A Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Repeated Intra-Articular Injection of SI-613 in Patients With Osteoarthritis of the Knee
Phase: PHASE2
Conditions: Osteoarthritis, Knee
Sponsor: Seikagaku Corporation

Seikagaku Corporation 
Protocol v3.0 
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CLINICAL STUDY PROTOCOL 
A Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy 
and Safety of Repeated Intra-Articular Injection of SI-613 in Patients with Osteoarthritis of the 
Knee 
Protocol Number:  
613/1121 
Phase: 
2 
Investigational Product: 
SI-613 
Version: 
3.0 
Date: 
01-September-2017
IND Applicant, Sponsor, and Product 
Manufacturer: 
SEIKAGAKU CORPORATION 
6-1, Marunouchi 1-chome Chiyoda-ku
Tokyo 100-0005, Japan
US Agent: 
Chiltern International 
4000 CentreGreen Way, Suite 300, 
Cary, NC 27513 
Contract Research 
Organization: 
Chiltern International 
4000 CentreGreen Way, Suite 300, 
Cary, NC 27513 
Central Laboratory: 
Central Imagining 
Organization: 
Eurofins Lancaster Laboratories 
Environmental, LLC 
2425 New Holland Pike 
Lancaster, PA 17605 
Biomedical Systems 
77 Progress Parkway  
Maryland Heights, MO 63043 
Confidentiality Statement 
The confidential information in this document is provided to you as an investigator or consultant for review by you, your 
staff, and the applicable Institutional Review Board.  Your acceptance of this document constitutes agreement that you will 
not disclose the information contained herein to others without written authorization from the sponsor. 

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INVESTIGATOR’S SIGNATURE 
 
 
I have received and read the investigator’s brochure for SI-613.  I have read protocol 613/1121 and 
agree to conduct the study as outlined.  I agree to maintain the confidentiality of all information 
received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 

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PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Study project manager 
 
 
 
 
Medical monitor 
 
  
 
 
 
 

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1. 
TABLE OF CONTENTS AND LIST OF TABLES  
1. 
TABLE OF CONTENTS AND LIST OF TABLES ....................................................5 
2. 
LIST OF ABBREVIATIONS.....................................................................................11 
3. 
INTRODUCTION ......................................................................................................13 
3.1. 
Background .................................................................................................................13 
3.2. 
Risks and Benefits ......................................................................................................14 
3.3. 
Rationale for Route of Administration, Dosage, and Dosing Regimen .....................14 
3.3.1. Route of Administration and Rationale ......................................................................14 
3.3.2. Dosage and Rationale .................................................................................................14 
3.3.3. Dosing Regimen and Rationale ..................................................................................15 
4. 
OBJECTIVES .............................................................................................................16 
4.1. 
Primary Efficacy Objective ........................................................................................16 
4.2. 
Secondary Efficacy Objectives ...................................................................................16 
4.3. 
Safety Objective ..........................................................................................................16 
5. 
INVESTIGATIONAL PLAN .....................................................................................17 
6. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................18 
6.1. 
Subject Inclusion Criteria ...........................................................................................18 
6.2. 
Subject Exclusion Criteria ..........................................................................................19 
6.3. 
Subject Withdrawal Criteria .......................................................................................22 
7. 
STUDY SCHEDULE AND PROCEDURES ............................................................24 
7.1. 
Study Schedule ...........................................................................................................24 
7.2. 
Study Procedures ........................................................................................................24 
7.2.1. Screening / Visit 1 (Week -2 to -1; Day -14 to -7) .....................................................24 
7.2.2. Randomization / Visit 2 (Week 0; Day 1) ..................................................................25 
7.2.3. Follow-up Visits 3 (Week 1; Day 8 ± 2), 4 (Week 2; Day 15 ± 2), 6 
(Week 6; Day 43 ± 6), 8 (Week 10; Day 71 ± 6), and 10 (Week 18; 
Day 127 ± 14)....................................................................................................26 
7.2.4. Additional Injection Visits 5 (Week 4; Day 29 ± 7) and 7 (Week 8; Day 
57 ± 7) ...............................................................................................................26 
7.2.5. Visit 9 (Week 12; Day 85 ± 7) ....................................................................................27 
7.2.6. Visit 11 (Week 26; Day 183 ± 14) ..............................................................................28 
7.2.7. Early Termination Visit ..............................................................................................29 
7.2.8. Unscheduled Visits .....................................................................................................29 
8. 
INVESTIGATIONAL PRODUCT INFORMATION AND 
MANAGEMENT .......................................................................................................32 

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8.1. 
Investigational Product ...............................................................................................32 
8.2. 
Investigational Product Packaging and Labeling .......................................................32 
8.3. 
Investigational Product Storage ..................................................................................32 
8.4. 
Investigational Product Administration ......................................................................32 
8.5. 
Investigational Product Accountability, Handling, and Disposal ...............................34 
9. 
TREATMENT OF SUBJECT ....................................................................................35 
9.1. 
Description of Investigational Product .......................................................................35 
9.2. 
Rescue Medication ......................................................................................................35 
9.3. 
Concomitant Medications and Therapies ...................................................................35 
9.3.1. Prohibited Medications ...............................................................................................35 
9.3.2. Prohibited Therapies ...................................................................................................36 
9.3.3. Restricted Medications and Therapies ........................................................................36 
9.4. 
Physical Exercise During the Study ...........................................................................36 
9.5. 
Compliance .................................................................................................................37 
9.6. 
Randomization and Blinding Procedures ...................................................................37 
10. 
ASSESSMENTS OF EFFICACY ..............................................................................38 
10.1. 
WOMAC .....................................................................................................................38 
10.2. 
PGIC ...........................................................................................................................38 
10.3. 
CGIC ...........................................................................................................................38 
10.4. 
SF-36...........................................................................................................................38 
10.5. 
PASE...........................................................................................................................38 
10.6. 
Daily Pain Diary .........................................................................................................38 
10.7. 
Acetaminophen Consumption ....................................................................................38 
11. 
SCREENING ASSESSMENTS .................................................................................39 
11.1. 
50-foot Walk Test .......................................................................................................39 
11.2. 
X-rays .........................................................................................................................39 
11.3. 
History of Target Knee Osteoarthritis ........................................................................39 
11.4. 
Vital Signs ..................................................................................................................40 
11.5. 
Body Mass Index ........................................................................................................40 
11.6. 
Medical History ..........................................................................................................40 
11.6.1. 
General Medical History ...................................................................................40 
11.6.2. 
Knee Osteoarthritis Treatment History .............................................................40 
11.7. 
Prohibited Medications ...............................................................................................40 
11.8. 
Concomitant Medications ...........................................................................................40 
11.9. 
Prohibited Therapies ...................................................................................................41 

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11.10. 
Concomitant Physical Therapies ................................................................................41 
11.11. 
Pregnancy Test ............................................................................................................41 
11.12. 
Laboratory Tests .........................................................................................................41 
12. 
ASSESSMENTS OF SAFETY ..................................................................................42 
12.1. 
Target Knee Examination ...........................................................................................42 
12.2. 
Synovial Assessment by MRI .....................................................................................42 
12.3. 
Vital Signs ..................................................................................................................42 
12.4. 
Laboratory Tests .........................................................................................................42 
12.5. 
Adverse and Serious Adverse Events .........................................................................42 
12.5.1. 
Definitions of Adverse Events/Effects ..............................................................43 
12.5.1.1. 
Adverse Event ..............................................................................................43 
12.5.1.2. 
Serious Adverse Event .................................................................................43 
12.5.1.3. 
Adverse Drug Reaction and Suspected Adverse Reaction ...........................44 
12.5.1.4. 
Unexpected Adverse Reaction .....................................................................44 
12.5.2. 
Severity of Adverse Events/Serious Adverse Events........................................45 
12.5.3. 
Relationship to Investigational Treatment ........................................................45 
12.5.4. 
Collecting and Recording Adverse Events .......................................................46 
12.5.4.1. 
Period of Collection .....................................................................................46 
12.5.4.2. 
Methods of Collection ..................................................................................46 
12.5.4.3. 
Recording Method ........................................................................................46 
12.5.4.3.1. Adverse Events ........................................................................................46 
12.5.4.3.2. Serious Adverse Events ...........................................................................47 
12.5.5. 
Reporting Adverse Events.................................................................................47 
12.5.5.1. 
Reporting Serious Adverse Events to the Sponsor .......................................47 
12.5.5.2. 
Reporting Serious Adverse Events to Health Authorities ............................47 
12.5.5.3. 
Reporting Serious Adverse Events to Institutional Review 
Boards ...........................................................................................................47 
12.6. 
Pregnancy ...................................................................................................................48 
12.7. 
Potential Device Malfunctions ...................................................................................48 
12.7.1. 
Malfunction .......................................................................................................48 
12.7.2. 
Injuries Caused by Device Malfunctions ..........................................................48 
13. 
STATISTICS ..............................................................................................................50 
13.1. 
Power and Sample Size Determination ......................................................................50 
13.2. 
Randomization ............................................................................................................50 
13.3. 
Analysis Populations ..................................................................................................50 

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13.4. 
Efficacy and Safety Analyses .....................................................................................50 
13.4.1. 
Background and Demographic Characteristics .................................................50 
13.4.2. 
Subjects Accountability ....................................................................................50 
13.4.3. 
Efficacy Analyses..............................................................................................51 
13.4.3.1. 
Primary Efficacy Analysis ...........................................................................51 
13.4.3.2. 
Secondary Efficacy Analyses .......................................................................51 
13.4.3.3. 
OMERACT-OARSI Responder ...................................................................52 
13.4.4. 
Safety Analyses .................................................................................................52 
13.4.5. 
Concomitant Medications and Concomitant Therapies ....................................52 
13.5. 
Other Statistical Considerations .................................................................................52 
13.5.1. 
Significance Levels ...........................................................................................52 
13.5.2. 
Missing Data .....................................................................................................52 
13.5.3. 
Visit Windows ...................................................................................................53 
13.5.4. 
Multiplicity ........................................................................................................53 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................54 
14.1. 
Study Monitoring ........................................................................................................54 
14.2. 
Source Documents ......................................................................................................54 
14.3. 
Data Collection and Management ..............................................................................54 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................56 
16. 
ETHICS ......................................................................................................................57 
16.1. 
Ethics Review .............................................................................................................57 
16.2. 
Ethical Conduct of the Study ......................................................................................57 
16.3. 
Written Informed Consent ..........................................................................................57 
16.3.1. 
Subject Information and Informed Consent ......................................................57 
16.3.2. 
Provision of New and Important Information Influencing Subject’s 
Consent and Revision of the Written Information ............................................57 
16.4. 
Subject Confidentiality ...............................................................................................58 
16.5. 
Publications of the Clinical Study ..............................................................................58 
16.6. 
Protocol Amendments and Deviations .......................................................................58 
17. 
DATA HANDLING AND RECORD KEEPING ......................................................59 
17.1. 
Inspection of Records .................................................................................................59 
17.2. 
Retention of Records ..................................................................................................59 
18. 
REFERENCES ...........................................................................................................60 
19. 
APPENDICES ............................................................................................................61 
19.1. 
Patient Global Impression of Change (PGIC) ............................................................61 

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19.2. 
Clinical Global Impression of Change (CGIC) ..........................................................63 
19.3. 
36-Item Short Form Health Survey (SF-36) ...............................................................65 
19.4. 
Physical Activity Scale for the Elderly (PASE) .........................................................72 
19.5. 
Daily Pain Diary .........................................................................................................80 
19.6. 
VAS Pain Scales for 50-foot Walk Test .....................................................................82 
 
 
 

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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Study Schedule ...........................................................................................................30 
Table 3: 
Attribution of Adverse Events ....................................................................................45 
 
 
  

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2. 
LIST OF ABBREVIATIONS 
The following abbreviations are used in this study protocol. 
Abbreviation 
Explanation 
ACR 
American College of Rheumatology 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AP 
anteroposterior 
AST 
aspartate aminotransferase 
BMI 
body mass index 
COX 
cyclooxygenase 
CBC 
complete blood count 
CGIC 
Clinical Global Impression of Change 
CFR 
Code of Federal Regulations 
DF 
diclofenac 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
FTA 
femoral-tibial angle 
GCP 
Good Clinical Practice 
GEE 
generalized estimating equations 
HA 
hyaluronate or hyaluronic acid 
IA 
intra-articular 
ICH 
International Conference on Harmonisation 
IRB 
institutional review board 
ITT 
intention-to-treat 
K-L 
Kellgren-Lawrence 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
NRS 
Numeric Rating Scale 
NSAID 
nonsteroidal anti-inflammatory drug 
OA 
osteoarthritis 
OMERACT-OARSI 
Outcome Measures in Rheumatology - Osteoarthritis Research 
Society International 
PASE 
Physical Activity Scale for the Elderly 
PGIC 
Patient Global Impression of Change 
PP 
per-protocol 

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SAE 
serious adverse event 
SAR 
suspected adverse reaction 
SF-36 
36-Item Short Form Health Survey (SF-36)  
SKK 
Seikagaku Corporation 
SOP 
standard operating procedure 
ULN 
upper limit of normal 
US 
United States 
VAS 
visual analogue scale 
WOMAC 
Western Ontario and McMaster Universities Osteoarthritis Index 
 

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3. 
INTRODUCTION 
3.1. 
Background 
Osteoarthritis (OA) is by far the most common joint disorder in the United States (US) and throughout 
the world, and it is one of the leading causes of disability in the elderly.1,2  Osteoarthritis is 
characterized by damage to joint structures such as hyaline cartilage and subchondral bone, and 
increases in prevalence with age.  Primary symptoms include joint pain and impairment of physical 
function.  The main clinical features are bony swelling, joint effusion, limitation of range of motion, 
malalignment, and deformation.  Treatment for OA aims to relieve pain and improve function.  Main 
treatment options for knee OA are conservative therapies such as exercise, physical therapy, and 
pharmacotherapy.  Pharmacotherapy includes use of oral or topical agents, such as acetaminophen or 
nonsteroidal anti-inflammatory drugs (NSAIDs), or intra-articular (IA) injections such as hyaluronic 
acid (HA) or corticosteroids.  Surgery is an option for patients when conservative therapy fails to 
improve symptoms and joint destruction progresses. 
Oral NSAIDs are among the most commonly used medications for mild or moderate knee OA pain.  
Nonsteroidal anti-inflammatory drugs have a fast-acting analgesic and anti-inflammatory effect and 
are considered to be effective for improving OA symptoms, but individual patient response varies 
widely.  An increase in upper gastrointestinal tract disorders has been reported in patients on long-
term use.3  In the 1990s, numerous selective cyclooxygenase (COX)-2 inhibitors were developed to 
reduce upper gastrointestinal tract disorders, but most of them were withdrawn from the market or 
their development was halted by 2004 due to concerns about cardiovascular adverse reactions.4  The 
same concerns with selective COX 2 inhibitors have also been reported with oral NSAIDs.5 
Intra-articular injection therapies also play an important role in the conservative therapy of knee OA.  
Corticosteroids and HA formulations are typical examples.  Corticosteroids have strong anti-
inflammatory effects and are given by IA knee injection to patients with moderate to severe knee OA.  
However, it is generally recommended that corticosteroid injections be limited to 3 or 4 times per year 
in most cases because of concern over potential progressive joint destruction through repeated 
injections into the knee joint.6  Although the mechanisms of action of IA HA injections are not fully 
understood, an array of research suggests that HA exerts anti-inflammatory, analgesic, and possibly 
chondroprotective effects on the joint cartilage.7  Due to their viscoelastic properties, IA HA 
injections also function as a lubricant and a shock absorber.  As a result of these effects, IA HA 
injections exert long-lasting pain relief for some patients with OA of the knee.8 
Seikagaku Corporation (SKK) has developed and evaluated various HA derivatives that are 
chemically linked with various NSAIDs and possess the advantages of both IA HA injections and 
NSAIDs.  SI-613, an HA derivative chemically linked with diclofenac (DF), was identified through a 
series of animal arthritis model studies.  As the result of data obtained from the nonclinical studies, a 
single IA injection of SI-613 is expected to provide analgesic effect for OA pain and to remain in joint 
tissues for a prolonged period of time to provide potent, sustained analgesia, and could be a highly 
effective and safe treatment for OA pain. 
A phase 1 clinical study performed in healthy Caucasian and Japanese male subjects showed that 
single IA knee injections of SI-613 were safe and well tolerated.  A phase 2 study in 121 Japanese 
subjects with knee OA was then conducted to explore the efficacy and safety of single IA knee 
injections of 15 mg SI-613 drug solution, 30 mg SI-613 drug solution, and placebo.  SI-613 was well 
tolerated, resulting in no major safety signals.  While the differences between treatment groups for the 
primary efficacy measurement, the Western Ontario and McMaster Universities Osteoarthritis Index 
(WOMAC) pain subscore, were not statistically significant, significant improvement compared with 

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placebo treatment was found for SI-613 treatment for some individual questions in WOMAC stiffness 
and WOMAC physical function subscores, which were secondary efficacy measurements.  Also, the 
number of individual WOMAC questions with significant improvements for SI-613 over placebo was 
larger for the 30 mg SI-613-treated group than for the 15 mg SI-613-treated group.  After a single IA 
injection of SI-613 drug solution or placebo, the estimated difference between the SI-613 and placebo 
groups in the WOMAC subscores tended to be larger for 30 mg SI-613 treatment than for 15 mg SI-
613 treatment from Weeks 1 through 8.   
A second phase 2 study in 176 Japanese subjects with knee OA was then conducted to explore the 
efficacy and safety of repeated IA knee injections (1 injection every 4 weeks, total of 3 injections) of 
30 mg SI-613 drug solution and placebo.  The repeated IA injections of 30 mg SI-613 drug solution 
showed significantly greater improvements than placebo in the primary endpoints of the WOMAC 
pain subscore and the subject daily pain score during Week 1 through Week 12.  As in the prior study, 
SI-613 was well tolerated, resulting in no major safety signals. 
Based on these results, SKK begins the US clinical program with this phase 2 study, which is 
designed to evaluate the efficacy and safety of repeated IA injections (1 injection every 4 weeks, with 
a total of 3 injections) of 30 mg SI-613 drug solution compared with placebo in subjects with 
symptomatic knee OA.  
3.2. 
Risks and Benefits 
For summary of the known and potential risks and benefits to human subjects, please see Sections 6.3 
of the SI-613 Investigator’s Brochure. 
3.3. 
Rationale for Route of Administration, Dosage, and Dosing 
Regimen 
3.3.1. 
Route of Administration and Rationale 
The route of administration of SI-613 is via IA injection into the knee joint. 
Intra-articular injection is a common route of administration in medical practice, with many similar 
injectable HA medical devices approved in the US for the treatment of OA knee pain.  Intra-articular 
injection makes it possible to place SI-613 drug substance directly into the joint cavity without 
diffusing it into other tissues, which contributes to low systemic exposure. 
3.3.2. 
Dosage and Rationale   
The volume of injection to be used for this study is 3 mL.  
 
 
 
 
 
The dosage to be used for this study is 30 mg. In the single-dose phase 2 study in Japanese patients 
with knee OA, it was suggested that a single injection of SI-613 was effective and that efficacy was 
higher with 30 mg SI-613 than with 15 mg SI-613.  The study also suggested that there were no major 
safety concerns with either dose of SI-613.  Based on the above results, 30 mg was selected as the 
final clinical dose.   

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3.3.3. 
Dosing Regimen and Rationale 
The dosing regimen of SI-613 will be repeated IA injections of 30 mg SI-613 administered once every 
4 weeks for a total of 3 IA injections at Weeks 0, 4, and 8.  In the nonclinical study in antigen-induced 
rabbit arthritis models, a single IA knee injection of SI-613 significantly inhibited knee joint swelling 
compared with injections in the control group up to 28 days after the injection.  In the repeat-dose 
phase 2 clinical study in Japanese patients with knee OA, IA knee injections of 30 mg SI-613 at 28-
day intervals resulted in statistically significant improvement in pain compared with placebo.  
Therefore, a 28-day (4-week) dosing interval was selected. 
 
 

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4. 
OBJECTIVES 
4.1. 
Primary Efficacy Objective 
The primary efficacy objective of the study is to investigate the efficacy of SI-613 for the treatment of 
OA knee pain by showing a greater reduction in pain as measured by the WOMAC visual analog 
scale (VAS) pain subscore over a 12-week evaluation period in subjects treated with SI-613 compared 
with subjects treated with placebo.  The primary efficacy objective will be tested using the null 
hypothesis that there is no difference in the mean change from the pretreatment measure of pain relief 
(WOMAC VAS pain subscore) between SI-613 and placebo over 12 weeks.   
4.2. 
Secondary Efficacy Objectives 
The secondary efficacy objectives are to investigate the effect of SI-613 on signs and symptoms of 
OA of the knee versus placebo as assessed by the following: 
 
WOMAC VAS pain subscore 
 
WOMAC VAS physical function subscore 
 
Patient Global Impression of Change (PGIC)  
 
Proportion of subjects experiencing a >30% or >50% improvement in WOMAC VAS 
pain subscore 
 
Outcome Measures in Rheumatology - Osteoarthritis Research Society International 
(OMERACT-OARSI) responder rate 
 
WOMAC VAS total score 
 
WOMAC VAS stiffness subscore 
 
36-Item Short Form Health Survey (SF-36) physical component score 
 
Amount of acetaminophen rescue medication consumed for the target knee 
 
Clinical Global Impression of Change (CGIC) 
 
Weekly average of daily pain scores 
 
Physical Activity Scale for the Elderly (PASE) 
4.3. 
Safety Objective 
The safety objective of the study is to support the overall safety of SI-613 by examining the 
following: 
 
Incidence of treatment-emergent adverse events (AEs)  
 
Vital signs readings 
 
Laboratory tests 
 
Target knee examinations 
 
Synovial assessment in the target knee by magnetic resonance imaging (MRI) 

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5. 
INVESTIGATIONAL PLAN 
This is a phase 2, multicenter, randomized, double-blind, placebo-controlled study to evaluate the 
efficacy and safety of a 3 mL IA knee injection of 30 mg SI-613 given every 4 weeks for the 
treatment of OA knee pain over 12 weeks.  The subject will be followed up for 26 weeks after 
randomization. 
Following screening, approximately 80 subjects will be randomized in a 1:1 ratio to treatment with 
SI-613 or placebo.  Randomization will be balanced based on baseline WOMAC VAS pain subscore, 
Kellgren-Lawrence (K-L) score, sex, and investigational site.  Screening may occur 1 to 2 weeks prior 
to injection (Week 0).  As part of the eligibility assessments, subjects will complete the WOMAC 
(with the VAS pain subscore being used as part of the eligibility assessment) and report their pain on 
a 100-mm VAS after a 50-foot walk test at Screening and at Week 0 prior to injection.  Subjects will 
be randomized to receive an injection every 4 weeks, a total of 3 injections of either 1% SI-613 or 
placebo and followed up for 26 weeks after randomization.  Subjects will have clinic visits at Weeks 0, 
1, 2, 4, 6, 8, 10, 12, 18 and 26.  Subjects will receive injections at Weeks 0, 4, and 8.  Because the SI-
613 and placebo preparations might be visually distinguished in the syringe caused by the difference 
of the viscosity, the injections will be administered by an unblinded injecting physician who is 
experienced in IA injection of the knee.  The unblinded injecting physician will be instructed on how 
to maintain blinding of other study team members and subjects from the treatment, and will be 
otherwise uninvolved with conducting the study, including outcome assessment.  At all visits, a 
blinded evaluating physician or a back-up blinded evaluating physician will conduct the assessments.  
Subjects will report their signs and symptoms of knee OA through the WOMAC at all visits and PGIC 
at all follow-up visits.  Subjects will also complete a daily diary recording their pain on the 11-point 
Numeric Rating Scale (NRS) before bed each evening.  In addition, the SF-36 will be completed at 
Weeks 0, 4, 8, 12, and 26 and the PASE will be completed at all visits.  The physician will complete 
the CGIC at all follow-up visits  and an examination of the target knee at all visits.  MRI will be taken 
at screening, Weeks 12 and 26 to monitor synovial changes of the target knee and assessed by an 
independent central imaging evaluator.  Subjects must switch to using acetaminophen as a rescue pain 
medication if they are currently using other pain medications.  Acetaminophen will be provided, and 
pill counts will be used to assess consumption between visits.   
The primary endpoint is the change in target knee pain from baseline (average of scores at Visits 1 
and 2) to post-treatment (defined as the repeated-measures model estimated average of post-treatment 
time points over Weeks 1 through 12), as measured on the WOMAC VAS.  Secondary efficacy 
analyses will include evaluations of the difference between the SI-613 and placebo groups in changes 
in the WOMAC VAS subscores for physical function, stiffness, and total score; proportion of subjects 
experiencing a >30% or >50% improvement in pain; OMERACT-OARSI responder rates; PGIC; 
CGIC; SF-36 physical component score; daily pain score; PASE; and acetaminophen consumption. 
The incidence of treatment-emergent AEs and the results of vital signs readings, laboratory tests, 
target knee examinations, and the synovial assessment of the target knee by MRI will be used to 
assess safety. 
 

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6. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
6.1. 
Subject Inclusion Criteria 
A subject must meet all of the following inclusion criteria to be eligible to enroll in the clinical trial: 
1. Provides their written informed consent. 
2. Is willing and able to complete efficacy and safety questionnaires and is able to read 
and understand study instructions. 
3. Is a male or female aged 40 to 75 years (inclusive) at the time of informed consent.  
4. Has a diagnosis at the time of screening of OA of the knee according to American 
College of Rheumatology (ACR) criteria: 
 Knee pain  
 Plus osteophytes 
 Plus at least 1 of 3 of the following criteria: 
o Age >50 years 
o Morning stiffness <30 minutes 
o Crepitus on active motion  
5. Has had OA pain in the target knee during at least the full 12 months (1 year) 
immediately preceding the screening visit. 
6. Has a grade 2 or 3 score on the K-L grading scale based on a bilateral standing 
anteroposterior (AP) x-ray of the target knee taken no longer than 6 months prior to 
Screening.  Kellegren-Lawrence grading will be assessed based on the following 
definitions: 
 
Grade 2:  definite osteophytes and possible narrowing of the joint space 
 
Grade 3:  moderate multiple osteophytes and definite narrowing of the joint space, 
some sclerosis and possible deformity of bone ends 
7. Has a pain score for the target knee of 50 to 90 mm (inclusive) on a 100-mm VAS at 
Screening and Day 1 before injection 1) for the mean of the 5 questions on the 
WOMAC VAS pain subscale prior to the 50-foot walk test and 2) on the pain 
assessment following a 50-foot walk test, which has no time constraint but must be 
completed without assistance of walking aids or other assistive devices or supports. 
8. Has a pain score for the contralateral knee of ≤30 mm on a 100-mm VAS at Screening 
and Day 1 before injection 1) for the mean of the 5 questions on the WOMAC VAS 
pain subscale prior to the 50-foot walk test and 2) on the pain assessment following a 
50-foot walk test, which has no time constraint but must be completed without 
assistance of walking aids or other assistive devices or supports. 
9. Is willing to switch to using acetaminophen as a rescue medication if currently using 
other pain medications.   
 
Acetaminophen will be provided for the treatment of breakthrough pain in the 
target knee.  This will be the only pain medication permitted for target knee pain. 

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 
Use of over-the-counter acetaminophen will be permitted for AEs, but the use 
will be limited to up to 3 days total between each visit for Visits 1 through 4 and 
up to 5 days total between each visit for Visits 5 through 9.   
A maximum of 3000 mg/day total of acetaminophen will be permitted.  The use of 
low-dose aspirin (one to two 81 mg doses/day) for thrombosis prophylaxis is permitted. 
10. Is willing to suspend the use of combination over-the-counter medications that may 
contain prohibited medications or acetaminophen. 
11. Is willing to suspend the use of rescue medication (acetaminophen), for both the target 
knee and any AEs, from the 2 days before to the end of each study visit. 
12. Failed at least one pharmacologic treatment (e.g., NSAID) in the management of the 
target knee OA. 
6.2. 
Subject Exclusion Criteria 
The presence of any of the following exclusion criteria excludes a subject from study enrollment: 
1. Has a body mass index (BMI) greater than or equal to 40 kg/m2 at Screening. 
2. Has any of the following: 
 
Grade 1 or grade 4 score on the K-L grading scale for the target knee. 
o Grade 1:  doubtful narrowing of the joint space and possible osteophytic 
lipping  
o Grade 4:  large osteophytes, marked narrowing of joint space, severe sclerosis, 
and definite deformity of bone ends 
 
Grade 3 score on the K-L grading scale for the target knee and exhibits at least 
1 characteristic of a grade 4 on the radiograph (large osteophytes, marked 
narrowing of joint space, severe sclerosis, or definite deformity of bone contour) 
 
Current or healing fracture of either leg 
 
Medical history of severe bone disease that could affect the lower limbs, either 
generalized (e.g., osteoporosis) or localized (e.g., osteonecrosis, joint deformity, 
or meniscal instability affecting either leg) 
3. Has any of the following in the target knee: 
 
Secondary OA resulting from trauma or other diseases  
 
History of chondrocyte transplantation 
 
History of ligament reconstruction 
 
Skin disorder or infection in the injection area of the target knee 
4. Has had joint replacement of the target knee at any time or a joint replacement of the 
contralateral knee in 1 year prior to Screening. 
5. Has diagnosed and treated OA of the hips, spine, or ankle within 2 years or has 
symptomatic OA of the hips, spine, or ankle at Screening or Week 0 pre-injection. 
6. Has any of the following, which may affect pain in 1 or both knees: 
 
Pain in either lower extremity that is sufficient to interfere with evaluation of the 
knees 

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 
Inflammatory disease other than OA or septic arthritis of either knee (e.g., joint 
infection) within 1 year prior to Screening or at Week 0 before injection  
 
Surgical procedure or invasive procedure (e.g., arthroscopy, joint lavage) in either 
lower extremity within 1 year prior to Screening 
 
IA HA injection(s) for the treatment of OA of either knee within 6 months prior 
to Screening 
7. Has received an IA injection(s) into any joint other than IA HA (e.g., corticosteroids, 
chondroitin sulfate, or glucosamine) within 90 days prior to Screening. 
8. Had IA fluid aspirated from either knee within 7 days prior to the start date of screening. 
9. Has taken any of the following prohibited medications within 7 days prior to Screening.  
Unless noted, these medications are prohibited in oral, injectable, and suppository 
forms, but they can be used in inhaled, nasal, or ophthalmic formulations.  Topical 
administration is permitted except for the lower extremity of the ipsilateral side of the 
target knee. 
 
NSAIDs (DF is prohibited by any route of administration) 
 
Medicines for neuropathic pain (e.g., pregabalin, gabepentin) 
 
Topical capsaicins 
 
Duloxetine (serotonin-norepinephrine reuptake inhibitors) 
 
Local anesthesia to either knee (local anesthesia to target knee during SI-613 
injection procedure is permitted)  
 
Anticonvulsant drugs, herbal medicines with analgesic properties 
Subjects who agree to discontinue use of these medications and for whom 
discontinuation of these medications is medically appropriate may return 7 days after 
discontinuation to complete screening. 
10. Has taken any of the following prohibited medications within 28 days prior to 
Screening.  Unless noted, oral, injectable, or suppository administration is prohibited, 
but topical administration is prohibited only for the lower extremity of the ipsilateral 
side of the target knee. 
 
Opioids (prohibited by any route of administration) 
 
Corticosteroids (note that IA administration is excluded within 90 days prior to 
screening per exclusion criterion #7) 
 
Antidepressant medications, antianxiety medications, antipsychotic medications, 
mood stabilizers, and sleeping drugs 
Subjects who agree to discontinue use of these medications, and for whom 
discontinuation of these medications is medically appropriate, may return 28 days after 
discontinuation to complete screening. 
11. Has had any block procedure (e.g., nerve block, epidural block, or facet block) within 
28 days prior to the start date of screening. 
12. Has begun taking an oral chondroprotective agent (chondroitin sulfate or glucosamine) 
for 14 days prior to Screening.  Subjects who have been taking a stable dose on a stable 
regimen for ≥15 days prior to the start date of screening can continue the stable dose 

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during the study.  Subjects who agree to stabilize their dose of these medications or to 
discontinue use of these medications, and for whom the adjustment made is medically 
appropriate, may return after ≥15 days to complete screening. 
13. Has begun treatment with any physical therapy (exercise therapy, Tai Chi, massage, 
balneotherapy, taping, insoles, knee braces, thermal agent, and/or transcutaneous 
electrical stimulation) for OA of the target knee for 28 days prior to the start date of 
screening.  Subjects who have continued at stable regime for ≥29 days prior to the start 
date of screening can continue during the study.  Subjects who agree to stabilize their 
therapy regimen or to discontinue therapy, and for whom the adjustment made is 
medically appropriate, may return after ≥29 days to complete screening.  Acupuncture 
is prohibited for either knee for 7 days prior to the start date of screening. 
14. Is a female subject who is pregnant or lactating. 
15. Is a female subject of childbearing potential who is not willing to use adequate 
contraceptive measures to avoid pregnancy.  All sexually active subjects must agree to 
practice an adequate method of birth control during the study.  Adequate methods of 
birth control include the following: 
 
Hormonal contraception 
 
Use of at least 1 acceptable barrier method; acceptable barrier methods include 
diaphragm plus a spermicidal agent or condoms (male or female) plus a 
spermicidal agent 
 
Vasectomy, hysterectomy, bilateral tubal ligation, intrauterine device, and/or an 
exclusive sexual partner for whom 1 of these methods applies 
Female subjects who have not menstruated within the past 2 years are considered 
postmenopausal and do not need to practice birth control. 
16. Has a history of aspirin-induced asthma (asthma attacks triggered by NSAIDs, etc.). 
17. Has a known allergy or contraindication to sodium HA products, any DF preparation, or 
acetaminophen. 
18. Has another disease that has been associated with any joint symptoms in the past 2 
years (e.g., chondrocalcinosis, gout, psoriasis). 
19. Has the following exclusionary laboratory test results at Screening:  
 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 times 
the upper limit of normal (ULN) 
 
Creatinine >1.5 times the ULN 
 
Positive hepatitis C antibodies or hepatitis B surface antigen 
20. Has a current malignancy or has received treatment for malignancy within the past 
5 years prior to informed consent.  
21. Has a history of recurrent, severe allergic or immune-mediated reactions or other 
autoimmune disorders. 
22. Has any of the following medical conditions that would interfere with safety or efficacy 
evaluation:  uncontrolled diabetes; immunodeficiency syndrome; significant 
cardiovascular, renal, or liver disease; severe anemia; clotting disorder or other blood 
diseases; serious infectious disease; fibromyalgia or other systemic chronic pain 

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disorder; rheumatoid arthritis; anserine bursa; lumbar radiculopathy; neurogenic or 
vascular claudication; vascular insufficiency of lower limbs; peripheral neuropathy 
severe enough to interfere with the study evaluations; seizure disorder; dementia; 
psychosis (or history thereof); current anxiety, depression, or other neuropsychiatric 
symptoms. 
23. Has presence or history of alcohol or drug abuse, or tests positive on urine drug screen 
or for blood alcohol.  Subjects should be advised not to drink alcohol within 24 hours of 
Screening.  Positive drug or alcohol tests cannot be repeated. 
24. Has any other psychiatric, medical, or social condition or situation that, in the opinion 
of the investigator, is likely to interfere with study conduct, confound interpretation of 
study results, or adversely affect the balance of benefits and risks of study participation. 
25. Has a contraindication to receiving an MRI of the target knee or is unwilling to have 
MRI performed. 
26. Is currently hospitalized or has a planned hospitalization during the life of the study. 
27. Is receiving worker’s compensation or is currently involved in litigation. 
28. Has participated in a clinical study of an investigational drug, device, or biologic within 
90 days prior to informed consent. 
29. Any condition that, in the opinion of the investigator, might interfere with the 
evaluation of the study objectives. 
6.3. 
Subject Withdrawal Criteria 
Subjects will be encouraged to adhere to the protocol and complete all required assessments.  A 
subject will be discontinued from the study for any of the following medical or administrative 
reasons: 
 
A treatment-emergent AE or considerable worsening of an AE that, in the judgment of 
the investigator or medical monitor, represents an unacceptable risk to the subject and 
warrants stopping the subject’s participation in the investigational study.  The investigator 
must follow the subject until the AE resolves or satisfactorily stabilizes. 
 
Pregnancy. 
 
Death of subject. 
 
Poor response of a subject to the investigational product such that the investigator 
determines that the subject needs treatment that excludes them from the protocol. 
 
A critical deviation from the inclusion or exclusion criteria that leads the investigator or 
medical monitor to determine that continued injections of SI-613 or placebo are not 
appropriate for ethical or safety reasons.  
 
Having joint replacement of the target knee 
 
Receiving an IA injection into the target knee joint (e.g., HA, corticosteroids, or 
chondroprotective agents) during the study. 
 
Participation in another clinical study. 
 
Development of human immunodeficiency virus infection (as assessed by a positive test 
for human immunodeficiency virus) or active hepatitis. 

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 
Development or diagnosis of alcohol or other substance abuse. 
 
If the investigator judges it impossible to continue the study for a subject because 
o The subject does not comply with protocol requirements 
o The subject is lost to follow up 
o There are technical issues at the site 
 
Investigator discretion at any time. 
 
Subject’s request. 
 
Sponsor’s discontinuation of the study at a site. 
 
Premature termination of the study by the sponsor. 
Any enrolled subjects desiring to discontinue prior to study completion should be encouraged to 
continue in the study and adhere to the protocol and subsequent regularly scheduled safety and 
efficacy evaluations.  Subjects who are discontinued outside of any scheduled visit will be encouraged 
to complete the early termination visit at the time of withdrawal.  Subjects who are discontinued 
during a scheduled visit will be encouraged to complete all assessments for both that study visit and 
the early termination visit at the time of withdrawal.  A subject who withdraws following the injection 
will not be replaced. 

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7. 
STUDY SCHEDULE AND PROCEDURES 
7.1. 
Study Schedule 
The study schedule can be found in Table 2. 
7.2. 
Study Procedures 
7.2.1. 
Screening / Visit 1 (Week -2 to -1; Day -14 to -7) 
Screening (Week -2 to -1) will occur 7 to 14 days prior to Visit 2 (Week 0).   
The following procedures will be performed at Screening / Visit 1: 
 
Prior to any study-specific procedures, obtain written informed consent for this study. 
 
Perform screening inclusion/exclusion criteria eligibility assessments, which include the 
following: 
o Confirm that the subject has not used any prohibited medications or therapies 
within the protocol-defined washout windows.  If a subject has used prohibited or 
restricted medications or therapies within the washout window, the subject may 
remain in the study and return after the appropriate washout period to continue 
the Screening visit. 
o Record the use of prior and current concomitant medications and therapies, 
confirming that the subject has been on a stable dose and regimens of chondroitin 
sulfate or glucosamine for at least 15 days and a stable regimen of physical 
therapy for at least 29 days.  If a subject has used varied doses of chondroitin 
sulfate or glucosamine within the past 15 days inclusive or a varied regimen of 
physical therapy within the past 29 days inclusive, the subject may begin a period 
of stable dosing/regimen and return after ≥15 days or ≥29 days, respectively, to 
recomplete the activities in the Screening visit. 
o Collect demographic data and medical history information, including diagnosis 
and history of OA. 
o Collect vital signs. 
o Measure the subject’s height and weight and use these data to calculate the 
subject’s BMI. 
o If no x-rays are available from the preceding 6 months, obtain an AP x-ray of the 
target knee joint with the subject in the standing position. 
o Assess K-L score. 
o Assess femoral-tibial angle (FTA). 
o Collect urine sample for a urine drug screen and for laboratory tests (qualitative 
urinalysis regarding glucose, protein and urobilinogen). 
o Collect blood sample for laboratory tests (complete blood count, complete 
metabolic profile, blood alcohol content, and hepatitis screening). 
o For females of childbearing potential, collect a blood sample to perform a serum 
pregnancy test. 

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 
Record baseline signs and symptoms as baseline for future potential AEs. 
 
Perform examination of the target knee. 
 
Assess patellar grinding via Clarke’s test. 
 
Administer the WOMAC. 
 
Conduct the 50-foot walk test and measure pain immediately following using a 100-mm 
VAS. 
 
Confirm that the subject meets all of the inclusion criteria and none of the exclusion 
criteria and is therefore eligible for the study. 
 
Obtain MRI of the target knee joint (MRI may be scheduled at another day within Day -
14 to -3 (from 3 to 14 days prior to Visit 2). 
 
Record AEs that have occurred during the study visit. 
 
Distribute subject daily diary. 
 
Distribute acetaminophen. 
7.2.2. 
Randomization / Visit 2 (Week 0; Day 1) 
Visit 2 must occur in a 7- to 14-day window following the Screening visit. 
The following procedures will be performed at Visit 2: 
 
Confirm no use of rescue acetaminophen in the previous 2 days and before the visit at the 
visit date. 
 
Review the medical history information. 
 
Review and update the use of prior and current concomitant medications and concomitant 
therapies, confirming that the subject has not used any prohibited medications or 
therapies and has not changed the dose and/or regimen of restricted medications or 
therapies since the previous visit. 
 
Collect vital signs. 
 
Collect urine and perform a dipstick urine pregnancy test. 
 
Collect the acetaminophen container from the previous visit and count acetaminophen 
usage. 
 
Collect the subject daily diary and assess compliance. 
 
Record AEs. 
 
Perform examination of the target knee. 
 
Administer the WOMAC. 
 
Administer the SF-36. 
 
Administer the PASE. 
 
Conduct the 50-foot walk test and measure pain immediately following using a 100-mm 
VAS. 
 
Confirm that the subject meets all of the inclusion criteria and none of the exclusion 
criteria and is therefore eligible for the study. 

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 
Randomize the subject. 
 
Perform the first injection. 
o The subject will be instructed to avoid any strenuous activities (such as jogging, 
tennis, and other active sports or heavy lifting) and prolonged weight-bearing 
activities (such as standing for more than 1 hour) for 48 hours following the IA 
injection. 
 
Record AEs that have occurred during the study visit.  
 
Distribute new subject daily diary. 
 
Distribute new acetaminophen tablets. 
7.2.3. 
Follow-up Visits 3 (Week 1; Day 8 ± 2), 4 (Week 2; Day 15 ± 2), 6 (Week 6; 
Day 43 ± 6), 8 (Week 10; Day 71 ± 6), and 10 (Week 18; Day 127 ± 14) 
The following procedures will be performed at Visits 3, 4, 6, 8 and 10: 
 
Confirm no use of rescue acetaminophen in the previous 2 days and before the visit at the 
visit date. 
 
Review and update the use of concomitant medications and therapies, confirming that the 
subject has not used any prohibited medications or therapies and has not changed the dose 
and/or regimen of restricted medications or therapies since the previous visit. 
 
Collect vital signs. 
 
Record AEs. 
 
Collect the acetaminophen container from the previous visit and count acetaminophen 
usage. 
 
Collect the subject daily diary and assess compliance. 
 
Perform examination of the target knee. 
 
Administer the WOMAC. 
 
Record the PGIC. 
 
Administer the PASE. 
 
Record the CGIC. 
 
Record AEs that have occurred during the study visit.  
 
Distribute new subject daily diary. 
 
Distribute new acetaminophen tablets. 
7.2.4. 
Additional Injection Visits 5 (Week 4; Day 29 ± 7) and 7 (Week 8; Day 57 ± 7) 
The following procedures will be performed at Visits 5 and 7: 
 
Confirm no use of rescue acetaminophen in the previous 2 days and before the visit at the 
visit date. 
 
Review and update the use of concomitant medications and therapies, confirming that the 
subject has not used any prohibited medications or therapies and has not changed the dose 
and/or regimen of restricted medications or therapies since the previous visit. 

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 
Collect vital signs. 
 
Collect urine and perform a dipstick urine pregnancy test. 
 
Collect urine sample for laboratory tests (qualitative urinalysis regarding glucose, protein 
and urobilinogen). 
 
Collect blood sample for laboratory tests (complete blood count and complete metabolic 
profile). 
 
Record AEs. 
 
Collect the acetaminophen container from the previous visit and count acetaminophen 
usage. 
 
Collect the subject daily diary and assess compliance. 
 
Perform examination of the target knee. 
 
Administer the WOMAC. 
 
Record the PGIC. 
 
Administer the SF-36. 
 
Administer the PASE. 
 
Record the CGIC. 
 
Perform the injection. 
o The subject will be instructed to avoid any strenuous activities (such as jogging, 
tennis, and other active sports or heavy lifting) and prolonged weight-bearing 
activities (such as standing for more than one hour) for 48 hours following the IA 
injection. 
 
Record AEs that have occurred during the study visit.  
 
Distribute new subject daily diary. 
 
Distribute new acetaminophen tablets. 
7.2.5. 
Visit 9 (Week 12; Day 85 ± 7) 
The following procedures will be performed at Visit 9: 
 
Confirm no use of rescue acetaminophen in the previous 2 days and before the visit at the 
visit date. 
 
Review and update the use of concomitant medications and therapies, confirming that the 
subject has not used any prohibited medications or therapies and has not changed the dose 
and/or regimen of restricted medications or therapies since the previous visit. 
 
Collect vital signs. 
 
Collect urine sample for laboratory tests (qualitative urinalysis regarding glucose, protein 
and urobilinogen). 
 
Collect blood sample for laboratory tests (complete blood count and complete metabolic 
profile). 
 
Record AEs. 

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 
Collect the acetaminophen container from the previous visit and count acetaminophen 
usage. 
 
Collect the subject daily diary and assess compliance. 
 
Perform examination of the target knee. 
 
Administer the WOMAC. 
 
Record the PGIC. 
 
Administer the SF-36. 
 
Administer the PASE. 
 
Record the CGIC. 
 
Obtain MRI of the target knee joint (MRI may be scheduled at another day within the 
window of this visit).  
 
Record AEs that have occurred during the study visit.  
 
Distribute new subject daily diary. 
 
Distribute new acetaminophen tablets. 
 
7.2.6. 
Visit 11 (Week 26; Day 183 ± 14) 
The following procedures will be performed at Visit 11: 
 
Confirm no use of rescue acetaminophen in the previous 2 days and before the visit at the 
visit date. 
 
Review and update the use of concomitant medications and therapies, confirming that the 
subject has not used any prohibited medications or therapies and has not changed the dose 
and/or regimen of restricted medications or therapies since the previous visit. 
 
Collect vital signs. 
 
Collect urine and perform a dipstick urine pregnancy test. 
 
Collect urine sample for laboratory tests (qualitative urinalysis regarding glucose, protein 
and urobilinogen). 
 
Collect blood sample for laboratory tests (complete blood count and complete metabolic 
profile). 
 
Record AEs. 
 
Collect the acetaminophen container from the previous visit and count acetaminophen 
usage. 
 
Collect the subject daily diary and assess compliance. 
 
Perform examination of the target knee. 
 
Administer the WOMAC. 
 
Record the PGIC. 
 
Administer the SF-36. 

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 
Administer the PASE. 
 
Record the CGIC. 
 
Obtain MRI of the target knee joint (MRI may be scheduled at another day within the 
window of this visit). 
 
Record AEs that have occurred during the study visit. 
 
Record the end of study form. 
7.2.7. 
Early Termination Visit 
If a subject must withdraw early from the study, all procedures normally included in the last visit of 
the study (i.e., Visit 11) will be performed.  In addition, the reason(s) for withdrawal from the study 
will be collected. 
7.2.8. 
Unscheduled Visits 
There may be situations in which the investigator decides to have a subject return for an unscheduled 
visit after the subject contacts them about an AE or other health information.  Therefore, additional 
examinations may be conducted as necessary to ensure the safety and well-being of subjects during 
the study.  Electronic case report forms (eCRFs) should be completed for each unscheduled visit.  The 
AE and all required information should be recorded on the appropriate eCRF, and the subject’s record 
should include all relevant information. 
 

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Table 2: 
Study Schedule 
 
Screening 
Randomization 
Follow-up 
Baseline 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Week 
-2 to -1 
0 
1 
2 
4 
6 
8 
10 
12 
18 
26/ Early 
Termination 
Day 
 
Day -14 to 
-7 
Day  
1 
Day 
8 
Day 
15 
Day  
29 
Day 
43 
Day  
57 
Day  
71 
Day 
85 
Day 
 127 
Day 
 183 
Window (days) 
 
 
± 2 
± 2 
± 7 
± 6 
± 7 
± 6 
± 7 
± 14 
± 14 
 
 
Before 
Injection 
Injection 
 
 
Before 
Injection 
Injection 
 
Before 
Injection 
Injection 
 
 
 
 
Informed Consent* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm Rescue 
Acetaminophen Washout1 
X 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
Wash Out Prohibited 
Medications/Therapies2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications and 
Therapies3 
X 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
Prior Medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signs4 
X 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
BMI (Height, Weight) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X-ray5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess K-L Score 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess femoral-tibial angle 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Tests6 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
Pregnancy Test7 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
Acetaminophen Consumption 
Assessment 
 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
Subject Daily Diary 
Collection and Compliance 
Assessment 
 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
Adverse Events8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Target Knee Examination 
X 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
Assess Patellar Grinding via 
Clarke’s test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
WOMAC Osteoarthritis 
X 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 

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Screening 
Randomization 
Follow-up 
Baseline 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Week 
-2 to -1 
0 
1 
2 
4 
6 
8 
10 
12 
18 
26/ Early 
Termination 
Day 
 
Day -14 to 
-7 
Day  
1 
Day 
8 
Day 
15 
Day  
29 
Day 
43 
Day  
57 
Day  
71 
Day 
85 
Day 
 127 
Day 
 183 
Index9 
PGIC 
 
 
 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
SF-36 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
PASE 
 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
CGIC 
 
 
 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
50-foot Walk Test9 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
MRI 
X10 
 
 
 
 
 
 
 
 
 
 
X11 
 
X11 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Injection 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
Distribute Subject Daily 
Diary 
X 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
 
Distribute Acetaminophen 
X 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X12 
End of Study Form 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
BMI = body mass index; CGIC = Clinical Global Impression of Change; FTA = femoral-tibial angle; K-L = Kellgren-Lawrence; PASE = Physical Activity Scale for the Elderly; 
PGIC = Patient Global Impression of Change;  SF-36 = 36-Item Short Form Health Survey ; WOMAC =Western Ontario and McMaster Universities Osteoarthritis Index 
* In principle, subjects are injected within 50 days after informed consent.  
1 Subject need to be suspend the use of rescue medication from the 2 days before to the end of the each  clinic visit. 
2 Subjects who agree to discontinue use of the prohibited medications and therapies may return to complete screening after the described washout periods, as described in Section 
9.3.  
3 Subject cannot have used any prohibited medications or therapies and has not changed the dose and/or regimen of restricted medications or therapies since the previous visit. 
4 Vital signs will include systolic and diastolic blood pressure, pulse rate, respiratory rate, and temperature. 
5 X-ray is required if subject has not had an x-ray within 6 months of Visit 1 (Screening). 
6 Laboratory tests at Screening will include complete blood count (CBC), complete metabolic profile, qualitative urinalysis, blood alcohol content, and hepatitis screening.  
Laboratory tests at other visits will include CBC, complete metabolic profile and qualitative urinalysis. Qualitative urinalysis is for glucose, protein and urobilinogen. 
7 Women of childbearing potential only.  A serum test will be performed at Screening, and a dipstick urine test will be performed prior to each injection and at the final study 
visit/early termination. 
8 Adverse events (AEs) will be assessed twice at each in-person study visit:  once at the beginning to capture AEs that have occurred since the last study visit, and once at the end 
to capture any AEs resulting from the study procedures. 
9 WOMAC visual analog scale; pain subscore and pain following a 50-foot walk test are assessed for the target and contralateral knees at the Screening visit and before injection 
on Day 1.  Other visits will include WOMAC assessment of the target knee only.  
10 MRI at the screening visit will be conducted between Day -14 to Day -3.  
11 If repeat MRI is needed after Visit 9 or Visit 11, the permissible lag time for repeat MRI ONLY will be extended by a maximum of an additional 14 days.   
12 Only if MRI is conducted on the separate date after Visit 11, acetaminophen will be provided as rescue medication.

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8. 
INVESTIGATIONAL PRODUCT INFORMATION AND 
MANAGEMENT 
8.1. 
Investigational Product 
Subjects will be randomized to treatment with SI-613 or placebo.  SI-613 combination product contains a 
drug component—a sterile, transparent, viscoelastic HA-DF hydrogel (fermented HA covalently linked to 
DF)—in a prefilled syringe (device component) to be administered by IA injection.  Each prefilled 
syringe contains 3 mL of 1% SI-613, which is a dose of 30 mg SI-613.  Placebo is vehicle, a citric acid- 
and sodium citrate-buffered (pH 4.8 - 5.4) solution, in a pre-filled syringe; each prefilled syringe contains 
3 mL of placebo.  The prefilled syringe is composed of a rubber piston (butyl rubber), rubber tip cap 
(butyl rubber), adapter grip, and plunger rod and is packaged in a molded plastic amorphous polyethylene 
terephthalate film blister with a Tyvek® lid. 
8.2. 
Investigational Product Packaging and Labeling 
All investigational products used in this study will be prepared, packaged, and labeled in accordance with 
the standard operating procedures (SOPs) of SKK or those of its designee, Good Manufacturing Practice 
guidelines, International Conference on Harmonisation (ICH) guidelines for Good Clinical Practice 
(GCP), and applicable regulations. 
Investigational products will be supplied by SKK, Japan.  These products will be labeled according to US 
requirements and the established randomization plan.  Prefilled syringes of 3.0 mL of SI-613 or 3.0 mL of 
placebo will be packed into blinded treatment kits containing 3 cartons, each containing a single syringe, 
1 for each injection in the study for a single subject.  The kits for the 2 treatment groups will be identical 
and will not reveal whether the syringes inside contain SI-613 or placebo.  Investigational product kits 
will be forwarded to participating sites once all regulatory requirements have been met.  
8.3. 
Investigational Product Storage 
Current ICH GCP guidelines require the investigator to ensure that investigational product deliveries from 
the designated vendor are received by a responsible person at the site.  The site will record that the 
investigational products are handled and stored safely and properly, and that the investigational products 
are used only to treat study subjects in accordance with the protocol. 
The investigational products will be stored securely at each site at the appropriate temperature (between 
35.6°F and 46.4°F.  DO NOT FREEZE.  Protect from light.) until used for treatment of a subject.  
Investigational products must be used before the package expiration date.  Any unused investigational 
products beyond the package expiration date must be returned to the designated vendor.  
8.4. 
Investigational Product Administration 
At Visit 2 (Week 0), Visit 5 (Week 4), and Visit 7 (Week 8), randomized study subjects will receive a 
single IA injection of either SI-613 or placebo.  Both the unblinded injecting physician and the blinded 
evaluating physician must be present at these visits.  All subject evaluations must be performed by the 
blinded evaluating physician at all visits.  The same blinded evaluating physician will perform evaluations 
at all the visits for a subject whenever possible. 

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Because the SI-613 and placebo preparations might be visually distinguished in the syringe caused by the 
difference of the viscosity, the injections will be administered by an unblinded injecting physician who is 
experienced in IA injection of the knee.  The unblinded injecting physician will be instructed on how to 
maintain blinding of other study team members and subjects from the treatment.  The unblinded injecting 
physician will administer the injections of SI-613 and placebo in an identical manner, taking appropriate 
measures to mask the treatment identity from the subject. 
The basic procedure for administration is as follows: 
One syringe carton will be removed from the treatment kit, which is stored in the refrigerator, 
approximately 30 to 60 minutes before injection so that it can reach room temperature.  Any syringes that 
will not be used for the current study visit should remain in the refrigerator.  Opening the syringe carton 
and removing the syringe must be conducted by the unblinded injecting physician.  The contents of the 
syringe must be used immediately after the blister packaging is opened.  
Warning:  Do not concomitantly use disinfectants containing quaternary ammonium salts or chlorhexidine 
for skin preparation because sodium HA, a component of SI-613, can precipitate in their presence. 
1.   Strict aseptic administration technique must be followed.  Prior to injection, the injecting 
physician must prepare the injection site with disinfectants. 
2.   Shield the subject from seeing the syringe containing the investigational product. 
3.   Injection of subcutaneous lidocaine or similar local anesthetic may be performed prior to 
injection of the investigational product.  Injection of anesthesia into the knee joint is 
prohibited. 
4.   At the second (Week 4) and third (Week 8) injections, aspiration of synovial fluid from the 
target knee immediately prior to injecting the investigational product is allowed if the 
investigator determines a clinical need.  Aspiration at the time of the first injection (Week 0) 
is prohibited.  When aspiration is conducted immediately prior to the second or third injection, 
the injector will maintain needle placement in the joint while disconnecting the syringe used 
to relieve joint effusion.  Discard the syringe containing the removed joint effusion.  The 
same syringe should not be used for both removing effusion and injecting the investigational 
product. 
5.   Peel off the blister Tyvek lid from the blister package and remove the syringe.  The contents 
of the syringe must be used immediately after the blister packaging is opened. 
6.   Carefully remove the tip cap of the syringe and aseptically attach the syringe to a 20- to 23-
gauge needle.  To ensure a tight seal and prevent leakage during administration, secure the 
needle tightly while firmly holding the luer lock.  If aspiration of synovial fluid was 
conducted immediately prior injecting the investigational product (at the second or third 
injection), keep the original needle used for aspiration in the joint and connect the 
investigational product syringe to the needle already placed in the joint.  A thicker than 20-
gauge needle may be used for both aspiration and administration if a thick needle is required 
for aspiration of the joint fluid.  Twist the tip cap before pulling it off to minimize leakage. 
7.   Inject the investigational product into the knee joint through the needle using aseptic injection 
technique.  Place the injection exactly into the knee joint because leakage of investigational 
product out of the joint cavity may cause pain.  Use of guidance for the injection, such as 
ultrasound guidance, per standard medical practice is allowed. 

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8.   Inject the full 3.0 mL of the investigational product into knee.   
9.   After the injection, a sterile swab or gauze will be applied, followed by a sterile bandage to 
cover the injection site. 
The subject will be instructed to keep the injected site clean following injection and to avoid any 
strenuous activities (such as jogging, tennis, and other active sports or heavy lifting) and prolonged 
weight-bearing activities (such as standing for more than 1 hour) for 48 hours following the IA injection. 
8.5. 
Investigational Product Accountability, Handling, and Disposal 
Following injection, the empty syringe should be returned to the empty carton and the carton should be 
resealed and returned to the subject’s treatment kit to allow reconciliation of the product accountability 
records.  These procedures will be conducted by the unblinded injecting physician to prevent unblinding 
of the treatment assignment at the site.  Between injections, kits for subjects who have injections 
remaining for the study will be stored under the storage conditions between 35.6°F and 46.4°F and 
protected from light.  At the conclusion of the study, all surplus or unused products, empty treatment kits, 
and resealed syringe cartons containing used syringes will be returned to SKK or its designee per the 
Returns Protocol devised by the product packaging and labeling vendor. 
Inventory and accountability records for the investigational products will be kept by the investigator or 
designee.  The following guidelines are therefore pertinent: 
 
The investigator agrees not to supply investigational products for treatment of any person 
except the subjects in this study. 
 
The investigator will keep the investigational products in a locked and secure storage facility.  
Access will be permitted only to those authorized by the investigator to dispense these 
investigational products. 
 
An investigational product inventory will be maintained by the investigator or appropriate 
designee.  The inventory will include details of materials received and a clear record of when 
they were dispensed and to which subjects. 
 
Deliveries will be recorded. 
 
Investigational products will be handled and stored safely and properly. 
 
Investigational products will be dispensed only to study subjects in accordance with the 
protocol. 
 
Any unused investigational product is to be returned per the instructions in the Returns 
Protocol. 
 
 

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9. 
TREATMENT OF SUBJECT 
9.1. 
Description of Investigational Product 
Subjects will be randomized to treatment with the SI-613 product, prefilled with HA-DF, or an identical 
investigational product prefilled with placebo (citric acid- and sodium citrate-buffered [pH 4.8 - 5.4] 
solution).  Please see the full description of the investigational product in Section 8. 
9.2. 
Rescue Medication 
Subjects will be provided with acetaminophen at each clinic visit to use as a rescue medication for 
breakthrough pain in the target knee, and subjects will be instructed to use the acetaminophen only if the 
pain in the target knee is of sufficient severity to require use of the rescue medication. No acetaminophen 
use is permitted from the 2 days before to the end of  each study visit.  Subjects will be asked to bring the 
acetaminophen container(s) with any remaining tablets to the next visit.  
Temporary use of over-the-counter acetaminophen is allowed for the treatment of other AEs, except for 
the periods from the 2 days before to the end of each study visit.  The use of over-the-counter 
acetaminophen should be limited to up to 3 days between each visit for Visits 1 through 4, up to 5 days 
between each visit for Visits 4 through 9, and up to 20 days between each visit for Visit 9 through 11.  
Subjects should report all over-the-counter acetaminophen use to the investigator at each visit.   
Subjects will be advised to limit their total acetaminophen use, from both the study-provided 
acetaminophen and over-the-counter sources, to 3000 mg/day.  Subjects will be required to abstain from 
all use of acetaminophen from the 2 days before to the end of each study visit. 
9.3. 
Concomitant Medications and Therapies 
Starting at the Screening visit, the following information use of all concomitant medications and 
concomitant therapies (concomitant therapies will be recorded only for the therapies conducted for the 
target knee), including any changes since the last visit, will be recorded in the subject’s eCRF, including 
all prescription drugs, over-the-counter medications, nutritional supplements, vitamins, minerals, herbal 
products, physical therapy, chiropractic care, etc.  The use of acetaminophen as a rescue medication will 
be recorded separately.  Information recorded for each concomitant medication or therapy will include the 
indication, dosage/regimen, route of administration, and start and stop dates, if applicable.  Upon entering 
the study, each subject will be instructed to report the use of any medication or other therapy to the 
investigator.  Subjects will also be instructed about the importance of not taking any prohibited 
medication or new medication during the study without first consulting the investigator, unless needed 
immediately for subject safety. 
Prohibited medications and therapies for this study are listed below and with the exclusion criteria in 
Section 6.2. 
9.3.1. 
Prohibited Medications 
The following medications are prohibited for the periods specified prior to Screening and through study 
completion.  Unless noted, the medications are prohibited in oral, injectable, and suppository forms, but 

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they can be used in inhaled, nasal, or ophthalmic formulations.  Topical administration is permitted except 
for the lower extremity of the ipsilateral side of the target knee. 
 
7 days:  NSAIDs (diclofenac is prohibited by any route of administration), medicines for 
neuropathic pain (e.g., pregabalin, gabapentin), topical capsaicins, duloxetine (serotonin-
norepinephrine reuptake inhibitors), local anesthesia to either knee (local anesthesia to target 
knee during SI-613 injection procedure is permitted), and anticonvulsant drugs or herbal 
medicines with analgesic properties 
 
28 days:  opioids (prohibited by any route of administration), corticosteroids (IA 
administration is prohibited within 90 days prior to screening), antidepressant medications, 
antianxiety medications, antipsychotic medications, mood stabilizers, and sleeping drugs 
 
90 days: IA injection(s) into any joint other than IA HA (e.g., corticosteroids, chondroitin 
sulfate, or glucosamine) 
 
6 months: IA HA injection in either knee 
The subject should also suspend the use of combination over-the-counter medications that may contain 
prohibited medications or acetaminophen for the prohibited period of those medications. 
9.3.2. 
Prohibited Therapies 
The following therapies are prohibited from the following specified prior to Screening and through study 
completion. 
 
7 days: Acupuncture in either knee   
 
28 days: Block procedure (ex; nerve block, epidural block, or facet block)  
 
 
1 year: Surgical procedure or invasive procedure (e.g., arthroscopy, joint lavage) in lower 
extremity 
9.3.3. 
Restricted Medications and Therapies 
Subjects who had been taking stable doses and/or regimens of oral chondroprotective agent (chondroitin 
sulfate or glucosamine), or physical therapy (exercise therapy, taping, insoles, knee braces, thermal agent, 
and/or transcutaneous electrical stimulation) for OA of the target knee, for the following specified days 
prior to the start date of screening can continue during the study. 
 
≥15 days: oral chondroprotective agents (chondroitin sulfate or glucosamine) 
 
≥29 days: physical therapy for OA of the target knee 
Removing joint effusion from either knee is prohibited within 7 days before Screening and through study 
completion.  Removing joint effusion from the target knee as part of the second or third injecting 
procedure is allowed if the investigator judges the need using a patellar tap test during the target knee 
examination.  Removal of joint effusion during the first injection procedure is prohibited. 
9.4. 
Physical Exercise During the Study 
Subjects will be instructed not to change their pattern of regular physical exercise (strength or frequency) 
from the time of signing the informed consent through study completion. 

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9.5. 
Compliance 
Compliance issues are not applicable to the product use in this study because the treatment consists only 
of injections performed by study personnel. 
The use of acetaminophen as a rescue medication will be assessed as described in Section 10.7.   
Subjects will be instructed to comply with the restrictions regarding the use of new and prohibited 
concomitant medications and to accurately communicate any use or changes in use to the study site 
personnel. 
9.6. 
Randomization and Blinding Procedures 
A web-based central randomization system will assign subjects to a treatment group.  This system will 
include components for emergency blind break and study drug tracking and will allow users to request 
reports summarizing system data.  If the blind of a subject’s treatment must be broken to determine the 
cause of an illness and proper treatment for the subject, as in the event of a medical emergency, an 
authorized individual will be able to determine the treatment assignment through the randomization 
system.  When possible, SKK or its designee should be notified prior to breaking the blind.  A notification 
of the unblinding, without revealing the treatment assignment of the individual, will then be 
communicated to other study staff members. 
Blinded treatment kits, each containing 3 prefilled syringes packaged in individual cartons, and individual 
syringe cartons will be labeled with unique identification numbers.  At Visit 2, each subject will be 
randomized to a treatment, and a kit of the appropriate treatment will be assigned to the subject from the 
available stock at the site.  Both the unblinded injecting physician and the blinded evaluating physician 
must be present at Randomization / Visit 2 (Day 1/Week 0), Visit 5 (Day 29/Week 4), and Visit 7 (Day 
57/Week 8).  All subject evaluations must be performed by the blinded evaluating physician at all visits.  
The same blinded evaluating physician should perform the evaluation for all visits of a subject whenever 
possible.  The unblinded injecting physician must administer the injection and not communicate the 
treatment allocation to other site staff, the blinded evaluating physician, or subjects.  The unblinded 
injecting physician must be a different individual from the blinded evaluating physician. 
All study site personnel will be blinded to the treatment assignment of all subjects except for the 
unblinded injecting physician, who will perform the injection procedures.  The blind for the treatment 
assignment will be maintained for the entire length of the study. 
 

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10. 
ASSESSMENTS OF EFFICACY 
10.1. 
WOMAC 
Subjects will complete the WOMAC version 3.1 with VAS scores at all clinic visits.  The WOMAC 
consists of 3 subscores. Five questions contribute to the pain subscore, 2 questions contribute to the 
stiffness subscore, and 17 questions contribute to the physical function subscore. 
10.2. 
PGIC 
The subject will complete the PGIC at all follow-up visits.  A sample can be found in Section 19.1. 
10.3. 
CGIC 
The blinded evaluating physician will complete the CGIC at all follow-up visits.  A sample can be found 
in Section 19.2. 
10.4. 
SF-36 
Subjects will complete the SF-36 at the indicated visits (Table 2).  A sample can be found in Section19.3. 
10.5. 
PASE 
Subjects will complete the PASE at the indicated visits (Table 2).  A sample can be found in Section 19.4. 
10.6. 
Daily Pain Diary 
Subjects will be provided a daily diary in which they will be asked to record their pain each day on the 
11-point NRS.  A new diary will be provided to study subjects at each clinic visit except for Visit 11.  The 
diary will be collected at the next visit, and the subject’s compliance with the completion of the diary 
assessed.  Retraining will be provided to the subject if compliance issues are identified.  A sample of the 
daily diary can be found in Section19.5. 
10.7. 
Acetaminophen Consumption 
Acetaminophen will be provided to subjects so that consumption of this rescue medication can be 
accurately assessed.  A new supply of acetaminophen will be provided to study subjects at each clinic 
visit except Visit 11.  The supply container will be collected at the next visit, and the remaining 
acetaminophen will be counted to record the total number of acetaminophen tablets used since the 
previous visit. 

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11. 
SCREENING ASSESSMENTS 
11.1. 
50-foot Walk Test 
The subject will walk 50 feet on a straight, unobstructed, level course at Visits 1 and 2.  The subject will 
be allowed as much time as needed to complete the 50-foot walk without the assistance of walking aids or 
other assistive devices or supports.  Following completion of the walk, the subject will sit and will be 
asked to indicate the levels of pain in the target knee and the contralateral knee on a 100-mm VAS.   
A sample of the VAS pain scale for use following the 50-foot walk test can be found in Section 19.6. 
11.2. 
X-rays 
If a subject has no knee x-rays available from the preceding 6 months, an AP x-ray of the target knee joint 
with the subject in the standing position will be obtained.  The x-rays will be evaluated by the evaluating 
physician at the site for radiographic evidence and the K-L score assessed using the following scale: 
Score 
Radiological findings 
0 
Normal 
1 
Doubtful narrowing of the joint space and possible osteophytic lipping 
2 
Definite osteophytes and possible narrowing of the joint space 
3 
Moderate multiple osteophytes and definite narrowing of the joint 
space  some sclerosis and possible deformity of bone ends 
4 
Large osteophytes, marked narrowing of joint space, severe sclerosis, 
and definite deformity of bone ends 
Subjects with a K-L score of grade 0, 1, or 4 will be excluded from the study.  Subjects with a K-L score 
of grade 3 who exhibit at least one characteristic of a grade 4 on the radiograph (large osteophytes, 
marked narrowing of joint space, severe sclerosis, or definite deformity of bone contour) will be also 
excluded. 
11.3. 
History of Target Knee Osteoarthritis 
The following information from the target knee will be recorded: 
 
Target knee (left or right) 
 
K-L score and the level of each characteristic: osteophytes, joint space narrowing, 
osteosclerosis, and bony deformity 
 
Date of diagnosis 
 
Start date of current knee pain 
 
FTA assessment from the X-rays 
 
Patella Grinding Test (Clarke’s test; negative or positive): The purpose of this test is to detect 
the presence of patellofemoral joint disorder.  The subject is positioned in a supine or long 
sitting position with the target knee extended.  The evaluating physician places the web space 

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of his hand on top of the patella and provides pressure while moving the patella to see if the 
action causes discomfort or sensitivity (pain = positive).  A positive on this test is indicative 
of pain in the patellofemoral joint. 
11.4. 
Vital Signs 
Systolic and diastolic blood pressure, pulse rate, respiratory rate, and temperature will be recorded. 
11.5. 
Body Mass Index 
The height and weight of the subject will be recorded at Screening and used to calculate a BMI.  Any 
subject with a BMI greater than or equal to 40 kg/m2 will be excluded from the study. 
11.6. 
Medical History 
11.6.1. 
General Medical History 
A brief medical history will be recorded, including the following: 
 
All concomitant diseases that the subject is experiencing at the time of informed consent; 
 
Musculoskeletal diseases of the lower extremities that required surgery; 
 
Other musculoskeletal diseases of the lower extremities in the 1 year prior to Screening; and 
 
Other diseases that the investigator considers to be important. 
11.6.2. 
Knee Osteoarthritis Treatment History 
A brief history of the following treatments, if they have been used, will be recorded, including: 
 
Medications (name of medication, dosage and dose regimen, periods of usage, intended use, 
and whether it is the most recent medication) used for the target knee in the 12 weeks prior to 
Screening or at Screening; 
 
Physical therapies (name of therapy, frequency, and periods of conduct) used for the target 
knee in the 12 weeks prior to Screening or at Screening; and 
 
Intra-articular injections (HA, corticosteroid, etc.) into knee(s) (name of medication, date of 
final injection, and injection site [left/right]) 
11.7. 
Prohibited Medications 
Each subject will be asked whether they have taken any of the prohibited medications for this study, listed 
in Section 9.3, in the 7 or 28 days preceding screening, depending on the medication.  If a subject fails 
this criterion but is willing to discontinue use of the prohibited medication(s), he or she can return after 
the protocol-defined washout window to complete the screening process. 
11.8. 
Concomitant Medications 
Each subject will be asked whether they have been on a stable dose of a chondroprotective agent 
(chondroitin sulfate or glucosamine) for at least 15 days prior to screening.  If a subject fails this criterion 

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but is willing to stabilize the dose/regimen, he or she can return after 15 days to recomplete the screening 
process. 
11.9. 
Prohibited Therapies 
Each subject will be asked whether they have used or are currently using any of the prohibited therapies 
for this study, listed in Section 9.3.  If a subject fails these criteria but is willing to discontinue use of the 
prohibited therapy(s), he or she can return after the protocol-defined washout window to complete the 
Screening process 
11.10. 
Concomitant Physical Therapies 
Each subject will be asked whether they have been on a stable regimen of any of the therapies listed in 
Section 6.2  for at least 29 days prior to screening.  If a subject fails this criterion but is willing to stabilize 
the regimen, he or she can return after 29 days to recomplete the screening process. 
11.11. 
Pregnancy Test 
At Screening, blood will be collected from any female subject of childbearing potential to perform a 
serum pregnancy test to confirm that the subject is not pregnant.  At visits when an injection will be given 
and at the last follow-up visit or an early termination visit, urine will be collected and a dipstick 
pregnancy test performed for these subjects to confirm that the subject is not pregnant. 
11.12. 
Laboratory Tests 
Urine will be collected from each subject to perform a drug screen and for qualitative urinalysis regarding 
glucose, protein and urobilinogen. 
Blood will be collected from each subject to perform a complete blood count, complete metabolic profile, 
blood alcohol content, and hepatitis screening.  The results of the laboratory tests will be reviewed before 
randomization at Visit 2 to confirm that the subject meets eligibility criteria.  In particular, a subject will 
be excluded if any of the following results are obtained from the laboratory tests: 
 
AST or ALT >2.5 times the ULN 
 
Creatinine >1.5 times the ULN 
 
Positive hepatitis C antibodies or hepatitis B surface antigen 

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12. 
ASSESSMENTS OF SAFETY 
12.1. 
Target Knee Examination 
At each clinic visit, the target knee will be examined by the blinded evaluating physician for observations 
of swelling, redness, effusion, or warmth.  A result of negative, borderline, or positive will be recorded.  
Changes in the overall condition of the target knee that, in the investigator’s opinion, are associated with 
or considered an untoward or unfavorable medical occurrence should be reported as an AE.  
12.2. 
Synovial Assessment by MRI 
T2 fat-saturated image in the sagittal and axial views by MRI for the target knee will be taken at Visit 1, 
Visit 9, and Visit 11 (or early termination).  The independent central imaging evaluator will conduct the 
synovial assessment of each subject based on the following imaging criteria:  
 
Hoffa’s synovitis score  and the synovitis-effusion score according to the semi-quantitative scoring 
methods of the MOAKS (MRI Osteoarthritis Knee Score)9  
 
Qualitative assessment for the knee joint synovial thickening   
The detailed method for MRI assessments will be defined in the separate independent review manual. 
Significant aggravations in the synovial assessments for Visit 9 and/or Visit 11 compared to Visit 1 
detected by the independent central imaging evaluator will be reported as an AE.  
12.3. 
Vital Signs 
Systolic and diastolic blood pressure, pulse rate, respiratory rate and temperature will be recorded at all 
clinic visits. 
Any abnormal results and changes that, in the investigator’s opinion, are associated with or considered an 
untoward or unfavorable medical occurrence should be reported as an AE. 
12.4. 
Laboratory Tests 
Blood will be collected from each subject at Visit 1 (Screening), Visit 5 (Day 29/Week 4), Visit 7 
(Day 57/Week8), Visit 9 (Day 85/Week 12), and Visit 11 (Day 183/Week 26 or early termination) to 
perform a complete blood count (CBC) and complete metabolic profile.  Urine will be collected from 
each subject at Visit 1 (Screening), Visit 5 (Day 29/Week 4), Visit 7 (Day 57/Week8), Visit 9 (Day 
85/Week 12), and Visit 11 (Day 183/Week 26 or early termination) for qualitative urinalysis regarding 
glucose, protein and urobilinogen. 
Any abnormal results for these tests will be noted, and changes in the test results that, in the investigator’s 
opinion, are associated with or considered an untoward or unfavorable medical occurrence should be 
reported as an AE. 
12.5. 
Adverse and Serious Adverse Events 
Adverse events will be assessed twice at each study visit:  once at the beginning of the visit to record any 
AEs since the last study visit, and once after all assessments and injections have been performed to 

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capture any AEs that occur as the result of these activities.  At the Screening visit, baseline signs and 
symptoms will be collected to serve as a baseline for possible future AEs. 
This section defines the types of AEs and outlines the procedures for appropriately collecting, grading, 
recording, and reporting them.  Information in this section complies with 21 Code of Federal Regulations 
(CFR) 312; ICH Guideline E2A:  Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting; and ICH Guideline E6:  Guideline for Good Clinical Practice. 
Adverse events will be recorded throughout the study and at early termination, and will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). 
The investigator is responsible for the detection and documentation of AEs, regardless of treatment group 
or suspected causal relationship to the investigational product.  For all AEs, the investigator must pursue 
and obtain information adequate to determine the outcome of the AE and to assess whether the AE meets 
the criteria for classification as a serious adverse event (SAE) requiring immediate notification to SKK or 
its designated representative 
12.5.1. 
Definitions of Adverse Events/Effects 
12.5.1.1. Adverse Event 
An AE is defined as any untoward or unfavorable medical occurrence associated with the subject’s 
participation in the research, whether or not considered related to the subject’s participation in the 
research (ICH Guideline E6:  Guideline for Good Clinical Practice).  Any medical condition that is 
present at the time that the subject is screened will be considered as medical history and not recorded as 
an AE; however, if the condition worsens at any time during the study, it will be recorded and reported as 
an AE. 
12.5.1.2. Serious Adverse Event 
An AE is considered “serious” if, in the view of either the investigator or SKK, it results in any of the 
following outcomes (21 CFR 312.32(a)): 
 
Death:  A death that occurs during the study or that comes to the attention of the investigator 
during the protocol-defined follow-up period must be reported to SKK or its designee 
whether it is considered treatment related or not. 
 
A life-threatening event:  An AE or suspected adverse reaction (SAR) is considered 
“life-threatening” if, in the view of either the investigator or SKK, its occurrence places the 
participant at immediate risk of death.  It does not include an AE or SAR that, had it occurred 
in a more severe form, might have caused death. 
 
Inpatient hospitalization or prolongation of existing hospitalization. 
 
Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions. 
 
An important medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based on appropriate medical judgment, it 
may jeopardize the participant and may require medical or surgical intervention to prevent 1 
of the outcomes listed above.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 

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dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
investigational product dependency or abuse. 
 
Congenital anomaly or birth defect. 
If an event meets any of the above definitions, regardless of the severity or relationship of the event to the 
study product, the event must be reported to SKK or its designee as described in Section 12.5.5.1.  Any 
malignancy will be considered “an important medical event.” 
Adverse events reported from clinical studies associated with hospitalization or prolongation of 
hospitalization are considered serious.  Any hospitalization except observational admissions of less than 
24 hours for logistical reasons meets these criteria.  This category also includes transfer within the 
hospital to an acute/intensive care unit (e.g., from a standard-of-care unit to an acute/intensive care unit). 
Hospitalization does not include the following: 
 
Rehabilitation facilities, hospice facilities, or respite care (e.g., caregiver relief) 
 
Nursing homes or skilled nursing facilities 
 
Emergency room visits 
 
Same-day surgeries (as outpatient/same day/ambulatory procedures) 
 
<24-hour admissions for observation or evaluation for logistical reasons 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical AE is not in 
itself an SAE.  Examples include: 
 
Admission for treatment of a preexisting condition that did not worsen 
o Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation for the individual subject 
 
Hospitalizations for cosmetic elective surgery, social, and/or convenience admissions 
 
Pre-planned treatments or surgical procedures should be noted in the baseline documentation 
for the individual subject 
12.5.1.3. Adverse Drug Reaction and Suspected Adverse Reaction 
An adverse drug reaction means any AE caused by a drug.   
Suspected adverse reaction means any AE for which there is a reasonable possibility that the drug caused 
the AE.  For the purposes of safety reporting, “reasonable possibility” means there is evidence to suggest 
a causal relationship between the drug and the AE.  A SAR implies a lesser degree of certainty about 
causality than an adverse drug reaction (21 CFR 312.32(a)). 
12.5.1.4. Unexpected Adverse Reaction 
Seikagaku Corporation is responsible for assessing AEs for expectedness.  With regards to reporting to 
the health authority, an AE is considered “unexpected” when its nature (specificity), severity, or rate of 
occurrence is not consistent with applicable product information as described in the safety information 
provided in the protocol and investigator’s brochure for SI-613.  “Unexpected,” as used in this definition, 
also refers to AEs or SARs that are mentioned in the investigator’s brochure as occurring with a class of 

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drugs or as anticipated from the pharmacological properties of the drug but are not specifically mentioned 
as occurring with the particular drug under investigation (21 CFR 312.32(a)). 
12.5.2. 
Severity of Adverse Events/Serious Adverse Events 
The study site will grade the severity of AEs experienced by study participants on a 3-point severity scale 
(mild, moderate, or severe), as follows: 
 
Mild:  causes no limitation of usual activities; causes slight limitation of usual activities 
without medication intervention or with only a brief medical intervention  
 
Moderate:  causes some limitation of usual activities and requires medical intervention 
 
Severe:  prevents or severely limits usual activities, or requires systemic intervention 
Note:  The terms serious and severe are not synonymous.  Serious criteria as defined in Section 12.5.1.2 
above serve as a guide for defining regulatory reporting obligations.  The term severe is often used to 
describe the intensity (severity) of a specific event (as in mild, moderate, or severe headache); the event 
itself, however, may be of relatively minor medical significance.  This is not the same as serious, which is 
based on patient/adverse outcome.  Therefore, an AE of severe headache might not be considered serious, 
but a moderate infection for which a subject is hospitalized should be reported as an SAE. 
12.5.3. 
Relationship to Investigational Treatment 
An investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE and must be provided for all 
AEs (serious and non-serious). 
Seikagaku Corporation’s determination of attribution will be used for reporting to the appropriate health 
authorities.  The relation of an AE to study participation will be determined using the descriptors and 
definitions provided in Table 3. 
Table 3: 
Attribution of Adverse Events 
Not Related 
The AE is clearly/most probably caused by other etiologies such as participant’s 
underlying condition, therapeutic intervention or concomitant therapy, or the delay 
between administration and the onset of the AE is incompatible with a causal relation, 
or the AE started before administration (screening phase).  Therefore, there is not a 
reasonable possibility that the AE was caused by the investigational product. 
Related 
There is a reasonable possibility that the AE was caused by the investigational product.  
The expression “reasonable possibility” is meant to convey in general that there are 
facts (evidence) or arguments to suggest a causal relationship (21 CFR 312.32(a)).   
The investigator should decide whether, in his or her medical judgment, there is a reasonable possibility 
that the event may have been caused by the investigational product.  Any AE that is suspected to be 
related to the investigational product will be classified as an adverse drug reaction. 

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12.5.4. 
Collecting and Recording Adverse Events 
12.5.4.1. Period of Collection 
All AEs, regardless of severity and/or the time of occurrence during the study, are to be recorded on the 
appropriate AE pages (either “serious” or “non-serious”) in the eCRF.  Recording of AEs will begin 
immediately upon a subject’s signing the informed consent form and continue through the final study visit.  
Recording of any adverse drug reaction will continue until the event resolves or stabilizes.  The 
investigator should complete all the details requested, including dates of onset, severity, action taken, 
outcome, and relationship to investigational product.  Each event should be recorded separately.   
All AEs and SAEs should be treated as medically appropriate.  Adverse events should be followed until 
stabilization or the final study visit; adverse drug reactions should be followed until resolution or 
stabilization; and SAEs (regardless of suspected relationship to the investigational product) should be 
followed until the event resolves, stabilizes, or becomes non-serious. 
12.5.4.2. Methods of Collection 
Adverse events may be collected as follows: 
 
Observing the participant 
 
Questioning the participant in an unbiased and non-leading manner 
 
Receiving an unsolicited complaint from the participant 
An abnormal value or result from a clinical or laboratory evaluation can also indicate an AE if it is 
determined by the investigator to be clinically significant.  If this is the case, it must be recorded in the 
source document and as an AE on the appropriate AE form(s).  The evaluation that produced the value or 
result should be repeated until that value or result returns to normal or is stabilized and the participant’s 
safety is not at risk. 
12.5.4.3. Recording Method 
12.5.4.3.1. Adverse Events 
All AEs occurring during this clinical study will be recorded by the investigator on the appropriate eCRF 
in precise medical terms, along with the date of onset and the date of resolution.  To avoid vague, 
ambiguous, or colloquial expressions, the AE should be recorded in standard medical terminology rather 
than the subject’s own words.  Whenever possible, the investigator should combine signs and symptoms 
into a single term that constitutes a single diagnosis.  Each AE is to be evaluated for duration, severity, 
seriousness, and relatedness to the investigational product.  The severity of the AE and its relationship to 
the investigational product will be assessed by the investigator. 
The investigator will treat participants experiencing AEs appropriately and observe them at suitable 
intervals until their symptoms resolve or their status stabilizes.  If any medication is administered in 
response to the AE, this medication should be noted on the concomitant medication eCRF as a 
concomitant medication administered.  The action taken and the outcome must also be recorded.  The 
terms of AE resolution (i.e., recovered/resolved, not recovered/not resolved, recovered/resolved with 
sequelae, recovering/resolving, fatal, unknown) should also be recorded. 

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12.5.4.3.2. Serious Adverse Events 
Serious adverse events will be recorded on the AE and SAE eCRFs, and health authorities will be notified 
as outlined in Section 12.5.5.2. 
12.5.5. 
Reporting Adverse Events 
12.5.5.1. Reporting Serious Adverse Events to the Sponsor 
The following process for reporting an SAE ensures compliance with 21 CFR 312 and ICH guidelines.  
After learning that a participant has experienced an SAE, the investigator or designee is responsible for 
reporting the SAE, regardless of relationship or expectedness, within 24 hours of becoming aware of the 
event.  The initial SAE report should include as much information as possible, but at a minimum must 
include the following: 
 
Reporter 
 
Subject identification number 
 
Study product or intervention 
 
Serious adverse event term 
 
Relationship to investigational product 
 
Reason why the event is serious 
Supplemental eCRF pages should be current at the time of SAE reporting:  medical history, concomitant 
medications, demographics, investigational product administration, and death, as applicable.  
Unavailable details of the event should not delay submission of the known information.  As additional 
details become available, the SAE eCRF should be updated and re-submitted. 
In the event that the eCRF is unavailable, a paper SAE Report Form should be completed and submitted 
via email or efax within 24 hours of becoming aware of the event. Once the eCRF becomes available, the 
SAE information should be entered as soon as possible. 
SAE Reporting Contact Information: 
email: 
 
efax: 
 
 
12.5.5.2. Reporting Serious Adverse Events to Health Authorities 
Seikagaku Corporation or its designated representative will provide Investigational New Drug safety 
reports to the Food and Drug Administration (FDA) and investigators in accordance with the FDA 
regulations detailed in 21 CFR 312.32. 
12.5.5.3. Reporting Serious Adverse Events to Institutional Review Boards 
It is the responsibility of the investigators to promptly notify their respective institutional review board 
(IRB) of Investigational New Drug safety reports or other matters involving risk to subjects as mandated 
by the IRB. 

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12.6. 
Pregnancy 
During the study, all female subjects should be instructed to contact the investigator immediately if they 
suspect they might be pregnant (e.g., missed or late menstrual period).  If pregnancy is confirmed, the 
subject will be withdrawn from the study and followed until the pregnancy comes to term.   
The investigator is responsible for reporting all available pregnancy information to SKK or its designee 
within 24 hours of becoming aware of the event, although pregnancy itself if not considered an AE.  
Monitoring of the participant should continue until the conclusion of the pregnancy.  Follow-up 
information detailing the outcome of the pregnancy and the health of the newborn should be reported as it 
becomes available.   
Partner pregnancies of a male subject do not need to be reported. 
12.7. 
Potential Device Malfunctions 
SI-613 investigational product is categorized as a combination product that contains HA-DF (drug 
component) in a pre-filled syringe (device component).  If any malfunction of the device components 
occurs, the following procedure is required. 
12.7.1. 
Malfunction 
A malfunction is the failure of a device to meet its performance specifications or otherwise perform as 
intended.  Performance specifications include all claims made in the labeling for the device [21 CFR 
803.3].  If any malfunction of the investigational product occurs, the investigational product must not be 
used.  It must be placed back in the original kit and kept until the site receives instructions from SKK or 
its designee.  The investigator or designee will report the details of the malfunction to SKK. 
12.7.2. 
Injuries Caused by Device Malfunctions 
After learning that a subject, injecting physician, or the other user has experienced any of the following 
events caused by a device malfunction, the investigator or designee is responsible for reporting the 
event(s) to SKK within 24 hours of becoming aware of the event. 
 
Device malfunction associated with a death or serious injury 
A serious injury means an injury or illness that: 
o Is life-threatening 
o Results in permanent impairment of a body function or permanent damage to a body 
structure, or 
o Necessitates medical or surgical intervention to preclude permanent impairment of a 
body function or permanent damage to a body structure 
 
This includes any adverse event resulting from insufficiencies or inadequacies in the labeling 
and the directions specified in the Investigational Product & Rescue Medication Manual, or 
any malfunction of the device component and any malfunction that would be likely to cause 
or contribute to a death or serious injury if the malfunction were to recur.  This includes any 
event that is a result of a user error or intentional misuse of the medical device. 
The investigator or designee will report all the injuries caused by a device malfunction on the appropriate 
AE pages (either “serious” or “non-serious”) in the eCRF. 

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Seikagaku Corporation or its designated representative will provide a summary of any reportable device 
malfunctions associated with a death or serious injury as an Investigational New Drug safety report to the 
FDA and investigators in accordance with the FDA regulations detailed in 21 CFR 312.32.  Any 
malfunctions leading to death or malfunctions resulting in serious injuries that are considered life-
threatening will be submitted to the FDA within 7 calendar days of receipt of the information from the 
investigator or designee.  All other malfunctions leading to a serious injury will be submitted to the FDA 
within 15 calendar days of receipt of the information from the investigator or designee.  Malfunctions not 
leading to a SAE will be included in the annual report. 

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13. 
STATISTICS 
13.1. 
Power and Sample Size Determination 
Approximately 80 subjects with symptomatic primary OA of the knee will be randomized.  Forty subjects 
per group (80 total subjects) were calculated to provide an 80% probability that a 3 mm (or greater) 
treatment difference point effect for the primary endpoint will be observed, but not necessarily at a 
statistically significant level.  This assumes that the true treatment difference is 7.5 mm and standard 
deviation is 23 mm based on the previous Japanese 613/1022 study. 
13.2. 
Randomization 
Immediately prior to injection at Week 0, subjects who meet all eligibility criteria will be randomized to a 
treatment group using a 1:1 ratio of SI-613:placebo.   
Subjects will be randomized using a dynamic procedure by a minimization protocol,10 balancing 
treatment assignment on K-L score, baseline WOMAC VAS pain score, sex, and investigational site. 
13.3. 
Analysis Populations 
The analysis populations are defined as follows: 
 
The safety population is defined as all randomized subjects who received the study injection, 
analyzed according to the treatments subjects received. 
 
The intention-to-treat (ITT) population is defined as all randomized subjects who received the 
study injection, analyzed according to the assigned treatment. 
 
The per-protocol (PP) population is defined as all ITT subjects who had no major protocol 
deviations that would affect the primary efficacy assessment.  The details of major protocol 
deviations will be defined in the statistical analysis plan. 
The efficacy analyses will be performed on the ITT population.  Efficacy analyses of the PP population 
will be supportive of the ITT analysis.  
The safety analyses will be performed on the safety population. 
13.4. 
Efficacy and Safety Analyses 
13.4.1. 
Background and Demographic Characteristics 
Baseline demographic and background variables will be summarized by treatment group and overall.  For 
categorical variables, frequencies and percentages will be presented.  For continuous variables, 
descriptive statistics including sample size, mean, median, standard deviation, minimum, and maximum 
will be presented.  A pretreatment score is the average of the scores at the Screening and Randomization 
visits. 
13.4.2. 
Subjects Accountability 
All enrolled subjects will be included in a summary of subject accountability for this study.  The 
frequencies and percentages of enrolled subjects, subjects who received each study injection, subjects 

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who presented at each visit, subjects who discontinued before study completion (including reason for 
discontinuation), and subjects who completed the study will be presented. 
13.4.3. 
Efficacy Analyses 
13.4.3.1. Primary Efficacy Analysis 
The primary efficacy analysis will be performed on the WOMAC VAS pain subscore using longitudinal 
analysis to incorporate information from pain scores assessed at Weeks 1, 2, 4, 6, 8, 10, and 12.  A direct 
likelihood approach as implemented in the SAS MIXED procedure will be used to estimate model 
parameters designed to reflect group-specific mean values over time.  The primary efficacy hypothesis 
concerns the over a 12-week evaluation period from Week 1 to Week 12, and the group comparison is 
defined as the average effect over assessments during these weeks.  Supporting analyses involve 
comparisons reflecting group differences at the various study visits, including landmark analysis at Week 
12 and early onset of efficacy at Week 1.  In all cases, model parameters will be used to determine 
comparisons for which statistical significance against null zero hypotheses and corresponding 95% 
confidence intervals will be provided.  The basic longitudinal model will be specified as a 
repeated-measures model that expresses the pain score as a linear function of treatment, time, 
treatment-by-time interaction, and clinically relevant covariates (pretreatment pain measurement, K-L 
score, and sex) and a fixed-site effect. 
The model is designed to account for correlations among responses over time and to use these correlations 
to implicitly impute missing values from the non-missing values.  The type=UN option in the SAS 
MIXED procedure will be used to model correlation patterns across time. 
13.4.3.2. Secondary Efficacy Analyses 
A longitudinal analysis model will be used as described in the primary efficacy analysis for the analysis 
of WOMAC VAS physical function subscore, WOMAC VAS stiffness subscore, WOMAC VAS total 
score, PGIC, CGIC, SF-36 scores, weekly average of daily pain scores, and PASE scores. 
Continuous responder analysis with WOMAC VAS pain subscore will be performed, and differences 
between the SI-613 and placebo groups in the percentages of subjects experiencing a >30% or  >50% 
improvement in WOMAC VAS pain subscore will be analyzed with Fisher’s exact test.  For the analysis 
of the percentages of OMERACT-OARSI responders,11,12 differences between the SI-613 and placebo 
groups in the percentages of positive responders over 12 weeks will be analyzed with generalized 
estimating equations (GEE) model.  For each post-treatment study visit, subjects will be defined as 
responders or nonresponders based on the OMERACT-OARSI set of criteria.  These repeated binary 
outcomes (responders/nonresponders) will be modeled with GEE, with the relevant pretreatment covariate 
of pain (average WOMAC VAS pain score from Visits 1 and 2), clinically relevant covariates (K-L score 
and sex), and a fixed-site effect.  A Wald test based on the estimated regression parameter for treatment 
group assignment will be used for hypothesis testing for this secondary efficacy objective.  For the 
analysis of the percentages of positive responders, subjects who discontinue from the study prior to Week 
12 because of either target knee-related AEs or lack of efficacy will be classified as not improved subjects 
or nonresponders in the efficacy analysis. 
For the analysis of the amount of acetaminophen rescue medication consumed for the target knee, the 
percentages of subjects using rescue medication will be presented. The analysis of the overall use of 
acetaminophen rescue medication over 12 weeks will be conducted in the analysis of covariance 

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(ANCOVA) model of the change from baseline of acetaminophen usage.  The baseline acetaminophen 
usage, K-L score and sex will be included as covariates in the ANCOVA model. 
Efficacy analyses will be repeated by using entire period from Week 1 to Week 26. 
13.4.3.3. OMERACT-OARSI Responder  
A subject will be considered an OMERACT-OARSI responder if he or she meets criteria for 
improvement in WOMAC VAS pain subscore, WOMAC VAS physical function subscore and PGIC.  
13.4.4. 
Safety Analyses 
Treatment-emergent AEs (any AEs recorded during or following the study injection) will be summarized 
by treatment group and categorized by severity, time of occurrence, and relationship to the study 
procedures and to the investigational product.  If a subject has more than 1 occurrence of the same AE, 
he/she will be counted only once within that preferred term in the summary tables.  The most severe 
occurrence of an AE, as well as the most extreme relationship of the AE to the study procedures and 
investigational product, will be indicated in cases of multiple occurrences of the same AE.  Serious 
adverse events and target knee AEs also will be summarized separately.  All AEs will be presented in a 
listing.  Additionally, listings of SAEs and AEs leading to discontinuation will be generated.  
Target knee examination and synovial assessments will be summarized by treatment group.  In addition, 
these relationships will be analyzed. 
13.4.5. 
Concomitant Medications and Concomitant Therapies 
Concomitant medications will be categorized using a standardized coding dictionary and listed.  
Concomitant therapies will be listed only. 
13.5. 
Other Statistical Considerations 
13.5.1. 
Significance Levels 
The type I error rate will be set at the 5% significance level for the primary efficacy analysis. 
All secondary and exploratory efficacy analyses will be performed at the 2-sided 5% significance level. 
13.5.2. 
Missing Data 
For the efficacy analysis based on repeated-measures models of continuous endpoints, missing data will 
be implicitly handled via a mixed-effect model, without explicit imputation.  Inferences based on this 
approach are unbiased under the assumption of missing at random, which is a weaker and more generally 
true assumption than missing completely at random. Sensitivity analysis based on multiple imputation 
methods which changes imputation methods by missing pattern such as discontinuations due to AEs, lack 
of efficacy, and other will be performed for the ITT population.  
For the efficacy analysis based on percentages of positive responders, subjects who discontinue the study 
because of target knee AEs or lack of efficacy and subsequently have missing efficacy data will be 
classified as nonresponders.  
No replacement of any missing data will be made for the safety analyses. 

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13.5.3. 
Visit Windows 
All data collected during study follow-up will be displayed and analyzed according to the actual visit data 
in the eCRF.  Assessments taken outside of windows described in the protocol will be displayed 
according to the eCRF assessment recorded by the investigator. 
13.5.4. 
Multiplicity 
Multiplicity will not be considered for the efficacy analyses. 

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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
According to ICH GCP guidelines, the sponsor of the study is responsible for ensuring the proper conduct 
of the study with regard to protocol adherence and validity of data recorded on the eCRFs.  Seikagaku 
Corporation or its designee is responsible for assigning the study monitor(s) to this study.  The study 
monitor’s duties are to aid the investigator and SKK or its designee in the maintenance of complete, 
accurate, legible, well-organized, and easily retrievable data.  The study monitor will advise the 
investigator of the regulatory necessity for study-related monitoring, audits, IRB review, and inspection 
by providing direct access to the source data/documents.  In addition, the study monitor will explain to 
and interpret for the investigator all regulations applicable to the clinical evaluation of an investigational 
product as documented in ICH guidelines. 
It is the study monitor’s responsibility to inspect the eCRFs throughout the study to protect the rights of 
the subjects; to verify adherence to the protocol; to verify completeness, accuracy, and consistency of the 
data; and to confirm adherence of study conduct to any local regulations.  Details will be outlined in the 
study monitoring plan. 
14.2. 
Source Documents 
Seikagaku Corporation or its designee requires that the investigator prepare and maintain adequate and 
accurate records for each subject treated with the investigational product.  Source documents such as any 
hospital, clinic, or office charts and the signed informed consent forms are to be included in the 
investigator’s files with the subject’s study records. 
Data will be captured electronically.  Study site personnel will enter eCRF data from source documents.  
Subjects will record selected study assessments directly into the eCRF.  If any data are first recorded onto 
documents such as laboratory reports, these documents will be considered source. 
14.3. 
Data Collection and Management 
This study will be conducted in compliance with the ICH document “Guidance for Industry:  E6 Good 
Clinical Practice:  Consolidated Guidance,” dated April 1996.  This study will also be conducted in 
accordance with the Declaration of Helsinki as currently accepted by the FDA (1998).  
This study will use electronic data collection (techniques to collect data directly from the investigational 
site using eCRFs).  The data will be stored centrally in a fully validated clinical database.  The 
investigator is responsible for ensuring that all sections of each eCRF are completed promptly and 
correctly and that entries can be verified against any source data.   
Study monitors will perform 100% source document verification to ensure there are no inconsistencies 
between the eCRFs and source documents.  Discrepancies will be resolved in accordance with the 
principles of GCP. 
Data from external sources (such as laboratory data and MRI assessments) will be processed outside the 
clinical database according to the study Data Management Plan. 

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At intervals throughout the study and upon completion, data will be exported from the database into SAS 
datasets. 
Data management will be coordinated by the data managers in accordance with their SOPs for data 
management and a formal study data management plan.  The data managers will provide a quality control 
statement following database lock.  
Adverse events will be coded with MedDRA.  Concomitant medications will be coded using World 
Health Organization – Drug Reference List. 
 

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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Quality assurance includes all the planned and systematic actions that are established to ensure that the 
clinical study is performed and the data are generated, documented (recorded), and reported according to 
ICH GCP and local/regional regulatory standards. 
A quality assurance representative from SKK (or a qualified delegate), who is independent of and 
separated from routine monitoring, may periodically arrange inspections/audits of the clinical study by 
reviewing the data obtained and procedural aspects.  These inspections may include on-site 
inspections/audits and source data checks.  Direct access to source documents is required for the purpose 
of these periodic inspections/audits. 

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16. 
ETHICS 
16.1. 
Ethics Review 
The investigator will not start this study, nor will investigational products be shipped to the investigator’s 
site, before the investigator provides SKK or its designee with evidence of IRB approval.  The 
investigator will promptly report to the IRB all changes in the research activity and all unanticipated 
problems involving risks to subjects.  The investigator will not make any changes in the research without 
IRB approval, except where necessary to eliminate apparent immediate hazards to the subjects.  The 
investigator will provide progress reports to the IRB as required by the IRB.  The investigator will 
provide a final report to the IRB after completion of participation in the study. 
16.2. 
Ethical Conduct of the Study 
The investigator should conduct the study in accordance with this protocol, the Declaration of Helsinki, 
and ICH GCP guidelines.  The investigator and SKK will sign the protocol and study contract to confirm 
agreement.  The investigator will not implement any amendment (deviation or changes of the protocol) 
without agreement by SKK and the IRB approval/information, except when necessary to eliminate 
immediate hazards to study subjects or when changes involve only logistical or administrative aspects of 
the study. 
16.3. 
Written Informed Consent 
16.3.1. 
Subject Information and Informed Consent 
The informed consent document will be approved by the IRB that is appropriate for each study site.  The 
investigator is responsible for ensuring that the subject fully understands the nature and purpose of the 
study.  Information should be given in both oral and written form whenever possible.  No subject should 
be obliged to participate in the study.  Subjects, their relatives, guardians, or (if applicable) legal 
representatives must be given ample opportunity to inquire about details of the study.  The information 
must make clear that refusal to participate in the study or withdrawal from the study at any stage is 
without any prejudice to the subject’s subsequent care.  Subjects must be allowed sufficient time to decide 
whether they wish to participate. 
The subject must be made aware of and give consent to direct access to his/her source medical records by 
study monitors, auditors, the IRB, and regulatory authorities.  The subject should be informed that such 
access will not violate subject confidentiality or any applicable regulations.  The subject should also be 
informed that he/she is authorizing such access by signing the informed consent form. 
Each subject will be given a signed copy of the informed consent form to keep for his/her records. 
16.3.2. 
Provision of New and Important Information Influencing Subject’s Consent and 
Revision of the Written Information 
When any new and important information that may be relevant to the subject’s consent is obtained, the 
investigator and SKK or its designee will consult with each other on how to deal with the information.  
When SKK or its designee and a responsible investigator judge it necessary, the investigator must 
immediately provide the subjects with such information, revise the written information and other 

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explanatory documents based on the new information, and obtain approval from the IRB.  In this instance, 
the investigator should also immediately inform subjects currently participating in the clinical study of 
such information, confirm their intention to continue participation, re-explain the study to them using the 
revised written information and other explanatory documents, and obtain written consent to continue 
participation based on their voluntary decision. 
16.4. 
Subject Confidentiality 
Individual subject medical information obtained as a result of this study is considered confidential, and 
disclosure to third parties is prohibited.  Information will be accessible to authorized parties or personnel 
only.  Medical information may be given to the subject’s physician or to other appropriate medical 
personnel responsible for the subject’s well-being.  Each subject will be asked to complete a form 
allowing the investigator to notify the subject’s primary health care provider of his/her participation in 
this study. 
16.5. 
Publications of the Clinical Study 
The clinical study plan and the results of the study will be published on www.ClinicalTrials.gov in 
accordance with 21 Code of Federal Regulations § 50.25(c).  The results of and data from this study 
belong to SKK.  
16.6. 
Protocol Amendments and Deviations 
No change or amendment to this protocol may be made by the investigator or SKK after the protocol has 
been agreed to and signed by all parties unless such change(s) or amendment(s) has (have) been agreed 
upon by the investigator and SKK.  Any change agreed upon will be recorded in writing, and the written 
amendment will be signed by the investigator and SKK.  Institutional review board approval is required 
prior to the implementation of an amendment, unless overriding safety reasons warrant immediate action, 
in which case the IRB will be promptly notified. 
No deviation from the protocol or investigational plan will be made except to protect the life or physical 
well-being of a subject in an emergency.  Except in such emergencies, prior approval of SKK, and the 
FDA or IRB if applicable, is required before deviations from the planned protocol.  All protocol 
deviations that occur during the study will be documented and reported to SKK or its designee and to the 
IRB, if applicable, according to regulations.  Major protocol deviations are defined as those deviations 
that are likely to have an impact on the subject’s rights, safety, and/or well-being, and/or on the validity of 
the data for primary analysis.  Further details about the documentation, evaluation, and follow-up of 
protocol deviations are detailed in this study’s clinical monitoring plan. 

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17. 
DATA HANDLING AND RECORD KEEPING 
17.1. 
Inspection of Records 
Seikagaku Corporation and its designee(s), the IRB, or regulatory authorities will be allowed to conduct 
site visits to the investigational facilities for the purpose of monitoring or inspecting any aspect of the 
study.  The investigator agrees to allow SKK and its designee(s), the IRB, or regulatory authorities to 
inspect the investigational product storage area, investigational product stocks, investigational product 
records, subject charts and study source documents, and other records relative to study conduct. 
17.2. 
Retention of Records 
The principal investigator must retain all documentation relating to the study for a period of at least 
2 years after the last marketing application approval or, if not approved, 2 years following the 
discontinuance of the test article for investigation.  If this requirement differs from any local regulations, 
the local regulations will take precedence unless the local retention policy is less than 2 years.   

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18. 
REFERENCES 
1. 
Buckwalter JA, Saltzman C, Brown T. The impact of osteoarthritis: implications for research.  
Clin Orthop Relat Res. 2004;427(Suppl):S6-15.  
2. 
Arthritis By The Numbers published from Arthritis Foundation. 2017 v1.2.: Section 2:9-16. 
3. 
Schaffer D, Florin T, Eagle C, Marschner I, Singh G, Grobler M, et al. Risk of serious 
NSAID-related gastrointestinal events during long-term exposure: a systematic review. Med J. 
2006;185:501-506. 
4. 
Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, et al. Cardiovascular 
events associated with rofecoxib in a colorectal adenoma chemoprevention trial. New Engl J Med. 
2005;352:1092-1102, doi:10.1056/NEJMoa050493. 
5. 
Trelle S, Reichenbach S, Wandel S, Hildebrand P, Tschannen B, Villiger PM, et al. 
Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 
2011;342: c7086, doi:10.1136/bmj.c7086. 
6. 
Tehranzadeh J, Booya F, Root J. Cartilage metabolism in osteoarthritis and the influence of 
viscosupplementation and steroid: a review. Acta Radiol. 2005;46: 288-296. 
7. 
Ghosh P, Guidolin D. Potential mechanism of action of intra-articular hyaluronan therapy in 
osteoarthritis: are the effects molecular weight dependent? Semin Arthritis Rheum. 2002;32:10-
37. 
8. 
Day R, Brooks P, Conaghan PG, Petersen M, Multicenter Trial Group. A double blind, 
randomized, multicenter, parallel group study of the effectiveness and tolerance of intraarticular 
hyaluronan in osteoarthritis of the knee. J Rheumatol. 2004;31:775-782. 
9. 
Hunter DJ, Guermazi A, Lo GH, Grainger AJ, Conaghan PG, Boudreau RM, Roemer FW. 
Evolution of semi-quantitative whole joint assessment of knee OA: MOAKS (MRI Osteoarthritis 
Knee Score). Osteoarthritis Cartilage. 2011;19(8):990-1002. 
10. 
Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the 
controlled clinical trial. Biometrics. 1975;31:103-115. 
11. 
Pham T, Van Der Heijde D, Lassere M, Altman RD, Anderson JJ, Bellamy N, et al.; 
OMERACT-OARSI.  Outcome variables for osteoarthritis clinical trials:  The 
OMERACT-OARSI set of responder criteria.  J Rheumatol.  2003;30(7):1648-54. 
12. 
Pham T, van der Heijde D, Altman RD, Anderson JJ, Bellamy N, Hochberg M, et al.  
OMERACT-OARSI initiative:  Osteoarthritis Research Society International set of responder 
criteria for osteoarthritis clinical trials revisited.  Osteoarthritis Cartilage.  2004;12(5):389-99. 

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19. 
APPENDICES 
19.1. 
Patient Global Impression of Change (PGIC) 
 
 

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Patient Global Impression of Change (PGIC)  
 
 
 
 
 
 
 
 
 
 
 
Since the start of the study, my overall status is:  
 
1  ☐ Very Much Improved 
2  ☐ Much Improved 
3  ☐ Minimally Improved 
4  ☐ No Change 
5  ☐ Minimally Worse 
6  ☐ Much Worse 
7  ☐ Very Much Worse 

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19.2. 
Clinical Global Impression of Change (CGIC) 
 
 

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Clinical Global Impression of Change (CGIC)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Since the start of the study, subject’s overall status is:  
 
1  ☐ Very Much Improved 
2  ☐ Much Improved 
3  ☐ Minimally Improved 
4  ☐ No Change 
5  ☐ Minimally Worse 
6  ☐ Much Worse 
7  ☐ Very Much Worse 

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19.3. 
36-Item Short Form Health Survey (SF-36)  

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19.4. 
Physical Activity Scale for the Elderly (PASE) 
 
 

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19.5. 
Daily Pain Diary 

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Daily Diary 
 
Please record your responses to the following items each day before you 
go to bed.   
Date (DD/MM/YYYY)       /     /_ _ _ _                             
 
Target Knee Pain 
Please record how bad you feel your osteoarthritis pain in the target knee 
was at its worst and on average in the last 24 hours. 
 
Please rate your pain by circling the one number that best describes your 
pain at its worst in the last 24 hours.  
 
0         1         2         3         4         5         6         7         8         9         10 
No Pain                                                                                                   Pain as bad as  
you can imagine 
 
 
Please rate your pain by circling the one number that best describes your 
pain on average in the last 24 hours. 
                        
0         1         2         3         4         5         6         7         8         9         10 
No Pain                                                                                                  Pain as bad as  
you can imagine 
 

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19.6. 
VAS Pain Scales for 50-foot Walk Test 
 
 
 
 
 

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       No pain 
 
 
 
 
 
                                     Extreme pain 
 
 
 
 
 
Evaluation after 50-foot Walk Test 
Pain in Target Knee 
 
You have just completed a 50-foot walk. On the scale below, 
please record the severity of your pain in the target knee by 
placing a mark along the line indicating the point that best 
describes the pain in your knee. 

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            No pain  
 
 
 
 
                                        Extreme pain 
 
Evaluation after 50-foot Walk Test 
Pain in Contralateral Knee 
 
You have just completed a 50-foot walk. On the scale below, 
please record the severity of you pain in the contralateral knee by 
placing a mark along the line indicating the point that best 
describes the pain in your knee.