A 56-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of a Single Injection of SM04690 Injected in the Target Knee Joint of Moderately to Severely Symptomatic Osteoarthritis Subjects
Phase: PHASE3
Conditions: Knee Osteoarthritis
Sponsor: Biosplice Therapeutics, Inc.

Confidential 
 
i 
 
 
 
 
 
A Phase 3, 56-Week, Multicenter, Randomized, 
Double-Blind, Placebo-Controlled Study Utilizing 
Patient-Reported and Radiographic Outcomes to Evaluate 
the Efficacy and Safety of a Single Injection of SM04690 
Injected in the Target Knee Joint of Moderately to Severely 
Symptomatic Osteoarthritis Subjects 
 
Study Number: SM04690-OA-11 
IND Sponsor: Samumed, LLC 
Version Number:  Amendment 03 Version 00 
Date: 05 November 2019 
 
 
 
 
 
 
 
This document is the sole property of Samumed, LLC. This document and any and all 
information contained herein must be considered and treated as strictly confidential. This 
document shall be used only for the purpose of the disclosure herein provided. No disclosure or 
publication shall be made without the prior written consent of Samumed, LLC. 
 
 
Original Protocol Date: 28 November 2018 
Amendment 01 Version 00: 14 March 2019 
Amendment 02 Version 00: 16 August 2019 
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SPONSOR SIGNATURE PAGE 
A Phase 3, 56-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study 
Utilizing Patient-Reported and Radiographic Outcomes to Evaluate the Efficacy and Safety of a 
Single Injection of SM04690 Injected in the Target Knee Joint of Moderately to Severely 
Symptomatic Osteoarthritis Subjects 
 
Protocol Number: 
SM04690-OA-11 AM03V00 
Date:  
 
05 November 2019 
 
Name & Title 
Signature 
 
Date 
Ismail Simsek, MD 
Medical Director 
Document has been electronically signed. Please see the 
final page of the viewable rendition for electronic 
signature(s). 
Mark Fineman, PhD 
Senior Vice President, Clinical 
Development 
Document has been electronically signed. Please see the 
final page of the viewable rendition for electronic 
signature(s). 
Christopher Swearingen, PhD 
Vice President, Clinical 
Outcomes and Analytics 
Document has been electronically signed. Please see the 
final page of the viewable rendition for electronic 
signature(s). 
Samumed commits to satisfying the requirements of the International Council for Harmonisation 
Guideline for Good Clinical Practice (ICH-GCP) E6 (R2) regarding the responsibilities of the Sponsor, 
the United States (US) Code of Federal Regulations (CFR) Title 21 Parts 50, 54, 56, 312, and 314, and 
GCP Guidelines, as applicable. 
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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ................................................................................................ II 
TABLE OF CONTENTS ............................................................................................................. 1 
LIST OF ABBREVIATIONS ...................................................................................................... 5 
STATEMENT OF COMPLIANCE ............................................................................................ 8 
1. 
PROTOCOL SUMMARY ................................................................................................... 9 
1.1 
SYNOPSIS ......................................................................................................................... 9 
2. 
INTRODUCTION ............................................................................................................... 17 
2.1 
STUDY RATIONALE ........................................................................................................ 17 
2.2 
BACKGROUND INFORMATION ........................................................................................ 17 
2.3 
RISK/BENEFIT ASSESSMENT .......................................................................................... 18 
2.3.1 
Known Potential Risks .............................................................................................. 18 
2.3.2 
Known Potential Benefits ......................................................................................... 19 
2.3.3 
Assessment of Potential Risks and Benefits ............................................................. 19 
3. 
OBJECTIVES AND ENDPOINTS ................................................................................... 19 
3.1 
OBJECTIVE ..................................................................................................................... 19 
3.2 
STUDY ENDPOINTS ......................................................................................................... 19 
3.2.1 
Primary Endpoint ...................................................................................................... 19 
3.2.2 
Secondary Endpoints ................................................................................................ 19 
3.2.3 
Safety Endpoints ....................................................................................................... 20 
3.2.4 
Other Endpoints ........................................................................................................ 20 
4. 
STUDY DESIGN ................................................................................................................. 20 
4.1 
DESCRIPTION OF THE STUDY DESIGN ............................................................................. 20 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN .................................................................. 21 
4.3 
JUSTIFICATION FOR DOSE............................................................................................... 21 
4.4 
END OF STUDY DEFINITION............................................................................................ 21 
5. 
STUDY POPULATION ..................................................................................................... 21 
5.1 
PARTICIPANT INCLUSION CRITERIA ............................................................................... 22 
5.2 
PARTICIPANT EXCLUSION CRITERIA .............................................................................. 23 
5.3 
LIFESTYLE GUIDELINES ................................................................................................. 25 
5.3.1 
Contraception ............................................................................................................ 25 
5.4 
SCREEN FAILURES.......................................................................................................... 26 
5.4.1 
Screen Failures .......................................................................................................... 26 
5.4.2 
Subject Rescreening .................................................................................................. 26 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION ......................................................... 26 
5.6 
PARTICIPANT WITHDRAWAL OR TERMINATION ............................................................. 26 
5.6.1 
Reasons for Withdrawal or Termination................................................................... 26 
5.6.2 
Handling of Participant Withdrawals or Termination .............................................. 27 
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5.7 
PREMATURE TERMINATION OR SUSPENSION OF STUDY ................................................. 27 
6. 
STUDY AGENT .................................................................................................................. 27 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION ............................................................. 27 
6.1.1 
Acquisition ................................................................................................................ 27 
6.1.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 28 
6.1.3 
Product Storage and Stability.................................................................................... 28 
6.1.4 
Preparation ................................................................................................................ 28 
6.1.5 
Dosing and Administration ....................................................................................... 28 
6.1.6 
Route of Administration ........................................................................................... 29 
6.1.7 
Starting Dose and Dose Escalation Schedule ........................................................... 29 
6.1.8 
Dose Adjustments/Modifications/Delays ................................................................. 29 
6.1.9 
Duration of Therapy .................................................................................................. 29 
6.1.10 Study Intervention Compliance ................................................................................ 29 
6.1.11 Device Specific Considerations ................................................................................ 29 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES ............................................................ 29 
7. 
STUDY PROCEDURES AND SCHEDULE .................................................................... 30 
7.1 
STUDY PROCEDURES/EVALUATIONS .............................................................................. 30 
7.1.1 
Study Specific Procedures ........................................................................................ 30 
7.1.2 
Standard of Care Study Procedures .......................................................................... 35 
7.2 
LABORATORY PROCEDURES/EVALUATIONS ................................................................... 35 
7.2.1 
Clinical Laboratory Evaluations ............................................................................... 35 
7.2.2 
Other Assays or Procedures ...................................................................................... 36 
7.2.3 
Specimen Preparation, Handling, and Storage ......................................................... 36 
7.2.4 
Specimen Shipment .................................................................................................. 36 
7.3 
STUDY SCHEDULE .......................................................................................................... 36 
7.3.1 
Prescreening .............................................................................................................. 36 
7.3.2 
Screening................................................................................................................... 37 
7.3.3 
Randomization .......................................................................................................... 38 
7.3.4 
Follow-Up ................................................................................................................. 39 
7.3.5 
Final Study Visit ....................................................................................................... 40 
7.3.6 
Early Termination (ET) Visit .................................................................................... 40 
7.3.7 
Schedule of Events Table .......................................................................................... 42 
7.3.8 
Schedule of Electronic Diary and Questionnaire Completion Table ........................ 44 
7.4 
JUSTIFICATION FOR SENSITIVE PROCEDURES ................................................................. 45 
7.5 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES ................................. 45 
7.5.1 
Precautionary Medications, Treatments, and Procedures ......................................... 45 
7.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES ...................................... 45 
7.7 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES ................................. 46 
7.8 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES ............................................. 46 
7.9 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE ....................................... 46 
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8. 
ASSESSMENT OF SAFETY ............................................................................................. 46 
8.1 
SPECIFICATION OF SAFETY PARAMETERS ...................................................................... 46 
8.1.1 
Definition of Adverse Events (AE)........................................................................... 46 
8.1.2 
Definition of Serious Adverse Events (SAE) ........................................................... 47 
8.1.3 
Definition of Unanticipated Problems (UP) ............................................................. 47 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT ...................................................................... 48 
8.2.1 
Severity of Event....................................................................................................... 48 
8.2.2 
Relationship to Study Agent ..................................................................................... 49 
8.2.3 
Expectedness ............................................................................................................. 49 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP ................. 49 
8.4 
REPORTING PROCEDURES .............................................................................................. 50 
8.4.1 
Adverse Event Reporting .......................................................................................... 50 
8.4.2 
Serious Adverse Event Reporting ............................................................................. 50 
8.4.3 
Unanticipated Problem Reporting............................................................................. 51 
8.4.4 
Events of Special Interest.......................................................................................... 51 
8.4.5 
Reporting of Pregnancy ............................................................................................ 51 
8.5 
STUDY HALTING RULES ................................................................................................. 51 
8.6 
SAFETY OVERSIGHT ....................................................................................................... 52 
9. 
CLINICAL MONITORING .............................................................................................. 52 
10. STATISTICAL CONSIDERATIONS .............................................................................. 52 
10.1 
STATISTICAL AND ANALYTICAL PLANS ......................................................................... 52 
10.2 
STATISTICAL HYPOTHESES ............................................................................................ 52 
10.3 
ANALYSIS DATASETS ..................................................................................................... 53 
10.4 
DESCRIPTION OF STATISTICAL METHODS ...................................................................... 53 
10.4.1 General Approach ..................................................................................................... 53 
10.4.2 Analysis of the Primary Endpoint ............................................................................. 53 
10.4.3 Analysis of the Secondary Endpoints(s) ................................................................... 54 
10.4.4 Safety Analyses ......................................................................................................... 54 
10.4.5 Other Endpoints ........................................................................................................ 54 
10.4.6 Baseline Descriptive Statistics .................................................................................. 54 
10.4.7 Planned Interim Analyses ......................................................................................... 55 
10.4.8 Exploratory Analyses ................................................................................................ 55 
10.4.9 SubGroup Analyses .................................................................................................. 55 
10.5 
SAMPLE SIZE .................................................................................................................. 55 
10.6 
MEASURES TO MINIMIZE BIAS ....................................................................................... 56 
10.6.1 Blinding Procedures .................................................................................................. 56 
10.6.2 Evaluation of Success of Blinding ............................................................................ 56 
10.6.3 Breaking the Study Blind/Participant Code .............................................................. 56 
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11. SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ......... 57 
12. QUALITY ASSURANCE AND QUALITY CONTROL ................................................ 57 
13. ETHICS/PROTECTION OF HUMAN SUBJECTS ....................................................... 58 
13.1 
ETHICAL STANDARD ...................................................................................................... 58 
13.2 
INSTITUTIONAL REVIEW BOARD .................................................................................... 58 
13.3 
INFORMED CONSENT PROCESS ....................................................................................... 58 
13.3.1 Consent/Assent and Other Informational Documents Provided to Participants ....... 58 
13.3.2 Consent Procedures and Documentation .................................................................. 58 
13.4 
PARTICIPANT AND DATA CONFIDENTIALITY .................................................................. 58 
13.4.1 Research Use of Stored Human Samples, Specimens, or Data ................................ 59 
13.5 
FUTURE USE OF STORED SPECIMENS ............................................................................. 59 
14. DATA HANDLING AND RECORD KEEPING ............................................................. 59 
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES ........................................... 59 
14.2 
STUDY RECORDS RETENTION ........................................................................................ 60 
14.3 
PROTOCOL DEVIATIONS ................................................................................................. 60 
14.4 
PUBLICATION AND DATA SHARING POLICY ................................................................... 60 
15. STUDY ADMINISTRATION ............................................................................................ 61 
15.1 
STUDY LEADERSHIP ....................................................................................................... 61 
15.2 
KEY ROLES .................................................................................................................... 61 
16. LITERATURE REFERENCES ........................................................................................ 62 
APPENDIX 1. 
AMERICAN COLLEGE OF RHEUMATOLOGY CLINICAL AND 
RADIOGRAPHIC CRITERIA FOR CLASSIFICATION OF OSTEOARTHRITIS OF 
THE KNEE 
....................................................................................................................... 63 
APPENDIX 2. 
PROHIBITED CONCOMITANT MEDICATIONS AND 
PROCEDURES (SUPPLEMENT) ............................................................................................ 64 
APPENDIX 3. 
AMENDMENTS ......................................................................................... 65 
 
 
 
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LIST OF ABBREVIATIONS 
 
Abbreviation 
Term 
ACR 
American College of Rheumatology 
AE  
Adverse event 
AESEV 
Severity/Intensity Scale for Adverse Events 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
β-CTX 
β-C-terminal telopeptide 
BMI 
Body mass index 
°C 
(degrees) Celsius 
CDISC 
Clinical Data Interchange Standards Consortium 
CFR 
Code of Federal Regulations 
CRF 
Case report form 
COMP 
Cartilage oligomeric matrix protein 
dL 
Deciliter  
EC 
Ethics Committee 
eCOA 
Electronic clinical outcomes assessment 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EOS 
End of study 
ET 
Early termination 
°F 
(degrees) Fahrenheit 
FAS 
Full analysis set 
FDA 
(US) Food and Drug Administration 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
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Abbreviation 
Term 
HIPAA 
Health Insurance Portability and Accountability Act 
HRQOL 
Health related quality of life 
HIV 
Human immunodeficiency virus 
IA 
Intra-articular 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation  
IP 
Investigational product 
IQRMP 
Integrated Quality and Risk Management Plan 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
KL 
Kellgren-Lawrence 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mJSW 
Medial joint space width  
mL 
Milliliter 
mm 
Millimeter 
MMRM 
Mixed-effects model for repeated measures 
mSv 
Millisievert 
NCS 
Not clinically significant 
NRS 
Numeric rating scale 
NSAID 
Nonsteroidal anti-inflammatory drug 
OA 
Osteoarthritis 
PA 
Posterior-anterior 
PCP 
Phencyclidine 
PINP 
N-terminal propeptides of procollagen type I 
PPAS 
Per-protocol analysis set 
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Abbreviation 
Term 
PRP 
Platelet-rich plasma 
RBC 
Red blood cell 
RTSM 
Randomization and Trial Supply Management 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Safety Analysis Set 
SD 
Standard deviation 
SF-36 
36-Item Short Form Health Survey 
SOP 
Standard operating procedure 
SS 
Symptom Severity 
SSQ2 
Symptom Severity Question 2 
UP 
Unanticipated problem 
US 
United States 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
WOMAC 
Western Ontario and McMaster Universities Arthritis Index 
WPI 
Widespread Pain Index 
WPI&SS 
Widespread Pain Index and Symptom Severity Form 
 
 
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STATEMENT OF COMPLIANCE 
Study Title 
A Phase 3, 56-Week, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study Utilizing Patient-Reported and Radiographic 
Outcomes to Evaluate the Efficacy and Safety of a Single Injection of 
SM04690 Injected in the Target Knee Joint of Moderately to Severely 
Symptomatic Osteoarthritis Subjects 
Protocol Number 
SM04690-OA-11 
Protocol Date 
05 November 2019 
Protocol Version 
AM03V00 
I have read and understand the protocol and agree to implement the study in accordance with the 
procedures set forth in the protocol and in accordance with the Sponsor's guidelines, all 
applicable government regulations, and the International Council for Harmonisation Guideline 
for Good Clinical Practice (ICH-GCP) E6 (R2). 
I will obtain Institutional Review Board/Ethics Committee (IRB/EC) approval of the protocol 
and Informed Consent Form (ICF) prior to enrollment of subjects in the study. I understand that 
any modifications to the protocol made during the course of the study must first be approved by 
the IRB/EC prior to implementation except when such modification is made to remove an 
immediate hazard to the subject. 
I will ensure that a fully executed IRB/EC-approved ICF is obtained from each subject prior to 
initiation of any study procedures.  
I will allow the Sponsor, Samumed, LLC and its agents, as well as the United States (US) Food 
and Drug Administration (FDA) and other regulatory agencies, to inspect study facilities and 
pertinent records at reasonable times and in a reasonable manner, ensuring subject 
confidentiality. If I am notified that this study is to be inspected by a regulatory agency, I will 
notify the Sponsor as soon as possible thereafter (no later than 48 hours). 
This protocol contains information that is proprietary to Samumed, LLC. The information 
contained herein is provided for the purpose of conducting a clinical trial for Samumed, LLC. 
The contents of this protocol may only be disclosed to study personnel under my supervision and 
to my IRB/EC. The contents of this protocol may not be disclosed to any other parties (unless 
such disclosure is required by government regulations or laws) without the prior written approval 
of Samumed, LLC. 
 
__________________________________________ 
_______________________ 
Investigator’s Signature 
 
 
 
 
Date 
 
__________________________________________ 
 
Investigator’s Printed Name 
 
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Protocol SM04690-OA-11  
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1. 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
Title: 
A Phase 3, 56-Week, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study Utilizing Patient-Reported and Radiographic 
Outcomes to Evaluate the Efficacy and Safety of a Single Injection of 
SM04690 Injected in the Target Knee Joint of Moderately to Severely 
Symptomatic Osteoarthritis Subjects 
Objective: 
 
The objective of this study is to determine the efficacy, safety, and 
tolerability of the SM04690 Injectable Suspension 0.07 milligram (mg) 
dose in the treatment of knee osteoarthritis (OA). 
Endpoints: 
Primary: 
Change from baseline OA pain in the target knee as assessed by the 
weekly average of daily pain numeric rating scale (NRS) at Week 12 
 
Secondary: 
1. Change from baseline OA pain in the target knee as assessed by 
the weekly averages of daily pain NRS at Weeks 24 and 52 
2. Change from baseline OA function in the target knee as assessed 
by Western Ontario and McMaster Universities Osteoarthritis 
Index (WOMAC) physical function subscore (WOMAC Function) 
at Weeks 12, 24, and 52 
3. Change from baseline OA disease activity as assessed by Patient 
Global Assessment at Weeks 12, 24, and 52 
4. Change from baseline in usage of nonsteroidal anti-inflammatory 
drugs (NSAIDs) and acetaminophen for target knee OA pain 
Safety: 
Safety of SM04690 Injectable Suspension as measured by: 
1. Adverse events (AEs), serious adverse events (SAEs), vital signs, 
and clinical laboratory measures for the duration of the study  
2. Change in serum bone biomarkers (N-terminal propeptides of 
procollagen type I [PINP] and β-C-terminal telopeptide [β-CTX]) 
from baseline, and change in a serum cartilage biomarker (cartilage 
oligomeric matrix protein [COMP]) from baseline at Week 56 
Other Endpoints: 
1. Change from baseline in medial joint space width (mJSW) as 
documented by radiograph of the target knee at Week 52 
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2. Change from baseline health-related quality of life (HRQOL) as 
assessed by the 36-Item Short Form Health Survey (SF-36) at 
Week 52 
3. Change from baseline OA pain in the target knee as assessed by 
WOMAC pain subscore (WOMAC Pain) at Weeks 12, 24, and 52 
4. Change from baseline OA pain, function, and stiffness as a 
composite outcome measure as assessed by WOMAC total score 
(WOMAC Total) at Weeks 12, 24, and 52 
Methodology: 
This study will be a multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study of a single dose of SM04690 
injected into the target knee joint of moderately to severely symptomatic 
OA subjects at Day 1.  
Approximately 725 subjects will be randomized at a ratio of 1:1 (0.07 mg 
SM04690 per 2 mL injection: 2 mL placebo). Subjects will participate in a 
7- to 11-day screening period followed by a single injection and a 56-week 
evaluation period. Clinic visits will be scheduled at the Screening Visit, 
Day 1, and Weeks 4, 12, 24, 36, 52, and 56 [End of study (EOS)] or at 
Early Termination (ET). Phone visits will be scheduled at Weeks 8, 16, 
20, 28, 32, 40, 44, and 48. Refer to Figure 1 for an overview of study 
design and endpoints.  
Radiographic images of the knees will be performed prior to study entry, 
at Week 24, and at Week 52 or ET. A Widespread Pain Index and 
Symptom Severity (WPI&SS) assessment will be administered at the 
Screening Visit and Day 1. An SF-36 assessment will be administered at 
Day 1 and Week 52. Bone and cartilage biomarkers will be assessed at the 
Screening Visit and at Week 56 or ET. Investigator assessment of 
NSAID/acetaminophen usage will be performed at all in-person and phone 
visits starting at Day 1. 
Subjects will be required to complete an electronic diary for the following: 
• Daily pain NRS (for target knee OA pain) through Week 56 
(EOS) 
• Patient Global Assessment at baseline and Weeks 4, 12, 24, 36, 
52, and 56 (EOS) 
• WOMAC at baseline and Weeks 4, 12, 24, 36, 52, and 56 (EOS) 
 
 
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Figure 1. Overview of study design and endpoints 
 
 
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Inclusion/ 
Exclusion 
Criteria: 
Criteria for Inclusion: 
1. Males and females between 40 and 80 years of age, inclusive, in 
general good health apart from their knee OA 
2. Ambulatory (single assistive devices such as canes allowed if 
needed less than 50% of the time, subjects requiring a walker are 
excluded) 
3. Diagnosis of femorotibial OA in the target knee by standard 
American College of Rheumatology (ACR) criteria at the 
Screening Visit (clinical AND radiographic criteria) (Appendix 1); 
OA of the knee is not to be secondary to any rheumatologic 
conditions (e.g., rheumatoid arthritis) 
4. mJSW by radiograph between 1.5 and 4 mm, inclusive, in the 
target knee within 12 weeks of the Screening Visit as assessed by 
independent central readers 
5. Radiographic disease Stage 2 or 3 in the target knee within 
12 weeks of the Screening Visit according to the 
Kellgren-Lawrence (KL) grading of knee OA as assessed by 
independent central readers 
6. Pain compatible with OA of the knee(s) for at least 26 weeks prior 
to the Screening Visit 
7. Primary source of pain throughout the body is due to OA in the 
target knee 
8. Body mass index (BMI) ≤40 kg/m2 at the Screening Visit 
9. Widespread Pain Index (WPI) score of ≤4 and a Symptom Severity 
Question 2 (SSQ2) score of ≤2 at the Screening Visit and Day 1 
10. Pain NRS scores recorded for the target knee on at least 4 out of 
the 7 days immediately preceding Day 1  
11. Pain NRS scores recorded for the nontarget knee on at least 4 out 
of the 7 days immediately preceding Day 1 
12. Daily OA knee pain diary average NRS intensity score ≥4 and ≤8 
in the target knee on the 11-point (0–10) NRS scale for the 7 days 
immediately preceding Day 1 
13. Daily OA knee pain diary average NRS intensity score <4 in the 
nontarget knee on the 11-point (0–10) NRS scale for the 7 days 
immediately preceding Day 1 
14. WOMAC Pain of 20–40 (out of 50) for the target knee at baseline 
regardless of if the subject is on symptomatic oral treatment 
(baseline questionnaire completed during the screening period 
prior to randomization) 
15. WOMAC Function of 68–136 (out of 170) for the target knee at 
baseline regardless of if the subject is on symptomatic oral 
treatment (baseline questionnaire completed during the screening 
period prior to randomization) 
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16. Willingness to use an electronic diary daily in the evening for the 
screening period and 56-week study duration 
17. Negative drug test for amphetamine, buprenorphine, cocaine, 
methadone, opiates, phencyclidine (PCP), propoxyphene, 
barbiturates, benzodiazepine, methaqualone, and tricyclic 
antidepressants, unless any of these drugs are allowed per protocol 
and prescribed by a physician to treat a specific condition  
18. Subjects with depression or anxiety must be clinically stable for at 
least 12 weeks prior to the Screening Visit and, if on treatment for 
depression or anxiety, be on at least 12 weeks of stable therapy 
19. Full understanding of the requirements of the study and 
willingness to comply with all study visits and assessments 
20. Subjects must have read and understood the informed consent form 
(ICF), and must have signed and dated it prior to any study-related 
procedure being performed 
Criteria for Exclusion: 
1. Pregnant women, breastfeeding women, and women who are not 
post-menopausal (defined as 12 months with no menses without an 
alternative medical cause) or permanently surgically sterile 
(includes hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy) who have a positive or indeterminate pregnancy 
test result at the Screening Visit or Day 1 
2. Women who are not post-menopausal or permanently surgically 
sterile who are sexually active, and who are not willing to use birth 
control (as outlined in Section 5.3.1) during the study period  
3. Men who are sexually active and of reproductive potential, who 
have partners who are capable of becoming pregnant, and who are 
not willing to use birth control as outlined in Section 5.3.1 during 
the study period 
4. Significant malalignment of anatomical axis (medial angle formed 
by the femur and tibia) of the target knee (varus >10°, valgus 
>10°) by radiograph within 12 weeks of the Screening Visit as 
assessed by independent central readers  
5. Partial or complete joint replacement in either knee 
6. Currently requires use of a lower extremity prosthesis, and/or a 
structural knee brace (i.e., a knee brace that contains hardware)  
7. Any surgery (e.g., arthroscopy) in either knee within 26 weeks 
prior to Day 1 
8. Intra-articular (IA) injection into the target knee with a therapeutic 
aim including, but not limited to, hyaluronic acid, platelet-rich 
plasma (PRP), and stem cell therapies within 26 weeks prior to 
Day 1, or IA glucocorticoids within 12 weeks prior to Day 1   
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9. Effusion of the target knee clinically requiring aspiration within 
12 weeks prior to Day 1 
10. Use of electrotherapy (refer to Appendix 2), acupuncture, physical 
therapy, therapeutic ultrasound, and/or chiropractic treatments for 
knee OA within 4 weeks prior to Day 1 
11. Any bone fracture(s) within 26 weeks prior to the Screening Visit  
12. Previous treatment with SM04690 
13. Subjects who have previously failed screening on this protocol and 
fail to meet rescreening criteria (see Section 5.4.2) 
14. Participation in a clinical research trial that included the receipt of 
an investigational product (IP) or any experimental therapeutic 
procedure within 26 weeks prior to the Screening Visit, or planned 
participation in any such trial  
15. Treatment with systemic (oral, intramuscular, or intravenous) 
glucocorticoids ≥10 mg prednisone or the equivalent per day 
within 4 weeks prior to Day 1, or subjects on <10 mg prednisone 
or the equivalent per day who have not maintained a stable 
regimen for at least 2 weeks prior to Day 1 in the opinion of the 
Investigator 
16. Use of centrally acting analgesics (refer to Appendix 2) within 
12 weeks prior to Day 1 
17. Use of anticonvulsants (refer to Appendix 2) within 12 weeks prior 
to Day 1 
18. Subjects requiring the use of opioids >1x per week within 
12 weeks prior to Day 1 
19. Topical local anesthetic agents (gels, creams, or patches such as 
the Lidoderm patch) used for the treatment of knee OA within 
7 days of Day 1 
20. Planned surgery scheduled during the study period, not including 
non-surgical invasive procedures conducted for a diagnostic or 
therapeutic purpose scheduled during the study period (refer to 
Section 7.6). 
21. History of malignancy within the last 5 years, not including 
subjects with prior history of adequately treated in situ cervical 
cancer or basal or squamous cell skin cancer 
22. Clinically significant abnormal screening hematology values, 
blood chemistry values, or urinalysis values as determined by the 
Investigator 
23. Any condition that, in the opinion of the Investigator, constitutes a 
risk or contraindication for participation in the study or that could 
interfere with the study objectives, conduct, or evaluation  
24. Other conditions that, in the opinion of the Investigator, could 
affect study endpoint assessments of either knee, including, but not 
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limited to, peripheral neuropathy (e.g., diabetic neuropathy), 
symptomatic hip osteoarthritis, symptomatic degenerative disc 
disease, and patellofemoral syndrome 
25. Comorbid conditions that could affect study endpoint assessments 
of the target knee, including, but not limited to, rheumatoid 
arthritis, psoriatic arthritis, systemic lupus erythematosus, gout or 
pseudogout, and fibromyalgia 
26. History of mania, bipolar disorder, psychotic disorder, 
schizophrenia, or schizoaffective disorder  
27. Any known active infections, including urinary tract infection, 
upper respiratory tract infection, sinusitis, suspicion of IA 
infection, hepatitis B or hepatitis C infection, and/or infections that 
may compromise the immune system such as human 
immunodeficiency virus (HIV) at Day 1 
28. Any chronic condition that has not been well controlled or subjects 
with a chronic condition who have not maintained a stable 
therapeutic regimen of a prescription therapy in the opinion of the 
Investigator  
29. Hemoglobin A1c (HbA1c) >9 at the Screening Visit 
30. If using NSAIDs and/or acetaminophen, subjects who have not 
maintained a stable regimen in the opinion of the Investigator for 
at least 4 weeks prior to Day 1  
31. Any contraindications for an IA injection in the target knee in the 
opinion of the Investigator 
32. Subjects who have a current or pending disability claim, workers’ 
compensation, or litigation(s) that may compromise response to 
treatment  
33. Subjects who are immediate family members (spouse, parent, 
child, or sibling; biological or legally adopted) of personnel 
directly affiliated with the study at any investigative site, or are 
directly affiliated with the study at any investigative site 
34. Subjects employed by Samumed, LLC, or any of its affiliates or 
development partners (that is, an employee, temporary contract 
worker, or designee) responsible for the conduct of the study, or 
who are immediate family members (spouse, parent, child, or 
sibling; biological or legally adopted) of said employees 
responsible for the conduct of the study 
Population: 
Approximately 725 subjects with moderately to severely symptomatic 
osteoarthritis of the knee 
Phase: 
3 
 
 
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Number of Sites 
Enrolling 
Participants: 
This study will be conducted at approximately 100 investigational centers 
in the US 
Description of 
Study Agent: 
SM04690 is a small-molecule Wnt pathway modulator that inhibits CLK2 
and DYRK1A intranuclear kinases and thereby potentially (a) reduces 
signs and symptoms of knee OA via an anti-inflammatory mechanism and 
(b) inhibits breakdown and enhances formation of cartilage through effects 
on progenitor cells and chondrocytes resident in the joint.  
Study Duration: Approximately 20 months 
Estimated date first subject consented: May 2019 
Estimated date last subject completed: June 2021 
Participant 
Duration: 
Up to approximately 60 weeks 
Criteria for 
Evaluation: 
Efficacy: 
Efficacy will be assessed by: 
• Weekly averages of daily pain NRS (for target knee OA pain) 
• mJSW by radiograph 
• WOMAC questionnaire for WOMAC Pain, Function, and Total for the 
target knee  
• Patient Global Assessment 
• HRQOL as assessed by SF-36 
• NSAID/acetaminophen usage 
Safety: 
The overall safety and tolerability of SM04690 will be assessed by the 
incidence, severity, and relationship of AEs and SAEs, and clinically 
significant changes in clinical laboratory measures and vital signs, as 
assessed by the Investigator. 
Safety will also be assessed by evaluating concentrations of biomarkers in 
the serum (COMP, PINP, β-CTX). 
 
 
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2. 
INTRODUCTION  
2.1 
STUDY RATIONALE  
Osteoarthritis (OA) is the most common form of arthritis and chronic joint disorder in humans 
(Dougados and Hochberg 2011). The exact cause of OA is unknown, but it is associated with 
aging and normal wear on a joint. OA is characterized by the destruction of the articular 
cartilage, subchondral bone alterations, and synovitis. Patients present with pain and stiffness in 
the joints, with the joints becoming more stiff and immobile over time (Dougados and Hochberg 
2011). OA is a leading cause of physical disability in the United States (US) (Lawrence, Felson 
et al. 2008).  
The Wnt pathway plays a central role in the initiation and progression of OA pathology and is 
crucial in normal joint metabolism (Hochberg, Altman et al. 2012). Wnt is a major regulator of 
joint development and is involved in the formation of bone, cartilage, and synovium. The 
transcription of Wnt target genes causes an increase in catabolic processes during the 
development of OA, and increased Wnt signaling may contribute to cartilage loss (Gelse, Ekici 
et al. 2012). Polymorphisms in genes involved in Wnt signaling are associated with an increased 
susceptibility to OA development (Wu, Huang et al. 2012). Established research suggests that 
modulation of Wnt signaling is an attractive target for treatment of OA. 
In order to address the need for effective pharmaceutical agents to treat OA, Samumed has used 
structure-based drug design to synthesize a small-molecule inhibitor of the Wnt pathway, 
SM04690, as a potential OA therapeutic to be administered in the form of a local injection in the 
affected joint. This study is being conducted to assess the effect of a single-dose SM04690 
injection on knee OA pain and function over a 56-week period. 
2.2 
BACKGROUND INFORMATION  
OA is the most common form of arthritis and the major cause of activity limitation and physical 
disability in older people. Today, 35 million people (13% of the US population) are 65 and older, 
and more than half of them have radiological evidence of OA in at least one joint. By 2030, 20% 
of Americans (about 70 million people) will have passed their 65th birthday and will be at risk 
for OA (Nevitt, Felson et al. 2006). 
Therapies available to treat OA are limited. Most current treatments are designed only to relieve 
pain and reduce or prevent the disability caused by bone and cartilage degeneration. Drug 
therapies target the symptoms but not the cause of this disease; no treatment inhibits or reverses 
the degenerative structural changes that are responsible for its progression (Nevitt, Felson et al. 
2006). 
Samumed, LLC (Samumed) is developing SM04690 for the treatment of OA. SM04690 is a 
small-molecule Wnt pathway modulator that inhibits CLK2 and DYRK1A intranuclear kinases 
and thereby potentially (a) reduces signs and symptoms of knee OA via an anti-inflammatory 
mechanism and (b) inhibits breakdown and enhances formation of cartilage through effects on 
progenitor cells and chondrocytes resident in the joint.  
SM04690 has been tested in a number of appropriate nonclinical and clinical studies. The results 
of those studies are included in the Investigator’s Brochure (IB). 
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2.3 
RISK/BENEFIT ASSESSMENT 
2.3.1 
KNOWN POTENTIAL RISKS  
Study Medication SM04690 
The study drug SM04690 and procedures have risks and discomforts. The study drug SM04690 
modulates the Wnt pathway. Refer to the IB for the known potential risks associated with 
SM04690. 
Study Placebo 
The placebo injection in this study will be 2 mL of vehicle, which is carboxymethylcellulose 
sodium and polysorbate 80 in phosphate buffered saline. Carboxymethylcellulose sodium and 
polysorbate 80 are inactive substances often used as food or drug excipients. There is a small risk 
of allergic reaction or hypersensitivity to these components.  
Risks of Injection 
Risks associated with knee joint injection include infection and local site reactions such as 
erythema, irritation, and edema. 
Risks of Topical Anesthetics 
Reactions to the topical anesthetic drug that may be applied to the subjects’ skin are rare and 
may consist of cutaneous lesions (patches of skin that contrast with surrounding skin due to 
differences in texture, thickness, and color), or urticaria (red, raised itchy bumps). In addition to 
the local reactions, systemic reactions, although much rarer than the local ones, can be seen and 
include edema, bradycardia, dizziness, drowsiness, paresthesia, nausea, vomiting, or 
anaphylactoid reactions (generalized itching and hives, swelling, wheezing and difficulty 
breathing, fainting, and/or other allergy symptoms). 
Blood Sampling 
There is some risk of pain or local bruising and infection at the site where blood is drawn for 
laboratory tests. There is also a small risk of a fainting episode, which can occur as a reaction to 
giving blood. 
Radiograph (X-ray) 
This study involves radiation exposure from 2 radiographs of the knees approximately 6 months 
apart; up to 3 retakes may be performed for each radiograph to obtain an acceptable image. As 
part of everyday living, everyone is exposed to a small amount of background radiation that 
comes from soil, rocks, outer space, and within the body itself. Each radiograph in this study 
exposes subjects to approximately 0.005 millisievert (mSv), equivalent to about one half day of 
background radiation in the US (National Council on Radiation Protection and Measurements 
2009). This radiation exposure may not be necessary for the subjects’ medical care, but it is 
necessary to obtain the research information desired.  
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2.3.2 
KNOWN POTENTIAL BENEFITS  
Taking part in this study may or may not provide any benefit to the subject. Information from 
this study may help doctors learn more about treatments for OA and this information may help 
future patients, even if it may not help the subjects in this study. 
2.3.3 
ASSESSMENT OF POTENTIAL RISKS AND BENEFITS 
SM04690 is being considered as a new option for the treatment of knee OA. The safety 
assessments of SM04690 rely on data from product development and previous clinical trials. 
Based on nonclinical and clinical data, the conduct of the trial is regarded as justifiable at the 
planned dose and duration. Previous clinical trials (SM04690-01, SM04690-OA-02, 
SM04690-OA-04) involving over 1000 subjects identified no SAEs that were considered related 
to study medication. In previous trials, SM04690 was safe and well tolerated at single doses of 
0.23 mg per injection, exceeding the 0.07 mg single dose used in the current study. Additional 
information about safety data from nonclinical and clinical studies of SM04690 is in the IB. 
Risks to subjects will be minimized by clinical safety oversight performed by centralized review 
and conducted by Medical Monitor(s) per the Medical Monitoring Plan. In addition, on-site 
review will be conducted by Clinical Research Associates. 
Taking the above information into account, an assessment of risks and benefits supports the 
current study designed to investigate SM04690 as a potential therapy for patients with knee OA.  
3. 
OBJECTIVES AND ENDPOINTS 
3.1 
OBJECTIVE 
The objective of this study is to determine the efficacy, safety, and tolerability of the SM04690 
Injectable Suspension 0.07 mg dose in the treatment of knee OA. 
3.2 
STUDY ENDPOINTS 
3.2.1 
PRIMARY ENDPOINT 
Change from baseline OA pain in the target knee as assessed by the weekly average of daily pain 
numeric rating scale (NRS) at Week 12 
3.2.2 
SECONDARY ENDPOINTS 
1. Change from baseline OA pain in the target knee as assessed by the weekly averages of 
daily pain NRS at Weeks 24 and 52 
2. Change from baseline OA function in the target knee as assessed by Western Ontario and 
McMaster Universities Osteoarthritis Index (WOMAC) physical function subscore 
(WOMAC Function) at Weeks 12, 24, and 52 
3. Change from baseline OA disease activity as assessed by Patient Global Assessment at 
Weeks 12, 24, and 52 
4. Change from baseline in usage of nonsteroidal anti-inflammatory drugs (NSAIDs) and 
acetaminophen for target knee OA pain 
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3.2.3 
SAFETY ENDPOINTS 
Safety of SM04690 Injectable Suspension as measured by: 
1. Adverse events (AEs), serious adverse events (SAEs), vital signs, and clinical laboratory 
measures for the duration of the study  
2. Change in serum bone biomarkers (N-terminal propeptides of procollagen type I [PINP] 
and β-C-terminal telopeptide [β-CTX]) from baseline, and change in a serum cartilage 
biomarker (cartilage oligomeric matrix protein [COMP]) from baseline at Week 56 
3.2.4 
OTHER ENDPOINTS  
1. Change from baseline in medial joint space width (mJSW) as documented by radiograph 
of the target knee at Week 52 
2. Change from baseline health-related quality of life (HRQOL) as assessed by the 36-Item 
Short Form Health Survey (SF-36) at Week 52 
3. Change from baseline OA pain in the target knee as assessed by WOMAC pain subscore 
(WOMAC Pain) at Weeks 12, 24, and 52 
4. Change from baseline OA pain, function, and stiffness as a composite outcome measure 
as assessed by WOMAC total score (WOMAC Total) at Weeks 12, 24, and 52 
4. 
STUDY DESIGN  
4.1 
DESCRIPTION OF THE STUDY DESIGN 
This study will be a multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study of a single dose of SM04690 injected into the target knee joint of moderately to severely 
symptomatic OA subjects at Day 1.  
Approximately 725 subjects will be enrolled and randomized at a ratio of 1:1 (0.07 mg SM04690 
per 2 mL injection: 2 mL placebo). Subjects will participate in a 7- to 11-day screening period 
followed by a single injection and a 56-week evaluation period. Site visits will be scheduled at 
the Screening Visit, Day 1, and Weeks 4, 12, 24, 36, 52, and 56 (EOS) or at ET. Phone visits will 
be scheduled at Weeks 8, 16, 20, 28, 32, 40, 44, and 48. Specific timing of protocol procedures is 
described in the Schedule of Events Table (Section 7.3.7). Specific timing of electronic diary and 
questionnaire completion is described in the Schedule of Electronic Diary and Questionnaire 
Completion Table (Section 7.3.8). 
This study will be conducted at approximately 100 investigational centers in the US.  
Radiographic images of the knees will be performed prior to study entry, Week 24, and Week 52 
or ET. A WPI&SS assessment will be administered at the Screening Visit and Day 1. An SF-36 
assessment will be administered at Day 1 and Week 52. Bone and cartilage biomarkers will be 
assessed at the Screening Visit and Week 56 or ET. Investigator assessment of 
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NSAID/acetaminophen usage will be performed at all in-person and phone visits starting at 
Day 1. 
Subjects will be required to complete an electronic diary for the following (see Section 7.3.8): 
• Daily pain NRS from the Screening Visit through Week 56 (EOS) 
• WOMAC at baseline and Weeks 4, 12, 24, 36, 52, and 56 (EOS)  
• Patient Global Assessment at baseline and Weeks 4, 12, 24, 36, 52, and 56 (EOS) 
In addition, general medical evaluations including physical examination, knee examination, and 
recording of vital signs will be performed at the Screening Visit, Day 1, and at Weeks 4, 12, 24, 
36, 52, and 56 (EOS) or ET. Height will be measured at the Screening Visit and weight will be 
measured at the Screening Visit and at Weeks 24 and 56 (EOS) or ET. Clinical laboratory 
evaluations will be performed at the Screening Visit and at Weeks 4, 12, 24, 36, 52, and 56 
(EOS) or ET.  
Recording of signs and symptoms of study medication intolerability and AE reporting will start 
following the injection of the study medication and continue at all subsequent in-person and 
phone visits until the subject completes Week 56 (EOS) or ET. All AEs, whether volunteered, 
elicited, or noted during examination, will be recorded throughout the study. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
This phase 3 study, SM04690-OA-11, is a multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study of a single concentration of 0.07 mg SM04690 per 2 mL 
injection injected into the target knee joint of moderately to severely symptomatic OA subjects at 
Day 1. The placebo to be used in this study is a vehicle-concurrent control. The placebo injection 
contains all components of the SM04690 injectable suspension with the exception of SM04690. 
Vehicle is considered the appropriate control in this study as it allows for evaluation of the 
efficacy, safety, and tolerability of the SM04690 molecule alone through comparison of the 
SM04690 and placebo arms. 
4.3 
JUSTIFICATION FOR DOSE 
The dose of 0.07 mg SM04690 was selected for this study based on evidence available from 
nonclinical studies and 3 completed clinical studies (SM04690-01, SM04690-OA-02, and 
SM04690-OA-04). Administration of the 0.07 mg dose resulted in the most consistently positive 
responses compared to control when the outcome measures of Pain NRS, WOMAC Function, 
and mJSW were assessed. 
4.4 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed all phases of 
the study including the last visit shown in the Schedule of Events Table (Section 7.3.7). 
5. 
STUDY POPULATION 
Eligibility of subjects will be determined by the following inclusion and exclusion criteria. 
Subjects should meet all the inclusion criteria and none of the exclusion criteria. 
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5.1 
PARTICIPANT INCLUSION CRITERIA 
In order to be eligible for the study, subjects must fulfill all of the following criteria: 
1. Males and females between 40 and 80 years of age, inclusive, in general good health 
apart from their knee OA 
2. Ambulatory (single assistive devices such as canes allowed if needed less than 50% of 
the time, subjects requiring a walker are excluded) 
3. Diagnosis of femorotibial OA in the target knee by standard American College of 
Rheumatology (ACR) criteria at the Screening Visit (clinical AND radiographic criteria) 
(Appendix 1); OA of the knee is not to be secondary to any rheumatologic conditions 
(e.g., rheumatoid arthritis) 
4. mJSW by radiograph between 1.5 and 4 mm, inclusive, in the target knee within 12 
weeks of the Screening Visit as assessed by independent central readers 
5. Radiographic disease Stage 2 or 3 in the target knee within 12 weeks of the Screening 
Visit according to the Kellgren-Lawrence (KL) grading of knee OA as assessed by 
independent central readers 
6. Pain compatible with OA of the knee(s) for at least 26 weeks prior to the Screening Visit 
7. Primary source of pain throughout the body is due to OA in the target knee 
8. Body mass index (BMI) ≤40 kg/m2 at the Screening Visit 
9. Widespread Pain Index (WPI) score of ≤4 and a Symptom Severity Question 2 (SSQ2) 
score of ≤2 at the Screening Visit and Day 1 
10. Pain NRS scores recorded for the target knee on at least 4 out of the 7 days immediately 
preceding Day 1  
11. Pain NRS scores recorded for the nontarget knee on at least 4 out of the 7 days 
immediately preceding Day 1 
12. Daily OA knee pain diary average NRS intensity score ≥4 and ≤8 in the target knee on 
the 11-point (0–10) NRS scale for the 7 days immediately preceding Day 1 
13. Daily OA knee pain diary average NRS intensity score <4 in the nontarget knee on the 
11-point (0–10) NRS scale for the 7 days immediately preceding Day 1 
14. WOMAC Pain of 20–40 (out of 50) for the target knee at baseline regardless of if the 
subject is on symptomatic oral treatment (baseline questionnaire completed during the 
screening period prior to randomization) 
15. WOMAC Function of 68–136 (out of 170) for the target knee at baseline regardless of if 
the subject is on symptomatic oral treatment (baseline questionnaire completed during the 
screening period prior to randomization) 
16. Willingness to use an electronic diary daily in the evening for the screening period and 
56-week study duration 
17. Negative drug test for amphetamine, buprenorphine, cocaine, methadone, opiates, 
phencyclidine (PCP), propoxyphene, barbiturates, benzodiazepine, methaqualone, and 
tricyclic antidepressants, unless any of these drugs are allowed per protocol and 
prescribed by a physician to treat a specific condition  
18. Subjects with depression or anxiety must be clinically stable for at least 12 weeks prior to 
the Screening Visit and, if on treatment for depression or anxiety, be on at least 12 weeks 
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of stable therapy 
19. Full understanding of the requirements of the study and willingness to comply with all 
study visits and assessments 
20. Subjects must have read and understood the informed consent form (ICF), and must have 
signed and dated it prior to any study-related procedure being performed 
5.2 
PARTICIPANT EXCLUSION CRITERIA 
Any potential subject who meets one or more of the following criteria will not be included in this 
study: 
1. Pregnant women, breastfeeding women, and women who are not post-menopausal 
(defined as 12 months with no menses without an alternative medical cause) or 
permanently surgically sterile (includes hysterectomy, bilateral salpingectomy, and 
bilateral oophorectomy) who have a positive or indeterminate pregnancy test result at the 
Screening Visit or Day 1 
2. Women who are not post-menopausal or permanently surgically sterile who are sexually 
active, and who are not willing to use birth control (as outlined in Section 5.3.1) during 
the study period  
3. Men who are sexually active and of reproductive potential, who have partners who are 
capable of becoming pregnant, and who are not willing to use birth control as outlined in 
Section 5.3.1 during the study period 
4. Significant malalignment of anatomical axis (medial angle formed by the femur and tibia) 
of the target knee (varus >10°, valgus >10°) by radiograph within 12 weeks of the 
Screening Visit as assessed by independent central readers  
5. Partial or complete joint replacement in either knee 
6. Currently requires use of a lower extremity prosthesis, and/or a structural knee brace (i.e., 
a knee brace that contains hardware)  
7. Any surgery (e.g., arthroscopy) in either knee within 26 weeks prior to Day 1 
8. Intra-articular (IA) injection into the target knee with a therapeutic aim including, but not 
limited to, hyaluronic acid, platelet-rich plasma (PRP), and stem cell therapies within 26 
weeks prior to Day 1, or IA glucocorticoids within 12 weeks prior to Day 1   
9. Effusion of the target knee clinically requiring aspiration within 12 weeks prior to Day 1 
10. Use of electrotherapy (refer to Appendix 2), acupuncture, physical therapy, therapeutic 
ultrasound, and/or chiropractic treatments for knee OA within 4 weeks prior to Day 1 
11. Any bone fracture(s) within 26 weeks prior to the Screening Visit  
12. Previous treatment with SM04690 
13. Subjects who have previously failed screening on this protocol and fail to meet 
rescreening criteria (see Section 5.4.2) 
14. Participation in a clinical research trial that included the receipt of an investigational 
product (IP) or any experimental therapeutic procedure within 26 weeks prior to the 
Screening Visit, or planned participation in any such trial  
15. Treatment with systemic (oral, intramuscular, or intravenous) glucocorticoids ≥10 mg 
prednisone or the equivalent per day within 4 weeks prior to Day 1, or subjects on 
<10 mg prednisone or the equivalent per day who have not maintained a stable regimen 
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for at least 2 weeks prior to Day 1 in the opinion of the Investigator 
16. Use of centrally acting analgesics (refer to Appendix 2) within 12 weeks prior to Day 1 
17. Use of anticonvulsants (refer to Appendix 2) within 12 weeks prior to Day 1 
18. Subjects requiring the use of opioids >1x per week within 12 weeks prior to Day 1 
19. Topical local anesthetic agents (gels, creams, or patches such as the Lidoderm patch) 
used for the treatment of knee OA within 7 days of Day 1 
20. Planned surgery scheduled during the study period, not including non-surgical invasive 
procedures conducted for a diagnostic or therapeutic purpose scheduled during the study 
period (refer to Section 7.6). 
21. History of malignancy within the last 5 years, not including subjects with prior history of 
adequately treated in situ cervical cancer or basal or squamous cell skin cancer 
22. Clinically significant abnormal screening hematology values, blood chemistry values, or 
urinalysis values as determined by the Investigator 
23. Any condition that, in the opinion of the Investigator, constitutes a risk or 
contraindication for participation in the study or that could interfere with the study 
objectives, conduct, or evaluation  
24. Other conditions that, in the opinion of the Investigator, could affect study endpoint 
assessments of either knee, including, but not limited to, peripheral neuropathy (e.g., 
diabetic neuropathy), symptomatic hip osteoarthritis, symptomatic degenerative disc 
disease, and patellofemoral syndrome 
25. Comorbid conditions that could affect study endpoint assessments of the target knee, 
including, but not limited to, rheumatoid arthritis, psoriatic arthritis, systemic lupus 
erythematosus, gout or pseudogout, and fibromyalgia 
26. History of mania, bipolar disorder, psychotic disorder, schizophrenia, or schizoaffective 
disorder  
27. Any known active infections, including urinary tract infection, upper respiratory tract 
infection, sinusitis, suspicion of IA infection, hepatitis B or hepatitis C infection, and/or 
infections that may compromise the immune system such as human immunodeficiency 
virus (HIV) at Day 1 
28. Any chronic condition that has not been well controlled or subjects with a chronic 
condition who have not maintained a stable therapeutic regimen of a prescription therapy 
in the opinion of the Investigator  
29. Hemoglobin A1c (HbA1c) >9 at the Screening Visit 
30. If using NSAIDs and/or acetaminophen, subjects who have not maintained a stable 
regimen in the opinion of the Investigator for at least 4 weeks prior to Day 1  
31. Any contraindications for an IA injection in the target knee in the opinion of the 
Investigator 
32. Subjects who have a current or pending disability claim, workers’ compensation, or 
litigation(s) that may compromise response to treatment  
33. Subjects who are immediate family members (spouse, parent, child, or sibling; biological 
or legally adopted) of personnel directly affiliated with the study at any investigative site, 
or are directly affiliated with the study at any investigative site 
34. Subjects employed by Samumed, LLC, or any of its affiliates or development partners 
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(that is, an employee, temporary contract worker, or designee) responsible for the 
conduct of the study, or who are immediate family members (spouse, parent, child, or 
sibling; biological or legally adopted) of said employees responsible for the conduct of 
the study  
5.3 
LIFESTYLE GUIDELINES 
5.3.1 
CONTRACEPTION  
Women of Childbearing Potential  
Women of childbearing potential (WOCBP) refers to women who are not post-menopausal 
(defined as 12 months with no menses without an alternative medical cause) or permanently 
surgically sterile (includes hysterectomy, bilateral salpingectomy, and bilateral oophorectomy). 
From the Screening Visit until Week 56 (EOS), sexually active WOCBP must agree to use an 
acceptable form of contraception. Acceptable forms of contraception are: 
1. Intrauterine device (IUD) 
2. Implantable rod 
3. Established hormonal contraceptive methods in combination with a barrier method. This 
includes injectable, oral, patch, and vaginal ring hormonal contraception. Females who 
are using hormonal contraceptives must have had consistent use of the same hormonal 
contraceptive product for at least 4 weeks. Barrier methods include male or female 
condom, diaphragm with spermicide, sponge with spermicide, or cervical cap with 
spermicide. 
4. Bilateral tubal ligation/occlusion/division 
5. Male partner who had a vasectomy provided that the partner is the sole sexual partner of 
the WOCBP, and that the vasectomized partner has received medical assessment of the 
success of the surgical procedure or had the vasectomy for at least 6 months  
Sexually active WOCBP who withdraw from the study after receiving study medication should 
remain on an acceptable form of contraception for 56 weeks after study medication injection at 
Day 1. 
Men  
For men who are sexually active with a female partner of childbearing potential, both partners 
must agree to use an acceptable form of contraception, as outlined below, from the Screening 
Visit until Week 56 (EOS): 
• A condom and one additional acceptable form of birth control: 
a. IUD 
b. Implantable rod  
c. Established hormonal contraceptive methods. This includes injectable, oral, patch, 
and vaginal ring hormonal contraception. Females who are using hormonal 
contraceptives must have had consistent use of the same hormonal contraceptive 
product for at least 4 weeks  
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d. Bilateral tubal ligation/occlusion/division  
e. Vasectomy in the male partner for at least 6 months or demonstrated success of the 
surgical procedure 
Men who are sexually active with a female partner of childbearing potential who withdraw from 
the study after receiving study medication should continue to use an acceptable form of 
contraception with their partners for 56 weeks after study medication injection at Day 1. 
5.4 
SCREEN FAILURES 
5.4.1 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently randomized or entered in the study. 
5.4.2 
SUBJECT RESCREENING 
Subjects are allowed to be rescreened once for this protocol and, if the subject is affected by an 
amendment(s) that changes the inclusion/exclusion criteria, they are additionally allowed to 
rescreen. Rescreens are limited to subjects who did not meet inclusion/exclusion criteria due to a 
transient reason or if the inclusion/exclusion criteria have changed. Transient refers to 
self-limiting and predictably resolving conditions or acute events (e.g., common cold or otitis 
media), reversible medical conditions that are successfully treated (e.g., anemia successfully 
treated by infusion), being unable to comply with study procedures due to administrative 
convenience (e.g., family issues or attending to a private matter), and/or being within the 
exclusion window for past medications and/or procedures, as outlined in Section 5.2. 
Subjects who failed any entry criteria for which no further treatment or spontaneous resolution is 
expected are not allowed to be rescreened. Daily OA knee pain diary noncompliance is not a 
transient event and subjects with knee pain diary noncompliance may not be rescreened. 
Any rescreened subject must be re-consented and should be assigned a new subject number. All 
screening procedures and assessments must be performed at rescreen; no results or data may be 
used from the previous screen. Target knee selection may not be changed at rescreen.  
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
A detailed recruitment and retention plan will be maintained by the Sponsor.  
5.6 
PARTICIPANT WITHDRAWAL OR TERMINATION 
5.6.1 
REASONS FOR WITHDRAWAL OR TERMINATION 
Because the study treatment requires only one injection, best efforts will be made to encourage 
subjects to attend all follow-up visits. Subjects will be informed they are free to withdraw from 
the study at any time and for any reason. A premature discontinuation from the study will occur 
when a subject who signed informed consent ceases participation in this study, regardless of 
circumstances, prior to completion of the defined study period. Subjects can be prematurely 
discontinued from the study for one of the following reasons:  
• AE 
• Total or partial knee replacement of the target knee 
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• Lost to follow-up after a minimum of 3 attempts have been made to contact the 
subject, including sending a registered letter 
• Withdrawal by subject for reason other than lack of efficacy 
• Subject noncompliance 
• Physician decision for reason other than lack of efficacy 
• Study terminated by Sponsor 
• Site terminated by Sponsor 
• Request by regulatory authority 
• Lack of efficacy 
• Pregnancy 
• Death 
• Randomized by mistake without study treatment 
• Other 
5.6.2 
HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 
In case of premature discontinuation of study participation, ET procedures should be conducted 
within 14 days of discontinuation for any subject who was randomized at the Day 1 visit, if 
possible. The date the subject is withdrawn from the study and the reason for the discontinuation 
should be recorded on the electronic case report form (eCRF). The Investigator or designee must 
complete all applicable eCRF pages for subjects who discontinue from the study prematurely.  
Replacement of subjects who withdraw or discontinue prematurely is not allowed. 
5.7 
PREMATURE TERMINATION OR SUSPENSION OF STUDY 
The Investigator and the Institutional Review Board/Ethics Committee (IRB/EC) reserve the 
right to prematurely terminate the study in the interest of subject safety and welfare. The Sponsor 
reserves the right to prematurely terminate the study at any time for administrative or safety 
reasons. Written notification, documenting the reason for study suspension or termination, will 
be provided by the suspending or terminating party to the Investigator, Sponsor, and regulatory 
authorities as appropriate. If the study is prematurely terminated or suspended, the Investigator 
will promptly inform the IRB and will provide the reason(s) for the termination or suspension.  
6. 
STUDY AGENT 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION 
6.1.1 
ACQUISITION 
The Sponsor will be responsible for the manufacturing, labeling, packaging, distribution, 
reconciliation of study medication, and ultimate destruction of unused study medication (both 
SM04690 drug product and placebo product). 
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6.1.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
SM04690 drug substance is an off-white powder. SM04690 drug product is a sterile suspension 
in diluent containing 0.5% carboxymethylcellulose sodium and 0.05% polysorbate 80 in pH 7.4 
phosphate buffered saline. SM04690 drug and placebo products are supplied as 2.4 mL of 
formulated suspension in vials. Placebo product contains 0.5% carboxymethylcellulose sodium 
and 0.05% polysorbate 80 in pH 7.4 phosphate buffered saline.  
Study medication will be supplied as single-use injections. SM04690 drug and placebo products 
will be supplied to the study pharmacist and labeled according to the applicable local and 
country regulations. For dispensing, dose preparation, and labeling instructions, refer to the 
Pharmacy Manual. 
6.1.3 
PRODUCT STORAGE AND STABILITY 
The study medication must be stored at the appropriate temperature (15°C–30°C [59°F–86°F]) 
and in a restricted area with limited access. Temperature excursions are to be evaluated on a 
case-by-case basis by the Sponsor. Study medication should not be frozen. 
6.1.4 
PREPARATION 
Each dose of study medication should be well mixed (the drug product is a suspension) prior to 
injecting 2 mL intra-articularly into the target knee. Refer to the Pharmacy Manual for detailed 
instructions on study medication preparation.  
6.1.5 
DOSING AND ADMINISTRATION 
SM04690 will be administered in the following dosage strengths:  
• SM04690 0.07 mg in 2 mL Injectable Suspension 
• SM04690 0 mg; 2 mL vehicle-only injection (placebo) 
The injectable drug product or placebo product is to be administered by the Unblinded 
Investigator as a single injection into the target knee joint once at Day 1. The Unblinded 
Investigator must minimize any contact with the subject following the injection and may not 
perform any study assessments throughout the duration of the study. All subject contact for the 
remainder of the study is limited to the Blinded Investigator and other appropriate blinded study 
personnel.  
Only 1 knee will be treated for each subject in this study. The injections can be done either 
through lateral or medial (including superior/suprapatellar, midpatellar, and inferior/anterior) 
approaches, based on the standard practice of the Unblinded Investigator or the knee examination 
of the subject. Although not required, the injections may be guided by ultrasound or fluoroscopy 
without contrast if it is the standard practice of the Unblinded Investigator.  
Only topical anesthetics are allowed prior to study injection. Local anesthetic injections are 
prohibited. 
Prior to administration of the IA knee injection, the subject should be blinded to observation of 
the study medication and injection procedure according to the processes specified in the 
Site-Specific Blinding Plan.  
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The Unblinded Investigator (injector) should place the needle into the joint and the total volume 
contained in the syringe is to be injected into the joint space. Because SM04690 drug product is a 
suspension, prior aspiration of synovial fluid into the syringe containing the injectate should be 
avoided to prevent trapping of particles within synovial aspirate/cellular content residues. If it is 
the standard practice of the injector to aspirate a small amount (0.3–0.5 mL) of joint fluid to 
confirm correct needle placement, this will have to be done with an empty sterile syringe. Using 
the same needle, the study medication should then be injected with a separate syringe. 
The Sponsor will provide sterile needles and syringes that should be used for the injection of 
study medication. 
6.1.6 
ROUTE OF ADMINISTRATION 
Injectable SM04690 drug product or placebo product is to be administered as a single IA 
injection into the target knee joint once at Day 1. 
6.1.7 
STARTING DOSE AND DOSE ESCALATION SCHEDULE 
Not applicable to this study. Each subject will be randomly assigned to SM04690 or placebo on 
Day 1. 
6.1.8 
DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS 
No modification in the specified dose concentration or volume (2 mL) of the study medication 
injected into the target knee joint will be allowed. 
6.1.9 
DURATION OF THERAPY 
Study medication is to be administered as a single IA injection into the target knee joint once at 
Day 1. 
6.1.10 
STUDY INTERVENTION COMPLIANCE 
Not applicable to this study. 
6.1.11 
DEVICE SPECIFIC CONSIDERATIONS 
Not applicable to this study.  
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES 
All used and unused vials of the study medication received must be returned and accounted for. 
All injections prepared and dispensed must also be logged. The log includes the following: 
• Subject number and initials 
• Date that study medication was injected 
• Quantity dispensed (drug product vial and placebo vial) 
• Quantity returned/used (drug product vial and placebo vial) 
All study medication dispensed by the Unblinded Investigator and/or unblinded designee will be 
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inventoried and accounted for throughout the study. The Unblinded Investigator and/or 
unblinded designee must maintain an accurate, up-to-date dispensing log for all study 
medications supplied by the Sponsor. Study medication dispensed for all subjects must be 
recorded on the drug accountability forms. The study medication dispensing log and remaining 
drug inventory will be reviewed by the Sponsor-designated unblinded clinical monitor. 
The study medications supplied for this study are for use only in subjects properly consented and 
randomized into this protocol. Used and unused study medications must be kept in a secure, 
blinded location physically separated from standard clinic or office drug supplies, and with 
access limited to the Unblinded Investigator and/or unblinded designee. Procedures for return or 
destruction of used and unused vials of the study medication will be provided in the Pharmacy 
Manual. 
7. 
STUDY PROCEDURES AND SCHEDULE 
7.1 
STUDY PROCEDURES/EVALUATIONS 
7.1.1 
STUDY SPECIFIC PROCEDURES  
Collection of Adverse Events Data 
Data regarding AEs will be collected in this study. AEs are events that occur during the study 
that are not present prior to Day 1 study medication injection, or, if present at the time of study 
medication injection, have worsened in severity during the study. AEs will be assessed at each 
in-person and phone visit from the time of study medication injection on Day 1 through Week 56 
(EOS) or ET.  
Each subject will be observed and queried by the Investigator or designee at each study visit for 
any continuing AEs or new AEs since the previous visit. The subject may be asked to return to 
the site for an unscheduled visit if an AE occurs between study visits, and if, in the opinion of the 
Investigator, the AE requires a study visit for full evaluation. The following information will be 
recorded within the eCRF for each AE: Description of the event, date of onset and resolution, 
etiology, and severity as assessed by the Investigator according to the Clinical Data Interchange 
Standards Consortium (CDISC) Severity/Intensity Scale for Adverse Events (AESEV) (Table 1), 
causal relationship to study medication, outcome, and any action taken.  
In this protocol, signs and symptoms of exacerbation or worsening of target knee OA will be 
captured in the context of efficacy assessments and recorded on specific pages of the eCRF or 
electronic diary. Anticipated fluctuations or anticipated deterioration (in the opinion of the 
Investigator) of the underlying disease (target knee OA) will not be considered as AEs nor 
captured on the AE page of the eCRF. 
Whenever possible, it is preferable to record a diagnosis as the AE term rather than a series of 
symptoms relating to a diagnosis. Fluctuations of pre-existing conditions that do not represent a 
clinically significant exacerbation or worsening, need not be considered AEs. 
AEs will be followed until the subject’s last visit or resolution, whichever comes first. For 
subjects who discontinue from the study within 30 days of their dose of study medication, AEs 
that are ongoing at the subject’s last visit will be followed for 30 days after administration of the 
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dose or until resolution, whichever comes first. Resolution is defined as the return to baseline 
status or stabilization of the condition. SAEs and selected AEs identified by the Investigator or 
the Sponsor to warrant further follow-up that are ongoing at a subject’s last visit will be followed 
until resolution.   
Medical History 
A medical history will be obtained at the Screening Visit and Day 1 with a follow-up at Week 56 
(EOS) or ET to capture End Dates of any ongoing medical history collected at the Screening 
Visit and Day 1. Medical history at Screening Visit will include demographic data (e.g., age, 
race, ethnicity) and use of assistive devices. In addition, medical information will also be 
recorded, including all (1) medical conditions and disease states that require current or ongoing 
therapy, and (2) other medical conditions and disease states that, in the opinion of the 
Investigator, are relevant to the subject’s study participation. Examples of medical conditions 
and disease states that should be considered relevant to the subject’s study participation include 
history of current disease, medical history that confirms the eligibility criteria of the subject, and 
asymptomatic medical history that could become symptomatic while on the study.  
Past Treatments for Knee OA Pain 
Subjects will be asked at the Screening Visit about their previous use, at any time in the past, of 
the following treatments for their knee OA pain: NSAIDs, acetaminophen, opioids, IA steroids, 
and IA hyaluronic acid. Responses will be recorded on the eCRF as Yes/No/Unknown. 
Physical Examination  
A general physical examination will be conducted at the Screening Visit, Day 1, and Weeks 4, 
12, 24, 36, 52, and 56 (EOS) or ET. Results of the physical examination will be noted in the 
source documents. Any clinically significant finding noted prior to study medication injection 
should be recorded as medical history. If it is found after study medication injection, it should be 
reported as an AE.  
Knee Examination 
A knee examination of both knees will be conducted at the Screening Visit, Day 1, and Weeks 4, 
12, 24, 36, 52, and 56 (EOS) or ET. Results of the knee examination will be noted in the source 
documents. Any clinically significant finding noted prior to study medication injection should be 
recorded as medical history. If it is found after study medication injection, it should be reported 
as an AE.  
Presence of unilateral or bilateral symptomatic knee OA will be recorded in the eCRF at the 
Screening Visit. If the subject has OA in both knees, the site is to establish the target knee as the 
knee with greater pain at the Screening Visit based on the subject’s evaluation and the 
Investigator’s clinical judgment. If the Investigator’s clinical judgement of the target knee differs 
from the subject-reported target knee (as reported during prescreen), sites should contact the 
Sponsor for further guidance. 
Vital Signs 
Vital signs will be measured by a qualified staff member at the Screening Visit, Day 1, and 
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Weeks 4, 12, 24, 36, 52, and 56 (EOS) or ET. 
At each time point, the following vital signs will be measured: 
• Body temperature 
• Pulse rate 
• Respiratory rate 
• Blood pressure (systolic and diastolic) after the subject rests (sitting or supine) for at 
least 5 minutes 
Any measurement that is, in the opinion of the Investigator, abnormal AND clinically significant 
must be recorded as medical history if found prior to study medication injection or as an AE if 
found after study medication injection.  
Height and Weight 
Height measurements will be taken at the Screening Visit only. Weight measurements will be 
taken at the Screening Visit and at Weeks 24 and 56 (EOS) or ET. 
Radiograph of Knee Joints 
Radiograph of the knee joints will be taken prior to study entry and at Weeks 24 and 52 or ET. 
Prior to the Screening Visit, the subject’s prescreen radiograph report must be reviewed to 
confirm eligibility for this study. At the Screening Visit, after confirmation of the target knee by 
the Investigator, the subject’s prescreen radiograph report must be reviewed for the target knee to 
confirm compliance with inclusion/exclusion criteria. 
Detailed instructions for obtaining and managing the Week 24 and Week 52 or ET radiographs 
will be provided to the investigational center prior to the initiation of subject enrollment. As 
described in the Image Review Charter – Image Acquisition Guidelines, radiographs should be 
obtained in the posterior-anterior (PA) view.   
Upon receipt of images, the central imaging vendor will assess the image quality as acceptable or 
unacceptable. If necessary, it is recommended that the Investigator attempt up to 4 image 
captures at Week 24 and/or Week 52 or ET in order to obtain acceptable images. At all times, the 
Investigator should use his/her clinical judgement to assess how many retakes a subject may 
require in order to obtain an acceptable image. 
All radiographs will be submitted to an independent radiologist at the central imaging vendor. 
The central imaging vendor does not provide medical advice, clinical diagnosis, or treatment 
recommendations. These imaging assessments and quantitative measurements provided to the 
Sponsor do not and shall not constitute a medical diagnosis, treatment recommendation, or 
medical advice, and are not intended to be used as a substitute for the study Investigator’s or 
other qualified health care professional’s medical diagnosis, treatment, or advice. If any AE or 
other unusual pathology is noted in the study images, the Sponsor will be notified of the finding 
and will promptly notify the Investigator. The Investigator will then assess the clinical 
significance as well as any follow-up procedures that need to be completed. Clinically significant 
findings that are not part of an existing diagnosis will be recorded as medical history or an AE as 
appropriate.   
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Widespread Pain Index and Symptom Severity (WPI&SS) Form 
The WPI&SS assessment consists of a body map that determines a subject’s areas of pain or 
tenderness (WPI) and symptom severity (SS) questions. The WPI&SS assessment used in this 
study is modified from that described in (Clauw 2014). A WPI&SS assessment will be 
completed by the subject at the Screening Visit and Day 1.  
Upon completion of the WPI&SS assessment, the subject will sign or initial the source document 
and date it to indicate that the assessment is reported accurately.  
The WPI&SS assessment sheets will be provided by the Sponsor and may not be reproduced. 
Electronic Diary Device Provision and Training 
Detailed instructions and site training regarding subject electronic questionnaire completion will 
be provided to the investigational center. Electronic diary device provisioning to the subject will 
occur at the Screening Visit and electronic diary devices are to be returned to the site at Week 56 
(EOS) or ET.  
Subject training for electronic diary and questionnaire completion on the electronic diary device 
is required at the Screening Visit prior to subject completion of the pain NRS, WOMAC, and 
Patient Global Assessment questionnaires. Training will remain available on the electronic diary 
device throughout the study in case subject retraining is needed.  
Additionally, at the Screening Visit, subjects will have training on accurate pain reporting and 
placebo response reduction prior to subject completion of the pain NRS, WOMAC, and Patient 
Global Assessment questionnaires. It is recommended that subjects complete the training on 
accurate pain reporting and placebo response reduction at Weeks 4, 12, 24, 36, and 52.  
Pain Numeric Rating Scale  
The pain NRS is an 11-point scale [0–10] for subject self-reporting of average knee pain in the 
last 24 hours. The NRS will be anchored by descriptors at each end (“No Pain” on the left and 
“Pain as bad as you can imagine” on the right). A pain NRS for each knee will be completed daily 
by the subject during the screening period from the Screening Visit until Day 1 to assess subject 
ability to be compliant with a daily pain assessment and to determine subject eligibility. During 
the screening period, daily pain NRS assessments will be completed by subjects in the evening 
(between 5:00 pm and 11:59 pm) remotely on their electronic devices for each knee to collect 
average knee pain in the last 24 hours. Subject eligibility and electronic diary compliance for 
daily pain NRS over the screening period will be reviewed at Day 1 prior to randomization. After 
screening, starting on Day 1, daily pain NRS assessments are to be completed by subjects in the 
evening (between 5:00 pm and 11:59 pm) remotely on their electronic devices for the target knee 
only. Refer to Section 7.3.8 for a schedule of electronic diary and questionnaire completion. 
Subjects will complete the pain NRS on the Sponsor-provided electronic device. Subjects will 
receive notifications reminding them to complete the daily pain NRS assessment.   
Western Ontario and McMaster Universities Arthritis Index (WOMAC) 
The WOMAC is a widely used, proprietary outcome measurement tool used by health 
professionals to evaluate the condition of patients with OA of the knee and hip, including pain, 
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stiffness, and physical functioning of a target joint. The WOMAC Version NRS 3.1 
questionnaire will be completed by the subject for their target knee in the evening (between 
5:00 pm and 11:59 pm) remotely on their electronic device 5 days after their Screening Visit 
(i.e., Screening Visit + 5 days) or up until the day before the Day 1 visit. WOMAC questionnaire 
completion will be reviewed at Day 1 prior to randomization to determine subject eligibility. The 
baseline WOMAC questionnaire should be completed within 9 days prior to Day 1. After Day 1, 
WOMAC assessments will be completed by the subject for their target knee in the evening 
(between 5:00 pm and 11:59 pm) remotely on their electronic device at Week 4 (with a window 
of ± 3 days) and Weeks 12, 24, 36, 52, and 56 (with windows of ± 7 days). Refer to Section 7.3.8 
for a schedule of electronic diary and questionnaire completion. 
Subjects will complete the WOMAC on the Sponsor-provided electronic device. Subjects will 
receive notifications reminding them to complete the WOMAC assessment. 
Patient Global Assessment of Disease Activity 
The Patient Global Assessment is an 11-point [0–10] NRS on which the subjects will rate how 
they feel their target knee OA is doing, considering all the ways in which their target knee OA 
may affect them. The NRS will be anchored by descriptors at each end (“Very Good” on the left 
and “Very Bad” on the right). The Patient Global Assessment will be completed by the subject in 
the evening (between 5:00 pm and 11:59 pm) remotely on their electronic device 5 days after 
their Screening Visit (i.e., Screening Visit + 5 days) or up until the day before the Day 1 visit. 
The baseline Patient Global Assessment questionnaire should be completed within 9 days prior 
to Day 1. After Day 1, Patient Global Assessments will be completed by the subject in the 
evening (between 5:00 pm and 11:59 pm) remotely on their electronic device at Week 4 (with a 
window of ± 3 days) and Weeks 12, 24, 36, 52, and 56 (with windows of ± 7 days). Refer to 
Section 7.3.8 for a schedule of electronic diary and questionnaire completion.  
Subjects will complete the Patient Global Assessment on the Sponsor-provided electronic device. 
Subjects will receive notifications reminding them to complete the Patient Global Assessment.  
36-Item Short Form Health Survey  
The SF-36 is a widely used questionnaire that relies upon subject self-reporting to measure the 
subject’s health-related quality of life. The SF-36 will be completed by the subject at Day 1 and 
Week 52. Upon completion of the SF-36, the subject will sign or initial, then date the source 
document to indicate that the quality of life assessment is reported accurately. 
The SF-36 questionnaires will be provided by the Sponsor and may not be reproduced. 
Assessment of NSAID/Acetaminophen Usage 
Information about NSAID and acetaminophen usage will be collected as part of concomitant 
medications at all visits. Subjects will be asked to recall the name, usual total daily dose, and 
usual number of days taken per week of any oral NSAID or acetaminophen medications during 
the previous 4 weeks. Subjects will be trained on what medications are NSAIDs at the Screening 
Visit Assessment of NSAID/acetaminophen usage on Day 1 prior to study medication 
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administration will be used to establish the subject’s baseline 4-week NSAID/acetaminophen 
usage and will be documented on the “NSAID/Acetaminophen Usage-Day 1” eCRF. 
Starting at Week 4 and at all subsequent in-person and phone visits until Week 56 (EOS) or ET, 
subjects will be asked about their NSAID/acetaminophen usage during the previous 4 weeks. 
This information (name, usual total daily dose, usual number of days taken per week) will be 
documented as concomitant medications. The Investigator will then compare the data with the 
baseline information obtained on Day 1. If there is a change from baseline, the Investigator will 
first assess whether the change was clinically relevant and, if clinically relevant, whether it was 
due to the subject’s target knee OA pain. Assessments will be documented on the 
“NSAID/Acetaminophen Usage (in Clinic Visits or Telephone Visits)” eCRF. 
7.1.2 
STANDARD OF CARE STUDY PROCEDURES  
All Investigators are to provide appropriate care to their subjects as they deem necessary; 
however, additional standard-of-care study procedures are not required by this protocol. 
7.2 
LABORATORY PROCEDURES/EVALUATIONS 
7.2.1 
CLINICAL LABORATORY EVALUATIONS  
Fasting specimens for clinical laboratory analysis by Medpace Central Laboratories will be 
collected by a qualified staff member at the Screening Visit and Weeks 4, 12, 24, 36, 52, and 56 
(EOS) or ET. Refer to the Laboratory Manual for details about collection of specimens.  
At a minimum, the following tests will be conducted: 
• Chemistry panel: Albumin, alkaline phosphatase (ALP), alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), blood urea nitrogen, bicarbonate, calcium, 
calcium (corrected total), chloride, creatinine, glucose, lactate dehydrogenase (LDH), 
potassium, sodium, bilirubin (total) 
• Hematology: Hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell 
(WBC) count with differential, and platelet count 
• Urinalysis: Clarity, specific gravity, pH, protein, glucose, ketones, nitrite, leukocyte 
esterase, and occult blood  
An HbA1c test will be performed on all subjects at the Screening Visit. 
Urine microscopy will be performed if urinalysis urine protein, leukocyte esterase (WBC 
esterase), occult blood, or nitrite values are out of range, or if the Investigator deems that the 
microscopy is clinically warranted. 
The Investigator or designee must review the results of each subject’s Screening Visit clinical 
laboratory test results prior to the Day 1 visit. The subject must not be randomized on Day 1 if 
any of the Screening Visit results are outside the normal range for the laboratory AND, in the 
opinion of the Investigator, are clinically significant.  
The results of the clinical laboratory tests will be reported on the laboratory’s standard reports. 
The Investigator must review all laboratory reports in a timely manner, noting “not clinically 
significant” (NCS) or comment on the clinical significance of any result that is outside the 
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normal range for the laboratory, then date and initial the report. The Investigator must report all 
laboratory results that are BOTH outside the normal range for the laboratory AND, in the 
opinion of the Investigator, are clinically significant. If any abnormal, clinically significant 
laboratory measure is found prior to study medication injection, the subject is to be excluded. If 
it is found after study medication injection, it should be reported as an AE. 
7.2.2 
OTHER ASSAYS OR PROCEDURES 
Pregnancy Test 
A serum-based pregnancy test will be performed on WOCBP at the Screening Visit and a 
urine-based pregnancy test will be performed on WOCBP at Day 1. Results from the pregnancy 
tests will be utilized to determine subject eligibility.  
WOCBP are women who are not post-menopausal (defined as 12 months with no menses 
without an alternative medical cause) or permanently surgically sterile (includes hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy). 
Drug Test 
A urine sample for drug testing will be collected at the Screening Visit. The urine drug test will 
include amphetamine, buprenorphine, cocaine, methadone, opiates, PCP, propoxyphene, 
barbiturates, benzodiazepine, methaqualone, and tricyclic antidepressants. Results from the drug 
test will be utilized to determine subject eligibility. 
Biomarkers 
Blood samples for biomarker analysis will be collected by a qualified staff member at the 
Screening Visit and Week 56 (EOS) or ET. Biomarkers that will be assessed include bone 
biomarkers (PINP and β-CTX) and a cartilage biomarker (COMP). 
7.2.3 
SPECIMEN PREPARATION, HANDLING, AND STORAGE 
Refer to the Laboratory Manual for Medpace Central Laboratories.  
7.2.4 
SPECIMEN SHIPMENT 
Refer to the Laboratory Manual for Medpace Central Laboratories. 
7.3 
STUDY SCHEDULE 
7.3.1 
PRESCREENING 
Prior to entry into a Samumed study for OA of the knee, subjects must have a radiograph taken 
and read by the Sponsor-specified central reader. This radiograph may qualify the subject for one 
or more Samumed studies. 
Prior to the Screening Visit, the subject’s prescreen radiograph report must be reviewed to 
confirm eligibility for this study. 
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7.3.2 
SCREENING 
Screening Visit 
The Screening Visit must occur within 7 to 11 days prior to Day 1. 
The Investigator or designee must explain the nature of the study protocol and associated risks to 
the potential study participant. The potential participant must be allowed to review the study 
information and to ask questions before being asked to sign and date the ICF. Written informed 
consent must be provided, signed, and dated by the potential study participant prior to initiation 
of any screening evaluations or other study-related procedures. The signature, date, and the name 
of the individual at the site who obtained the informed consent will be recorded. After written 
informed consent is obtained, the subject will be assigned a subject number.  
Investigators will maintain a confidential log of all subjects who have been screened for 
participation in the study whether or not the subject was eligible for study participation. 
Subjects should fast for 8 hours prior to this visit. The following procedures and assessments will 
be performed initially during the Screening Visit: 
• Physical examination, including knee examination of both knees and selection of 
target knee 
• Review of prescreen radiograph report for target knee 
• Documentation of demographic information, including date of birth, sex, race, and 
ethnicity 
• Subject NSAID training 
• Documentation of current and past medical history including prior procedures and 
non-drug therapies, assistive device usage, documentation of current medications, and 
review of prior medication excluded by the protocol 
• Documentation of past treatments for knee OA 
• WPI&SS assessment 
• Height and weight measurements 
• Vital sign measurements (pulse rate, blood pressure, respiratory rate, and 
temperature) 
It is recommended that the results from these evaluations be compared with inclusion/exclusion 
criteria to determine subject eligibility. If the subject is confirmed eligible, the following 
procedures and assessments will be performed: 
• Pregnancy test (serum-based) in WOCBP 
• Urine drug test  
• Venipuncture and collection of samples for clinical laboratory tests and biomarker 
analysis 
• Electronic diary device provision and subject training for electronic diary and 
questionnaire completion on the electronic device 
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• Training on accurate pain reporting and placebo response reduction 
Starting on the day of the Screening Visit, after the site visit, subjects will begin completion of 
daily pain NRS assessments remotely on their electronic devices in the evening (between 
5:00 pm and 11:59 pm). 
Note: Five days after the Screening Visit (or up until the day before the Day 1 visit), subjects 
will complete the WOMAC and Patient Global Assessment, in addition to the pain NRS 
assessment, in the evening (between 5:00 pm and 11:59 pm) remotely on their electronic devices. 
Refer to Section 7.3.8 for a schedule of electronic diary and questionnaire completion. 
7.3.3 
RANDOMIZATION 
Day 1 
This visit must occur within 7 to 11 days of the Screening Visit. 
The following procedures and assessments will be performed at Day 1 prior to randomization: 
• Review of current and past medical history, documentation of current medications, 
and review of prior medication excluded by the protocol 
• WPI&SS assessment 
• SF-36 questionnaire 
• Review of pain NRS electronic diary compliance from the Screening Visit to Day 1 
• Electronic questionnaire review (WOMAC) 
• Assessment of NSAID/acetaminophen pain medication usage to establish/document 
baseline usage  
• Physical examination, including knee examination of both knees 
• Vital sign measurements (pulse rate, blood pressure, respiratory rate, and 
temperature) 
• Pregnancy test (urine-based) for WOCBP 
Results from the Screening Visit and Day 1 evaluations will be compared with 
inclusion/exclusion criteria to determine subject eligibility. 
The following procedures and assessments will be performed at Day 1 following randomization: 
• IA injection of randomized study medication by the Unblinded Investigator (injector) 
• Collection of AE and concomitant procedures/medication data 
Note: After the Day 1 site visit, subjects will complete the following in the evening (between 
5:00 pm and 11:59 pm) remotely on their electronic devices: 
− Daily pain NRS assessments 
− WOMAC and Patient Global Assessment questionnaires at Week 4 (with a 
window of ± 3 days) and Weeks 12, 24, 36, 52, and 56 (with windows of ± 7 
days) 
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Refer to Section 7.3.8 for a schedule of electronic diary and questionnaire completion. 
7.3.4 
FOLLOW-UP  
Weeks 4, 12, and 36 
The Week 4 visit should occur on Day 29 (with a window of ± 3 days), the Week 12 visit should 
occur on Day 85 (with a window of ± 7 days), and the Week 36 visit should occur on Day 253 
(with a window of ± 7 days). Subjects should fast for 8 hours prior to these visits. 
The following procedures and assessments will be performed at these visits: 
• Collection of AE and concomitant procedures/therapies/medication data 
• Assessment of NSAID/acetaminophen usage  
• Physical examination, including knee examination of both knees  
• Vital sign measurements (pulse rate, blood pressure, respiratory rate, and 
temperature) 
• Venipuncture and collection of samples for clinical laboratory tests  
Weeks 8, 16, 20, 28, 32, 40, 44, and 48 (Phone Visits) 
Sites will contact subjects for phone visits on Days 57, 113, 141, 197, 225, 281, 309, and 337 
(with windows of ± 7 days). The following assessments will be performed at each visit: 
• Collection of AE and concomitant procedures/therapies/medication data 
• Assessment of NSAID/acetaminophen usage  
Week 24  
The Week 24 visit should occur on Day 169 (with a window of ± 7 days). Subjects should fast 
for 8 hours prior to this visit.  
The following procedures and assessments will be performed at this visit: 
• Collection of AE and concomitant procedures/therapies/medication data 
• Assessment of NSAID/acetaminophen usage  
• Physical examination, including knee examination of both knees  
• Weight measurement  
• Vital sign measurements (pulse rate, blood pressure, respiratory rate, and 
temperature) 
• Venipuncture and collection of samples for clinical laboratory tests 
• Radiograph – bilateral in weight-bearing fixed flexion position, PA view X-ray 
Week 52  
The Week 52 visit should occur on Day 365 (with a window of ± 7 days). Subjects should fast 
for 8 hours prior to this visit. 
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The following procedures and assessments will be performed at this visit: 
• Collection of AE and concomitant procedures/therapies/medication data 
• Assessment of NSAID/acetaminophen usage  
• SF-36 questionnaire 
• Physical examination, including knee examination of both knees  
• Vital sign measurements (pulse rate, blood pressure, respiratory rate, and 
temperature) 
• Venipuncture and collection of samples for clinical laboratory tests  
• Radiograph – bilateral in weight-bearing fixed flexion position, PA view X-ray* 
*If the Week 52 radiograph is assessed as unacceptable quality by central imaging vendors, 
radiographs may be taken up to 3 additional times between Week 52 (± 7 days) and Week 56 
(± 7 days) to obtain an acceptable image. 
7.3.5 
FINAL STUDY VISIT 
Week 56 End of Study  
This final study visit should occur on Day 393 with a window of ± 7 days. Subjects should fast 
for 8 hours prior to this visit. 
The following procedures and assessments will be performed at Week 56 (EOS): 
• Collection of AE and concomitant procedures/therapies/medication data 
• Review of medical history 
• Assessment of NSAID/acetaminophen usage  
• Physical examination, including knee examination of both knees 
• Weight measurement 
• Vital sign measurements (pulse rate, blood pressure, respiratory rate, and 
temperature) 
• Venipuncture and collection of samples for clinical laboratory tests and biomarker 
analysis 
7.3.6 
EARLY TERMINATION (ET) VISIT 
If possible, the following procedures and assessments should be performed within 14 days of 
subject premature withdrawal or termination. Subjects should fast for 8 hours prior to this visit. 
• Collection of AE and concomitant procedures/therapies/medication data 
• Review of medical history 
• Assessment of NSAID/acetaminophen usage 
• Physical examination, including knee examination of both knees 
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• Weight measurement 
• Vital sign measurements (pulse rate, blood pressure, respiratory rate, and 
temperature) 
• Radiograph – bilateral in weight-bearing fixed flexion position, PA view X-ray*† 
• Venipuncture and collection of samples for clinical laboratory tests and biomarker 
analysis† 
*Radiograph should only be performed if ET occurs on or after Week 24.  
†Radiograph and biomarkers are only to be performed/collected at the ET visit if not performed 
within 4 weeks prior to this visit. 
 
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7.3.7 
SCHEDULE OF EVENTS TABLE 
 
Procedure 
Screening 
Visita 
(Days -11 
to -7)  
Day 1b 
Week 4  
(Day 29  
±3 days) 
Weeks 8, 16, 
20, 28, 32, 40, 
44, 48c (±7 days) 
(Phone Visits) 
Week 12  
(Day 85 
±7 days) 
Week 24  
(Day 169  
±7 days) 
Week 36 
(Day 253 
±7 days) 
Week 52  
(Day 365  
±7 days)  
Week 56 
(EOS) 
(Day 393  
±7 days) 
Early 
Termin-
ation 
(ET) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion & exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
Xd 
Xd 
Current and prior  
procedures/medications 
X 
X 
 
 
 
 
 
 
 
 
Past treatments for knee 
OA pain 
X 
 
 
 
 
 
 
 
 
 
Subject NSAID training 
X 
 
 
 
 
 
 
 
 
 
Urine drug test 
X 
 
 
 
 
 
 
 
 
 
WPI&SS 
X 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Knee examination 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Selection of target knee 
X 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
X 
 
 
X 
X 
Vital signs 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Radiograph 
X 
(Review) 
 
 
 
 
X 
 
Xe 
 
Xf 
Serum pregnancy testg 
X 
 
 
 
 
 
 
 
 
 
Urine pregnancy testg 
 
X 
 
 
 
 
 
 
 
 
Clinical laboratory 
samplingh 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Biomarker blood samples 
X 
 
 
 
 
 
 
 
X 
Xf 
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Procedure 
Screening 
Visita 
(Days -11 
to -7)  
Day 1b 
Week 4  
(Day 29  
±3 days) 
Weeks 8, 16, 
20, 28, 32, 40, 
44, 48c (±7 days) 
(Phone Visits) 
Week 12  
(Day 85 
±7 days) 
Week 24  
(Day 169  
±7 days) 
Week 36 
(Day 253 
±7 days) 
Week 52  
(Day 365  
±7 days)  
Week 56 
(EOS) 
(Day 393  
±7 days) 
Early 
Termin-
ation 
(ET) 
Electronic diary and 
questionnaire training 
Xi 
 
 
 
 
 
 
 
 
 
Investigator assessment of 
NSAID/ 
acetaminophen usage  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SF-36 
 
X 
 
 
 
 
 
X 
 
 
Pain NRS 
 
Xj 
(Review) 
 
 
 
 
 
 
 
 
WOMAC 
 
Xk 
(Review) 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Intra-articular injection 
 
X 
 
 
 
 
 
 
 
 
AEs and concomitant 
procedures/therapies/medic
ations 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a  The screening period is a minimum of 7 days and a maximum of 11 days. The Screening Visit should only occur after review of the prescreen radiograph report 
for eligibility in this study. 
b  At Day 1, all procedures should be performed prior to study medication injection except for collection of AE and concomitant procedures/therapies/medication 
data. 
c  Phone visits should take place on Days 57, 113, 141, 197, 225, 281, 309, and 337 (± 7 days for all visits). 
d  Review medical history to capture End Date(s), if applicable, of any ongoing medical history(ies) collected at the Screening Visit and Day 1. 
e  The Week 52 radiograph may repeated up to 3 times between Week 52 (± 7 days) and Week 56 (± 7 days) to obtain an acceptable image. 
f  Radiograph and biomarkers are only to be performed/collected at the ET visit if not performed within 4 weeks prior to the ET visit.  
g  Serum and urine pregnancy tests are to be performed on WOCBP only.  
h Subjects should fast for 8 hours prior to clinical laboratory sampling. 
i  Electronic diary devices will be provided to subjects at the Screening Visit; subject electronic diary and questionnaire training including accurate pain reporting 
and placebo response reduction training will be conducted at the Screening Visit. Accurate pain reporting and placebo response reduction training is 
recommended at Weeks 4, 12, 24, 36, and 52.  
j  Electronic diary compliance and assessment of target and non-target knee pain scores for daily pain NRS over the screening period will be reviewed at Day 1 
prior to randomization to determine subject eligibility. 
k  WOMAC questionnaire will be reviewed at Day 1 prior to randomization to determine subject eligibility. 
 
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7.3.8 
SCHEDULE OF ELECTRONIC DIARY AND QUESTIONNAIRE COMPLETION TABLE 
 
 
WOMAC and Patient Global Assessment 
Daily pain NRS 
Study Week/Day  
WOMAC and Patient Global Assessment will be 
completed by subjects 5 days after the Screening Visit 
(or up until the day before the Day 1 visit), at Week 4 
(with a window of ± 3 days), and at Weeks 12, 24, 36, 
52, and 56 (with a window of ± 7 days) in the evening 
(between 5:00 pm and 11:59 pm) local time remotely 
on their electronic devices, as outlined below; ranges 
shown are inclusive.  
Pain NRS should be completed daily starting after the 
Screening Visit. Subjects will complete the diary in the 
evening (between 5:00 pm and 11:59 pm) local time remotely 
on their electronic devices. Diary completion should occur 
every day including on study visit days. 
Screening Visit  
  
  
  
  
Complete daily starting on the same day of the Screening Visit 
(after the visit); pain NRS assessments are to be completed for 
each knee. 
5 days after the 
Screening Visit 
Baseline WOMAC and Patient Global Assessment 
questionnaires  
(or up until the day before the Day 1 visit) 
Day 1 
 N/A 
Starting on the same day of Day 1 (after the visit), pain NRS 
assessments are to be completed for the target knee only. 
Complete daily.    
Week 4 (Day 29) 
Complete between Day 26 and 32  
Week 12 (Day 85) 
Complete between Day 78 and 92 
Week 24 (Day 169) 
Complete between Day 162 and 176 
Week 36 (Day 253) 
Complete between Day 246 and 260 
Week 52 (Day 365) 
Complete between Day 358 and 372 
Week 56 (Day 393) 
Complete between Day 386 and 400 
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7.4 
JUSTIFICATION FOR SENSITIVE PROCEDURES 
Not applicable for this study. 
7.5 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES  
Details regarding the name, indication, route of administration, dose, and frequency of all 
medications taken within 30 days prior to the Screening Visit through Week 56 (EOS) or ET will 
be recorded in the “Prior and Concomitant Medications” eCRF. “All medications” should 
include prescription, over the counter, supplements, as well as herbal or alternative medications.  
Procedures or non-drug therapies that are ongoing, new, or modified at or after the Screening 
Visit must be recorded on the “Procedures and Non-Drug Therapies” eCRF. 
AE assessments should include consideration of any new or modified concomitant therapies 
administered to the subject.  
7.5.1 
PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES 
Not applicable to this study. 
7.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES  
Prohibited Concomitant Medications and Procedures: 
• Any IA injection, including glucocorticoids, hyaluronic acid derivatives, PRP, stem 
cell therapies, or other agents with therapeutic intent, into either knee is prohibited 
while the subject is on study; IA injection of glucocorticoids, hyaluronic acid 
derivatives, PRP, stem cells, or other therapeutic agents into joints other than the knee 
is allowed. 
• The following medications are prohibited while the subject is on study: 
− Opioids; short-term use of opioids as part of anesthesia or procedural sedation 
during the study period is permitted 
− Centrally acting analgesics (e.g., duloxetine) (refer to Appendix 2)  
− Topical local anesthetic agents; short-term use as part of anesthesia, including for 
study injections during the study period is permitted 
− Other anticonvulsants not listed in Appendix 2  
− Systemic glucocorticoids ≥10 mg of prednisone per day or the equivalent; 
epidural, inhaled, intranasal, and topical glucocorticoids are permitted  
− Drugs screened to assess eligibility, unless clinically indicated and allowed by the 
protocol: amphetamine, buprenorphine, cocaine, methadone, opiates, PCP, 
propoxyphene, barbiturates, benzodiazepine, methaqualone, and tricyclic 
antidepressants  
• Electrotherapy (refer to Appendix 2), acupuncture, therapeutic ultrasound, and/or 
chiropractic treatments for knee OA are prohibited while the subject is on study. 
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• Any new formalized (i.e., prescribed by a medical professional) physical therapy 
exercise programs for knee OA are prohibited while the subject is on study; 
continuation of formalized physical therapy exercise programs that are already in 
progress at the time of screening are allowed. 
• Elective surgery, including arthroscopy, is prohibited while the subject is on the 
study. Nonsurgical invasive procedures conducted for a diagnostic or therapeutic 
purpose that are scheduled during the study period are not prohibited. Examples 
include, but are not limited to the following: endoscopy, colonoscopy, bronchoscopy, 
cystoscopy, radiologic procedures such as coronary artery catheterization with or 
without intervention, and nonsurgical cosmetic procedures such as Botox or other 
cosmetic injections. 
• Subjects are prohibited from participating in any other clinical research trial that 
includes the receipt of an IP or any experimental therapeutic procedure. Subjects are 
also prohibited from participating in any observational research trial while on study. 
The Investigator should notify the Samumed Medical Monitor(s) immediately if any prohibited 
therapies are required to ensure subject safety.  
7.7 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES  
Not applicable to this study. 
7.8 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES  
Subjects are allowed to remain on their stable regimen of NSAIDs/acetaminophen during this 
study and may change their usage as needed for pain management, including for the rescue of 
knee pain.  
7.9 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE  
Not applicable to this study. 
8. 
ASSESSMENT OF SAFETY 
8.1 
SPECIFICATION OF SAFETY PARAMETERS 
Safety assessments include physical examinations, vital signs, clinical laboratory tests, collection 
of AEs and SAEs and concomitant medications, and general medical evaluations.  
8.1.1 
DEFINITION OF ADVERSE EVENTS (AE) 
AEs in the eCRF will be classified according to the most recent US FDA definitions and in a 
manner consistent with ICH-GCP guidelines. As such the following definitions will be used: 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with 
the use of an IP or other protocol-imposed intervention, regardless of attribution. An AE may 
include intercurrent illnesses or injuries that represent an exacerbation (increase in frequency, 
severity, or specificity) of preexisting conditions (e.g., worsening of asthma).  
Whenever possible, it is preferable to record a diagnosis as the AE term rather than a series of 
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symptoms relating to a diagnosis. Fluctuations of pre-existing conditions, including the disease 
under study, that do not represent a clinically significant exacerbation or worsening, need not be 
considered AEs. In order to classify AEs and diseases, preferred terms will be assigned by the 
Sponsor to the original terms entered on the eCRF, using the Medical Dictionary for Regulatory 
Activities (MedDRA).   
In this protocol, signs and symptoms of exacerbation or worsening of target knee OA will be 
captured in the context of efficacy assessments and recorded on specific pages of the eCRF or 
electronic diary. Anticipated fluctuations or anticipated deterioration (in the opinion of the 
Investigator) of the underlying disease (target knee OA) will not be considered as AEs nor 
captured on the AE page of the eCRF. 
8.1.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
According to the ICH-GCP Guidelines E6 (R2), an SAE is any untoward medical occurrence 
during the course of a clinical investigation that is characterized by one or more of the following: 
• Results in death 
• Is life threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is an important medical event, defined as an event that does not fit one of the other 
outcomes, but may jeopardize the subject and may require medical or surgical 
intervention (treatment) to prevent one of the other outcomes. Examples include 
allergic bronchospasm (a serious problem with breathing) requiring treatment in an 
emergency room (ER), serious blood dyscrasias (blood disorders), or 
seizure/convulsion that does not result in hospitalization. The development of drug 
dependence or drug abuse would be other examples of important medical events.  
The term "life-threatening" in the definition of "serious" refers to an event in which the subject 
was at risk of death at the time of the event; it does not refer to an event that hypothetically might 
have caused death if it were more severe. 
“Inpatient hospitalization” is clarified as hospitalization lasting ≥24 hours. Admission to the 
hospital or prolongation of hospitalization qualifies as an SAE only if it is the result of an AE.  
All SAE information must be recorded on the SAE form approved by the Sponsor. Additional 
follow-up information (e.g., test results, autopsy, and discharge summary) may be requested to 
supplement the SAE report form and can be attached as de-identified records. 
8.1.3 
DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
An AE observed during the conduct of a study should be considered an Unanticipated Problem 
(UP) involving risk to human subjects, and be reported to the IRB, only if it was unexpected, 
serious, and would have implications for the conduct of the study (e.g., requiring a significant, 
and usually safety-related, change in the protocol, such as revising inclusion/exclusion criteria or 
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including a new monitoring requirement, informed consent, or IB). The occurrence of such an 
event would suggest that the research places study participants or others at a greater risk of harm.  
FDA recommends that there be careful consideration of whether an AE is a UP that must be 
reported to IRBs. In summary, FDA believes that only the following AEs should be considered 
as UPs that must be reported to the IRB:  
• A single occurrence of a serious, unexpected event that is uncommon and strongly 
associated with drug exposure (such as angioedema, agranulocytosis, hepatic injury, 
or Stevens-Johnson syndrome)  
• A single occurrence, or more often a small number of occurrences, of a serious, 
unexpected event that is not commonly associated with drug exposure, but 
uncommon in the study population (e.g., tendon rupture, progressive multifocal 
leukoencephalopathy)  
• An AE that is described or addressed in the IB, protocol, or informed consent 
documents, but occurs at a specificity or severity that is inconsistent with prior 
observations  
• An SAE that is described or addressed in the IB, protocol, or informed consent 
documents, but for which the rate of occurrence in the study represents a clinically 
significant increase in the expected rate of occurrence (ordinarily, reporting would 
only be triggered if there were a credible baseline rate for comparison)  
• Any other AE or safety finding (e.g., based on animal or epidemiologic data) that 
would cause the sponsor to modify the IB, study protocol, or informed consent 
documents, or would prompt other action by the IRB to ensure the protection of 
human subjects  
8.2 
CLASSIFICATION OF AN ADVERSE EVENT 
8.2.1 
SEVERITY OF EVENT 
The Investigator will assess AEs for severity utilizing the CDISC AESEV, which classifies AEs 
as mild, moderate, or severe (Table 1). 
Table 1: 
CDISC Definitions of Adverse Event Severity 
CDISC Submission 
Value 
CDISC Definition 
MILD 
A type of adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with 
usual activities of daily living. 
MODERATE 
A type of adverse event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant. 
SEVERE 
A type of adverse event that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. 
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8.2.2 
RELATIONSHIP TO STUDY AGENT 
The relationship of the study treatment to an AE will be determined by the Investigator based on 
the following definitions: 
Not Related 
The AE is not related if (1) exposure to the study medication or administration of the study 
injection has not occurred or (2) the occurrence of the AE is not reasonably related in time or 
(3) the AE is considered related to another event, medical condition, or product not associated 
with the study medication or the study injection. 
Unlikely Related 
The AE is unlikely related if (1) the AE is unlikely related in time or (2) the AE is considered 
unlikely to be related to use of the study medication or study injection (i.e., there are no facts 
[evidence] or arguments to suggest a causal relationship), or the AE is considered possibly 
related to another event, medical condition, or product not associated with the study medication. 
Possibly Related 
The AE is possibly related if (1) the study medication or the study injection and AE are 
considered reasonably related in time and (2) the AE could equally be explained by causes other 
than exposure to the study medication or the study injection. 
Probably Related 
Exposure to study medication or administration of the study injection and AE are probably 
related if (1) the study medication or study injection and AE are considered reasonably related in 
time and (2) the study medication or study injection is more likely than other causes to be 
responsible for the AE or is the most likely cause of the AE. 
8.2.3 
EXPECTEDNESS  
The Sponsor will be responsible for determining whether an AE/SAE is expected or unexpected. 
An AE/SAE will be considered unexpected if the nature, severity, or frequency of the event is 
not consistent with the risk information previously described for the study agent in the IB or is 
not listed in the IB at the specificity or severity that has been observed.  
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The reporting period for AEs starts after the injection of study medication on Day 1 and ends 
after the final study visit. 
AEs will be followed until the subject’s last visit or resolution, whichever comes first. For 
subjects who discontinue from the study within 30 days of their dose of study medication, AEs 
that are ongoing at the subject’s last visit will be followed for 30 days after administration of the 
dose or until resolution, whichever comes first. Resolution is defined as the return to baseline 
status or stabilization of the condition. SAEs and selected AEs identified by the Investigator or 
the Sponsor to warrant further follow-up that are ongoing at a subject’s last visit will be followed 
until resolution.  
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8.4 
REPORTING PROCEDURES 
8.4.1 
ADVERSE EVENT REPORTING  
The Investigator is responsible for reporting AEs to the Sponsor via the eCRF and to the IRB 
according to the protocol and 21 Code of Federal Regulations (CFR) Parts 50, 56, and 312. The 
Investigator is responsible for ensuring accurate AE information is reviewed and recorded in the 
subject source and the AE eCRF in a timely manner. The Sponsor is responsible for submitting 
reports of AEs associated with the use of study medication that are both serious and unexpected 
to the FDA according to 21 CFR 312.32. All Investigators participating in ongoing studies with 
the study medication will receive copies of these reports from the Sponsor for prompt submission 
to their IRB/EC according to their institution’s requirements.  
8.4.2 
SERIOUS ADVERSE EVENT REPORTING  
The Investigator is responsible for reporting SAEs to the Sponsor and IRB according to 21 CFR 
Parts 50, 56, and 312.  
Using the SAE Report Form, SAEs must be reported within 24 hours of study site personnel’s 
knowledge of the event, regardless of the Investigator assessment of the relationship of the event 
to study drug. The Investigator should review the SAE information and sign the SAE report, and 
the Investigator or designee should submit the SAE report to the Samumed Study SAE email 
address: sae@samumed.com or FAX: +1 858 408 4470.  
The initial report should include, at a minimum, the following: 
• Investigator name 
• Subject number, sex, and age 
• Details of study drug administration 
• The date of the report 
• A description of the SAE (including event term and serious criteria) 
• Causal relationship to the study drug 
• If the subject died, the report should include the cause of death as the event term 
(with fatal outcome) and whether or not the death was related to study drug, as well 
as the autopsy findings if available. 
Follow-up information must be detailed in a follow-up SAE report and reported to the Samumed 
Study SAE email address or fax number as it becomes available. The Investigator also must 
report all SAEs promptly to the appropriate IRB/EC as required by the institution. Sponsor 
contact information for questions regarding SAE reporting is provided in Table 2. 
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Table 2: 
Sponsor Contact Information for Questions on SAE Reporting 
Primary Contact 
Alternative Contact 
Roza Amin, MD, Medical Reviewer, Drug 
Safety and Pharmacovigilance  
Sherry Beckman, Scientist, Drug Safety and 
Pharmacovigilance  
Cellular: (858) 732-2386 
Cellular: (858) 500-6021 
Email:  roza@samumed.com 
Email:  sherryb@samumed.com 
8.4.3 
UNANTICIPATED PROBLEM REPORTING  
Incidents or events that meet the criteria for UP (see Section 8.1.3) require the creation and 
completion of an UP report. It is the site Investigator’s responsibility to report UPs to their IRB 
and to the Sponsor. The UP report will include the following information:  
• Protocol identifying information: protocol title and number, Investigator’s name, and 
the IRB project number  
• A detailed description of the event, incident, experience, or outcome; and  
• An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:  
• UPs that are SAEs will be reported to the Sponsor and the IRB within 24 hours of the 
Investigator becoming aware of the event on the SAE report form 
• Any other UP will be reported to the IRB and to the Sponsor within the IRB-required 
reporting timeframe  
8.4.4 
EVENTS OF SPECIAL INTEREST  
Not applicable to this study. 
8.4.5 
REPORTING OF PREGNANCY  
If the subject or partner of the subject becomes pregnant, the pregnancy is to be followed until 
the outcome is known. An IRB-approved Pregnant Subject or Pregnant Partner Data Release 
Form should be completed by the subject or the subject’s pregnant partner in order to obtain 
consent to follow the progress of the pregnancy and birth, and the health of the infant.  
Any pregnancy will be collected on a Samumed Pregnancy Report Form. Information will be 
collected for any pregnancy in a female subject or the pregnant female partner of a male subject 
(if consenting), which occurs during the study, including perinatal and neonatal outcome. Infants 
resulting from such pregnancies should be followed for a minimum of 12 weeks. 
8.5 
STUDY HALTING RULES  
Not applicable to this study. 
 
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8.6 
SAFETY OVERSIGHT 
Clinical safety oversight will be performed by centralized review conducted by Medical 
Monitor(s) per the Medical Monitoring Plan. In addition, on-site review will be conducted by 
Clinical Research Associates. 
9. 
CLINICAL MONITORING 
All aspects of the study will be monitored by the Sponsor or the Sponsor’s designees with 
respect to current GCP and Standard Operating Procedures (SOPs) for compliance with 
applicable government regulations. It is the responsibility of the Investigator to provide all study 
records, including eCRFs and source documents among other records, for review and inspection 
by the clinical monitor. 
Clinical monitoring will be performed per the Clinical Monitoring Plan. Clinical monitors will 
periodically evaluate the progress of the study, including the verification of appropriate consent 
form procedures and the verification of the accuracy and completeness of eCRFs. Clinical 
monitors will also ensure that all protocol requirements, applicable US FDA regulations, other 
regulatory requirements, and the Investigator’s obligations are being fulfilled. 
Centralized data monitoring will be performed per the Centralized Data Monitoring Plan in order 
to periodically evaluate study progress and risks. A regular report of risks will be utilized 
together with centralized data monitoring to direct overall monitoring focus and activities to the 
areas of greatest risk which have the most potential to impact subject safety and data quality. 
The accuracy of the data will be verified by reviewing the documents described in Section 11. 
10. 
STATISTICAL CONSIDERATIONS  
10.1 
STATISTICAL AND ANALYTICAL PLANS 
This section describes the planned statistical analyses in general terms. A complete description of 
the statistical analyses will be specified in a statistical analysis plan (SAP), finalized prior to 
database lock.   
10.2 
STATISTICAL HYPOTHESES 
The statistical hypotheses being tested in this study include: 
• The least squares estimate of improvement from baseline in weekly average of daily 
pain NRS at Week 12 is greater for subjects who received SM04690 compared to 
placebo. 
• The least squares estimate of improvement from baseline in weekly average of daily 
pain NRS at Week 24 is greater for subjects who received SM04690 compared to 
placebo. 
• The least squares estimate of improvement from baseline in weekly average of daily 
pain NRS at Week 52 is greater for subjects who received SM04690 compared to 
placebo. 
• The least squares estimate of improvement from baseline in WOMAC Function at 
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Week 12 is greater for subjects who received SM04690 compared to placebo. 
• The least squares estimate of improvement from baseline in WOMAC Function at 
Week 24 is greater for subjects who received SM04690 compared to placebo. 
• The least squares estimate of improvement from baseline in WOMAC Function at 
Week 52 is greater for subjects who received SM04690 compared to placebo. 
• The least squares estimate of improvement from baseline in Patient Global 
Assessment at Week 12 is greater for subjects who received SM04690 compared to 
placebo. 
• The least squares estimate of improvement from baseline in Patient Global 
Assessment at Week 24 is greater for subjects who received SM04690 compared to 
placebo. 
• The least squares estimate of improvement from baseline in Patient Global 
Assessment at Week 52 is greater for subjects who received SM04690 compared to 
placebo. 
The familywise error rate will be controlled in the strong sense using the closed, fixed sequence 
testing method (Dmitrienko, Tamhane et al. 2010). All hypothesis tests will be evaluated in a 
prespecified sequential order that will be documented in the SAP. 
10.3 
ANALYSIS DATASETS 
Full Analysis Set (FAS): All subjects who are randomized and receive a study injection. The 
FAS is used to describe the analysis set which is as complete as possible and as close as possible 
to the intent-to-treat ideal of including all randomized subjects. 
Per-Protocol Analysis Set (PPAS): FAS subjects who complete the study and do not have any 
major protocol deviations. 
Safety Analysis Set (SAS): All subjects who receive a study injection. 
10.4 
DESCRIPTION OF STATISTICAL METHODS  
10.4.1 
GENERAL APPROACH 
For continuous variables, the number of subjects in the analysis, mean, standard deviation (SD), 
median, minimum, and maximum will be reported. All categorical endpoints will be summarized 
using frequencies and percentages. 
10.4.2 
ANALYSIS OF THE PRIMARY ENDPOINT 
Change over time in weekly average of daily pain NRS will be characterized using a 
mixed-effects model for repeated measures (MMRM) in order to estimate change from baseline 
with treatment group, week, treatment × week interaction and baseline value as covariates. The 
model will be evaluated at Week 12. Unadjusted 95% confidence intervals and P values will be 
reported. The potential confounding effect of change in NSAID/acetaminophen usage on the 
treatment effect will be considered for sensitivity analysis. 
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10.4.3 
ANALYSIS OF THE SECONDARY ENDPOINTS(S) 
Change over time in secondary endpoints will be characterized using MMRM in order to estimate 
change from baseline with treatment group, week, treatment × week interaction and baseline 
value as covariates. The model will be evaluated for weekly average of daily pain NRS at 
Weeks 24 and 52 and WOMAC Function and Patient Global Assessment at Weeks 12, 24, and 
52, as well as change in NSAID/acetaminophen usage. Unadjusted 95% confidence intervals and 
P values will be reported. The potential confounding effect of change in NSAID/acetaminophen 
usage on the treatment effect will be considered for sensitivity analysis of pain NRS, WOMAC 
Function, and Patient Global Assessment. 
10.4.4 
SAFETY ANALYSES 
Safety analyses will be performed on subjects who receive a study injection. Safety assessments 
include physical examinations, vital signs, clinical laboratory tests, solicitation of AEs and 
concomitant medications, and general medical evaluations. No formal statistical analyses are 
planned. Safety will be evaluated based on the incidence, seriousness, severity, and relationship 
of AEs and by changes in clinical laboratory parameters and vital signs, relative to baseline.  
Analysis of covariance (ANCOVA) will be used to analyze the change in biomarkers COMP, 
PINP, and β-CTX. Change will be assessed from baseline between the SM04690 and placebo 
treatment groups. The models will be adjusted for baseline and evaluated at Week 56. 
Unadjusted 95% confidence intervals and P values will be reported. 
10.4.5 
OTHER ENDPOINTS 
ANCOVA will be used to analyze the change in SF-36 domain scores and summary component 
scores. Change will be assessed from baseline between the active and placebo treatment groups. 
The models will be adjusted for baseline and evaluated at Week 52. Unadjusted 95% confidence 
intervals and P values will be reported. 
Change over time in WOMAC Pain and WOMAC Total will be characterized using MMRM in 
order to estimate change from baseline with treatment group, week, treatment × week interaction 
and baseline value as covariates. The model will be evaluated at Weeks 12, 24, and 52. 
Unadjusted 95% confidence intervals and P values will be reported. 
In addition, baseline-adjusted ANCOVA will be used to analyze the change in mJSW between 
SM04690 and placebo treatment groups at Week 52. 
10.4.6 
BASELINE DESCRIPTIVE STATISTICS 
Baseline is defined as the last value recorded for any given parameter prior to study medication 
injection unless otherwise specified. If a radiograph is rated unacceptable by central imaging 
vendors and follow-up radiographs are also rated unacceptable, the first radiograph will serve as 
the baseline assessment. If a subject never received a study injection, baseline is defined as the 
last value recorded prior to study termination. 
Baseline descriptive statistics will include age, sex, race, height, weight, BMI, KL grade, and the 
presence of symptomatic and radiographic OA. 
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10.4.7 
PLANNED INTERIM ANALYSES  
Not applicable to this study.  
10.4.7.1 
SAFETY REVIEW 
Medical monitoring of study safety assessment data will be performed during periodic safety 
reviews detailed in the Medical Monitoring Plan. 
10.4.7.2 
EFFICACY REVIEW 
Not applicable to this study.  
10.4.8 
EXPLORATORY ANALYSES 
Not applicable to this study.  
10.4.9 
SUBGROUP ANALYSES 
• Intermarginal distance by both variability (i.e., change) and actual measurement 
• Bilateral radiographic disease (KL grade 2-3 in both knees) 
10.5 
SAMPLE SIZE 
A sample size of approximately 725 subjects was selected for this study in order to yield 
325 evaluable subjects per treatment group assuming 10% dropout. 
One thousand Monte Carlo simulations generated baseline and follow-up data from a bivariate 
normal distribution for each treatment group and estimated the least squares difference between 
treatment and placebo in an outcome’s change using a baseline-adjusted ANCOVA. The 
proportion of statistically significant results at α=0.05 was estimated as the approximate power 
for a sample size of 325 subjects per group. 
The following assumptions were made based upon observed data in the SM04690-OA-02 and 
SM04690-OA-04 studies: 
• For weekly average of daily pain NRS, assuming a baseline mean (SD) of 6.0 (1.5), 
follow-up mean (SD) of 3.0 (3.0) for SM04690 and 3.8 (3.0) for placebo (presumed 
treatment difference -0.8), and a baseline to follow-up correlation of 0.25, power is 
estimated to be 93.5%. 
• For WOMAC Function, assuming a baseline mean (SD) of 60 (14), follow-up mean 
(SD) of 30 (29) for SM04690 and 37.5 (29) for placebo (presumed treatment 
difference -7.5), and a baseline to follow-up correlation of 0.25, power is estimated to 
be 92.0%. 
• For Patient Global Assessment, assuming a baseline mean (SD) of 55 (20), follow-up 
mean (SD) of 35 (27) for SM04690 and 42.5 (27) for placebo (presumed treatment 
difference -7.5), and a baseline to follow-up correlation of 0.25, power is estimated to 
be 95.3%. 
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• For mJSW, assuming a baseline mean (SD) of 3.0 (0.7) mm, follow-up mean (SD) of 
3.0 (1.0) mm for SM04690 and 2.85 (1.0) mm for placebo (presumed treatment 
difference 0.15 mm), and a baseline to follow-up correlation of 0.9, power is 
estimated to be 99.0%. 
10.6 
MEASURES TO MINIMIZE BIAS 
10.6.1 
BLINDING PROCEDURES 
This is a double-blind study. Study medication will be provided to the investigational center, 
which must identify unblinded personnel who are able to prepare and perform the injection of 
study medication. Study personnel administering or preparing study medication must minimize 
any contact with the subject following the injection and may not perform any study assessments 
throughout the duration of the study. Each site will be required to document a blinding plan that 
identifies the blinded and unblinded personnel at the investigational center and describes how the 
study blind will be maintained. 
Subjects will be assigned a subject number at their Screening Visit. On Day 1, eligible subjects 
will be randomized via the Medidata Rave database. Upon randomization of a subject, an email 
with the subject’s corresponding kit number will be sent from Medidata (Medidata-
Notification@mdsol.com) to the investigational staff member designated to dispense study 
medication. Subjects will be randomized 1:1 (0.07 mg active per 2 mL injection: 2 mL placebo) 
to each treatment group using a permuted block design. Specific information regarding the use of 
Medidata Rave Randomization and Trial Supply Management (RTSM) to store and implement 
the permuted block design will be detailed within the SAP. 
10.6.2 
EVALUATION OF SUCCESS OF BLINDING  
Not applicable to this study. 
10.6.3 
BREAKING THE STUDY BLIND/PARTICIPANT CODE 
The blind may be broken by a qualified physician who is an Investigator in this study in the 
event of a medical emergency in which knowledge of the identity of the study medication is 
critical to the management of the subject’s immediate course of treatment. Before breaking the 
blind, the Investigator should determine that the information is necessary (i.e., that it will alter 
the subject’s immediate course of treatment).  
If deemed necessary to break the blind for a study subject, the Samumed Medical Monitor(s) is 
to be contacted to obtain concurrence. If it is not possible to contact the Medical Monitor(s) 
beforehand, he or she should be contacted as soon as possible after breaking the blind for a 
subject. Details regarding the emergency unblinding will be documented in Medidata Rave 
RTSM and medical records. Instructions on how to unblind treatment assignment will be 
provided to each Investigator and kept within a guidance document at each site. No other blinded 
site users will have access roles to Medidata Rave RTSM that will allow treatment assignment 
unblinding. 
Any subject whose blind has been broken will continue their follow-up visits as per protocol.   
In circumstances when the blind is unintentionally broken at the investigational center, the 
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breaking of the blind should be reported to the designated Sponsor-unblinded Clinical Research 
Associate as soon as possible after breaking the blind for a subject. 
11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
The Investigator must maintain required records for all study subjects. Source data are all 
information, original records of clinical findings, observations, or other activities in a clinical 
trial necessary for the reconstruction and evaluation of the trial. Source data for this study will be 
recorded in the subject’s source documents and on the eCRFs, unless otherwise noted. All data 
on these eCRFs should be recorded completely and promptly. A copy of the completed eCRFs 
for each subject will be retained by the investigational center. 
The Investigator must maintain adequate and accurate source documents upon which eCRFs for 
each subject are based. They are to be separate and distinct from eCRFs, except for cases in 
which the Sponsor has predetermined that direct data entry into specified pages of the subject’s 
eCRF is appropriate (e.g., electronic clinical outcomes assessment [eCOA] questionnaires). The 
source documents should include detailed notes on the following: 
• The oral and written communication with the subject regarding the study (including 
the risks and benefits of the study), both at the site and by phone, and the date of 
informed consent(s) must be recorded in the source documentation 
• The subject’s medical and disease history before participation in the study 
• The subject’s basic identifying information, such as subject number, that links the 
subject’s source documents with the eCRFs 
• The results of all diagnostic tests performed, diagnoses made, therapy provided, and 
any other data on the condition of the subject 
• All AEs  
• The subject’s exposure to any concomitant therapy (including start and stop dates, 
route of administration, and dosage)  
eCOA questionnaire data is considered electronic source data created as subjects enter responses 
into the electronic device. Once submitted, responses cannot be changed or modified by the 
subject or any other user. There is no source data verification required for such data as is it 
directly attributable to the subject once electronically stored. Therefore, eCOA questionnaire 
results are not transferred to eCRFs. 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL 
This study will be organized, performed, and reported in compliance with the protocol, SOPs, 
site/Investigator training, and applicable regulations and guidelines. Clinical Investigator sites 
will be trained at the Investigator Meeting and/or individual, on-site visits. All aspects of the 
study will be monitored carefully by the Sponsor’s designees with respect to current GCP and 
SOPs for compliance with applicable government regulations. It is the responsibility of the 
Investigator to provide all study records, including case report forms (CRFs) and source 
documents, among other records, for review and inspection by the clinical monitor. 
The Integrated Quality and Risk Management Plan (IQRMP) details the trial specific quality 
management plans to indicate how risks are mitigated and data quality is addressed in the clinical 
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trial.  
13. 
ETHICS/PROTECTION OF HUMAN SUBJECTS  
13.1 
ETHICAL STANDARD  
The study will be conducted in accordance with the Declaration of Helsinki (1964), including all 
amendments up to and including the Brazil revision (2013). The Investigator will ensure that this 
study is conducted in full conformity with Regulations for the Protection of Human Subjects of 
Research set forth in US 21 CFR Part 50, 21 CFR Part 56, and/or the ICH-GCP E6 (R2). 
13.2 
INSTITUTIONAL REVIEW BOARD  
The Investigator agrees to provide the IRB/EC with all appropriate material, including a copy of 
the ICF. The study will not be initiated until the Investigator obtains written approval of the 
research plan and the ICF from the appropriate IRB/EC and copies of these documents are 
received by the Sponsor. Appropriate reports on the progress of this study will be made by the 
Investigator to the IRB/EC and Sponsor in accordance with applicable government regulations 
and in agreement with the policies established by the Sponsor and the IRB/EC. Any amendment 
to the protocol will require review and approval by the IRB before the changes are implemented 
to the study. All changes to the consent form will be IRB-approved; a determination will be 
made regarding whether previously consented participants need to be re-consented. The Sponsor 
ensures that the IRB/EC complies with the requirements set forth in US 21 CFR Part 56.  
13.3 
INFORMED CONSENT PROCESS  
13.3.1 
CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS 
PROVIDED TO PARTICIPANTS 
Consent forms describing in detail the study procedures and risks will be given to the potential 
participant and written documentation of informed consent is required prior to starting any 
screening evaluations or other study-related procedures.   
13.3.2 
CONSENT PROCEDURES AND DOCUMENTATION 
The informed consent and consent process should be in accordance with the current Declaration 
of Helsinki, ICH, GCP, federal, state, and local regulations. The Investigator or designee must 
explain the nature of the study protocol and associated risks to the potential study participant. 
The potential participant must be allowed to review the study information and to ask questions 
before being asked to sign and date the ICF. Written informed consent must be provided (signed 
and dated) by the potential study participant prior to initiation of any screening evaluations or 
other study-related procedures. A copy of the ICF will be given to the participants for their 
records. The signature, date, and the name of the individual at the site who obtained the informed 
consent will be recorded.  
13.4 
PARTICIPANT AND DATA CONFIDENTIALITY  
The Investigator(s) and the Sponsor or its authorized representative will preserve the 
confidentiality of all subjects participating in a study, in accordance with current GCP, federal, 
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state, and local regulations, including, to the extent applicable, the Health Insurance Portability 
and Accountability Act of 1996 (HIPAA). 
In order to maintain subject confidentiality, all eCRFs, study reports, and communications 
relating to the study will identify subjects by initials and assigned subject numbers; subjects 
should not be identified by name. If a subject name appears on any document, it must be 
obliterated before a copy of the document is supplied to the Sponsor or its authorized 
representative. Study findings stored on a computer will be stored in accordance with federal, 
state, and local data protection laws. Subjects will be told that representatives of the Sponsor, its 
authorized representative, IRB or EC, or regulatory authorities may inspect their medical records 
to verify the information collected, and that all personal information will be held in strict 
confidence and in accordance with applicable data protection laws. The Investigator or designee 
will maintain a personal subject identification list (subject numbers with the corresponding 
subject names) to make it possible for records to be identified.  
Clinical information will not be released without written permission from the subject, except as 
necessary for monitoring by the IRB/EC, the FDA, or the study Sponsor.  
Any information, inventions, or discoveries (whether patentable or not), innovations, 
suggestions, ideas, and reports made or developed by the Investigator(s) as a result of conducting 
this study shall be promptly disclosed to the Sponsor and shall be the sole property of the 
Sponsor. The Investigator agrees, upon the Sponsor’s request and at the Sponsor’s expense, to 
execute such documents and to take such other actions, as the Sponsor deems necessary or 
appropriate, to obtain patents in the Sponsor’s name covering any of the foregoing. 
13.4.1 
RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS, OR DATA 
Not applicable to this study. 
13.5 
FUTURE USE OF STORED SPECIMENS  
Not applicable to this study. 
14. 
DATA HANDLING AND RECORD KEEPING  
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
As defined by ICH guidelines, the CRF is a printed, optical, or electronic document designed to 
record all protocol-required information to be reported to the Sponsor on each study subject. 
Data required by the protocol will either be collected within eCRFs of the study-specific 
Medidata Rave database or provided directly to the Sponsor via data transfers. Medidata Rave is 
a validated electronic data capture (EDC) system fully compliant with regulatory expectations 
for software developers and service providers within the global regulatory environment, 
including but not limited to ICH-GCP E6 (R2) and US 21 CFR Parts 312, 812, and 11. Data to 
be transferred external to Rave may include eCOA questionnaires, central laboratory data, and 
imaging results. 
Data collection on the eCRF will follow the instructions described in the eCRF Completion 
Guidelines. The Investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the eCRF. The Investigator or designee as identified on Form FDA 1572 
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will electronically sign the completed eCRF to attest to its accuracy, authenticity, and 
completeness. Copies of the completed eCRFs will be retained by each investigational center as 
well as the Sponsor. 
Clinical data management activities will be conducted by the Sponsor as described in the 
study-specific Data Management Plan. 
14.2 
STUDY RECORDS RETENTION  
During this study, the Investigator is required to prepare and maintain adequate and accurate case 
histories designed to record all observations and other data pertinent to the investigation on each 
individual treated with the IP or entered as a control in the investigation. CRFs will be provided 
for each subject by the Sponsor. Data reported on the eCRFs and derived from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
completed eCRFs must be promptly reviewed, and electronically signed and dated in EDC by a 
qualified physician who is an Investigator on the study once all data is considered final. During 
this study, the Investigator must retain copies of eCRFs (or electronic files), and source 
documents for the maximum period required by (1) applicable regulations and guidelines or 
institution procedures or (2) for the period specified by the Sponsor, whichever is longer. The 
Investigator must contact the Sponsor prior to destroying any records associated with the study. 
The Sponsor will notify the Investigator when the study records are no longer needed. 
In the event the Investigator withdraws from the study (e.g., relocation, retirement), the records 
shall be transferred to a mutually agreed-upon designee (e.g., another Investigator). Notice of 
such transfer will be given in writing to the Sponsor. 
The Investigator must ensure that clinical study records are retained according to national 
regulations, as documented in the Clinical Trial Agreement entered into with the Sponsor in 
connection with this study. For example, US federal laws require that an Investigator maintain all 
study records for the indication under investigation for 2 years following the date of a New Drug 
Application approval or, if no application is filed or if the application is not approved for such 
indication, until 2 years after the investigation is discontinued and the FDA is notified. 
The Sponsor will maintain correspondence with the Investigator after study closeout to ensure 
that study documentation is retained for the appropriate amount of time. Subject files and other 
source data must be kept for the maximum period of time permitted by the hospital, institution, 
or private practice and should be retained in accordance with applicable regulations. The 
Investigator must inform the Sponsor immediately if any documents are to be destroyed, to be 
transferred to a different facility, or to be transferred to a different owner. 
14.3 
PROTOCOL DEVIATIONS  
The Investigator and study staff will apply due diligence to avoid protocol deviations. If protocol 
deviations do occur, the Investigator or study staff must report them to the local IRB/EC per their 
guidelines.  
14.4 
PUBLICATION AND DATA SHARING POLICY 
The Sponsor encourages the scientific publication of data from clinical research studies. 
Investigators, however, may not present or publish partial or complete study results individually 
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without the participation of the Sponsor. The Investigator(s) and the Sponsor may propose 
appropriate scientific manuscripts or abstracts from the study data. All proposed publications 
must be reviewed and commented on by the Sponsor before submission for publication. The 
detailed procedures for the review of publications are set out in the Clinical Trial Agreement 
entered into with the Sponsor in connection with this study. These procedures are in place to 
ensure coordination of study data publication and adequate review of data for publication against 
the validated study database for accuracy. Names of all Investigators and Sponsor representatives 
responsible for designing the study and analyzing the results will be included in the 
publication(s). 
15. 
STUDY ADMINISTRATION 
15.1 
STUDY LEADERSHIP 
The study will be led and conducted by Samumed, LLC.  
15.2 
KEY ROLES 
Medical monitor 
Ismail Simsek, MD - Medical Director 
Samumed, LLC 
9381 Judicial Dr. 
San Diego, CA 92121 
(858) 926-2968 
ismail@samumed.com 
Back-up medical monitor 
Naina Rastalsky, MD – Study Physician  
Samumed, LLC 
9381 Judicial Dr. 
San Diego, CA 92121 
(858) 371-3874 
naina@samumed.com  
Central radiology reader 
Medical Metrics, Inc. (MMI) 
2121 Sage Road, Suite 300 
Houston, Texas 77056 
(713) 850-7500 
Electronic clinical outcomes 
assessment (eCOA) 
YPrime 
9 Great Valley Parkway 
Malvern, PA 19355 
(888) 201-7988 
Central laboratory 
Medpace Central Laboratories 
5365 Medpace Way 
Cincinnati, Ohio 45227 
(800) 749-1737 
 
 
 
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16. 
LITERATURE REFERENCES  
Altman, R., E. Asch, D. Bloch, G. Bole, D. Borenstein, K. Brandt, W. Christy, T. D. Cooke, R. 
Greenwald, M. Hochberg and et al. (1986). "Development of criteria for the classification and 
reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and 
Therapeutic Criteria Committee of the American Rheumatism Association." Arthritis Rheum 
29(8): 1039-1049. 
 
Clauw, D. J. (2014). "Fibromyalgia: a clinical review." JAMA 311(15): 1547-1555. 
 
Dmitrienko, A., A. C. Tamhane and F. Bretz (2010). Multiple testing problems in pharmaceutical 
statistics. Boca Raton, FL, Chapman & Hall/CRC. 
 
Dougados, M. and M. C. Hochberg (2011). Management of osteoarthritis. Rheumatology. M. C. 
Hochberg, A. J. Silman, J. S. Smolen, M. E. Weinblatt and M. H. Weisman. PA, USA, Elsevier: 
1793-1799. 
 
Gelse, K., A. B. Ekici, F. Cipa, B. Swoboda, H. D. Carl, A. Olk, F. F. Hennig and P. Klinger 
(2012). "Molecular differentiation between osteophytic and articular cartilage--clues for a 
transient and permanent chondrocyte phenotype." Osteoarthritis Cartilage 20(2): 162-171. 
 
Hochberg, M. C., R. D. Altman, K. T. April, M. Benkhalti, G. Guyatt, J. McGowan, T. Towheed, 
V. Welch, G. Wells, P. Tugwell and R. American College of (2012). "American College of 
Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic 
therapies in osteoarthritis of the hand, hip, and knee." Arthritis Care Res (Hoboken) 64(4): 465-
474. 
 
Lawrence, R. C., D. T. Felson, C. G. Helmick, L. M. Arnold, H. Choi, R. A. Deyo, S. Gabriel, R. 
Hirsch, M. C. Hochberg, G. G. Hunder, J. M. Jordan, J. N. Katz, H. M. Kremers, F. Wolfe and 
W. National Arthritis Data (2008). "Estimates of the prevalence of arthritis and other rheumatic 
conditions in the United States. Part II." Arthritis Rheum 58(1): 26-35. 
 
National Council on Radiation Protection and Measurements (2009). Ionizing radiation exposure 
of the population of the United States. Bethesda, MD, National Council on Radiation Protection 
and Measurements. 
 
Nevitt, M. C., D. T. Felson and G. Lester (2006). " A Knee Health Study." "The Osteoarthritis 
Initiative.". 
 
Wu, L., X. Huang, L. Li, H. Huang, R. Xu and W. Luyten (2012). "Insights on biology and 
pathology of HIF-1alpha/-2alpha, TGFbeta/BMP, Wnt/beta-catenin, and NF-kappaB pathways in 
osteoarthritis." Curr Pharm Des 18(22): 3293-3312. 
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APPENDIX 
Appendix 1. 
American College of Rheumatology Clinical and Radiographic Criteria for 
Classification of Osteoarthritis of the Knee  
Per American College of Rheumatology (ACR) clinical and radiographic classification criteria 
(Altman, Asch et al. 1986), the presence of all 3 of the following items classifies knee OA in 
patients: 
1. Knee pain,  
2. Osteophytes, AND 
3. At least 1 of 3:  
• Age >50 years 
• Morning stiffness <30 minutes duration 
• Crepitus on active motion 
 
 
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Appendix 2. 
Prohibited Concomitant Medications and Procedures (Supplement) 
 
1) Excluded and prohibited centrally acting analgesics include, but are not limited to, the 
following: 
• Gabapentin (Neurontin, Horizant, Gaberone, Gralise, Fusepaq Fanatrex) 
• Pregabalin (Lyrica) 
• Carbamazepine (Tegretol, Carbatrol, Epitol, Equetrol) 
• Duloxetine (Cymbalta, Irenka) 
• Milnacipran (Savella) 
• Orphenadrine Citrate (Norflex, Orfro, Orphenate, Mio-Rel, Antiflex) 
• Amitriptyline (Elavil, Vanatrip) 
• Clomipramine (Anafranil) 
• Nortriptyline (Aventyl, Pamelor) 
• Desipramine (Norpramin) 
• Imipramine (Tofranil) 
• Doxepin (Prudoxin, Sinequan, Zonalon, Silenor) 
• Ketamine (Ketalar) 
• Sodium Oxybate (Xyrem, GHB)  
 
2) Other non-listed anticonvulsants are also prohibited. 
 
3) Excluded and prohibited electrotherapy treatments include, but are not limited to, the 
following: 
• Diathermy 
• TENS 
• NMES 
• Interferential therapy 
• Shortwave therapy 
• Iontophoresis 
• LASER 
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Appendix 3. 
Amendments 
AMENDMENT 03 VERSION 00 SUMMARY OF CHANGES 
Study Title: 
A Phase 3, 56-Week, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study Utilizing Patient-Reported and 
Radiographic Outcomes to Evaluate the Efficacy and Safety of a 
Single Injection of SM04690 Injected in the Target Knee Joint of 
Moderately to Severely Symptomatic Osteoarthritis Subjects 
Purpose: 
The purpose of this amendment is to refine the study design; 
significant changes include revising the screening process and 
updating inclusion/exclusion criteria. 
Summary of Changes: The table below provides a list of changes and their rationale. 
Change 
Sections Affected 
Rationale 
Protocol Amendment 03 Version 00 has been 
added on the title page. 
Title Page 
Change was made to capture the dates 
of previous and current protocol 
versions. 
Protocol date and version have been updated as 
applicable 
All 
Change was made to reflect current 
protocol amendment. 
Sponsor signatory list was revised. 
Sponsor Signature 
Page 
Change was made for administrative 
reasons. 
Screening Visit 1 and Screening Visit 2 were 
combined into a single Screening Visit. The 
radiograph will be performed at a prescreening 
visit outside of this study.  
Section 1.1, 4.1, 7.1, 
7.3.1, 7.3.2, 7.3.7, 
7.3.8, 7.5 
Change was made to refine study 
design.  
Figure 1 was updated. 
Section 1.1, Figure 1 
Change was made for clarity. 
A new Appendix 1 was added to clarify ACR 
clinical and radiographic criteria for classification 
of knee OA. 
Sections 1.1 and 5.1, 
Appendix 1  
Change was made to clarify the 
criteria noted in inclusion criterion #3. 
Inclusion criteria #4 and #5 were revised to be 
“within 12 weeks” of the Screening Visit. 
Sections 1.1 and 5.1 
Change was made to clarify timing. 
Inclusion criterion #8 was revised: “Body mass 
index (BMI) ≤ 35 kg/m2 at the Screening Visit”. 
Sections 1.1 and 5.1 
Change was made to clarify timing. 
Inclusion criterion #18 was edited to include “at 
least 12 weeks…”. 
Sections 1.1 and 5.1 
Change was made to clarify required 
duration.  
Exclusion criterion #1 (pregnant and breastfeeding 
women and positive pregnancy test) was 
reworded. 
Sections 1.1 and 5.2 
Changes were made to clarify the 
exclusion criterion. 
Definitions of post-menopausal and permanently 
surgically sterile were removed from exclusion 
criterion #2. 
Sections 1.1 and 5.2 
Change was made to remove 
redundancy with exclusion 
criterion #1. 
Exclusion criterion #3 (men of reproductive 
potential) was reworded. 
Sections 1.1 and 5.2 
Changes were made to clarify the 
exclusion criterion. 
“within 12 weeks of the Screening Visit” was 
added to exclusion criterion #4 (malalignment). 
Sections 1.1 and 5.2 
Change was made to allow for use of 
the prescreen radiograph. 
Exclusion criterion #7 (any surgery) was revised 
from Screening Visit to Day 1.  
Sections 1.1 and 5.2 
Changes were made to account for any 
surgery that may occur between the 
Screening Visit and Day 1.  
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Change 
Sections Affected 
Rationale 
Exclusion criterion #8 (IA injections) was 
reworded and revised from Screening Visit 1 to 
Day 1. 
Sections 1.1 and 5.2 
Changes were made to clarify the 
exclusion criterion and account for IA 
injections that may occur between the 
Screening Visit and Day 1. 
Exclusion criterion #9 (effusion of the target knee) 
was revised from Screening Visit 1 to Day 1. 
Sections 1.1 and 5.2 
Changes were made to refine the 
exclusion criterion and account for 
effusion that may occur between the 
Screening Visit and Day 1. 
Exclusion criterion #10 (electrotherapy, 
acupuncture, etc.) was revised to include physical 
therapy and therapeutic ultrasound and revised 
from Screening Visit 1 to Day 1. 
Sections 1.1 and 5.2 
Changes were made to refine the 
exclusion criterion and account for 
any electrotherapy, acupuncture, etc. 
that may occur between the Screening 
Visit and Day 1.  
“for knee OA” was deleted from exclusion 
criterion #14. 
Sections 1.1 and 5.2 
Change was made because 
participation in any clinical research 
trial described is exclusionary. 
Exclusion criteria #15 was revised from Screening 
Visit to Day 1 and revised to include “subjects on 
< 10 mg prednisone or the equivalent per day who 
have not maintained a stable regimen for at least 
2 weeks prior to Day 1 in the opinion of the 
Investigator”. 
Sections 1.1 and 5.2 
Change was made to clarify and refine 
the exclusion criterion. 
Exclusion criteria #16, 17, 20, and 21 were 
reworded. 
Sections 1.1 and 5.2 
Grammatical changes were made to 
clarify the exclusion criteria. 
Exclusion criteria #18 (opioids) and 19 (topical 
local anesthetic agents) were revised from 
Screening Visit to Day 1.  
Sections 1.1 and 5.2 
Change was made to account for use 
of opioids or topical local anesthetic 
agents that may occur between the 
Screening Visit and Day 1.  
The following was deleted from exclusion 
criterion #23: “including laboratory findings not 
included in the Screening Visit 2 laboratory tests 
and findings in the medical history or in the pre-
study assessments” 
Sections 1.1 and 5.2 
Change was made because the deleted 
text was unnecessary/redundant.  
Exclusion criterion #26 was reworded and “major 
depressive disorder or generalized anxiety 
disorder” was deleted.  
Sections 1.1 and 5.2 
Change was made to clarify and refine 
the exclusion criterion. 
“Hemoglobin A1c (HbA1c) > 9 at the Screening 
Visit” was made into a separate exclusion criterion 
(#29).  
Sections 1.1 and 5.2 
Change was made for clarity.  
Exclusion criterion #30 (NSAIDs and/or 
acetaminophen use) was revised from Screening 
Visit to Day 1.  
Sections 1.1 and 5.2 
Change was made to account for 
NSAIDs and/or acetaminophen use 
that may occur between the Screening 
Visit and Day 1. 
Exclusion criterion #31 was added: “Any 
contraindications for an IA injection in the target 
knee in the opinion of the Investigator” 
Sections 1.1 and 5.2 
Change was made to refine exclusion 
criteria and exclude contraindications 
for an IA injection in the target knee 
Number of sites enrolling participates was 
changed from 70 to 100. 
Sections 1.1 and 4.1 
Change was made for accuracy 
Estimated date first subject consented and 
estimated date last subject completed were 
updated to May 2019 and June 2021, respectively.  
Section 1.1 
Change was made for accuracy.  
Schematic of study design was deleted because it 
was no longer an accurate depiction of the study 
design.  
Section 1.1 
Change was made for clarity. 
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Change 
Sections Affected 
Rationale 
Edits were made to reflect that there will be 
2 radiographs in this study and up to 3 retakes 
each are allowed to obtain an acceptable 
radiograph. 
Sections 2.3.1 
and 7.1.1 
Change was made to refine study 
design. 
Section 5.3.1 Contraception was revised to clarify 
lifestyle guidelines pertaining to WOCBP and 
men. 
Section 5.3.1 
Changes were made to clarify 
contraception guidelines.  
Section 5.4.2 Subject Rescreening was revised to 
remove information related to knee radiographs. 
Section 5.4.2 
Changes were made to align with 
removal of screening radiograph. 
“Total or partial knee replacement of the target 
knee” was added as a reason for premature 
discontinuation.  
Section 5.6.1 
Change was made to refine reasons for 
withdrawal or termination.  
The following edit was made in Section 5.6.2: ET 
procedures should be conducted for any subject 
who discontinues after was randomized at the 
Day 1 visit.  
Section 5.6.2 
Change was made to refine when ET 
procedures should be conducted. 
“Study medication should not be frozen” was 
added to Section 6.1.3 Product Storage and 
Stability.  
Section 6.1.3 
Change was made to refine 
instructions for study medication 
storage and stability.  
Guidance on administration of study medication 
was updated. 
Section 6.1.5 
Changes were made to clarify 
guidance on study medication 
injections. 
“Collection of Adverse Events Data” was updated 
to clarify information recorded and length of 
follow-up.  
Sections 7.1.1 and 8.3 
Changes were made to clarify 
collection of AEs. 
Information regarding malalignment of the target 
knee was deleted from the Knee Examination 
section.  
Section 7.1.1 
Change was made because assessment 
of malalignment is already covered in 
the “Radiograph of Knee Joints” 
section. 
“Radiograph of Knee Joints” was updated to 
clarify the timing of the study radiographs and the 
prescreen radiograph report.  
Sections 7.1.1 and 
7.3.4 
Change was made to refine study 
assessment timepoints. 
Training on accurate pain reporting and placebo 
response reduction is recommended at Day 1 and 
Weeks 4, 12, 24, 36, and 52. 
Sections 7.1.1,  7.3.4, 
and 7.3.7 
Change was made to refine study 
assessment timepoints. 
The names of the NSAID/Acetaminophen usage 
eCRFs were corrected. 
Section 7.1.1 
Change was made for alignment with 
the database. 
“Calcium” was added to the chemistry panel under 
Clinical Laboratory Evaluations. 
Section 7.2.1 
Change was made for completeness. 
Clarification was added that pregnancy tests will 
only be performed on WOCBP. 
Section 7.2.2, 7.3.2, 
7.3.3, and 7.3.7 
Change was made for clarity. 
Section 7.3.1 Prescreening was added for 
clarification of study design.  
Section 7.3.1 
Change was made for clarity.  
The Schedule of Events Table in Section 7.3.7 was 
updated to reflect any and all changes made 
throughout this amendment.  
Section 7.3.7 
Changes were made for clarity.  
The sentence regarding concomitant therapy in 
relation to AE assessments was revised. 
Section 7.5 
Change was made to clarify the 
meaning of the sentence. 
Section 7.6 Prohibited Medications, Treatments, 
and Procedures was updated. 
Section 7.6 
Change was made to refine and clarify 
prohibited concomitant medications 
and procedures. 
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Change 
Sections Affected 
Rationale 
Clarification was added regarding the 
“life-threatening” bullet point in the SAE 
definition. 
Section 8.1.2 
Change was made to clarify what 
constitutes “life-threatening” as it 
pertains to an SAE. 
Guidance on SAE reporting was updated. 
Section 8.4.2 
Change was made to refine and clarify 
SAE reporting procedures. 
Sponsor contact information for questions on SAE 
reporting was updated. 
Section 8.4.2 
Change was made for administrative 
reasons. 
Information regarding procedures for pregnancy 
reporting were added. 
Section 8.4.5 
Change was made to update 
pregnancy reporting procedures. 
Section 10.4 Description of Statistical Methods 
header was added. 
Section 10.4 
Header was missing from original 
protocol. 
The following was added to Section 10.4.2 and 
10.4.3: “Unadjusted 95% confidence intervals and 
P values will be reported.” 
Section 10.4.2 and 
10.4.3 
Addition was made to refine the 
description of statistical methods. 
Section 14.3 Protocol Deviations was updated. 
Section 14.3 
Changes were made to provide 
updated guidance on protocol 
deviations.  
The Medical Monitor was changed to Ismail 
Simsek and Naina Rastalsky was included as a 
backup Medical Monitor. The address for YPrime 
was updated. 
Section 15.2 
Change was made for administrative 
reasons. 
Appendix 2 Prohibited Concomitant Medications 
and Procedures was modified.  
Appendix 2 
Changes were made for clarity and 
accuracy. 
Formatting, spelling, and grammar/terminology 
were refined. 
Throughout 
Changes were made for clarity and 
presentation. 
 
AMENDMENT 02 VERSION 00 SUMMARY OF CHANGES 
Study Title: 
A Phase 3, 56-Week, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study Utilizing Patient-Reported and 
Radiographic Outcomes to Evaluate the Efficacy and Safety of a 
Single Injection of SM04690 Injected in the Target Knee Joint of 
Moderately to Severely Symptomatic Osteoarthritis Subjects 
Purpose: 
The purpose of this amendment is to refine inclusion/exclusion criteria 
and other aspects of the study design. 
Summary of Changes: The table below provides a list of changes and their rationale. 
Change 
Sections Affected 
Rationale 
Protocol Amendment 02 Version 00 has been 
added on the title page. 
Title Page 
Change was made to capture the dates 
of previous and current protocol 
versions 
Protocol date and version have been updated as 
applicable 
All 
Change was made to reflect current 
protocol amendment 
Added “serious adverse events (SAEs), vital signs, 
and clinical laboratory measures” to the safety 
endpoint. 
Sections 1.1 and 3.2.3, 
Figure 1 
Change was made to refine the safety 
endpoint 
Inclusion criterion #4 was revised to “mJSW by 
radiograph between 1.5 to 4 mm…” (previously 2 
to 4 mm). 
Sections 1.1 and 5.1 
Change was made to refine inclusion 
criteria to allow for increased 
enrollment 
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Change 
Sections Affected 
Rationale 
Exclusion criterion #13 was edited to include the 
correct section reference. 
Sections 1.1 and 5.2 
Change was made to correct an error 
Exclusion criterion #15 was edited to clarify 
systemic as “(oral, intramuscular, or intravenous)”.  
Sections 1.1 and 5.2 
Change was made to clarify what 
constitutes systemic glucocorticoids 
Exclusion criterion #26 was edited to: “History of 
mania, bipolar disorder, psychotic disorder, 
schizophrenia, schizoaffective disorder, major 
depressive disorder, or generalized anxiety 
disorder” 
Sections 1.1 and 5.2 
Change was made to refine exclusion 
criteria 
Description of Study Agent was updated. 
Section 1.1 
Change was made to include most 
current information available 
Edit was made to Study Placebo risks: “There is a 
small risk of allergic reaction or hypersensitivity to 
these components the vehicle substances.” 
Section 2.3.1 
Change was made for clarity 
Minor clarifications were made in Section 4 and 
5.4. 
Sections 4.1, 4.2, and 
5.4.2 
Changes were made for clarity  
Subject re-screening language was updated; 
subjects who did not meet inclusion/exclusion 
criteria may be re-screened if those criteria are 
revised in a protocol amendment. 
Section 5.4.2 
Changes were made to refine and 
clarify subject re-screening guidance 
“Ready to use” was removed from the description 
of the drug and placebo products.  
Section 6.1.2 and 6.1.4 
Change was made to avoid confusion; 
further information is provided in the 
pharmacy manual 
Temperature excursion guidance was updated to, 
“Temperature excursions are to be evaluated on a 
case by case basis by the Sponsor.”  
Section 6.1.3 
Change was made to remove specific 
temperature excursion guidance as 
these should be evaluated on a case by 
case basis 
Further information was added regarding lateral or 
medial study medication injections. 
Section 6.1.5 
Change was made to provide guidance 
regarding study medication injections. 
Collection of AE Data was revised to reflect that 
efficacy assessments are “recorded on specific 
pages of the eCRF or electronic diary.” 
Sections 7.1.1 and 
8.1.1 
Change was made for accuracy  
Timing of AE follow-up/reporting was revised. 
Sections 7.1.1 and 8.3 
Changes were made to refine 
definitions and timing of collection 
Medical History collection was clarified: “…with 
a follow-up at Week 56 (EOS) or ET to capture 
End Dates of any ongoing medical history 
collected at Screening Visit 1 and Day 1.” 
Sections 7.1.1 and 
7.3.7 
Change was made for accuracy  
Revised vital sign terminology. 
Sections 7.1.1 and 7.3 
Changes were made to align with 
CDISC standard terminology  
Deleted requirement for same resting position to 
be used for all blood pressure measurements. 
Section 7.1.1 
Change was made because same 
resting position is not critical for 
blood pressure measurements  
Deleted “Increases in pain should only be 
considered AEs if reported by the subject, 
regardless of pain NRS scores.” from the Pain 
NRS subsection.  
Section 7.1.1 
Change was made to align with 
definition of AEs  
The following was added to the Assessment of 
NSAID/Acetaminophen Usage sub-section: 
“Subjects will be trained on what medications are 
NSAIDs at Screening Visit 1.” 
Sections 7.1.1 and 7.3 
Change was made to refine study 
procedures 
Urinalysis testing was corrected to include 
leukocyte esterase (previously referred to only as 
“leukocytes”).  
Section 7.2.1 
Change was made for correctness  
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The following deletion was made: “Assessment of 
NSAID/acetaminophen usage for target knee OA 
pain.”  
Sections 1.1, 7.3.4, 
7.3.5, and 7.3.6 
Change was made because any usage 
of NSAIDs/acetaminophen will be 
collected  
The following edit was made in Section 9: “A 
regular report of risks will be utilized together 
with on-site and off-site centralized data 
monitoring…” 
Section 9 
Change was made for correctness 
Fentanyl was removed from Appendix 1 as it is 
not a centrally acting analgesic. 
Appendix 1 
Change was made for accuracy 
Formatting, spelling, and grammar/terminology 
were refined 
Throughout 
Changes were made for clarity, 
consistency, and presentation 
 
AMENDMENT 01 VERSION 00 SUMMARY OF CHANGES 
Study Title: 
A Phase 3, 56-Week, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study Utilizing Patient-Reported and 
Radiographic Outcomes to Evaluate the Efficacy and Safety of a 
Single Injection of SM04690 Injected in the Target Knee Joint of 
Moderately to Severely Symptomatic Osteoarthritis Subjects 
Purpose: 
The purpose of this amendment is to refine the study design following 
feedback from regulatory authorities. 
Summary of Changes: The table below provides a list of changes and their rationale. 
Change 
Sections Affected 
Rationale 
Protocol Amendment 01 Version 00 has been 
added on the title page. 
Title Page 
Change was made to capture the dates 
of previous and current protocol 
versions 
Protocol date and version have been updated as 
applicable 
All 
Change was made to reflect current 
protocol amendment 
Changed from electronic signatures to wet 
signatures 
Sponsor Signature 
Page 
Change was made for administrative 
reasons 
Name of control treatment has changed from 
“Vehicle” to “Placebo” 
All 
Change was made to more precisely 
describe control treatment 
Updated titles for Hutch Humphreys and Ismail 
Simsek; added Cristina Damatarca and Mark 
Fineman as signatories and removed Anita 
DiFrancesco 
Sponsor Signature 
Page, Section 15.2 
Changes were made for administrative 
reasons 
Updated List of Abbreviations 
List of Abbreviations 
Change was made due to new 
abbreviations 
Added Figure 1 as an overview of study design 
and endpoints 
Protocol Summary 
Change was made to facilitate 
understanding of the study design 
Moved mJSW endpoint from Secondary to Other 
Endpoints 
Protocol Summary, 
Sections 3.2.2, 10.4.3 
Decision was made to reorder 
endpoints prior to trial start 
Added usage of NSAIDs and acetaminophen for 
target knee OA pain as a secondary endpoint 
Protocol Summary, 
Sections 3.2.2, 10.4.3 
Based on guidance from the FDA to 
capture usage of pain medications as 
an endpoint during the trial 
Removed dual energy X-ray absorptiometry 
(DXA) as a procedure and endpoint 
Throughout  
Change was made to refine study 
procedures  
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Usage of NSAIDs and acetaminophen for target 
knee OA pain will be assessed at each visit starting 
at Day 1 
Protocol Summary, 
Sections 4.1, 7.1.1, 7.3 
Change was made to collect 
information on pain medication usage 
and allow rescue medications 
Changed the SF-36 questionnaire from an 
electronic to a paper submission and moved to 
Day 1 from Screening Visit 2 
Protocol Summary, 
Sections 4.1, 7.1.1, 
7.3.8 
Change was made to better collect 
data 
Rearranged inclusion and exclusion criteria 
Protocol Summary, 
Sections 5.1 and 5.2 
Similar items were grouped together 
Modified inclusion criteria #4: “Baseline mJSW 
by radiograph” 
Protocol Summary, 
Section 5.1 
“Baseline” is a statistical term that 
does not fit an inclusion criterion  
Modified inclusion criteria #5: “Radiographic 
disease Stage 2 or 3 in both knees the target knee 
at Screening Visit 1…” 
Protocol Summary, 
Section 5.1 
Decision made to refine study design 
regarding bilateral knee OA 
Modified inclusion criteria #20: “Subjects must 
have read and understood the informed consent 
form … signed and dated it …” 
Protocol Summary, 
Section 5.1 
Change was made to be consistent 
with documentation requirements 
Revised exclusion criterion #5: “Subjects who 
have had a single or bilateral, Partial or complete 
joint replacement in either knee or hip 
replacement “ 
Protocol Summary, 
Section 5.2 
The reason to exclude subjects with 
hip replacement was the DXA 
procedure that was removed 
Changed HbA1c exclusion (#28) from > 8 to > 9 
Protocol Summary, 
Section 5.2 
Change was made to meet current 
standards for subject exclusion 
Revised exclusion criteria #8 (IA injections) and 
#14 (different experimental drug or procedure) to 
26 weeks exclusion prior to Screening Visit 1 
Protocol Summary, 
Section 5.2 
Change was made for consistency 
with other criteria 
Revised exclusion criteria #29: If using NSAIDs 
for the treatment of OA pain and/or 
acetaminophen, subjects who have not maintained 
a stable regimen in the opinion of the Investigator 
for at least 4 weeks prior to at Screening Visit 1 
Protocol Summary, 
Section 5.2 
Change was made to establish 
timeline for stable usage of pain 
medications prior to trial 
Modified exclusion criterion #32: 
“Subjects employed by Samumed, LLC, or any of 
its affiliates or development partners (that is, an 
employee, temporary contract worker, or designee) 
responsible for the conduct of the study, or who 
are immediate family members (spouse, parent, 
child, or sibling; biological or legally adopted) of 
said employees responsible for the conduct of the 
study 
Protocol Summary and 
Section 5.2 
Change was made to ensure that 
family members of employees of the 
Sponsor are excluded 
Revised criteria for evaluation: “…measures and 
vital signs, as assessed by the Investigator.” 
Protocol Summary 
Change was made to clarify that these 
measures will be determined by 
Investigator assessment 
Revised Study Duration 
Protocol Summary 
Change was made to revise study 
schedule 
Updated Schematic of Study Design  
Section 1.2 
Change was made to remove DXA 
and add monthly phone visits 
Removed several listings from Key Roles, moved 
Key Roles to from Section 1 to Section 15; 
reordered Introduction, Objectives, and Endpoint 
sections; added sections on “Assessment of 
Potential Risks and Benefits,” “Justification for 
Dose,” “End of Study Definition,” “Study 
Population,” and “Screen Failures;” renamed 
Throughout 
Changes were made to align with 
FDA protocol template v1.0 (April 
2017) 
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“Tracking of Dose” as “Study Intervention 
Compliance”. 
Modified description of study placebo risks: “ 
The control placebo injection in this study will be 
2 mL of vehicle, which is the inactive substance 
carboxymethylcellulose sodium and polysorbate 
80 in phosphate buffered saline. The inactive 
substance Carboxymethylcellulose sodium and 
polysorbate 80 are inactive substances often used 
as food or drug excipients. There is a small risk of 
reaction to the vehicle substances. There is a small 
risk of reaction to the vehicle substances. Refer to 
the IB for the potential risks associated with the 
study vehicle. 
Section 2.3.1 
Changes was made to refine 
description and to align protocol with 
current IB. 
Modified description of study injection risks: “ 
“Risks associated with knee joint injection include 
bleeding, bruising, infection, pain at the injection 
and local site swelling of the knee, and/or injury to 
the knee joint reactions such as erythema, 
irritation, and edema. 
Section 2.3.1 
Change was made to refine 
description and to align protocol with 
current IB. 
Modified description of radiograph risks:  
This study involves radiation exposure from 3 
radiographs of the knees and 2 DXA scans of the 
spine and both hips, approximately 6 months to 1 
year apart. As part of everyday living, everyone is 
exposed to a small amount of background 
radiation that comes from soil, rocks, outer space, 
and within the body itself. The radiation dose for 
all radiographs that the subject will receive in this 
study is expected to be about 0.015 mSv or 
equivalent to approximately < 1 day of 
background radiation in the US. The radiation 
dose for all DXA scans that the subject will 
receive in this study is expected to be about 0.012 
mSv or equivalent to approximately < 1 day of 
background radiation in the US. The risks from 
these doses are small Each radiograph in this 
study exposes subjects to approximately 0.005 
millisievert (mSv), equivalent to about ½ day of 
background radiation in the US (National 
Council on Radiation Protection and 
Measurements 2009). The total exposure from 
the planned radiographs in this study is equivalent 
to about 1.5 days of background radiation in the 
US. This radiation exposure may not be necessary 
for the subjects’ medical care, but it is necessary to 
obtain the research information desired.  
Section 2.3.1 
Changes were made to update 
radiation numbers, provide a 
reference, and allow sites to calculate 
exposure on a per radiograph basis. 
Added the following sentence to contraception 
guidelines: “WOCBP who withdraw from the 
study after receiving study medication should 
remain on an acceptable form of contraception for 
56 weeks after Day 1.” An identical sentence was 
added to cover men.  
Section 5.3.1 
Added sentence for situations in 
which a subject withdraws early, to 
remind sites that subjects should 
remain on contraception.  
Also, men cannot bear children. 
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Also changed description to “Men of Childbearing 
Reproductive Potential” 
Added following as reason for subject re-
screening: “…being unable to comply with study 
procedures due to administrative convenience 
(e.g., family issues or attending to a private 
matter), and/or being within the exclusion window 
for past medications and procedures, as outlined in 
Section 5.2. Subjects who were screen failed 
because of unacceptable knee radiographs as 
assessed by the central imaging vendor may also 
be re-screened for this protocol.” 
Section 5.4.2 
Added to cover transient situations in 
which subjects may be eligible for the 
study at a later time. 
Added following to Reasons for Withdrawal: 
• Withdrawal by subject for reason other than 
lack of efficacy 
• Physician decision for reason other than lack of 
efficacy 
Section 5.6.1 
Phrase was added to distinguish these 
from the category of “Lack of 
Efficacy” 
Removed “Screen failure” as a Reason for 
Withdrawal 
Section 5.6.1 
Subjects who fail screening in this 
protocol are not enrolled into the trial 
and as such cannot withdraw 
Referred to treatment arms throughout as “study 
drug” (or “SM04690”) and “placebo” and the two 
together as “study medication”. 
Section 6 
Change was made to clarify language 
about treatments. 
Removed drug product manufacturer and type of 
vials 
Section 6.1.2 
Identity of manufacturer is not 
necessary in the protocol. 
Added following information on blinding: 
“The unblinded Investigator must minimize any 
contact with the subject following the injection 
and may not perform any study assessments 
throughout the duration of the study. All subject 
contact for the remainder of the study is limited to 
the blinded Investigator and other appropriate 
blinded study personnel.” 
Section 6.1.5 
Drug product and placebo have 
different appearances; injections 
therefore must be performed by 
unblinded personnel. Change was 
made to inform sites that unblinded 
Investigators who administer 
injections should not participate in any 
study evaluations 
Added following: “The Sponsor will provide 
sterile needles and syringes that are to be used for 
the injection of study medication.” 
Section 6.1.5 
Change was made to help sites by 
providing needles and syringes to be 
used with study medication 
Changed scale for collecting adverse events from 
“Guidance for Industry: Toxicity Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in 
Preventative Vaccine Trials” to “Clinical Data 
Interchange Standards Consortium (CDISC) 
Severity/Intensity Scale for Adverse Events 
(AESEV).” 
Section 7.1.1, 
Appendix 1  
The Toxicity Scale is applicable for 
vaccine trials with healthy volunteers, 
whereas this is a Phase 3 trial of a 
non-vaccine drug 
Reworded timing of AE reporting:  
 
AEs that are not serious and are ongoing at a the 
subject’s last visit will be recorded on source 
documents and eCRFs as ongoing events and will 
be followed for 30 days or until resolution, 
whichever comes first. Resolution is defined as the 
return to baseline status or stabilization of the 
condition with the expectation that it may remain 
chronic. All information obtained regarding AEs 
after a subject’s last study visit will be done 
Sections 7.1.1 and 8.3 
Changes were made to refine 
definitions and timing of collection 
and to ensure that procedures after 
close of clinical database were still 
captured. 
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outside of the clinical database. until the study 
close-out visit, if requested by the Sponsor. If not 
requested, AEs that are not serious and are 
ongoing at the subject’s last visit will be followed 
for a maximum of 30 days. Serious adverse events 
(SAEs) that are not resolved or stabilized during 
this time period will be followed until resolution 
or stabilization.  
Added procedures “Past Treatments for Knee OA 
pain” and “Assessment of NSAID/Acetaminophen 
Usage” 
Sections 7.1.1 and 7.3 
Changes were made to capture new 
information about past history with 
pain medications, and new secondary 
endpoint for NSAID/acetaminophen 
usage  
Clarified number of radiographs to take to get an 
acceptable image:  
“Upon receipt of images, the central imaging 
vendor will assess the image quality as acceptable 
or unacceptable. It is recommended that the 
Investigator attempt one additional image capture 
at Screening Visit 1 and Week 24 in order to 
obtain an acceptable image. Subjects that do not 
have an acceptable image at Screening Visit 1 will 
be screen failed.  
At Week 52, it is recommended that the 
investigator attempt up to two additional images in 
order to obtain an acceptable image. At all times, 
the investigator should use his/her clinical 
judgement to assess how many retakes a subject 
may require in order to obtain an acceptable 
image.” 
Sections 7.1.1 and 
7.3.4 
Change was made to ensure 
compliance with eligibility criteria and 
to ensure adequate data collection at 
the end of trial 
Altered wording about paper questionnaires 
WPI&SS and SF-36: 
“subject will sign/ or initial and date the source 
document and date it to… 
Section 7.1.1 
Change was made because original 
wording created confusion 
Clarified description of assessment: “The 
WPI&SS assessment used in this study is modified 
from that described in (Clauw 2014)” 
Section 7.1.1 
Change was made to indicate that our 
assessment is not the same as that in 
reference 
Added additional information about electronic 
diaries including accurate pain reporting and 
placebo response.  
Section 7.1.1 and 7.3.1 
Change was made to clarify study 
procedures and add new training as 
procure 
Added anchor descriptors to Pain NRS.  
Section 7.1.1 
Changes were made to clarify 
procedures  
Removed methamphetamine as tested drug 
Protocol Summary, 
Sections 5.2, 7.1.1, 7.6 
Drug is included with 
“Amphetamines” in the list of drugs 
Added phone visits at Weeks 8, 16, 20, 28, 32, 40, 
44, and 48 
Section 7.3.4 
Change was made to allow monthly 
collection of NSAID usage 
Clarified ET procedures:  
“Radiograph should only be performed if ET 
occurs on or after Week 24. Radiograph and 
biomarkers are only to be performed/collected at 
the ET visit if not performed within 4 weeks prior 
to this visit.” 
Section 7.3.6 
Change was made to prevent 
unnecessary radiographs or blood 
collection. 
Updated Schedule of Events Table 
Section 7.3.7 
Change was made to update 
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procedures 
Added sentence to Rescue Medications:  
“Subjects are allowed to remain on their stable 
regimen of NSAIDs/acetaminophen during this 
study and may change their usage as needed for 
pain management, including for the rescue of knee 
pain.” 
Section 7.8 
Change was made following FDA 
feedback to allow subjects to rescue 
pain during the study. 
Added following to Definitions of Adverse 
Events:  
“In this protocol, signs and symptoms of 
exacerbation or worsening of target knee OA will 
be captured in the context of efficacy assessments 
and recorded on specific pages of the eCRF. 
Anticipated fluctuations or anticipated 
deterioration (in the opinion of the Investigator) of 
the underlying disease (target knee OA) will not 
be considered as AEs nor captured on the AE page 
of the eCRF.” 
Sections 7.1.1 and 
8.1.1 
Change was made because knee pain 
is an endpoint and this information 
will be captured as part of efficacy 
measures 
The following was added to definitions of SAEs: 
“Admission to the hospital or prolongation of 
hospitalization qualifies as an SAE only if it is the 
result of an AE.” 
Section 8.1.2 
Change was made to align with 
current ICH definitions of SAEs. 
Descriptions for Unanticipated Problems (UPs) 
changed. 
Sections 8.1.3 and 
8.4.3 
Change was made for clarity and to 
align with current reporting 
guidelines. 
Added following to definition of “Unlikely 
Related”: 
“…or the AE is considered possibly related to 
another event, medical condition, or product not 
associated with the IP (or placebo).” 
 
Also added “medical condition” as other possible 
explanation of AE 
Section 8.2.2 
Changes were made to clarify 
definitions of relatedness to study 
drug 
Added following:  
“The Investigator should review the SAE 
information and sign the SAE report, and the…” 
Section 8.4.2 
Change was made to clarity reporting 
requirements 
Added Kathleen Toscano as Alternative Contact 
for SAE Reporting and to Key Role overseeing 
Drug Safety and Pharmacovigilance 
Section 8.4.2 
Changes were made for administrative 
reasons 
Removed text from UP Reporting: 
1: “A description of any changes to the protocol or 
other corrective actions that have been taken or are 
proposed in response to the UP.”  
2: “All UPs should be reported to appropriate 
institutional officials (as required by an 
institution’s written reporting procedures) and IRB 
within the timeframe specified by the institution 
procedures and IRB.” 
Section 8.4.3 
Changes were made because 1) 
Investigators are not responsible for 
protocol changes, and 2) This 
information was already indicated in 
section 
Removed phrase: 
“The Investigator and Samumed will manage 
reporting of pregnancies according to the study 
document “Guidelines for the Management of 
Serious Adverse Events (SAEs) and Pregnancies”. 
Section 8.4.5 
Change was made because document 
is no longer used. 
Modified Statistical Hypothesis 
Section 10.2 
Change was made because of new 
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endpoints 
Added following to Analysis of Secondary 
Endpoints: “…as well as change in 
NSAID/acetaminophen usage. The potential 
confounding effect of change in 
NSAID/acetaminophen usage on the treatment 
effect will be considered for sensitivity analysis.” 
Section 10.3.3 
Change was made because of new 
endpoint 
Added following to Baseline Descriptive 
Statistics: “If a radiograph is rated unacceptable 
and follow-up radiograph(s) are also rated 
unacceptable, the first radiograph will serve as the 
baseline assessment.” 
Section 10.3.6 
Change was made to provide an 
unbiased way to handle situations in 
which there are two radiographs of 
equal quality. 
Added two subgroup analyses: 
• Intermarginal distance by both variability (i.e., 
change) and actual measurement 
• Bilateral radiographic disease (KL grade 2-3 in 
both knees) 
Section 10.4.9 
Change was made to refine data 
collection 
Changed e-mail for Medidata notification to sites 
Section 10.6.1 
Change was made for administrative 
reasons 
Removed Appendix 1 (Toxicity Vaccine Scale) 
Appendix 1 
Scale was replaced by CDISC scale 
for AE collection 
Added Table of Changes in Amendment 01 
Appendix 3 
Change was made to list changes in 
this version 
Formatting, spelling, and grammar were refined 
Throughout 
Changes were made for clarity and 
presentation 
 
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Signature Page for VV-TMF-116105 v1.0
Signature Page for VV-TMF-116105 v1.0
Reason for signing: Approved
Name: Christopher Swearingen
Role: Vice President, Clinical Outcomes and
Analytics
Date of signature: 06-Nov-2019 17:04:51 GMT+0000
Reason for signing: Approved
Name: Mark  Fineman
Role: Vice President, Clinical Development
Date of signature: 06-Nov-2019 20:20:18 GMT+0000
Reason for signing: Approved
Name: Ismail Simsek
Role: Medical Director
Date of signature: 06-Nov-2019 23:23:34 GMT+0000
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