A 26 Week Prospective Open Label Clinical Study Evaluating A Single Intra-Articular Injection of Durolane 3ml for Treatment of Osteoarthritis Pain of the Shoulder
Phase: NA
Conditions: Osteoarthritis
Sponsor: Bioventus LLC

Protocol 13DUR503 Amendment 02 
 
 
 
1. 
TITLE PAGE 
DUROLANE®  
 
13DUR503 
 
A 26 WEEK PROSPECTIVE OPEN LABEL CLINICAL 
STUDY EVALUATING A SINGLE INTRA-ARTICULAR 
INJECTION OF DUROLANE® 3ML FOR TREATMENT 
OF OSTEOARTHRITIS PAIN OF THE SHOULDER 
 
Protocol Amendment 02  
 
Date: 20Mar15 
 
 
 
 
 

Protocol 13DUR503 Amendment 02 
 
 
 
SPONSOR INFORMATION PAGE 
 
Sponsor: 
Bioventus LLC 
4721 Emperor Blvd., Ste. 100 
Durham, NC 27703 
USA 
Telephone: 919-474-6700 
In some countries, the clinical trial sponsor may be the local Bioventus affiliate company 
(or designee).  Where applicable, the details of the Sponsor and contact person will be 
provided to the relevant regulatory authority as part of the clinical trial submission. 
 
Sponsor Medical Monitor Contact Information for Unanticipated Adverse Events 
(UAE) and Adverse Device Effect (UADE): 
Peter Heeckt, M.D.  
Telephone:  919-474-6794 
Mobile:    
901-277-6974  

Protocol 13DUR503 Amendment 02 
 
 
 
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable Canadian 
regulations and ICH guidelines. 
 
 
Investigator Printed Name 
 
 
 
Investigator Signature 
  
Date 
 

Protocol 13DUR503 Amendment 02 
 
 
 
2. 
SYNOPSIS 
Name of Sponsor/Company: 
Bioventus LLC 
Name of Investigational Product: 
DUROLANE®  
Name of Active Ingredient: 
Hyaluronic Acid 
Title of Study:  
A 26 Week Prospective Open Label Clinical Study Evaluating a Single Intra-Articular Injection 
of DUROLANE® 3mL for Treatment of Osteoarthritis Pain of the Shoulder 
Principal Investigator(s):  Michael McKee, MD 
Phase of Development: EU Post-Marketing Commitment 
Trial Objectives:  
 
Primary: 
To evaluate the efficacy of a single intra-articular (IA) injection of DUROLANE® 3mL 
given for the relief of pain in the treatment of symptomatic osteoarthritis (OA) of the 
shoulder followed over a 26-week time period  
Secondary:  
To evaluate the efficacy of a single IA injection of DUROLANE® 3mL given for treatment 
of symptomatic OA of the shoulder followed over a 26-week time period for 
 
shoulder pain at night  
 
shoulder range of motion   
 
shoulder pain rescue medication use  
To evaluate the safety and tolerability of a single IA injection of DUROLANE® 3mL over 
a 26-week time period 
Trial Assessments: 
Effectiveness: 
Primary: 
Shoulder pain on movement (SPOM) visual analogue scale (VAS) (0-100mm)  
Secondary : 
 
Shoulder pain at night (SPAN) VAS (0-100mm)  
 
American Shoulder and Elbow Surgeons (ASES) Standardized Shoulder 
Assessment Form (physician range of motion and patient self-evaluation VAS pain 

Protocol 13DUR503 Amendment 02 
 
 
 
today and activities of daily living only) (Richards, et al.,1994) 
 
Patient Global Assessment (PGA) VAS (0-100mm)  
 
Shoulder pain rescue medication diary 
Safety: 
 
Adverse events 
 
Concomitant medications 
 
Physical exams, as needed 
Methodology:  
Open label, prospective, single cohort study 
Number of Subjects (planned):  
A minimum of 36 subjects will be enrolled.  
Diagnosis and main criteria for inclusion:  
Pain due to mild to moderate osteoarthritis in the shoulder  
Investigational Product, dosage and mode of administration:  
DUROLANE® 3mL single IA injection 
Duration of treatment and study participation:  
Subjects will receive a single injection and participation will be approximately 28 weeks 
(including an up to 2 week  screening period) 
Eligibility Criteria: 
 
Inclusion 
1. Females or males between the ages of 19 and 85 years of age 
2. Diagnosis of glenohumeral osteoarthritis (GH-OA), confirmed by radiographs taken 
within the previous six months, with GH-OA being the primary source of pain; OA in the 
contralateral shoulder is permissible provided that OA symptoms are greater in the trial 
shoulder 
3. Shoulder pain on movement (SPOM) visual analogue scale (VAS) (0-100mm)  score 
≥50mm for the study shoulder 
4. Must be willing to discontinue use of oral and topical analgesia other than rescue use of 
acetaminophen for the study shoulder. Must also be willing to discontinue rescue 
medication for at least 24 hours before each visit 
5. Abstinence from any IA or peri-articular injections for the shoulder during the course of 
the trial, except for the assigned Investigational Product 
6. Patients with chronic shoulder pain lasting more than 6 months without clinically 
significant improvement in shoulder pain over the past one month 

Protocol 13DUR503 Amendment 02 
 
 
 
7. Pain at least 50% of the days during the previous month 
8. Patients who have failed conventional therapy including but not limited to the following: 
nonsteroidal anti-inflammatory drugs (NSAIDs); one or more intra-articular or local peri-
articular steroid injections and physiotherapy (a minimum of one month of previous 
physiotherapy treatment is required) 
9. Patients with a retained active range of motion (ROM) of at least 30% in all directions to 
rule out frozen shoulder (>30° for abduction with scapula fixed, >30° for external 
rotation, and >20° for internal rotation)  
10. Cooperative and able to communicate effectively with the Investigators 
11. Must agree not to participate in any other clinical research (interventional) studies while 
participating in this study  
12. Body mass index (BMI) ≤ 35 kg/m2 
13. English literacy and ability to understand and complete all informed consent procedures 
 
Exclusion 
1. Significant pain from other joints or low back pain requiring chronic ongoing analgesic 
therapy 
2. Presence of one or more conditions besides OA that could confound pain and functional 
assessments in the study shoulder  
3. Clinically-apparent tense effusion or gross  misalignment or instability in the study  
shoulder  
4. Shoulder x-ray findings of acute fractures, severe loss of bone density, avascular 
necrosis and/or severe deformity  
5. Surgery of the study joint within the previous 12 months. 
6. Treatment with NSAIDs or any pain management medications (including topical agents 
for the study shoulder) during the last week (or five half-lives of the drug, whichever is 
longer) prior to Baseline Visit. 
7. Inability to tolerate acetaminophen for rescue medication use. 
8. Use of acetaminophen or any other analgesics during the 24 hours preceding the 
baseline visit. 
9. IA or local peri-articular corticosteroid injections to the study joint or shoulder within the 
previous three months; or to any other joint within the previous month; or any oral 
corticosteroid within the previous month. Steroid inhalants are permitted if the patient 
has been on a stable regimen for the past month and remains on this regimen 
throughout the course of the trial 
10. IA injections with hyaluronic acid in the study shoulder within the last 9 months  
11. Previous allergic reaction to a HA or local anesthetic such as lidocaine. 

Protocol 13DUR503 Amendment 02 
 
 
 
12. Treatment with glucosamine/chondroitin sulfate initiated within the past three months, or 
dosage not stable for the past three months 
13. Change in physical therapy for the study shoulder within one month preceding 
screening, or expected change in physical therapy during the study 
14. Planned surgical procedure during the study period. 
15. Previous history or presence of septic arthritis in study joint   
16. Active skin disease or infection in the area of the injection site 
17. Alcohol or drug abuse as determined by the Investigator or use of alcohol for control of  
pain 
18. Use of illicit drugs including cannabis  
19. Systemic inflammatory condition or autoimmune disease or infection such as 
rheumatoid arthritis, inflammatory arthritis, ankylosing spondylitis, psoriatic arthritis, 
reactive arthritis, gout/ acute pseudo gout or any other connective tissue disease 
20. Uncontrolled hypothyroidism 
21. Use of  aspirin  (acetylsalicylic acid) as analgesic (up to 325 mg/day for anticoagulant 
treatment is permissible) 
22. Any medical condition which in the opinion of the investigator makes the patient 
unsuitable for inclusion (e.g., severe progressive chronic disease, malignancy, bleeding 
disorder, fibromyalgia)  
23. Pregnant or breast-feeding woman or woman of child-bearing potential not practicing 
adequate contraception. 
24. Subjects that in the opinion of the investigator are unsuitable for inclusion (e.g., subjects 
not likely to avoid other therapies, subjects not likely to stay in the study or with plans to 
relocate during the  study period, or subjects likely to be unreliable)  
25. Concurrent participation in any other clinical study or participation within the preceding 
30 days 
Statistical Methods: 
General: 
There is a single pre-planned hypothesis test for the primary variable. There are no pre-
planned hypotheses tests for secondary or exploratory efficacy variables or safety variables. 
Any inferential statistic for these variables is exploratory. All variables will be summarized using 
descriptive statistics such as sample size, mean, standard deviation, median, minimum and 
maximum and frequencies, i.e. counts and percents. 
Effectiveness: 
Primary Variable: 
 
VAS (0-100mm) SPOM over weeks 0, 6, 12, 18 and 26  
Primary hypothesis: 

Protocol 13DUR503 Amendment 02 
 
 
 
Ho:   
VAS SPOM over weeks 6, 12, 18 and 26 ≥ VAS SPOM at week 0 (baseline) 
Ha:   
VAS SPOM over weeks 6, 12, 18 and 26 < VAS SPOM at week 0 (baseline) 
Primary hypothesis statistical test method: 
A mixed effect repeated measures (MERM) regression will be used. VAS SPOM will be the 
dependent variable. The weeks 0 (baseline), 6, 12, 18, and 26 visits will be a fixed effect 
covariate. Subjects will be random effects. The correlation structure will be unstructured. If 
convergence is problematic then an alternative covariance structure will be necessary. A 
contrast will be constructed to test the hypothesis of a VAS SPOM reduction from baseline. 
Trial success criteria: 
If the weeks 6, 12, 18, and 26 VAS SPOM least square mean versus week 0 (baseline) VAS 
SPOM least square mean contrast achieves the 0.05 type I error level of statistical significance 
this trial will be considered a success. 
Secondary variables: 
The weeks 0, 6, 12, 18 and 26: 
 
SPAN VAS (0-100mm) 
 
ASES patient self-evaluation (PSE) Shoulder Score Index (SSI): (range: 0-100) 
 
PGA VAS (0-100mm) 
 
Shoulder pain rescue medication consumed (unit: average mg per week) 
The weeks 0, 6, 12, and 26: 
 
ASES physician assessment (PA) range of motion (ROM): 5 questions (right and left, 
active and passive; total 10 assessments) (unit: degrees) 
 
Exploratory ASES variables (patient self-evaluation only): 
The weeks 0, 6, 12, 18 and 26: 
 
ASES PSE pain today: VAS (range: 0-10cm) 
 
ASES PSE activity of daily living: 10 questions (range: 0,1,2,3) 
 
Safety variables: 
Over the entire study: 
 
MedDRA coded adverse events  
 
WHO coded concomitant medications  
 
Physical exams (range: 0,1,2,3) 
 

Protocol 13DUR503 Amendment 02 
 
 
 
Sample Size: 
 
The sample size was estimated for a repeated measures ANOVA using method MOT2 in 
nQuery Advisor 7.0 statistical software. A sample size of 29 will be capable of detecting a 
reduction in mean VAS pain on movement score of 15 mm (25% reduction from a baseline 
mean of 60mm) over the course of the study with 80% power under the following assumptions: 
 
Type I error rate, α, 
 
 
 
 
 
= 0.05  
 
Standard deviation within time point  
= 25 mm 
 
Correlation between visits 
 
 
 
= 0.5 
 
Mean VAS (0-100mm) results at: 
 
 
0 weeks (baseline) 
 
 
 
 
= 60 mm 
 
 
6 weeks 
 
 
 
 
 
 
 
= 55 mm 
 
 
12 weeks  
 
 
 
 
 
 
= 50 mm 
 
 
26 weeks  
 
 
 
 
 
 
= 45 mm 
A minimum of 36 subjects will be enrolled into the study to allow the power of the study to be 
maintained in the case of a drop-out rate of up to 20%.  
 

Protocol 13DUR503 Amendment 02 
 
 
 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE .................................................................................................. 1 
SPONSOR INFORMATION PAGE ................................................................................. 2 
INVESTIGATOR PROTOCOL AGREEMENT PAGE ...................................................... 3 
2. 
SYNOPSIS ..................................................................................................... 4 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ........ 10 
4. 
LIST OF ABBREVIATIONS AND SPECIALIST TERMS .............................. 15 
5. 
INTRODUCTION .......................................................................................... 17 
5.1. 
Background Information ............................................................................... 17 
5.1.1. 
Pre-Clinical Documentation .......................................................................... 18 
5.1.2. 
Clinical Documentation of HA use in Shoulder Studies ................................ 19 
5.2. 
Rationale ...................................................................................................... 21 
5.3. 
Potential Risks and Benefits ........................................................................ 23 
5.3.1. 
Potential Risks ............................................................................................. 23 
5.3.1.1. 
Risks Associated with the Use of DUROLANE ............................................ 23 
5.3.1.2. 
Risks Associated with Injection .................................................................... 24 
5.3.2. 
Known Potential Benefits ............................................................................. 24 
6. 
TRIAL OBJECTIVES AND PURPOSE ......................................................... 25 
6.1. 
Study Objectives .......................................................................................... 25 
6.1.1. 
Primary Objective ......................................................................................... 25 
6.1.2. 
Secondary Objectives .................................................................................. 25 
6.2. 
Study Outcome Measures ............................................................................ 25 
6.2.1. 
Primary Outcome Measures ........................................................................ 25 
6.2.2. 
Secondary Outcome Measures .................................................................... 25 
7. 
INVESTIGATIONAL PLAN ........................................................................... 26 
7.1. 
Overall Study Design ................................................................................... 26 
7.2. 
Number of Subjects ...................................................................................... 26 
7.3. 
Treatment Assignment ................................................................................. 26 
7.4. 
Study Schedule ............................................................................................ 26 
7.4.1. 
Screening Visit ............................................................................................. 27 

Protocol 13DUR503 Amendment 02 
 
 
 
7.4.2. 
Enrollment/Baseline ..................................................................................... 28 
7.4.3. 
Follow-up Visits (Weeks 6, 12 and 18) ......................................................... 30 
7.4.4. 
Final Study Visit (Week 26) .......................................................................... 30 
7.4.5. 
Early Withdrawal .......................................................................................... 31 
7.4.6. 
Unscheduled Visit ........................................................................................ 31 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..................................... 32 
8.1. 
Subject Inclusion Criteria ............................................................................. 32 
8.2. 
Subject Exclusion Criteria ............................................................................ 33 
8.3. 
Screen Failures ............................................................................................ 34 
8.4. 
Subject Compliance ..................................................................................... 34 
8.5. 
Subject Withdrawals ..................................................................................... 34 
8.5.1. 
Reasons for Withdrawal ............................................................................... 34 
8.5.2. 
Handling of Withdrawals .............................................................................. 35 
8.6. 
Study Pause ................................................................................................. 35 
8.7. 
Termination of Study .................................................................................... 35 
9. 
INVESTIGATIONAL PRODUCT .................................................................. 36 
9.1. 
Investigational Product Description .............................................................. 36 
9.2. 
Investigational Product Packaging and Labeling .......................................... 36 
9.3. 
Investigational Product Storage and Stability ............................................... 36 
9.4. 
Investigational Product Administration ......................................................... 36 
9.4.1. 
General Instructions ..................................................................................... 36 
9.4.2. 
Injection of DUROLANE ............................................................................... 37 
9.4.3. 
Anesthetization of the Injection Site ............................................................. 37 
9.4.4. 
Use of Imaging Guidance ............................................................................. 37 
9.4.5. 
Arthrocentesis .............................................................................................. 37 
9.4.6. 
Post-Injection Care ....................................................................................... 37 
9.4.7. 
Documentation of Treatment Procedure ...................................................... 38 
9.4.8. 
Reporting Technical Complaints .................................................................. 38 
9.5. 
Investigational Product Accountability .......................................................... 38 
10. 
CONCOMITANT MEDICATIONS /TREATMENTS ...................................... 40 
11. 
CLINICAL EVALUATIONS ........................................................................... 41 
11.1. 
Demographics (Screening Visit) ................................................................... 41 
11.2. 
Medical and Medications History (Screening Visit/Baseline Visit) ................ 41 

Protocol 13DUR503 Amendment 02 
 
 
 
11.3. 
Concomitant Medications (All Visits) ............................................................ 41 
11.4. 
Non-pharmacological treatment (All Visits) .................................................. 41 
11.5. 
Physical Examination of Shoulder (All Visits) ............................................... 42 
11.6. 
Pregnancy Test (Baseline Visit) ................................................................... 42 
12. 
ASSESSMENT OF EFFICACY .................................................................... 43 
12.1. 
Shoulder Pain on Movement (SPOM) VAS (0-100mm)  (All Visits) .............. 43 
12.2. 
Shoulder Pain at Night (SPAN) VAS (0-100mm) (All Visits) ......................... 44 
12.3. 
American Shoulder and Elbow Surgeons (ASES) ........................................ 44 
12.3.1. 
ASES Range of Motion (ROM) (Screening, Baseline, Week 6, Week 
12 and Week 26) .......................................................................................... 44 
12.3.2. 
ASES Patient Self-Evaluation (All Visits) ..................................................... 44 
12.4. 
Patient Global Assessment (PGA) (All Visits) .............................................. 45 
12.5. 
Recorded Use of Rescue Medication ........................................................... 45 
13. 
ASSESSMENT OF SAFETY ........................................................................ 46 
14. 
STATISTICS ................................................................................................ 47 
14.1. 
Methods ....................................................................................................... 47 
14.1.1. 
General ........................................................................................................ 47 
14.1.2. 
Safety ........................................................................................................... 47 
14.1.3. 
Efficacy ........................................................................................................ 48 
14.1.3.1. Primary Variable ........................................................................................... 48 
14.1.3.2. Primary hypothesis ....................................................................................... 48 
14.1.3.3. Primary hypothesis statistical test method ................................................... 48 
14.1.3.4. Trial success criteria .................................................................................... 48 
14.1.3.5. Secondary variables ..................................................................................... 48 
14.1.3.6. Exploratory variables .................................................................................... 49 
14.2. 
Sample Size Considerations ........................................................................ 49 
14.3. 
Planned Interim Analyses ............................................................................ 50 
14.4. 
Statistical software ....................................................................................... 50 
15. 
STUDY DATA .............................................................................................. 51 
15.1. 
Study Monitoring .......................................................................................... 51 
15.2. 
Audits and Inspections ................................................................................. 52 
15.3. 
Inspection of Records .................................................................................. 53 
15.4. 
Retention of Records ................................................................................... 53 

Protocol 13DUR503 Amendment 02 
 
 
 
16. 
ETHICS ........................................................................................................ 54 
16.1. 
Ethical Standards ......................................................................................... 54 
16.2. 
Research Ethics Board (REB) ...................................................................... 54 
16.3. 
Written Informed Consent ............................................................................ 54 
16.4. 
Subject Confidentiality .................................................................................. 55 
16.5. 
Study Discontinuation Notification ................................................................ 55 
17. 
LIST OF REFERENCES .............................................................................. 57 
APPENDICES ............................................................................................................... 61 
APPENDIX 1. PERMITTED TREATMENTS/MEDICATIONS ..................................... 62 
APPENDIX 2. PROHIBITED TREATMENTS/MEDICATIONS .................................... 63 
APPENDIX 3. DEVICE SAFETY AND VIGILANCE GUIDELINES ............................. 64 
APPENDIX 4. ADVERSE EVENT REPORTING FLOWCHART ................................. 65 
APPENDIX 5. INSTRUCTIONS FOR USE ................................................................. 66 
APPENDIX 6. OSTEOARTHRITIS CLASSIFICATION SYSTEMS ............................. 67 
 
  
 

Protocol 13DUR503 Amendment 02 
 
 
 
LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms ............................................................. 15 
Table 2: 
Schedule of Events ...................................................................................... 27 
 
 

Protocol 13DUR503 Amendment 02 
 
 
 
4. 
LIST OF ABBREVIATIONS AND SPECIALIST TERMS 
 
The following abbreviations and specialist terms are used in this study protocol. 
 
Table 1: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Explanation 
ADE 
Adverse Device Effect 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ASADE 
Anticipated Serious Adverse Device Effect 
ASES 
American Shoulder and Elbow Surgeons 
BMI 
Body mass index 
CDRH 
Center for Devices and Radiological Health 
CFB 
Change from Baseline 
CRF 
Case Report Form 
CTA 
Clinical Trial Agreement 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GH 
Glenohumeral 
GH-OA 
Glenohumeral Osteoarthritis 
Ha: 
Alternative hypothesis  
Ho: 
Test hypothesis 
HA 
Hyaluronic Acid 
IA 
Intra-Articular 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ISO 
International Organization for Standardization 
Investigational Product 
DUROLANE Hyaluronic Acid, Stabilized Single Injection 
MDD 
Medical Device Directives 
MedDRA 
Medical Dictionary for Regulatory Activities 
MERM 
Mixed Effect Repeated Measures 
MW 
Molecular Weight 

Protocol 13DUR503 Amendment 02 
 
 
 
Abbreviation or Specialist Term 
Explanation 
N 
Number (typically refers to subjects) 
NASHA 
Non Animal derived Stabilized Hyaluronic Acid 
NSAID 
Nonsteroidal Anti-Inflammatory Drugs 
OA 
Osteoarthritis 
PA 
Physician Assessment 
PGA 
Patient Global Assessment 
PSE 
Patient Self Evaluation 
REB 
Research Ethics Board 
ROM 
Range of Motion 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SAP 
Statistical Analysis Plan 
SPAN 
Shoulder Pain at Night 
SPOM 
Shoulder Pain on Movement 
SS 
Study Shoulder 
SSI 
Shoulder Score Index 
UADE 
Unanticipated Serious Adverse Device Effect 
US 
United States 
VAS 
Visual Analog Scale 
WHO 
World Health Organization 
 

Protocol 13DUR503 Amendment 02 
 
 
 
5. 
INTRODUCTION 
5.1. 
Background Information 
The glenohumeral (GH) joint, commonly known as the shoulder joint, is a ball-and-
socket joint made up of the top rounded head portion of the humerus and the concave 
surface on the lateral portion of the scapula, known as the glenoid. In the normal GH 
joint, the head of the humerus and the glenoid articulate smoothly. This smooth efficient 
joint motion is facilitated by the presence of cartilage, which surrounds the articular 
portion of the bones.  
With age and normal wear and tear, degeneration of the cartilage takes place in many 
joints of the body. As the cartilage begins to deteriorate, the smooth surface becomes 
asymmetric, and the bone becomes exposed, allowing the unprotected surfaces of the 
bones in the joint to interact causing pain, swelling and loss of function. Over time bone 
spurs can form, further magnifying the asymmetric interaction of these joint surfaces. 
Degenerative changes in the GH joint can be characterized as GH osteoarthritis (GH-
OA), which can be painful and debilitating and can compromise the functional capacity 
to perform activities of daily living.   
For diagnostic purposes, a subject with GH-OA is identified using standard shoulder 
radiographs. Radiographic findings consistent with this condition include GH joint-space 
narrowing, subchondral bony sclerosis, osteophyte formation, glenoid bone erosion, and 
posterior humeral head displacement. 
Initial treatment for GH-OA includes activity modification and nonsteroidal anti-
inflammatory drugs (NSAIDs).  Physical therapy can be utilized to maintain motion and 
strength, but it should be carefully monitored to prevent symptomatic aggravation. 
Corticosteroid injections are frequently administered for treatment of shoulder pain and 
have been effective in clinical trials. However, guidelines of the American Academy of 
Orthopaedic Surgeons suggest that such injections are not routinely recommended for 
patients with GH-OA.   In addition, the potential risk of damage to the collagen matrix of 
tendons and ligaments suggests caution in the use of corticosteroid injections, 
especially with repeated administrations over time. Ultimately, shoulder replacement 
surgery may be indicated in advanced cases of GH-OA that have failed conservative 
management. 
DUROLANE® is a clear, transparent, viscous gel of highly purified non-animal HA 
derived via a bacterial fermentation process (Agerup, et al., 2005). The gel is 
manufactured by Q-Med, a division of Galderma, AB (Uppsala, Sweden) using 
NASHA™ technology, a proprietary process that is designed specifically to provide 
stabilization of the HA. In this process, the natural entanglements that exist in normal 
HA are combined with the introduction of a minute (~1%) number of synthetic cross-
links to create a three-dimensional gel network. Mechanical sieving is used to prepare 
NASHA gel particles of approximately 300µm. DUROLANE product is a suspension of 
NASHA gel particles in phosphate buffered saline with a concentration of 20mg/mL. 

Protocol 13DUR503 Amendment 02 
 
 
 
The product is distributed as a 1mL or 3mL glass syringe. The content of the syringes is 
sterilized by moist heat; the outside of the syringe is not sterile. The shelf life of 
DUROLANE is 36 months. The device has undergone extensive pre-clinical testing to 
demonstrate its safety and to characterize its properties related to the NASHA gel 
structure. 
The three mL version of DUROLANE has been marketed outside of the United States 
since 2001 for use in knee and hip OA. The product was originally introduced into the 
European market and since that time, it has been granted marketing authorization in 
Canada and select markets of the Middle East, Asia, and Latin America. In 2010, 
indications were expanded within the EU to include pain relief associated with OA in 
joints of all sizes (except temporomandibular and facet) and in the treatment of post-
arthroscopic pain. A 1mL product was concurrently introduced as DUROLANE SJ to 
meet the injection needs of smaller joints. Durolane is currently marketed in the EU for 
use in hip, knee, ankle, fingers and toes. 
This study is part of the post-approval commitment to BSi, the European Notified Body 
which granted the expanded indications of the product in 2010. Specifically, it aims to 
evaluate the effectiveness of a single IA injection of DUROLANE 3mL given for the relief 
of pain in patients with diagnosed and symptomatic shoulder osteoarthritis followed over 
a 26-week time period as measured by VAS pain on movement. It also seeks to 
evaluate the product’s safety and tolerability.  
5.1.1. 
Pre-Clinical Documentation 
The composition of DUROLANE is very similar to a product manufactured by Q-Med for 
correction of facial wrinkles and folds, Restylane® (NASHA 20 mg/mL). Therefore, the 
biocompatibility of DUROLANE is primarily based on data obtained for Restylane 
(Restylane IFU, 2011). The biocompatibility tests for Restylane were performed in 
accordance with current requirements for medical devices, i.e., FDA/CDRH guidance 
document G95-1 and the ISO standard 10993 for biological evaluation of medical 
devices (CDRH, 2013). The overall conclusion of these studies was that Restylane 
fulfilled the current biocompatibility requirements for medical devices (Q-Med, 2004). 
The clinical safety of both products is well documented.   
As of today, more than 10,000,000 treatments have been given with Restylane and 
approximately 350,000 treatments with DUROLANE®.  The clinical safety of both 
products is well documented. 
Two pre-clinical studies of DUROLANE in rabbits were conducted at the University of 
Calgary, Canada. The first study was a single IA injection study with a three-week 
follow-up. In the second study, follow-up doses were given six weeks and 12 weeks 
after the first injection. In both studies DUROLANE (0.25 mL) was injected intra-
articularly in the right knee joint and the same volume of saline was injected into the left 
knee joint. Assessments included general health of the rabbits and histopathological 
evaluation which showed no untoward changes or any other adverse reactions. The 
results indicated that DUROLANE was well tolerated and no safety concerns were noted 
(Q-Med, 2000).  

Protocol 13DUR503 Amendment 02 
 
 
 
An additional preclinical study was carried out in Sweden to investigate the IA duration 
of 14C-labeled DUROLANE in a rabbit model. This study shows that DUROLANE has a 
half-life of 32 days in the rabbit knee joint, which is much longer compared to half-lives 
reported in the literature data on HA and other modified HA products (Edsman, et al., 
2011).  
5.1.2. 
 Clinical Documentation of HA use in Shoulder Studies 
There have been 12 studies on the effect of intra-articular HA in reducing pain and 
improving functional outcome in patients with shoulder pathologies published to date. Of 
these, seven included patients with osteoarthritis (Leardini, et al., 1988; Brander, et al., 
2010; Tagliafico, et al., 2011; Noel, et al., 2009; Blaine, et al., 2008; Merolla, et al., 
2011; Silverstein, et al., 2007; Kwon et al., 2013). The rest were indicated for shoulder 
periarthritis/adhesive capsulitis, rotator cuff tear arthropathy and hemophilic chronic 
arthropathy (Rovetta, et al., 1998; Fernández-Palazzi, et al., 2002; Lee, et al., 2009; 
Calis, et al., 2006; Itokazu, et al., 1995).  
Of the 12 shoulder HA studies published to date, seven were prospectively documented 
as a single cohort study (Noel, et al., 2009; Silverstein, et al., 2007; Itokazu, et al., 
1995), one was saline controlled (Blaine, et al., 2008), three were active treatment 
controlled (corticosteroid and physiotherapy arms) (Calis, et al., 2006) and one was a 
controlled study investigating guided and unguided injection techniques (Lee, et al., 
2009). 
Within these studies, five different HA products were used: Hyalgan (Blaine, et al., 
2008); Hylan G-F 20 (Brander, et al., 2010; Noel, et al., 2009; Merolla, et al., 2011; 
Silverstein, et al., 2007); Orthovisc (Calis, et al., 2006); Synvisc (Fernández-Palazzi, et 
al., 2002; unknown HA (Leardini, et al., 1988; Tagliafico, et al., 2011; Rovetta, et al., 
1998; Lee, et al., 2009; Itokazu, et al., 1995). Both Hylan G-F 20 and Orthovisc are 
indicated for use in the shoulder within the EU. The other products appear to be off-
label application for use in the shoulder, although as described, favorable results were 
achieved in this joint. 
Therapeutic regimes ranged from one to 8 injections at intervals from 3 days to 1 month 
between injections with injection volumes of 1-2mL (volume was not identified in one 
study) using needle sizes where specified of 18G – 23G. 
In total 802 patients, treating 805 shoulder joints with HA have been reported in twelve 
studies. Seventy-two patients (73 shoulders) were treated with corticosteroid as active 
control; 221 patients (221 shoulders) received saline control; 21 patients (21 shoulders) 
received physiotherapy; and 20 patients (20 shoulders) performed stretching exercise 
as therapy. 
All studies that evaluated clinically meaningful patient outcomes relating to symptoms 
reported improvement in the HA groups over baseline. Uncontrolled studies 
demonstrated significant improvements in pain and function outcomes out to six months 
over baseline. The controlled studies provide favorable evidence for the effectiveness of 
HA in comparison to physiotherapy, intra-articular saline or intra-articular corticosteroid. 

Protocol 13DUR503 Amendment 02 
 
 
 
It is of note that the large Level 1 study reported significant results in pain reduction over 
saline controls only in patients with OA with no associated pathologies, such as rotator 
cuff tears and/or adhesive capsulitis (Blaine, et al., 2008). The retrospective controlled 
trial by Merolla et al. echoes this finding. The study reported lower clinical advantages in 
patients with greater degree of OA and rotator cuff tears (Merolla, et al., 2011). This 
data does not appear to be in discordance with the adhesive capsulitis study by Calis et 
al. (Calis, et al., 2006) as rotator cuff problems were excluded in this study and 
presence of OA of the shoulder was not mentioned, therefore it is not clear if these 
patients did or did not have OA of the shoulder in addition to a diagnosis of adhesive 
capsulitis. This study revealed significant effects of HA in pain and function outcomes at 
three months over baseline (although physical therapy overall appeared to be the best 
treatment overall).  
Five articles dealing with intra-articular infiltration of HA in patients with shoulder OA 
were prospectively documented as a single cohort. Two studies resulted in a total of 69 
patients who improved on VAS pain after 3 months; improvement is considered 
statistically significant and clinically relevant (Brander, et al., 2010; Noel, et al., 2009). 
Silverstein et al did not provide the statistical difference or range for VAS pain, and 
cannot be pooled (Silverstein, et al., 2007). Leardini et al described a series of 
heterogeneous group of patients with several types of shoulder pain-inducing pathology. 
On all measures of treatment effectiveness, including joint mobility, pain, and analgesic 
consumption, the patients showed rapid and significant improvement (Leardini, et al., 
1988). Tagliafico et al treated 30 patients with cuff tear arthropathy (all patients with 
advanced shoulder OA) showing statistically significant improvement in VAS and 
Constant scores in the first 4 month follow-up with a complete relapse to the same VAS 
pain as pre-injection at 6 months after treatment (Tagliafico, et al., 2011). 
No trends in favor of any one of the preparations were identified. It is of note that the 
study by Noel at al. (Noel, et al., 2009) demonstrated that a single injection of HA, as 
compared to two injections, resulted in superior responder rates (although patient 
populations for single and two injections was different).  
A 2010 meta-analysis of HA use in chronic shoulder conditions (Saito, et al., 2010) 
considered saline controlled clinical studies (which included corticosteroid controlled 
studies). The meta-analysis concluded that HA injection is effective in relief of pain and 
is a safe alternative therapy for chronic painful shoulder. Improvement in pain 
outcomes, and total functional scores was noted with standardized mean differences of 
0.39 (95% CI 0.26-0.53) and 0.36 (95% CI 0.01-0.71), respectively. No improvement in 
shoulder range of movement was found. Lastly it was noted that HA injection was 
modestly more effective than corticosteroid injection. 
Adverse events were not considered or reported in five studies (Merolla, et al., 2011; 
Rovetta, et al., 1998; Calis, et al., 2006) and no adverse events were reported in the 
study conducted by Leardini et al and Itokazu et al (Itokazu, et al., 1995). 
Blaine et al (Blaine, et al., 2008), reported the adverse events most likely to be 
considered to be related to the study treatment were injection-site pain. This occurred in 
3.2% of patients receiving five HA injections as compared to 1.4% of patients receiving 
three HA injections (+ two saline injections) and 1.4% in the saline control group (five 

Protocol 13DUR503 Amendment 02 
 
 
 
saline injections). Tagliafico et all noted no safety concerns during the study except mild 
vagal reactions in 1/30 patients (3%) which occurred in association with the 
percutaneous procedure (Tagliafico, et al., 2011). Overall, all treatments were 
considered to be well tolerated (Leardini, et al., 1988; Brander, et al., 2010; Tagliafico, 
et al., 2011; Blaine, et al., 2008; Itokazu, et al., 1995). Serious adverse events were less 
frequent in both the HA groups than the saline control group. Noel et al., (2009) 
observed ten adverse events in eight patients that were all mild to moderate injection 
site pain.  
Time to resolution was not noted in the publication. Silverstein et al., (2007) reported 
that no adverse events were considered related to the study device and no local pain or 
swelling or injection site irritation was observed. 
Taken together, the data reported indicate the safety and effectiveness of a number of 
HA preparations and therapeutic regimes in the treatment of different forms of OA of the 
shoulder and possibly in degenerative conditions such as adhesive capsulitis. 
5.2. 
Rationale 
Osteoarthritis (OA) is a disease of the synovial joints characterized by the loss of 
cartilage, subchondral sclerosis, cyst formation, joint deterioration and new bone 
(osteophytes) formation around the joint. In addition, the properties of synovial fluid, to 
act as a shock absorber and lubricant for the joint surfaces, are impaired (Balazs, et al., 
1993). In the shoulder joint, osteoarthritis is a common disorder that leads to pain, 
progressive loss of function and diminished quality of life. Glenohumeral osteoarthritis 
usually presents as gradual pain and loss of motion in patients older than 50 years 
(Self, 2002; Iannotti, et al., 2005; Stevenson, et al., 2002). A history of arthritis, previous 
shoulder surgery, pain, crepitus, and decreased motion is consistent with the diagnosis.  
Currently, no curative therapy is available for osteoarthritis, and thus the overall goals of 
management are to reduce pain and prevent disability. Traditional treatments for OA 
include simple analgesics, NSAIDs, IA corticosteroid injections, physiotherapy, activity 
modification, weight reduction, orthotics, and surgery (Hochberg, et al., 2012). NSAIDs 
have proven therapeutic efficacy, but have been noted to have important adverse 
effects such as gastrointestinal bleeding, liver or kidney toxicity, and cardiac disorders. 
In addition the economic burden of providing medical treatment for adverse events 
(AEs) of NSAIDs has been estimated to be more than US $4 billion a year. Intra-
articular corticosteroid injections, although useful for moderate to severe OA not 
responsive to conservative treatments, is contraindicated in diabetics and osteoporotic 
patients or those at risk.  Normally, all other treatment options should be fully exploited 
prior to surgical management of OA, which is expensive, painful, and not risk-free. 
Taking into consideration that chronic use of some oral pain medications may be 
contraindicated, a locally-delivered therapy with no known drug interactions and an 
excellent safety profile is a valuable treatment option for patients. 
Hyaluronic acid is an important component of synovial fluid and cartilage matrix and 
contributes to the homeostasis of the joint environment. Various clinical trials in the 
recent years have shown that hyaluronic acid replacement showed significant 
improvement compared with baseline (Colen, et al., 2012). The OARSI (Osteoarthritis 

Protocol 13DUR503 Amendment 02 
 
 
 
Research Society International) has concluded that intra-articular injection of hyaluronic 
acid may be useful in patients with knee or hip OA. Hyaluronic acid can be used in 
patients with contraindications to NSAIDS and corticosteroids or in patients not suitable 
for operative treatment. Hyaluronic acid (HA) is a polysaccharide secreted into the 
normal joint space by type B synoviocytes or fibroblasts, and it has viscoelastic 
properties for lubrication and chondroprotective effects. Recent studies of human 
synoviocytes from osteoarthritic joints have revealed that exogenous hyaluronic acid 
stimulates de novo synthesis of hyaluronic acid (Smith, et al., 1987), inhibits release of 
arachidonic acid, and inhibits interleukin-1α-induced prostaglandin E2 synthesis by 
human synoviocytes, which reduces the anti-inflammatory response (Yasui, et al., 
1992).  Hence, replenishing the hyaluronic acid component of normal synovial fluid may 
play a role in supplementing the elastic and viscous properties of synovial fluid (Balazs, 
1993; Balazs, 1982), which may help relieve signs and symptoms related to OA and 
improve shoulder function. 
Recently a large (660 subjects) randomized, double-blind, multicenter trial was 
conducted in the United States to compare the HA product Hyalgan® (HA) (Sanofi-
Aventis) to saline injections over a 6-month period for the treatment of chronic shoulder 
pain. Based on radiographic criteria, subjects were stratified at baseline into two major 
groups: those with GH osteoarthritis (GH-OA) (60%) and those without GH-OA (40%). 
Using MRI and other clinical criteria, subjects were further sub-categorized by presence 
of adhesive capsulitis and rotator cuff pathology at baseline. The subjects were 
randomized into one of three treatment groups: five injections of saline, five injections of 
HA, or three injections of HA and two injections of saline. The intent to treat (ITT) 
longitudinal analysis revealed the five HA injection group and the three HA plus two 
saline injection group improved significantly more than the group receiving five saline 
injections over the 6-month period.  There were no significant differences between the 
groups receiving three or five HA injections. Although all groups demonstrated 
improvements from baseline, the greatest treatment benefit was seen in the group of 
patients with GH-OA.  In addition, statistically significant improvement in pain was 
observed in the OA group, regardless of the presence of other shoulder pathologies 
including rotator cuff tears or adhesive capsulitis.  The improvement in pain in the non-
OA group was not statistically different from the saline control group.  These findings 
suggest HA’s therapeutic effect on the shoulder was related to the presence of OA and 
not to other pathologies such as rotator cuff tears.  The safety profile was favorable, 
with a low incidence of injection site pain (<1%) and no significant differences in pain 
between the HA and saline groups. 
HA product injections exert their therapeutic effects on pain by a non-pharmacologic 
mechanism, are not associated with any catabolic actions on the joint tissue, and have 
been repeatedly administered over several years in both the knee and hip. DUROLANE 
has been proven to be an effective treatment for OA in the knee with a low percentage 
of adverse events (AEs). Because DUROLANE has demonstrated a successful history 
of pain relief in the knee with a very low rate of AEs, we believe it will demonstrate 
similar effectiveness for pain relief in the shoulder. 
The purpose of this study is to assess whether the use of a HA-containing synovial fluid 
substitute (DUROLANE®) will relieve pain and result in an improvement of joint function 

Protocol 13DUR503 Amendment 02 
 
 
 
in patients presenting with persistent shoulder pain due to OA. It also seeks to evaluate 
its safety and tolerability. Clinical trials with DUROLANE and other HAs have shown a 
sustained response to treatment up to 26 weeks at least (Agerup, et al., 2005; Edsman, 
et al., 2009). Using this as a basis, the effectiveness and safety assessments for this 
study will be collected over 26 weeks. 
In conclusion, the results of this study should support the current indications in the EU, 
specifically, for symptomatic treatment associated with mild to moderate osteoarthritis 
pain in the shoulder joint. 
5.3. 
Potential Risks and Benefits 
5.3.1. 
Potential Risks 
5.3.1.1. 
Risks Associated with the Use of DUROLANE 
There is a lack of published data related to the use of viscosupplementation for joints 
other than the hip and knee (e.g. ankle, shoulder, temporal mandibular joint, etc.). The 
majority of the reported adverse reactions in DUROLANE clinical studies of the knee 
and hip were described as transient pain, swelling and/or stiffness locally in the joint. It 
is unclear if these adverse reactions were related to the injection procedure or 
DUROLANE. These adverse reactions were mild or moderate in intensity and only 
occasionally required treatment with analgesics. A review of the literature related to the 
use of other HA preparations in other joints did not reveal any additional unique AEs 
(Durolane IFU, 2012). The type of adverse reactions associated with the use of 
DUROLANE in shoulder are likely to be the same as those observed in hip and knee.   
The differences in physical and chemical properties between DUROLANE and other HA 
preparations have been assessed not to influence the safety and tolerability when 
injected intra-articularly (Q-Med, 2012). The risks associated with the IA injection will be 
minimized by only allowing clinicians to participate who have adequate education and 
are experienced in the delivery of IA shoulder therapies.  
As with any treatment, unexpected reactions may occur. The study contains an 
exclusion criterion for those subjects with a previous history of an allergic response to a 
HA-based product. However, should a reaction occur, the subjects will be informed to 
contact the study site immediately and be given immediate advice about any necessary 
medical treatment. 
Many subjects with shoulder pain receive treatment with anti-inflammatory drugs. 
Subjects who decide to take part and are receiving anti-inflammatory drugs must stop 
such treatment for a time sufficient for the given medication to clear the body (at least 5 
half-lives of drug activity) before the shoulder injection is made and refrain from using 
such medications during the rest of the study period. This may increase the risk that 
study subjects experience shoulder or other bodily pain. However, to mitigate such risk, 
all subjects will be allowed to take rescue medication (acetaminophen) during the study 
for such pain. Other analgesics are prohibited.  
All subject use of rescue medication will be recorded in the CRF. 

Protocol 13DUR503 Amendment 02 
 
 
 
5.3.1.2. 
 Risks Associated with Injection 
Certain risks are specifically associated with insertion of a needle into the IA joint space, 
irrespective of the device. Such risks include bleeding, infection, and joint injury, all of 
which are rare.  
The risks associated with IA injections can be minimized by choosing appropriate 
technique, and ensuring accurate needle placement into the IA joint space. Image 
guidance of the needle (via ultrasound or fluoroscopy) is allowed but not required in this 
study. Additionally, strict aseptic procedures should be maintained during the procedure 
to reduce the risk of infection. 
5.3.2. 
Known Potential Benefits 
Taking part in this study may improve the subject’s shoulder OA pain.  
Information from this study may help Investigators learn more about symptomatic 
shoulder OA, treatment for persistent shoulder pain or help identify who is more likely to 
benefit from DUROLANE treatment. 
This information may help future patients with shoulder OA pain. 

Protocol 13DUR503 Amendment 02 
 
 
 
6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Study Objectives 
6.1.1. 
Primary Objective 
To evaluate the efficacy of a single intra-articular (IA) injection of DUROLANE 3mL 
given for the relief of pain in the treatment of symptomatic osteoarthritis (OA) of the 
shoulder followed over a 26-week time period.  
6.1.2. 
Secondary Objectives 
To evaluate the efficacy of a single IA injection of DUROLANE 3mL given for treatment 
of symptomatic OA of the shoulder followed over a 26-week time period for: 
• 
shoulder pain at night  
• 
shoulder range of motion   
• 
shoulder pain rescue medication use  
To evaluate the safety and tolerability of a single IA injection of DUROLANE 3mL over a 
26-week time period 
6.2. 
Study Outcome Measures 
6.2.1. 
Primary Outcome Measures 
The primary outcome measure is the Shoulder Pain on Movement (SPOM) VAS (0-
100mm) scale.   
6.2.2. 
Secondary Outcome Measures 
Secondary outcome measures will include the Shoulder pain at night (SPAN) VAS (0-
100mm) scale, American Shoulder and Elbow Surgeons (ASES) Standardized Shoulder 
Assessment (which includes range of motion and patient self-evaluation of pain today 
and activities of daily living), Patient Global Assessment (PGA) VAS (0-100mm) scale 
and Shoulder pain rescue medication diary.  
Safety and tolerability of DUROLANE 3mL will be assessed through the collection of 
concomitant medications, SAEs and AEs related to the injection procedure and the 
device. Physical exams will be performed as needed. Consumption of rescue 
medication will be collected via subject diaries. 
 
 

Protocol 13DUR503 Amendment 02 
 
 
 
7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a prospective, open-label, single-cohort study to evaluate pain and function 
outcomes and safety following a single IA injection of DUROLANE 3mL in subjects with 
symptomatic shoulder OA. The study will be performed at one site in Canada with 
potential to add additional sites to boost recruitment, if required.  
Adult subjects who have been clinically diagnosed with symptomatic mild to moderate 
OA of the shoulder that meet the inclusion and exclusion criteria will be recruited after 
providing written informed consent. Patients reporting pain per the SPOM VAS (0-
100mm) scale ≥50mm and radiographic evidence of OA will be screened for eligibility. 
Subjects should be willing to discontinue use of oral analgesia, other than 
acetaminophen use. Subjects with significant pain from other joints (neck, hand, hip, 
knee, ankle), or report of >20mm on SPOM VAS (0-100mm) scale for the contralateral 
shoulder, will not be eligible to enroll in the study.   
The study will consist of a screening visit, a Baseline Visit (Week 0) during which an IA 
shoulder injection will be given and follow-up clinic visits at Week 6, Week 12, and 
Week 26 after the Baseline Visit. There will be a telephone contact at Week 18 to collect 
efficacy assessments (excluding the physician range of motion assessment), adverse 
events, concomitant and rescue medication use.   
The effectiveness assessments (excluding range of motion) are completed by the 
patient and the same evaluating investigator should preferably see the patient at all 
visits including the eligibility check at the screening visit. 
7.2. 
Number of Subjects 
In total, approximately 39 subjects will be screened and 36 subjects will be enrolled for 
up to 29 evaluable subjects.  
7.3. 
Treatment Assignment 
This is an open-label, single-treatment study. Qualified subjects will be assigned to 
DUROLANE 3mL only. 
7.4. 
Study Schedule 
Written informed consent will be obtained from prospective subjects prior to enrollment 
to the study. The assessments to be done at each visit are shown in Table 2. In case of 
any withdrawal (subject drop-out before the completion of the intended follow-up 
period), the date and reason for withdrawal will be collected in the CRF.  
 

Protocol 13DUR503 Amendment 02 
 
 
 
Table 2: 
Schedule of Events 
 
Activities 
Visit 1 
(screening) 
Visit 2 
(baseline) 
Visit 3 
Visit 4 
Visit 5 (telephone 
contact) 
Visit 6 (final 
study visit) 
Week -1 to -2 
(≤ 14 days) 
Week 0  
(Day 0) 
Week 6  
(±7 
days) 
Week 
12  
(±7 
days) 
Week 18  
(±7 days) 
Week 26  
(±7 days) 
Informed consent 
X 
 
 
 
 
 
Review of inclusion/exclusion criteria 
X 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical history, including shoulder OA 
X 
 
 
 
 
 
X-ray of the study shoulder 
X1 
 
 
 
 
 
Review of concomitant medications/therapies 
X 
X 
X 
X 
X 
X 
Physical examination including height and weight, vital 
signs 
X 
X 
2 
2 
 
X 
Physical examination of the study shoulder (SS) 
X 
X 
X 
X 
 
X 
Physical examination of the contralateral shoulder 
X 
X 
 
 
 
 
Washout of analgesics 
X3 
X3,4 
X4 
X4 
X4,6 
X4 
Urine pregnancy test 
 
X5 
 
 
 
 
VAS Shoulder pain on movement – contralateral 
shoulder 
X 
X 
 
 
 
 
VAS Shoulder pain on movement – SS 
X 
X 
X 
X 
X6 
X 
VAS Shoulder pain at night – SS 
 
X 
X 
X 
X6 
X 
VAS Patient global assessment 
 
X 
X 
X 
X6 
X 
ASES Patient self-evaluation (VAS pain today and ADL 
only) – SS 
 
X 
X 
X 
X6 
X 
ASES Physician assessment range of motion only – SS 
 
X 
X 
X 
 
X 
Dispense Week 18 VAS pain, PGA, and ASES patient 
self-evaluation forms 
 
 
 
X 
 
 
Intra-articular shoulder injection 
 
X 
 
 
 
 
Instruct subject on rescue medication use 
X 
X 
X 
X 
X 
 
Dispense shoulder pain rescue medication diary 
X 
 
 
 
 
 
Review shoulder pain rescue medication diary and 
record intake on CRF 
 
X 
X 
X 
X 
X 
Review and report adverse events (AEs) 
 
X 
X 
X 
X 
X 
Collect shoulder pain rescue medication diary 
 
 
 
 
 
X 
1. 
If a radiograph was not taken within 6 months of the screening visit, then a radiograph must be taken as standing x-rays in the 
anterior-posterior and lateral plane views.  Radiographs must be read by a local radiologist or the orthopaedic surgeon.  
2. 
As clinically indicated. 
3. 
At least 5 half-lives of current analgesic must have passed before Baseline Visit to confirm eligibility.  
4. 
No acetaminophen is to be taken for 24 hours before each study visit (Weeks 0, 6, 12, 18, 26). No other analgesic is to be 
taken during the course of the study. 
5. 
Urine pregnancy test will be performed on all females of childbearing potential. 
At the Week 12 visit VAS pain, PGA, and ASES patient self-evaluation forms will be dispensed to the subject to be completed 
at the time of the Week 18 telephone contact. 
 
7.4.1. 
Screening Visit 
The prospective subject must be informed about the study both orally and in writing, and 
the ICF must be signed prior to initiation of any study related procedure. Inclusion into 
this study requires literacy in English sufficient to complete the informed consent 
process and ability to complete effectiveness assessment forms. A study number will be 
assigned chronologically to each subject screened per the Screening and Enrollment 
log. Based on a chart review and discussion with the subject, the following demographic 
data will be recorded in the CRF: anonymized subject initials, gender, date of birth, 
ethnic origin, weight, and height. Medical history, including OA history and concurrent 
diseases will be queried and recorded on the CRF. The assessments of OA history at 
the screening visit will consist of: duration of diagnosed shoulder OA (i.e., time since 

Protocol 13DUR503 Amendment 02 
 
 
 
diagnosis), duration of persistent shoulder pain, OA in joints other than the shoulder, 
clinically-significant pain from other parts of the body than the shoulder, and history of 
prior medications and interventions for shoulder OA (including IA injections, surgical 
procedures, and any traumatic injury). Concomitant medications and non-
pharmacological treatment of shoulder OA will be recorded in CRF logs. 
A full physical examination including vital signs, height and weight will be conducted.  
Physical examination of both shoulders will be performed. Evidence of joint 
inflammation, as reflected by clinically-tense effusion and tenderness on palpation will 
exclude the subject from the study.  
Radiographs of the study shoulder will be performed, if a radiograph taken within six 
months of the screening visit does not exist. Assessment of radiographs will be made by 
either the Study Investigator or the local radiologist. The SPOM VAS (0-100mm) 
assessment will be completed for both shoulders. A pain score ≥50mm is required for 
the study shoulder and must be <20mm for the contralateral shoulder to be eligible.  
For eligibility, symptomatic OA of the contralateral shoulder should be responsive to 
acetaminophen and not require any protocol prohibited therapies that would confound 
measurement of pain in the study shoulder. Also, low back pain requiring chronic 
ongoing analgesic therapy is an exclusion criterion. 
The subject will receive, as part of the informed consent, a written explanation of 
shoulder OA and the anticipated AEs associated with DUROLANE injection. Subjects 
should also be informed about medications which are permitted and medications which 
are prohibited during the study period (see Appendix 2). In addition, subjects should be 
informed about post-injection procedures (see Section 9.4.6). 
Acetaminophen will be purchased by the research subject as needed. The research site 
staff will provide written instructions that the dose should not exceed 4g/day and no 
analgesics are to be taken 24 hours prior to any study visit. No other analgesic 
medication is permitted during study participation. A shoulder pain rescue medication 
diary will be provided to record intake of rescue medication and other concomitant 
medications used throughout study participation. The shoulder pain rescue medication 
diary will have written instructions on how to record use of rescue and concomitant 
medications. In addition, instructions on rescue medication dosing and wash-out periods 
prior to study visits will also be provided.  
Screen failures will be recorded in the Screening Log, including a clear description for 
screen failure rationale. For subjects determined to be eligible, the date of enrollment 
will be entered into the Enrollment Log.   
7.4.2. 
Enrollment/Baseline 
No more than two weeks after the screening visit, the subject will return to the clinic for 
the Baseline Visit. This visit must take place after at least five half-lives of pre-screening 
analgesic medication have elapsed and the assessment of radiographs by the 
radiologist or study investigator.  
Subjects should be queried about his/her use of analgesics during the previous 24 
hours and the shoulder pain rescue medication diary checked and rescue medication 

Protocol 13DUR503 Amendment 02 
 
 
 
consumption recorded on the CRF. If acetaminophen was used in the previous 24 
hours, the visit MUST be rescheduled.  
If an analgesic other than acetaminophen was used prior to the visit, ensure the 
appropriate wash-out period (i.e., at least five half-lives) was observed, and if otherwise, 
reschedule the visit. If a reschedule that ensures appropriate wash-out of analgesic 
would fall outside the visit window, then the subject will be excluded from the study and 
recorded as screen failure in the Screening Log.  
A urine pregnancy test should be performed for all women of childbearing potential. A 
positive result excludes the subject from the study. Pregnancy after enrollment must be 
communicated to the investigator. No other mandatory clinical chemistry or hematology 
tests will be performed during this study. 
Before administering the study injection, SPOM VAS (0-100mm) ASES pain on 
movement assessment will be completed for both shoulders. A pain score ≥50mm is 
required for the study shoulder and no more than 20mm for the contralateral shoulder to 
be eligible. The SPAN VAS (0-100mm), ASES patient self-evaluation (VAS pain today 
and activities of daily living only), ASES physician ROM assessment will be completed 
for the study shoulder only. The PGA (0-100mm) will also be completed at this visit. 
A full physical examination including vital signs, height and weight will be conducted. 
Physical examination of both shoulders will be performed. The investigator will 
determine if the study shoulder has a clinically-apparent tense effusion or signs of 
misalignment or instability. If it has either, then the subject must be excluded.   
The inclusion/exclusion criteria will be verified. If a subject fails any of these 
inclusion/exclusion criteria the subject should be recorded as a screen failure in the 
Screening and Enrollment Log and will be excluded from the study.  
Subjects will be informed about possible anticipated AEs following the IA injection. The 
shoulder pain rescue medication diary will be reviewed and any necessary counseling 
regarding use of rescue and other concomitant medication will be given as needed. The 
shoulder pain rescue medication diary will be returned to the subject at each visit 
starting from the Screening Visit to record intake of rescue medication and other 
concomitant medications. 
Instructions on how to take acetaminophen as rescue medication will be provided. The 
subject will again be reminded that the acetaminophen intake should not exceed 4g/day 
and that none is to be taken 24 hours prior to any study visit. Subjects will also again be 
reminded that no other analgesia should be used during study participation.  
If for any reason, injection is not possible during the Baseline Visit (Week 0), the 
injection may be rescheduled for up to two days after the Baseline Visit provided it is 
within 14 days from the Screening Visit. Subsequent study visits will be based on 
calendar days from the date of the Day 0 injection. Eligibility must be reconfirmed prior 
to injection. 
Thereafter, at Investigator’s discretion, topical anesthesia (using ethyl chloride or 
lidocaine spray) or subcutaneous lidocaine may be given followed by the IA injection of 
DUROLANE. If effusion is found in the shoulder upon needle placement in the joint 

Protocol 13DUR503 Amendment 02 
 
 
 
space, it must be removed (arthrocentesis) before DUROLANE is injected. The amount 
of fluid removed will be documented in the CRF. The injection procedure will be 
conducted by the Investigator. See Section 9.4 for more details. 
Image-guidance may be used to ensure proper IA placement of the treatment with the 
assumption that the investigator is experienced with the use of the type of imaging 
used. 
To monitor for possible injection procedure-related events, subjects should remain at 
the study site for 30 minutes following injection. Acetaminophen to relieve post-injection 
pain is allowed. All subjects should be informed about post-injection procedures (see 
Section 9.4.6). 
7.4.3. 
Follow-up Visits (Weeks 6, 12 and 18) 
Weeks 6 and 12: Subjects will return to the clinic for Visit 3 (Week 6) and Visit 4 (Week 
12) after the baseline injection of DUROLANE. The SPOM VAS (0-100mm), SPAN VAS 
(0-100mm), ASES patient self-evaluation (VAS pain today and activities of daily living 
only), and ASES physician ROM assessment will be completed for the study shoulder 
only. The PGA (0-100mm) will also be completed at this visit.  If clinically indicated, a 
full physical examination will be performed. 
Week 18: Patients will receive a follow-up telephone call from the research staff at Visit 
5 (Week 18) after the baseline injection of DUROLANE. The subject will be asked to 
complete the SPOM VAS (0-100mm), SPAN VAS (0-100mm), and ASES patient self-
evaluation (VAS pain today and activities of daily living only) for the study shoulder. The 
PGA (0-100mm) will also be completed at this visit. All efficacy assessments will be 
returned to the study site by mail.  
At all visits: Subjects will be queried about any AEs since the last visit. The subject diary  
for rescue and other concomitant medications will be reviewed and any necessary 
counseling regarding use of rescue and other concomitant medication will be given as 
needed. Use of rescue medication and concomitant medication since last visit will be 
recorded on the CRF. Instructions that the acetaminophen dose should not exceed 
4g/day and that the 24-hour wash-out prior to any study visit will be discussed with each 
subject at length. The subject shall also be reminded that no other analgesia should be 
used.  
Return the shoulder pain rescue medication diary to subjects at each clinic visit 
(excluding Week 18), unless a replacement is needed. This enables the subject to 
record their intake of rescue medication and other concomitant medications used 
between clinic visits. 
7.4.4. 
Final Study Visit (Week 26) 
Subjects will return for the final visit of the study, Visit 6, 26 weeks after injection of 
DUROLANE at baseline. The SPOM VAS (0-100mm), SPAN VAS (0-100mm), ASES 
patient self-evaluation (VAS pain today and activities of daily living only), and ASES 
physician ROM assessment will be completed for the study shoulder. The PGA (0-

Protocol 13DUR503 Amendment 02 
 
 
 
100mm) will also be completed at this visit.  A full physical examination will be 
performed. 
Subjects will be queried about any AEs since the last visit. The diary for rescue and 
other concomitant medications will be reviewed for use of rescue medication and 
concomitant medication since the last visit will be recorded on the CRF. The shoulder 
pain rescue medication diary will be collected at the Final Study Visit.   
7.4.5. 
Early Withdrawal 
The End of Study form will be completed for all subjects, including withdrawals. For 
subjects who wish to withdraw from the trial, monitoring of outcome measures by 
registered mail must be offered. All assessments scheduled for the Week 26 visit must 
be completed for early withdrawals. Completion of the questionnaires will document 
data on the safety and efficacy of the injection throughout the study. 
For subjects who wish to withdraw completely and are not amenable to being followed 
and for other subjects who had to be discontinued prematurely, the primary reason for 
discontinuation must be recorded.  
Subjects lost to follow-up are defined as those who are unrecoverable for the final 
Week 26 visit assessments.  
7.4.6. 
Unscheduled Visit  
An unscheduled visit may be performed at any time during the study at the subject’s 
request or as deemed necessary by the site Investigator. The date and reason for the 
unscheduled visit will be recorded in the source documentation and CRF.  
 

Protocol 13DUR503 Amendment 02 
 
 
 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Subjects will be recruited from outpatient clinics. Referrals from general practitioners 
and extended scope practitioners such as physiotherapists will be accepted. A Dear 
Healthcare Provider letter and/or an advertisement (approved by the REB) in a local 
newspaper may be used if considered appropriate.  
Informed consent will be administered to the potential subjects prior to screening. Each 
patient must have met all eligibility criteria before the IA injection is given at the Baseline 
Visit. 
8.1. 
Subject Inclusion Criteria 
1. Females or males between the ages of 19 and 85 years of age 
2. Diagnosis of glenohumeral osteoarthritis (GH-OA), confirmed by radiographs 
taken within the previous six months, with GH-OA being the primary source of 
pain; OA in the contralateral shoulder is permissible provided that OA symptoms 
are greater in the trial shoulder 
3. Shoulder pain on movement (SPOM) visual analogue scale (VAS) (0-100mm)  
≥50mm for the study shoulder 
4. Must be willing to discontinue use of oral and topical analgesia other than rescue 
use of acetaminophen for the study shoulder. Must also be willing to discontinue 
rescue medication for at least 24 hours before each visit 
5. Abstinence from any IA or peri-articular injections for the shoulder during the 
course of the trial, except for the assigned Investigational Product 
6. Patients with chronic shoulder pain lasting more than 6 months without clinically 
significant improvement in shoulder pain over the past one month 
7. Pain at least 50% of the days during the previous month 
8. Patients who have failed conventional therapy including but not limited to the 
following: nonsteroidal anti-inflammatory drugs (NSAIDs); one or more intra-
articular or local peri-articular steroid injections and physiotherapy (a minimum of 
one month of previous physiotherapy treatment is required) 
9. Patients with a retained active range of motion (ROM) of at least 30% in all 
directions to rule out frozen shoulder (>30° for abduction with scapula fixed, >30° 
for external rotation, and >20° for internal rotation)  
10. Cooperative and able to communicate effectively with the Investigators 
11. Must agree not to participate in any other clinical research (interventional) studies 
while participating in this study  
12. Body mass index (BMI) ≤ 35 kg/m2 
13. English literacy and ability to understand and complete all informed consent 
procedures 

Protocol 13DUR503 Amendment 02 
 
 
 
8.2. 
Subject Exclusion Criteria 
1. Significant pain from other joints or low back pain requiring chronic ongoing 
analgesic therapy 
2. Presence of one or more conditions besides OA that could confound pain and 
functional assessments in the study  shoulder 
3. Clinically-apparent tense effusion or gross  misalignment or instability in the 
study  shoulder  
4. Shoulder x-ray findings of acute fractures, severe loss of bone density, avascular 
necrosis and/or severe deformity  
5. Surgery of the study joint within the previous 12 months. 
6. Treatment with NSAIDs or any pain management medications (including topical 
agents for the study shoulder) during the last week (or five half-lives of the drug, 
whichever is longer) prior to Baseline Visit. 
7. Inability to tolerate acetaminophen for rescue medication use. 
8. Use of acetaminophen or any other analgesics during the 24 hours preceding the 
baseline visit. 
9. IA or local peri-articular corticosteroid injections to the study joint or shoulder 
within the previous three months; or to any other joint within the previous month; 
or any oral corticosteroid within the previous month. Steroid inhalants are 
permitted if the patient has been on a stable regimen for the past month and 
remains on this regimen throughout the course of the trial 
10.  IA injections with hyaluronic acid in the study shoulder within the last 9 months  
11.  Previous allergic reaction to a HA or local anesthetic such as lidocaine. 
12. Treatment with glucosamine/chondroitin sulfate initiated within the past three 
months, or dosage not stable for the past three months 
13. Change in physical therapy for the study shoulder within one month preceding 
screening, or expected change in physical therapy  during the study 
14. Planned surgical procedure during the study period. 
15. Previous history or presence of septic arthritis in study joint   
16.  Active skin disease or infection in the area of the injection site 
17.  Alcohol or drug abuse as determined by the Investigator or use of alcohol for 
control of  pain 
18.  Use of illicit drugs including cannabis  
19. Systemic inflammatory condition or autoimmune disease or infection such as 
rheumatoid arthritis, inflammatory arthritis, ankylosing spondylitis, psoriatic 
arthritis, reactive arthritis, gout/ acute pseudo gout or any other connective tissue 
disease 

Protocol 13DUR503 Amendment 02 
 
 
 
20. Uncontrolled hypothyroidism 
21. Use of  aspirin  (acetylsalicylic acid) as an analgesic (up to  325 mg/day for 
anticoagulant treatment is permissible) 
22. Any medical condition which in the opinion of the investigator makes the patient 
unsuitable for inclusion (e.g., severe progressive chronic disease, malignancy, 
bleeding disorder, fibromyalgia)  
23. Pregnant or breast-feeding woman or woman of child-bearing potential not 
practicing adequate contraception. 
24. Subjects that in the opinion of the investigator are unsuitable for inclusion (e.g., 
subjects not likely to avoid other therapies, subjects not likely to stay in the study 
or with plans to relocate during the  study period, or subjects likely to be 
unreliable)  
25. Concurrent participation in any other clinical study or participation within the 
preceding 30 days 
8.3. 
Screen Failures 
A screen failure is a subject who signed the ICF, but never received treatment with 
Investigational Product. Screen failure reasons will be documented in the Screening and 
Enrollment logs and all study assessments completed through determination of 
ineligibility will be documented. 
8.4. 
Subject Compliance 
Subject compliance describes how well the subject follows the prescription of the 
treatment and instructions of dosing. As the Investigator will give the treatment to the 
subject at the center, no other measurements of subject compliance will be performed. 
8.5. 
Subject Withdrawals 
8.5.1. 
Reasons for Withdrawal 
Participants may voluntarily withdraw from the study for any reason at any time. The 
Principal Investigator also may withdraw subjects from the study to protect their safety 
and/or if they are unwilling or unable to comply with required study procedures, after 
consultation with the Sponsor. Subjects also may be withdrawn if the Sponsor or site 
REB terminates the study prior to its planned end date. Every reasonable effort is made 
to complete a final evaluation of subjects who withdraw or are withdrawn from the study 
prior to completing follow-up. Study staff members will record the reason(s) for all 
withdrawals in subjects’ study records. In the event that subjects who voluntarily 
withdraw from the study wish to re-join the study, they may resume follow-up through 
their originally scheduled study exit date, pending consultation with the Sponsor.  
Use of analgesics other than rescue medication (acetaminophen) for pain management 
is not allowed. Increased acetaminophen usage may signal worsening of the disease 
under study or of a pre-existing disease other than shoulder pain. Investigator plans to 

Protocol 13DUR503 Amendment 02 
 
 
 
withdraw a subject for any reason must be communicated to the Sponsor. Subjects’ 
safety must always take precedence. The Sponsor must be informed within 24 hours of 
all study subjects who are withdrawn due to an AE. 
8.5.2. 
Handling of Withdrawals 
If the patient consents, monitoring for subject reported outcomes and for any AE should 
continue via certified letter within the prescribed study visit window. For subjects who do 
not wish to be followed but had an AE which, according to the Investigator’s 
assessment, is related to the use of the Investigational Product and remains ongoing at 
the time of the withdrawal, the AE must be followed until the event resolves or is 
assessed by the Investigator to be “chronic” or “stable”. 
8.6. 
Study Pause  
Following a decision from the Sponsor, study enrollment may be suspended at any time 
on medical grounds. Examples of these findings are the number of SAEs overall, the 
number of occurrences of a particular type of SAE, severe AEs/reactions, or increased 
frequency of events. In the event of enrollment suspension, the Sponsor will promptly 
inform the investigator/hospital, the competent authorities and research ethics 
committee, stating the reasons for this decision.  
8.7. 
Termination of Study  
The Sponsor reserves the right to end the study at any time prior to inclusion of the 
intended number of subjects, but intends to exercise this right only for valid scientific or 
administrative reasons.  
After such a decision, all delivered unused Investigational Product and other study 
materials must be collected without delay and the CRFs completed. 

Protocol 13DUR503 Amendment 02 
 
 
 
9. 
INVESTIGATIONAL PRODUCT  
9.1. 
Investigational Product Description 
DUROLANE is a clear, transparent, viscous gel of highly purified non-animal hyaluronic 
acid derived via a bacterial fermentation process. The content of the syringes are 
sterilized by moist heat, the outside of the syringe is not sterile.  
9.2. 
Investigational Product Packaging and Labeling 
Commercially-available DUROLANE 3mL will be used as Investigational Product. The 
Investigational Product is manufactured, packaged, and labeled by Q-Med.  
9.3. 
Investigational Product Storage and Stability 
The expiry dates are indicated on the package. The syringes should be stored at up to 
30C, protected from sunlight and freezing. The storage of Investigational Product at the 
study site must be kept separate from other supplies and in a secure location. 
Packages/syringes must be opened by designated personnel only. Once the 
package/syringes have been opened, the sterile barrier is broken. Opened 
packages/syringes should not be re-used. The shelf life of DUROLANE is 36 months. 
9.4. 
Investigational Product Administration      
9.4.1. 
General Instructions 
The treatment will be injected by the Investigator or treating physician into the study 
shoulder of each subject. Use of imaging is optional. The recommended needle size for 
the IA injection for the shoulder is between18 to 22 G with appropriate length. The 
needle is not provided in the investigational product package. 
The Investigational Product is intended for single use and strict aseptic administration 
technique must be followed. The contents of the syringe must be used immediately after 
the syringe has been removed from its packaging.  
Strict aseptic technique must be followed. The injection site should be disinfected 
carefully according to standard medical practice. Disinfectants containing quaternary 
ammonium salts, such as benzalkonium chloride, which may induce precipitation of HA, 
should be avoided. 
The date, whether complete or incomplete device contents were administered, and 
which shoulder was treated will be recorded in the CRF by the Investigator. After having 
made the injection, the syringe and packages should be discarded in an appropriate 
manner.  

Protocol 13DUR503 Amendment 02 
 
 
 
9.4.2. 
Injection of DUROLANE  
The injections will be performed by Investigators who are very well experienced with this 
type of administration. He or she will have previously chosen the most appropriate 
injection route based on the anatomy of the subject's shoulder. 
Remove the pre-filled 3mL syringe from its packaging and use only if the packaging has 
not been opened or damaged. The Investigational Product is intended for single use 
and strict aseptic administration technique must be followed.  
Syringes used for aspiration prior to injection and needles for injection of Investigational 
Product will be supplied by the sites. Required sizes of needles will be in the range of 
18 to 22G with appropriate length. 
9.4.3. 
Anesthetization of the Injection Site  
Anesthetization of the injection site is not required. However, the Investigator or treating 
physician may administer at his/her discretion a topical anesthetic (e.g., ethyl chloride or 
lidocaine spray) or subcutaneous lidocaine as part of the injection procedure. 
9.4.4. 
Use of Imaging Guidance 
Injection by image guidance is at the discretion of the Investigator. Use of image 
guidance will be recorded in the CRF. 
9.4.5. 
Arthrocentesis 
The presence of clinically-apparent tense effusion in the study shoulder will exclude the 
subject from inclusion in the study. If effusion is found in the shoulder upon needle 
placement in the joint space, it must be removed (arthrocentesis) before study/reference 
product is injected.  
Strict aseptic technique must be followed. The same needle will be used for 
arthrocentesis and the IA injection. Needles from 18 to 22G will be supplied by each 
study site and the study personnel will choose an appropriate needle. 
Gentle aspiration will be performed prior to injection of the study treatment for each 
subject in an attempt to ascertain that the needle has been placed within the joint 
space. Any joint fluid will be withdrawn using an empty 20mL syringe (supplied by each 
study site) and the volume of the aspirated fluid will be recorded in the CRF.  
Leaving the needle in the joint space, the aspiration syringe will be removed and 
replaced by the pre-filled 3mL syringe containing DUROLANE. Care must be taken 
when exchanging syringes to avoid displacement of the needle and to ensure the 
syringe with Investigational Product is securely attached prior to injection. 
9.4.6. 
Post-Injection Care 
To monitor for possible injection procedure-related events, subjects should remain at 
the study site for 30 minutes following injection. 

Protocol 13DUR503 Amendment 02 
 
 
 
The subjects should be encouraged to rest the injected joint as much as possible for at 
least 24 hours. Subjects are allowed to return to work, but strenuous activities and 
driving long distances should be avoided the first 48 hours after injection.  
Subjects should be informed that there could be pain associated with the injection 
procedure. For post-injection pain management, subjects should rest and apply ice at 
the injection site for 20-minute intervals, if needed. In the event of persistent pain, the 
subject may take recommended rescue medication (see Section 10). All 
pharmacological and non-pharmacological treatments of post-injection pain must be 
captured in the CRF. 
9.4.7. 
Documentation of Treatment Procedure 
All procedures will be carefully documented in the medical notes and in the CRF. The 
subject number, date and time of injection, study shoulder, needle size, possible use of 
topical, subcutaneous and intra-articular anesthetics, arthrocentesis volume, volume of 
Investigational Product (3mL) injected and possible technical or medical problems with 
the injection will be recorded in the CRF by the Investigator. 
After the injection, the syringe and packages should be discarded according to 
approved institutional disposal policy. An Investigational Product Dispensing Log is to 
be maintained by the site. 
9.4.8. 
Reporting Technical Complaints 
All technical complaints regarding the Investigational Product are to be reported to the 
Sponsor promptly. 
AEs and other clinical findings prior, during or immediately post-injection must be 
recorded. Subjects experiencing pain and swelling at the study shoulder or any other 
AEs will be instructed to contact the study staff. 
9.5. 
Investigational Product Accountability 
The product will be released to each Investigator (or pharmacy located at the study site) 
after approvals of the protocol have been received from the REB and the Clinical Trial 
Agreement (CTA) has been finalized and signed by the study site. 
The Investigator must ensure that the Investigational Product is kept under secure 
conditions, with access limited to those authorized by the Investigator per the 
Delegation of Authorities Log. 
The Investigational Products must be traceable from the manufacturer to their use in 
subjects and the Investigator must maintain accurate product accountability records, 
i.e., documentation of deliveries and return of Investigational Product between the 
Sponsor or their representative and the Investigator, and documentation of 
administration of product to the subject.  
A log will be kept of all Investigational Product received from the Sponsor. In addition, 
dispensing logs will be maintained including the date, amount dispensed, and the 

Protocol 13DUR503 Amendment 02 
 
 
 
subject receiving Investigational Product. Logs for all accountability procedures are 
provided by the Sponsor. 
When the study is completed, all unused investigational product at each study site must 
be returned to the Sponsor for destruction, with proper documentation, unless otherwise 
instructed by the Sponsor. 
Products deliberately or accidentally destroyed during shipment or at a study site should 
be accounted for and documented. Used syringes should be destroyed according to the 
procedures at the clinic. Disposal of hazardous material, i.e., syringes and needles, 
must conform to applicable laws and regulations. The Investigational Product must not 
be used outside the study.  

Protocol 13DUR503 Amendment 02 
 
 
 
10. 
CONCOMITANT MEDICATIONS /TREATMENTS 
Except as noted below, concomitant medications or other treatments or procedures may 
be given at the discretion of the Investigator when medically necessary. All concomitant 
therapy used during the study, should be recorded in the CRFs, by the name (generic 
name for pharmacological therapy), start and end date, and indication.  
The restrictions on treatments and the specified time periods prior to and during the 
study are provided in the inclusion/exclusion criteria. Except for analgesic given for 
management of persistent post-injection pain and for short-term relief of pain other than 
shoulder pain, the Investigator should contact the Sponsor prior to implementation of 
these therapies. All such therapy used during the study is to be recorded in the CRF. 
For rescue medication, subjects will be instructed to take as needed of acetaminophen 
not to exceed 4g/day. Subjects will be required to purchase this for themselves as 
needed. A shoulder pain rescue medication diary will be provided to the subject at the 
screening visit to record intake of rescue medication. The diary will be reviewed at 
baseline, Week 6, Week 12, Week 18 (via phone) and Week 26. Any use of rescue 
medication since last visit will be recorded in the CRF. 
Acetaminophen is also the preferred analgesic for other types of body pains while the 
subject is in the study. Usage will be documented in the subject’s shoulder pain rescue 
medication diary and Concomitant Medications CRF page.  
Any concomitant medications, including over-the-counter (OTC) medications, 
administered during the study are also to be recorded in the CRF and in the shoulder 
pain rescue medication diary. 
 

Protocol 13DUR503 Amendment 02 
 
 
 
11. 
CLINICAL EVALUATIONS 
11.1. 
Demographics (Screening Visit) 
The demographic data will consist of: subject study number, sex, age, race, ethnicity, 
height, weight, body mass index, and child-bearing potential for females. 
11.2. 
Medical and Medications History (Screening Visit/Baseline 
Visit) 
Medical history and concurrent diseases will be reviewed. History will be obtained from 
interview and review of medical records. History of analgesic use will be elucidated, an 
appropriate wash-out period will be prescribed and Baseline Visit will be scheduled for 
the end of this period, and within 14 days of the screening visit.  
11.3. 
Concomitant Medications (All Visits) 
Any therapies for other diseases that are considered necessary for the subject's welfare 
may be given at the discretion of the Investigator. All concomitant therapy used during 
the study, should be recorded in the CRFs by the name (generic name for 
pharmacological therapy), the start and end date, and indication.  
Acetylsalicylic acid up to 325mg per day is allowed during the study as thrombosis 
prophylaxis. Acetylsalicylic acid for analgesic purposes is not allowed. The prohibition 
for taking any analgesic 24 hours before a visit also applies.  
No other product under investigation may be used concomitantly with the Investigational 
Product.  
11.4. 
Non-pharmacological treatment (All Visits) 
Non- pharmacological therapy will be noted in the CRF. This may include but are not 
limited to: 
 resting the shoulder joint 
 physical therapy 
 range-of-motion exercises 
 appropriate application of ice and moist heat  
 patient education 
 self-management programs 
 personalized social support through telephone contact 
 aerobic and muscle-strengthening exercises  
 occupational therapy 
 joint protection and energy conservation 

Protocol 13DUR503 Amendment 02 
 
 
 
 assistive devices for activities of daily living 
New therapies may not be initiated during the study. See Appendix 2 .  
11.5. 
Physical Examination of Shoulder (All Visits) 
The physical examination of the study shoulder at screening will include assessment for 
joint inflammation seen as joint effusion and/or tenderness on palpation. The skin over 
the study shoulder will also be observed for any infection. 
11.6. 
Pregnancy Test (Baseline Visit) 
At the Baseline Visit, a urine pregnancy test should be performed for all women of 
childbearing potential to be processed locally. A positive result excludes the subject 
from the study. No other mandatory clinical chemistry or hematology tests will be 
performed during this study. 
 
 

Protocol 13DUR503 Amendment 02 
 
 
 
12. 
ASSESSMENT OF EFFICACY 
The choice of outcome measures in this study is based on recommendations on 
measures to be used in clinical studies on OA of the shoulder. Effectiveness 
assessments will be completed by subjects at each scheduled study visit at Week 6, 
Week 12, Week 18 and Week 26 after the injection visit. 
The primary efficacy assessment will be the VAS (0-100mm) shoulder pain on 
movement. A Visual Analog Scale (VAS) is a measurement instrument that measures a 
characteristic or attitude that is believed to range across a continuum of values and 
cannot be objectively recorded. A VAS is a horizontal line, 100mm in length, anchored 
by word descriptors (i.e., no pain, worst pain imaginable) at each end. For this study, 
the subject will mark the line at the point that they feel represents their perception of his 
or her pain in the last 24 hours. The VAS score is determined by measuring in 
millimeters from the left end of the line to the point that the subject marks (Burckhardt, 
et al., 2003; Johnson, 2005; Paul-Dauphin, et al., 1999)   
The secondary efficacy variables will include the VAS (0-100mm) shoulder pain at night, 
American Shoulder and Elbow Surgeons patient self-evaluation (VAS pain today and 
activities of daily living only), ASES physician ROM assessment, and PGA. In addition 
to the efficacy assessments described above, the consumption of rescue medication will 
be accessed.  
In this study the SPOM, SPAN, ASES patient self-evaluation (VAS pain today and 
activities of daily living only) and PGA are completed by the patient at each study visit. 
The ASES physician ROM is completed by the Investigator. The same evaluating 
investigator should preferably see the patient at all visits in order to present the 
questionnaires for the patient in a uniform way throughout the study. If more than one 
investigator has assessed any patient at any time-point during the study, it should be 
documented in the CRF. 
At baseline all efficacy assessments have to be performed before the study product is 
injected. All assessments should be made without comparing the data from the 
assessments at previous visits. 
12.1. 
Shoulder Pain on Movement (SPOM) VAS (0-100mm)  (All 
Visits) 
The SPOM VAS (0-100mm) scale will be completed both for the study shoulder and the 
untreated shoulder on the screening visit to exclude significant pain on the contralateral 
shoulder that might affect pain assessments. 
The self-administered SPOM VAS (0-100mm) scale will contain the instruction below for 
the subject: 
“How severe has your pain on movement been in the last 24 hours? Place a vertical 
mark in the line below to indicate how severe your pain has been.” 
 

Protocol 13DUR503 Amendment 02 
 
 
 
  
12.2. 
Shoulder Pain at Night (SPAN) VAS (0-100mm) (All Visits) 
 
The self-administered SPAN VAS (0-100mm) scale will contain the instruction below for 
the subject: 
“How severe has your pain at night been in the last 24 hours? Place a vertical mark in 
the line below to indicate how severe your pain has been.” 
 
12.3. 
American Shoulder and Elbow Surgeons (ASES)  
 
In 1993 the American Shoulder and Elbow Surgeons society (ASES) adopted a 
standardized form for the assessment of shoulder function.  The ASES form contains a 
patient self-evaluation section and a physician assessment section.  The form is used to 
measure baseline shoulder function and is applicable to all subjects regardless of their 
diagnoses.  
12.3.1. 
ASES Range of Motion (ROM) (Screening, Baseline, Week 6, Week 12 
and Week 26) 
 
The ASES physician-administered ROM will contain instructions for the assessment of 
the subject’s shoulder active range of motion (measured in degrees) for the movements 
of abduction, extension, forward elevation, external rotation, internal rotation, cross-
body adduction will be taken using a 41 cm universal goniometer.  
 
12.3.2. 
ASES Patient Self-Evaluation (All Visits) 
The ASES patient self-evaluation (PSE) portion contains a VAS for pain today and 
instability and a questionnaire for activities of daily living (ADL).  In this study, patients 
will only complete the VAS pain today and activities of daily living only sections of the 
patient self-evaluation form. The ADL questionnaire is marked on a four-point ordinal 
scale that can be converted to a cumulative ADL index. A Shoulder Score Index (SSI) 
can then be derived from the VAS pain today score and the cumulative ADL score.   
 
The patient self-evaluation section consists of eleven items divided into two areas: 
1. Pain (one item): The question asked is: “How bad is your pain today?” the 
patient’s response to the pain today question is marked on a 0-10cm (equal to 0-
100mm) VAS scale anchored with verbal descriptors at 0 (No pain at all) and 
100mm (Pain as bad as it can be). 

Protocol 13DUR503 Amendment 02 
 
 
 
2. Function (ten items): the items in the function area assess activities of daily 
living (1. put on a coat, 2. sleep on your painful or affected side, 3. wash back/do 
up bra in back, 4. managing toilette, 5. comb hair), demanding activities (6. reach 
a high shelf, 7. lift 10 pounds above shoulder, 8. throw a ball overhand) and 
general activities (9. do usual work, 10. do usual sport). The possible responses 
are 0 (unable to do), 1 (very difficult to do), 2 (somewhat difficult), and 3 (not 
difficult). 
 
12.4. 
Patient Global Assessment (PGA) (All Visits) 
The VAS Patient Global Assessment (PGA) asks a patient to rate on a scale how they 
feel overall. The scale goes from 0 (zero) to 10. Only the two extremes have text: level 0 
is defined as “Very poor” and level 100 as “Excellent”. 
 
The self-administered PGA will contain the instruction below for the subject: 
“Considering all the ways your target shoulder affects you, how are you doing today?” 
The subject should mark the alternative that he/she finds appropriate (Pincus, et al., 
1989). 
12.5. 
Recorded Use of Rescue Medication 
Subjects will be advised to take acetaminophen as rescue medication for study shoulder 
pain as required. Acetaminophen intake will be recorded in the shoulder pain rescue 
medication diary which will be transcribed on the CRF. 

Protocol 13DUR503 Amendment 02 
 
 
 
13. 
 ASSESSMENT OF SAFETY 
 
All AEs which occur during the course of the subject’s involvement in the clinical 
investigation shall be appropriately recorded and reported to ensure their continuing 
safety. The Medical Devices Regulations SOR/98-282 and the Guidance Document for 
Mandatory Problem Reporting for Medical Devices provides guidance for Post-Market 
Vigilance Reporting and sets out specific requirements for the management of AEs. 
Each type of AE is subject to different reporting requirements.  
All AEs must be followed until they are resolved or the study has ended. In addition, all 
serious, as well as, non-serious AEs with a causal relationship to the device under 
investigation and/or its usage must continue to be followed until resolved or until the 
Investigator assesses them as chronic or stable, even if the subject's participation in the 
study is otherwise completed.  See Appendix 3 for more details. 
 

Protocol 13DUR503 Amendment 02 
 
 
 
14. 
STATISTICS 
14.1. 
Methods 
14.1.1. 
General 
There is a single pre-planned hypothesis test for the primary variable. There are no pre-
planned hypotheses tests for secondary or exploratory efficacy variables or safety 
variables. Any inferential statistic for these variables is exploratory. All variables will be 
summarized using descriptive statistics such as sample size, mean, standard deviation, 
median, minimum and maximum and frequencies, i.e. counts and percents. All other 
analyses details will be described in a statistical analysis plan (SAP). 
14.1.2. 
Safety 
The incidences of all AEs and serious AEs, complaints and complications will be 
monitored for all subjects that signed an informed consent.  However, safety analysis 
shall be carried out on those subjects that were enrolled into the study and received the 
DUROLANE 3mL injection (the Safety Population). Since this is a single arm study 
there are no inter-group comparisons. Nevertheless, all events will be reviewed by the 
Investigator and categorized in terms of both severity and the likelihood that these 
events were caused as a result of using DUROLANE 3mL. Enrollment will be paused 
for thorough review in the event of any serious AE deemed to be as a direct result of 
using the treatment. 
Below are general considerations for summary and display of AEs and concomitant 
medications. Additional safety analyses will be described in a SAP. 
Adverse Events 
 AEs will be coded using the current MedDRA dictionary. 
 All AEs will be summarized by MedDRA primary system organ class (SOC) 
and preferred term (PT). If a subject has more than one occurrence of the 
same preferred term then they will be counted only once in a summary table 
for that preferred term. 
 A listing by subject of all AEs will be provided. Listings of serious AEs and 
AEs leading to discontinuation will also be provided.  
Concomitant Medications 
 Concomitant medications will be coded using the WHO dictionary. 
 All concomitant medications will be summarized by WHO generic term. If a 
subject has more than one occurrence of the same generic term then they will 
be counted only once in summary tables for that generic term. 
 A listing by subject of all concomitant medications will be provided. 
 

Protocol 13DUR503 Amendment 02 
 
 
 
Physical Exams (performed as needed): 
 A listing by subject of all abnormal physical exams will be provided. 
14.1.3. 
Efficacy 
14.1.3.1. Primary Variable 
 
VAS (0-100mm) SPOM over weeks 0, 6, 12, 18 and 26  
14.1.3.2. Primary hypothesis 
 
Ho:   VAS SPOM over weeks 6, 12, 18 and 26 ≥ VAS SPOM at week 0 (baseline) 
Ha:   VAS SPOM over weeks 6, 12, 18 and 26 < VAS SPOM at week 0 (baseline) 
14.1.3.3. Primary hypothesis statistical test method 
A mixed effect repeated measures (MERM) regression will be used. VAS SPOM will be 
the dependent variable. The weeks 0 (baseline), 6, 12, 18, and 26 visits will be a fixed 
effect covariate. Subjects will be random effects. The correlation structure will be 
unstructured. If convergence is problematic then an alternative covariance structure will 
be necessary. A contrast will be constructed to test the hypothesis of a VAS SPOM 
reduction from baseline. 
14.1.3.4. Trial success criteria 
If the weeks 6, 12, 18, and 26 VAS SPOM least square mean versus week 0 (baseline) 
VAS SPOM least square mean contrast achieves the 0.05 type I error level of statistical 
significance this trial will be considered a success. 
The mean VAS result at baseline is estimated to be 60 mm and that, a reduction in VAS 
result of 25%, i.e., 15 mm, will be achieved. The magnitude of the improvement in VAS 
was assumed to be equal between successive time points, i.e. the VAS results of 60, 
55, 50 and 45 mm are expected at baseline, and Weeks 6, 12, 18 and 26, respectively.  
The magnitude of what is considered a minimally clinically meaningful change from an 
individual patient perspective has been cited in the literature as 10-22% from baseline to 
endpoint following a given treatment as reported on the VAS instrument (Erich, et al., 
2000; Dworkin, et al., 2008; Angst, et al., 2002). In this context, the established trial 
success criteria of a 25% reduction in pain from baseline values represents a clinically 
meaningful change in patients’ pain as it exceeds this threshold range.  
14.1.3.5. Secondary variables 
 
The weeks 0, 6, 12, 18 and 26: 
• 
VAS (0-100mm) SPAN 
• 
ASES patient self-evaluation (PSE) Shoulder Score Index (SSI): (range: 0-100) 
• 
VAS (0-100mm) PGA  

Protocol 13DUR503 Amendment 02 
 
 
 
• 
Shoulder pain rescue medication consumed (unit: average mg per week) 
 
The weeks 0, 6, 12, and 26: 
• 
ASES physician assessment (PA) range of motion (ROM): 5 questions (active 
and passive; total 10 assessments) (unit: degrees) 
 
14.1.3.6. Exploratory variables 
 
Exploratory ASES variables (patient self-evaluation only): 
 
The weeks 0, 6, 12, 18 and 26: 
• 
ASES PSE pain today: VAS (range: 0-10cm) 
• 
ASES PSE activity of daily living: 10 questions (range: 0,1,2,3) 
 
14.2. 
Sample Size Considerations 
The sample size was estimated for a univariate one-way repeated measures ANOVA 
using method MOT2 in nQuery Advisor 7.0 statistical software. A sample size of 29 will 
be capable of detecting a reduction in mean VAS pain on movement score of 15 mm 
(25% reduction from a baseline mean of 60mm) over the course of the study with 80% 
power under the following assumptions: 
 
 
Type I error rate, α,  
 
 
 
 
= 0.05  
 
Standard deviation within time point = 25 mm 
 
Correlation between visits  
 
 
= 0.5 
 
Mean VAS (0-100mm) results at: 
 
 
0 weeks (baseline)  
 
 
 
= 60 mm 
 
 
6 weeks  
 
 
 
 
 
 
= 55 mm 
 
 
12 weeks  
 
 
 
 
 
 
= 50 mm 
 
 
26 weeks  
 
 
 
 
 
 
= 45 mm 
Hence, when the sample size is 29, a single-group repeated measures analysis of 
variance with a 0.05 significance level will have at least 80% power to detect a 
difference in means across the 4 time-points for the individual subjects characterized by 
an effect size of 0.1 (i.e., a Variance of means, V=∑(µi-µ)2/M, of 31.25, a standard 
deviation at each time-point of 25 mm, and a constant between time-point correlation of 
0.5). 
Assuming a 20% drop-out rate a minimum of 36 subjects will be enrolled to maintain 
80% power. It is noted that the sample size estimation does not include the week 18 
time point.  

Protocol 13DUR503 Amendment 02 
 
 
 
14.3. 
Planned Interim Analyses  
There are no planned interim analyses. 
14.4. 
Statistical software 
The analysis will be conducted using SAS® version 9.3 or higher statistical software. 
 

Protocol 13DUR503 Amendment 02 
 
 
 
15. 
STUDY DATA 
Investigators should protect the source data of this clinical research to ensure a 
subject’s rights and confidentiality. The investigator must give the 
monitor/auditor/inspector access to all relevant source documents to confirm their 
consistency with the CRF entries so source data and progression can be authenticated. 
If any data cannot be traced from source documents, investigators should help the 
monitor/auditor/inspector to confirm further information’s quality control.  
The Principal Investigator/Institution shall permit study-related monitoring, audits, REB 
review and regulatory inspections, and shall provide direct access to the source 
data/medical record as legally required. 
The Sponsor shall verify that each subject has consented in writing to direct access to 
the original medical record/source data (by the use of written subject information and 
signed informed consent). During the monitoring, the data recorded in the CRFs by the 
Investigator will be checked for consistency with the source documents/medical record 
by the study monitor (source data verification). Any discrepancies of data shall be 
documented, clarified by the Investigator in source documents and explained in the 
monitoring reports. 
To be able to make source data verification, information about each subject’s 
participation in the study must be detailed in the medical record. 
The Source Data Location Log specifies what data that should be available in the 
medical record. 
The Source Data Location Log should also specify the data for which the CRF serves 
as the source document. Such data only need to be recorded into the CRF and are 
typically associated with protocol-specific procedures and not with normal clinical care 
practice. For this type of study data, the Investigator would not be expected to duplicate 
the information into the medical record. 
15.1. 
Study Monitoring 
This study will be regularly monitored by the sponsor. To ensure compliance with Good 
Clinical Practice (GCP) and other applicable regulatory requirements, the sponsor 
representative is responsible for monitoring that sites conduct the study according to the 
protocol, standard operating procedures, and other written instructions and regulatory 
guidelines. Monitoring visits by the sponsor representative will be arranged in advance, 
at a mutually-acceptable time, with site personnel. The site personnel must allow 
sufficient time for the sponsor representative to review CRFs and relevant source 
documents and queries. During recruitment, monitoring shall take place regularly 
according to a schedule planned jointly by the sponsor and the Investigator per the 
study monitoring plan. During these monitoring visits, the sponsor representative shall 
check the subject's information and consent forms, verify the completed CRF, compare 
the data recorded on these forms with the source data (verify there is no missing, 
incorrect, illegible data), and ensure that the study is conducted in compliance with the 

Protocol 13DUR503 Amendment 02 
 
 
 
trial protocol and Good Clinical Practice as put forth in the ICH Guidelines. The 
Investigator and/or his/her team must be available to answer questions and or resolve 
data clarifications. During this interview, the Investigator will also be available to make 
any corrections to the CRFs (these will be clearly marked and the amendment must be 
dated and signed by the Investigator). 
The verification of data recorded in CRFs compared with the source data will cover at 
least the following data: 
 Date of signing of the consent form by the subject, 
 Confirmation of the diagnosis of the indication required for the study, 
 Inclusion/Exclusion Criteria check, 
 Participation of the subject in this study must be mentioned in his or her 
medical file, 
 Outcome measures, 
 Any adverse event, serious or not, observed or reported by the subject, 
 Concomitant treatments. 
The sponsor representative shall verify the correct use of the investigational product.  
At the end of the study, a final inspection is carried out during which the sponsor 
representative shall finalize the monitoring, update the paperwork, verify the remaining 
products, and organize the return of these products to the Sponsor. 
The sponsor representative will verify at each review, that all AEs observed during the 
study have been reported promptly to the Sponsor and/or REB, if applicable. 
15.2. 
Audits and Inspections 
Quality assurance audits of this trial may be conducted by the sponsor or a mandated 
auditor. GCP audits can also be performed by the authorities. The quality assurance 
auditor should have access to all medical records, the investigator's trial-related files 
and correspondence, and the informed consent documentation that is relevant to this 
clinical trial. 
The Sponsor may organize an audit inspection to ensure the successful completion of 
the study and to verify the documents related to the study. The Investigator shall be 
informed of the results of this audit. 
In addition, representatives from a Competent Authority, Research Ethics Board, or 
appointed Notified Body may inspect the trial center at any time. The Investigator shall 
immediately inform the Sponsor as soon as he or she is aware that an audit will take 
place. 
The investigator is responsible to ensure the accuracy, completeness, and timeliness of 
the data reported. All source documents should be completed in a neat, legible manner 
to ensure accurate interpretation of data. Copies of the CRF will be provided for use and 
maintained for recording data for each subject enrolled in the study. Data reported in the 

Protocol 13DUR503 Amendment 02 
 
 
 
CRF derived from source documents should be consistent with the source documents 
or the discrepancies should be explained. The investigator must provide formal approval 
of all subject information in the CRFs and changes to the CRFs to endorse the final 
submitted data for the subjects for which he or she is responsible. The audit trail entry 
shall show the user’s identification information and the date and time of any corrections.  
CRFs should be completed in a timely manner and every effort should be made to have 
forms completed and up-to-date in anticipation of a visit by the Sponsor’s monitor or 
designee. Specific instructions will be provided to each site. All requested information 
must be entered on the CRF in the spaces provided. If an item is not available or is not 
applicable, it should be documented as such.  
CRF completion may be delegated to other study personnel; however, such delegation 
must be documented in writing. If, for any reason, certain data are lacking to complete 
an individual report form, the investigator will provide a written statement explaining the 
reasons for the lack of data. 
Sponsor or designee will retain the CRF data and corresponding audit trails.  
15.3. 
Inspection of Records 
Sponsor will be allowed to conduct site visits to the investigation facilities for the 
purpose of monitoring any aspect of the study. The Investigator agrees to allow the 
monitor to inspect the investigational product storage area, investigational product 
stocks, investigational product accountability records, subject charts and study source 
documents, and other records relative to study conduct. 
15.4. 
Retention of Records 
The Investigator and Sponsor must retain essential study documents until at least five 
years after the last marketing approval of the investigational product, or 15 years after 
the conduct of the study is complete, whichever is longer. In this case, the Investigator 
is required to keep documents for 15 years. For discontinued product, the essential 
documents will be retained until at least two years have elapsed since the formal 
discontinuation (via notification of the appropriate regulatory agency). The Investigator 
will retain these documents for a longer period if required by the applicable local laws. 
If an Investigator is unable to hold these records in his or her archives, the Investigator 
must ask the Sponsor for permission to make alternative arrangements. If an 
Investigator leaves the institution at which the study was conducted, another 
responsible party must be designated to maintain the records. Details of these 
arrangements must be documented in writing to the Sponsor. 

Protocol 13DUR503 Amendment 02 
 
 
 
16. 
ETHICS 
16.1. 
Ethical Standards 
The trial will be carried out in accordance with the principles stated in the Declaration of 
Helsinki (5th revision, 2000), and in accordance with ICH-GCP, ISO 14155, and 
applicable regulatory requirements.  
16.2. 
Research Ethics Board (REB)  
The Sponsor or designee will supply all necessary information to the Investigator for 
submission of the protocol and consent form to the REB for review and approval. The 
Investigator agrees to provide the REB all appropriate material. The trial may not 
commence until the Investigator has obtained appropriate REB approval. A copy of the 
approval letter and approved consent form must be submitted to the Sponsor. The 
Investigator will request from the REB a composition of the members reviewing the 
protocol and informed consent. 
The Investigator is responsible for checking what reporting procedures are applicable 
for his/her REB regarding serious AEs and other reports, and to comply with such 
reporting procedures during the study period. The Sponsor will notify the site when the 
REB may be notified of study completion. The Investigator is responsible for notifying 
the REB when the study ends. This includes study discontinuation, whether it is 
permanent or temporary. The Investigator shall then send a copy of the site REB’s 
acknowledgement of study completion to the Sponsor. 
The Investigator will discuss any proposed protocol changes with the Sponsor and no 
modifications will be made without prior written approval by the Sponsor, except where 
clinical judgment requires an immediate change for reasons of subject welfare. The 
REB will be informed of any amendments to the protocol or consent form, and approval, 
when appropriate, will be obtained before implementation. No protocol amendments are 
allowed without REB approval. 
16.3. 
Written Informed Consent 
The Principal Investigator or his/her designated representative, is responsible for 
obtaining informed consent from each subject prior to initiation of any study procedures, 
including screening assessments, full and adequate verbal and written information 
regarding the objective and procedures of the study and the possible risks involved. The 
subject must be informed about his/her right to withdraw from the study at any time, and 
that such withdrawal will not affect his/her future medical care, treatment or benefits to 
which the subject is otherwise entitled.  
In obtaining and documenting informed consent, the investigator should comply with 
any applicable regulatory requirements, and should adhere to ICH-GCP and the 
Declaration of Helsinki. 

Protocol 13DUR503 Amendment 02 
 
 
 
Before informed consent is obtained the subject should be allowed ample time and 
opportunity to read the subject information, to enquire about details of the trial, and to 
decide whether or not to participate. 
If the subject wishes to participate, the written ICF should be completed as appropriate 
and then signed and personally dated by the subject and the Investigator or authorized 
designee who conducted the informed consent discussions. The Investigator will 
countersign and date if a designee conducted the informed consent. A copy of the 
signed and dated written informed consent and any other written information must be 
provided to the subject prior to participation in the trial. Similarly, the subject should also 
receive copies of any consent form updates or new information during the trial. 
The Investigator will confirm the receipt of informed consent from each subject by a 
recording in the CRF. The signed ICFs shall be filed in the Investigator File for possible 
future audits and inspections. 
If the investigator uses a device without obtaining informed consent, the investigator 
shall submit a protocol deviation report indicating the circumstances for the occurrence 
to the Sponsor and to the reviewing REB within applicable timelines after the use 
occurs. 
16.4. 
Subject Confidentiality 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, 
and the Sponsor and their agents. This confidentiality is extended to cover testing of 
biological samples in addition to the clinical information relating to participating subjects. 
The study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be 
released to any unauthorized third party without prior written approval of the Sponsor. 
The study monitor or other authorized representatives of the Sponsor may inspect all 
documents and records required to be maintained by the Investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
subjects in this study. The clinical study site will permit access to such records. All 
CRFs identify subjects through unique subject identifiers and subject initials. No date of 
birth, subject names, addresses or contact details will be transferred to the Sponsor. 
16.5. 
Study Discontinuation Notification 
In the event of premature termination or suspension of the study, the Sponsor will 
promptly inform the investigator / hospital, the Competent Authorities and ethics board, 
stating the reasons for this decision. The subjects will be informed as soon as possible 
by the Investigator of study discontinuation. Any unresolved AE will be reviewed per 
Section 13. The Sponsor or authorized representative will schedule site close-out visit 
as soon as practicable. 
Following the completion of the study, Sponsor or authorized representative will conduct 
a closeout visit to ensure that all data queries have been resolved, any protocol 
deviations are documented appropriately, all possible study data have been retrieved, 

Protocol 13DUR503 Amendment 02 
 
 
 
that study treatment and clinical supplies have been/will be properly returned to the 
Sponsor and that the Investigator has copies of all study-related data/information on file. 
 
 
 

Protocol 13DUR503 Amendment 02 
 
 
 
17. 
LIST OF REFERENCES 
 
Adams, M., et al., The role of viscosupplementation with hylan G-F 20 (Synvisc®) in the 
treatment of osteoarthritis of the knee: a Canadian multicenter trial comparing hylan G-F 
20 alone, hylan G-F 20 with non-steroidal anti-inflammatory drugs (NSAIDs) and 
NSAIDs alone. Osteoarthritis and Cartilage, 1995. 3: p. 213-226. 
 
Agerup, B., P. Berg, and C. Akermark, Non-Animal Stabilized Hyaluronic Acid: A New 
Formulation for the Treatment of Osteoarthritis. Biodrugs, 2005. 19(1): p. 23-30. 
 
Angst, F., et al., Minimal clinically important rehabilitation effects in patients with 
osteoarthritis of the lower extremities. J Rheumatol, 2002. 29(1): p. 131-139. 
 
Balazs, E.A., The physical properties of synovial fluid and the special role of hyaluronic 
acid, in Disorders of the Kneww, A.J. Helfet, Editor. 1982, JB Lippincott: Philadelphia. p. 
61-74. 
 
Balazs, E. and J. Denlinger, Viscosupplementation: A New Concept in the Treatment of 
Osteoarthritis. J Rheumatol.,1993. 20(39): p. 3-9. 
 
Blaine, T., et al., Treatment of persistent shoulder pain with sodium hyaluronate: A 
randomized, controlled trial. Journal of Bone and Joint Surgery-American Volume, 2008. 
90A (5): p. 970-979. 
 
Brander, V., et al., Efficacy and safety of hylan G-F 20 for symptomatic glenohumeral 
osteoarthritis: a prospective, pilot study. PM&R, 2010. 2(4): p. 259-67. 
 
Burckhardt, C.S. and K.D. Jones, Adult measures of pain: The McGill Pain 
Questionnaire (MPQ), Rheumatoid Arthritis Pain Scale (RAPS), Short-Form McGill Pain 
Questionnaire (SF-MPQ), Verbal Descriptive Scale (VDS), Visual Analog Scale (VAS), 
and West Haven-Yale Multidisciplinary Pain Inventory (WHYMPI). Arthritis & 
Rheumatism, 2003. 49(S5): p. S96-S104. 
 
Calis, M., et al., Is intraarticular sodium hyaluronate injection an alternative treatment in 
patients with adhesive capsulitis? Rheumatology International, 2006. 26(6): p. 536-540. 
 
CDRH, Use of International Standard ISO-10993, "Biological Evaluation of Medical 
Devices Part 1: Evaluation and Testing", 2013, US Food and Drug Administration. 
 
Colen S, et al., Hyaluronic Acid for the Treatment of Osteoarthritis in all Joints Except 
the Knee: What is the Current Evidence? BioDrugs, 2012. 26(2): p. 101-12. 
 
Dworkin, R.H., et al., Interpreting the clinical importance of treatment outcomes in 
chronic pain clinical trials: IMMPACT recommendations. J Pain, 2008. 9(2): p. 105-21. 
 

Protocol 13DUR503 Amendment 02 
 
 
 
DUROLANE® Instructions for Use, November 2012, Bioventus LLC. 
 
Edsman, K., H. Melin, and J. Näsström, A study of the ability of Durolane to withstand 
degradation by free radicals while maintaining its viscoelastic, in 55th Annual Meeting of 
the Orthopaedic Research Society 2009. 
 
Edsman, K., et al., Intra-articular Duration of DurolaneTM after Single Injection into the 
Rabbit Knee. Cartilage, 2011. 2(4): p. 384-388. 
 
Ehrich, E.W., et al., Minimal perceptible clinical improvement with the Western Ontario 
and McMaster Universities osteoarthritis index questionnaire and global assessments in 
patients with osteoarthritis. J Rheumatol., 2000. 27(11): p. 2635-41. 
 
Fernández-Palazzi, F., et al., Intra-articular hyaluronic acid in the treatment of 
haemophilic chronic arthropathy. Haemophilia., 2002. 8(3): p. 375-81. 
 
Guidelines on Medical Devices Vigilance System, in MEDDEV 2.12 Rev. 8, E. 
Commission, Editor 2012. p. 1-64 
 
Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012: 
Recommendations for the Use of Nonpharmacologic and Pharmacologic Therapies in 
Osteoarthritis of the Hand, Hip, and Knee. Arthritis Care & Research, 2012. 64(4):p. 
465-474. 
 
Iannotti JP, Kwon YW. Management of persistent shoulder pain. a treatment algorithm. 
Am J Orthop. 2005; 34(12 suppl):16-23. 
 
Itokazu, M. and T. Matsunaga, Clinical-Evaluation of High-Molecular-Weight Sodium 
Hyaluronate for the Treatment of Patients with Periarthritis of the Shoulder. Clinical 
Therapeutics, 1995. 17(5): p. 946-955. 
 
Johnson, C., Measuring Pain. Visual Analog Scale Versus Numeric Pain Scale: What is 
the Difference? J Chiropr Med., 2005. 4(1): p. 43-4. 
 
Kwon, YW, Eisenberg, G, and Zuckerman, JD. Sodium hyaluronate for the treatment of 
chronic shoulder pain associated with glenohumeral osteoarthritis: a multicenter, 
randomized, double-blind, placebo-controlled trial. J Shoulder Elbow Surg., 2013. 22(5): 
p. 584-94. 
Leardini, G., et al., Intra-articular injections of hyaluronic acid in the treatment of painful 
shoulder. Clin Ther 1988. 10 (5): p. 521-6. 
 
Lee, H.J., et al., Randomized controlled trial for efficacy of intra-articular injection for 
adhesive capsulitis: ultrasonography-guided versus blind technique. Arch Phys Med 
Rehabil, 2009. 90(12): p. 1997-2002. 
 

Protocol 13DUR503 Amendment 02 
 
 
 
Merolla, G., et al., Efficacy of Hylan G-F 20 versus 6-methylprednisolone acetate in 
painful shoulder osteoarthritis: a retrospective controlled trial. Musculoskelet Surg. , 
2011. 95(3): p. 215-24. 
 
Noel, E., et al., Efficacy and safety of Hylan G-F 20 in shoulder osteoarthritis with an 
intact rotator cuff. Open-label prospective multicenter study. Joint Bone Spine, 2009. 
76(6): p. 670-3. 
 
Norkin C and W. J, Measurement of Joint Motion: A Guide to Goniometry. Second ed 
1995: F.A. Davis Company. 
 
Paul-Dauphin, A., et al., Bias and precision in visual analogue scales: a randomized 
controlled trial. Am J Epidemiol. , 1999. 150(10): p. 11177-1127. 
 
Pincus T, C.L., Brooks RH, Fuchs HA, Olsen NJ, Kaye JJ., Self-report questionnaire 
scores in rheumatoid arthritis compared with traditional physical, radiographic, and 
laboratory measures. Ann Intern Med. , 1989. 110(4): p. 259-66. 
 
Q-Med, Restylane (NASHA 20 mg/ml) biological evaluation studies., 2004. 
 
Q-Med, Study of the tissue responses to Gel-OA following intra-articular (joint) injection 
in rabbits., 2000. 
 
Q-Med, Risk Management Report, October 2012. 
 
Restylane Instructions for Use, October 2011, Medicus Asthetics Inc. 
 
Rovetta, G. and M. P., Intraarticular injection of sodium hyaluronate plus steroid versus 
steroid in adhesive capsulitis of the shoulder. Int J Tissue React., 1998. 20(4): p. 125-
30. 
 
Saito, S., T. Furuya, and S. Kotake, Therapeutic effects of hyaluronate injections in 
patients with chronic painful shoulder: A meta-analysis of randomized controlled trials. 
Arthritis Care Res, 2010. E-pub ahead of print. 
 
Self EB. Clinical guidelines for shoulder pain. In: Norris TR, ed. Orthopaedic Knowledge 
Update: Shoulder and Elbow 2. 2nd ed. Rosemont, Ill.: American Academy of 
Orthopaedic Surgeons, 2002:443-467 
 
Silverstein, E., R. Leger, and K.P. Shea, The use of intra-articular hylan G-F 20 in the 
treatment of symptomatic osteoarthritis of the shoulder - A preliminary study. American 
Journal of Sports Medicine, 2007. 35(6): p. 979-985. 
 
Smith, M.M. and P. Ghosh, The synthesis of hyaluronic acid by human synovial 
fibroblasts is influenced by the nature of the hyaluronate in the extracellular 
environment. Rheumatol Int, 1987. 7: p. 113-122. 

Protocol 13DUR503 Amendment 02 
 
 
 
 
Stevenson JH, Trojian T. Evaluation of shoulder pain. J Fam Pract. 2002; 51(7):605-
611. 
 
Tagliafico, A., et al., Ultrasound-guided viscosupplementation of subacromial space in 
elderly patients with cuff tear arthropathy using a high weight hyaluronic acid: 
prospective open-label non-randomized trial. Eur Radiol, 2011 Jan. 21(1): p. 182-7. 
 
Yasui, T., et al., The effect of hyaluronan on interleukin-1 alpha-induced prostaglandin 
E2 production in human osteoarthritic synovial cells. Agents Actions., 1992. 37(1-2): p. 
155-156. 
 
 
 
 
 
 

Protocol 13DUR503 Amendment 02 
 
 
 
APPENDICES 
 

Protocol 13DUR503 Amendment 02 
 
 
 
APPENDIX 1. PERMITTED TREATMENTS/MEDICATIONS 
Treatments Allowed 
Restrictions 
Any treatment for a pre-existing condition, outside 
the study indication.  
 
Subject has to have met the inclusion/exclusion 
criteria. 
Treatment must not be listed as prohibited. 
Rescue medication: Acetaminophen 
Not to exceed 4g/day and not taken within 24 
hours prior to visit. 
Low dose ASA anticoagulant therapy 
Not to exceed 325mg/day 
Topical corticosteroids for skin irritations  
Allowed at any site other than the study shoulder  
Inhaled corticosteroids for pulmonary disease  
None 
Nonpharmacologic therapy (including physical 
therapy) 
 
Allowable if started before Screening, not to be 
initiated or substantially altered during the study 
except for discontinuation 
 

Protocol 13DUR503 Amendment 02 
 
 
 
APPENDIX 2. PROHIBITED TREATMENTS/MEDICATIONS 
Prohibited Treatments/Medications 
Restriction 
Pain medications other than acetaminophen 
Beginning at screening and lasting throughout 
the duration of the trial (or study discontinuation) 
 
Chronic use of narcotics 
Systemic corticosteroids (oral or injected) 
Any planned surgical procedure 
Heparin or anti-vitamin K (e.g., crystalline 
warfarin) anticoagulant therapy 
Viscosupplementation injected into any joint other 
than as required by the protocol 
 
Local corticosteroid injection into any joint or 
periarticular structure 
Within 3 months prior to Screening 
Previous IA injection/s with hyaluronic acid in the 
study shoulder  
Within 9 months prior to Screening  
Any investigational drug, device or biologic 
Within 30 days prior to Screening and lasting 
throughout the duration of the trial (other than as 
required by the protocol) 
Physical therapy for the lower extremities 
May not be initiated during the study  
 
 

Protocol 13DUR503 Amendment 02 
 
 
 
APPENDIX 3. DEVICE SAFETY AND VIGILANCE GUIDELINES  
 

Protocol 13DUR503 Amendment 02 
 
 
 
APPENDIX 4. ADVERSE EVENT REPORTING FLOWCHART 
 
 

Protocol 13DUR503 Amendment 02 
 
 
 
APPENDIX 5. INSTRUCTIONS FOR USE 
 

Protocol 13DUR503 Amendment 02 
 
 
 
APPENDIX 6. OSTEOARTHRITIS CLASSIFICATION SYSTEMS 
Osteoarthritis is diagnosed if subject presents with shoulder pain plus ≥3 of 6 clinical 
findings: 
1. age>50 years 
morning stiffness>30 minutes duration 
crepitus on active motion 
tenderness of the bony margins of the joint 
bony enlargement noted on examination 
a lack of palpable warmth of the synovium