Randomized, Double-Blind, Active Comparator Controlled, Multi-Center Study of a Single Injection Cross-Linked Sodium Hyaluronate Combined With Triamcinolone Hexacetonide (Cingal™) to Provide Symptomatic Relief of Osteoarthritis of the Knee
Phase: PHASE3
Conditions: Knee Osteoarthritis
Sponsor: Anika Therapeutics, Inc.

 
 
ANIKA THERAPEUTICS, INC. 
32 Wiggins Avenue 
Bedford, MA 01730 
www.anikatherapeutics.com 
Cover Letter - Cingal 16-02 Protocol Version 4.0
A Randomized, Double-Blind, Active Comparator Controlled, Multi-Center 
Study of a Single Injection Cross-Linked Sodium Hyaluronate Combined 
with Triamcinolone Hexacetonide (Cingal®) to Provide Symptomatic Relief 
of Osteoarthritis of the Knee
NCT # 03191903
Date of Protocol: 05 December 2017

Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 1 of 85
A Randomized, Double-Blind, Active Comparator Controlled, Multi-Center Study of a 
Single Injection Cross-Linked Sodium Hyaluronate Combined with Triamcinolone 
Hexacetonide (Cingal®) to Provide Symptomatic Relief of Osteoarthritis of the Knee
Protocol Number: Cingal 16-02
Protocol Version 4.0 
Date: 05 December 2017
EudraCT Number 2017-000355-46
     Signatures for the Sponsor that have reviewed and approved the protocol
Author: 
Director of Clinical Affairs or 
Designee:
Adrian Orr
Signature
Date
Vice President of 
Regulatory/Clinical Affairs or 
Designee:
Steven Chartier
Signature
Date
Anika’s President or Designee: 
Charles Sherwood, Ph.D.
Signature
Date
SPONSORED BY:
Anika Therapeutics, Inc.
32 Wiggins Avenue
Bedford, MA 01730
United States of America
Phone: +1 781-457-9000
Fax: +1 781-305-9720

Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 2 of 85
PROTOCOL SIGNATURE PAGE
Title: A Randomized, Double-Blind, Active Comparator Controlled, Multi-Center Study 
of a Single Injection Cross-Linked Sodium Hyaluronate Combined with Triamcinolone 
Hexacetonide (Cingal®) to Provide Symptomatic Relief of Osteoarthritis of the Knee
Version: 4.0 
Date: 05 December2017
Sponsor: Anika Therapeutics, Inc.
My signature below confirms that I have read and understand the clinical protocol contained herein 
and agree to conduct the study according to this protocol and in accordance with the ethical 
principles of the Declaration of Helsinki, International Conference on Harmonization (ICH) 
Guidelines on Good Clinical Practice, Directive 2001/20/EC and Commission Directive 2005/28/EC, 
International Organization for Standardization (ISO) 14155, 21 CFR part 11, 50, 56, 312 and local 
ethical and legal requirements.
Principal Investigator:
________________________________________________________
___________
Print Name
Date
_________________________________________________________
Signature

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 3 of 85
1 
LIST OF ABBREVIATIONS...........................................................................................................6 
2 
DEFINITIONS...............................................................................................................................8 
3 
STUDY SYNOPSIS ......................................................................................................................9 
4 
INTRODUCTION ........................................................................................................................13 
6 
PRINCIPAL INVESTIGATOR .....................................................................................................15 
7 
STUDY OBJECTIVES ................................................................................................................16 
8 
ENDPOINTS...............................................................................................................................16 
8.1 
Primary Efficacy Endpoint ....................................................................................................16 
8.2 
Secondary Efficacy Endpoints..............................................................................................16 
8.3 
Exploratory Endpoints ..........................................................................................................16 
8.4 
Safety Endpoint:...................................................................................................................17 
9 
STUDY DESIGN.........................................................................................................................18 
9.1 
Diagram................................................................................................................................18 
9.2 
Trial Design..........................................................................................................................19 
10 
ELIGIBILITY ............................................................................................................................20 
10.1 
Screening Enrollment Criteria............................................................................................20 
10.1.1 
Screening Inclusion Criteria ........................................................................................20 
10.1.2 
Screening Exclusion Criteria.......................................................................................21 
10.2 
Baseline Enrollment Criteria..............................................................................................23 
10.2.1 
Baseline Inclusion Criteria ..........................................................................................23 
10.2.2 
Baseline Exclusion Criteria .........................................................................................23 
11 
STUDY PROCEDURES ..........................................................................................................24 
11.1 
Schedule of Events ...........................................................................................................24 
11.2 
Procedure Description.......................................................................................................25 
11.2.1 
Informed Consent Form (ICF).....................................................................................25 
11.2.2 
Demographics ............................................................................................................25 
11.2.3 
Physical Exam (PE)....................................................................................................25 
11.2.4 
Vital Signs...................................................................................................................25 
11.2.5 
Pregnancy Test...........................................................................................................25 
11.2.6 
Chemistry/Hematology/Urinalysis ...............................................................................25 
11.2.7 
Knee X-rays/Assessment of Kellgren-Lawrence Score ...............................................26 
11.2.8 
Medical History ...........................................................................................................27 
11.2.9 
Physical Evaluation of Knee........................................................................................27 
11.2.10 
Range of Motion .........................................................................................................28 
11.2.11 
WOMAC .....................................................................................................................28 
11.2.12 
Medications ................................................................................................................28 
11.2.13 
Subject Diary ..............................................................................................................29 
11.2.14 
EuroQoL EQ-5D .........................................................................................................29 
11.2.15 
Patient Global Assessment.........................................................................................30 
11.2.16 
Evaluator Global Assessment.....................................................................................30 
11.2.17 
Blinding.......................................................................................................................30 
11.3 
Screening..........................................................................................................................31 
11.4 
Baseline ............................................................................................................................32 
11.5 
Randomization ..................................................................................................................32 
11.6 
Treatment..........................................................................................................................33 
11.7 
Injection Technique...........................................................................................................33 
11.8 
Post-Treatment Follow-Up ................................................................................................35 
11.8.1 
1 Week ± 3 Days ........................................................................................................35 
11.8.2 
3 Weeks ± 3 Days.......................................................................................................36 
11.8.3 
6 Weeks ± 3 Days.......................................................................................................36 

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 4 of 85
11.8.4 
12 Weeks ± 3 Days.....................................................................................................36 
11.8.5 
18 Weeks ± 7 Days.....................................................................................................37 
11.8.6 
26 Weeks ± 7 Days.....................................................................................................37 
12 
ADVERSE EVENTS / ADVERSE REACTIONS.......................................................................38 
12.1 
Definitions – Device Adverse Events.................................................................................38 
12.2 
Definitions – Drug Adverse Events....................................................................................39 
12.3 
Relationship ......................................................................................................................39 
12.4 
Severity.............................................................................................................................40 
12.5 
Reporting ..........................................................................................................................40 
12.5.1 
Adverse Events...........................................................................................................40 
12.5.2 
Serious Adverse Events/Serious Adverse Device Effects/Serious Adverse Reactions 41 
12.5.3 
Expedited Reporting ...................................................................................................41 
12.5.4 
Independent Data Monitoring Committee....................................................................42 
12.5.5 
Study Discontinuation .................................................................................................42 
13 
STATISTICAL CONSIDERATIONS.........................................................................................42 
13.1 
Sample Size......................................................................................................................42 
13.1.1 
Primary Efficacy Endpoint...........................................................................................43 
13.1.2 
Secondary Efficacy Endpoints ....................................................................................43 
13.1.3 
Exploratory Endpoints.................................................................................................48 
13.2 
Statistical Methods............................................................................................................48 
13.3 
Demographic and Baseline Characteristics.......................................................................49 
13.4 
Adverse Events.................................................................................................................49 
13.5 
Subject Populations ..........................................................................................................49 
13.6 
Additional Analyses...........................................................................................................50 
14 
DATA MANAGEMENT CONSIDERATIONS............................................................................50 
14.1 
Electronic Data Capture (EDC) System.............................................................................50 
14.2 
Data Collection..................................................................................................................51 
14.3 
Data Management.............................................................................................................51 
14.4 
Data Retention ..................................................................................................................52 
15 
CLINICAL SUPPLIES..............................................................................................................52 
15.1 
Packaging and Labeling....................................................................................................52 
15.2 
Storage Requirements ......................................................................................................52 
15.3 
Instructions for Use ...........................................................................................................52 
15.3.1 
Contraindications........................................................................................................52 
15.3.2 
Anticipated Adverse Reactions ...................................................................................54 
15.4 
CTM Accountability ...........................................................................................................55 
15.5 
Emergency Unblinding ......................................................................................................55 
16 
DATA QUALITY ASSURANCE................................................................................................55 
17 
REGULATORY OBLIGATIONS...............................................................................................55 
17.1 
Clinical Trial Information....................................................................................................56 
17.2 
Regulatory Approval..........................................................................................................56 
17.3 
Ethics Committee (EC) Approval.......................................................................................56 
17.4 
Amendments to the Protocol .............................................................................................56 
17.5 
Pre-Study Documentation .................................................................................................57 
17.6 
Investigator Responsibilities..............................................................................................57 
17.7 
Sponsor’s Responsibilities ................................................................................................60 
17.8 
Informed Consent..............................................................................................................64 
17.9 
Protocol Adherence...........................................................................................................65 
17.10 
Adverse Event Reporting ..................................................................................................66 
17.11 
Permission to Review Subject's Source Records ..............................................................66 
17.12 
Change in Investigator ......................................................................................................66 
17.13 
Records Retention ............................................................................................................66 

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 5 of 85
17.14 
Study Monitoring ...............................................................................................................67 
17.15 
Case Report Form.............................................................................................................68 
17.16 
Auditing.............................................................................................................................68 
17.17 
Use and Publication of Study Results................................................................................69 
17.18 
Confidentiality ...................................................................................................................69 
17.19 
Early Study Discontinuation ..............................................................................................69 
17.20 
Subject Withdrawal ...........................................................................................................70 
18 
GENERAL INFORMATION .....................................................................................................71 
18.1 
Study Contact Information.................................................................................................71 
18.2 
Study Administrative Structure ..........................................................................................72 
19 
REFERENCES........................................................................................................................73 
Appendix 1 WOMAC .........................................................................................................................74 
Appendix 2 Global Assessment of Disease Activity...........................................................................80 
Appendix 3  EQ-5D ...........................................................................................................................81 
Appendix 4 Kellgren-Lawrence Grading Scale ..................................................................................83 

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 6 of 85
1
LIST OF ABBREVIATIONS
ACL
Anterior Cruciate Ligament
ADE
Adverse Device Effect 
AE
Adverse Event
ALT/SGPT 
Alamine Transaminase/Serum Glutamic Pyruvic Transaminase
ANOVA
Analysis of Variance
AP
Anterior Posterior
AR
Adverse Reaction
AST/SGOT
Aspartate Aminotransferase/Serum Glutamic Oxaloacetic Transaminase
BMI
Body Mass Index
CFR
Code of Federal Regulations
cm
Centimeters
CRO
Contract Research Organization
CTM
Clinical Trial Material
CV
Curriculum Vitae
D/C
Discontinued
DMP
Data Management Plan
eCRF
electronic Case Report Form 
EDC
Electronic Data Capture
EQ-5D
EuroQoL 5 Dimension
EQ VAS
EuroQoL Visual Analog Scale
EULAR
European League Against Rheumatism
FDA
Food and Drug Administration
g, mg, kg
gram, milligram, kilogram
GCP
Good Clinical Practices
GEE
Generalized Estimating Equations
h
hour(s)
HA
Hyaluronan / Sodium Hyaluronate / Hyaluronic Acid
HIPAA
Health Insurance Portability and Accountability Act
IA 
Intraarticular
ICF
Informed Consent Form
ICH
International Conference on Harmonization
ID
Identification
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IFU
Instructions for Use
IND
Investigational New Drug
ISO
International Organization for Standardization
ITT
Intent-to-Treat
K-L
Kellgren-Lawrence classification
MedDRA
Medical Dictionary for Regulatory Activities
mL, mm, m
milliliter, millimeter, meter
NSAIDs
Non-steroidal anti-inflammatory drug
OA
Osteoarthritis
OARSI 
Osteoarthritis Research Society International
OMERACT
Outcomes Measures for Rheumatic Arthritis Clinical Trials
PA
Posterior Anterior 
PE
Physical Exam
PI
Principal Investigator
PP
Per Protocol
RBC
Red Blood Cell

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 7 of 85
ROM
Range of Motion
SADE
Serious Adverse Device Effect
SAE
Serious Adverse Event
SAR
Serious Adverse Reaction
SAP
Statistical Analysis Plan
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction 
TEAE
Treatment Emergent Adverse Events
TH
triamcinolone hexacetonide
UADE
Unanticipated Adverse Device Effect
UK
United Kingdom
US
United States
VAS
Visual Analog Scale
WBC
White Blood Cell
WOMAC
Western Ontario and McMaster Universities Osteoarthritis Index

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 8 of 85
2
DEFINITIONS
Baseline: The assessments performed prior to the study injection after the Screening Visit.
Blinded Evaluator: The Blinded Evaluator will be a physician, research nurse, registered 
physiotherapist or physician assistant trained by the PI to perform the assessments outlined in the 
protocol. The Blinded Evaluator will complete the physical evaluation of both knees, range of motion
(ROM) assessment of both knees, and the Evaluator Global Assessment.
End of Study: End of study is defined as the last subject’s last visit.
Enrolled: A subject who has signed the informed consent form (ICF) is enrolled.
Index Knee: The knee that meets the eligibility criteria for treatment. The index knee may also be 
termed the “study knee”. In subjects with bilateral knee Osteoarthritis (OA), where both knees meet 
eligibility criteria, the more symptomatic knee is the index knee.       
Ethics Committee (EC): EC refers to an independent body (e.g. Research Ethics Boards, Independent 
Ethics Committees) whose responsibility is to ensure the protection of rights, safety and well-being of 
human subjects involved in a trial. Committees with these responsibilities will be referred to in this 
document as Ethics Committees.
Rescue Medication: Acetaminophen/paracetamol will be distributed as the rescue medication. It is
the only medication that should be taken for knee pain during the entire study. Rescue medication will 
be discontinued at least 48 hours prior to Baseline and all follow-up visits.  
Treating Physician: The Treating Physician will most often be the Principal Investigator (PI). He/she 
will administer the Cingal® Monovisc® or steroid injection but will not participate in the efficacy 
evaluation. 
Treatment Failure: A subject who undergoes a procedure or uses a medication (other than the 
rescue medication) for the treatment of OA in the index knee at any time after the study injection 
through the 26 week visit.

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 9 of 85
3
STUDY SYNOPSIS
Title
A Randomized, Double-Blind, Active Comparator Controlled, Multi-Center Study of a 
Single Injection Cross-Linked Sodium Hyaluronate Combined with Triamcinolone 
Hexacetonide (Cingal) to Provide Symptomatic Relief of Osteoarthritis of the Knee
Study 
Objective
To evaluate the efficacy and safety of a single injection of Cingal for relief of joint pain in 
subjects with Osteoarthritis (OA) of the knee who have not responded to conservative 
treatment.
Investigational 
Product
Cingal: A chemically cross-linked sodium hyaluronate supplied as a 4-mL unit dose with 
a nominal 18 mg of triamcinolone hexacetonide (TH) in a 5-mL glass syringe.                      
Comparator 
Product
Triamcinolone Hexacetonide (TH): 20 mg/ml supplied as 1 mL unit dose in a glass 
ampoule.
Monovisc™: A chemically cross-linked sodium hyaluronate supplied as a 4-mL unit 
dose in a 5-mL glass syringe.
Mode of 
Delivery
Cingal, Triamcinolone Hexacetonide, or Monovisc will be injected into the intraarticular
(IA) space of the index knee using an 18-21 gauge needle.
Study Design
Multi-center, randomized, double-blind, parallel group, 3-arm, active comparator 
controlled study    
Phase
Phase III
Sample Size
A total of 576 subjects will be enrolled.
This equates to 256 subjects injected with Cingal, 256 subjects injected with Monovisc
and 64 subjects injected with TH.
Study Duration
The entire study duration from first subject in to last subject out will be approximately one 
year. The enrollment phase will be approximately 5-6 months with a follow-up phase of 6
months. Visits will be scheduled at 1 week, 3 weeks, 6 weeks, 12 weeks, 18 weeks, and
26 weeks post treatment. 
Inclusion 
Criteria
Screening Inclusion Criteria
1.
Subject is 40-75 years old, with a Body Mass Index (BMI) NJP2.
2.
Subject has Kellgren-Lawrence (K-L) severity grade I, II or III in the index knee as 
determined by X-ray.  Contralateral knee: K-L severity grade 0, I or II.
3.
Subject has had at least two signs and at least two symptoms of OA disease (based 
on the European League Against Rheumatism (EULAR) recommendations for 
diagnosing knee OA) in the index knee for at least 6 months despite conservative 
treatment (weight reduction, physical therapy, pain medications, etc.). The EULAR 
signs and symptoms are as follows:
o
Signs: crepitus, restricted movement and bony enlargement 
o
Symptoms: persistent knee pain, limited morning stiffness and reduced function 
4.
Subject must be willing to abstain from other IA treatments of the knee for the 
duration of the study.
5.
Subject is willing to discontinue all analgesics including NSAIDs, except 
acetaminophen/paracetamol, at least seven days before the treatment injection and 
through the completion of the study.
6.
Subject is willing to use only acetaminophen/paracetamol (up to a maximum of 4.0
grams per day per the package insert) for the treatment of joint pain for the duration 
of the study. At least forty eight hours prior to the Baseline Visit and each follow-up
visit, the subject is willing to discontinue use of acetaminophen/paracetamol. 
7.
Subject is willing to maintain a stable dose of oral glucosamine and/or chondroitin 
sulfate products throughout the study, if taken prior to signing the informed consent
form (ICF).
8.
Subject is able to understand and comply with the requirements of the study and 
voluntarily provides consent.

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 10 of 85
Exclusion 
Criteria
Screening Exclusion Criteria
1.
Subject received an IA injection of Hyaluronic Acid (HA) and/or steroid in either 
knee within 6 months of signing the informed consent form (ICF). A subject will 
be excluded if they are planning to receive an HA or steroid injection (other 
than the study injection) in either knee during the course of this study.
2.
Subject had an arthroscopy of either knee within 3 months of signing the ICF.
3.
Subject had an open surgical procedure of either knee or hip or any surgery of 
the spine within 12 months of signing ICF. Subject plans to have knee, hip or 
spine surgery within the study period. 
4.
Subject has intra-articular trauma to the index knee. Subject has concurrent 
multi-system or multi-limb trauma.
5.
Subject has evidence or medical history of the following diseases in the index 
knee: septic arthritis; inflammatory joint disease; history of Reiter’s syndrome; 
gout; chondrocalcinosis associated with recurrent episodes of acute synovitis of 
the knee consistent with pseudogout; osteochondritis dissecans, Paget disease 
of the bone; ochronosis; acromegaly; hemochromatosis; primary 
osteochondromatosis; known history of Wilson disease; heritable disorders or 
collagen gene mutations.
6.
Subject has a history of cartilage repair surgery in the index knee within 3 years 
of signing the ICF.
7.
Subject has a history of ACL repair, reconstruction or injury in the index knee 
within 3 years of signing the ICF.
8.
Subject has X-ray findings of acute fractures, severe bone loss, avascular 
necrosis, severe bone or joint deformity in the index knee.
9.
Subject has significant varus or valgus deformity greater than 10 degrees in 
either knee.
10. Subject has a clinically apparent tense effusion of the index knee.
11. Subject has knee instability in either knee per the Investigator’s assessment.
12. Subject requires consistent use of an assistive device (e.g. wheelchair, walker, 
etc.) Occasional use of a cane is acceptable.
13. Subject has medical condition(s) which could affect study assessments or may 
adversely affect the safety and/or success of the study treatment. This includes 
but is not limited to the following: a. Peripheral neuropathy severe enough to 
interfere with evaluation of the subject, b. Vascular insufficiency severe enough 
to interfere with evaluation of the subject, c. Active fibromyalgia, d. Hemiparesis 
involving either lower extremity, e. Immunocompromised or 
immunosuppressive disorder or receiving medications to treat 
immunosuppressive disorders, f. Systemic bleeding disorder(s), g. Current 
malignancy or treatment within the last 5 years, except for non-melanoma skin 
cancer,  h. Significant psychiatric disorder, i. Active drug and/or alcohol abuse 
within the past year, j. Uncontrolled diabetes with a screening HbA1c of >7%.
14. Subject is taking medications at the time the subjects signs the ICF which could 
interfere with the treatment procedure, healing and/or assessments. This 
includes but is not limited to oral or injectable anticoagulant treatments, anti-
aggregant platelet treatment, chronic opioid analgesics. Low dose aspirin used 
for cardiovascular protection is allowed if a stable regimen is maintained for the 
duration of the study.
15. Subject is receiving treatment using electromagnetic stimulation and/or low 
intensity ultrasound in the index knee at the time of signing the ICF, within 3 
months of signing the ICF or plans to receive treatment any time during the 
study period.
16. Subjects who had an oral, intramuscular, intravenous, rectal suppository or 
topical (excluded in index knee only) corticosteroid within 30 days of signing the 
ICF are excluded. Topical corticosteroid use at any site other than the index 
knee is allowed.
17. Subject has a pre-treatment contraindication to IA injections or aspiration of the 
index knee, including cutaneous infection in the injection site area, active IA

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 11 of 85
infection (as suggested by moderate or marked effusion), knee deformity or 
condition which, in the opinion of the Investigator could jeopardize the sterility 
or delivery of the IA injection.
18. Subjects with a history of hypersensitivity to any of the ingredients in the 
hyaluronan or previous hypersensitivity to the administration of corticosteroids 
or an inability to tolerate acetaminophen/paracetamol.
19. Subject has any contraindication to the receipt of a corticosteroid.
20. Subject is receiving or in litigation for worker’s compensation.
21. Subject is a woman who is pregnant or breastfeeding at the Screening Visit or a 
woman of child bearing potential who refuses to use effective contraception 
during the course of the study.
22. Subject was involved in any other research study involving an investigational 
product, or a new application of an approved product, within 60 days of signing 
the ICF.
Baseline Inclusion Criteria
1.
Subject has a Western Ontario and McMaster Universities Osteoarthritis Index
(WOMAC) pain-sub-VFRUHPPDQGPPLQWKHDIIHFWHGNQHHDQG mm 
in the contralateral knee on a 100 mm Visual Analog Scale (VAS) scale.
Baseline Exclusion Criteria
1.
Subject has a decrease of 20 mm in the WOMAC pain-sub-score (average of 5 
pain scales) from Screening to Baseline in the index knee on a 100 mm Visual 
Analog Scale (VAS) scale.
2.
Subject has a synovial fluid aspirate volume > 20 mL in the index knee.
3.
Subject has a contraindication to continue with the study treatment injection based 
on the visual appearance of the synovial fluid aspirate unless the fluid is examined 
microscopically prior to injection with no clinically significant findings (e.g. bacteria, 
crystals or blood).
4.
Subject has range of motion of less than 100° flexion in either knee.
Criteria for 
Evaluation
Efficacy:
Primary Endpoint:
x
The change from baseline in knee pain as measured by the WOMAC 
Pain Score (100 mm VAS) at 26 weeks post treatment comparing the 
Cingal group to the TH group.
Secondary Endpoints: 
x
The change from baseline in knee pain as measured by the WOMAC 
Pain Score (100 mm VAS) at 3 weeks post treatment comparing the 
Cingal group to the Monovisc group. 
x
The responder rate as identified by the Outcomes Measures for 
Rheumatic Arthritis Clinical Trials-Osteoarthritis Research Society
International (OMERACT-OARSI) responder index at 26 weeks post 
treatment comparing the Cingal group to the TH group.
x
The change from baseline in WOMAC Physical Function score at 26
weeks post treatment comparing the Cingal group to the TH group.
x
The change from baseline in WOMAC Stiffness score at 26 weeks post 
treatment comparing the Cingal group to the TH group.
x
The change from baseline in Total WOMAC score at 26 weeks post 
treatment comparing the Cingal group to the TH group.
x
The change from baseline in the Patient Global Assessment at 26 
weeks post treatment in the Cingal group compared to the TH group.
x
The change from baseline in the Evaluator Global Assessment at 26 
weeks post treatment in the Cingal group compared to the TH group.

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 12 of 85
x
The change from baseline in knee pain as measured by the WOMAC 
Pain Score (100 mm VAS) at 1 week post treatment comparing the 
Cingal group and the Monovisc group,.
x
The usage of rescue medication through 26 weeks post treatment in 
the Cingal group compared to the TH group.
Exploratory Endpoints: 
Any comparisons between groups (Cingal, Monovisc, TH), within groups 
and / or time points (from baseline through to 26 weeks) not described in 
the primary or secondary endpoints may be presented in the exploratory 
endpoints including:
x
EuroQol (EQ-5D)
x
WOMAC Pain Score (100mm VAS)
x
OMERACT-OARSI
x
Total WOMAC
x
WOMAC Stiffness Score
x
WOMAC Physical Function
x
Patient Global Assessment
x
Evaluator Global Assessment
x
Range of Motion 
x
Rescue Medication Usage
x
Number of Treatment Failures due to Additional Procedure or Use of 
Disallowed Medication 
Safety:
The incidence, timing, severity, and relationship to treatment of all Adverse Events (AE) 
will be collected and coded using Medical Dictionary for Regulatory Activities 
(MedDRA).  Local injection site and non-local events will be recorded separately.
Statistical 
Analysis
The primary analysis on the endpoints will be performed on the ITT (Intent to Treat) 
populations using the Multiple Imputation Methodology.  The Multiple Imputation 
Methodology will use a mixed effects repeated measures model to predict the missing 
values.  All Primary and Secondary endpoints will be analyzed using the ITT population.
A secondary analysis will be conducted on the Per Protocol (PP) population.   Since the 
primary endpoint is at 26 weeks, this is all subjects who complete the 26 week visit and 
who are not major violators of the protocol.  For all other visits, this is defined as the 
subjects who complete those visits according to the protocol.
All safety analyses will be conducted on all subjects who undergo treatment in any 
group.
Sites
Up to 40 clinical sites within Europe may participate.
Sponsor
Anika Therapeutics, Inc.
32 Wiggins Avenue
Bedford, MA 01730,
United States of America
Phone: + 1 781-457-9000 Fax: + 1 781-305-9720

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 13 of 85
4
INTRODUCTION
Osteoarthritis (OA) is the most prevalent joint disorder worldwide and is associated with significant pain 
and disability [1]. It is a progressive disease that can affect any joint but most often involves the weight 
bearing joints such as the knee. The European Project on Osteoarthritis reported on prevalence rates 
for knee OA in Europe and the United Kingdom (UK). For subjects aged 65-74 years, the rate of knee 
OA based on clinical judgment was 36.7% in Italy and 18.6 % in the UK. For subjects aged 75 years or 
older the rate, based on clinical judgment was 50.8% in Italy. In the Netherlands, the self-reported rate 
of knee OA in subjects 65-74 years was 23.6% and for subjects 75 years or older was 31.4% [2].
Because of the high prevalence of knee OA, this disease ranked as either the top or second leading 
cause of disability [3].  In particular, this disease accounted for more dependence on others in climbing 
stairs, housekeeping and walking a mile than any other disease after adjustment for age, sex and 
comorbidity [3].
Osteoarthritis is defined as a “heterogenous group of conditions that leads to joint symptoms and signs 
which are associated with defective integrity of articular cartilage in addition to related changes in the 
underlying bone and at the joint margins” [4]. OA is characterized by a decreased concentration of HA 
in synovial fluid and a slow degradation of cartilage over years [5, 6].  The decreased concentration of 
HA in the synovial fluid of an osteoarthritic joint is probably caused by dilution from exudation, a 
decreased production of hyaluronans, and increased degradation [6]. Accordingly, the average 
molecular weight is diminished resulting in a loss of the viscoelastic properties of the synovial fluid for 
which HA is responsible [5].
Corticosteroids have long been used to alleviate pain and inflammation by injecting into the intra-
articular space. Commonly used corticosteroids have been triamcinolone acetonide (TA) and 
triamcinolone hexacetonide (TH) which have been reviewed in the literature and found to be safe and 
effective for short term relief of the symptoms of osteoarthritis.[7] Standard dosing for intra-articular 
injections to the knee for triamcinolone hexacetonide (TH) have been reported as a 1 ml injection at a 
concentration of 20 mg/ml which will be the proposed dose for the active control in this trial.[7]
Viscosupplements are believed to restore the concentration of hyaluronans in synovial fluid, elevate 
the viscosity and improve the lubricating and cushioning properties of the synovial fluid to a healthier
state to alleviate pain in OA [6].  HA in synovial fluid binds to chondrocytes, supporting a role for HA in 
healthy cartilage [5]. HA has been studied as a substance capable of restoring the normal properties 
of synovial fluid and cartilage, thereby reducing pain and stiffness in the osteoarthritic joints. 

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 14 of 85
Exogenously administered HA immediately restores the synovial fluid’s viscoelastic (or rheologic) 
properties [6]. 
Bellamy et al (2006) conducted a systematic analysis of 76 single and double-blinded studies and 
concluded that viscosupplements are an effective treatment for OA of the knee with beneficial effects 
on pain, function and Patient Global Assessment from a 5 to 13 week post injection period showing a 
percent improvement from baseline of 28% to 54% for pain and 9% to 32% for function [8].
Because data show a delayed treatment effect of HA, Anika Therapeutics wanted to create a product 
(Cingal) that could provide quicker pain relief for subjects suffering from osteoarthritis while still 
providing the established pain relief of an HA product. 
Cingal is a sterile, biocompatible, non-pyrogenic, viscoelastic, uniform white/off white opaque solution 
composed of molecules of HA and triamcinolone hexacetonide (TH).  Cingal is indicated in the 
treatment on pain in osteoarthritis (OA) of the knee in patients who have failed to respond to 
conservative non-pharmacological therapy and to simple analgesics, e.g., acetaminophen.  Cingal 
functions as a viscoelastic supplement or a replacement for synovial fluid in human joints with short 
term pain relief is provided by triamcinolone hexacetonide. This clinical trial will evaluate the efficacy 
and safety of a single injection of Cingal for relief of joint pain in subjects with OA of the knee who have
not responded to conservative treatment.

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 15 of 85
6
PRINCIPAL INVESTIGATOR
Principal Investigator
Laszlo Hangody, M.D., Ph.D., D.Sc.
Address: Uzsoki Hospital, Orthopedic and Trauma Department,
Uzsoki str. 29. Budapest, Hungary, 1145
Co-investigator
Agnes Berta M.D. 
Address: Uzsoki Hospital, Orthopedic and Trauma Department,
Uzsoki str. 29. Budapest, Hungary, 1145
Research Facilities
Uzsoki Hospital, Orthopedic and Trauma Department,
Uzsoki str. 29. Budapest, Hungary, 1145
Ethics Committee
Uzsoki Utcai Kórház Intézményi Kutatásetikai Bizottsága,
H-1145 Budapest, Uzsoki utca 29-41., 
Tel: +1-467-3750, Fax.: +1-251-5488.

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 16 of 85
7
STUDY OBJECTIVES
The objective of this study is to evaluate the efficacy and safety of a single injection of Cingal for relief 
of joint pain in subjects with OA of the knee who have not responded to conservative treatment (weight 
reduction, physical therapy, pain medications, etc.).
8
ENDPOINTS
8.1
Primary Efficacy Endpoint 
x
The change from baseline in knee pain as measured by the WOMAC Pain Score (100 mm 
VAS) at 26 weeks post treatment comparing the Cingal group to the Triamcinolone 
Hexacetonide (TH) group. 
8.2
Secondary Efficacy Endpoints 
x
The change from baseline in knee pain as measured by the WOMAC Pain Score (100 mm 
VAS) at 3 weeks post treatment comparing the Cingal group to the Monovisc group. 
x
The responder rate as identified by the Outcomes Measures for Rheumatic Arthritis Clinical 
Trials-Osteoarthritis Research Society International (OMERACT-OARSI) responder index 
at 26 weeks post treatment comparing the Cingal group to the TH group.
x
The change from baseline in WOMAC Physical Function score at 26 weeks post treatment 
comparing the Cingal group to the TH group.
x
The change from baseline in WOMAC Stiffness score at 26 weeks post treatment comparing 
the Cingal group to the TH group.
x
The change from baseline in Total WOMAC score at 26 weeks post treatment comparing 
the Cingal group to the TH group.
x
The change from baseline in the Patient Global Assessment at 26 weeks post treatment in 
the Cingal group compared to the TH group.
x
The change from baseline in the Evaluator Global Assessment at 26 weeks post treatment 
in the Cingal group compared to the TH group.
x
The change from baseline in knee pain as measured by the WOMAC Pain Score (100 mm 
VAS) at 1 week post treatment comparing the Cingal group and the Monovisc group.
x
The usage of rescue medication through 26 weeks post treatment in the Cingal group 
compared to the TH group.
8.3
Exploratory Endpoints 

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 17 of 85
Any comparisons between groups (Cingal, Monovisc, TH), within groups and / or time points 
(from baseline through to 26 weeks) not described in the primary or secondary endpoints may 
be presented in the exploratory endpoints including:
x
EuroQol (EQ-5D)
x
WOMAC Pain Score (100mm VAS)
x
OMERACT-OARSI
x
Total WOMAC
x
WOMAC Stiffness Score
x
WOMAC Physical Function
x
Patient Global Assessment
x
Evaluator Global Assessment
x
Range of Motion 
x
Rescue Medication Usage
x
Number of Treatment Failures due to Additional Procedure or Use of Disallowed Medication  
8.4
Safety Endpoint: 
The incidence, timing, severity, and relationship to treatment of all Adverse Events (AE) will be collected 
and coded using Medical Dictionary for Regulatory Activities (MedDRA).  Local injection site and non-
local events will be recorded separately.

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 18 of 85
9
STUDY DESIGN
9.1
Diagram
SCREENING
All Screening Inclusion/Exclusion Criteria Met
BASELINE
All Baseline Inclusion/Exclusion Criteria Met
RANDOMIZATION
n=576
CINGAL INJECTION
n=256
MONOVISC INJECTION
n=256
TH INJECTION
n=64
FOLLOW-UP VISITS POST TREATMENT
1, 3, 6, 12, 18, and 26 Weeks after Baseline Injection

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 19 of 85
9.2
Trial Design
This is a multi-center, randomized, double-blind, parallel group, active comparator controlled trial to 
evaluate the efficacy and safety of a single injection of Cingal for the relief of joint pain in subjects with
OA of the knee. 
Subjects with OA defined as Kellgren-Lawrence (K-L) I-III in the index knee will be eligible for this study
[9, 10]. Felson et al 2004, encouraged the use of both OA symptoms and radiographic changes in the 
assessment of OA [11].  This study will employ both methods to screen subjects.  Structural severity 
will be evaluated with the K-L classification score, a composite index of the presence and severity of 
joint space narrowing, osteophytes, sclerosis, deformity and cysts (see Appendix 4) [9, 10].
For the evaluation of symptomatic severity, two main domains are important [12].  The first is pain and 
the second is functional impairment.  Other domains often used include subject’s overall assessment, 
ROM and performance.  Domains identified by OMERACT as core variables to be used in clinical trials 
involving OA are pain, function and the Patient Global Assessment which will be captured as part of 
this study [12].
Baseline and post-treatment pain, physical function and stiffness will be measured using the WOMAC 
questionnaire.  Range of Motion, Patient and Evaluator Global Assessment and the EuroQol will be 
used to assess symptomatic severity throughout the study.  In addition, the number of 
acetaminophen/paracetamol pills taken will be captured as an indirect measure of pain and will be done 
at each visit. 
Subjects meeting the inclusion/exclusion criteria will be randomized to receive a single injection of 
Cingal, Monovisc or triamcinolone hexacetonide (TH) in the index knee. Since there is a difference in 
volume between Cingal, Monovisc and TH, the treating physician will not be considered blinded.  To 
maintain the double-blind design of the study, there will be a person assigned to the role of Treating 
Physician and one person assigned to the role of Blinded Evaluator. The Treating Physician, most often 
the PI, will administer the injection but will not participate in the evaluation of study treatment 
effectiveness. A second individual, designated as the Blinded Evaluator, is blinded to treatment and will 
complete the pre- and post-treatment Evaluator Global Assessment, knee exams and ROM 
measurements. To maintain the subject blinding, the injection syringe will be prepared separate from 
the patient and the injection will be masked from the subject.  
The subject will be trained on how to complete the WOMAC, Patient Global Assessment and EuroQol.
The subject should complete these questionnaires prior to any physical evaluation that must be done 

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 20 of 85
at each follow-up visit.
The Blinded Evaluator will collect and record AEs from the subjects and consult the Treating Physician 
only as needed in the management of AEs.  The Blinded Evaluator will be a physician, research nurse,
registered physiotherapist or physician assistant trained to perform the assessments outlined in the 
protocol (Section, 11.1 Schedule of Events ).
Up to 40 sites in Europe may participate in the study to enroll 576 subjects. Subject participation will 
last approximately 7 months with follow-up visits scheduled at weeks 1, 3, 6, 12, 18, and 26 after the 
treatment injection.
10 ELIGIBILITY
10.1 Screening Enrollment Criteria 
10.1.1 Screening Inclusion Criteria
1. Subject is 40-\HDUVROGZLWKD%RG\0DVV,QGH[%0,NJP2.
2. Subject has Kellgren-Lawrence (K-L) severity grade I, II or III in the index knee as determined 
by X-ray.  Contralateral knee: K-L severity grade 0, I or II.
3. Subject has had at least two signs and at least two symptoms of OA disease (based on the 
European League Against Rheumatism (EULAR) recommendations for diagnosing knee 
OA[13]in the index knee for at least 6 months despite conservative treatment (weight 
reduction, physical therapy, pain medications, etc.). The EULAR signs and symptoms are as 
follows: 
x
Signs: crepitus, restricted movement and bony enlargement 
x
Symptoms: persistent knee pain, limited morning stiffness and reduced function 
4. Subject must be willing to abstain from other intraarticular (IA) treatments of the knee for the 
duration of the study.
5. Subject is willing to discontinue all analgesics including NSAIDs, except 
acetaminophen/paracetamol, at least seven days before the treatment injection and through 
the completion of the study.
6. Subject is willing to use only acetaminophen/paracetamol (up to a maximum of 4.0 grams per 
day per the package insert) for the treatment of joint pain for the duration of the study. At least 
forty eight hours prior to the Baseline Visit and each follow-up visit the subject is willing to 
discontinue use of acetaminophen/paracetamol. 
7. Subject is willing to maintain a stable dose of oral glucosamine and/or chondroitin sulfate 

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 21 of 85
products throughout the study, if taken prior to signing the ICF.
8. Subject is able to understand and comply with the requirements of the study and voluntarily 
provide consent.
10.1.2 Screening Exclusion Criteria
1. Subject received an IA injection of Hyaluronic Acid (HA) and/or steroid in either knee within 6 
months of signing the ICF. A subject will be excluded if they are planning to receive an HA or 
steroid injection (other than the study injection) in either knee during the course of this study.
2. Subject had an arthroscopy of either knee within 3 months of signing the ICF.
3. Subject had an open surgical procedure of either knee or hip or any surgery of the spine 
within 12 months of signing the ICF. Subject plans to have knee, hip or spine surgery within 
the study period. 
4. Subject has intra-articular trauma to the index knee. Subject has concurrent multi-system or 
multi-limb trauma.
5. Subject has evidence or medical history of the following diseases in the index knee: septic 
arthritis; inflammatory joint disease; history of Reiter’s syndrome; gout; chondrocalcinosis 
associated with recurrent episodes of acute synovitis of the knee consistent with pseudogout; 
osteochondritis dissecans, Paget disease of the bone; ochronosis; acromegaly; 
hemochromatosis; primary osteochondromatosis; known history of Wilson disease; heritable 
disorders or collagen gene mutations.
6. Subject has a history of cartilage repair surgery in the index knee within 3 years of signing the 
ICF.
7. Subject has a history of ACL repair, reconstruction or injury in the index knee within 3 years of 
signing the ICF.
8. Subject has X-ray findings of acute fractures, severe bone loss, avascular necrosis, severe 
bone or joint deformity in the index knee.
9. Subject has significant varus or valgus deformity greater than 10 degrees in either knee.
10. Subject has a clinically apparent tense effusion of the index knee.
11. Subject has knee instability in either knee per the Investigator’s assessment.
12. Subject requires consistent use of an assistive device (e.g. wheelchair, walker, etc.)
Occasional use of a cane is acceptable.
13. Subject has medical condition(s) which could affect study assessments or may adversely 
affect the safety and/or success of the study treatment. This includes but is not limited to the 
following:
a. Peripheral neuropathy severe enough to interfere with evaluation of the subject,

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 22 of 85
b. Vascular insufficiency severe enough to interfere with evaluation of the subject,
c. Active fibromyalgia, 
d. Hemiparesis involving either lower extremity, 
e. Immunocompromised or immunosuppressive disorder or receiving medications to treat 
immunosuppressive disorders,
f. Systemic bleeding disorder(s), 
g. Current malignancy or treatment within the last 5 years, except for non-melanoma skin 
cancer,  
h. Significant psychiatric disorder, 
i. Active drug and/or alcohol abuse within the past year, 
j. Uncontrolled diabetes with a screening HbA1c of >7%.
14. Subject is taking medications at the time of signing the ICF which could interfere with the 
treatment procedure, healing and/or assessments. This includes but is not limited to oral or 
injectable anticoagulant treatments, anti-aggregant platelet treatment, chronic opioid 
analgesics. Low dose aspirin used for cardiovascular protection is allowed if a stable regimen 
is maintained for the duration of the study.
15. Subject is receiving treatment using electromagnetic stimulation and/or low intensity 
ultrasound in the index knee at the time of signing the ICF, within 3 months of signing the ICF
or plans to receive treatment any time during the study period. 
16. Subjects who had an oral, intramuscular, intravenous, rectal suppository or topical (excluded 
in index knee only) corticosteroid within 30 days of signing the ICF are excluded.  Topical 
corticosteroid use at any site other than the index knee is allowed.
17. Subject has a pre-treatment contraindication to IA injections or aspiration of the index knee, 
including cutaneous infection in the injection site area, active IA infection (as suggested by 
moderate or marked effusion), knee deformity or condition which, in the opinion of the 
investigator could jeopardize the sterility or delivery of the IA injection.
18. Subjects with a history of hypersensitivity to any of the ingredients in the hyaluronan or 
previous hypersensitivity to the administration of corticosteroids or an inability to tolerate 
acetaminophen/paracetamol.
19. Subject has any contraindication to the receipt of corticosteroids.
20. Subject is receiving or in litigation for worker’s compensation.
21. Subject is a woman who is pregnant or breastfeeding at the Screening Visit or a woman of 
child bearing potential who refuses to use effective contraception during the course of the 
study.
22. Subject was involved in any other research study involving an investigational product, or a 

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 23 of 85
new application of an approved product, within 60 days of signing the ICF.
10.2 Baseline Enrollment Criteria 
10.2.1 Baseline Inclusion Criteria
1. Subject has a Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)
pain-sub-VFRUHPPDQGPPLQWKHDIIHFWHGNQHHDQG0 mm in the contralateral 
knee on a 100 mm Visual Analog Scale (VAS) scale.
10.2.2 Baseline Exclusion Criteria
1. Subject KDVDGHFUHDVHRI20 mm in the WOMAC pain-sub-score (average of 5 pain scales) 
from Screening to Baseline in the index knee on a 100 mm Visual Analog Scale (VAS) scale.
2. Subject has a synovial fluid aspirate volume > 20 mL in the index knee.
3. Subject has a contraindication to continue with the study treatment injection based on the 
visual appearance of the synovial fluid aspirate unless the fluid is examined microscopically 
prior to injection with no clinically significant findings (e.g. bacteria, crystals or blood).
4. Subject has ROM of less than 100° flexion in either knee.

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 24 of 85
11 STUDY PROCEDURES
11.1 Schedule of Events
Pre-
Treatment
Treatment
Post-Treatment Follow-Up Visits
Assessments
-7 to
-14
Days
Day 0
(7-14 days after 
screening visit)
1 week
3
weeks
6
weeks
12 
weeks 
18 
weeks
26 
weeks
Screening
Baseline
Treatment
±3 days
± 1 week
Informed Consent
X
Demographics
Medical History
X
Physical Exam, Vitals, BMI
X
Urine / Blood Pregnancy Test
X
Chemistry/Hematology/Urinalysis
X
Bilateral Knee X-rays
and assessment of K-L
X
Review of X-rays by Independent 
Radiologist
X
Physical Evaluation (Both Knees) 
X
X
X
X
X
X
X
X
ROM (Index Knee)
X
X
X
X
X
X
X
X
ROM (Contralateral Knee)
X
X
X
X
WOMAC (Both Knees)
X
X
X
X
X
X
X
X
Evaluation of Enrollment Criteria
X
X
X
Stop Analgesics/NSAIDs except 
Acetaminophen/Paracetamol
X
Assess D/C 
Acetaminophen/Paracetamol 48
hours before Visit
X
X
X
X
X
X
X
Acetaminophen/Paracetamol 
Dispense/Pill Count
X
X
X
X
X
X
X
X
Distribute Subject Diary
X
Randomization
X
Aspiration/ Evaluation of Synovial Fluid
X
IA Injection
X
Evaluate Diary
X
X
X
X
X
X
X
EuroQol
X
X
X
X
X
X
X
Patient Global Assessment
X
X
X
X
X
X
X
Evaluator Global Assessment
X
X
X
X
X
X
X
Concomitant Medication Assessment
Throughout the study
Adverse Event Assessment
Throughout the study 

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 25 of 85
11.2 Procedure Description
11.2.1 Informed Consent Form (ICF)
The subject will be asked to sign the ICF prior to undergoing any study related procedures.
11.2.2 Demographics
The following demographic information will be collected at the Screening Visit: Age, Gender, Race and 
Ethnicity.
11.2.3 Physical Exam (PE)
The PE will be performed at the time points included in Section 11.1 Schedule of Events. The PE will 
include an assessment of general appearance, chest and lungs, heart, abdomen, skin, musculoskeletal
system, neurologic systems and other (as applicable).  This PE will include an assessment of height 
and weight for calculation of a BMI.
11.2.4 Vital Signs
Vital signs (blood pressure, pulse, temperature) will be collected at the time points included in Section
11.1 Schedule of Events.
11.2.5 Pregnancy Test
For females of childbearing potential, a urine or blood pregnancy test will be performed at the
Screening Visit. Women who can confirm that they are surgically sterile or have been 
postmenopausal for at least 1 year prior to signing the ICF need not undergo a pregnancy test.  
11.2.6 Chemistry/Hematology/Urinalysis
For all subjects, the blood tests in Table 1 will be performed to assist in assessing subject eligibility at 
the Screening Visit. A routine and microscopic analysis of the urine will be conducted at the Screening
Visit. Subjects will be excluded if any results are deemed clinically significant.  Subjects will be eligible 
to repeat screening after a minimum of 14 days at the discretion of the Investigator and with approval 
of the Sponsor.

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 26 of 85
Table 1 Laboratory Analytes
Hematology
Clinical Chemistry
Hematocrit
Sodium
AST/SGOT
Hemoglobin
Potassium
ALT/SGPT
RBC count
Chloride
Alkaline Phosphatase
WBC count
Glucose
Total protein
Differential WBC count
Urea nitrogen
Albumin
Platelet count
Creatinine
HbA1c (for diabetics only)
Total bilirubin
Triglycerides
Calcium
11.2.7 Knee X-rays/Assessment of Kellgren-Lawrence Score
Subjects will be asked to have the following X-rays of both knees collected at the Screening Visit:
x
Long Limb Standing Anterior Posterior (AP) view
x
Fixed Flexion Posterior Anterior (PA) view 
These screening images will be transferred to, as well as handled by, the Central Imaging Core lab 
according to their Standard Operating Procedures (SOPs). An independent radiologist from the Central 
Imaging Core lab will evaluate the Screening plain films of both knees for osteoarthritic changes using 
the K-L scoring system (Appendix 4) and exclude subjects with K-L severity grade of IV in the index 
knee or K-L severity grade III or IV in the contralateral knee. Additionally, varus/ valgus alignment will 
be assessed in both knees and subjects with greater than 10 degrees of malalignment in either knee 
will be excluded.
The independent radiologist will furthermore evaluate the screening X-rays to determine the following 
exclusion criteria for the index knee:
x
Presence of osteochondromatosis
x
History of ACL repair, reconstruction or injury
x
History of cartilage repair surgery
x
X-ray findings of acute fracture(s)
x
Severe loss of bone density
x
Avascular necrosis

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 27 of 85
x
Severe bone or joint deformity in the index knee
x
Advanced cases of gout
x
Advanced cases of Paget
x
Acromegaly
x
Osteochondritis dissecans
The independent radiologist will confirm the eligibility of screened subjects based on the imaging 
enrollment criteria. In the event the independent radiologist determines that a subject is ineligible 
based on an imaging finding, the decision of the independent radiologist will prevail.
All the Screening X-rays are paid for by this research study and are free of charge to the subject. 
The images acquired for this trial will be transferred from the imaging site to the Central Imaging Core 
lab electronically. The X-rays will be identified by the subject’s study identification (ID) number. No 
personal identifiable information will be included on the image.
11.2.8 Medical History
A complete medical history will be obtained at the Screening Visit.  The medical history will include an 
inquiry of past medical conditions in the following body systems: neurological, psychological, 
cardiovascular, hematological, respiratory, endocrine/metabolic, musculoskeletal, and immunologic
(including allergies). The medical history will also include an assessment of the subject’s history of the 
following:
x
History/duration of knee OA
x
History of operative arthroscopies
x
History of open surgical procedures of either knee
x
History of open surgical procedures of either hip
x
History of IA injections including HA and steroid
x
History of electromagnetic stimulation therapy
x
History of other OA surgeries
x
History of other OA procedures
x
History of other OA abnormalities
11.2.9 Physical Evaluation of Knee
The Blinded Evaluator will perform the physical evaluation of the knee at the time points included in 
Section 11.1, Schedule of Events. This will include assessment of effusion grade of both knees (none, 

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 28 of 85
mild, moderate or marked), symptoms (e.g.  persistent knee pain, limited morning stiffness and reduced 
function) and signs (crepitus, restricted movement and bony enlargement).  Knee circumference in cm 
will also be measured in the index knee.
11.2.10
Range of Motion
The ROM will assess the maximum flexion and extension in degrees using a goniometer at the time 
points included in Section 11.1, Schedule of Events. The ROM will be documented as a hyphenated 
number. For instance, normal ROM in the knee is about 0-140 degrees.
11.2.11
WOMAC
The WOMAC index is self-administered and assesses the three dimensions of pain, disability and 
joint stiffness in knee and hip osteoarthritis using a battery of 24 questions (5 pain, 2 stiffness,17 
physical function) [14]. This trial will utilize the VAS version of the WOMAC index. The subject will be 
trained on how to complete the WOMAC which will be collected at the time points indicated in Section 
11.2.12
Medications
Medications that the subject may have been taking prior to study enrollment for conditions unrelated to 
the treatment of knee osteoarthritis, other than analgesics including NSAIDs, may be continued as long 
as they will not interfere with study assessments.  If the subject was taking oral glucosamine and/or 
chondroitin sulfate products for the treatment of knee osteoarthritis prior to signing the informed consent
form, the products may be continued, but the subject must maintain a stable regimen for the duration 
of the study.
11.2.12.1
Restricted Medications
All analgesics other than acetaminophen/paracetamol are prohibited during the study.  This includes, 
but is not restricted to, NSAIDs, opioids and topical agents for treatment of OA in the index knee. Topical 
corticosteroids are allowed at any other site other than the index knee. The analgesic medication use 
will be monitored at each subject visit through review of the subject diary. 
The use of IA injection of steroids in any joint and the use of IA injection of viscosupplements in the 
knee joint is prohibited throughout the study. 
The use of immunosuppressive agents such as 
cyclosporine, methotrexate are prohibited throughout the study.
11.2.12.2
Rescue Medications
Acetaminophen/paracetamol (up to a maximum of 4.0 grams per day per the package insert or as per 

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 29 of 85
regional limitations) will be allowed as the rescue medication for the treatment of joint pain for the 
duration of the study. At least forty eight hours prior to the Baseline Visit and each follow-up visit the 
subject should discontinue use of the rescue medication.
At the Screening Visit, the rescue acetaminophen/paracetamol will be dispensed. The subject should 
be instructed to bring the rescue medication with them to each follow-up visit for a pill count. Additional 
rescue acetaminophen/paracetamol will be dispensed as needed at the follow-up visits.
11.2.12.3
Concomitant Medications
A medication is considered concomitant if taken after signing the ICF and up to and including the last 
follow-up visit.  Data on medications will include: medication name, dose, unit, route, frequency, start 
date, stop date, indication and whether the medication was taken for an AE.
At each study visit, the subject will be asked about any new medications that were started since the 
last visit.  Indications for any new medications during the study period will be recorded as AEs, unless 
the medications are administered for a pre-existing condition.
11.2.13
Subject Diary
The subject diary will be dispensed at the Screening Visit and the subject will receive training on when 
and how to complete the diary. The subject diary will be used to collect information on medication usage
including rescue medications, concomitant therapies (e.g. physical therapy) and AEs. The subject diary 
will be reviewed by site staff to determine if there are AEs that need to be captured within the Electronic 
Data Capture (EDC) system and to assess rescue medication usage and compliance with the protocol.
11.2.14
EuroQoL EQ-5D
Outcomes information from the subject-completed EuroQol EQ-5D will be obtained at all evaluation 
points specified in Section 9.1, Schedule of Events [15, 16] (Appendix 3).  The EQ-5D is a standardized 
measure of health status developed by the EuroQol Group which is applicable to a wide range of health 
conditions and treatments. The EQ-5D provides a simple descriptive profile and a single index value 
for health status that can be used in the clinical and economic evaluation of health care as well as in 
population health surveys [15].
The EQ-5D is designed for self-completion by respondents and consists of 2 pages - the EQ-5D 
descriptive system and the EQ visual analog scale (EQ VAS). The EQ-5D descriptive system comprises 
the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression
[15].  The subject is asked to indicate his/her health state by ticking (or placing a cross) in the box 

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 30 of 85
against the most appropriate statement in each of the 5 dimensions. The EQ VAS records the subject’s 
self-rated health on a vertical VAS where the endpoints are labeled ‘Best health you can imagine’ and 
‘Worst health you can imagine’ as shown in Appendix 3. This information is used as a quantitative 
measure of health outcome as judged by the individual respondents [15].
11.2.15
Patient Global Assessment
The Patient Global Assessment (Appendix 2) is a VAS that will be completed by the subject at time points 
specified in Section 9.1, Schedule of Events, to determine the Patient Global Assessment of response 
to therapy score. “Considering all the ways the osteoarthritis in your study knee affects you, what is 
your assessment of how much your study knee is bothering you today?”
11.2.16
Evaluator Global Assessment
The Evaluator Global Assessment (Appendix 2) will be completed by the Blinded Evaluator at the time
points delineated in Section 9.1, Schedule of Events. To reduce the potential for bias, it is important for 
the Blinded Evaluator to complete the Evaluator Global Assessment prior to collecting the Patient 
Global Assessment.
The Blinded Evaluator will be asked “Considering all the ways the osteoarthritis in the patient’s index 
knee affect him/her, what is your assessment of how much the patient’s knee is bothering him/her 
today?”
11.2.17
Blinding
Although the identity of the syringes will not be revealed, it is recognized that there is a visible difference 
in the Clinical Trial Material (CTM) in the syringes as well as a difference in the extrusion force among
Cingal, Monovisc and triamcinolone hexacetonide (TH) and a difference in volume. To maintain the 
double-blind design of the study, the following measures will be taken. To maintain the blind of the 
subject, a drape will be used to shield the view of the subject, or the patient will be positioned in such 
a manner, that they cannot observe the syringe or injection.  Furthermore, due to the lack of 
proprioceptive receptors in the cartilage of the knee [17], the subject should not be able to detect the
viscosity or volume of the CTM being injected.  
The Treating Physician will be aware of the differences and will be unblinded, therefore; there will be a 
Treating Physician (unblinded) and a Blinded Evaluator (blinded) at each site with clearly defined 
roles.
x
Treating Physician: The Treating Physician is most often the PI. He/she will administer the 

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 31 of 85
Cingal, Monovisc or Triamcinolone Hexacetonide (TH) injection but will not participate in the 
efficacy evaluation.  
x
Blinded Evaluator: The Blinded Evaluator will be a physician, research nurse, registered 
physiotherapist or physician assistant trained by the PI to perform the assessments outlined in 
the protocol. The Blinded Evaluator will complete the physical evaluation of both knees, ROM
assessments of both knees, and the Evaluator Global Assessment.
11.3 Screening
Each subject will indicate his or her willingness to participate in the study by signing the ICF. Subjects
will receive a unique subject ID (e.g., 01-001) where the first two digits represent the number assigned 
to the investigative site and the last three digits represent the subject number. The number will be 
recorded on the Enrollment Log and in the subject’s electronic Case Report Forms (eCRFs). Subjects
will be identified by the unique subject ID for the duration of their participation in the study. 
The following screening and eligibility data will be collected 7-14 days prior to the Baseline/Treatment 
Visit:
x
Informed Consent
x
Demographics (age, gender, ethnic origin)
x
Medical History
x
Physical Examination including BMI and Vitals
x
Screening Laboratory Testing
o
Chemistry
o
Hematology
o
Urinalysis
x
Pregnancy Test (women of childbearing potential)
x
Enrollment Criteria Assessment
x
Bilateral Knee X-ray and Assessment of K-L Severity Grade
x
Review of X-rays by Independent Radiologist
x
Physical Evaluation (Both Knees)
x
Range of Motion Evaluation (Both Knees)
x
WOMAC (Both Knees)
x
Distribute Subject Diary
x
Assess AEs
x
Assess Concomitant Medications

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 32 of 85
x
Dispense Rescue Medication
During the Screening Visit inform the subject about discontinuation of all analgesics including NSAIDs 
except acetaminophen/paracetamol. Acetaminophen/paracetamol will be used as a rescue pain 
medication through the completion of the study, however; acetaminophen/paracetamol should be 
discontinued at least 48 hours before each follow-up study visit. Subjects who are taking oral 
glucosamine and chondroitin sulfate products should be informed that a stable dose of these 
supplements must be maintained for the duration of the study.
Subjects who fail to meet screening eligibility criteria may, at the discretion of the investigator and with 
Sponsor approval, be rescreened after a minimum of 14 days. A new subject number will be assigned.
11.4 Baseline
The Baseline Visit will occur 7-14 days after the Screening Visit. The following assessments will take 
place during this visit:
x
Evaluation of Enrollment Criteria 
x
Confirm Rescue and Prohibited Medication Washout
x
Count/Dispense Rescue Medication Pills 
x
Evaluate Subject Diary
x
Physical Evaluation (Both Knees)
x
Range of Motion (Both Knees)
x
WOMAC (Both Knees)
x
Patient Global Assessment
x
EuroQol
x
Evaluator Global Assessment
x
Assess Concomitant Medications
x
Assess AEs
Pre-Treatment Screening
Evaluate the subject for the baseline enrollment criteria (Section 8.2, Baseline Enrollment Criteria)
regarding the WOMAC and ROM. 
11.5 Randomization
If the subject has met the Screening and Baseline enrollment criteria (except assessment of intra-
articular fluid), he/she will be randomized using the EDC system. The EDC system will indicate which 

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 33 of 85
blinded carton should be used for that injection using a kit number (__ __ __ __ __ ). 
11.6 Treatment
The Treating Physician will prep and drape the subject's index knee. The Treating Physician will always 
perform the index knee injection for each subject and will not participate in the efficacy evaluation. 
Using a sterile syringe and an 18-21 gauge needle, the Treating Physician should penetrate the joint 
space, aspirate to dryness and retain any synovial fluid for measurement of volume and laboratory 
analysis (if needed).  Aspiration should be attempted on all subjects, regardless of whether there is 
clinical appearance of effusion.  
Evaluate the subject for the baseline enrollment criteria (Section 8.2, Baseline Enrollment Criteria)
regarding the volume and appearance of the synovial fluid aspirate. If needed, the aspirate should be 
sent for microscopic examination and results evaluated prior to the injection. The injection should be 
postponed until the results of the microscopic examination are received and the Treating Physician 
determines it is safe to proceed with the study injection. Any subject found to not meet the 
inclusion/exclusion criteria will be excluded from the study.  If this possibility is anticipated, an alternate 
plan for treatment should be pre-arranged.   
For the triamcinolone hexacetonide arm, an ampoule of triamcinolone hexacetonide will be provided 
by the Sponsor as Clinical Trial Material. The Treating Physician will draw the triamcinolone 
hexacetonide into an empty syringe as standard practice for an intra-articular injection.
Once the synovial fluid characteristics and volume are confirmed to be acceptable, the Treating 
Physician should inject the entire contents of the syringe into the joint space unless this volume is felt 
to be too much. The Treating Physician should advise each subject to avoid heavy physical activities 
(including jogging, tennis, heavy lifting, prolonged standing) for 24 hours after the study injection.
The Blinded Evaluator must not be present for the injection.  
11.7 Injection Technique
It is recommended that a lateral midpatellar injection be performed in accordance with the findings of 
Jackson et al. (2002) who demonstrated a greater rate of injection accuracy when compared to 
anterolateral and anteromedial injections [18]. Because this study is enrolling subjects with K-L I, II 
and III in the index knee, it should be noted that in a study by Toda et al (2008), it was found that the 

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 34 of 85
best injection approach may be determined by the severity of knee OA [19]. However, each treating 
physician may utilize the preferred method of injection based on their clinical practice.
To perform a lateral midpatellar injection, the lower limb is extended on the examination table. The 
patella will be manually everted and moved laterally by the physician’s free hand. The needle will be 
advanced transversely between the articular surfaces of the patellofemoral joint at the midpoint of the
patella [18].
Diagram showing the lateral midpatellar portal [18]. 
P = patella,F = femur, T = tibia, and FP = fat pad.
Post-Treatment Assessments and Instructions
Prior to leaving the clinic, the subject should be evaluated for local and non-local AEs and the index 
knee assessed for local AEs.  All post-treatment signs and symptoms that are unexpected should be 
recorded as AEs.  The expected appearance of the index knee should be discussed with the subject
with a request that all unexpected symptoms be reported to a member of the study team. 
Subjects who exhibit significant complications, (e.g., significant inflammation or significant swelling of 
the joint) may warrant diagnostic or therapeutic procedures as determined by the Treating Physician in 
conjunction with the Blinded Evaluator.  All subjects will be evaluated for safety for the duration of the 
study.   Inclusion of the subject in the efficacy evaluation will be decided on a case by case basis.

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 35 of 85
11.8 Post-Treatment Follow-Up
All study subjects will have follow-up assessments at 1, 3, 6, 12, 18, and 26 weeks after injection day 
to evaluate effectiveness of the treatment and to assess AEs and protocol compliance.  The Blinded 
Evaluator will evaluate the clinical status of the subject at each visit.  
More than 48 hours prior to the visit, the subject will be reminded of the visit date and time, the need to 
abstain from acetaminophen/paracetamol for at least 48 hours prior to each follow-up visit and the 
requirement to bring their subject diary and the acetaminophen/paracetamol for a pill count with them 
to the appointment.
If the subject arrives for a study visit without discontinuing acetaminophen/paracetamol for at least 48 
hours prior to the visit, the visit should be rescheduled within the allowed window of time. Study 
assessments should be performed as soon as possible and the protocol deviation, if applicable,
recorded in the source and eCRF.  The subject must be re-educated about the importance of protocol 
compliance.
If the subject does not come in at the expected time, at least three attempts will be made to contact the 
subject in order to accomplish maximum subject compliance with the follow-up schedule.  
The following post-treatment visits will be performed. The subject will be asked whether any 
concomitant medications have been taken.  All assessments will be done by the Blinded Evaluator.
11.8.1 1 Week ± 3 Days
x
Confirm Rescue Medication Washout 
x
Evaluate Subject Diary
x
Count/Dispense Rescue Medication Pills (if needed) 
x
Physical Evaluation (both knees)
x
ROM (index knee)
x
WOMAC (Both Knees)
x
Patient Global Assessment
x
Evaluator Global Assessment
x
EuroQol
x
Assess Concomitant Medications
x
Assess AEs

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 36 of 85
11.8.2 3 Weeks ± 3 Days
x
Confirm Rescue Medication Washout 
x
Evaluate Subject Diary
x
Count/Dispense Rescue Medication Pills (if needed) 
x
Physical Evaluation (both knees)
x
ROM (index knee)
x
WOMAC (Both Knees)
x
Patient Global Assessment
x
Evaluator Global Assessment
x
EuroQol
x
Assess Concomitant Medications
x
Assess AEs
11.8.3 6 Weeks ± 3 Days
x
Confirm Rescue Medication Washout 
x
Evaluate Subject Diary
x
Count/Dispense Rescue Medication Pills (if needed) 
x
Physical Evaluation (both knees)
x
ROM (index knee)
x
WOMAC (Both Knees)
x
Patient Global Assessment
x
Evaluator Global Assessment
x
EuroQol
x
Assess Concomitant Medications
x
Assess AEs
11.8.4 12 Weeks ± 3 Days
x
Confirm Rescue Medication Washout 
x
Evaluate Subject Diary
x
Count/Dispense Rescue Medication Pills (if needed) 
x
Physical Evaluation (both knees)
x
ROM (both knees)
x
WOMAC (Both Knees)
x
Patient Global Assessment
x
Evaluator Global Assessment

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 37 of 85
x
EuroQol
x
Assess Concomitant Medications
x
Assess AEs
11.8.5 18 Weeks ± 7 Days
x
Confirm Rescue Medication Washout 
x
Evaluate Subject Diary
x
Count/Dispense Rescue Medication Pills (if needed) 
x
Physical Evaluation (both knees)
x
ROM (index knee)
x
WOMAC (Both Knees)
x
Patient Global Assessment
x
Evaluator Global Assessment
x
EuroQol
x
Assess Concomitant Medications
x
Assess AEs
11.8.6 26 Weeks ± 7 Days
x
Confirm Rescue Medication Washout 
x
Evaluate Subject Diary
x
Count/Dispense Rescue Medication Pills (if needed) 
x
Physical Evaluation (both knees)
x
ROM (both knees)
x
WOMAC (Both Knees)
x
Patient Global Assessment
x
Evaluator Global Assessment
x
EuroQol
x
Assess Concomitant Medications
x
Assess AEs

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 38 of 85
12 ADVERSE EVENTS / ADVERSE REACTIONS
12.1 Definitions – Device Adverse Events
Adverse Event (AE): An AE is any untoward medical occurrence in a subject administered the CTM, 
which does not necessarily have a causal relationship with the treatment.  An AE can therefore be any 
unfavorable and unintended sign, (including an abnormal laboratory finding) symptom or disease 
temporally associated with the use of the CTM, whether or not related to the CTM.
Adverse Device Effect (ADE): An AE related to the use of an investigational medical device.
NOTE 1: This definition includes Adverse Events resulting from insufficient or inadequate 
instructions for use, deployment, implantation, installation, or operation, or any malfunction of 
the investigational medical device.
NOTE 2: This definition includes any event resulting from use error or from intentional misuse 
of the investigational medical device.
Anticipated Serious Adverse Device Effect: An effect which by its nature, incidence, severity or 
outcome has been identified in the Investigator Brochure.
Serious Adverse Event (SAE): Any untoward medical occurrence that:
x
Results in death;
x
Is life-threatening ("Life-threatening" refers to an event in which the subject was at risk of 
death at the time of the event. It does not refer to an event which hypothetically might have 
caused death if it were more severe.);
x
Requires inpatient hospitalization or prolongation of existing hospitalization;
x
Results in persistent or significant disability/incapacity;
x
Is a congenital anomaly/birth defect;
x
Required intervention to prevent permanent impairment or damage.
Serious Adverse Device Effect (SADE): An ADE that has resulted in any of the consequences 
characteristic of a serious adverse event.
Unanticipated Serious Adverse Device Event: An SAE effect which by its nature, incidence, severity 
or outcome has not been identified in the current version of the Investigator’s Brochure.

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 39 of 85
12.2 Definitions – Drug Adverse Events
Adverse Event (AE): An adverse event (sometimes referred to as an adverse experience) means any 
untoward medical occurrence associated with the use of a drug in humans, whether or not considered 
drug related.  
Suspected Adverse Reaction (SAR): A suspected adverse reaction means any adverse event for 
which there is a reasonable possibility that the drug caused the event.
Adverse Reaction (AR):  An adverse reaction means any adverse event caused by a drug.  Adverse 
reactions are a subset of all suspected adverse reactions where there is reason to conclude that the 
drug caused the event.
Unexpected AE/SAR/AR:  An adverse event, suspected adverse reaction or adverse reaction is 
considered “unexpected” if it not listed in the Investigator Brochure.
Serious AE/SAR/AR:  An adverse event, suspected adverse reaction or adverse reaction is 
considered “serious” if, in the view of either the investigator or sponsor, it results in death, a life-
threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, 
or a congenital anomaly/birth defect.  If either the investigator or sponsor believes that an event is 
serious, the event will be considered serious and evaluated by the sponsor for expedited reporting.
Suspected Unexpected Serious Adverse Reaction (SUSAR):  An adverse event, suspected adverse 
reaction or adverse reaction is considered a SUSAR if it meets the criteria of both “Unexpected” and
“Serious” as defined in this section.  Any event believed to be a SUSAR by the investigator and/or the 
sponsor will be evaluated by the sponsor for expedited reporting.
12.3 Relationship
The Relationship between an AE and the CTM will be determined by the Investigator on the basis of 
his or her clinical judgment and the following definitions: 
Definitely Related: The AE follows a reasonable temporal sequence from administration of the CTM;
the AE follows a known or expected response pattern to the CTM.

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 40 of 85
Probably Related: The AE follows a reasonable temporal sequence from administration of the CTM;
the AE follows a known or expected response pattern to the CTM; and the AE could not be reasonably 
explained by the known characteristics of the subject’s clinical state.
Possibly Related:  The AE follows a reasonable temporal sequence from administration of the CTM; 
the AE follows a known or expected response pattern to the CTM, but could readily have been produced 
by a number of other factors.
Unlikely Related: The AE which etiology is unlikely related to the CTM even if event may follow a 
known or expected response pattern to the CTM, and likely to be produced by a number of other factors.  
Sufficient information is not available at the time of the AE to determine its causality.
Not Related:  An AE for which sufficient information exists to indicate that the etiology is unrelated to 
the CTM. One or more of the following variables apply:
x
The AE does not follow a reasonable temporal sequence following administration of the CTM;
x
The AE is readily explained by the subject’s clinical state or other therapies.
For events that are determined to be definitely, probably or possibly related, additional information on 
the relationship and timing of the event in relation to the athrocentesis and study injection will be 
captured.
12.4 Severity
The severity of AEs will be assessed according to the following definitions:
Mild: The Adverse Event is noticeable to the subject, but does not interfere with routine activity.  
Moderate:  The Adverse Event interferes with routine activity but responds to symptomatic therapy or 
rest.  
Severe: The Adverse Event significantly limits the subject's ability to perform routine activities despite 
symptomatic therapy.  
12.5 Reporting  
12.5.1 Adverse Events
All AEs that occur after signing the ICF will be recorded.  At each visit during the trial, AEs that have 
occurred since the previous visit must be recorded. All subjects will be questioned and evaluated for 

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 41 of 85
AEs or complications associated with the procedure. Complications of the injection include, but are not 
necessarily limited to: pain, swelling and/or inflammation at the injection site. The Investigator will
determine the severity and relationship of each event, as defined above.
AEs observed during the course of this study, regardless of severity or relationship to the injection will 
be recorded on the appropriate eCRF. Each reported complication/AE will also include the duration, 
action taken to address the AE, and the resolution status (e.g. ongoing, resolved). These subjects will 
continue to be evaluated for safety and efficacy at all scheduled follow-up points. 
The sponsor must report the results of an evaluation of an unanticipated adverse device effect (UADE) 
to relevant regulatory agencies and all reviewing ECs and investigators within timelines required by the 
regulatory agencies.
12.5.2 Serious Adverse Events/Serious Adverse Device Effects/Serious Adverse Reactions
All SAE/SADE/SAR/ SUSAR must be reported to the Sponsor or designee within 24 hours of the 
investigative site becoming aware of its occurrence.  This requirement is irrespective of whether the 
SADE/SAE is thought to be possibly related to the CTM or not. 
SAE/SADE/SAR/ SUSAR Reporting Procedures 
Information such as the investigator name, study name/protocol number, subject ID number, the name 
of the SAE/SADE/SAR, the investigator’s assessment as to the relationship to the CTM, and the 
reporting source should be included in the initial report.  Any additional supporting documentation (e.g., 
autopsy report, hospital records, etc.) must be submitted to the Sponsor or designee.  This also includes 
forwarding pertinent follow-up information (e.g., hospital discharge summary) as it becomes available.  
A completed SAE/SADE/SAR/ SUSAR form needs to be submitted with each follow-up.  The subject 
must be monitored carefully until the condition disappears or the etiology is identified.
All SAE/SADE/SAR/ SUSAR will be entered into the EDC system. The EDC system will automatically 
notify the medical monitor and the Sponsor or designee.
12.5.3 Expedited Reporting
Any unexpected fatal or life-threatening AEs will be reported by the Sponsor or designee to the 
appropriate regulatory authorities in accordance with applicable expedited reporting guidelines. Any 
event considered serious by either the investigator or sponsor will be evaluated by the sponsor for 
expedited reporting.

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 42 of 85
12.5.4 Independent Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) will review the data to assess if the trial should be 
revised or closed.  This IDMC will be made up of individuals who have expertise in the field, experience 
in the conduct of clinical trials, and/or statistical knowledge without conflicts of interest which may affect 
objectivity.  The IDMC will operate in accordance to the IDMC Charter. A Sponsor signed and dated 
original of this document will be kept in the Sponsor’s study files.
12.5.5 Study Discontinuation
Enrollment and treatment will be suspended if a subject experiences a serious and/or life-threatening 
AE that is probably or definitely related to the study injection. The study will be stopped if in the opinion 
of the PI, medical monitor, and Sponsor that the safety of subjects is uncertain.  The decision to resume 
enrollment and treatment, permanently discontinue the trial, or otherwise modify the study will be made 
by the Medical Monitor in consultation with the IDMC.  Additionally, the triggering of the stopping rules 
will prompt notification to the appropriate regulatory agencies including the Competent Authorities and 
the ECs.
13 STATISTICAL CONSIDERATIONS
The statistical analysis of the study is described in detail in a separate version-controlled prospective 
Statistical Analysis Plan (SAP).  However, the statistical methodology described in this section of the 
protocol will be the basis for the detailed SAP.
13.1 Sample Size
The primary comparison in the study will be between Cingal and triamcinolone hexacetonide with 
respect to the difference in the change in the WOMAC pain score from baseline at 26 weeks after study 
injection.  The first secondary comparison will be between Cingal and Monovisc with respect to the 
difference in the change in the WOMAC pain score from baseline at 3 weeks after study injection.  All 
comparisons will be made using a 5% significance level.  The primary comparison will be powered at 
90% power and in a 2:1 randomization requires 128 patients in the Cingal group and 64 in the 
triamcinolone hexacetonide group. It is assumed that the difference in the mean responses for Cingal 
and triamcinolone hexacetonide at 26 weeks would be 10 mm based on previous clinical trials of similar 
viscosupplementation products [20, 21] and the Cingal 13-01 trial with a standard deviation of 20. The 
sample size calculation is based upon a t-test. The sample size that is necessary to detect that specified 
difference at a power of 90% with a significance level of 5% in a 2:1 enrollment ratio is 128 in the Cingal 

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 43 of 85
group and 64 in the triamcinolone hexacetonide group.  
It is further assumed that the difference between Cingal and Monovisc at 3 weeks will be 5 mm and a 
standard deviation of 20 mm, thus it will require a minimum of 253 patients in each group to detect that 
difference at 80% power.  With the triamcinolone hexacetonide group set at 64 patients, the number of 
patients in the Cingal and Monovisc groups will be increased to provide a 4: 1 randomization ratio. This 
will yield 256 in the Cingal group, 256 in the Monovisc group and 64 in the triamcinolone hexacetonide 
group. This provides a total sample size of 576 patients.
Since the primary analysis in this study is an intent to treat analysis and the missing data for a patient 
will be imputed using mixed effects models, no drop out rate will be assumed for this study.  Thus the 
total sample size will be 576 patients.   
13.1.1 Primary Efficacy Endpoint
The primary efficacy endpoint is the change from baseline in knee pain as measured by the WOMAC 
Pain Score (100 mm VAS) at 26 weeks post treatment comparing the Cingal group to the triamcinolone 
hexacetonide (TH) group.
Data will be analyzed via an analysis of variance (ANOVA) with a term for treatment and baseline pain 
score as a covariate.  The primary hypothesis will be tested by a predefined contrast for comparing the 
Cingal group to the triamcinolone hexacetonide group.  Formally, the hypothesis to be tested is:
H0: μDC = μDT versus HA: μDC DT.
Where μDC is the mean change from baseline in the WOMAC Pain Score for the Cingal group at 26
weeks and μDT is the mean change from baseline in the WOMAC Pain Score for the triamcinolone 
hexacetonide group at 26 weeks.  Since there are three treatment groups in this study, this hypothesis 
will be tested using a one way ANOVA and constructing a contrast for this hypothesis.  This process is 
the same as using a baseline pain adjusted two-sample t-test with the common variance estimate from 
the ANOVA.
13.1.2 Secondary Efficacy Endpoints
There are multiple secondary endpoints.  In order to preserve the integrity of the Type I error, these 
will be tested in a hierarchical manner.  The order of the testing is as the order presented here. 
The change from baseline in knee pain as measured by the WOMAC Pain Score (100 mm VAS) 

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 44 of 85
at 3 weeks post treatment comparing the Cingal group to the Monovisc group. 
This secondary efficacy endpoint is the change from baseline in knee pain as measured by the WOMAC 
Pain Score (100 mm VAS) at 3 weeks post treatment comparing the Cingal group to the Monovisc
group.
Data will be analyzed via an analysis of variance (ANOVA) with a term for treatment and baseline pain 
score as a covariate.  The hypothesis will be tested by a predefined contrast for comparing the Cingal 
group to the Monovisc group.  Formally, the hypothesis to be tested is:
H0: μDC = μDM versus HA: μDC DM.
Where μDC is the mean change from baseline in the WOMAC Pain Score for the Cingal group at 3 
weeks and μDM is the mean change from baseline in the WOMAC Pain Score for the Monovisc group 
at 3 weeks.  Since there are three treatment groups in this study, this hypothesis will be tested using a 
one way ANOVA and constructing a contrast for this hypothesis.  This process is the same as using a 
baseline pain adjusted two-sample t-test with the common variance estimate from the ANOVA.
The responder rate as identified by the OMERACT-OARSI responder index at 26 weeks post 
treatment comparing the Cingal group to the triamcinolone hexacetonide group[22, 23]
The response rate for the Cingal group and Triamcinolone Hexacetonide (TH) group will be calculated 
and tested using Fisher’s exact test.  Formally, the hypothesis to be tested is:
+ʌC  ʌT versus  HAʌC ʌT
:KHUHʌC LVWKHUHVSRQGHUUDWHIRUWKH&LQJDOJURXSDQGʌT is the responder rate for the triamcinolone 
hexacetonide group. 
The change from baseline in WOMAC Physical Function score at 26 weeks post treatment 
comparing the Cingal group to the triamcinolone hexacetonide group. 
This secondary efficacy endpoint is the change from baseline in WOMAC Physical Function Score at
26 weeks post treatment comparing the Cingal group to the TH group.
Data will be analyzed via an analysis of variance (ANOVA) with a term for treatment and baseline 
Physical Function score as a covariate.  The hypothesis will be tested by a predefined contrast for 
comparing the Cingal group to the TH group.  Formally, the hypothesis to be tested is:

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 45 of 85
H0: μDC = μDT versus HA: μDC DT.
Where μDC is the mean change from baseline in the WOMAC Physical Function Score for the Cingal 
group at 26 weeks and μDT is the mean change from baseline in the WOMAC Physical Function Score 
for the TH group at 26 weeks.  
The change from baseline in WOMAC Stiffness score at 26 weeks post treatment comparing the 
Cingal group to the triamcinolone hexacetonide group. 
This secondary efficacy endpoint is the change from baseline in WOMAC Stiffness Score at 26 weeks 
post treatment comparing the Cingal group to the TH group.
Data will be analyzed via an analysis of variance (ANOVA) with a term for treatment and baseline 
Stiffness score as a covariate.  The hypothesis will be tested by a predefined contrast for comparing 
the Cingal group to the TH group.  Formally, the hypothesis to be tested is:
H0: μDC = μDT versus HA: μDC DT.
Where μDC is the mean change from baseline in the WOMAC Stiffness Score for the Cingal group at
26 weeks and μDT is the mean change from baseline in the WOMAC Stiffness Score for the TH group 
at 26 weeks.  
The change from baseline in Total WOMAC score at 26 weeks post treatment comparing the 
Cingal group to the triamcinolone hexacetonide group. 
This secondary efficacy endpoint is the change from baseline in Total WOMAC Score at 26 weeks post 
treatment comparing the Cingal group to the TH group.
Data will be analyzed via an analysis of variance (ANOVA) with a term for treatment and baseline Total 
WOMAC score as a covariate.  The hypothesis will be tested by a predefined contrast for comparing 
the Cingal group to the TH group.  Formally, the hypothesis to be tested is:
H0: μDC = μDT versus HA: μDC DT.
Where μDC is the mean change from baseline in the Total WOMAC Score for the Cingal group at 26 
weeks and μDT is the mean change from baseline in the Total WOMAC Score for the TH group at 26
weeks.  

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 46 of 85
The change from baseline in the Patient Global Assessment at 26 weeks post treatment 
comparing the Cingal group to the triamcinolone hexacetonide group.
Since this is a secondary endpoint the data will be analyzed for each time point individually with no 
adjustment for multiplicity.  Data will be analyzed via an analysis of variance with a term for treatment
and baseline Patient Global Assessment as a covariate.  The primary hypothesis will be tested by a 
predefined contrast for comparing the Cingal group to the Triamcinolone Hexacetonide group.  
Formally, the hypothesis to be tested is:
H0: μDC = μDT versus HA: μDC DT.
Where μDC is the mean change from baseline in the Patient Global Assessment Score for the Cingal 
group and μDT is the mean change from baseline in the Patient Global Assessment Score for the 
triamcinolone hexacetonide group.  Since there are three treatment groups in this study, this hypothesis 
will be tested using a one way ANOVA and constructing a contrast for this hypothesis.  This process is 
the same as using a two-sample t-test with the common variance estimate from the ANOVA.
The change from baseline in the Evaluator Global Assessment at 26 weeks post treatment 
comparing the Cingal group to the triamcinolone hexacetonide group.
Since this is a secondary endpoint the data will be analyzed for each time point individually with no 
adjustments for multiplicity.  Data will be analyzed via an analysis of variance with a term for treatment 
and baseline Evaluator Global Assessment as a covariate.  The primary hypothesis will be tested by a 
predefined contrast for comparing the Cingal group to the triamcinolone hexacetonide group.  Formally, 
the hypothesis to be tested is:
H0: μDC = μDT versus HA: μDC DT
Where μDC is the mean change from baseline in the Evaluator Global Assessment for the Cingal group 
at 26 weeks and μDT is the mean change from baseline in the Evaluator Global Assessment for the 
triamcinolone hexacetonide group at 26 weeks.  Since there are three treatment groups in this study, 
this hypothesis will be tested using a one way ANOVA and constructing a contrast for this hypothesis.  
This process of constructing a contrast is the same as using a two-sample t-test with the common 
variance estimate from the ANOVA.
The change from baseline in knee pain as measured by the WOMAC Pain Score (100 mm VAS) 

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 47 of 85
at 1 week post treatment comparing the Cingal group and the Monovisc group, 
Since this is a secondary endpoint and the study is not powered to detect the anticipated differences 
between the treatment groups at these time points, only the estimation of the relative efficacies to 
evaluate the individual profiles and assess the individual contributions of triamcinolone hexacetonide 
and Monovisc to the efficacy of Cingal will be performed. 
Data will be analyzed via an analysis of variance (ANOVA) with a term for treatment and baseline pain 
score as a covariate.  The hypothesis will be tested by a predefined contrast for comparing the Cingal 
group to the Monovisc group.  Formally, the hypothesis to be tested is:
H0: μDC = μDM versus HA: μDC DM.
Where μDC is the mean change from baseline in the WOMAC Pain Score for the Cingal group at 1 week 
and μDM is the mean change from baseline in the WOMAC Pain Score for the Monovisc group at 1week.  
Since there are three treatment groups in this study, this hypothesis will be tested using a one way 
ANOVA and constructing a contrast for this hypothesis.  This process is the same as using a baseline 
pain adjusted two-sample t-test with the common variance estimate from the ANOVA.
The mean change from baseline in the WOMAC Pain Score for the Cingal group and the Monovisc 
group, at 1 week will be estimated via point estimates and confidence intervals.  Also, the least squared 
mean differences and the associated confidence intervals will also be presented.
The usage of rescue medication through 26 weeks post treatment comparing the Cingal group
to the triamcinolone hexacetonide group. 
This secondary efficacy endpoint is the usage of rescue medications through 26 weeks post treatment 
comparing the Cingal group to the TH group.
The hypothesis will be tested by a predefined contrast for comparing the Cingal group to the TH group.  
Formally, the hypothesis to be tested is:
H0: μDC = μDT versus HA: μDC DT.
Where μDC is the total usage of rescue medications for the Cingal group at 26 weeks and μDT is the 
mean change from baseline in the WOMAC Pain Score for the TH group at 26 weeks.  

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 48 of 85
13.1.3 Exploratory Endpoints
Any comparisons between groups (Cingal, Monovisc, TH), within groups and / or time points (from 
baseline through to 26 weeks) not described in the primary or secondary endpoints may be presented 
in the exploratory endpoints including:
x
EuroQoL (EQ-5D)
x
WOMAC Pain Score (100mm VAS)
x
OMERACT-OARSI
x
Total WOMAC
x
WOMAC Stiffness Score
x
WOMAC Physical Function Score
x
Patient Global Assessment
x
Evaluator Global Assessment
x
Range of Motion
x
Rescue Medication Usage: Difference in analgesic use measured by number of pills taken 
between visits will be compared between treatment groups descriptively.
x
Number of Subjects Considered Treatment Failures: Treatment Failure: A subject who 
undergoes a procedure or uses a medication (other than the rescue medication) for the 
treatment of OA in the index knee at any time after the study injection through the 26 week visit.
For the exploratory analyses, the continuous variables will be analyzed via an analysis of variance and 
contrasts used to assess the prescribed comparisons.  For the discrete variables, a Fisher’s exact test 
will be used to assess the desired comparisons.
13.2 Statistical Methods
Tabulation of summary statistics, graphical presentations, and statistical analyses will be performed 
using SAS® software 9.1.3 or higher version. Where not otherwise specified, the last pre-treatment 
observation will be used as baseline for calculating post-treatment changes from baseline. The primary 
presentations and analyses will be based on data pooled across study centers. Relevant summaries 
for individual centers, or combinations of centers, may be presented for primary data. All testing and 
confidence intervals will use a significance level of 5%.

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 49 of 85
13.3 Demographic and Baseline Characteristics
All demographic and baseline characteristics will be tabulated by treatment group and a test of 
homogeneity between the treatment groups will be conducted. For continuous variables (e.g. age, 
height, weight) a one way ANOVA will be used. For categorical variables (e.g. gender, race), a Fisher's 
exact test or chi-squared test will be used. Medical history findings, physical examinations and 
concomitant medications will be tabulated by treatment group.
The baseline Chemistry, Hematology, Urinalysis, Vital Signs, and BMI data will be summarized via 
descriptive statistics and tested for homogeneity using a one way ANOVA.
13.4 Adverse Events
All AEs will be coded according to MedDRA. Safety assessments will include Treatment-Emergent 
Adverse Events (TEAEs) which are defined as AEs with an Investigator assessment of definitely, 
probably, or possibly related to CTM.  TEAEs will be summarized with frequencies and percentages by 
system organ class and preferred term, severity, and relationship to study CTM for each treatment 
group.  In summaries of TEAEs by severity and relationship to CTM for subjects reporting multiple 
episodes, all reported events will be included, not only the worst reported case.  Serious Adverse 
Events will also be presented by relationship to the CTM.
The number of subjects with at least one AE will be tabulated for each treatment group. Differences 
between the treatment groups will be tested using Fisher's exact test. Then the number of AEs for each 
treatment group will also be tabulated.
The number of subjects and the number of AEs will be tabulated by severity, relationship, and local 
injection site specific events versus non local events.
13.5 Subject Populations  
All safety analyses will be conducted on all subjects who undergo treatment in any group.    
The primary analysis on the primary endpoint will be performed on the ITT populations using the 
Multiple Imputation Methodology.  The Multiple Imputation Methodology will use a mixed effects 
repeated measures model to predict the missing values.  All Primary and Secondary endpoints will be 
analyzed using the ITT population.
It has been determined that any missing data in this study will follow the Missing at Random (MAR) 
assumption and is justified by the following section from the guide on missing data.[25]

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 50 of 85
Missing Data Because of Attrition in the Course of the Study The longer the planned length of a 
clinical trial, the greater the chance that participants will drop out of the trial due to their moving out of 
the area or otherwise experiencing changes in their lives that preclude or complicate further 
participation. If dropping out due to these situations is known to be unrelated to changes in health 
status, an MAR assumption for the missing values seems justified;
Since none of these patients are likely to be in a life threatening disease situation and many have had 
knee pain for a period of time, the missing data will unlikely be due to any treatment effect or lack 
thereof.  Previous studies have demonstrated a missing data rate of less than 1%.  Thus, any missing 
data in this study follows that paradigm and thus should be considered MAR.  Under this MAR 
assumption, it is well known that the mixed effects repeated measures analysis yields unbiased 
estimates of the treatment effects and thus will be utilized in the analysis.  However, since the primary 
and secondary analyses are being performed at a single time point using an ANCOVA model and not 
a repeated measures model, missing data will be imputed using a multiple imputation EM algorithm.  
The missing data for the WOMAC pain, WOMAC function, and PGA will be imputed in this algorithm.
A secondary analysis will be conducted on the Per Protocol (PP) population.   Since the primary 
endpoint is at 26 weeks, this is all subjects who complete the 26 week visit and who are not major 
violators of the protocol.  For all other visits, this is defined as the subjects who complete those visits
according to the protocol.  Also, to complete this sensitivity analysis, a mixed models analysis of 
variance will be performed without imputing data for missing values.
13.6 Additional Analyses
All of the analyses are performed on the data without covariates or other factors assumed in the 
model.  If it is determined that certain factors may influence the outcomes of the endpoints, then
additional analyses will be performed.  For the continuous variables, the factors will be added to the 
ANOVA model and evaluated in a stepwise fashion for significance.  For the discrete variables, the 
data will be analyzed via a GEE model with the factors added to the model. 
14 DATA MANAGEMENT CONSIDERATIONS
14.1 Electronic Data Capture (EDC) System
The EDC system to be used in this study will be 21CFR part 11 compliant and have appropriate Quality 
Management Systems in place.

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 51 of 85
All sites will receive appropriate training on using the EDC System including completing the eCRF and 
responding to queries.  Each designated site participant will receive a unique electronic signature:
consisting of a user name and password, after training has been completed in order to access the EDC 
System.
14.2 Data Collection 
One eCRF will be completed for each study subject based on the source documents. Once a subject
eCRF has been completed by the site, the data management group will begin the data cleaning 
process. The details of completing the eCRF by the site can be found in the eCRF Completion 
Guidelines.
14.3 Data Management
Once the eCRF is ready for review, the data management group will complete automated and manual 
validation checks according to the Data Management Plan (DMP) to ensure the quality, consistency, 
and completeness of all data entered. Instances of incomplete, uninterpretable or inconsistent data will 
be resolved with the site through issuing a query or other means of communication as necessary. The 
site is responsible to respond and / or correct the data for all queries issued in a timely manner. All 
queries and changes to the data will be tracked.

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 52 of 85
14.4 Data Retention
At the end of the study, an electronic transfer of all data will be provided to the Sponsor. The Contract 
Research Organization (CRO) and Sponsor will be responsible for retaining all data and documents 
pertaining to this study for a period of at least 5 years after study completion or longer depending on 
the applicable regulatory requirements.  The Sponsor will be responsible for retaining the final data set 
and documents pertaining to this study for a period of at least 5 years after study completion or longer 
depending on the applicable regulatory requirements
15 CLINICAL SUPPLIES
15.1 Packaging and Labeling
Clinical Trial Materials will be provided enclosed in a carton containing required labeling and caution 
statements and a unique identifying kit number.    An independent third party will maintain the master 
randomization scheme. The ampoules of triamcinolone hexacetonide will be supplied by the Sponsor 
to the Investigational Sites for use in the trial. The third party will ship the CTM to the sites as needed.  
Specific instructions for ordering CTM will be provided to the sites.
15.2 Storage Requirements
The storage requirements for CTM are to be maintained in a secure controlled environment at room 
temperature below 77 deg F / 25 deg C. DO NOT FREEZE. 
15.3 Instructions for Use
Instructions for Use (IFU) will be supplied to each site.  The IFU document contains the following risk 
information:
15.3.1 Contraindications
Cingal:
CINGAL is composed of cross-linked hyaluronic acid and an ancillary corticosteroid triamcinolone 
hexacetonide (TH). The following pre-existing conditions may constitute relative or absolute 
contraindications to the use of CINGAL:
x
Hypersensitivity to the active substance or to any of the excipients contained in CINGAL
x
Pre-existing infections of the skin region of the intended injection site
x
Infection of the index joint

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 53 of 85
x
Systemic bleeding disorders
The ancillary medicinal substance, triamcinolone hexacetonide, is contraindicated in the case of:
x
Hypersensitivity to triamcinolone hexacetonide
x
Active tuberculosis
x
Herpes simplex keratitis
x
Acute psychoses
x
Systemic mycoses and parasitoses (strongyloid infections)
Monovisc:
Monovisc™ is a sterile, non-pyrogenic, viscoelastic solution of hyaluronan contained in a single-use 
syringe. Monovisc™ consists of high molecular weight, ultra-pure, natural hyaluronan, a complex 
sugar of the glycosaminoglycan family. The hyaluronan in Monovisc™ is derived from bacterial cells 
and is cross-linked with a proprietary cross-linker.
The following pre-existing conditions may constitute relative or absolute contraindications to the use 
of Monovisc:
x
Hypersensitivity (allergy) to hyaluronate preparations
x
Hypersensitivity (allergy) to gram positive bacterial proteins
x
Infections or skin diseases in the area of the infection site or joint
x
Systemic bleeding disorders 
Triamcinolone hexacetonide:
Lederlon® 20 mg is a glucocorticoid (adrenal cortex hormone) that acts on the metabolism, the salt 
(electrolyte) balance and tissue functions. Glucocorticoids have anti-inflammatory and other 
therapeutic properties. The glucocorticoid in Lederlon® 20 mg is called triamcinolone hexacetonide.
Lederlon® 20 mg may NOT be used in the event of:
x
Known hypersensitivity to triamcinolone hexacetonide or one of the following other ingredients 
in this medication: benzyl alcohol (9 mg per 1 ml), polysorbate 80, sorbitol (Ph. Eur.)
x
Infections within or in direct proximity of the joint to be treated
x
Joint inflammation due to bacterial infections (bacterial arthritis)
x
Instability of the joint to be treated
x
Tendency toward bleeding, either spontaneously or due to taking medications to inhibit 
coagulation (anticoagulants)
x
Calcium deposits around joints
x
Bone necrosis due to sporadic or persistent perfusion disorders (non-vascularized bone 
necrosis)
x
Ruptured tendon
x
Joint disease due to decreased pain perception in the joint (neuropathic arthropathy)

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 54 of 85
15.3.2 Anticipated Adverse Reactions
Reported adverse reactions associated with the IA use of hyaluronic acid:
Intra-articular injection of sodium hyaluronate preparations has occasionally been associated with 
allergic/anaphylactic reactions and transient hypotension, which have generally resolved 
spontaneously or after conservative treatment.
The most common reported adverse events associated with Monovisc are the following: arthralgia, joint 
swelling and injection site pain.
Incidences of rash, headache, dizziness, chills, hives, itching, nausea, muscle cramps, peripheral 
edema, and malaise have also been reported in association with intra-articular injections.
A study conducted by Anika Therapeutics, Inc. on Monovisc recorded information on AEs that were 
possibly, probably and definitely related to the study injection. Patients who received Monovisc had 
7.1% of AEs related to the study injection and 5.4% of patients who received saline had an AE related 
to the study injection. Most of the AEs were minor complications that required little or no treatment. 
These included injection site events, joint swelling, joint pain, and limb pain. The rate of joint pain and 
limb pain not related to the study injection was higher than the rate related to the study injection [26].
Reported adverse reactions associated with the IA use of corticosteroids:
Dermatologic: Whitening of the skin at the injection site, local fat atrophy.
Musculoskeletal: Joint infection, joint swelling and pain several hours after injection, tendon rupture, 
pain, swelling, ligament damage.
Neurological: Nerve damage.
General: Infection, local bleeding, allergic reactions.

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 55 of 85
15.4 CTM Accountability
It is important to account for the disposition of all CTM received by a clinical site.  Required information 
includes the date received, date injected, batch number, quantity injected, expiry date and the subject
who received the CTM.
The site will use a form to document CTM disposition which will be reviewed by the study monitor during 
routine monitoring visits.  Each time CTM is dispensed, the following information should be recorded: 
the subject's initials, subject ID, the subject randomization number, date, the number of the CTM
dispensed, and the initials of the person dispensing the CTM.  At the termination of the study, Anika 
Therapeutics, Inc. will instruct sites on the disposition of unused CTM.
15.5 Emergency Unblinding
Unblinding should only occur when a SAE requires the allocation code in order to enable clinical 
treatments to be planned. The PI, in consultation with the clinical team and medical monitor should 
assess the need for unblinding as time permits. The allocation details can then be provided. Upon 
unblinding, the site personnel should record withdrawal of the subject and the allocation in the clinical 
trial notes. 
16 DATA QUALITY ASSURANCE
Anika Therapeutics, Inc. performs quality assurance checks on all clinical trials that it sponsors.  Before 
enrollment of a subject in this study, a monitor (from Anika or designee) and the site staff will review 
the protocol, the eCRFs and instructions for completing them, the procedure for obtaining informed 
consent, the procedure for reporting AEs and all other relevant study procedures and forms.  Site 
monitoring visits will be performed on a regular basis according to the Monitoring Plan.
17 REGULATORY OBLIGATIONS
The Principal Investigator agrees that the study will be conducted according to the principles of the ICH 
E6 (R1) Guideline for Good Clinical Practice (GCP) Step 6, ISO 14155:2011, Directive 2001/20/EC and 
Commission Directive 2005/28/EC, 21 CFR part 11, 50, 56, 312 and the ethical principles that have 
their origins in the World Medical Association Declaration of Helsinki, and local ethical and legal 
requirements. To ensure compliance the Investigator agrees, by written consent to this protocol, to fully 
cooperate with compliance checks by allowing access to all documentation by authorized individuals.  
The Investigator must conduct the trial as outlined in the protocol and in accordance with Declaration 
of Helsinki, as well as all applicable government regulations.  

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 56 of 85
17.1 Clinical Trial Information
Before the beginning of the study the Investigator will be given the latest Investigator’s Brochure.  If the 
Investigator’s Brochure is revised during the study, the Investigator will receive a copy of the revised 
version. The Investigator’s Brochure and the protocol are confidential communications of Anika 
Therapeutics, Inc. Acceptance constitutes the agreement by the recipient that no unpublished 
information therein contained will be published or disclosed without Anika Therapeutics Inc.’s prior 
written approval except that these documents must be submitted in accordance with the SOPs of the 
EC and other applicable oversight committees with the agreement that these committees are required 
to keep the information confidential.
17.2 Regulatory Approval
The study outlined in this protocol will only be conducted following written approval by the appropriate 
regulatory authorities for sites located in the European Union (EU).
17.3 Ethics Committee (EC) Approval
The protocol and the ICF must have the approval of a properly constituted EC responsible for approving 
clinical trials for each investigational site.  Any additional requirements imposed by the EC shall be 
addressed in the protocol amendments. The signed EC approval letter must identify that the documents 
approved, list the Investigator's name, the Anika Therapeutics, Inc. protocol title, and the date of 
approval of the protocol and the ICF.  Any advertisements used to recruit subjects or any subject
handouts should also be reviewed and approved by the EC.  Anika Therapeutics, Inc. or designee will 
not ship any CTM to a site until an approval letter has been received from the EC and a Clinical Trial 
Agreement has been fully executed.
The Investigator is committed in accordance with local requirements to inform the EC of any emergent 
problem, SADEs/SAEs, and/or protocol amendments. 
17.4 Amendments to the Protocol
Any amendment to the study protocol must be agreed upon between the Investigator(s) and Anika 
Therapeutics, Inc.  Once a protocol amendment has received approval from Anika Therapeutics Inc., 
the Investigators will submit it to the EC and regulatory agencies (as required) for written approval.  The 
approval letter, signed by the EC, should refer specifically to the Investigator, Anika Therapeutics, Inc., 
protocol title, the protocol amendment number, and the date of the protocol amendment.  Anika 

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 57 of 85
Therapeutics, Inc. will submit a copy of the protocol amendment to the appropriate regulatory agencies.
The protocol amendment may be implemented after it has been approved by the EC and the 
appropriate regulatory agencies, unless immediate implementation of the change is necessary for 
subject safety in which case a protocol change must be documented in an amendment and reported to 
the EC and regulatory agencies, as required within the required timeframe.
17.5 Pre-Study Documentation
The Investigator must provide the following documents prior to the enrollment of any subjects as 
appropriate to local country regulation:
x
Completed and signed Investigator Agreement/Form FDA 1572 signed by Principal Investigator. 
x
Signed and dated protocol signature page by the Principal Investigator (Investigator) and all 
Sub-Investigators (including Blinded Evaluator).
x
Signed and dated protocol amendment(s) signature page by the Investigator and all Sub-
Investigators (including Blinded Evaluator), when applicable.
x
Current curriculum vitae (CV) for the Investigator and all Sub-Investigators (including Blinded 
Evaluator)
x
Current medical license for the Principal Investigator and all Sub-Investigators (if applicable).
x
Financial disclosure statements signed and dated by the Investigator and all Sub-Investigator 
(including Blinded Evaluator).
x
Copy of the EC approval letter for the protocol and any other pertinent documents.
x
List of EC committee members. 
x
Copy of the EC-approved ICF to be used.
x
Fully executed Clinical Trial Agreement.
x
Delegation of Authority form.
x
Certified translations of EC approval letters, and approved ICF document (when applicable).
x
Insurance certificate as required.
17.6 Investigator Responsibilities
x
The Investigator should be qualified by education, training, and experience to assume 
responsibility for the proper conduct of the clinical study.

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 58 of 85
x
The Investigator must have knowledge on the use, application, implementation or administration 
of the CTM and the requirements for clinical, efficacy and safety follow-up. 
x
The Investigator should be familiar with and trained on the appropriate use of CTM as described 
in the protocol and in the current Investigator's Brochure.
x
The Investigator is responsible to ensure that the CTM is administered only by trained personnel 
in accordance with the protocol and instructions for use.
x
The Investigator should disclose any potential conflicts of interest, including financial, that 
interfere with the conduct of the clinical investigation or interpretation of the results.
x
The Investigator should be trained on and comply with GCP regulations and the applicable 
regulatory requirements.
x
The Investigator should demonstrate that the proposed Clinical Trial Site has the following:
o
One or more qualified Investigators; 
o
Qualified site staff;
o
Adequate facilities for the foreseen duration of the clinical study;
o
Required number of eligible subjects needed within the agreed recruitment period.
x
The Investigator must create and maintain source documentation throughout the clinical study 
and make it available as requested during monitoring visits and audits.
x
The Investigator should permit monitoring and auditing by the Sponsor or Sponsor’s designee
and inspection by the appropriate regulatory authorities. Investigator should be accessible 
(when possible) to the monitor to respond to questions.
x
The Investigator should have sufficient time to conduct and oversee the trial.
x
The Investigator should ensure the EC has the most up to date study related documentation 
(e.g. Investigator’s Brochure, Protocol).
x
The Investigator should inform the subject’s primary physician about the subject’s participation 
in the trial if permitted to do so by the subject.
x
The Investigator will provide the Sponsor with copies of any clinical-investigation-related 
communications between the Investigator and the EC.
x
The Investigator will give each subject participating in the clinical trial an alert card, which has 
been previously agreed by the Sponsor and approved by the EC, containing at minimum the 

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 59 of 85
name of the subject, the investigator contact number and blinded information regarding the 
medical treatment.
x
The Investigator must be aware of the AE and adverse reaction reporting process, including 
reactions related to application of the CTM.
x
The Investigator shall ensure accuracy, completeness legibility and timeliness of the data 
reported to the Sponsor in the eCRFs and in all required reports. 
x
The Investigator must have knowledge of the risk analysis of the CTM, knowledge of the 
requirements for storage, handling, administration, and destruction or disposal of the CTM
including any hazard to those handling the product and close contacts and the risk to the 
environment. Investigator will also maintain CTM accountability records.
x
The Investigator must ensure that the particular requirements for the application of the CTM,
such as standardization of injection procedures if possible and training of the healthcare 
professionals involved, are communicated to the site staff including the surgeons or other 
specialists involved.
x
The Investigator shall ensure maintenance and calibration of the equipment relevant for the 
assessment of the clinical study is appropriately performed and documented, when applicable.
x
The Investigator must be knowledgeable with the method of obtaining informed consent.
x
The Investigator shall ensure and document appropriate training if any authorized designee is 
appointed to conduct the informed consent process. 
x
The Investigator must inform the trial subject of the particular issues that arise for the CTM. In 
particular, both the ICF and any other written information to be provided to the subjects should 
include an explanation of the following:
o
Provisions for subject data protection and confidentiality;
o
The arrangements for follow-up before and after the end of the trial, including after 
subjects withdraw from the study and including the information (alert card) to be provided 
to the subject for use in the event of problems arising after the end of the trial;
o
The length of follow-up;
o
The definition of the end of the trial and its relationship to the follow-up after the end of 
the trial;
o
The need to keep an accurate subject diary;

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 60 of 85
o
The irreversible nature of the CTM;
o
The need, where applicable, for the presence of a representative of the Sponsor for 
assistance during the administration of the CTM and the rationale for this.
x
The Investigator shall provide adequate medical care to a subject during and after subject’s 
participation in a clinical study in the case of AEs.
x
The Investigator shall ensure that clinical records are clearly marked to indicate that the subject 
is enrolled in a particular clinical study.
x
The Investigator must provide the subject with the following:
o
Any necessary instructions on the proper use, handling, storage, and return of the 
rescue medications. Investigator shall retain all clinical-investigation-related records;
o
Information on any new significant findings occurring during the clinical study, including 
the need for additional medical care that may be required;
o
Well-defined procedures for possible emergency situations to the clinical study and 
make arrangements for emergency treatment, including decoding procedures for 
blinded/masked clinical studies;
o
Some means of showing the subjects participation in the clinical study, together with 
identification and compliance information for the concomitant treatment measures (If 
appropriate).
x
The Investigator shall sign the Clinical Investigation Report at the close-out of the clinical study.
17.7 Sponsor’s Responsibilities
x
Anika Therapeutics, Inc. may delegate some of the responsibilities to a CRO but will maintain 
oversight of the clinical study. Anika shall define, establish and allocate all the roles and 
responsibilities related to the clinical study in one or more written agreements. 
x
Anika Therapeutics, Inc. shall implement and maintain written clinical quality procedures to 
ensure that the clinical study is designed, conducted and monitored, and that data are 
generated, documented, recorded and reported in compliance with ISO 14155:2011 and ICH 
E6, this protocol, any subsequent amendments, and any other applicable standards and 
regulatory requirements.
x
Anika Therapeutics, Inc. will ensure that there is written agreement with the 
Investigator/institution and any other parties involved with the clinical study. 

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 61 of 85
x
Anika Therapeutics, Inc. will designate appropriately qualified medical personnel to advise on 
medical questions or problems.
x
Anika Therapeutics Inc. will utilize appropriately qualified individuals to supervise the overall 
conduct of the trial, to handle the data, to verify the data, to conduct the statistical analyses, and 
to prepare the trial reports. 
x
Anika Therapeutics, Inc. will select Investigators/institutions that are qualified by training and 
experience with adequate resources to properly conduct this trial for which the Investigator is 
selected. Anika will also select a coordinating Investigator, if appropriate.  Anika Therapeutics, 
Inc. will ensure members of the site staff and their designated authorization(s) are identified in 
a log with details.
x
Anika Therapeutics, Inc. will ensure that all Investigators and all other parties involved are given 
instructions on uniformly assessing and documenting clinical and laboratory findings.
x
Anika Therapeutics Inc. will establish the particular requirements for the application of the CTM,
and train the Investigator in the requirements for storage, handling, administration, and 
destruction or disposal of the CTM including hazards to those handling the product and close 
contacts and the risk to the environment. 
x
Anika Therapeutics, Inc. will designate or appoint one or more monitors, or otherwise assume 
the responsibilities of the monitor(s) and ensure documentation of training, experience and 
scientific or clinical knowledge for all the relevant parties involved in order to adequately conduct 
the clinical study. This includes training on the following:
o
Use of the CTM
o
Accountability procedures
o
Investigator’s Brochure
o
Protocol
o
eCRFs and instructions for completion
o
The written ICF and informed consent process as well as other written information 
provided to subjects
o
Sponsors written procedures; ISO 14155:2011; and any other applicable regulatory 
procedures.

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 62 of 85
x
Anika Therapeutics, Inc. will receive disclosures of conflicts of interest from PIs and 
Investigators.
x
Anika Therapeutics, Inc. will assure the accuracy of any translations, as applicable.
x
Anika Therapeutics, Inc. will establish an IDMC to assess the progress of a clinical study, 
including the safety data and the critical efficacy endpoints at intervals, and to recommend to 
the Sponsor whether to continue, modify, or stop a trial.
x
Anika Therapeutics, Inc. will ensure that any electronic trial data handling and/or remote 
electronic trial data systems, are validated with the following characteristics:
o
Data changes are allowed with an audit trail;
o
System is secure and does not allow for unauthorized access to the data;
o
A list of the individuals who are authorized to make data changes is maintained;
o
Adequate backup of the data is maintained; 
o
An unambiguous subject ID is used to allow identification of all the data reported for 
each subject.
x
Anika Therapeutics, Inc. will ensure maintenance of sponsor-specific essential documents 
pertaining to the trial in conformance with the applicable regulatory requirement(s) of the 
country(ies) where the product is approved, and/or where the sponsor intends to apply for 
approval(s). 
x
Anika Therapeutics, Inc. will inform the Investigator/institution in writing of the need for record 
retention and will notify the Investigator/institution in writing when the trial related records are 
no longer needed. 
x
Anika Therapeutics, Inc. will provide insurance or indemnify the Investigator/institution against 
claims arising from the trial, except for claims that arise from malpractice and/or negligence. 
x
Anika Therapeutics, Inc. will obtain the following information documentation from each 
participating EC: 
o
The name and address of the EC. 
o
A statement obtained from the EC that it is organized and operates according to GCP 
and the applicable laws and regulations. 
o
Documented EC approval/favorable opinion for the protocol and any subsequent 
amendments (as applicable) and re-approvals.

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 63 of 85
x
Anika Therapeutics, Inc. will update the Investigator's Brochure as significant new information 
becomes available. 
x
Anika Therapeutics, Inc. will ensure the CTM is transported at the acceptable storage 
temperatures and transport conditions. 
x
Anika Therapeutics, Inc. will not supply an Investigator/institution with the CTM until it obtains 
all required documentation ensuring the site has a signed contract with the sponsor, and EC, or 
other regulatory approvals as required.
x
Anika Therapeutics, Inc. will verify that each subject has consented, in writing, to direct access 
to his/her original medical records for trial-related monitoring, audit, EC review, and regulatory 
inspection. 
x
Anika Therapeutics, Inc. is responsible for the ongoing safety evaluation of the CTM.
x
Anika Therapeutics, Inc. will notify all concerned Investigators/institutions and the regulatory 
authority(ies) of findings that could affect adversely the safety of subjects, impact the conduct
of the trial, or alter the EC approval/favorable opinion to continue the trial. 
x
Anika Therapeutics, Inc. will submit any required application(s) to the appropriate authority(ies) 
for review, acceptance, and/or permission (as required by the applicable regulatory 
requirement(s)) to begin the trial(s). 
x
Anika Therapeutics, Inc. will ensure that all required EC, or other regulatory approvals are 
obtained and documented; and that appropriate provisions are made to meet any specific 
conditions imposed by the EC. Anika will ensure that any modification(s) required by the EC or
other regulatory authority are made and documented by the PI and have gained the approval 
of the EC or other regulatory authority.
x
Anika 
Therapeutics, 
Inc. 
will 
expedite 
the 
reporting 
to 
all 
concerned 
Investigator(s)/institutions(s), to the EC, where required, and to the regulatory authority(ies) of 
all ADEs that are both serious and unexpected. 
x
Anika Therapeutics, Inc. will submit to the regulatory authority(ies) all safety updates and 
periodic reports, as required by applicable regulatory requirement(s).
x
Anika Therapeutics, Inc. will ensure that an ongoing risk analysis, based on existing knowledge 
of the type of product and its intended use, is performed and provided to the Investigator 
involved in a clinical study with the CTM, through the Investigator’s Brochure or updates to it 
and to the subject through the ICF or updates to it.

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 64 of 85
x
Anika Therapeutics, Inc. will also incorporate the risk analysis and risk management plan of the 
CTM and share this with the Investigators;
x
Anika Therapeutics, Inc. shall be responsible for:
o
Accountability of the CTM throughout clinical study;
o
Documenting correspondence with all parties involved in the clinical study, including the 
EC and regulatory authorities;
o
Ensuring that the clinical study is appropriately monitored by determining the extent and 
nature of the monitoring;
o
Reviewing the monitoring reports and follow-up on actions required in the monitoring 
report;
o
Taking prompt action to secure compliance with all clinical study requirements;
o
Submitting progress reports, including safety summary deviations, when requested, to 
all reviewing EC’s and the regulatory authorities.
17.8 Informed Consent
All subjects in this study are to be completely informed, in accordance with local EC or other regulatory 
authority requirements, concerning the pertinent details and purpose of the study. Informed consent for 
each subject will be obtained in accordance with ICH Guidance for Industry E6 Good Clinical Practice:
Consolidated Guidance (ICH Topic E 6 (R1) Guideline for Good Clinical Practice). One copy of the 
signed ICF document must be given to each subject in his/her native language and one signed copy 
must be retained in the subject’s file.
All subjects must sign and personally date an approved ICF after receiving detailed written and verbal 
information about the reason, the nature and the possible risks associated with the administration of 
the CTM. An ICF will be required for all subjects.
All foreseeable risks and potential benefits which might occur with the use of the CTM will be discussed 
with the subject. The subject will be informed that, should an unanticipated adverse product-related 
event occur, which presents an unreasonable risk to participating subjects, he/she will be notified. The 
subject will be informed that his/her medical records are subject to review by representatives of the 
Sponsor, EC, or the appropriate regulatory authorities, as necessary. The subject will be informed that 
the information obtained during the study will be used to evaluate the safety and efficacy of the CTM.
However, his/her confidentiality will be maintained at all times. The subject will be told that he/she is 

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 65 of 85
free to refuse study participation or to withdraw from the study at any time without compromising future 
medical care.
The subject must be made aware and agree that personal information may be scrutinized during an
audit by competent authorities and properly authorized persons. However, personal information will be 
treated as strictly confidential and will not be publicly available.  
A sample ICF template with standard wording suggested for this study will be provided to each 
Investigator. Prior to EC submission, the Investigator must send a copy of the ICF to be used at their 
institution to Anika Therapeutics Inc. or designee for review to assure compliance with the ICH 
requirements. The approved written consent form is to be supplied by the Investigator and will be 
understood and signed by each subject prior to enrolling in the study. An ICF will be required for all 
subjects. The Investigator is responsible for maintaining each subject's ICF in the study file and 
providing each subject with a copy of the ICF.
17.9 Protocol Adherence
The Investigator agrees to conduct the study according to the protocol and agrees that all persons 
delegated to perform study procedures will do so as well. The Investigator must read the protocol 
thoroughly and must follow the instructions exactly. Investigators shall propose to Anika Therapeutics, 
Inc. any appropriate modifications to the Protocol or of the use of the CTM. Any change should be 
agreed to by prior discussion between Anika Therapeutics Inc. and the Investigator, with written 
protocol amendments made prior to affecting the changes agreed upon. The Investigator is not to 
conduct any protocol modifications without prior written permission from Anika Therapeutics Inc. 
Investigator will refrain from implementing any modifications to the protocol without agreement from the 
Sponsor, EC and regulatory authorities, if applicable. Each Investigator will be responsible for enrolling 
only those subjects who have met protocol eligibility criteria.
Deviations from the protocol include, but are not limited to, the use of prohibited medications or 
therapies, out of window visits, etc.  All protocol deviations should be documented and explained.  Major 
protocol violations are defined as those that could impact the efficacy evaluation such as a subject is 
ineligible, missing key data, received an unauthorized treatment, etc.  All subjects with protocol 
deviations will continue to be followed for safety and efficacy assessments.  Analysis of study data will 
be done on both the ITT and PP populations.

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 66 of 85
17.10 Adverse Event Reporting
The Investigator agrees to document and report all AEs / ARs to Anika Therapeutics, Inc. or its 
designee.  The Investigator is further responsible for ensuring that any Sub-Investigator promptly brings 
AEs / ARs to the attention of the Investigator.  The Investigator is also responsible for informing the 
participating EC and other regulatory authorities (as applicable) of any reportable events and adhering 
to local EC requirements. The Investigator agrees to supply Anika Therapeutics Inc., upon request, any 
additional information related to the safety reporting of a particular event. The Investigator shall inform 
the subject of the nature and possible cause of any AEs/ ARs experienced.
17.11 Permission to Review Subject's Source Records
The Investigator agrees that Anika Therapeutics, Inc., its employees or agents, and the respective 
Competent Authorities will have the right from time to time, both during and after this trial, to audit and 
review pertinent medical records related to the clinical study.  A signed statement will be obtained from 
each subject who participates in the trial that permits the release of his or her medical records as 
necessary for inspection by authorized personnel from Anika Therapeutics, Inc., its designee or 
participating Competent Authority.  Subjects will not be identified by name, and confidentiality of 
information in medical records will be preserved.
17.12 Change in Investigator
If any Investigator retires, relocates, or withdraws from an investigation, the responsibility for conducting 
the study and maintaining records may be transferred to another person who will accept the 
responsibility at the same institution. Anika Therapeutics, Inc. must be notified of and agree to the 
change. 
17.13 Records Retention
All documents related to this clinical study should be kept in appropriate study files.  Copies of the 
protocol, subject ID, eCRF, source data, ICF and other documents pertaining to the study conduction 
must be retained until at least 5 years after study completion or longer depending on the applicable 
regulatory requirements. It is the responsibility of the Sponsor to inform the Investigator/institution as 
to when these documents no longer need to be retained. No study document will be destroyed without 
prior written agreement between Anika Therapeutics, Inc. and the Investigator.

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 67 of 85
17.14 Study Monitoring
An appropriate representative of Anika Therapeutics, Inc. or designee (Study Monitor) will maintain 
contact with the Investigator and will visit the Clinical Trial Site for the purpose of overseeing the 
progress of the study, and ensuring it is conducted, recorded and reported in accordance with the 
protocol, SOPs, GCP and applicable regulatory requirements.
An initiation visit will be made by the Study Monitor to discuss the protocol and the obligations of both 
the Sponsor and the Investigator.  The Investigator must allow the Study Monitor to perform periodic, 
interim monitoring visits.  The purposes of these visits are:
x
Verify that written informed consent was obtained prior to each subject’s participation in the trial
x
Ensure the conduct of the trial is in compliance with the currently approved 
protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s)
x
Ensure the rights and well-being of human subjects are protected 
x
Ensure the reported trial data are accurate, complete, and verifiable from source documents. 
x
Assess the progress of the study
x
Review the compliance with the study protocol
x
Determine whether the Investigator is maintaining the essential documents
x
Discuss any emergent problem(s)
x
Assess adequate documentation of CTM accountability
x
Act as the main line of communication between the Sponsor and the Investigator
x
Ensure that the Investigator receives the current Investigator's Brochure, all documents, and all 
trial supplies needed to conduct the trial properly and to comply with the applicable regulatory 
requirement(s) 
x
Ensure that the Investigator and the Investigator's site staff are adequately informed about the 
trial 
x
Verify that the Investigator and the Investigator's site staff are performing the specified trial 
functions, in accordance with the protocol and any other written agreement between the 
Sponsor and the Investigator/institution, and have not delegated these functions to unauthorized 
individuals 
x
Verify that the Investigator is enrolling only eligible subjects

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 68 of 85
x
Inform the Investigator of any eCRF entry error, omission, or illegibility 
x
Determine whether all AEs are appropriately reported within the time periods required by GCP, 
the protocol, the EC, the Sponsor, and the applicable regulatory requirement(s) 
x
Communicating deviations from the protocol, SOPs, GCP, and the applicable regulatory 
requirements to the Investigator and ensuring that the site staff takes appropriate action 
designed to prevent recurrence of the detected deviations 
All data required by the protocol must be reported accurately on the eCRFs and must be consistent 
with the source documents. Source documents are original documents, data and records (e.g., hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects' diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, photographic 
negatives, microfilm or magnetic media, X-rays or other diagnostic images, subject’s files, pharmacy 
records and laboratory records).  The Investigator will make available the source documents for 
inspection.  This information will be considered as confidential.
The Study Monitor will perform a closeout visit at the conclusion of the Investigator’s involvement in the 
study.
17.15 Case Report Form
Electronic Case Report Forms must be completed for each subject in accordance with the DMP and
any eCRF Completion Guidelines.  The Investigator must ensure data are reported into the eCRF in a 
timely fashion and that data recorded in the eCRF is consistent with the source documents or the 
discrepancies should be explained. Any change or correction should have an audit trail and explanation 
of the change.
17.16 Auditing
The Investigator will make all pertinent records available including source documentation for inspection 
by regulatory authorities and for auditing by the Sponsor. This information will be considered as 
confidential. The Sponsor's audit will be independent of and separate from routine monitoring or quality 
control function and will serve to evaluate the trial conduct and compliance with the protocol, SOPs,
GCP, and the applicable regulatory requirements.

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 69 of 85
17.17 Use and Publication of Study Results
All unpublished documentation (including the protocol, eCRF and Investigator's Brochure) given to the 
Investigator is strictly confidential.  All recipients must agree not to disclose the information herein 
contained to any person without the prior written authorization of Anika Therapeutics, Inc. The 
submission of these documents to the EC is expressly permitted. The Investigator agrees that Anika 
Therapeutics, Inc. maintains the right to use the results of this study in their original form and/or in a 
global report for submission to governmental and regulatory authorities of any country.
The results of the study may be presented during scientific symposia or published in a scientific journal 
only after review by Anika Therapeutics, Inc. in accordance with the guidelines set forth in the applicable 
publication or the Investigator agreement. 
17.18 Confidentiality
All information that is provided to the Investigator dealing with the CTM is regarded as confidential. 
Subjects will be told that data will be handled in compliance with Health Insurance Portability and 
Accountability Act (HIPAA), European Union Data Protection Directive and other national laws on the 
protection of personal data.  Subjects will be informed that the Anika Therapeutics, Inc. or designee will 
have access to their medical records. Subject’s participation in the study will be treated as confidential 
and subject’s will not be referred to by name in any report of the study.   The identity of the subjects will 
not be disclosed in any study records and subjects’ data will be described with a unique subject
identifier. Subject data will be processed electronically to determine the outcome of this study, and to 
provide to health authorities. Subjects will be advised that all data may be transferred to other countries.
17.19 Early Study Discontinuation
If the Sponsor, Investigator, or Study Medical Monitor discover conditions during the study that indicate 
that the study or Clinical Trial Site should be terminated, this action may be taken after appropriate 
consultation between the Sponsor, Investigator, and Study Medical Monitor.
Conditions that may warrant termination of the Clinical Trial Site include, but are not limited to:
• The discovery of any unexpected, serious, or unacceptable risk to subjects enrolled in the study,
• The decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or development 
of the CTM.
• Failure of the Investigator to comply with GCP guidelines,
• Submission of knowingly false information from the research facility to the Sponsor,

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 70 of 85
Clinical Monitor, or regulatory authorities,
• Insufficient adherence to protocol requirements.
If Anika Therapeutics, Inc. and/or the Investigator should discover conditions arising during the study 
that indicate it should be terminated, an appropriate schedule for termination will be instituted. Anika 
Therapeutics, Inc. also reserves the right to discontinue this study for administrative reasons at any 
time. 
If a trial is suspended, Anika Therapeutics Inc. will promptly inform the Investigators/institutions, and 
the regulatory authority(ies) of the termination or suspension and the reason(s) for the termination or 
suspension. The Investigator should notify the EC promptly and provided the reason(s) for the 
termination or suspension by the Sponsor or by the Investigator/institution.
17.20 Subject Withdrawal
Each subject is free to discontinue from the study at any time, for any reason. If a subject discontinues 
the study, the Investigator will record the reason for withdrawal on the eCRF. Examples of reasons for 
premature withdrawal of a subject from the study include:
• Inter-current illness that would, in the judgment of the Investigator, affect study assessment to a 
significant degree
• Subject noncompliance with follow-up assessments 
• Subject request to withdraw
• Subject lost to follow-up
• Termination of the site’s study participation by Anika Therapeutics, Inc., the institution, EC or other 
regulatory authority
• Other (reason to be documented in the eCRF)
Every effort shall be made to have withdrawn subjects return for the required safety evaluations as 
detailed in the protocol.

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 71 of 85
18 GENERAL INFORMATION
18.1 Study Contact Information
Sponsor:
Anika Therapeutics, Inc.
32 Wiggins Avenue
Bedford, MA 01730
Phone: 781-457-9000
Fax: 781-305-9720
Medical Monitor EU:
During Office Hours:
Dr. Josep-Maria Badenas
Address: SynteractHCR Iberica, SL 
Príncep Jordi, 21-23, Esc. B, Entlo. 1-B
08014 Barcelona, Spain
Tel: + 34 674 746 106
Contract Research Organization (CRO):
SynteractHCR
5909 Sea Otter Place 
Carlsbad, CA 92010
Phone:  +1 760 268 8200 
Fax:    +1 760 929 1419 
Central Core Imaging Laboratory:
Qmetrics Technologies
1250 Pittsford-Victor Road
Suite 110, Building 200
Pittsford, NY 14534
Phone: 585.301.4300
Fax: 585-301-4300 X250

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 72 of 85
18.2 Study Administrative Structure
Name/Affiliation
Address/Phone Number
Responsibility
Adrian Orr
Director of Clinical Affairs
Anika Therapeutics Inc. 
32 Wiggins Avenue 
Bedford, MA 01730 USA 
Tel: (781) 457-9226
Fax: (781) 305-9720 
Email: aorr@anikatherapeutics.com
Sponsor Project 
Manager
Josep-Maria 
Badenas M.D.
SynteractHCR Iberica, SL 
Príncep Jordi, 21-23, Esc. B, Entlo. 1-B
08014 Barcelona, Spain
Phone: + 34 674 746 106
Medical Monitor
EU
SynteractHCR, 
Inc.
CRO
5909 Sea Otter Place 
Carlsbad, CA 92010
Phone: 760.268.8200
Safety, Site 
Management and 
Monitoring
Qmetrics Clinical 
Services
Core Imaging Laboratory
1250 Pittsford-Victor Road, Bldg 2, Suite 110
Pittsford, NY 14534
Phone: 585.301.4300
Imaging
Axiom Real-Time 
Metrics Inc.
EDC Vendor 
50 Ronson Drive, Suite 190
Toronto, ON M9W 1B3
Phone: 416.804.1110
EDC and Data 
Management
In case of emergency, refer to the study manual of operations for alternate contact information.

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 73 of 85
19 REFERENCES
1.
Bellamy, N., et al., Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane Database of 
Systematic Reviews, 2006( 2).
2.
Schaap, L.A., et al., European Project on OSteoArthritis (EPOSA): methodological challenges in harmonization 
of existing data from five European population-based cohorts on aging. BMC musculoskeletal disorders, 2011. 
12: p. 272.
3.
Guccione, A.A., et al., The effects of specific medical conditions on the functional limitations of elders in the 
Framingham Study. American journal of public health, 1994. 84(3): p. 351-8.
4.
Altman, R., et al., Development of criteria for the classification and reporting of osteoarthritis. Classification of 
osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism 
Association. Arthritis and rheumatism, 1986. 29(8): p. 1039-49.
5.
Moreland, L.W., Intra-articular hyaluronan (hyaluronic acid) and hylans for the treatment of osteoarthritis: 
mechanisms of action. Arthritis research & therapy, 2003. 5(2): p. 54-67.
6.
Stitik, T.P. and J.A. Levy, Viscosupplementation (biosupplementation) for osteoarthritis. American journal of 
physical medicine & rehabilitation / Association of Academic Physiatrists, 2006. 85(11 Suppl): p. S32-50.
7.
Neustadt, D.H., Intra-articular injections for osteoarthritis of the knee. Cleve Clin J Med, 2006. 73(10): p. 897-8, 
901-4, 906-11.
8.
Bellamy, N., et al., Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database of 
Systematic Reviews 2006(2).
9.
Kellgren, J.H. and J.S. Lawrence, Radiological assessment of osteo-arthrosis. Annals of the rheumatic diseases, 
1957. 16(4): p. 494-502.
10.
Kellgren, J. and J. Lawrence, Atlas of standard radiographs:  The epidemiology of chronic rheumatism.  , in 
Blackwell Scientific Publications. 1963, Oxford.
11.
Felson, D.T. and M.C. Nevitt, Epidemiologic studies for osteoarthritis: new versus conventional study design 
approaches. Rheumatic diseases clinics of North America, 2004. 30(4): p. 783-97, vii.
12.
Bellamy, N., et al., Recommendations for a core set of outcome measures for future phase III clinical trials in 
knee, hip, and hand osteoarthritis. Consensus development at OMERACT III. The Journal of rheumatology, 1997. 
24(4): p. 799-802.
13.
Zhang, W., et al., EULAR evidence-based recommendations for the diagnosis of knee osteoarthritis. Ann Rheum 
Dis, 2010. 69(3): p. 483-9.
14.
WOMAC.  [cited 2012 December 12]; Available from: http://www.womac.org/womac/index.htm.
15.
Cheung, K., et al. EQ-5D User Guide-Basic Information on how to use the EQ-5D, 2009. 2009; Available from: 
www.euroqol.org.
16.
Brooks, R., EuroQol: the current state of play. Health Policy, 1996. 37(1): p. 53-72.
17.
Knoop, J., et al., Proprioception in knee osteoarthritis: a narrative review. Osteoarthritis Cartilage, 2011. 19(4): 
p. 381-8.
18.
Jackson, D.W., N.A. Evans, and B.M. Thomas, Accuracy of needle placement into the intra-articular space of the 
knee. J Bone Joint Surg Am, 2002. 84-A(9): p. 1522-7.
19.
Toda, Y. and N. Tsukimura, A comparison of intra-articular hyaluronan injection accuracy rates between three 
approaches based on radiographic severity of knee osteoarthritis. Osteoarthritis Cartilage, 2008. 16(9): p. 980-5.
20.
Strand, V., et al., A multicenter, randomized controlled trial comparing a single intra-articular injection of Gel-
200, a new cross-linked formulation of hyaluronic acid, to phosphate buffered saline for treatment of 
osteoarthritis of the knee. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society, 2012. 20(5): p. 
350-6.
21.
Day, R., et al., A double blind, randomized, multicenter, parallel group study of the effectiveness and tolerance of 
intraarticular hyaluronan in osteoarthritis of the knee. The Journal of rheumatology, 2004. 31(4): p. 775-82.
22.
Pham, T., et al., OMERACT-OARSI initiative: Osteoarthritis Research Society International set of responder 
criteria for osteoarthritis clinical trials revisited. Osteoarthritis Cartilage, 2004. 12(5): p. 389-99.
23.
Pham, T., et al., Outcome variables for osteoarthritis clinical trials: The OMERACT-OARSI set of responder 
criteria. J Rheumatol, 2003. 30(7): p. 1648-54.
24.
Pham, T., et al., Outcome variables for osteoarthritis clinical trials: The OMERACT-OARSI set of responder 
criteria. The Journal of rheumatology, 2003. 30(7): p. 1648-54.
25.
The Preventions and Treatment of Missing Data in Clinical Trials. 2010, Washington, DC: The National 
Academies Press.
26.
Monovisc Study Data: "A Randomized, Double-Blind, Placebo Controlled, Multi-Center Study of a Single 
Injection Cross-linked Sodium Hyaluronate to Provide Symptomatic Relief of Osteoarthritis of the Knee". 2009.

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 74 of 85
Appendix 1 WOMAC

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 75 of 85

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 76 of 85

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 77 of 85

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 78 of 85

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 79 of 85

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 80 of 85
Appendix 2 Global Assessment of Disease Activity
A VAS is to be completed by the subject and the evaluating physician at time points specified in 
Section 7.1 for determining the Patient’s and the Evaluator’s Global Assessment of response to 
therapy score.
EVALUATOR GLOBAL ASSESSMENT (VAS SCALE)
Record your response with an “X”: 
“Considering all the ways the osteoarthritis in the patient’s index knee affect him/her, what is your 
assessment of how much the patient’s knee is bothering him/her today?” 
                          No pain
Extreme pain
PATIENT GLOBAL ASSESSMENT (VAS SCALE)
Record your response with an “X”: 
Think about the pain you felt in your STUDY knee caused by your osteoarthritis during the last 24 
hours.  
“Considering all the ways the osteoarthritis in your STUDY knee affects you, what is your assessment 
of how much your STUDY knee is bothering you today?” 
                          No pain
Extreme pain

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 81 of 85
Appendix 3 EQ-5D

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 82 of 85

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 83 of 85
Appendix 4 Kellgren-Lawrence Grading Scale
Grade 1: doubtful narrowing of joint space and possible osteophytic lipping
Grade 2: definite osteophytes, definite narrowing of joint space
Grade 3: moderate multiple osteophytes, definite narrowing of joint space, some sclerosis and 
possible deformity of bone contour
Grade 4: large osteophytes, marked narrowing of joint space, severe sclerosis and definite deformity 
of bone contour

Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 84 of 85
Change History
Location of Change 
Original Text
Changed Text
Reason
Page 1, Throughout
Protocol version 3.0
Date 21 July 2017
Protocol version 4.0
Date: 28 November 2017
Revision to version 4.0
Page 1
Vice President of Regulatory/Clinical Affairs or Designee
Vice President of Regulatory/Clinical Affairs or 
Designee: Steven Chartier
Addition of Steven Chartier as 
signatory
Section 3 & 8.2, 13.1.2, 
13.1.3
Synopsis: 
Secondary Endpoints
x
The change from baseline in knee pain as measured 
by the WOMAC Pain Score (100 mm VAS) at 3 
weeks post treatment comparing the Cingal group to 
the Monovisc group. 
x
The responder rate as identified by the Outcomes 
Measures for Rheumatic Arthritis Clinical Trials-
Osteoarthritis Research Society International 
(OMERACT-OARSI) responder index at 26 weeks 
post treatment comparing the Cingal group to the TH 
group.
x
The change from baseline in the Patient Global 
Assessment 26 weeks post treatment in the Cingal 
group compared to the TH group.
x
The change from baseline in the Evaluator Global 
Assessment at 26 weeks post treatment in the Cingal 
group compared to the TH group.
x
The change from baseline in knee pain as measured 
by the WOMAC Pain Score (100 mm VAS) through 
12 weeks post treatment in the Cingal group 
compared to the TH group. 
x
The responder rate as identified by the Outcomes 
Measures for Rheumatic Arthritis Clinical Trials-
Osteoarthritis Research Society International 
(OMERACT-OARSI) responder index at 12 weeks 
post treatment comparing the Cingal group to the TH 
group.
x
The change from baseline in the Patient Global 
Assessment through 12 weeks post treatment in the 
Cingal group to the TH group. 
x
The change from baseline in the Evaluator Global 
Assessment through 12 weeks post treatment in the 
Cingal group compared to the TH group.
x
The change from baseline in knee pain as measured 
by the WOMAC Pain Score (100 mm VAS) at 1 week 
post treatment comparing the Cingal group, the 
Monovisc group, and the TH group.
x
The change from baseline in knee pain as measured 
by the WOMAC Pain Score (100 mm VAS) at 3 
weeks post treatment comparing the Cingal group, 
the Monovisc group, and the TH group.
Synopsis: 
Secondary Endpoints
x
The change from baseline in knee pain as 
measured by the WOMAC Pain Score (100 mm 
VAS) at 3 weeks post treatment comparing the 
Cingal group to the Monovisc group. 
x
The responder rate as identified by the 
Outcomes Measures for Rheumatic Arthritis 
Clinical Trials-Osteoarthritis Research Society 
International (OMERACT-OARSI) responder 
index at 26 weeks post treatment comparing the 
Cingal group to the TH group.
x
The change from baseline in WOMAC Physical 
Function score at 26 weeks post treatment 
comparing the Cingal group to the TH group.
x
The change from baseline in WOMAC Stiffness 
score at 26 weeks post treatment comparing the 
Cingal group to the TH group.
x
The change from baseline in Total WOMAC 
score at 26 weeks post treatment comparing the 
Cingal group to the TH group.
x
The change from baseline in the Patient Global 
Assessment at 26 weeks post treatment in the 
Cingal group compared to the TH group.
x
The change from baseline in the Evaluator 
Global Assessment at 26 weeks post treatment 
in the Cingal group compared to the TH group.
x
The change from baseline in knee pain as 
measured by the WOMAC Pain Score (100 mm 
VAS) at 1 week post treatment comparing the 
Cingal group and the Monovisc group,
x
The usage of rescue medication through 26 
weeks post treatment in the Cingal group 
compared to the TH group.
Added secondary endpoints for 
WOMAC Physical Function, 
WOMAC Stiffness, Total 
WOMAC score and usage of 
rescue medications for Cingal 
compared to TH Group at 26 
weeks. Considered more 
significant endpoints.
Secondary endpoints moved to 
exploratory endpoints:
x
Comparison of Cingal to 
TH at 1 week and 12
weeks 
x
Comparison of Cingal to 
Monovisc for Patient 
Global Assessment and 
Evaluator Assessment at 1 
and 3 weeks
These endpoints are not 
required in hierarchical 
assessment since Cingal is 
compared to TH at 26-week
and Monovisc at 3 weeks. 
These endpoints may be 
presented as exploratory 
endpoints.

Anika Therapeutics, Inc.
Cingal 16-02
Cingal Protocol 16-02 05 Dec 2017 V4.0 Clean
     Confidential
Page 85 of 85
Location of Change 
Original Text
Changed Text
Reason
x
The change from baseline in the Patient Global 
Assessment at 1 week post treatment in the Cingal 
group compared to the Monovisc Group. 
x
The change from baseline in the Patient Global 
Assessment at 3 weeks post treatment in the Cingal 
group compared to the Monovisc Group. 
x
The change from baseline in the Evaluator Global 
Assessment at 1 week post treatment in the Cingal 
group compared to the Monovisc Group. 
x
The change from baseline in the Evaluator Global 
Assessment at 3 weeks post treatment in the Cingal 
group compared to the Monovisc Group. 
Corrections to align time points described in the 
endpoints with the statistical analysis text.
To align statistical text with the 
secondary endpoints.
Exploratory Endpoints: 
x
EuroQol (EQ-5D)
x
Total WOMAC
x
WOMAC Stiffness Score
x
WOMAC Physical Function
x
Range of Motion 
x
Rescue Medication Usage
x
Number of Treatment Failures due to Additional 
Procedure or Use of Disallowed Medication  
Exploratory Endpoints: 
Any comparisons between groups (Cingal, Monovisc, 
TH), within groups and / or time points (from baseline 
through to 26 weeks) not described in the primary or 
secondary endpoints may be presented in the 
exploratory endpoints including:
x
EuroQol (EQ-5D)
x
OMERACT-OARSI
x
Total WOMAC
x
WOMAC Stiffness Score
x
WOMAC Physical Function
x
Patient Global Assessment
x
Evaluator Global Assessment
x
Range of Motion 
x
Rescue Medication Usage
x
Number of Treatment Failures due to Additional 
Procedure or Use of Disallowed Medication  
Clarification of all iterations to 
be considered for exploratory 
endpoints. Included endpoints 
moved from secondary 
endpoints.
Section 18.1 & 18.2
SynteractHCR
5759 Fleet Street, Suite 100
Carlsbad, CA 92008
SynteractHCR
5909 Sea Otter Place 
Carlsbad, CA 92010
Change of CRO address