences in the 
mean ASES scores between the 
REGENETEN cohort and the 
comparison cohort at 3 months 
post-treatment.  The significance 
tests and hypothesis testing will be 
two-sided, performed at the 5% 
significance level. Resulting p-

 
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Section 
 
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characteristics between the two 
 
values will be quoted and 95% 
two-sided confidence intervals will 
be generated where appropriate. 
The analysis will be adjusted for 
baseline ASES score and for 
differences in baseline 
characteristics between the two 
cohorts. 
 
The minimal clinically important 
difference (MCID) will be used to 
determine the clinical importance 
of the mean difference between 
treatment groups for the ASES 
score and all other patient-reported 
outcomes (i.e. SANE, Constant-
Murley score). The MCID defines 
the change in the outcome score 
that results in the smallest, 
appreciable clinical improvement. 
The MCID for the ASES is 11.1 
points for patients with rotator cuff 
disease.The criteria for 
determining the clinical importance 
of the mean difference will be as 
follows:  
 If the confidence interval of 
the mean difference is 
completely above the MCID, 
the difference is considered 
 
the mean difference contains 
the MCID, the difference is 
 
 If the confidence interval of 
the mean difference is 
completely below the MCID, 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 85 of 105 
 
 
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intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Section 
 
Current Text  
DD-MMM-YYYY Version # 
 
12-Dec-2018, V 2.0 
Revised Text  
DD-MMM-YYYY Version # 
 
10-Sep-2019, V 3.0 
the difference is considered 
 
 
The assessment of clinical 
importance will be reported along 
with the confidence intervals for 
each outcome.  
10.4.2 
Table 2 summarizes the 
secondary efficacy endpoint(s) 
and summary of planned 
analyses. The statistical tests 
in Table 2 assume that the data 
will be normally distributed.  
The SAP will provide 
alternative approaches should 
the assumption of normality not 
be met.  
Table 2 summarizes the 
secondary efficacy endpoint(s) and 
planned analysis for select 
secondary outcomes. Unless 
otherwise stated, point estimates in 
the form of mean differences or 
odds ratios along with 95% 
confidence intervals will be 
reported descriptively for 
secondary outcomes. 
 
An exploratory assessment using 
the MCID will be done for select 
secondary outcomes. The MCID 
will be used to explore the clinical 
importance of the mean difference 
between treatment groups for all 
patient-reported outcomes (i.e. 
ASES, SANE, and Constant-
Murley score). The MCID used for 
outcomes related to the ASES 
score, SANE score and Constant-
Murley score will be 11.1 points, 
29.4 points, and 5.5 points, 
respectively. For outcomes 
involving the ASES-VAS pain 
score, the MCID used will be 1.37 
cm.  
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
Statistical Test for Secondary 
linear regression adjusting for 
baseline ASES score and 
Statistical Test for Secondary 
regression adjusting for baseline 
ASES score and differences in 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 86 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
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intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Section 
 
Current Text  
DD-MMM-YYYY Version # 
 
12-Dec-2018, V 2.0 
Revised Text  
DD-MMM-YYYY Version # 
 
10-Sep-2019, V 3.0 
differences in baseline 
 
baseline characteristics. The mean 
ASES scores will be compared 
using an MCID of 11.1 points.  
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
Statistical Test for Secondary 
linear regression adjusting for 
baseline SANE score and 
differences in baseline 
 
Statistical Test for Secondary 
regression adjusting for baseline 
SANE score and differences in 
baseline characteristics. The mean 
SANE scores will be compared 
 
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
Statistical Test for Secondary 
linear regression adjusting for 
baseline VAS pain score and 
differences in baseline 
 
Statistical Test for Secondary 
regression adjusting for baseline 
VAS pain score and differences in 
baseline characteristics. The mean 
ASES-VAS pain score will be 
compared using an MCID of 1.37 
 
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
Statistical Test for Secondary 
neralized 
linear regression adjusting for 
baseline ASES score and 
differences in baseline 
 
Statistical Test for Secondary 
regression adjusting for baseline 
ASES score and differences in 
baseline characteristics. The mean 
ASES scores will be compared 
 
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
Statistical Test for Secondary 
linear regression adjusting for 
baseline SANE score and 
differences in baseline 
 
Statistical Test for Secondary 
regression adjusting for baseline 
SANE score and differences in 
baseline characteristics. The mean 
SANE scores will be compared 
using an MCID of 29.4 
 
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
Statistical Test for Secondary 
linear regression adjusting for 
baseline ASES score and 
differences in baseline 
 
Statistical Test for Secondary 
Objecti
regression adjusting for baseline 
VAS pain score and differences in 
baseline characteristics. The mean 
ASES-VAS pain score will be 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 87 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
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intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Section 
 
Current Text  
DD-MMM-YYYY Version # 
 
12-Dec-2018, V 2.0 
Revised Text  
DD-MMM-YYYY Version # 
 
10-Sep-2019, V 3.0 
compared using an MCID of 1.37 
 
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
N/A 
 
benefits (within 12 months of 
surgery) of arthroscopic surgical 
treatment of high-grade (>50%) 
partial thickness rotator cuff 
tears using REGENETEN on 
participant reported shoulder 
stiffness compared to standard 
 
 Removed associated 
outcome measure  
 Removed associated 
statistical test 
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
N/A 
 
surgical treatment of high-grade 
(>50%) partial-thickness rotator 
cuff tears using REGENETEN 
statistically improved participant-
reported and examiner-assessed 
shoulder pain and function 
compared to standard surgical 
repair techniques over 24 
months from the index shoulder 
 
 Added Outcome Measure 
associated with secondary 
-
Murley Score at 3, 6, 12 
 
 Added Statistical Test 
associated with secondary 
linear regression adjusting 
for baseline Constant-
Murley score and 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 88 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Section 
 
Current Text  
DD-MMM-YYYY Version # 
 
12-Dec-2018, V 2.0 
Revised Text  
DD-MMM-YYYY Version # 
 
10-Sep-2019, V 3.0 
differences in baseline 
characteristics. The mean 
Constant-Murley score will 
be compared using an 
 
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
N/A 
 Added 
To determine if participants who 
undergo arthroscopic surgical 
treatment of high-grade (>50%) 
partial-thickness rotator cuff 
tears using REGENETEN use 
significantly less opioids to treat 
the index shoulder compared to 
standard surgical repair over the 
initial 3 months following index 
 
 Added Outcome Measure 
associated with secondary 
objective #8: 
use from post-surgery to 3-
months post-surgery. 
Defined daily dose (DDD) 
will be used as the 
 
 Added Statistical Test 
associated with secondary 
linear regression adjusting 
for baseline opioid use and 
differences in baseline 
 
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
N/A 
 
To determine if participants who 
undergo arthroscopic surgical 
treatment of high-grade (>50%) 
partial-thickness rotator cuff 
tears using REGENETEN use 
significantly less non-opioid 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 89 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Section 
 
Current Text  
DD-MMM-YYYY Version # 
 
12-Dec-2018, V 2.0 
Revised Text  
DD-MMM-YYYY Version # 
 
10-Sep-2019, V 3.0 
prescription medication to treat 
the index shoulder compared to 
standard surgical repair over the 
initial 3 months following index 
 
 Added Outcome Measure 
associated with secondary 
objective #9: 
-
opioid prescription pain 
medication use from post-
surgery to 3-months post-
surgery. DDD will be used 
as the outcome measure.  
 Added Statistical Test 
associated with secondary 
linear regression adjusting 
for baseline non-opioid 
prescription pain 
medication use and 
differences in baseline 
 
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
 Secondary Objective #8: 
 Outcome Measure: 
use from post-surgery 
to 12-months post-
 
 
way ANOVA adjusting 
for baseline opioid use 
and differences in 
baseline 
 
 Secondary Objective #10: 
 Revised Outcome 
opioid use from post-
surgery to 12-months post-
surgery. DDD will be used 
 
 Revised Statistical Test: 
Generalized linear 
regression adjusting for 
baseline opioid use and 
differences in baseline 
 
10.4.2  Table 2 
(Analysis of 
 Secondary Objective #9: 
 Outcome Measure: 
-
 Secondary Objective #11: 
 Revised Outcome 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 90 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Section 
 
Current Text  
DD-MMM-YYYY Version # 
 
12-Dec-2018, V 2.0 
Revised Text  
DD-MMM-YYYY Version # 
 
10-Sep-2019, V 3.0 
Secondary 
Endpoints) 
opioid prescription pain 
medication use from 
post-surgery to 12-
months post-
 
 
way ANOVA adjusting 
for baseline non-opioid 
prescription pain 
medication use and 
differences in baseline 
 
 
non-opioid prescription pain 
medication use from post-
surgery to 12-months post-
surgery. DDD will be used 
 
 Revised Statistical Test: 
regression adjusting for 
baseline non-opioid 
prescription pain 
medication use and 
differences in baseline 
 
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
 Secondary Objective #10: 
 
regression analysis, 
adjusting for differences 
in baseline 
 
 
 Secondary Objective #12: 
 Removed Statistical Test  
 
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
 Secondary Objective #11: 
 
way ANOVA, adjusting 
for type of occupation 
and for differences in 
baseline 
character
 
 
 Secondary Objective #13: 
 Revised Statistical Test: 
Generalized linear 
regression, adjusting for 
type of occupation and for 
differences in baseline 
 
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
 Secondary Objective #12: 
 
way ANOVA, adjusting 
for differences in 
baseline 
 
 
 Secondary Objective #14: 
 Removed Statistical Test  
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
 Secondary Objective #13: 
 
way ANOVA, adjusting 
for baseline level of 
 Secondary Objective #15: 
 Revised Statistical Test: 
Generalized linear regression, 
adjusting for baseline level of 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 91 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Section 
 
Current Text  
DD-MMM-YYYY Version # 
 
12-Dec-2018, V 2.0 
Revised Text  
DD-MMM-YYYY Version # 
 
10-Sep-2019, V 3.0 
sporting activity and 
differences in baseline 
 
 
sporting activity and differences 
in 
 
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
 Secondary Objective #14: 
 
regression analysis 
adjusting for baseline 
opioid use and for 
differences in baseline 
 
 
 Secondary Objective #16: 
 Removed Statistical Test 
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
 Secondary Objective #15: 
 
regression analysis 
adjusting for differences 
in baseline 
 
 
 Secondary Objective #17: 
 Removed Statistical Test 
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
N/A 
 
#18: To determine if participants 
who undergo arthroscopic 
surgical treatment of high-grade 
(>50%) partial-thickness rotator 
cuff tears using REGENETEN 
have increased percent filling of 
the rotator cuff (based on MRI 
assessment) compared to 
participants who had standard 
surgical repair at 12 months from 
 
 Added Outcome Measure 
associated with secondary 
Percent 
filling (based on MRI 
assessment) at 12-months 
post-
 
10.4.2  Table 2 
(Analysis of 
N/A 
 
#19: To determine if participants 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 92 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Section 
 
Current Text  
DD-MMM-YYYY Version # 
 
12-Dec-2018, V 2.0 
Revised Text  
DD-MMM-YYYY Version # 
 
10-Sep-2019, V 3.0 
Secondary 
Endpoints) 
who undergo arthroscopic 
surgical treatment of high-grade 
(>50%) partial-thickness rotator 
cuff tears using REGENETEN 
have increased percent filling of 
the rotator cuff (based on MRI 
assessment) compared to 
participants who had standard 
surgical repair at 24 months from 
 
 Added Outcome Measure 
associated with secondary 
filling (based on MRI 
assessment) at 24-months 
post-
 
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
N/A 
 
#20: To determine if participants 
who undergo arthroscopic 
surgical treatment of high-grade 
(>50%) partial-thickness rotator 
cuff tears using REGENETEN 
have improvements in rotator 
cuff tendon thickness (based on 
MRI assessment) compared to 
participants who had standard 
surgical repair at 12 months from 
 
 Added Outcome Measure: 
thickness (based on MRI 
assessment) at 12-months 
post-
 
 Added Statistical Test: 
regression adjusting for 
baseline tendon thickness 
and differences in baseline 
 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 93 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
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intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Section 
 
Current Text  
DD-MMM-YYYY Version # 
 
12-Dec-2018, V 2.0 
Revised Text  
DD-MMM-YYYY Version # 
 
10-Sep-2019, V 3.0 
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
N/A 
 
#21: To determine if participants 
who undergo arthroscopic 
surgical treatment of high-grade 
(>50%) partial-thickness rotator 
cuff tears using REGENETEN 
have improvements in rotator 
cuff tendon thickness (based on 
MRI assessment) compared to 
participants who had standard 
surgical repair at 24 months from 
 
 Added Outcome Measure: 
thickness (based on MRI 
assessment) at 24-months 
post-
 
 Added Statistical Test: 
regression adjusting for 
baseline tendon thickness 
and differences in baseline 
 
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
N/A 
 
#22: To determine if participants 
who undergo arthroscopic 
surgical treatment of high-grade 
(>50%) partial-thickness rotator 
cuff tears using REGENETEN 
have a statistically lower fatty 
infiltration of the rotator cuff 
(based on MRI assessment) 
compared to participants who 
had standard surgical repair at 
12 months from the index 
 
 Added Outcome Measure 
associated with secondary 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 94 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Section 
 
Current Text  
DD-MMM-YYYY Version # 
 
12-Dec-2018, V 2.0 
Revised Text  
DD-MMM-YYYY Version # 
 
10-Sep-2019, V 3.0 
classification of rotator cuff 
(based on MRI 
assessment) at 12-months 
post-
 
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
N/A 
 
#23: To determine if participants 
who undergo arthroscopic 
surgical treatment of high-grade 
(>50%) partial-thickness rotator 
cuff tears using REGENETEN 
have a statistically lower fatty 
infiltration of the rotator cuff 
(based on MRI assessment) 
compared to participants who 
had standard surgical repair at 
24 months from the index 
 
 Added Outcome Measure 
associated with secondary 
classification of rotator cuff 
(based on MRI 
assessment) at 24-months 
post-
 
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
N/A 
 
#24: To determine if participants 
who undergo arthroscopic 
surgical treatment of high-grade 
(>50%) partial-thickness rotator 
cuff tears using REGENETEN 
have statistically improved 
rotator cuff integrity (based on 
MRI assessment) compared to 
participants who had standard 
surgical repair techniques at 12 
 
 Added Outcome Measure 
associated with secondary 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 95 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Section 
 
Current Text  
DD-MMM-YYYY Version # 
 
12-Dec-2018, V 2.0 
Revised Text  
DD-MMM-YYYY Version # 
 
10-Sep-2019, V 3.0 
score (based on MRI 
assessment) at 12-months 
post-
 
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
N/A 
 
#25: To determine if participants 
who undergo arthroscopic 
surgical treatment of high-grade 
(>50%) partial-thickness rotator 
cuff tears using REGENETEN 
have statistically improved 
rotator cuff integrity (based on 
MRI assessment) compared to 
participants who had standard 
surgical repair techniques at 24 
 
 Added Outcome Measure 
associated with secondary 
score (based on MRI 
assessment) at 24-months 
post-
 
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
 Secondary Objective #17: 
 Statistical Test: 
total healthcare 
utilization costs 
between the two 
cohorts using multiple 
linear regression 
adjusting for baseline 
 
 
 Secondary Objective #27: 
 Removed Statistical Test 
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
 Secondary Objective #18: 
 
way ANOVA, adjusting 
for differences in 
baseline 
 
 
 Secondary Objective #28: 
 Revised Statistical Test: 
regression, adjusting for 
differences in baseline 
 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 96 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Section 
 
Current Text  
DD-MMM-YYYY Version # 
 
12-Dec-2018, V 2.0 
Revised Text  
DD-MMM-YYYY Version # 
 
10-Sep-2019, V 3.0 
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
 Secondary Objective #19: 
 
-
 
  
 Secondary Objective #29: 
 Removed Statistical Test 
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
 Secondary Objective #20: 
 Statistical Test: 
analysis adjusting for 
differences in baseline 
 
  
 Secondary Objective #30: 
 Removed Statistical Test 
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
 Secondary Objective #21: 
 Statistical Test: 
analysis adjusting for 
differences in baseline 
 
  
 Secondary Objective #31: 
 Removed Statistical Test 
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
 Secondary Objective #22: 
 
-
Whitney U test 
adjusting for differences 
in baseline 
 
  
 Secondary Objective #32: 
 Removed Statistical Test 
10.4.2  Table 2 
(Analysis of 
Secondary 
Endpoints) 
N/A 
Revised numbering in Table 2 as 
required 
10.6 
Not Applicable 
Added Interim Analysis: 
extract will be completed when the 
last enrolled participant has 
completed their three-month 
follow-up visit. A report will not 
accompany this data extract but 
the findings may be presented as 
possible podium or conference 
activity.  
 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 97 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
Section 
 
Current Text  
DD-MMM-YYYY Version # 
 
12-Dec-2018, V 2.0 
Revised Text  
DD-MMM-YYYY Version # 
 
10-Sep-2019, V 3.0 
An interim analysis will be 
conducted when the last enrolled 
participant has completed their 
one-year follow-up from index 
surgery. This analysis will include a 
simplified statistical report and a 
possible peer-reviewed 
 
11  Sample Size 
Justification 
The sample size calculation 
was conducted for 80% power 
and an alpha of 0.05. The 
minimal clinically important 
difference (MCID) used as the 
difference to detect for was 12 
points on the American 
Shoulder and Elbow Surgeons 
(ASES) score at 3 months 
following index surgery  
conducted for 80% power and an 
alpha of 0.05. The minimal 
clinically important difference 
(MCID) used as the difference to 
detect for was 11.1 points on the 
American Shoulder and Elbow 
Surgeons (ASES) score at 3 
 
20 
N/A 
References and reference 
numbers updated as required 
 
21.2 PRINCIPAL INVESTIGATOR OBLIGATIONS (ISO14155) 
1. General:  
a. 
The role of the PI is to implement and manage the day-to-day conduct of the clinical 
investigation as well as ensure data integrity and the rights, U, and well-being of the 
participants involved in the clinical investigation.  
2. Qualification of the PI. The PI shall: 
a. 
be qualified by education, training, and experience to assume responsibility for the 
proper conduct of the clinical investigation in accordance with this International Standard; 
evidence of such qualifications of the PI and key members of the investigation site team 
shall be provided to the Sponsor through up-to-date Curriculum Vitae (CV) or other 
relevant documentation, 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 98 of 105 
 
 
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intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
b. 
be experienced in the field of application and trained in the use of the investigational 
device under consideration, 
c. 
disclose potential conflicts of interest, including financial, that interfere with the conduct 
of the clinical investigation or interpretation of results, and 
d. 
be knowledgeable with the method of obtaining informed consent. 
3. Qualification of investigation site. The PI shall be able to demonstrate that the proposed 
investigation site: 
a. 
has the required number of eligible participants needed within the agreed recruitment 
period, and 
b. 
has one or more qualified investigators, a qualified investigation site team and adequate 
facilities for the foreseen duration of the clinical investigation. 
4. Communication with the IEC. The PI shall:  
a. 
provide the Sponsor with copies of any clinical-investigation-related communications 
between the PI and the IEC, 
b. 
comply with the requirements described in 4.5 of ISO 14155: 
i. 
Submit to the IEC the following information, any amendments and any additional 
documentation required by the IEC: the Protocol; IB or equivalent; informed 
consent form and any other written information provided to participants; 
procedures for recruiting participants and advertising materials, if any; a copy of 
the CV of the PI(s) for with the IEC has oversight. 
ii. 
Provide documentation of the IECs approval/favorable opinion, identifying the 
documents and amendments on which the opinion was based, to the Sponsor, 
prior to commencing the clinical investigation.  
iii. 
Submit the following to the IEC if required by national regulations, the protocol or 
IEC, whichever is more stringent: 
1. 
SAEs 
2. 
Requests for deviations, and reports of deviations, if the deviation affects 
participant
, and well-being, or the scientific integrity of the 
clinical investigation. Document and report to the Sponsor and IEC a report of 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 99 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
deviations made to protect the rights, safety, and well-being of human 
participants under emergency circumstances.  
3. 
Progress reports, including safety summary and deviations 
4. 
Amendments to any documents already approved by the IEC.  
5. 
If applicable, notifications of suspension or premature termination 
6. 
If applicable, justification and request for resuming the clinical investigation 
after suspension.  
7. 
Clinical investigation report or summary. 
iv. 
As a minimum, during the clinical investigation, the following information shall be 
obtained in writing from the IEC prior to implementation: 
1. 
Approval/favorable opinion of amendments 
2. 
Approval of the request for deviations that can affect the participant
rights, 
safety, and well-being or scientific integrity of the clinical investigation 
3. 
Approval for resumption of a suspended clinical investigation if applicable.  
c. 
obtain the written and dated approval/favorable opinion of the IEC for the clinical 
investigation before recruiting participants and implementing all subsequent 
amendments, if required, 
d. 
promptly report any deviations from the protocol that affect the rights, safety or well-being 
of the participant or the scientific integrity of the clinical investigation, including those 
which occur under emergency circumstances, if required by the IEC, protocol or national 
regulations. In particular circumstances, the communication with the IEC can be 
performed by the Sponsor, partly or in full, in which case the Sponsor shall keep the 
Principal Investigator informed. 
5. Informed consent process. The PI shall: 
a. 
General: 
i. 
Informed consent shall be obtained in writing from the participant and the process 
shall be documented before any procedure specific to the clinical investigation is 
applied to the participant; except when special circumstances for emergency 
treatments apply (see below) 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 100 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
ii. 
The informed consent form consists of an information form and informed consent 
signature form. These two forms can either be combined in one document or 
separated into two documents 
b. 
Process of obtaining informed consent. The general process for obtaining informed 
consent shall be documented in the protocol and shall comply with the following. These 
requirements also apply with respect to informed consent obtained from a participant
legally authorized representative:  
i. 
Ensure that the PI or his/her authorized designee conducts the informed consent 
process 
ii. 
Include all aspects of the clinical investigation that are relevant to the participant
decision to participate throughout the clinical investigation 
iii. 
Avoid any coercion or undue improper influence on, or inducement of, the 
participant to participate 
iv. 
Not waive or appear to waive the participant
 
v. 
Use native non-technical language that is understandable to the participant 
vi. 
Provide ample time for the participant to read and understand the informed consent 
form and to consider participation in the clinical investigation 
vii. 
Include personally dated signatures and the PI or an authorized designee 
responsible for conducting the informed consent process 
viii. 
Show how informed consent will be obtained in special circumstances (see below) 
where the participant is unable to provide him or herself, and  
ix. 
Ensure important new information is provided to new and existing participants 
throughout the clinical investigation.  
c. 
Special circumstances for informed consent (the following provisions are subject to 
national regulations): 
i. 
Participant needing legally authorized representatives:  informed consent may be 
given by the legally authorized representative only if a participant is unable to make 
the decision to participate in a clinical investigation (e.g. infant, child, or juvenile, 
seriously ill or unconscious participant, mentally ill person, mentally handicapped 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 101 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
person). In such cases, the subject shall also be informed about the clinical 
investigation within his/her ability to understand.  
ii. 
Participant unable to read or write: informed consent shall be obtained through a 
supervised oral process if a participant or legally authorized representative is 
unable to read or write. An independent witness shall be present throughout the 
process. The written informed consent form and any other information shall be read 
aloud and explained to the prospective participant or his/her legally authorized 
representative and, whenever possible, either shall sign and personally date the 
informed consent form. The witness also signs and personally dates the informed 
consent for attesting that the information was accurately explained and that the 
informed consent was freely given.  
iii. 
Emergency treatments:  
1. 
For clinical investigations involving emergency treatments, when prior 
informed consent of the participant is not possible because of the participant
medical condition, the informed consent of the participant
representative, if present, shall be requested.  
2. 
When it is not possible to obtain prior informed consent from the participant, 
and the participant
lly authorized representative, is not available, the 
participant may still be enrolled if a specific process has been described in the 
protocol.  
3. 
Arrangements shall be made to inform the participant or legally authorized 
representative, as soon as possible, about the participant
clinical investigation and about all aspects of the clinical investigation.  
4. 
The participant shall be asked to provide informed consent for continued 
participation as soon as his/her medical condition allows.  
d. 
The Principal Investigator may not enroll a participant without obtaining informed consent 
of the participant or his/her legally authorized representative only when the following 
conditions are fulfilled: the prospective participant fulfils the emergency conditions and is 
obviously in a life-threatening situation; no sufficient clinical benefits are anticipated from 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 102 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
the currently available treatment; there is a fair possibility that the life-threatening risk to 
the prospective participant can be avoided if the investigational device is used; 
anticipated risks are outweighed by the potential benefits of applying the investigational 
device ; the legally authorized representative cannot be promptly reached and informed.  
e. 
Information provided to the participant. All information pertinent to the clinical 
investigation, including at least the following, shall be provided in writing and in native, 
non-technical language that is understandable to the participant (or the participant
legally authorized representative): 
i. 
Description and purpose 
ii. 
Potential benefits 
iii. 
Risks and inconveniences or the participant and, when applicable, for any embryo, 
foetus or nursing infant 
iv. 
Alternative procedures 
v. 
Confidentiality 
vi. 
Compensation 
vii. 
Anticipated expenses, if any, to be borne by the subject for participating in the 
clinical investigation 
viii. 
Information on the role of Sponsor
 
ix. 
Contact persons 
x. 
Statement declaring that new findings or the reasons for any amendment to the 
protocol that affect the participant
made available 
to the participant.  
xi. 
Statement indicating that, upon the participant
participant
personal physician will be informed of the participant
investigation 
xii. 
Termination procedures 
f. 
Informed consent signature shall contain the following:  
i. 
The voluntary agreement to participate in the clinical investigation and follow the 
 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 103 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
ii. 
A statement declaring that refusal of participation incurs no penalty for the 
participant 
iii. 
A statement declaring that discontinuation at any time incurs no penalty for the 
participant 
iv. 
A statement with regard to the possible consequences of withdrawal 
v. 
An acknowledgement of the information provided and confirmation that all the 
participant
red 
vi. 
A statement confirming that the participant or his/her legally authorized 
representative agrees to the use of the participant
purpose of the clinical investigation 
vii. 
A statement confirming that the participant or his/her legally authorized 
representative agrees that Sponsor
IEC representatives will be granted direct access to the participant
records.  
g. 
New information: if new information becomes available that can significantly affect a 
participant
participant(s) affected in written form. If relevant, all affected participants shall be asked 
to confirm their continuing consent in writing.  
h. 
ensure compliance with the applicable regulatory requirements and ethical principles for 
the process of obtaining informed consent, and 
i. 
ensure and document appropriate training if an authorized designee is appointed to 
conduct the informed consent process. 
6. Compliance with the protocol. The Principal Investigator shall: 
a. 
indicate his/her acceptance of the protocol in writing, 
b. 
conduct the clinical investigation in compliance with the protocol, 
c. 
create and maintain source documents throughout the clinical investigation and make 
them available as requested during monitoring visits or audits, 
d. 
ensure that the investigational device is used solely by authorized users as specified in 
6.2, and in accordance with the protocol and instructions for use, 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 104 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
e. 
propose to the Sponsor any appropriate modification(s) of the protocol or investigational 
device or of the use of the investigational device, 
f. 
refrain from implementing any modifications to the protocol without agreement from the 
Sponsor, IEC and regulatory authorities, if required, 
g. 
document and explain any deviation from the approved protocol that occurred during the 
course of the clinical investigation, 
h. 
ensure that an adequate investigation site team and facilities exist and are maintained 
and documented during the clinical investigation, 
i. 
ensure that maintenance and calibration of the equipment relevant for the assessment 
of the clinical investigation is appropriately performed and documented, where 
applicable, 
j. 
ensure the accuracy, completeness, legibility and timeliness of the data reported to the 
Sponsor in the CRF and in all required reports, 
k. 
maintain the device accountability records, 
l. 
allow and support the Sponsor to perform monitoring and auditing activities, 
m. be accessible to the monitor and respond to questions during monitoring visits, 
n. 
allow and support regulatory authorities and the IEC when performing auditing activities, 
o. 
ensure that all clinical-investigation-related records are retained as required taking 
measures to prevent accidental or premature destruction, and 
p. 
review and sign the clinical investigation report, as applicable. 
7. Medical care of participants. The Principal Investigator shall 
a. 
provide adequate medical care to a participant during and after a participant's 
participation in a clinical investigation in the case of adverse events,  
b. 
inform the participant of the nature and possible cause of any adverse events 
experienced, 
c. 
provide the participant with the necessary instructions on proper use, handling, storage, 
and return of the investigational device, when it is used or operated by the participant, 
d. 
inform the participant of any new significant findings occurring during the clinical 
investigation, including the need for additional medical care that may be required, 

 
Study Protocol
Device 
Prospective multi-center study comparing REGENETEN in 
lieu of standard arthroscopic repair of high-grade (>50%) 
partial-thickness tears 
Number: 
REGEN.PUB.2018.09 
Version: 3.0, 10SEP2019 
Page: Page 105 of 105 
 
 
CONFIDENTIAL AND PROPRIETARY 
This document contains information that is confidential and proprietary to Smith & Nephew PLC and Smith & Nephew, Inc. and is 
intended for use only by Smith & Nephew and its manufacturer. It shall not be reproduced or copied in whole or in part, nor shall the 
contents be disclosed by any means without prior written permission from Smith & Nephew, nor shall anyone make any use of it that 
is contrary to the expressed or implied wishes of Smith & Nephew. 
 
e. 
provide the participant with well-defined procedures for possible emergency situations 
related to the clinical investigation, and make the necessary arrangements for 
emergency treatment, including decoding procedures for blinded/masked clinical 
investigations, as needed, 
f. 
ensure that clinical records are clearly marked to indicate that the participant is enrolled 
in a particular clinical investigation, 
g. 
if appropriate, participants enrolled in the clinical investigation shall be provided with 
some means of showing their participation in the clinical investigation, together with 
identification and compliance information for concomitant treatment measures (contact 
address and telephone numbers shall be provided), 
h. 
inform, with the participant's approval or when required by national regulations, the 
participant's personal physician about the participant's participation in the clinical 
investigation, and  
i. 
make all reasonable efforts to ascertain the reason(s) for a participant's premature 
withdrawal from the clinical investigation while fully respecting the participant's rights. 
8. Safety reporting. The Principal Investigator shall: 
a. 
record every adverse event and observed device deficiency, together with an 
assessment, 
b. 
report to the Sponsor, without unjustified delay, all serious adverse events and device 
deficiencies that could have led to a serious adverse device effect; this information shall 
be promptly followed by detailed written reports, as specified in the protocol, 
c. 
c) report to the IEC serious adverse events and device deficiencies that could have led 
to a serious adverse device effect, if required by the national regulations or protocol or 
by the IEC, 
d. 
report to regulatory authorities serious adverse events and device deficiencies that could 
have led to a serious adverse device effect, as required by the national regulations, and 
e. 
supply the Sponsor, upon Sponsor's request, with any additional information related to 
the safety reporting of a particular event.