Clinical trial NCT03122860
Conditions: Knee Osteoarthritis
Keywords: SM04690 Wnt pathway inhibitor osteoarthritis Samumed
Sponsor: Biosplice Therapeutics, Inc.
Start date: 2017-04-24; Completion date: 2018-04-30
Enrollment: 700 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase 2 study is a placebo-controlled, double-blind, parallel group study of four concentrations of SM04690 (0.03, 0.07, 0.15, and 0.23 mg per 2 mL injection) injected intraarticularly (IA) into the target knee joint of subjects with moderately to severely symptomatic osteoarthritis (OA). Based on previous studies of SM04690, key phenotypes of laterality (unilateral vs bilateral) as well as chronic pain (as measured by the Widespread Pain Index) were identified as confounding variables impacting the overall assessment of both radiologic and clinical efficacy outcomes. The design of SM04690-OA-04 is based upon previous study designs while assessing strategies to combat the confounding impact of laterality and chronic pain. To evaluate the effect of IA vehicle injection on patient-reported outcomes (PRO) such as pain, stiffness, and function in OA, this study also includes one cohort that receives a 2 mL IA injection of vehicle (placebo), and one cohort that receives a sham injection (i.e., a needle stick with 0 mL vehicle injected).

Detailed description:

Arms: arm 1: Single intra-articular injection of 0.03 mg SM04690 in 2 mL vehicle arm 2: Single intra-articular injection of 0.07 mg SM04690 in 2 mL vehicle arm 3: Single intra-articular injection of 0.15 mg SM04690 in 2 mL vehicle arm 4: Single intra-articular injection of 0.23 mg SM04690 in 2 mL vehicle arm 5: Single intra-articular injection of 0 mg SM04690 in 2 mL vehicle arm 6: Single intra-articular injection of 0 mg SM04690 in 0 mL vehicle
Interventions: intervention 1: SM04690 intervention 2: Placebo intervention 3: Sham
Intervention descriptions: intervention 1: Healthcare professional-administered intra-articular injection performed once on Day 1 of the study intervention 2: Healthcare professional-administered intra-articular injection performed once on Day 1 of the study intervention 3: Healthcare professional-administered intra-articular injection performed once on Day 1 of the study

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
PROTOCOL SM04690-OA-04 
(Amendment 03 Version 00, 23 April 2018) 
 
 
 
 A Phase 2, 24-Week, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study Evaluating the Safety and Efficacy of 
SM04690 for the Treatment of Moderately to Severely 
Symptomatic Knee Osteoarthritis 
 
 
NCT03122860 


 
A Phase 2, 24-Week, Multicenter, Randomized, Double-
Blind, Placebo-Controlled Study Evaluating the Safety and 
Efficacy of SM04690 for the Treatment of Moderately to 
Severely Symptomatic Knee Osteoarthritis 
 
Study Number: SM04690-OA-04 
IND Sponsor: Samumed, LLC 
Version Number:  Amendment 03 Version 00 
Date: 23 April 2018 
 
 
 
Original Protocol Date: 24 January 2017 
Amendment 01 Version 00:  27 March 2017 
Amendment 02 Version 00:  28 June 2017 


SPONSOR SIGNATURE PAGE
A Phase 2, 24-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study
Evaluating the Safety and Efficacy of SM04690 for the Treatment of Moderately to Severely
Symptomatic Knee Osteoarthritis
Protocol Number:
SM04690-OA-04 AM03V00
23 April 2018
Date:
Name & Title
Signature
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Samumed commits to satisfying the requirements of the ICH-GCP Guidelines regarding the
responsibilities of the Sponsor, the US Code of Federal Regulations 21 CFR parts 50, 54, 56, 312, and
314, and Good Clinical Practice 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 
PROTOCOL SUMMARY ........................................................................................................... 9 
SCHEMATIC OF STUDY DESIGN ........................................................................................ 16 
1. 
KEY ROLES ....................................................................................................................... 17 
2. 
INTRODUCTION: BACKGROUND INFORMATION & SCIENTIFIC 
RATIONALE .............................................................................................................................. 17 
2.1 
BACKGROUND INFORMATION ........................................................................................ 17 
2.2 
RATIONALE .................................................................................................................... 18 
2.3 
POTENTIAL RISKS AND BENEFITS................................................................................... 20 
2.3.1 Known Potential Risks .............................................................................................. 20 
2.3.2 Known Potential Benefits ......................................................................................... 22 
3. 
OBJECTIVES AND PURPOSE ........................................................................................ 22 
4. 
STUDY DESIGN AND ENDPOINTS ............................................................................... 22 
4.1 
DESCRIPTION OF THE STUDY DESIGN ............................................................................. 22 
4.2 
STUDY ENDPOINTS ......................................................................................................... 24 
4.2.1 Primary Endpoints .................................................................................................... 24 
4.2.2 Secondary Endpoints ................................................................................................ 24 
4.2.3 Exploratory Endpoints .............................................................................................. 24 
5. 
STUDY ENROLLMENT AND WITHDRAWAL ........................................................... 25 
5.1 
PARTICIPANT INCLUSION CRITERIA ............................................................................... 25 
5.2 
PARTICIPANT EXCLUSION CRITERIA .............................................................................. 25 
5.3 
LIFESTYLE GUIDELINES ................................................................................................. 28 
5.3.1 Contraception ............................................................................................................ 28 
5.4 
STRATEGIES FOR RECRUITMENT AND RETENTION ......................................................... 28 
5.5 
PARTICIPANT WITHDRAWAL OR TERMINATION ............................................................. 28 
5.5.1 Reasons for Withdrawal or Termination................................................................... 28 
5.5.2 Handling of Participant Withdrawals or termination ................................................ 29 
5.6 
PREMATURE TERMINATION OR SUSPENSION OF STUDY ................................................. 29 
6. 
STUDY AGENT .................................................................................................................. 29 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION ............................................................. 29 
6.1.1 Acquisition ................................................................................................................ 29 
6.1.2 Formulation, Appearance, Packaging, and Labeling ................................................ 30 
6.1.3 Product Storage and Stability.................................................................................... 30 


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6.1.4 Preparation ................................................................................................................ 30 
6.1.5 Dosing and Administration ....................................................................................... 30 
6.1.6 Route of Administration ........................................................................................... 31 
6.1.7 Starting Dose and Dose Escalation Schedule ........................................................... 31 
6.1.8 Dose Adjustments/Modifications/Delays ................................................................. 31 
6.1.9 Duration of Therapy .................................................................................................. 31 
6.1.10 Tracking of Dose....................................................................................................... 31 
6.1.11 Device Specific Considerations ................................................................................ 31 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES ............................................................. 32 
7. 
STUDY PROCEDURES AND SCHEDULE .................................................................... 32 
7.1 
STUDY PROCEDURES/EVALUATIONS .............................................................................. 32 
7.1.1 Study specific procedures ......................................................................................... 32 
7.1.2 Standard of care study procedures ............................................................................ 37 
7.2 
LABORATORY PROCEDURES/EVALUATIONS ................................................................... 37 
7.2.1 Clinical Laboratory Evaluations ............................................................................... 37 
7.2.2 Other Assays or Procedures ...................................................................................... 38 
7.2.3 Specimen Preparation, Handling, and Storage ......................................................... 38 
7.2.4 Specimen Shipment .................................................................................................. 38 
7.3 
STUDY SCHEDULE .......................................................................................................... 38 
7.3.1 Screening................................................................................................................... 38 
7.3.2 Randomization .......................................................................................................... 40 
7.3.3 Follow-up .................................................................................................................. 41 
7.3.4 Final Study Visit ....................................................................................................... 41 
7.3.5 Early Termination Visit ............................................................................................ 41 
7.3.6 Schedule of Events Table .......................................................................................... 42 
7.3.7 Schedule of Electronic Diary and Questionnaire Completion Table ........................ 44 
7.4 
JUSTIFICATION FOR SENSITIVE PROCEDURES ................................................................. 47 
7.5 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES ................................. 47 
7.5.1 Precautionary Medications, Treatments, and Procedures ......................................... 47 
7.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES ...................................... 47 
7.7 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES ................................. 48 
7.8 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES ............................................. 48 
7.9 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE ...................................... 48 
8. 
ASSESSMENT OF SAFETY ............................................................................................. 48 
8.1 
SPECIFICATION OF SAFETY PARAMETERS ...................................................................... 48 
8.1.1 Definition of Adverse Events (AE)........................................................................... 48 
8.1.2 Definition of Serious Adverse Events (SAE) ........................................................... 49 
8.1.3 Definition of Unanticipated Problems (UP) ............................................................. 49 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT ...................................................................... 49 
8.2.1 Severity of Event....................................................................................................... 49 
8.2.2 Relationship to Study Agent ..................................................................................... 50 


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8.2.3 Expectedness ............................................................................................................. 50 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP ................. 50 
8.4 
REPORTING PROCEDURES .............................................................................................. 51 
8.4.1 Adverse Event Reporting .......................................................................................... 51 
8.4.2 Serious Adverse Event Reporting ............................................................................. 51 
8.4.3 Unanticipated Problem Reporting............................................................................. 51 
8.4.4 Events of Special Interest.......................................................................................... 52 
8.4.5 Reporting of Pregnancy ............................................................................................ 52 
8.5 
STUDY HALTING RULES ................................................................................................. 52 
8.6 
SAFETY OVERSIGHT ....................................................................................................... 52 
9. 
CLINICAL MONITORING .............................................................................................. 52 
10. 
STATISTICAL CONSIDERATIONS .......................................................................... 53 
10.1 
STATISTICAL AND ANALYTICAL PLANS ......................................................................... 53 
10.2 
STATISTICAL HYPOTHESES ............................................................................................ 53 
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(s)......................................................................... 53 
10.4.3 Analysis of the Secondary Endpoint(s)..................................................................... 54 
10.4.4 Safety Analyses ......................................................................................................... 54 
10.4.5 Baseline Descriptive Statistics .................................................................................. 54 
10.4.6 Planned Interim Analyses ......................................................................................... 54 
10.4.7 Exploratory Analyses ................................................................................................ 55 
10.4.8 Additional Sub-Group Analyses ............................................................................... 55 
10.5 
SAMPLE SIZE .................................................................................................................. 56 
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 
11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .... 57 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL ............................................ 58 
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 .................................................................. 59 
13.4 
PARTICIPANT AND DATA CONFIDENTIALITY .................................................................. 59 
13.4.1 Research Use of Stored Human SAMPLES, SPECIMENS or Data ........................ 59 


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13.5 
FUTURE USE OF STORED SPECIMENS ............................................................................. 59 
14. 
DATA HANDLING AND RECORD KEEPING ......................................................... 60 
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES ........................................... 60 
14.2 
STUDY RECORDS RETENTION ........................................................................................ 60 
14.3 
PROTOCOL DEVIATIONS ................................................................................................. 61 
14.4 
PUBLICATION AND DATA SHARING POLICY ................................................................... 61 
15. 
STUDY ADMINISTRATION ....................................................................................... 61 
15.1 
STUDY LEADERSHIP ....................................................................................................... 61 
16. 
LITERATURE REFERENCES .................................................................................... 62 
APPENDIX 1. 
GUIDANCE FOR INDUSTRY: TOXICITY SCALE FOR HEALTHY 
ADULT AND ADOLESCENT VOLUNTEERS ENROLLED IN PREVENTIVE 
VACCINE TRIALS .................................................................................................................... 63 
APPENDIX 2. 
PROHIBITED CONCOMITANT MEDICATIONS AND 
PROCEDURES (SUPPLEMENT) ............................................................................................ 67 
APPENDIX 3. 
AMENDMENTS ......................................................................................... 68 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Term 
ACR 
American College of Rheumatology 
AE  
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
CFR 
Code of Federal Regulations 
CRF 
Case report form 
DLT 
Dose-limiting toxicity 
EC 
Ethics Committee 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EOS 
End of study 
ePRO 
Electronic patient reported outcomes 
ER 
Emergency room 
ET 
Early termination 
FAS 
Full Analysis Set 
FDA 
(US) Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
IA 
Intra-articular 
IB 
Investigator Brochure 


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Abbreviation 
Term 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization  
IND 
Investigational new drug 
IP 
Investigational product 
IQRMP 
Integrated Quality and Risk Management Plan 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
JSW 
Joint space width 
KOOS 
Knee injury and Osteoarthritis Outcome Score 
KOOS-PS 
Knee injury and Osteoarthritis Outcome Score Physical function Short 
form 
LDH 
Lactate dehydrogenase 
MCP-Mod 
Multiple Comparison Procedure Modelling 
MedDRA 
Medical Dictionary for Regulatory Activities 
mFAS 
Modified Full Analysis Set 
mg 
Milligram 
mL 
Milliliter 
mm 
Millimeter 
mSv 
Millisievert 
NCS 
Not clinically significant 
NRS 
Numeric rating scale 
NSAID 
Nonsteroidal anti-inflammatory drug 
OA 
Osteoarthritis 
OTC 
Over the counter 
PA 
Posterior-anterior 
PI 
Principal Investigator 
PP 
Per-protocol 
PPAS 
Per-Protocol Analysis Set 


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Abbreviation 
Term 
PRO 
Patient reported outcomes  
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 
SD 
Standard deviation 
SOP 
Standard operating procedure 
SS 
Symptom Severity 
SSQ 
Symptom Severity Question  
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of the normal range 
UP 
Unanticipated problem 
US 
United States 
VAS 
Visual Analog Scale 
WBC 
White blood cell 
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 2, 24-Week, Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study Evaluating the Safety and Efficacy of SM04690 for the 
Treatment of Moderately to Severely Symptomatic Knee Osteoarthritis 
Protocol Number 
SM04690-OA-04 
Protocol Date 
23 April 2018 
Protocol Version 
AM03 V00 
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 Conference on Harmonization Good 
Clinical Practice Guidelines E6 (ICH-GCP). 
I will obtain Institutional Review Board/Ethics Committee (IRB/EC) approval of the protocol 
and Informed Consent Form 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 Informed Consent Form 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 SUMMARY 
Title: 
A Phase 2, 24-Week, Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study Evaluating the Safety and Efficacy of SM04690 for the 
Treatment of Moderately to Severely Symptomatic Knee Osteoarthritis 
Objectives: 
 
Primary: 
The primary objective of this study is to determine the effective dose(s) of 
SM04690 for the treatment of knee OA. 
Secondary: 
The secondary objective of this study is to evaluate the safety and 
tolerability of SM04690. 
Endpoints: 
Primary: 
1. Evaluate change from baseline OA pain in the target knee as 
assessed by the weekly averages of daily pain Numeric Rating 
Scale (NRS) at Week 24 
2. Evaluate change from baseline OA pain in the target knee as 
assessed by Western Ontario and McMaster Universities 
Osteoarthritis Index (WOMAC) pain subscore at Week 24  
3. Evaluate change from baseline OA function in the target knee as 
assessed by WOMAC physical function subscore at Week 24 
4. Evaluate change from baseline in medial joint space width (JSW) 
as documented by radiograph of the target knee at Week 24 
 
Secondary: 
1. Evaluate the safety of SM04690 as measured by treatment-
emergent adverse events (TEAEs) 
2. Evaluate change from baseline OA disease activity as assessed by 
Patient Global Assessment at Week 24 
 
Exploratory:  
1. Evaluate change from baseline OA pain in the target knee as 
assessed by WOMAC pain subscore at Week 4, 8, 12, 16, and 20 
2. Evaluate change from baseline OA function in the target knee as 
assessed by WOMAC physical function subscore at Week 4, 8, 12, 
16, and 20  
3. Evaluate change from baseline symptoms of OA in the target knee 
as assessed by WOMAC total score at Week 4, 8, 12, 16, 20, and 
24 
4. Evaluate change from baseline OA pain in the target knee at each 
week (aside from Week 24) as assessed by weekly averages of 
daily pain NRS  


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5. Evaluate change from baseline OA disease activity as assessed by 
Patient Global Assessment at Week 4, 8, 12, 16, and 20 
6. Evaluate change from baseline OA function in the target knee as 
assessed by Knee Injury and Osteoarthritis Outcome Score 
(KOOS) at Week 4, 8, 12, 16, 20, and 24 
7. Evaluate change from baseline OA function in the target knee at 
each week as assessed by KOOS Physical Function Short Form 
(KOOS-PS) 
8. Evaluate change from baseline OA disease activity as assessed by 
Physician Global Assessment at Week 4, 12, and 24 
9. Evaluate change over time in NSAID usage as assessed by weekly 
averages of daily pain medication electronic diary responses at 
every week 
10. Evaluate subject perception of study treatment received at Week 24 
11. Evaluate outcome differences between treatment with sham or 
placebo injections at Week 4, 8, 12, 16, 20, and 24 
Methodology: 
This study will be a multicenter, randomized, double-blind, placebo-
controlled, parallel group study of four different concentrations of 
SM04690 injected into the target knee joint of moderately to severely 
symptomatic osteoarthritis subjects. 
Approximately 630 subjects will be consented and randomized using a 
permuted block design to 6 treatment arms (0.03 mg active per 2 mL 
injection : 0.07 mg active per 2 mL injection : 0.15 mg active per 2 mL 
injection : 0.23 mg active per 2 mL injection : 0.0 mL vehicle : 2.0 mL 
vehicle). Subjects will participate in a screening period of a minimum of 
10 days and up to 22 days and a 24-week follow-up period. Clinic visits 
will be scheduled at Screening Visit 1, Screening Visit 2, Day 1, and 
Weeks 4, 12, and 24 [End of study (EOS)]/Early Termination (ET). 
Subjects will be required to complete an electronic diary for the following: 
• Daily pain NRS (for target knee OA pain) 
• Daily monitoring of usage of NSAIDs  
• Weekly completion of the KOOS-PS 
• Monthly completion of the WOMAC 
• Monthly completion of KOOS 
• Monthly completion of Patient Global Assessment  
Inclusion/ 
Exclusion 
Criteria: 
Criteria for Inclusion: 
1. Males and females between 40 and 80 years of age, inclusive, in 
general good health 
2. Ambulatory  
3. Diagnosis of femorotibial OA in the target knee by standard 
American College of Rheumatology (ACR) criteria at Screening 


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Visit 1 (clinical AND radiographic criteria); OA of the knee is not 
to be secondary to any rheumatologic conditions (e.g., rheumatoid 
arthritis) 
4. Pain compatible with OA of the knee(s) for at least 26 weeks prior 
to Screening Visit 1 
5. Primary source of pain throughout the body is due to OA in the 
target knee  
6. 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 
7. Pain NRS scores recorded for the target knee on at least 4 out of 
the 7 days immediately preceding Day 1  
8. Daily OA knee pain diary average NRS intensity score <4 in the 
non-target knee on the 11-point (0-10) NRS scale for the 7 days 
immediately preceding Day 1 
9. Pain NRS scores recorded for the non-target knee on at least 4 out 
of the 7 days immediately preceding Day 1 
10. Total WOMAC score of 96-192 (out of 240) 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) 
11. Willingness to use an electronic diary on a daily basis in the 
evening for the screening period and 24-week study duration 
12. Negative drug test for opioids and drugs of abuse, except alcohol 
and marijuana, at Screening Visit 1 
13. Subjects with depression or anxiety must be clinically stable for 12 
weeks prior to Screening Visit 1 and, if on treatment for depression 
or anxiety, be on 12 weeks of stable therapy  
14. Full understanding of the requirements of the study and willingness 
to comply with all study visits and assessments 
15. Subjects must have read and understood the informed consent 
form, and must have signed it prior to any study-related procedure 
being performed 
16. Subject’s Screening Visit 1 visit must occur while enrollment into 
the randomization cohort for which they are eligible is open 
 
Criteria for Exclusion: 
1. Women who are pregnant, lactating, or have a positive pregnancy 
result at Screening Visit 1 
2. Women of child bearing potential who are sexually active and are 
not willing to use a highly effective method of birth control during 
the study period that includes double barrier, IUD, hormonal 


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contraceptive combined with single barrier, or abstinence 
3. Males who are sexually active and have a partner who is capable of 
becoming pregnant, neither of whom have had surgery to become 
sterilized or whom are not using a highly effective method of birth 
control    
4. Body mass index (BMI) > 35 
5. Partial or complete joint replacement in either knee 
6. Currently requires: 
a. regular use of ambulatory assistive devices (e.g., 
wheelchair, parallel bars, walker, canes, or crutches), or 
b. use of a lower extremity prosthesis, and/or a structural knee 
brace (i.e., a knee brace that contains hardware)  
7. Radiographic disease Stage 0, 1, or 4 in the target knee at 
Screening Visit 1 according to the Kellgren-Lawrence grading of 
knee OA as assessed by independent central readers 
8. Previous participation in a Samumed clinical trial investigating 
SM04690 
9. Any surgery (e.g., arthroscopy) in either knee within 26 weeks 
prior to Screening Visit 1 
10. Any planned surgery during the study period. Non-surgical 
invasive procedures conducted for a diagnostic or therapeutic 
purpose scheduled during the study period are not prohibited (refer 
to Section 7.6). 
11. Significant and clinically evident misalignment of either knee that 
would impact subject function, as determined by the Investigator 
12. History of malignancy within the last 5 years; however, subjects 
with prior history of in situ cancer or basal or squamous cell skin 
cancer are eligible if completely excised. Subjects with other 
malignancies are eligible if they have been continuously disease 
free for at least 5 years prior to any study injection 
13. Clinically significant abnormal screening hematology values, blood 
chemistry values, or urinalysis values as determined by the 
Investigator 
14. Any condition, including laboratory findings (not included in the 
Screening Visit 1 laboratory tests) and findings in the medical 
history or in the pre-study assessments, 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 
15. 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 


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16. 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 
17. Any diagnosed psychiatric condition that includes, but is not 
limited to, a history of mania, bipolar disorder, psychotic disorder, 
schizophrenia, schizoaffective disorder, major depressive disorder, 
or generalized anxiety disorder 
18. Participation in a clinical research trial that included the receipt of 
an investigational product or any experimental therapeutic 
procedure, or an observational research trial related to osteoarthritis 
within 8 weeks prior to any study injection, or planned 
participation in any such trial; the last date of participation in the 
trial, not the last date of receipt of investigational product, must be 
at least 8 weeks prior to Screening Visit 1 
19. Treatment of the target knee with intra-articular glucocorticoids 
(e.g., methylprednisolone) within 12 weeks prior to Screening Visit 
1 
20. Any intra-articular injection into the target knee with a therapeutic 
aim including, but not limited to, viscosupplementation (e.g., 
hyaluronic acid), PRP, and stem cell therapies within 24 weeks 
prior to Screening Visit 1; treatment of the target knee with intra-
articular glucocorticoids greater than 12 weeks prior to Screening 
Visit 1 is allowed 
21. Treatment with systemic glucocorticoids greater than 10 mg 
prednisone or the equivalent per day within 4 weeks prior to 
Screening Visit 1  
22. Effusion of the target knee clinically requiring aspiration within 12 
weeks prior to Screening Visit 1 
23. Use of electrotherapy, acupuncture, and/or chiropractic treatments 
for knee OA within 4 weeks prior to Screening Visit 1 (refer to 
Appendix 2) 
24. Any known active infections, including urinary tract infection, 
upper respiratory tract infection, sinusitis, suspicion of intra-
articular 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 
25. Use of centrally acting analgesics (e.g., duloxetine) (refer to 
Appendix 2) within 12 weeks prior to Screening Visit 1  
26. Use of anticonvulsants not listed in Appendix 2 within 12 weeks 
prior to Screening Visit 1, unless used for seizure or migraine 
prophylaxis   


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27. Subjects requiring the  usage of opioids >1x per week within 12 
weeks prior to Screening Visit 1 
28. Topical local anesthetic agents (gels, creams, or patches such as the 
Lidoderm patch) used for the treatment of knee OA within 7 days 
of Screening Visit 1  
29. 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. In addition, subjects with a baseline HbA1c >9 will be 
excluded. 
30. If on NSAIDs for the treatment of OA pain, subjects who have not 
maintained a stable regimen in the opinion of the Investigator at 
Screening Visit 1 
31. Subjects who have a current or pending disability claim, workers’ 
compensation, or litigation(s) that may compromise response to 
treatment  
32. 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  
33. 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 630 subjects with moderately to severely symptomatic 
osteoarthritis of the knee 
Phase: 
2 
Number of Sites 
enrolling 
participants: 
This study will be conducted at approximately 80 investigational centers in 
the United States 
Description of 
Study Agent: 
SM04690 is a small molecule inhibitor of the Wnt pathway important in 
driving progenitor cells resident in the joint to become chondrocytes, 
potentially enhancing cartilage formation 
Study Duration: Approximately 11 months 
Estimated date first subject consented: April 2017 
Estimated date last subject completed: March 2018 


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Participant 
Duration: 
Up to approximately 27 weeks 
Criteria for 
evaluation: 
Efficacy: 
Efficacy will be assessed by: 
• Weekly averages of daily pain NRS (for target knee OA pain) 
• Monthly WOMAC total score as well as WOMAC pain and 
function subscores for the target knee 
• Weekly KOOS-PS 
• Daily collection of NSAID usage  
• Monthly KOOS 
• Monthly Patient Global Assessment 
• Physician Global Assessment at clinic visits  
• Medial JSW by radiograph 
 
Safety: 
The overall safety and tolerability of SM04690 will be determined by 
the incidence, seriousness, severity, and relationship of TEAEs and 
clinically significant changes in clinical laboratory measures and vital 
signs. Changes from baseline in the amount and duration of NSAID 
usage will be monitored. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SCHEMATIC OF STUDY DESIGN 
 
 
 
 
 
 
 
Total N = 630
Obtain informed consent. Screen subjects by criteria; obtain history, document.
Radiograph
Screening
Visit 1
Screening
Visit 2
Electronic diary and questionnaire training
*
Confirm eligibility and randomize
I
I
I
I
I
I
0.03 mg
SM04690
n = 105
0.07 mg
SM04690
n = 105
0.15 mg
SM04690
n = 105
0.23 mg
SM04690
n = 105
Vehicle
n = 105
Sham
n = 105
Day 1
i
i
i
i
i
i
**
Intra-articular injection
Refer to Section 7.3.6 Schedule of Events Table
Follow-up assessments of study endpoints and safety
Refer to Section 7.3.6 Schedule of Events Table
Week 4
Follow-up assessments of study endpoints and safety
Refer to Section 7.3.6 Schedule of Events Table
Week 12
Week 24
(EOS)
Radiograph and final follow-upassessments of study endpoints and safety
Refer to Section 7.3.6 Schedule of Events Table
* Daily pain NRS and NSAIDs electronic diary, baseline assessments
**Daily pain NRS and NSAIDs electronic diary, weekly KOOS-PS, monthly WOMAC, KOOS,
Patient Global Assessment. Refer to Section 7.3.7 Schedule of Electronic Diary and
Questionnaire Completion Table.


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1. 
KEY ROLES 
Medical monitor 
 
 
 
 
 
 
Regulatory specialist 
 
 
 
 
 
 
Biostatistician 
 
   
 
 
 
 
 
Data manager 
 
 
 
 
 
 
Central radiology reader 
 
 
 
 
Electronic patient reported 
outcomes (ePRO) 
eResearchTechnology, Inc. (ERT) 
1818 Market St. 
Suite 1000  
Philadelphia, PA 19103  
(215) 972-0420 
Central laboratory 
ACM Global Central Laboratory 
160 Elmgrove Park 
Rochester, NY 14624 
(800) 525-5227 
2. 
INTRODUCTION: BACKGROUND INFORMATION & SCIENTIFIC 
RATIONALE  
2.1 
BACKGROUND INFORMATION  
Osteoarthritis (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 1 joint. By 2030, 20% of Americans (about 70 million people) will have passed their 65th 


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birthday and will be at risk for OA (Nevitt 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 et al. 2006). 
Samumed, LLC (Samumed) is developing SM04690 for the treatment of OA. SM04690 is a 
small molecule inhibitor of the Wnt pathway.  
SM04690 has been tested in a number of appropriate nonclinical studies. The results of those 
studies are included in the Investigator Brochure (IB). 
2.2 
RATIONALE  
Osteoarthritis is the most common form of arthritis and chronic joint disorder in man (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 US (Lawrence 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 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 et al. 2012). Polymorphisms in 
genes involved in Wnt signaling are associated with an increased susceptibility to OA 
development (Wu 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. 
SM04690 was tested in a single phase 1 clinical trial (SM04690-01) in subjects with moderately 
to severely symptomatic OA of the knee, which was completed on 17Sep2015. The trial was a 
placebo-controlled, double-blind, dose-escalation study of three concentrations of SM04690 
(0.03, 0.07, and 0.23 mg per 2 mL injection), conducted in the US. In each dose cohort, subjects 
were randomized to active or vehicle at a ratio of 16 active: 4 vehicle. Subject clinic visits 
occurred on Day 1 and 2, and Weeks 1, 2, 4, 8, 12, and 24. Each successively higher 
concentration cohort was enrolled after completion of treatment and review of safety data from 
the previous cohort by a Safety Review Committee. The Safety Review Committee was 
comprised of the Samumed medical monitor, the site Investigators, and an independent 
rheumatologist. A total of 33/61 (54.1%) exposed subjects reported no AEs. One SAE 
(paroxysmal tachycardia) reported was deemed unrelated to study medication by the reporting 
Investigator. No clinically significant safety concerns or differences among study groups were 
noted with regard to vital signs, clinical laboratory results, ECGs, or AEs. Based upon these data, 
a single intra-articular (IA) injection of SM04690 into the knee of OA subjects appeared safe and 


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well-tolerated. 
SM04690 is currently being tested in a phase 2 clinical trial in subjects with moderately to 
severely symptomatic OA of the knee. The trial is a placebo-controlled, double-blind, parallel 
group study of three concentrations of SM04690 (0.03, 0.07, and 0.23 mg per 2 mL injection) 
injected into the target knee joint, conducted in the US. Subjects were randomized at a ratio of 
1:1:1:1 (0.03 mg active per 2 mL injection: 0.07 mg active per 2 mL injection: 0.23 mg active 
per 2 mL injection: placebo). Clinic visits occurred on Treatment Visit Day 1 and Follow-up 
Weeks 4, 13, 26, 39 and 52 [End of study (EOS)]/Early Termination (ET). As of 30Jun2016, 455 
subjects have been randomized. An interim analysis was conducted after all subjects had 
completed their Week 26 visit. Unblinding in support of the interim analysis occurred on 
20Oct2016. As of this date, there has been no obvious dose response or difference from placebo 
with respect to the most frequently reported AEs, SAEs, or in AEs that led to subject withdrawal.   
A phase 3, long-term extension study (SM04690-OA-05) is also being performed to monitor the 
long-term safety, tolerability, and efficacy of treatment of SM04690 or placebo previously 
injected in the target knee joints of subjects with moderately to severely symptomatic OA from a 
Samumed-sponsored SM04690-OA phase 2 or phase 3 study. This study is a multicenter, 
observational study in subjects that have previously been treated with SM04690 or placebo 
injected into the target knee joint. Approximately 2000 subjects will be consented and will 
participate in a 60 month follow-up period. Clinic visits are scheduled at Months 6, 12, 24, 36, 
48, and 60 [End of study (EOS)]/Early Termination (ET). 
This phase 2 study, SM04690-OA-04, is a placebo-controlled, double-blind, parallel group study 
of four concentrations of SM04690 (0.03, 0.07, 0.15, and 0.23 mg per 2 mL injection) injected 
into the target knee joint of subjects with moderately to severely symptomatic OA. Based upon 
the interim data analysis of SM04690-OA-02, key phenotypes of laterality (unilateral vs 
bilateral) as well as chronic pain (as measured by the Widespread Pain Index) were identified as 
confounding variables impacting the overall assessment of both radiologic and clinical efficacy 
outcomes. The design of SM04690-OA-04 is based upon the SM04690-OA-02 design while 
assessing strategies to combat the confounding impact of laterality and chronic pain. 
Additionally, although many clinical trials with IA therapies commonly use IA saline injections 
as a placebo comparator arm, there has been growing recognition that the administration of IA 
saline may have a treatment effect. Several meta-analyses quantifying the effect of IA saline 
injections on patient-reported outcomes (PRO) such as pain, stiffness, and function in OA 
clinical trials have found statistically and clinically meaningful improvement in PROs up to 6 
months after injection (Zhang et al. 2008, Altman et al. 2016, Saltzman et al. 2016). Clinically 
noticeable improvements after IA saline injections ultimately call into question the use of such 
injections as a null control group for comparison to investigative trial arms, as saline may 
significantly impact clinical symptoms. One hypothesis for this mechanism of action is the 
dilution of inflammatory mediators within the knee, providing relief of perceived pain, function, 
as well as stiffness (Zhang et al. 2008, Altman et al. 2016, Saltzman et al. 2016). Determining an 
adequate control to IA saline injection would remain challenging, while it is suggested that a 
sham group with a simple needle stick into the joint would remedy some concerns for the 
potential therapeutic effect of IA saline injections (Saltzman et al. 2016). 
 


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2.3 
POTENTIAL RISKS AND BENEFITS  
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. Potential risks associated with modulation of this pathway include 
gastrointestinal distress, inhibition of bone formation, and myelosuppression. 
SM04690 drug product is a suspension of SM04690 in diluent containing 
carboxymethylcellulose sodium and polysorbate 80 in phosphate buffered saline. Potential risks 
associated with carboxymethylcellulose sodium and polysorbate 80 include allergic reaction and 
hypersensitivity. Serious allergic reactions may be associated with increased risk of death, but 
serious allergic reactions are rare and, as of 28 June 2017, have not been reported in any subject 
on human studies testing SM04690. Symptoms of an allergic reaction may include rash, 
wheezing and difficulty breathing, dizziness and fainting, swelling around the mouth, throat or 
eyes, a fast pulse, or sweating.  
SM04690 has been tested in a single phase 1 clinical trial (SM04690-01) in humans with 
osteoarthritis (OA) of the knee. In this trial, there was no obvious dose response or difference 
from placebo with respect to the most frequently reported AEs, regardless of whether or not 
considered related to study medication. A total of 72 AEs were reported by 28/61 (45.9%) 
subjects during the study. Sixteen AEs, reported by 8/61 (13.1%) subjects, were considered 
related to study medication by the reporting investigator. The system organ class with the most 
reported AEs was Musculoskeletal and connective tissue disorders with 11/61 (18.0%) subjects 
reporting 19 AEs consisting of 5 preferred terms (arthralgia, back pain, joint swelling, joint 
stiffness, and musculoskeletal chest pain). Eight of these events comprising three preferred terms 
(arthralgia, joint swelling, and joint stiffness), reported by 5/61 (8.2%) subjects, were considered 
related to study medication by the reporting investigator. The AE (preferred term) reported most 
was Headache, with 7/61 (11.5%) subjects reporting 7 events of mild or moderate headache: 2 
reports by 2 (11.8%) subjects in the 0.03 mg treatment group, no reports in the 0.07 mg treatment 
group, 4 reports by 4 (25.0%) subjects in the 0.23 mg treatment group, and 1 report by 1 (9.1%) 
subject in the placebo group. One of these events (0.23 mg treatment group) was considered 
related to study medication by the reporting investigator. Headache was the only AE with an 
incidence greater than 10%. The AE (preferred term) with the most events considered related to 
study medication was Arthralgia with 4/61 (6.6%) subjects reporting 4 events which were 
considered treatment related. 3/61 (4.9%) additional subjects reported 5 events of arthralgia 
which were considered unrelated to study medication. 
A single SAE of “tachycardia paroxysmal” occurred during the study in a subject enrolled in the 
0.07 mg treatment group. The event was a report of tachycardia paroxysmal in a 72 year old 
white male, with previous medical history of tachycardia. This event was considered unrelated to 
study drug administration by the reporting investigator. Nevertheless, as the FDA requested that 
all AEs in this initial study of SM04690 be considered related to study drug, this event was 
reported in an expedited manner to the IND. 


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Two DLTs were reported on the trial, both occurring in the 0.07 mg treatment group (increased 
knee pain and tachycardia paroxysmal [also an SAE as noted above]). The DLT of increased 
knee pain was considered probably related to treatment by the reporting investigator. 
Single intra-articular injections of SM04690 at doses of 0.03 mg, 0.07 mg, and 0.23 mg in a 2 
mL suspension into the target knee joint appeared to be safe and well-tolerated in subjects with 
moderately to severely symptomatic OA of the knee. No clinically significant safety concerns or 
differences between active and placebo treatment groups were noted with regard to AEs, clinical 
laboratory results, vital signs, ECGs, assessment of bone loss, assessment of bone marrow 
edema, or assessment of inflammatory cytokines.  
An interim analysis of the phase 2 SM04690-OA-02 study was performed in October 2016 after 
all subjects completed their Week 26 visit. Summarizing the safety events occurring within these 
26 weeks and summarized in the interim analysis, 8 SAEs have been reported in 7/452 (1.5%) 
subjects. The SAEs reported have been Hypertensive crisis, Cholecystitis acute, Gall bladder 
adenocarcinoma, Uterine prolapse, Diverticulitis, Patella fracture, Osteoarthritis (of the hip), and 
Non-cardiac chest pain. These events were felt to be either not related or unlikely related to study 
medication by investigator assessment. 
Study Placebos 
The 2 possible placebo injections in this study will be either 2 mL of vehicle, which is the 
inactive substance carboxymethylcellulose sodium and polysorbate 80, or a 0 mL sham injection. 
The inactive substance carboxymethylcellulose sodium and polysorbate 80 is often used as a 
food or drug additive. Potential risks associated with carboxymethylcellulose sodium and 
polysorbate 80 include allergic reaction and hypersensitivity.   
The placebo sham injection contains no substance and has the same risks associated with the 
knee joint injection which include bleeding, bruising, infection, pain at the injection site, 
swelling of the knee, and/or injury to knee joint. 
Risks of Injection 
Risks associated with knee joint injection include bleeding, bruising, infection, pain at the 
injection site, swelling of the knee, and/or injury to knee joint. 
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 
donating blood. 


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Knee Radiograph 
This study involves radiation exposure from a total of 2 radiographs of the subjects’ knees on 2 
different days, each approximately 6 months 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 knee X-rays that the subject will receive in this 
study is expected to be approximately 0.01 mSv and is less than 1 days’ equivalent dose from 
background radiation. The risk from this dose is small. This radiation exposure may not be 
necessary for the subjects’ medical care, but it is necessary to obtain the research information 
desired. 
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 subjects, even if it may not help the subjects in this study. 
3. 
OBJECTIVES AND PURPOSE 
The purpose of this study is to evaluate the safety and efficacy of SM04690 injected in the target 
knee joint of moderately to severely symptomatic OA subjects. 
 
Primary objective: 
The primary objective of this study is to determine the effective dose(s) of SM04690 for the 
treatment of knee OA. 
Secondary objective: 
The secondary objective of this study is to evaluate the safety and tolerability of SM04690. 
4. 
STUDY DESIGN AND ENDPOINTS 
4.1 
DESCRIPTION OF THE STUDY DESIGN 
This study is a multicenter, randomized, double-blind, placebo-controlled, parallel group study 
of four different concentrations of SM04690 injected into the target knee joint of moderately to 
severely symptomatic OA subjects. 
Approximately 630 subjects will be consented and randomized using a permuted block design to 
6 treatment arms (0.03 mg active per 2 mL injection : 0.07 mg active per 2 mL injection : 0.15 
mg active per 2 mL injection : 0.23 mg active per 2 mL injection : 0.0 mL vehicle : 2.0 mL 
vehicle). To support the primary objective, active treatment groups will be compared to both 
vehicle (2.0 mL vehicle) and sham (0.0 mL vehicle). Subjects will participate in a screening 
period of a minimum of 10 days and up to 22 days and a 24-week follow-up period. Clinic visits 
will be scheduled at Screening Visit 1, Screening Visit 2, Day 1, and Weeks 4, 12, and 24 
(EOS)/ET. Specific timing of protocol procedures is described in the Schedule of Events Table 
(Section 7.3.6). Specific timing of electronic diary and questionnaire completion is described in 
the Schedule of Electronic Diary and Questionnaire Completion Table (Section 7.3.7). 


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This study will be conducted at approximately 80 investigational centers in the US.  
In this study, subjects will be required to complete an electronic diary for the following: 
• Daily pain NRS 
• Daily monitoring of usage of NSAIDs  
• Weekly completion of the KOOS-PS 
• Monthly completion of the WOMAC 
• Monthly completion of KOOS 
• Monthly completion of Patient Global Assessment  
A Widespread Pain Index and Symptom Severity (WPI&SS) assessment will be administered at 
Screening Visit 1. Physician Global Assessment will be performed at Day 1 and Weeks 4, 12, 
and 24 (EOS)/ET. Evaluation of the success of blinding will be performed at Day 1 (post intra-
articular injection) and Week 24 (EOS)/ET.   
In addition, general medical evaluations including physical examination, knee examination, and 
recording of vital signs will be performed at Screening Visit 1, Day 1, and Weeks 4, 12, and 24 
(EOS)/ET. Height will be measured at Screening Visit 1 and weight will be measured at 
Screening Visit 1 and Week 24 (EOS)/ET. Clinical laboratory evaluations will be performed at 
Screening Visit 1 and Weeks 4, 12, and 24 (EOS)/ET. Radiographic imaging of the knees will be 
performed at Screening Visit 1 and Week 24 (EOS)/ET. 
Recording of signs and symptoms of study medication intolerability and TEAE reporting will 
start following the injection of the study medication and continue until the subject completes 
Week 24 (EOS)/ET. All TEAEs, whether volunteered, elicited, or noted during examination, will 
be recorded throughout the study. 
Subject Re-Screening 
Subjects are allowed to be re-screened once. Re-screens are limited to subjects who did not meet 
inclusion/exclusion criteria due to a transient reason. 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), 
and/or being unable to comply with study procedures due to administrative convenience (e.g., 
family issues or attending to a private matter). Diary non-compliance is not a transient event and 
subjects with diary non-compliance may not be re-screened. 
Subjects who failed any entry criteria for which no further treatment or spontaneous resolution is 
expected are not allowed to be re-screened.  
Any re-screened subject must be re-consented and will be issued a new subject number. All 
screening procedures and assessments, except for the knee radiograph (if taken at previous 
screen), must be performed at re-screen; no results or data, except for the knee radiograph, may 
be used from the previous screen. Target knee selection may not be changed at re-screen.  
 
 
 


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4.2 
STUDY ENDPOINTS 
4.2.1 PRIMARY ENDPOINTS 
1. Evaluate change from baseline OA pain in the target knee as assessed by the weekly 
averages of daily pain Numeric Rating Scale (NRS) at Week 24 
2. Evaluate change from baseline OA pain in the target knee as assessed by Western Ontario 
and McMaster Universities Osteoarthritis Index (WOMAC) pain subscore at Week 24  
3. Evaluate change from baseline OA function in the target knee as assessed by WOMAC 
physical function subscore at Week 24 
4. Evaluate change from baseline in medial joint space width (JSW) as documented by 
radiograph of the target knee at Week 24  
4.2.2 SECONDARY ENDPOINTS 
1. Evaluate the safety of SM04690 as measured by treatment-emergent adverse events 
(TEAEs) 
2. Evaluate change from baseline OA disease activity as assessed by Patient Global 
Assessment at Week 24 
4.2.3 EXPLORATORY ENDPOINTS 
1. Evaluate change from baseline OA pain in the target knee as assessed by WOMAC pain 
subscore at Week 4, 8, 12, 16, and 20 
2. Evaluate change from baseline OA function in the target knee as assessed by WOMAC 
physical function subscore at Week 4, 8, 12, 16, and 20  
3. Evaluate change from baseline symptoms of OA in the target knee as assessed by 
WOMAC total score at Week 4, 8, 12, 16, 20, and 24 
4. Evaluate change from baseline OA pain in the target knee at each week (aside from Week 
24) as assessed by weekly averages of daily pain NRS  
5. Evaluate change from baseline OA disease activity as assessed by Patient Global 
Assessment at Week 4, 8, 12, 16, and 20 
6. Evaluate change from baseline OA function in the target knee as assessed by Knee Injury 
and Osteoarthritis Outcome Score (KOOS) at Week 4, 8, 12, 16, 20, and 24 
7. Evaluate change from baseline OA function in the target knee at each week as assessed 
by KOOS Physical Function Short Form (KOOS-PS) 
8. Evaluate change from baseline OA disease activity as assessed by Physician Global 
Assessment at Week 4, 12, and 24 
9. Evaluate change over time in NSAID usage as assessed by weekly averages of daily pain 
medication electronic diary responses at every week 
10. Evaluate subject perception of study treatment received at Week 24 
11. Evaluate outcome differences between treatment with sham or placebo injections at 
Week 4, 8, 12, 16, 20, and 24 


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5. 
STUDY ENROLLMENT AND WITHDRAWAL 
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. 
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 
2. Ambulatory  
3. Diagnosis of femorotibial OA in the target knee by standard American College of 
Rheumatology (ACR) criteria at Screening Visit 1 (clinical AND radiographic criteria); 
OA of the knee is not to be secondary to any rheumatologic conditions (e.g., rheumatoid 
arthritis) 
4. Pain compatible with OA of the knee(s) for at least 26 weeks prior to Screening Visit 1 
5. Primary source of pain throughout the body is due to OA in the target knee  
6. 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 
7. Pain NRS scores recorded for the target knee on at least 4 out of the 7 days immediately 
preceding Day 1  
8. Daily OA knee pain diary average NRS intensity score <4 in the non-target knee on the 
11-point (0-10) NRS scale for the 7 days immediately preceding Day 1 
9. Pain NRS scores recorded for the non-target knee on at least 4 out of the 7 days 
immediately preceding Day 1 
10. Total WOMAC score of 96-192 (out of 240) 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) 
11. Willingness to use an electronic diary on a daily basis in the evening for the screening 
period and 24-week study duration 
12. Negative drug test for opioids and drugs of abuse, except alcohol and marijuana, at 
Screening Visit 1 
13. Subjects with depression or anxiety must be clinically stable for 12 weeks prior to 
Screening Visit 1 and, if on treatment for depression or anxiety, be on 12 weeks of stable 
therapy  
14. Full understanding of the requirements of the study and willingness to comply with all 
study visits and assessments 
15. Subjects must have read and understood the informed consent form, and must have 
signed it prior to any study-related procedure being performed 
16. Subject’s Screening Visit 1 visit must occur while enrollment into the randomization 
cohort for which they are eligible is open 
5.2 
PARTICIPANT EXCLUSION CRITERIA 
Any potential subject who meets one or more of the following criteria will not be included in this 


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study: 
1. Women who are pregnant, lactating, or have a positive pregnancy result at Screening 
Visit 1 
2. Women of child bearing potential who are sexually active and are not willing to use a 
highly effective method of birth control during the study period that includes double 
barrier, IUD, hormonal contraceptive combined with single barrier, or abstinence 
3. Males who are sexually active and have a partner who is capable of becoming pregnant, 
neither of whom have had surgery to become sterilized or whom are not using a highly 
effective method of birth control    
4. Body mass index (BMI) > 35 
5. Partial or complete joint replacement in either knee 
6. Currently requires: 
a. regular use of ambulatory assistive devices (e.g., wheelchair, parallel bars, walker, 
canes, or crutches), or 
b. use of a lower extremity prosthesis, and/or a structural knee brace (i.e., a knee 
brace that contains hardware)  
7. Radiographic disease Stage 0, 1, or 4 in the target knee at Screening Visit 1 according to 
the Kellgren-Lawrence grading of knee OA as assessed by independent central readers 
8. Previous participation in a Samumed clinical trial investigating SM04690 
9. Any surgery (e.g., arthroscopy) in either knee within 26 weeks prior to Screening Visit 1 
10. Any planned surgery during the study period. Non-surgical invasive procedures 
conducted for a diagnostic or therapeutic purpose scheduled during the study period are 
not prohibited (refer to Section 7.6). 
11. Significant and clinically evident misalignment of either knee that would impact subject 
function, as determined by the Investigator 
12. History of malignancy within the last 5 years; however, subjects with prior history of in 
situ cancer or basal or squamous cell skin cancer are eligible if completely excised. 
Subjects with other malignancies are eligible if they have been continuously disease free 
for at least 5 years prior to any study injection 
13. Clinically significant abnormal screening hematology values, blood chemistry values, or 
urinalysis values as determined by the Investigator 
14. Any condition, including laboratory findings (not included in the Screening Visit 1 
laboratory tests) and findings in the medical history or in the pre-study assessments, 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 
15. 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 
16. 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 


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17. Any diagnosed psychiatric condition that includes, but is not limited to, a history of 
mania, bipolar disorder, psychotic disorder, schizophrenia, schizoaffective disorder, 
major depressive disorder, or generalized anxiety disorder 
18. Participation in a clinical research trial that included the receipt of an investigational 
product or any experimental therapeutic procedure, or an observational research trial 
related to osteoarthritis within 8 weeks prior to any study injection, or planned 
participation in any such trial; the last date of participation in the trial, not the last date of 
receipt of investigational product, must be at least 8 weeks prior to Screening Visit 1 
19. Treatment of the target knee with intra-articular glucocorticoids (e.g., 
methylprednisolone) within 12 weeks prior to Screening Visit 1 
20. Any intra-articular injection into the target knee with a therapeutic aim including, but not 
limited to, viscosupplementation (e.g., hyaluronic acid), PRP, and stem cell therapies 
within 24 weeks prior to Screening Visit 1; treatment of the target knee with intra-
articular glucocorticoids greater than 12 weeks prior to Screening Visit 1 is allowed 
21. Treatment with systemic glucocorticoids greater than 10 mg prednisone or the equivalent 
per day within 4 weeks prior to Screening Visit 1  
22. Effusion of the target knee clinically requiring aspiration within 12 weeks prior to 
Screening Visit 1 
23. Use of electrotherapy, acupuncture, and/or chiropractic treatments for knee OA within 
4 weeks prior to Screening Visit 1 (refer to Appendix 2) 
24. Any known active infections, including urinary tract infection, upper respiratory tract 
infection, sinusitis, suspicion of intra-articular 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 
25. Use of centrally acting analgesics (e.g., duloxetine) (refer to Appendix 2) within 12 
weeks prior to Screening Visit 1  
26. Use of anticonvulsants not listed in Appendix 2 within 12 weeks prior to Screening Visit 
1, unless used for seizure or migraine prophylaxis   
27. Subjects requiring the usage of opioids >1x per week within 12 weeks prior to Screening 
Visit 1 
28. Topical local anesthetic agents (gels, creams, or patches such as the Lidoderm patch) 
used for the treatment of knee OA within 7 days of Screening Visit 1  
29. 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. In addition, subjects with a baseline HbA1c >9 will be 
excluded. 
30. If on NSAIDs for the treatment of OA pain, subjects who have not maintained a stable 
regimen in the opinion of the Investigator at Screening Visit 1 
31. Subjects who have a current or pending disability claim, workers’ compensation, or 
litigation(s) that may compromise response to treatment  
32. 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  


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33. 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 
5.3 
LIFESTYLE GUIDELINES 
5.3.1 CONTRACEPTION  
From Screening Visit 1 until Week 24 (EOS)/ET, all subjects must agree to be strictly abstinent 
from sexual intercourse or use an acceptable form of contraception as defined by this protocol if 
the subject or their partner is capable of becoming pregnant. 
Sexually active subjects must use one of the following methods of contraception from Screening 
Visit 1 until Week 24 (EOS)/ET: 
1. Use of a condom for males with a vasectomy (vasectomy must have been performed at 
least 6 months prior to Screening Visit 1) 
2. Males without a vasectomy or a vasectomy performed within 6 months prior to Screening 
Visit 1 must use a condom and be instructed that their female partner(s), if any, must be 
of nonchildbearing potential or use another form of highly effective birth control which 
includes the following: 
a. Double barrier methods of contraception such as condom plus diaphragm or 
cervical/vault cap with spermicide (i.e., physical plus chemical) 
b. Established hormonal contraceptive methods. Females who are using hormonal 
contraceptives must have had consistent use of the same hormonal contraceptive 
product for at least 4 weeks prior to dosing and must continue to use the same 
contraceptive during the study 
c. Intrauterine device (IUD) 
d. Surgically sterile (e.g., bilateral tubal ligation/occlusion, hysterectomy) 
e. Postmenopausal  
3. Women of childbearing potential must agree to use a highly effective method of 
contraception (as described in #2 above) and be instructed that their male partner(s), if 
any, must use a condom 
5.4 
STRATEGIES FOR RECRUITMENT AND RETENTION 
A detailed recruitment and retention plan will be maintained by the Sponsor.  
5.5 
PARTICIPANT WITHDRAWAL OR TERMINATION 
5.5.1 REASONS FOR WITHDRAWAL OR TERMINATION 
As the study treatment requires only a single injection, best efforts will be made to encourage 
subjects to attend all follow-up visits. Subjects will be informed that they are free to withdraw 


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from the study at any time and for any reason. A premature discontinuation from 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:  
• Death 
• Lost to follow-up after a minimum of 3 attempts have been made to contact the 
subject, including sending a registered letter 
• Subject withdraws consent 
• TEAE 
• Subject non-compliance 
• Request by regulatory authority 
• Study terminated by Sponsor 
The Investigator may remove a subject from the study if, in the Investigator's opinion, it is not in 
the best interest of the subject to continue in the study. 
5.5.2 HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 
In case of premature discontinuation of study participation, Week 24 (EOS)/ET procedures 
should be conducted within 14 days of discontinuation for any subject who discontinues after 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 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. 
5.6 
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 
Samumed will be responsible for the manufacturing, labeling, packaging, distribution, 
reconciliation, and destruction of study medication product and vehicle product related to the 
study. 


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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 product is supplied as 2.4 mL of formulated 
suspension in a 3 mL Type I glass vial. A separate 3 mL Type I glass vial contains 2.4 mL of 
vehicle to be used as a diluent. SM04690 vehicle product contains 0.5% carboxymethylcellulose 
sodium and 0.05% polysorbate 80 in pH 7.4 phosphate buffered saline. The placebo will be 
vehicle only or a sham injection. 
SM04690 and vehicle are manufactured by PrimaPharma, Inc. (San Diego, CA) and will be 
supplied as single-use injections. SM04690 and vehicle 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 and vehicle must be stored at the appropriate temperature (15°-30°C or 
59°-86°F) and in a restricted area with limited access. Temperature excursions are allowed 
between 2°-60°C (36°-140°F) for a time period not to exceed a cumulative of 72 hours.  
6.1.4 PREPARATION 
Each dose will be prepared by taking a known volume of SM04690 drug product and adding to a 
vehicle (diluent) vial, mixing well to re-suspend the product, then 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 0.03 mg in 2 mL Injectable Suspension 
• SM04690 0.07 mg in 2 mL Injectable Suspension 
• SM04690 0.15 mg in 2 mL Injectable Suspension  
• SM04690 0.23 mg in 2 mL Injectable Suspension 
• SM04690 0 mg; 2 mL vehicle injection only 
• SM04690 0 mg; 0 mL sham injection (intra-articular injection procedure is performed 
identically to all other treatment groups but without the injection of any liquid) 
Each subject will be consented and randomized using a permuted block design to 1 of 6 
treatment arms at Day 1. The injectable investigational product or vehicle, or the sham injection 
is to be administered by the unblinded Investigator as a 1-time single injection into the target 
knee joint. Only 1 knee will be treated for each subject in this study. Although not required, the 
injection may be guided by ultrasound if it is the standard practice of the Investigator.  
Only topical anesthetic (absolutely no invasive anesthetic) is allowed for the study injections. 


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Anesthetic, if used, may not be combined with the study medication prior to injection. 
Prior to administration of the intra-articular 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.  
The unblinded Investigator (injector) should place the needle into the joint and, while not 
required, if it is the standard practice of the Investigator, a small amount (0.3-0.5 mL) of joint 
fluid can be aspirated (if present) in order to confirm correct needle placement; the aspirated 
fluid does not need to be re-injected. Thereafter, the total volume contained in the syringe is to 
be injected into the joint space of subjects that were randomized to either active or vehicle arms. 
In subjects randomized to sham injection (only intra-articular positioning of the needle without 
volume application), while not required, if it is the standard practice of the Investigator, a small 
amount (0.3-0.5 mL) of joint fluid can be aspirated (if present) in order to confirm correct needle 
placement. The duration that the needle remains inside the joint as well as the pressure that is 
applied should be similar to the active and vehicle injections in order to minimize subject 
awareness that they are receiving a sham injection. Unblinded Investigators (injectors) 
participating in the trial should also inform subjects that they may or may not feel any sensation 
related to the injection.  
6.1.6 ROUTE OF ADMINISTRATION 
The injectable investigational product or vehicle, or the sham injection is to be administered as a 
1-time single intra-articular injection into the target knee joint. 
6.1.7 STARTING DOSE AND DOSE ESCALATION SCHEDULE 
Not applicable to this study. Each subject will be randomly assigned to a dose on Day 1. 
6.1.8 DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS 
No modification in the specified dose concentration or the volume (2 mL, or 0 mL for sham) of 
the study medication or vehicle injected into the target knee joint will be allowed. 
6.1.9 DURATION OF THERAPY 
The injectable investigational product or vehicle, or the sham injection is to be administered as a 
1-time single intra-articular injection into the target knee joint. 
6.1.10 TRACKING OF DOSE 
Not applicable to this study. 
6.1.11 DEVICE SPECIFIC CONSIDERATIONS 
Not applicable to this study. 
 


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6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES 
All used and unused study medication and vehicle vials 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 prepared/injected 
• Quantity dispensed (active vial, vehicle vial) 
• Quantity returned/used (active vial, vehicle vial) 
All study medication and vehicle prepared and dispensed by the unblinded Investigator and/or 
unblinded designee will be 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 and vehicle 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 
Investigator return or destruction of used and unused vials of the study medication and vehicle 
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 treatment-emergent adverse events (TEAEs) will be collected in this study. 
TEAEs are events that occur during the course of 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 course of the study. TEAEs will be assessed at each study visit 
from the time of study medication injection on study visit Day 1 through Week 24 (EOS)/ET.  
Each subject will be observed and queried by the Investigator or the Investigator’s designee at 
each study visit for any continuing TEAEs or new TEAEs since the previous visit. The subject 
may be asked to return to the site for an unscheduled visit if a TEAE occurs between study visits, 
and if, in the opinion of the Investigator, the TEAE requires a study visit for full evaluation. Any 
TEAE reported by the subject or noted by the Investigator or the Investigator’s designee will be 
recorded within the eCRF. The following information will be recorded for each TEAE: 
description of the event, date of onset and resolution, etiology, and severity as assessed by the 
Investigator according to the “Guidance for Industry: Toxicity Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Trials” (Appendix 1), causal relationship 


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to study medication, outcome, and any treatment given.  
TEAEs that are not serious and are ongoing at the subject’s last visit will be followed until the 
study close-out visit, if requested. Serious adverse events that are not resolved or stabilized 
during this time period will be followed until resolution or stabilization. 
Medical History 
A medical history will be obtained at Screening Visit 1 and Day 1 with a follow-up at Week 24 
(EOS)/ET. Medical history at Screening Visit 1 will include demographic data (e.g., age, race, 
ethnicity) and usage 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. Review of medical history at the Week 24 (EOS)/ET 
visit will only be to capture End Dates of any ongoing medical history collected at screening. 
Physical Examination  
A general physical examination will be conducted at Screening Visit 1, Day 1, and Weeks 4, 12, 
and 24 (EOS)/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 a TEAE.  
Knee Examination 
A knee examination of both knees will be conducted at Screening Visit 1, Day 1, and Weeks 4, 
12, and 24 (EOS)/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 a TEAE.  
Presence of bilateral knee OA (yes/no) will be recorded in the eCRF at Screening Visit 1. If the 
subject has OA in both knees, the site is to establish the target knee as the knee with greater pain 
at Screening Visit 1 based on the subject’s evaluation and the Investigator’s clinical judgment. 
Misalignment of both knees will be assessed by the Investigator during the knee examination at 
Screening Visit 1. In the opinion of the Investigator, subjects with significant and clinically 
evident misalignment in either knee that would impact subject function must be excluded from 
the study. 
Vital Signs 
Vital signs will be measured by a qualified staff member at Screening Visit 1, Day 1, and Weeks 
4, 12, and 24 (EOS)/ET. 
At each time point, the following vital signs will be measured: 
• Body temperature 
• Pulse rate 
• Respiration rate 
• Blood pressure (systolic and diastolic) after the subject rests (sitting or supine) for at 
least 5 minutes; same resting position should be used for all blood pressure 


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measurements throughout the study 
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 a TEAE if 
found after study medication injection.  
Height and Weight 
Height measurements will be taken at Screening Visit 1 only. Weight measurements will be 
taken at Screening Visit 1 and Week 24 (EOS)/ET. 
Radiograph of Knee Joints 
Radiograph of the knee joints will be taken at Screening Visit 1 and Week 24 (EOS)/ET.  
Detailed instructions for obtaining and managing the radiographs will be provided to the 
investigational center prior to the initiation of subject enrollment. The intent (as described in the 
Image Review Charter – Image Acquisition Guidelines) is that radiographs should be obtained in 
the posterior-anterior (PA) view, whenever possible.  
All radiographs will be submitted to an independent radiologist who will document disease stage 
according to the Kellgren-Lawrence grading scale for compliance with inclusion/exclusion 
criteria, as well as JSW for efficacy assessments. 
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 [Widespread Pain Index (WPI)] and symptom severity (SS) questions (Clauw 2014). 
A WPI&SS assessment will be completed by the subject at Screening Visit 1 on paper.  
Upon completion of the WPI&SS assessment, the subject will sign/initial and date the source 
document to indicate that the assessments are reported accurately. 
The WPI&SS assessment sheets will be provided by the Sponsor and may not be reproduced. 
Electronic Diary Device Provision and Training 
Electronic diary device provision will occur at Screening Visit 2. Subjects will be trained on 
electronic diary and questionnaire completion at Screening Visit 2. Subject training will include 
details on what medications are NSAIDs. Detailed instructions for subject training and electronic 
questionnaire completion will be provided to the investigational center. Electronic devices are to 
be returned to the site at Week 24 (EOS)/ET. 
Electronic devices will store completed questionnaire data for up to 30 days. Therefore, it is 
recommended that site personnel review study subject ePRO data and compliance reports in the 
ePRO vendor web portal (StudyWorks) at least once a week or more frequently as needed to 
ensure timely subject completion and transmission of questionnaire data between study visits. 
Pain Numeric Rating Scale (NRS) 
The pain NRS is an 11-point scale (0-10) for subject self-reporting of average knee pain in the 
last 24 hours. A pain NRS for each knee will be completed daily by the subject during the 
screening period from Screening Visit 2 until Day 1 to assess subject ability to be compliant with 
a daily pain assessment. During the screening period, daily pain NRS assessments will be 


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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 
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 7.3.7 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. If a subject 
does not complete the electronic dairy for pain NRS for at least 4 out of 7 days in a given week, 
this will be considered a protocol deviation due to subject non-compliance, but the subject 
should not be removed from the study unless the Investigator determines it is in the best interest 
of the subject. 
Increases in pain should only be considered TEAEs if reported by the subject, regardless of pain 
NRS scores.  
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Electronic Diary  
The daily electronic diary of NSAID usage will document subject usage of any NSAID 
medication as “yes” or “no” in response to the following question, “Did you take any medication 
that is an NSAID in the last 24 hours?”.  Starting on the day of Screening Visit 2 after the site 
visit, daily electronic diary of NSAID usage is to be completed by subjects in the evening 
(between 5:00 pm and 11:59 pm) remotely on their electronic devices. Refer to Section 7.3.7 for 
a schedule of electronic diary and questionnaire completion. 
Subjects will complete electronic diary of NSAID usage on the Sponsor-provided electronic 
device. Subjects will receive notifications reminding them to complete the electronic diary of 
NSAID usage. If a subject does not complete the electronic diary of NSAID usage for at least 4 
out of 7 days in a given week, this will be considered a protocol deviation due to subject non-
compliance, but the subject should not be removed from the study unless the Investigator 
determines it is in the best interest of the subject. 
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, 
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 devices on Screening Visit 2 + 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. After Day 1, monthly (every 4 weeks) 
WOMAC assessments will be completed by the subjects for their target knee in the evening 
(between 5:00 pm and 11:59 pm) remotely on their electronic devices. Refer to Section 7.3.7 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 monthly WOMAC assessment. 


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Knee Injury and Osteoarthritis Outcome Score (KOOS) 
KOOS is a widely-used, non-proprietary tool used by health professionals to assess a subject’s 
opinion about their knee and associated problems. KOOS evaluates pain, symptoms, 2 types of 
physical function, and knee-related quality of life. The KOOS 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 devices on Screening Visit 2 + 5 days (or up until the day before the Day 1 visit). 
After Day 1, monthly (every 4 weeks) KOOS questionnaires will be completed by the subjects in 
the evening (between 5:00 pm and 11:59 pm) remotely on their electronic devices. Refer to 
Section 7.3.7 for a schedule of electronic diary and questionnaire completion. 
Subjects will complete the KOOS questionnaire on the Sponsor-provided electronic device. 
Subjects will receive notifications reminding them to complete the monthly KOOS assessment. 
KOOS Physical Function Short Form (KOOS-PS) 
KOOS-PS is derived from the KOOS and is used to assess a subject’s opinion about the 
difficulties they experience with activity due to problems with their knee. The KOOS-PS 
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 devices on Screening Visit 2 + 5 days (or up until 
the day before the Day 1 visit). After Day 1, weekly (every 7 days) KOOS-PS questionnaires 
will be completed by the subjects in the evening (between 5:00 pm and 11:59 pm) remotely on 
their electronic devices. Refer to Section 7.3.7 for a schedule of electronic diary and 
questionnaire completion. 
Subjects will complete the KOOS-PS questionnaire on the Sponsor-provided electronic device. 
Subjects will receive notifications reminding them to complete the weekly KOOS-PS 
assessment. 
Patient Global Assessment of Disease Activity 
The Patient Global Assessment is a 50 mm visual analog scale (VAS) on which the subjects will 
rate how well they are doing, considering all the ways in which illness and health conditions may 
affect them. The VAS will be anchored by descriptors at each end (“Very Well” on the left and 
“Very Poorly” 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 devices on Screening 
Visit 2 + 5 days (or up until the day before the Day 1 visit). After Day 1, monthly (every 4 
weeks) Patient Global Assessments will be completed by the subjects in the evening (between 
5:00 pm and 11:59 pm) remotely on their electronic devices. Refer to Section 7.3.7 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 monthly Patient Global 
Assessment.  
Physician Global Assessment of Disease Activity 
The Physician Global Assessment is a 100 mm VAS on which the Investigator will rate the 
subject’s disease activity independent of the patient’s self-assessment. The VAS will be 
anchored by descriptors at each end (“Very Good” on the left and “Very Bad” on the right). The 
Physician Global Assessment will be performed on paper at Day 1 and Weeks 4, 12, and 24 


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(EOS)/ET.  
The Investigator completing the Physician Global Assessment must sign/initial and date the 
source document to indicate that the assessment is reported accurately. A study staff member 
will record the Physician Global Assessment score in the eCRF. The score is determined by 
measuring the distance (mm) between the “Very Good” anchor and the Investigator’s mark, 
providing a range of scores from 0 to 100. 
The Physician Global Assessment of Disease Activity questionnaires will be provided by the 
Sponsor and may not be reproduced.  
Evaluation of Success of Blinding  
At Day 1 (post intra-articular injection) and Week 24 (EOS)/ET, subjects will complete a 
questionnaire on paper as to which treatment arm of the study they believe they were assigned to 
in order to evaluate the effectiveness of blinding. The questionnaire will capture responses of 
“Study drug injection,” “Injection of 2 mL inactive vehicle substance,” “Needle insertion into the 
knee with no vehicle substance injected,” and “Do not know.” 
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  
Non-fasting samples for clinical laboratory analysis by ACM Global Central Laboratory will be 
collected by a qualified staff member at Screening Visit 1 and Weeks 4, 12, and 24 (EOS)/ET. 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 
(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, leukocytes, 
and occult blood  
An HbA1c test will be performed on all subjects at Screening Visit 1. 
Urine microscopy will be performed if urinalysis urine protein, leukocyte esterase (WBC 
esterase), occult blood, or nitrites values are out of range, or if the Investigator deems that the 
microscopy is clinically warranted. 
The Investigator or the Investigator’s designee must review the results of each subject’s 
Screening Visit 1 clinical laboratory test results prior to the Day 1 visit. The subject must not be 
randomized on Day 1 and, if results are available for review prior to Screening Visit 2, is not 


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recommended to proceed to Screening Visit 2 if any of the Screening Visit 1 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 (clinically significant: yes/no) of any 
result that is outside the normal range for the laboratory or has a toxicity grade of 1 or greater, 
then date and initial the report. The Investigator must report all laboratory results that are BOTH 
outside the normal range for the laboratory or has a toxicity grade of 1 or greater 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 a TEAE. 
7.2.2 OTHER ASSAYS OR PROCEDURES 
Pregnancy Test 
A serum-based pregnancy test will be performed on female subjects at Screening Visit 1. Results 
from the pregnancy test will be utilized to determine subject eligibility. 
Drug Test 
A urine sample for drug testing will be collected at Screening Visit 1. The urine drug test will 
include: cocaine, opioids, methamphetamine, amphetamine, phencyclidine, barbiturates, 
methadone, oxycodone, and ecstasy. Results from the drug test will be utilized to determine 
subject eligibility. 
7.2.3 SPECIMEN PREPARATION, HANDLING, AND STORAGE 
Refer to the Laboratory Manual for ACM Global Laboratory.  
7.2.4 SPECIMEN SHIPMENT 
Refer to the Laboratory Manual for ACM Global Laboratory. 
7.3 
STUDY SCHEDULE 
7.3.1 SCREENING 
Screening Visit 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 the informed consent form. Written 
informed consent must be provided 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 in the subject’s source 
record. After written informed consent is obtained, the subject will be assigned a subject number.  


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The following procedures and assessments will be performed 10-22 days prior to Day 1: 
• Documentation of demographic information, including date of birth, gender, race, and 
ethnicity 
• Documentation of current and past medical history including assistive device usage, 
documentation of current medications, and review of prior medication excluded by 
the protocol 
• Physical examination, including knee examination of both knees and selection of 
target knee 
• Vital signs measurements (pulse, blood pressure, respiration rate, and temperature) 
• Height and weight measurements 
• Venipuncture and collection of samples for clinical laboratory tests 
• Pregnancy test (serum-based) 
• Urine drug test  
• WPI&SS assessment 
• Radiograph – bilateral in weight-bearing fixed flexion position, posterior-anterior 
(PA) view X-ray 
Results from these evaluations will be compared with inclusion/exclusion criteria to determine 
subject eligibility. In order to complete randomization, WPI&SS scores and subject 
bilateral/unilateral OA of the knee status from Screening Visit 1 must be entered into EDC prior 
to the study reaching the enrollment caps described in Section 7.3.2.  
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. 
Screening Visit 2 
This visit must occur at least 3 days after Screening Visit 1 and between 7 to 12 days (inclusive) 
prior to Day 1.  
This visit should occur after confirmation of eligible pregnancy test (if applicable), radiograph, 
clinical laboratory, and urine drug test report results.  
The following procedures and assessments will be performed at Screening Visit 2: 
• Electronic diary device provision and subject training for electronic diary and 
questionnaire completion  
Starting on the day of Screening Visit 2, after the site visit, subjects will begin completion of 
daily pain NRS assessments and NSAIDs electronic diary completion remotely on their 
electronic devices in the evening (between 5:00 pm and 11:59 pm). 
 
Note: On Screening Visit 2 + 5 days (or up until the day before the Day 1 visit), subjects will 
complete the WOMAC, KOOS, KOOS-PS, and Patient Global Assessment, in addition to the 
pain NRS assessment and NSAIDs electronic diary, in the evening (between 5:00 pm and 11:59 


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pm) remotely on their electronic devices. Refer to Section 7.3.7 for a schedule of electronic diary 
and questionnaire completion. 
7.3.2 RANDOMIZATION 
Day 1 
This visit must occur within 10 to 22 days of Screening Visit 1. Subjects with a period of more 
than 12 days between Screening Visit 2 and Day 1 are to be screen failed due to the lengthened 
time between baseline questionnaires and study medication injection. 
The following procedures and assessments will be performed at Day 1 prior to randomization: 
• Review and/or documentation of current and past medical history, documentation of 
current medications, and review of prior medication excluded by the protocol 
• Physical examination, including knee examination of both knees 
• Vital signs measurements (pulse, blood pressure, respiration rate, and temperature) 
• Review of pain NRS electronic diary compliance from Screening Visit 2 to Day 1 
• Electronic questionnaire review (WOMAC) 
Results from these evaluations will be compared with inclusion/exclusion criteria to determine 
subject eligibility. 
Physician Global Assessment will also be performed prior to randomization; however, results 
from this assessment do not determine eligibility. 
The following randomization cohorts will be available until the associated subject counts are 
reached: 
• Unilateral OA with WPI ≤ 4 and SSQ2 ≤ 2 – 240 subjects 
• Bilateral OA with WPI ≤ 4 and SSQ2 ≤ 2 – 240 subjects 
• Unilateral OA with WPI > 4 and/or SSQ2 > 2 – 60 subjects 
• Bilateral OA with WPI > 4 and/or SSQ2 > 2 – 60 subjects 
In order for a subject to be eligible for randomization, WPI&SS scores and subject 
bilateral/unilateral OA of the knee status from Screening Visit 1 must be entered into EDC prior 
to the study reaching the enrollment caps described above. 
The following procedures and assessments will be performed at Day 1 following randomization: 
• Intra-articular study medication injection (or placebo) 
• Collection of TEAE and concomitant procedures/medication data 
• Evaluation of success of blinding  
Note: After the Day 1 site visit, subjects will complete monthly (every 4 weeks) WOMAC, 
KOOS, and Patient Global Assessment, weekly (every 7 days) KOOS-PS, and daily pain NRS 
and NSAIDs electronic diary completion in the evening (between 5:00 pm and 11:59 pm) 
remotely on their electronic devices. Refer to Section 7.3.7 for a schedule of electronic diary and 


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questionnaire completion. 
7.3.3 FOLLOW-UP  
Week 4 and Week 12 
The Week 4 and Week 12 visits should occur on Day 29 (with a window of + 3 days) and Day 
85 (with a window of + 3 days), respectively.  
The following procedures and assessments will be performed at each of these visits: 
• Collection of TEAE and concomitant procedures/medication data 
• Physical examination, including knee examination of both knees  
• Vital signs measurements (pulse, blood pressure, respiration rate, and temperature) 
• Venipuncture and collection of samples for clinical laboratory tests 
• Physician Global Assessment  
7.3.4 FINAL STUDY VISIT 
Week 24 End of Study (EOS) 
This final study visit should occur on Day 169 with a window of + 7 days. 
The following procedures and assessments will be performed at Week 24 (EOS): 
• Collection of TEAE and concomitant procedures/therapies/medication data 
• Review of medical history 
• Vital signs measurements (pulse, blood pressure, respiration rate, and temperature) 
• Physical examination, including knee examination of both knees 
• Weight measurement 
• Venipuncture and collection of samples for clinical laboratory tests 
• Radiograph – bilateral in weight-bearing fixed flexion position, posterior-anterior 
(PA) view X-ray 
• Physician Global Assessment 
• Evaluation of success of blinding 
• Return of electronic device 
7.3.5 EARLY TERMINATION VISIT 
If possible, the following procedures and assessments should be performed within 14 days of 
subject premature withdrawal or termination: 
• Collection of TEAE and concomitant procedures/therapies/medication data 
• Review of medical history 
• Vital signs measurements (pulse, blood pressure, respiration rate, and temperature) 


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• Physical examination, including knee examination of both knees 
• Weight measurement 
• Venipuncture and collection of samples for clinical laboratory tests 
• Radiograph – bilateral in weight-bearing fixed flexion position, posterior-anterior 
(PA) view X-ray 
• Physician Global Assessment 
• Evaluation of success of blinding  
• Return of electronic device 
 
7.3.6 SCHEDULE OF EVENTS TABLE 
 
Procedure 
Screening Perioda 
(Days -22 to -1) 
Day 1b 
Week 4  
(Day 29  
+3 days) 
Week 12  
(Day 85 
+3 days) 
Week 24 
(EOS) 
(Day 169 +7 
days) / ET 
Screening Visit 1 
(Days -22 to -10) 
Screening Visit 2 
Days (-12 to -7) 
Informed consent 
X 
 
 
 
 
 
Inclusion & exclusion 
criteria 
X 
 
X 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical history 
X 
 
X 
 
 
Xc 
Current and prior 
procedures/medications 
X 
 
X 
 
 
 
Serum pregnancy test 
X 
 
 
 
 
 
Radiograph 
X 
 
 
 
 
X 
Physical examination 
X 
 
X 
X 
X 
X 
Knee examination 
X 
 
X 
X 
X 
X 
Selection of target knee 
X 
 
 
 
 
 
Height 
X 
 
 
 
 
 
Weight 
X 
 
 
 
 
X 
Vital signs 
X 
 
X 
X 
X 
X 
Clinical laboratory 
sampling 
X 
 
 
X 
X 
X 
Urine drug test 
X 
 
 
 
 
 
Electronic diary and 
questionnaire trainingd 
 
X (eDiary device 
provision and 
training) 
 
 
 
 
WPI&SSe 
X 
 
 
 
 
 
Pain NRSf 
 
 
X (Review) 
 
 
 
WOMACg 
 
 
X (Review) 
 
 
 


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Procedure 
Screening Perioda 
(Days -22 to -1) 
Day 1b 
Week 4  
(Day 29  
+3 days) 
Week 12  
(Day 85 
+3 days) 
Week 24 
(EOS) 
(Day 169 +7 
days) / ET 
Screening Visit 1 
(Days -22 to -10) 
Screening Visit 2 
Days (-12 to -7) 
Physician Global 
Assessment 
 
 
X 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
Intra-articular injection 
 
 
X 
 
 
 
TEAEs and concomitant 
procedures/medications 
 
 
X 
X 
X 
X 
Evaluation of success of 
blinding 
 
 
X 
 
 
X 
Return of electronic 
device 
 
 
 
 
 
X 
a The screening period is a minimum of 10 days and a maximum of 22 days and includes Screening Visit 1 and Screening 
Visit 2; Screening Visit 2 should occur at least 3 days after Screening Visit 1, at between 7 to 12 days prior to Day 1, and 
after confirmation of eligible pregnancy test (if applicable), radiograph, clinical laboratory, and urine drug test report 
results. 
b At Day 1, all procedures should be performed prior to study medication injection except for collection of TEAE and 
concomitant procedures/medication data and the evaluation of success of blinding. 
c Review medical history to capture End Date(s), if applicable, of any ongoing medical history(ies) collected at screening. 
d Electronic diary devices will be provided to subjects at Screening Visit 2; subject electronic diary and questionnaire 
training will be conducted at Screening Visit 2. 
e WPI&SS will be administered on site at Screening Visit 1. 
f Electronic diary compliance for daily pain NRS over the screening period will be reviewed at Day 1 prior to 
randomization to determine subject eligibility. 
g WOMAC questionnaire will be reviewed at Day 1 prior to randomization to determine subject eligibility. 


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7.3.7 SCHEDULE OF ELECTRONIC DIARY AND QUESTIONNAIRE COMPLETION TABLE 
 
Monthly WOMAC, KOOS, and 
Patient Global Assessment 
Weekly KOOS-PS 
Daily pain NRS and  
NSAIDs electronic diary 
Study Visit or Day 
 
WOMAC, KOOS, and Patient Global 
Assessment will be completed by 
subjects on Screening Visit 2 + 5 days 
(or up until the day before the Day 1 
visit) and monthly in the evening 
(between 5:00 pm and 11:59 pm) 
remotely on their electronic devices. 
Monthly questionnaires should be 
performed in the 2 days prior to each 
month (4 weeks) as outlined below.  
KOOS-PS will be completed by 
subjects on Screening Visit 2 + 5 days 
(or up until the day before the Day 1 
visit) and weekly in the evening 
(between 5:00 pm and 11:59 pm) 
remotely on their electronic devices. 
KOOS-PS should be performed in the 
2 days prior to each week as outlined 
below.  
Pain NRS and NSAIDs electronic 
diary should be completed daily 
starting after Screening Visit 2. 
Subjects will complete the diary in the 
evening (between 5:00 pm and 11:59 
pm) remotely on their electronic 
devices. Diary completion should 
occur every day including on study 
visit days. 
Screening Visit 1 
  
  
  
  
  
  
  
Screening Visit 2 
  
  
  
  
  
  
Complete daily starting on the same 
day of Screening Visit 2 (after the 
visit); pain NRS assessments are to be 
completed for each knee. 
Screening Visit 2 + 5 days 
Baseline monthly questionnaires  
(or up until the day before the  
Day 1 visit) 
Baseline weekly questionnaire  
(or up until the day before the  
Day 1 visit) 
  
  
  
  
  
Day 1 
  
  
  
  
Complete on Day 6 or 7 
Starting on the same day of Day 1 
(after the visit), pain NRS assessments 
are to be completed for the target knee 
only.  
  
Week 1 (Day 8) 
  
  
  
  
Complete on Day 13 or 14 
Week 2 (Day 15) 
  
  
  
  
Complete on Day 20 or 21 
  


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Monthly WOMAC, KOOS, and 
Patient Global Assessment 
Weekly KOOS-PS 
Daily pain NRS and  
NSAIDs electronic diary 
Week 3 (Day 22) 
  
  
 Complete daily 
  
Complete on Day 27 or 28 
Complete on Day 27 or 28 
  
Week 4 (Day 29) 
Questionnaires should NOT be completed on same day as a study visit. 
  
  
  
Complete on Day 34 or 35 
  
Week 5 (Day 36) 
  
  
  
  
  
Complete on Day 41 or 42 
  
Week 6 (Day 43) 
  
  
  
  
  
Complete on Day 48 or 49 
  
Week 7 (Day 50) 
  
  
  
  
Complete on Day 55 or 56 
Complete on Day 55 or 56 
  
Week 8 (Day 57) 
  
  
  
  
  
Complete on Day 62 or 63 
  
Week 9 (Day 64) 
  
  
  
  
  
Complete on Day 69 or 70 
  
Week 10 (Day 71) 
  
  
  
  
  
Complete on Day 76 or 77 
  
Week 11 (Day 78) 
  
  
  
  
Complete on Day 83 or 84 
Complete on Day 83 or 84 
  
Week 12 (Day 85) 
Questionnaires should NOT be completed on same day as a study visit. 
  
  
  
Complete on Day 90 or 91 
  
Week 13 (Day 92) 
  
  
  
  
  
Complete on Day 97 or 98 
  
Week 14 (Day 99) 
  
  
  
  
  
Complete on Day 104 or 105 
  
Week 15 (Day 106) 
  
  
  
  
Complete on Day 111 or 112 
Complete on Day 111 or 112 
  
Week 16 (Day 113) 
  
  
  


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Monthly WOMAC, KOOS, and 
Patient Global Assessment 
Weekly KOOS-PS 
Daily pain NRS and  
NSAIDs electronic diary 
  
  
Complete on Day 118 or 119 
 Complete daily 
Week 17 (Day 120) 
  
  
  
  
  
Complete on Day 125 or 126 
  
Week 18 (Day 127) 
  
  
  
  
  
Complete on Day 132 or 133 
  
Week 19 (Day 134) 
  
  
  
  
Complete on Day 139 or 140 
Complete on Day 139 or 140 
  
Week 20 (Day 141) 
  
  
  
  
  
Complete on Day 146 or 147 
  
Week 21 (Day 148) 
  
  
  
  
  
Complete on Day 153 or 154 
  
Week 22 (Day 155) 
  
  
  
  
  
Complete on Day 160 or 161 
  
Week 23 (Day 162) 
  
  
  
  
Complete on Day 167 or 168 
Complete on Day 167 or 168 
  
Week 24 (Day 169) 
Questionnaires should NOT be completed on same day as a study visit. 
  
 
 


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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 Screening Visit 1 through Week 24 (EOS)/ET will be 
recorded in the eCRF. “All medications” should include prescription, over the counter, 
supplements, as well as herbal or alternative medications. Subjects with a “yes” response for 
daily NSAID usage in their electronic diary should have a corresponding NSAID recorded in the 
eCRF. 
Procedures or non-drug therapies that are ongoing, new, or modified at or after the Screening 
Visits must be recorded on the “Procedures and Non-Drug Therapies” page of the eCRF. 
Any new or modified concomitant therapy must be considered to determine if it is related to a 
TEAE.  
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 intra-articular 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; intra-articular 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)  
 Other anticonvulsants not listed in Appendix 2 are also prohibited unless used for 
seizure or migraine prophylaxis 
 Systemic glucocorticoids greater than 10 mg of prednisone per day or the 
equivalent  
 Drugs of abuse except alcohol and marijuana  
• Electrotherapy (refer to Appendix 2), acupuncture, and/or chiropractic treatments for 
knee OA are prohibited while the subject is on study. 
• 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 


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progress at the time of screening are allowed. 
• Planned or elective surgery, including arthroscopy, is prohibited while the subject is 
on the study. Non-surgical 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: endoscopy, colonoscopy, bronchoscopy, 
cystoscopy, radiologic procedures such as coronary artery catheterization with or 
without intervention, and non-surgical 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 investigational product or any experimental therapeutic 
procedure. Subjects are also prohibited from participating in any observational 
research trial related to osteoarthritis while on study. 
The Investigator should notify the Samumed Medical Monitor 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  
Not applicable to this study. 
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, 
solicitation of TEAEs and concomitant medications, and general medical evaluations.  
8.1.1 DEFINITION OF ADVERSE EVENTS (AE) 
TEAEs in the eCRF will be classified according to the most recent US FDA definitions and in a 
manner consistent with ICH guidelines. As such the following definitions will be used: 
An adverse event (AE) is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational (medicinal) product (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 TEAE term rather than a series of 
symptoms relating to a diagnosis. In order to classify TEAEs and diseases, preferred terms will 
be assigned by the Sponsor to the original terms entered on the eCRF, using the Medical 


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Dictionary for Regulatory Activities (MedDRA).   
8.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
According to the ICH Guidelines for Good Clinical Practice (E6), an SAE is any untoward 
medical occurrence during the course of a clinical investigation that is characterized by 1 or 
more of the following: 
• Results in death 
• Is life threatening 
• Requires nonscheduled (not routine or planned) subject hospitalization or 
prolongation of existing hospitalization for ≥ 24 hours and admission to the hospital 
• 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, 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.  
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 unanticipated problem is defined as, in general, any incident, experience, or outcome that 
meets all of the following criteria:  
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the participant 
population being studied;  
• 
Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and  
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized.  
8.2 
CLASSIFICATION OF AN ADVERSE EVENT 
8.2.1 SEVERITY OF EVENT 
The Investigator will assess TEAEs for severity utilizing the “Guidance for Industry: Toxicity 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Trials”. This 


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toxicity scale is presented in Appendix 1. Laboratory values not listed on the toxicity scale will 
be assessed for severity by the clinical Investigator. 
8.2.2 RELATIONSHIP TO STUDY AGENT 
The relationship of the study treatment to a TEAE will be determined by the Investigator based 
on the following definitions: 
1.  Not Related 
The TEAE is not related if (1) exposure to the investigational product (or placebo) or 
administration of the study injection has not occurred or (2) the occurrence of the TEAE is not 
reasonably related in time or (3) the TEAE is considered related to another event or product not 
associated with the investigational product (or placebo) or the study injection. 
2.  Unlikely Related 
The TEAE is unlikely related if (1) the TEAE is unlikely related in time or (2) the TEAE is 
considered unlikely to be related to use of the investigational product (or placebo) or study 
injection (i.e., there are no facts [evidence] or arguments to suggest a causal relationship). 
3.  Possibly Related 
The TEAE is possibly related if (1) the investigational product (or placebo) or the study injection 
and TEAE are considered reasonably related in time and (2) the TEAE could be explained by 
causes other than exposure to the investigational product (or placebo) or administration of the 
study injection. 
4.  Probably Related 
Exposure to the investigational product (or placebo) or administration of the study injection and 
TEAE are probably related if (1) the investigational product (or placebo) or study injection and 
TEAE are considered reasonably related in time and (2) the investigational product (or placebo) 
or study injection is more likely than other causes to be responsible for the TEAE or is the most 
likely cause of the TEAE. 
8.2.3 EXPECTEDNESS  
The Sponsor will be responsible for determining whether a TEAE/SAE is expected or 
unexpected. A TEAE/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 TEAEs starts after the injection of study medication on Day 1 and ends 
after the final study visit. 
TEAEs must be followed until resolution by the Investigator. Resolution is defined as the return 
to baseline status or stabilization of the condition with the expectation that it will remain chronic. 
TEAEs that are not serious and are ongoing at the subject’s last visit will be followed until the 


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study close-out visit, if requested. Serious adverse events that are not resolved or stabilized 
during this time period will be followed until resolution or stabilization. 
8.4 
REPORTING PROCEDURES 
8.4.1 ADVERSE EVENT REPORTING  
The Investigator is responsible for reporting TEAEs to the Sponsor and IRB according to the 
protocol as well as 21 Code of Federal Regulations (CFR) part 50, part 56, and part 312. The 
Investigator is responsible for ensuring accurate TEAE information is reviewed and recorded in 
the subject source and the TEAE eCRF in a timely manner. The Sponsor is responsible for 
submitting reports of TEAEs associated with the use of study medication that are both serious 
and unexpected to the FDA according to 21 Code of Federal Regulations (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 Code 
of Federal Regulations (CFR) part 50, part 56, and part 312. The Investigator and Samumed will 
manage SAEs according to the study document “Guidelines For The Management Of Serious 
Adverse Events (SAEs) And Pregnancies”. 
All SAEs must be reported as described in the study manual by the Investigator, Study 
Coordinator, other designated study personnel, or Clinical Research Associate within 24 hours of 
notification of the SAE. 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. 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 1. 
Table 1: 
Sponsor Contact Information for Questions on SAE Reporting 
Primary Contact 
Alternative Contact 
 
 
  
 
  
 
  
 
  
 
  
 
  
 
8.4.3 UNANTICIPATED PROBLEM REPORTING  
Incidents or events that meet the criteria for unanticipated problem 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:  


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• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number;  
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP; and 
• 
A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the 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 IRB and to the Sponsor within 24 hours of the 
investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and to the Sponsor within the IRB-required 
reporting timeframe.  
• 
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.   
8.4.4 EVENTS OF SPECIAL INTEREST  
Not applicable to this study. 
8.4.5 REPORTING OF PREGNANCY  
Although pregnancy is not a formal SAE, if a study participant or the partner of a study 
participant becomes pregnant while the study participant is on study, the pregnancy is to be 
reported via SAE reporting procedures. 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”. 
8.5 
STUDY HALTING RULES  
Not applicable to this study. 
8.6 
SAFETY OVERSIGHT 
Clinical safety oversight will be performed by centralized review conducted by Medical 
Monitors 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 Good Clinical Practice (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 


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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 on-site and off-site 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 
No formal hypotheses are being tested in this study. 
10.3 
ANALYSIS DATASETS 
Full Analysis Set (FAS): All subjects who are randomized and receive a study injection. Full 
analysis set 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. 
Modified Full Analysis Set (mFAS): FAS subjects who receive a protocol specified injection. 
Subjects who are administered a treatment that is not prescribed by the protocol will be excluded 
from this analysis set. 
Per-Protocol Analysis Set (PPAS): mFAS 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(S) 
Analysis of covariance (ANCOVA) will be used to estimate the least squares difference in the 
change in weekly average of daily pain NRS, WOMAC Pain, WOMAC Function, and medial 


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JSW adjusting for baseline value. Change will be assessed from baseline between each treatment 
group and the vehicle placebo group. Unadjusted 95% confidence intervals and P values will be 
reported.  
Multiple Comparison Procedure Modelling (MCP-Mod) will estimate SM04690 dose response 
compared to vehicle using the results of the primary efficacy endpoint analyses.  
As the study is stratified based upon known clinical phenotypes of OA, all primary efficacy 
analyses will be completed in three subject populations: 1) subjects with unilateral symptomatic 
OA, 2) subjects with unilateral symptomatic OA and without widespread pain (WPI ≤ 4 and 
SSQ2 ≤ 2), and 3) all subjects. 
10.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
The number and percent of subjects experiencing TEAEs will be summarized by seriousness, 
severity, and relationship for each treatment group. 
ANCOVA will be used to estimate the least squares difference in the change in Patient Global 
Assessment adjusting for baseline value. Change will be assessed from baseline between each 
treatment group and the vehicle placebo group. Unadjusted 95% confidence intervals and P 
values will be reported.  
MCP-Mod will estimate SM04690 dose response compared to vehicle using the results of the 
secondary efficacy endpoint analyses.  
As the study is stratified based upon known clinical phenotypes of OA, all secondary efficacy 
analyses will be completed in three subject populations: 1) subjects with unilateral symptomatic 
OA, 2) subjects with unilateral symptomatic OA and without widespread pain (WPI ≤ 4 and 
SSQ2 ≤ 2), and 3) all subjects. 
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 TEAEs 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 TEAEs and by changes in clinical laboratory parameters and vital signs, relative to baseline. 
Changes from baseline in the amount and duration of NSAID usage will be monitored. 
10.4.5 BASELINE DESCRIPTIVE STATISTICS 
For comparisons with baseline within each analysis population, baseline is defined as the last 
value recorded for any given parameter prior to study medication injection at Day 1. 
10.4.6 PLANNED INTERIM ANALYSES  
Not applicable to this study.  
 


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10.4.6.1 
SAFETY REVIEW 
Medical monitoring of study safety assessment data will be performed during periodic safety 
reviews detailed in the Medical Monitoring Plan. 
10.4.6.2 
EFFICACY REVIEW 
Not applicable to this study.  
10.4.7 EXPLORATORY ANALYSES 
Change from baseline will be summarized with descriptive statistics at Weeks 4, 8, 12, 16, and 
20 for WOMAC pain subscore, WOMAC function subscore, and Patient Global Assessment; at 
Weeks 4, 8, 12, 16, 20, and 24 for WOMAC total score, and KOOS (five subscales [Pain, 
Symptoms, ADL, Sport/Rec and QOL] as well as aggregate scores KOOS4 and KOOS5); and at 
Weeks 4, 12, and 24 for Physician Global Assessment. Change from baseline will also be 
statistically described for weekly KOOS-PS and weekly averages of daily pain NRS (aside from 
Week 24). Change over time in weekly NSAID usage will also be assessed at every week. 
ANCOVA will be used to estimate the least squares difference in the change from baseline in 
exploratory outcomes between each of the four active treatment groups and the vehicle group, 
adjusted for baseline value. Additionally, ANCOVA will be used to estimate the least squares 
difference in the change from baseline in all outcomes (including primary and secondary) 
between the vehicle group and the sham group, adjusted for baseline value. Unadjusted 95% 
confidence intervals and P values will be reported.  
MCP-Mod will estimate SM04690 dose response compared to vehicle using the results of the 
exploratory efficacy endpoint analyses.  
As the study is stratified based upon known clinical phenotypes of OA, all exploratory efficacy 
analyses will be completed in three subject populations: 1) subjects with unilateral symptomatic 
OA, 2) subjects with unilateral symptomatic OA and without widespread pain (WPI ≤ 4 and 
SSQ2 ≤ 2), and 3) all subjects. 
Evaluation of subject awareness of randomized treatment given and the success of blinding in 
this trial will be estimated using an appropriate categorical analysis. Specifically, the percentage 
of subjects accurately identifying the assigned treatment group will be estimated. 
10.4.8 ADDITIONAL SUB-GROUP ANALYSES 
Efficacy analyses described in Section 10.4.2 and Section 10.4.7 will be further analyzed by 
additional, complementary clinical phenotypes of OA not already defined in the primary 
analysis. Details on these sub-group analyses will be provided in the SAP.  
The additional clinical phenotypes of OA will include, but are not limited to: 
• Bilateral Symptomatic OA 
• WPI ≤ 4 and SSQ2 ≤ 2 
• WPI > 4 and/or SSQ2 > 2 
• Unilateral Symptomatic OA with WPI > 4 and/or SSQ2 > 2 


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• Bilateral Symptomatic OA with WPI ≤ 4 and SSQ2 ≤ 2 
• Bilateral Symptomatic OA with WPI > 4 and/or SSQ2 > 2 
10.5 
SAMPLE SIZE 
A sample size of approximately 630 subjects will be randomized at a ratio of 1:1:1:1:1:1 (0.03 
mg active per 2 mL injection : 0.07 mg active per 2 mL injection : 0.15 mg active per 2 mL 
injection : 0.23 mg active per 2 mL injection : 0.0 mL vehicle : 2.0 mL vehicle). The sample size 
for this study was based upon accepted dose finding statistical practice (Ting et al. 2017). 
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. The 
investigational center must identify unblinded personnel who will be responsible for preparing 
the appropriate dilution of the study medication and who are able to perform the injection of 
study medication and/or vehicle. Study personnel administering or preparing study medication 
and reference therapy 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 1. On Day 1, eligible subjects 
will be randomized via the Medidata database. Upon randomization of a subject, a Treatment 
Arm Notification email will be sent from noreply@mdsol.com to the unblinded investigational 
staff member designated in the Site-Specific Blinding Plan. Subjects will be randomized 
1:1:1:1:1:1 (0.03 mg active per 2 mL injection : 0.07 mg active per 2 mL injection : 0.15 mg 
active per 2 mL injection : 0.23 mg active per 2 mL injection : 0.0 mL vehicle : 2.0 mL vehicle) 
to each treatment group using a permuted block design stratified by presence of bilateral knee 
OA (50% bilateral, 50% unilateral) and WPI&SS (80% WPI ≤ 4 and SSQ2 ≤ 2, 20% WPI > 4 
and/or SSQ2 > 2). Specific information regarding the use of Medidata Balance to store and 
implement the permuted block design will be detailed within the SAP. 
10.6.2 EVALUATION OF SUCCESS OF BLINDING  
Subjects will be queried regarding the perceived effectiveness of blinding. Details of this 
analysis will be provided in the SAP. 
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 is to 


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be contacted to obtain concurrence. If it is not possible to contact the Medical Monitor 
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 Balance 
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 site users will have 
access roles to Balance 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 
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. 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., ePRO 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); the date and time 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 TEAEs (All TEAEs may be documented in the source document but only those 
defined in the protocol will be transferred to the eCRFs) 
• The subject’s exposure to any concomitant therapy (including start and stop dates, 
route of administration, and dosage) (All concomitant therapies may be documented 
in the source document but only those defined in the protocol will be transferred to 
the eCRFs) 
ePRO 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, ePRO questionnaire 


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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 individual, on-site, Site Initiation 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 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 
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 Code of Federal Regulations Part 50, 21 Code of Federal 
Regulations Part 56, and/or the ICH E6. 
13.2 
INSTITUTIONAL REVIEW BOARD  
The Investigator agrees to provide the IRB/EC with all appropriate material, including a copy of 
the informed consent form (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 Code of Federal Regulations 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.   
 


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13.3.2 CONSENT PROCEDURES AND DOCUMENTATION 
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 the ICF. Written informed consent 
must be provided 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 in the subject’s source record.  
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 GCP, federal, 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 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. 
 


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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 of the 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 Samumed via data transfers. Medidata Rave is a 
validated electronic data capture system fully compliant with regulatory expectations for 
software developers and service providers within the global regulatory environment, including 
but not limited to ICH E6 and US 21 CFR parts 312, 812, and 11. Data to be transferred external 
to Rave may include ePRO questionnaires 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 
will 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 Samumed. 
Clinical Data Management activities will be conducted by Samumed as described in the study-
specific Data Management Plan. 
14.2 
STUDY RECORDS RETENTION  
During this study, an 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. 


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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 legislation. 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  
A protocol deviation is any noncompliance with the clinical trial protocol requirements. The 
noncompliance may be either on the part of the subject, the Investigator, or the study site staff. 
As a result of deviations, corrective actions are to be developed by the site and implemented 
promptly. Protocol deviations must be sent to the site IRB per their guidelines. The site PI/study 
staff is responsible for knowing and adhering to their IRB requirements.  
Refer to the current version of Samumed SOP-300-013 Protocol Deviations for Sponsor 
procedures related to protocol deviations. 
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 
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.  
 
 
 
 
 
 
 
 


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16. 
LITERATURE REFERENCES  
Altman R. D., Devji T., Bhandari M., Fierlinger A., Niazi F. and Christensen R. (2016). "Clinical 
benefit of intra-articular saline as a comparator in clinical trials of knee osteoarthritis treatments: 
A systematic review and meta-analysis of randomized trials." Semin Arthritis Rheum. 46(2): 151-
159. 
 
Clauw D. J. (2014). "Fibromyalgia: a clinical review." JAMA. 311(15): 1547-1555. 
 
Dougados M. and Hochberg M. C. (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., Ekici A. B., Cipa F., Swoboda B., Carl H. D., Olk A., Hennig F. F. and Klinger P. 
(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., Altman R. D., April K. T., Benkhalti M., Guyatt G., McGowan J., Towheed T., 
Welch V., Wells G., Tugwell P. and American College of R. (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., Felson D. T., Helmick C. G., Arnold L. M., Choi H., Deyo R. A., Gabriel S., 
Hirsch R., Hochberg M. C., Hunder G. G., Jordan J. M., Katz J. N., Kremers H. M., Wolfe F. 
and National Arthritis Data W. (2008). "Estimates of the prevalence of arthritis and other 
rheumatic conditions in the United States. Part II." Arthritis Rheum. 58(1): 26-35. 
 
Nevitt M. C., Felson D. T. and Lester G. (2006). " A Knee Health Study." "The Osteoarthritis 
Initiative.". 
 
Saltzman B. M., Leroux T., Meyer M. A., Basques B. A., Chahal J., Bach B. R., Jr., Yanke A. B. 
and Cole B. J. (2016). "The Therapeutic Effect of Intra-articular Normal Saline Injections for 
Knee Osteoarthritis." Am J Sports Med: 363546516680607. 
 
Ting N., Chen D.-G., Ho S. and Cappelleri J. C. (2017). Phase II Clinical Development of New 
Drugs. Singapore, Springer Singapore. 
 
Wu L., Huang X., Li L., Huang H., Xu R. and Luyten W. (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. 
 
Zhang W., Robertson J., Jones A. C., Dieppe P. A. and Doherty M. (2008). "The placebo effect 
and its determinants in osteoarthritis: meta-analysis of randomised controlled trials." Ann Rheum 
Dis. 67(12): 1716-1723. 
 
 


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APPENDIX 
Appendix 1. 
Guidance for Industry: Toxicity Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Trials  
Table A1: Tables for Clinical Abnormalities  
Local Reaction to  
Injectable Product  
Mild (Grade 1)  
Moderate (Grade 
2)  
Severe (Grade 3)  
Potentially Life  
Threatening  
(Grade 4)  
Pain  
Does not interfere  
with activity  
Repeated use of 
non-narcotic pain 
reliever > 24 hours 
or interferes with 
activity  
Any use of narcotic 
pain reliever or 
prevents daily  
activity  
Emergency room  
(ER) visit or  
hospitalization  
Tenderness  
Mild discomfort to 
touch  
Discomfort with 
movement  
Significant  
discomfort at rest  
ER visit or 
hospitalization  
Erythema/Redness *  2.5 – 5 cm  
5.1 – 10 cm  
> 10 cm  
Necrosis or 
exfoliative dermatitis 
Induration/Swelling 
**  
2.5 – 5 cm and does 
not interfere  
with activity  
5.1 – 10 cm or  
interferes with  
activity  
> 10 cm or  
prevents daily  
activity  
Necrosis  
* In addition to grading the measured local reaction at the greatest single diameter, the measurement should be 
recorded as a continuous variable. 
** Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement. 
Vital Signs *  
Mild (Grade 1)  
Moderate (Grade 
2)  
Severe (Grade 3)  
Potentially Life  
Threatening  
(Grade 4)  
Fever (°C) **  
(°F) **  
38.0 – 38.4  
100.4 – 101.1  
38.5 – 38.9  
101.2 – 102.0  
39.0 – 40  
102.1 – 104  
> 40  
> 104  
Tachycardia - beats 
per minute  
101 – 115  
116 – 130  
> 130  
ER visit or  
hospitalization for  
arrhythmia  
Bradycardia - beats 
per minute***  
50 – 54  
45 – 49  
< 45  
ER visit or  
hospitalization for  
arrhythmia  
Hypertension 
(systolic) - mm Hg  
141 – 150  
151 – 155  
> 155  
ER visit or 
hospitalization for  
malignant  
hypertension  
Hypertension 
(diastolic) - mm Hg  
91 – 95  
96 – 100  
> 100  
ER visit or  
hospitalization for  
malignant  
hypertension  
Hypotension 
(systolic) - mm Hg  
85 – 89  
80 – 84  
< 80  
ER visit or  
hospitalization for  
hypotensive shock  
Respiratory Rate – 
breaths per minute  
17 – 20  
21 – 25  
> 25  
Intubation  
* 
Subject should be at rest for all vital sign measurements.  
** 
Oral temperature; no recent hot or cold beverages or smoking.  
*** When resting heart rate is between 60 – 100 beats per minute. Use clinical judgment when characterizing 
bradycardia among some healthy subject populations, for example, conditioned athletes. 


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Systemic (General)  Mild (Grade 1)  
Moderate (Grade 
2)  
Severe (Grade 3)  
Potentially Life  
Threatening  
(Grade 4)  
Nausea/vomiting  
No interference  
with activity or 1 – 
2 
episodes/24 hours  
Some interference  
with activity or > 2  
episodes/24 hours  
Prevents daily 
activity, requires 
outpatient IV 
hydration  
ER visit or  
hospitalization for  
hypotensive shock  
Diarrhea  
2 – 3 loose stools or 
< 400 gms/24 hours 
4 – 5 stools or  
400 – 800 gms/24  
hours  
6 or more watery  
stools or >800gms 
/24 hours or 
requires  
outpatient IV  
hydration  
ER visit or  
hospitalization  
Headache  
No interference 
with 
activity  
Repeated use of 
non-  
narcotic pain 
reliever > 24 hours 
or some interference  
with activity  
Significant; any  
use of narcotic  
pain reliever or  
prevents daily  
activity  
ER visit or  
hospitalization  
Fatigue  
No interference 
with 
activity  
Some interference  
with activity  
Significant; 
prevents daily 
activity  
ER visit or  
hospitalization  
Myalgia  
No interference 
with 
activity  
Some interference  
with activity  
Significant; 
prevents daily 
activity  
ER visit or  
hospitalization  
 
Systemic Illness 
 
Mild (Grade 1) 
Moderate (Grade 
2) 
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Illness or clinical 
adverse event (as 
defined according to 
applicable 
regulations) 
 
No interference 
with activity 
 
Some interference 
with activity not 
requiring medical 
intervention 
Prevents daily 
activity and requires 
medical intervention 
ER visit or 
hospitalization 
 
 
 
 
 
 


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Table A2: 
Tables for Laboratory Abnormalities  
Serum *  
Mild (Grade 1) Moderate 
(Grade 2)  
Severe  
(Grade 3)  
Potentially Life  
Threatening (Grade 
4)**  
Sodium – Hyponatremia 
mEq/L  
132 – 134  
130 – 131  
125 – 129  
< 125  
Sodium – Hypernatremia 
mEq/L  
144 – 145  
146 – 147  
148 – 150  
> 150  
Potassium – Hyperkalemia 
mEq/L  
5.1 – 5.2  
5.3 – 5.4  
5.5 – 5.6  
> 5.6  
Potassium – Hypokalemia 
mEq/L  
3.5 – 3.6  
3.3 – 3.4  
3.1 – 3.2  
< 3.1  
Glucose – Hypoglycemia 
mg/dL  
65 – 69  
55 – 64  
45 – 54  
< 45  
Glucose – Hyperglycemia  
Fasting – mg/dL  
Random – mg/dL  
100 – 110  
110 – 125  
111 – 125  
126 – 200  
>125  
>200  
Insulin requirements or 
hyperosmolar coma  
Blood Urea Nitrogen  
BUN mg/dL  
23 – 26  
27 – 31  
> 31  
Requires dialysis  
Creatinine – mg/dL  
1.5 – 1.7  
1.8 – 2.0  
2.1 – 2.5  
> 2.5 or requires dialysis  
Calcium – hypocalcemia 
mg/dL  
8.0 – 8.4  
7.5 – 7.9  
7.0 – 7.4  
< 7.0  
Calcium – hypercalcemia 
mg/dL  
10.5 – 11.0  
11.1 – 11.5  
11.6 – 12.0  
> 12.0  
Magnesium – 
hypomagnesemia mg/dL  
1.3 – 1.5  
1.1 – 1.2  
0.9 – 1.0  
< 0.9  
Phosphorous – 
hypophosphatemia mg/dL  
2.3 – 2.5  
2.0 – 2.2  
1.6 – 1.9  
< 1.6  
CPK – mg/dL  
1.25 – 1.5 x 
ULN***  
1.6 – 3.0 x ULN 3.1 –10 x ULN  > 10 x ULN  
Albumin – Hypoalbuminemia 
g/dL  
2.8 – 3.1  
2.5 – 2.7  
< 2.5  
--  
Total Protein – 
Hypoproteinemia g/dL  
5.5 – 6.0  
5.0 – 5.4  
< 5.0  
--  
Alkaline phosphate –  
increase by factor  
1.1 – 2.0 x ULN 2.1 – 3.0 x ULN 3.1 – 10 x ULN  > 10 x ULN  
Liver Function Tests –ALT, 
AST  
increase by factor  
1.1 – 2.5 x ULN 2.6 – 5.0 x ULN 5.1 – 10 x ULN  > 10 x ULN  
Bilirubin – when accompanied  
by any increase in Liver 
Function Test increase by 
factor  
1.1 – 1.25 x 
ULN  
1.26 – 1.5 x 
ULN  
1.51 – 1.75 x 
ULN  
> 1.75 x ULN  
Bilirubin – when Liver 
Function Test is normal; 
increase by factor  
1.1 – 1.5 x ULN 1.6 – 2.0 x ULN 2.0 – 3.0 x ULN > 3.0 x ULN  
Cholesterol  
201 – 210  
211 – 225  
> 226  
---  
Pancreatic enzymes – amylase, 
lipase  
1.1 – 1.5 x ULN 1.6 – 2.0 x ULN 2.1 – 5.0 x ULN > 5.0 x ULN  
* 
The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate.  


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** The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the 
laboratory abnormalities as Potentially Life Threatening (Grade 4). For example, a low sodium value that falls 
within a grade 3 parameter (125-129 mE/L) should be recorded as a grade 4 hypernatremia event if the subject 
had a new seizure associated with the low sodium value.  
*** 
“ULN” is the upper limit of the normal range.  
Hematology *  
Mild (Grade 1)  Moderate  
(Grade 2)  
Severe 
(Grade 3)  
Potentially Life  
Threatening (Grade 
4)  
Hemoglobin (Female) - gm/dL  
11.0 – 12.0  
9.5 – 10.9  
8.0 – 9.4  
< 8.0  
Hemoglobin (Female)  
change from baseline value - 
gm/dL  
Any decrease – 
1.5  
1.6 – 2.0  
2.1 – 5.0  
> 5.0  
Hemoglobin (Male) - gm/dL  
12.5 – 13.5  
10.5 – 12.4  
8.5 – 10.4  
< 8.5  
Hemoglobin (Male)  
change from baseline value – 
gm/dL  
Any decrease – 
1.5  
1.6 – 2.0  
2.1 – 5.0  
> 5.0  
WBC Increase - cell/mm
3 
10,800 – 15,000  15,001 – 
20,000  
20,001 –        
25, 000  
> 25,000  
WBC Decrease - cell/mm
3 
2,500 – 3,500  
1,500 – 2,499  
1,000 – 1,499  
< 1,000  
Lymphocytes Decrease - cell/mm
3 
750 – 1,000  
500 – 749  
250 – 499  
< 250  
Neutrophils Decrease - cell/mm
3 
1,500 – 2,000  
1,000 – 1,499  
500 – 999  
< 500  
Eosinophils - cell/mm
3 
650 – 1500  
1501 - 5000  
> 5000  
Hypereosinophilic  
Platelets Decreased - cell/mm
3 
125,000 – 
140,000  
100,000 – 
124,000  
25,000 – 
99,000  
< 25,000  
PT – increase by factor  
(prothrombin time)  
1.0 – 1.10 x 
ULN**  
1.11 – 1.20 x 
ULN  
1.21 – 1.25 x 
ULN  
> 1.25 ULN  
PTT – increase by factor  
(partial thromboplastin time)  
1.0 – 1.2 x 
ULN  
1.21 – 1.4 x 
ULN  
1.41 – 1.5 x 
ULN  
> 1.5 x ULN  
Fibrinogen increase - mg/dL  
400 – 500  
501 – 600  
> 600  
--  
Fibrinogen decrease - mg/dL  
150 – 200  
125 – 149  
100 – 124  
< 100 or associated  
with gross bleeding  
or disseminated 
intravascular 
coagulation (DIC)  
* 
The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 
** 
“ULN” is the upper limit of the normal range. 
 
Urine *  
Mild (Grade 1)  
Moderate  
(Grade 2)  
Severe (Grade 3)  
Potentially Life  
Threatening  
(Grade 4)  
Protein  
Trace  
1+  
2+  
Hospitalization or  
dialysis  
Glucose  
Trace  
1+  
2+  
Hospitalization for  
hyperglycemia  
Blood (microscopic) – 
red blood cells per high 
power field (rbc/hpf)  
1 - 10  
11 – 50  
> 50 and/or gross 
blood  
Hospitalization or 
packed red blood cells 
(PRBC) transfusion  
* 
The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 


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Appendix 2. 
Prohibited Concomitant Medications and Procedures (Supplement) 
 
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) 
Tramadol (Ultram, Ryzolt, Conzip, Rybix ODT, Fusepaq Synapryn) 
Tapentadol (Nucynta) 
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) 
Other non-listed anticonvulsants are also prohibited while use for seizure prophylaxis or 
migraine prophylaxis would be permitted. 
 
Excluded and prohibited electrotherapy treatments include, but are not limited to, the following: 
Diathermy 
TENS 
NMES 
Interferential therapy 
Shortwave therapy 
Iontophoresis 
LASER 
Ultrasound 


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Appendix 3. 
Amendments 
 
AMENDMENT 03 VERSION 00 SUMMARY OF CHANGES 
Study Title: 
A Phase 2, 24-Week, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study Evaluating the Safety and Efficacy of 
SM04690 for the Treatment of Moderately to Severely Symptomatic 
Knee Osteoarthritis 
 
Purpose: 
The primary purpose of this amendment is to refine and clarify the 
analytical design. Additional administrative changes and corrections 
are also made.  
Summary of Changes: The table below provides a list of changes and their rationale 
Change 
Sections Affected 
Rationale 
“Amendment 03 Version 00” and 
updated date have been added on the title 
page. 
Title Page 
Change was made to capture the dates 
of all previous and current protocol 
versions 
Protocol date and version have been 
updated as applicable. 
All 
Change was made to reflect current 
protocol amendment 
Titles have been updated for Christopher 
Swearingen and Ismail Simsek. 
Sponsor Signature Page 
and Section 1 
Change was made for administrative 
reasons 
List of Abbreviations was updated. 
List of Abbreviations 
Change was made to capture additions 
and removal of various abbreviations 
in this amendment. 
The following was added as a Secondary 
Endpoint: “Evaluate change from 
baseline OA disease activity as assessed 
by Patient Global Assessment at Week 
24” 
Protocol Summary, 
Section 4.2.2, and Section 
10.4.3 
Change was made to refine study 
outcomes in alignment with regulatory 
labeling requirements. 
The following was added as an 
Exploratory Endpoint: “Evaluate 
outcome differences between treatment 
with sham or placebo injections at Week 
4, 8, 12, 16, 20, and 24” 
Protocol Summary, 
Section 4.2.3, and Section 
10.4.7 
Change was made to refine the 
analytical design to more accurately 
reflect the investigational rationale for 
including the sham procedure. 
A correction was made in the Primary 
Endpoints section. #4 erroneously said 
“Week 2” instead of “Week 24”. 
Section 4.2.1 
Change was made to correct an error 
and align with the Protocol Summary 
A correction was made to Section 7.1.1 
which incorrectly noted the WOMAC 
version as “NR3.1”. This was corrected 
to “NRS 3.1”.  
Section 7.1.1 
Change was made to correct an error 
The following edit was made in Section 
8.3: “TEAEs that are not serious and are 
ongoing at the subject’s last visit will be 
followed for a maximum of 30 days until 
the study close-out visit, if requested.” 
Section 8.3 
Change was made to align with update 
to Section 7.1.1 made in Amendment 
02 Version 00.  
Analysis dataset definitions were revised.  
Section 10.3 
Change was made to align with 


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accepted statististical practice and ICH 
guidance. 
Details were added regarding the MCP-
Mod approach.  
Section 10.4.2, Section 
10.4.3, and Section 10.4.7 
Change was made to clarify the 
analytical approach. 
Subject populations were defined.  
Section 10.4.2, Section 
10.4.3, and Section 10.4.7 
Change was made to refine the 
analytical design to more accurately 
reflect the investigational rationale for 
stratifying by disease phenotype. 
Sham was removed from ANCOVA 
models.  
Section 10.4.2  
Change was made to refine the 
analytical design and remove 
comparison to sham control as part of 
the analysis of primary endpoints. 
Clarification was added regarding the 
KOOS analysis. Subscales and two 
aggregate scoring modalities were 
specified. 
Section 10.4.7 
Change was made to clarify the 
outcomes of the instrument. 
Sub-group definitions were modified.  
Section 10.4.8 
Change was made to refine the 
analytical design to more accurately 
reflect the investigational rationale for 
stratifying by disease phenotype. 
 
 
 


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AMENDMENT 02 VERSION 00 SUMMARY OF CHANGES 
Study Title: 
A Phase 2, 24-Week, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study Evaluating the Safety and Efficacy of 
SM04690 for the Treatment of Moderately to Severely Symptomatic 
Knee Osteoarthritis 
 
Purpose: 
The purpose of this amendment is to refine and clarify the study design 
Summary of Changes: The table below provides a list of changes and their rationale 
Change 
Sections Affected 
Rationale 
“Amendment 02 Version 00” and 
updated date have been added on the title 
page. 
Title Page 
Change was made to capture the dates 
of all previous and current protocol 
versions 
Protocol date and version have been 
updated as applicable. 
All 
Change was made to reflect current 
protocol amendment 
The screening window was changed from 
21 days to 22 days. Screening Visit 1 
must occur between Days -22 to -10 and 
Screening Visit 2 must occur between 
Days -12 and -7. 
Protocol Summary, 
Section 4.1, Section 7.3.1, 
and Section 7.3.6  
Change was made to refine study 
design; baseline questionnaires can be 
completed up to 7 days prior to Day 1 
Approximate number of subjects to be 
enrolled was updated from 330 to 630.  
Protocol Summary, 
Schematic of Study 
Design, Section 4.1, and 
Section 10.5 
Change was made to refine study 
design; sample size is being increased 
in accord with current dose-finding 
statistical practice 
Subjects will complete a daily electronic 
diary of NSAID usage generally, not just 
for the treatment of OA pain. 
Protocol Summary, 
Section 4.1, Section 4.2.3, 
Section 7.1.1, Section 
10.4.4, and Section 10.4.7 
Change was made to refine study 
design; subjects will document any 
NSAID usage  
Edits were made to Exclusion Criterion 
#6 for clarification; “regular use” applies 
only to ambulatory assistive devices and 
“structural knee braces” are braces that 
contain hardware. 
Protocol Summary and 
Section 5.2 
Change was made to clarify the 
exclusion criterion 
“Corticosteroids” was replaced with 
“glucocorticoids” throughout the 
protocol.  
Protocol Summary, 
Section 5.2, and Section 
7.6 
Change was made for clarity and 
correctness; not all corticosteroids are 
excluded (e.g., mineralocorticoids are 
allowed), but all glucocorticoids are 
excluded 
Study duration and estimated date of last 
subject complection were updated. 
Protocol Summary 
Change was made for accuracy 
Risks and symptoms associated with 
serious allergic reactions were added to 
Section 2.3.1. 
Section 2.3.1 
Change was made to align with the 
Informed Consent Form 
The following edits were made:  
-Deleted, “Re-screens are limited to 
subjects who did not meet 
inclusion/exclusion criteria at Screening 
Visit 1 due to a transient reason.” 
-Added, “Diary non-compliance is not a 
Section 4.1 
Change was made to refine study 
design; re-screens are allowed if 
subjects screen fail due to transient 
reasons at Screening Visit 2 or Day 1 


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transient event and subjects with diary 
non-compliance may not be re-screened.” 
Additional reasons for withdrawal or 
early termination were added:  
•Request by regulatory authority 
•Study terminated by Sponsor 
Section 5.5.1 
Change was made for completeness  
The following was added in Section 
6.1.5: “…if it is the standard practice of 
the Investigator, a small amount (0.3-0.5 
mL) of joint fluid can be aspirated (if 
present) in order to confirm correct 
needle placement; the aspirated fluid 
does not need to be re-injected.” 
Section 6.1.5 
Change was made to clarify the 
procedure 
The following addition was made in 
Section 6.2: “Quantity returned/used 
(active vial, vehicle vial)” 
Section 6.2 
Change was made to clarify the study 
drug accountability procedures 
The following addition was made in 
Section 6.2: “Procedures for Investigator 
return or destruction of used and unused 
vials of the study medication and vehicle 
will be provided in the Pharmacy 
Manual.” 
Section 6.2 
Change was made for completeness as 
some sites may destroy used and 
unused vials of medication   
The following edit was made in the 
Collection of Adverse Events Data 
section: “The subject will may be asked 
to return to the site for an unscheduled 
visit if a TEAE occurs between study 
visits…” 
Section 7.1.1 
Change was made for correctness 
The etiology of all TEAEs will be 
recorded in the eCRF. 
Section 7.1.1 
Change was made to refine study 
design 
The following edit was made in the 
Collection of Adverse Events Data 
section: “TEAEs that are not serious and 
are ongoing at the subject’s last visit will 
be followed for a maximum of 30 days 
until the study site close-out visit, if 
requested.” 
Section 7.1.1 
Change was made to refine study 
design; non-serious TEAEs may be 
followed until the study site close-out 
visit 
The following was added to the Day 1 
Visit description: “Subjects with a period 
of more than 12 days between Screening 
Visit 2 and Day 1 are to be screen failed 
due to the lengthened time between 
baseline questionnaires and study 
medication injection.” 
Section 7.3.2 
Change was made to emphasize the 
importance of the screening visit 
windows 
The following edit was made to Section 
10.5: "The sample size for this study was 
based upon accepted dose finding 
statistical practice (Ting 2017).” 
Section 10.5, Section 16 
Change was made to align with more 
recent dose finding knowledge 
A correction was made to the AM01V00 
Appendix 3 
Change was made to correct an error 


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Summary of Changes: “other cosmetic 
injections are also prohibited allowed 
during the study” 
 
 
 


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AMENDMENT 01 VERSION 00 SUMMARY OF CHANGES 
Study Title: 
A Phase 2, 24-Week, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study Evaluating the Safety and Efficacy of 
SM04690 for the Treatment of Moderately to Severely Symptomatic 
Knee Osteoarthritis 
 
Purpose: 
The purpose of this amendment is to refine and clarify the study design 
partially in response to site and IRB feedback  
Summary of Changes: The table below provides a list of changes and their rationale 
Change 
Sections Affected 
Rationale 
“Amendment 01 Version 00” and 
“Original Protocol Date” have been 
added on the title page. 
Title Page 
Change was made to capture the dates 
of all previous and current protocol 
versions 
Protocol date and version have been 
updated as applicable. 
All 
Change was made to reflect current 
protocol amendment 
Additional terms were added to the List 
of Abbreviations.  
List of Abbreviations 
Change was made for completeness; 
new abbreviations were used in the 
amendment   
Primary and secondary objectives were 
revised. 
Summary and Section 3 
Change was made to better clarify 
primary and secondary objectives 
The timepoint of the pain NRS primary 
enpoint was revised to Week 24 instead 
of Week 12. Evaluation of change from 
baseline OA pain and OA function at 
Week 24 and in medial JSW at Week 24 
were added as primary endpoints. 
Analysis of primary endpoints in the 
Statistical Considerations section was 
revised accordingly.  
Summary, Section 4.2.1, 
and Section 10.4.2 
Change was made to further refine 
study endpoints 
Secondary endpoints were narrowed 
down to evaluation of safety of SM04690 
as measured by TEAEs. Analysis of 
secondary endpoints in the Statistical 
Considerations section was revised 
accordingly. 
Summary, Section 4.2.2, 
and Section 10.4.3 
Change was made to further refine 
study endpoints 
Remaining secondary endpoints were 
added to exploratory endpoints. 
Exploratory analyses in the Statistical 
Considerations section were revised 
accordingly.  
Summary, Section 4.2.3, 
and Section 10.4.7 
Change was made to further refine 
study endpoints 
“Evaluate subject perception of study 
treatment received at Week 24” was 
added as an exploratory objective. 
Exploratory analyses in the Statistical 
Considerations section were revised 
accordingly. 
Summary, Section 4.2.3, 
and Section 10.4.7 
Change was made to further refine 
study endpoints 
“Monthly” and “weekly” descriptors 
Summary, Section 4.2.2, 
Change was made to further refine 


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were removed from study endpoints. 
and Section 4.2.3 
study endpoints 
The screening period was increased from 
14 days to 21 days. Participant duration 
was changed to “Up to approximately 
2627 weeks.” Screening Visit windows 
were added. 
Summary, Section 4.1, 
Section 7.3.1, Section 
7.3.2, and Section 7.3.6 
Change was made per site feedback to 
allow a larger screening window 
The interim analysis has been removed 
from the study.  
Summary, Section 4.1, 
Section 10 
Change was made to align with 
updated study endpoints; an interim 
analysis is no longer necessary 
The following was deleted from inclusion 
criterion #2: “(single assistive devices 
such as canes allowed if needed less than 
50% of the time) 
Summary and Section 5.1 
Change was made to refine inclusion 
criteria; information regarding 
assistive devices was added to 
exclusion criterion #6 
The following was added to inclusion 
criterion #5: “Primary source of pain 
throughout the body is due to OA in the 
target knee.” 
Summary and Section 5.1 
Change was made to clarify that the 
primary source of pain throughout the 
body, not just in the knee, should be 
due to OA in the target knee 
Inclusion criterion #10 was revised: Total 
WOMAC score of 96-192 (out of 240) 
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) 
Summary and Section 5.1 
Change was made for consistency with 
terminology; baseline WOMAC 
scores, which will be assessed during 
the screening period, will be used for 
eligibility 
Inclusion criterion #12 was revised. 
Amphetamines were deleted. Prohibited 
concomitant medications were revised 
accordingly. 
Summary, Section 5.1, and 
Section 7.6  
Change was made for accuracy; 
subjects must test negative for 
methamphetamines and are prohibited 
from using methamphetamines while 
on the study; methamphetamines are 
already covered under “drugs of 
abuse” 
Inculsion criterion #16 was revised to 
“Subject’s Day 1 Screening Visit 1 visit 
must occur while…” 
Summary and Section 5.1 
Change was made as subjects who are 
screened before the cohort closes will 
still be allowed to enroll if all other 
eligibiligy criteria are met 
Exclusion criterion #6 was revised: 
“Currently requires regular use of 
ambulatory assistive devices (e.g., 
wheelchair, parallel bars, walker, canes, 
or crutches) or use of a walker, lower 
extremity prosthesis, and/or a structural 
patellofemoral knee brace” 
Summary and Section 5.2 
Change was made to refine exclusion 
criteria; regular use of ambulatory 
assistive devices is excluded 
The timing of exclusion criteria #9, 18 
(previously 19), 19 (previously 20), 22 
(previously 23), and 23 (previously 24) 
were revised to “Screening Visit 1.” 
Summary and Section 5.2 
Change was made for consistency with 
other exclusion criteria  
“Gout or pseudogout” was added to 
exclusion criterion #15 and exclusion 
criterion #16 was deleted.  
Summary and Section 5.2 
Change was made to refine exclusion 
criteria; gout or pseudogout are 
excluded altogether 


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Exclusion criterion #18 (previously 19) 
was revised. Participation in an 
observational research trial related to 
osteoarthritis or planned participation in 
clinical research trials are excluded. The 
prohibited medications, treatments, and 
procedures section was updated 
accordingly. 
Summary, Section 5.2, and 
Section 7.6 
Change was made to refine exclusion 
criteria and prohibited medications, 
treatments, and therapies; participation 
in the noted clinical trials is excluded 
and prohibited 
“Glucocorticosteroids”, “corticosteroids”, 
and “glucocorticoids” were revised to 
only “corticosteroids.” 
Summary, Section 5.2, and 
Section 7.6 
Change was made for consistency and 
simplicity  
New exclusion criterion #20 was added: 
Any intra-articular injection into the 
target knee with a therapeutic aim 
including but not limited to 
viscosupplementation (e.g., hyaluronic 
acid), PRP, and stem cell therapies within 
24 weeks prior to Screening Visit 1; 
treatment of the target knee with intra-
articular corticosteroids greater than 12 
weeks prior to Screening Visit 1 is 
allowed.  
-Exclusion criterion #22 regarding 
viscosupplementation was deleted as it 
was merged with the new #20.  
-The prohibited medications, treatments, 
and procedures section was updated 
accordingly. 
Summary, Section 5.2, and 
Section 7.6 
Change was made to refine exclusion 
criteria; any IA injection into the target 
knee with therapeutic intent is 
excluded 
Exclusion criterion #21 was revised from 
“equivalent to 10 mg prednisone or 
more” to “greater than 10 mg prednisone 
or the equivalent…” The prohibited 
medications, treatments, and procedures 
section was updated accordingly.  
Summary, Section 5.2, and 
Section 7.6 
Change was made to refine exclusion 
criteria and prohibited medications; 
greater than 10 mg prednisone or the 
equivalent is excluded and prohibited 
Exclusion criterion #25 (previously 26) 
was revised to: “Subjects requiring the 
chronic use (i.e., regular use for ≥ 12 
weeks) Use of centrally acting analgesics 
(e.g. duloxetine) (refer to Appendix 2) 
within 12 weeks prior to Screening Visit 
1.” The prohibited medications, 
treatments, and procedures section and 
Appendix 2 was updated accordingly. 
Summary, Section 5.2, 
Section 7.6, and Appendix 
2 
Change was made to refine the 
exclusion criterion; any use of 
centrally acting analgesics within 12 
weeks of Screening Visit 1 is 
excluded/prohibited 
New exclusion criterion #26 was added: 
“Use of anticonvulsants not listed in 
Appendix 2 within 12 weeks prior to 
Screening Visit 1, unless used for seizure 
or migraine prophylaxis” 
Summary, Section 5.2, 
Section 7.6, and Appendix 
2 
Change was made to refine the 
exclusion criterion; any use of 
anticonvulsants not listed in Appendix 
2 is excluded/prohibited, unless used 
for seizure or migraine prophylaxis 
Definition of chronic use in exclusion 
criterion #27 was changed from “regular 
use for ≥ 12 weeks” to “usage > 1x per 
Summary and Section 5.2 
Change was made to clarify the 
definition of chronic opioid usage 


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week.” 
New exclusion criterion #30 was added:  
If on NSAIDs for the treatment of OA 
pain, subjects who have not maintained a 
stable regimen in the opinion of the 
Investigator at Screening Visit 1. 
Summary and Section 5.2 
Change was made to refine exclusion 
criteria; subjects should be on a stable 
regimen of NSAIDs (if using them for 
OA pain) prior to the study 
Exclusion criterion #32 (previously 31) 
was revised to state “…any investigative 
site…” 
Summary and Section 5.2 
Change was made to refine exclusion 
criteria; subjects who are directly 
affiliated or are immediate family 
members of personnel directly 
affiliated with the study at any 
investigative site are excluded 
Exclusion criterion #33 (previously 32) 
was revised to add immediate family 
members. 
Summary and Section 5.2 
Change was made to refine exclusion 
criteria; subjects employed by 
Samumed or its affiliates and their 
immediate family members are 
excluded 
The number of investigational centers 
was changed from 35 to 80.  
Summary and Section 4.1 
Change was made for accuracy 
Minor corrections were made to the study 
design schematic. 
Schematic of Study Design 
Changes were made to ensure the 
study design schematic accurately 
represented the study 
Job title for Todd Smith was updated. 
Section 1 
Change was made for administrative 
reasons 
Rationale for the use of a sham injection 
in this study was added to Section 2.2. 
Section 2.2 
Change was made per the request of 
the IRB 
Additional information regarding 
possible risks associated with study 
vehicle were added to Section 2.3.1 
(Study Medication SM04690). 
Section 2.3.1 
Change was made for completeness; 
there are some risks associated with 
study vehicle 
Edits were made to the interim analysis 
description in Section 2.3.1 (Study 
Medication SM04690). 
Section 2.3.1 
Change was made for accuracy; the 
OA-02 safety summary provided is per 
the interim analysis data (not a locked 
database). Extra information was 
deleted for consistency with the IB 
Known potential risks related to the study 
placebos were added to Section 2.3.1. 
Section 2.3.1 
Change was made for completeness; 
there are some risks associated with 
placebo injections 
The following was added to Section 4.1: 
“To support the primary objective, active 
treatment groups will be compared to 
both vehicle (2.0 mL vehicle) and sham 
(0.0 mL vehicle).” 
Section 4.1 
Change was made to clarify study 
design 
“Seasonal allergies” was deleted from 
examples of transient reasons for screen 
failure. 
Section 4.1 
Change was made because seasonal 
allergies was not a good example of a 
transient reason 
Details regarding the evaluation of the 
success of blinding were added to the 
Section 4.1, Section 7.1.1, 
Section 7.3.4, Section 
Change was made for completeness; 
the evaluation was previously 


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protocol.  
7.3.5, and Section 7.3.6, 
and Section 10.4.7 
mentioned in Section 10.6.2 without 
further details 
The following was added to Section 
6.1.5: “Although not required, the 
injection may be guided by ultrasound if 
it is the standard practice of the 
investigator.” 
Section 6.1.5 
Change was made per site request; 
clarification regarding ultrasound 
guidance was needed 
Information regarding how to perform the 
intra-articular injections (active vs. 
vehicle vs. sham) was added to Section 
6.1.5.  
Section 6.1.5 
Change was made per the request of 
the IRB 
The following deletion was made in 
Section 6.2: “All study medication and 
vehicle received, prepared, and 
dispensed…” 
Section 6.2 
Change was made for accuracy; study 
medication and vehicle may be 
received by blinded and unblinded 
staff. 
Widespread Pain Index and Symptom 
Severity Form terminology was updated 
throughout. 
Sections 4.1, 7.1.1, 7.3.1, , 
7.3.6, 10.4.8, and 10.6.1 
Changes were made for consistency 
with Sponsor terminology  
The WPI&SS assessment will be 
performed at Screening Visit 1 instead of 
Screening Visit 2. 
Sections 4.1, 7.1.1, 7.3.1, 
and 7.3.6 
Change was made to aid with 
stratification of cohorts 
The following was deleted from the Knee 
Examination description: “Presence of 
significant misalignment in either knee 
(yes/no) will be recorded in the eCRF.” 
Section 7.1.1 
Change was made because this 
information will not be recorded in the 
eCRF; this information would be 
captured via exclusion criterion #11 
The Vital Signs description was revised: 
“Blood pressure (systolic and diastolic) 
after the subject sitsrests (sitting or 
supine) for at least 5 minutes; same 
resting position should be used for all 
blood pressure measurements throughout 
the study” 
Section 7.1.1 
Change was made to allow subjects to 
rest in either sitting or supine position 
as long as it is used for all BP 
measurements throughout the study 
Regarding the WPI&SS, the following 
deletions were made: “Upon completion 
of the WPI&SS assessment, both the 
subject and the study staff member will 
sign/initial and date…” 
Section 7.1.1 
Change was made because study staff 
are not required to sign the WPI&SS 
form 
Additional detail regarding data storage 
was added to the Electronic Diary Device 
Provision and Training section.  
Section 7.1.1 
Change was made to inform sites of 
the duration of data storage to ensure 
data and reports are reviewed in a 
timely manner 
The Pain Numeric Rating Scale (NRS) 
description was modified to indicate that 
the subject would be reporting “average 
knee pain in the last 24 hours.” 
Section 7.1.1 
Change was made to clarify the pain 
NRS assessment  
The description of “just prior to going to 
bed” was removed throughout the 
protocol.  
Sections 7.1.1, 7.3.1, 7.3.2, 
and 7.3.7 
Change was made to avoid confusion; 
bedtimes may vary so subjects are just 
required to complete the 
questionnaires between 5 pm and 


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11:59 pm 
The description of “from home” was 
replaced with “remotely on their 
electronic devices” throughout the 
protocol.  
Sections 7.1.1, 7.3.1, 7.3.2, 
and 7.3.7 
Change was made to avoid confusion; 
questionnaires need only be performed 
remotely 
Definitions of non-compliance (missing 
greater than 3 of 7 entries in a given 
week) were added to the pain NRS and 
NSAIDs electronic diary descriptions.  
Section 7.1.1 
Change was made per site request to 
clarify the definition of non-
compliance and subsequent courses of 
action 
The timeframe to complete baseline 
questionnaires was updated to Screening 
Visit 2 + 5 days (or up until the day 
before the Day 1 visit).  
Sections 7.1.1, 7.3.1, and 
7.3.7 
Change was made per site request to 
allow for a larger window to complete 
baseline questionnaires 
The Patient Global Assessment 
description was changed from 100 mm 
VAS to 50 mm VAS. 
Section 7.1.1 
Change was made for accuracy; the 
Patient Global Assessment is a 50 mm 
VAS 
It was clarified that the WPI&SS 
assessment and the Physician Global 
Assessment will be performed on paper. 
Section 7.1.1 
Change was made for clarity; these 
assessments will not be performed on 
the electronic device 
Section 7.2.1 was revised to state, “Urine 
microscopy will be performed if 
urinalysis urine protein, leukocyte 
esterase (WBC esterase), occult blood, or 
nitrites values are out of range or if the 
investigator deems that the microscopy is 
clinically warranted.”  
Section 7.2.1 
Change was made per site feedback 
Section 7.2.1 was revised to state: “The 
subject must not be randomized on Day 1 
and, if results are available for review 
prior to Screening Visit 2, is not 
recommended to be scheduled for 
proceed to Screening Visit 2…” 
Section 7.2.1 
Change was made for clarity; if 
laboratory results are available, it is 
recommended that they are reviewed 
prior to the Screening 2 visit  
“MDMA” was replaced with “ecstasy” in 
the urine drug test panel.  
Section 7.2.2 
Change was made to align with ACM 
laboratory test description  
ACM Global Central Laboratory was 
changed to ACM Global Laboratory.  
Section 7.2.3 and Section 
7.2.4 
Change was made to align with the 
laboratory’s name change. 
The following was added to Screening 
Visit 1: “In order to complete 
randomization, WPI&SS scores and 
subject bilateral/unilateral status from 
Screening Visit 1 must be entered into 
EDC prior to the study reaching the 
enrollment caps described in Section 
7.3.2.” 
Section 7.3.1  
Change was made to remind sites to 
enter WPI&SS scores and subject 
bilateral/unilateral status into the EDC 
after Screening Visit 1 
The screening window was increased to 
21 days: SV1 (Day -21 to -10) and SV2 
Day -11 to Day -7). 
Section 7.3.1 and Section 
7.3.6 
Change was made per site request to 
allow a larger screening window 
Section 7.3.2 was renamed 
Section 7.3.2  
Change was made for accuracy; the 
Day 1 visit neither qualified as the 


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“Randomization”. 
consent or baseline visit (some 
baseline assessments are to be 
performed prior to Day 1) 
Information regarding randomization 
cohorts and eligibility for randomization 
was added to the Day 1 visit.  
Section 7.3.2 
Change was made for clarity; 
randomization cohorts were previously 
mentioned without a description 
In Section 7.3.2, “with a window of -2 
days” was deleted from the description of 
monthly and weekly assessments. 
Section 7.3.2 
Change was made to avoid confusion; 
details on questionnaire completion 
are provided in Section 7.3.7 
“Return of electronic device” was added 
to the EOS and ET visits. The study 
procedures description and schedule of 
events table were revised accordingly.  
Section 7.1.1, Section 
7.3.4, Section 7.3.5, and 
Section 7.3.6 
Change was made for completeness; 
subjects are to return their devices at 
the EOS or ET visit 
The following sentences were deleted 
from Section 7.6: “Subjects will be 
encouraged to remain on a stable dose of 
any allowed medications throughout the 
study. The use of aspirin (325 mg/day) 
for thrombosis prophylaxis is permitted.” 
Section 7.6 
Change was made to avoid confusion; 
NSAIDs are allowed on this study 
The first bullet point of the prohibited 
concomitant medications and procedures 
list was revised to cover any intra-
articular injection into either knee.  
Section 7.6 
Change was made for clarification; 
any intra-articular injections into either 
knee are prohibited during the study 
New formalized (i.e., prescribed by a 
medical professional) exercise physical 
therapy exercise programs for knee OA 
were added to the list of prohibited 
concomitant medications and procedures. 
Section 7.6 
Change was made to refine prohibited 
therapies; subjects are not allowed to 
start new physical therapy programs 
for knee OA while on the study. 
The following addition was made to the 
prohibited concomitant medications and 
procedures list: “…non-surgical cosmetic 
procedures such as Botox or other 
cosmetic injections.” 
Section 7.6 
Change was made for clarification; 
other cosmetic injections are also 
allowed during the study 
A new phone number was provided for 
the Medical Monitor. 
Section 8.4.2 
Change was made for administrative 
reasons 
Fax numbers were removed from Table 
1. 
Section 8.4.2 
Change was made to avoid confusion; 
SAEs should not be reported using the 
sponsor contact fax numbers 
Clarifications were made to the additional 
sub-group analyses. 
Section 10.4.8 and Section 
10.6.1 
Change was made for clarification of 
subgroups 
References were added due to additions 
to the rationale section.  
Section 16 
Change was made for completeness; 
new references were used in the 
rationale section 
Various spelling, abbreviation, and 
grammar corrections. 
Throughout 
Changes were made for correctness 
and consistency 
 
 
 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN SM04690-OA-04 
(Version 01, 13 September 2018) 
 
 
 
A Phase 2, 24-Week, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study Evaluating the Safety and Efficacy of 
SM04690 for the Treatment of Moderately to Severely 
Symptomatic 
Knee Osteoarthritis 
 
 
 
 
NCT03122860 


 
 
SM04690-OA-04 SAP V01 
 
Confidential 
Page 1 of 17 
 
 
 
STATISTICAL ANALYSIS PLAN SM04690-OA-04 
 
 
 
Study Title:  
A Phase 2, 24-Week, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study Evaluating the Safety and Efficacy of 
SM04690 for the Treatment of Moderately to Severely Symptomatic 
Knee Osteoarthritis 
 
 
Protocol Number:  
SM04690-OA-04 
 
Protocol Version: 
Amendment 03 Version 00, April 23, 2018 
 
SAP Version: 
01 
 
Investigational Product: 
SM04690 Injectable Suspension  
 
Clinical Phase:  
Phase 2 
 
 
 
 
Sponsor: 
Samumed, LLC.  
 
9381 Judicial Dr., Suite 160  
 
San Diego, CA 92121 
 
(858) 926-2900 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 




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Page 3 of 17 
 
TABLE OF CONTENTS 
SAP SIGNATURE PAGE ................................................................................................................... 2 
TABLE OF CONTENTS ..................................................................................................................... 3 
1. 
INTRODUCTION ............................................................................................................ 5 
2. 
STUDY OBJECTIVES .................................................................................................... 5 
2.1. 
Primary Objective ............................................................................................................. 5 
2.2. 
Secondary Objective ......................................................................................................... 5 
3. 
STUDY DESIGN ............................................................................................................. 5 
3.1. 
Sample Size ....................................................................................................................... 5 
3.2. 
Randomization .................................................................................................................. 5 
3.3. 
Study Medication Dosing ................................................................................................. 6 
4. 
STUDY ENDPOINTS ..................................................................................................... 6 
4.1. 
Primary Endpoints ............................................................................................................ 6 
4.2. 
Secondary Endpoint .......................................................................................................... 6 
4.3. 
Exploratory Endpoints ...................................................................................................... 7 
5. 
STUDY OUTCOME MEASURES ................................................................................. 7 
5.1. 
Safety Outcome Measures................................................................................................ 7 
5.2. 
Efficacy Outcome Measures ............................................................................................ 7 
5.2.1. 
Pain Numeric Rating Scale .............................................................................................. 8 
5.2.2. 
Western Ontario and McMaster Universities Arthritis Index ........................................ 8 
5.2.3. 
Knee Injury and Osteoarthritis Outcome Score .............................................................. 8 
5.2.4. 
Knee Injury and Osteoarthritis Outcome Score – Short Form ....................................... 8 
5.2.5. 
Patient Global Assessment of Disease Activity .............................................................. 9 
5.2.6. 
Physician Global Assessment of Disease Activity ......................................................... 9 
5.2.7. 
Nonsteroidal Anti-Inflammatory Drug Usage ................................................................ 9 
5.2.8. 
Evaluation of Success of Blinding ................................................................................... 9 
5.2.9. 
Joint Space Width ............................................................................................................. 9 
6. 
ANALYSIS DATASETS ................................................................................................. 9 
6.1. 
Full Analysis Set ............................................................................................................... 9 
6.2. 
Modified Full Analysis Set ............................................................................................ 10 
6.3. 
Per-Protocol Analysis Set............................................................................................... 10 
6.4. 
Safety Analysis Set ......................................................................................................... 10 


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7. 
EFFICACY ANALYSIS ................................................................................................ 10 
7.1. 
General Considerations .................................................................................................. 10 
7.2. 
ANCOVA Model for Continuous Efficacy Outcomes................................................. 10 
7.3. 
Analysis of Primary Efficacy Endpoints ....................................................................... 11 
7.4. 
Analysis of Secondary Efficacy Endpoints ................................................................... 11 
7.5. 
Analysis of Exploratory Efficacy Endpoints ................................................................ 11 
7.5.1. 
Additional Timepoints and Outcome Measures ........................................................... 11 
7.5.2. 
Mixed-Effects Model for Repeated Measures .............................................................. 11 
7.5.3. 
Subject Perception of Treatment.................................................................................... 12 
7.5.4. 
Comparison of Vehicle and Sham ................................................................................. 12 
7.5.5. 
Subgroup Analysis .......................................................................................................... 12 
7.5.6. 
Concordance Analysis .................................................................................................... 13 
7.6. 
Dose Selection ................................................................................................................ 13 
8. 
SAFETY ANALYSIS .................................................................................................... 13 
8.1. 
Adverse Events ............................................................................................................... 13 
8.2. 
Clinical Laboratory ......................................................................................................... 13 
8.3. 
Vital Signs ....................................................................................................................... 14 
8.4. 
Concomitant Medications .............................................................................................. 14 
8.5. 
Extent of Exposure ......................................................................................................... 14 
9. 
STATISTICAL CONSIDERATIONS .......................................................................... 14 
9.1. 
Baseline ........................................................................................................................... 14 
9.2. 
Early Termination ........................................................................................................... 14 
9.3. 
Electronic Device Entries ............................................................................................... 14 
9.4. 
Handling of Missing Data .............................................................................................. 15 
10. 
STUDY SUBJECTS ....................................................................................................... 15 
10.1. 
Disposition of Subjects ................................................................................................... 15 
10.2. 
Demographic and Baseline Characteristics ................................................................... 15 
10.3. 
Medical History .............................................................................................................. 15 
11. 
PROTOCOL DEVIATIONS ......................................................................................... 16 
12. 
ANALYSIS SOFTWARE ............................................................................................. 16 
13. 
REFERENCES ............................................................................................................... 17 
 


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1. 
INTRODUCTION 
Osteoarthritis (OA) is the most common form of arthritis and causes degenerative structural 
change that results in pain and decreased mobility. Samumed, LLC is developing SM04690, a 
small-molecule inhibitor of the Wnt pathway, for the treatment of OA. The purpose of this study 
is to assess the safety and efficacy of four different strengths of SM04690 administered by intra-
articular injection into the target knee joint of moderately to severely symptomatic OA subjects. 
 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of this study is to determine the effective dose(s) of SM04690 for the 
treatment of knee OA. 
2.2. 
Secondary Objective 
The secondary objective of this study is to evaluate the safety and tolerability of SM04690. 
 
3. 
STUDY DESIGN 
This study is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study 
of four different concentrations of SM04690 injected into the target knee joint of moderately to 
severely symptomatic OA subjects. 
3.1. 
Sample Size 
A sample size of approximately 630 subjects was randomized at a ratio of 1:1:1:1:1:1 (0.03 mg 
active per 2 mL injection : 0.07 mg active per 2 mL injection : 0.15 mg active per 2 mL injection 
: 0.23 mg active per 2 mL injection : 0.0 mL vehicle : 2.0 mL vehicle). The sample size for this 
study was based upon accepted dose-finding statistical practice (Ting et al. 2017). 
3.2. 
Randomization 
Subjects were randomized to each treatment group using a permuted block design. Prior to 
randomization, the presence of unilateral or bilateral knee OA was determined by the 
investigator and subjects were required to complete the Widespread Pain Index and Symptom 
Severity (WPI&SS) questionnaire. 
The Widespread Pain Index (WPI) is a body map consisting of 19 prespecified areas where 
subjects can indicate the presence of pain during the past seven days with a possible score 0-19. 
Question 2 of the Symptom Severity section of the questionnaire (SSQ2) focuses on the presence 
and severity of three prespecified symptoms (1. fatigue, 2. trouble thinking or remembering, 3. 
waking up tired) during the past seven days with a possible score of 0-9. 
For permuted block randomization, subjects were stratified by knee OA laterality (50% 
unilateral, 50% bilateral) and WPI&SS score (80% WPI ≤ 4 and SSQ2 ≤ 2, 20% WPI > 4 and/or 
SSQ2 > 2). A randomization list with a block size of 6 was generated and stored in Medidata 
Balance. The block size of 6 was selected to accommodate the 6 possible treatment assignments 


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and limit the possibility of imbalance. Since the study was not stratified by site, predictability 
with a small block size was not a concern due to competitive enrollment across all sites. 
Details on the configuration of Medidata Balance for randomization design and list generation 
were documented in the Randomization Configuration Plan. The seed used to generate the 
randomization list was randomly assigned and captured in the Medidata Balance audit trail. The 
randomization lists and seeds were not accessible to blinded study personnel. 
3.3. 
Study Medication Dosing 
SM04690 will be administered in the following dosage strengths: 
• SM04690 0.03 mg in 2-mL Injectable Suspension 
• SM04690 0.07 mg in 2-mL Injectable Suspension 
• SM04690 0.15 mg in 2-mL Injectable Suspension 
• SM04690 0.23 mg in 2-mL Injectable Suspension 
• SM04690 0 mg; 2 mL vehicle injection only 
• SM04690 0 mg; 0 mL sham injection (intra-articular injection procedure is performed 
identically to all other treatment groups but without the injection of any liquid) 
 
4. 
STUDY ENDPOINTS 
4.1. 
Primary Endpoints 
The primary endpoints of this study include: 
1. Evaluate change from baseline OA pain in the target knee as assessed by the weekly 
averages of daily pain Numeric Rating Scale (Pain NRS) at Week 24 
2. Evaluate change from baseline OA pain in the target knee as assessed by Western Ontario 
and McMaster Universities Osteoarthritis Index (WOMAC) Pain subscore at Week 24 
3. Evaluate change from baseline OA function in the target knee as assessed by WOMAC 
Physical Function (WOMAC Function) subscore at Week 24 
4. Evaluate change from baseline in medial joint space width (mJSW) as documented by 
radiograph of the target knee at Week 24 
4.2. 
Secondary Endpoint 
The secondary endpoints of this study include: 
1. Evaluate the safety of SM04690 as measured by treatment-emergent adverse events 
(TEAEs) 
2. Evaluate change from baseline OA disease activity as assessed by Patient Global 
Assessment (PTGA) at Week 24 


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4.3. 
Exploratory Endpoints 
Additional exploratory endpoints of this study include: 
1. Evaluate change from baseline OA pain in the target knee as assessed by WOMAC Pain 
at Weeks 4, 8, 12, 16, and 20 
2. Evaluate change from baseline OA function in the target knee as assessed by WOMAC 
Function at Weeks 4, 8, 12, 16, and 20 
3. Evaluate change from baseline symptoms of OA in the target knee as assessed by 
WOMAC Total at Weeks 4, 8, 12, 16, 20, and 24 
4. Evaluate change from baseline OA pain in the target knee at each week (aside from Week 
24) as assessed by Pain NRS 
5. Evaluate change from baseline OA disease activity as assessed by PTGA at Weeks 4, 8, 
12, 16, and 20 
6. Evaluate change from baseline OA function in the target knee as assessed by Knee Injury 
and Osteoarthritis Outcome Score (KOOS) at Weeks 4, 8, 12, 16, 20, and 24 
7. Evaluate change from baseline OA function in the target knee at each week as assessed 
by KOOS Physical Function Short Form (KOOS-PS) 
8. Evaluate change from baseline OA disease activity as assessed by Physician Global 
Assessment (PGA) at Weeks 4, 12, and 24 
9. Evaluate change over time in NSAID usage as assessed by electronic diary responses at 
every week 
10. Evaluate subject perception of study treatment received at Day 1 and Week 24 
11. Evaluate outcome differences between treatment with sham and vehicle injections at 
Weeks 4, 8, 12, 16, 20 and 24 
 
5. 
STUDY OUTCOME MEASURES 
5.1. 
Safety Outcome Measures 
Safety will be assessed by summarizing and evaluating TEAEs, clinical laboratory results, vital 
signs and concomitant medications.  
5.2. 
Efficacy Outcome Measures 
Knee pain was assessed by the subject using Pain NRS. Knee pain and function was assessed by 
the subject using the WOMAC, KOOS and KOOS-PS questionnaires. Disease activity was 
assessed by the PTGA and PGA. NSAID usage was assessed by subject self-report of taking an 
NSAID via electronic diary. The subjects’ perception of study treatment was assessed by a paper 
questionnaire administered immediately after treatment and again at the end of the study. JSW 
was assessed with radiograph imaging of the target knee. 


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5.2.1. 
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, where 0 represents no pain and 10 represents extreme pain. Subjects were 
prompted to report average pain in the target knee daily on their electronic device (between 5:00 
pm and 11:59 pm) from Screening Visit 2 through the end of the study. An average weekly score 
(referred to as weekly Pain NRS) was calculated for each subject if they had provided a response 
for at least 4 out of 7 days in a given week. Weeks are defined as Day -7 through Day -1 (day 
before treatment) for baseline, Day 1 (day of treatment) through Day 7 for Week 1, Day 8 
through Day 14 for Week 2, and so on. 
5.2.2. 
Western Ontario and McMaster Universities Arthritis Index  
The WOMAC Version NRS 3.1 instrument is a patient-reported outcome measure to assess the 
symptoms of OA. Subjects were prompted to complete the WOMAC instrument monthly on 
their electronic device. The devices required subjects to enter a response for each item before 
proceeding to the next. 
WOMAC consists of 24 questions in three domains: physical function (17 questions), pain (5 
questions) and stiffness (2 questions). The response for each question in the NRS format ranges 
from 0 to 10. Each domain subscore as well as a total score are calculated by adding together the 
numerical responses for a range of 0 to 240 total points. For analysis, WOMAC Total score as 
well as all three subscores will be linearly transformed to a 0-100 scale, where 0 represents no 
difficulty and 100 represents extreme difficulty. 
5.2.3. 
Knee Injury and Osteoarthritis Outcome Score  
KOOS is a widely used, non-proprietary tool intended to evaluate pain, symptoms, 2 types of 
physical function and knee-related quality-of-life. Subjects were prompted to complete the 
KOOS questionnaire monthly on their electronic device. The devices required subjects to enter a 
response for each item before proceeding to the next. 
Subjects were instructed to answer each item with one of 5 standardized Likert responses. Each 
item is assigned a score of 0-4 and a normalized score of 0-100 is calculated for each of the 5 
subscales (Pain, Symptoms, Activities of Daily Living, Sport and Recreation, Quality of Life) 
based on the August 2012 scoring instructions (KOOSscoring2012.pdf). Per these instructions, 
two composite scores are also calculated: KOOS5 (the average of all 5 subscales) and KOOS4 
(the average of 4 subscales, excluding ADL). For all subscale and composite scores, 100 
represents no difficulty and 0 represents extreme difficulty. 
5.2.4. 
Knee Injury and Osteoarthritis Outcome Score – Short Form 
KOOS-PS is a 7-item measure that is used to assess physical function. Subjects were prompted 
to complete the KOOS-PS questionnaire weekly on their electronic device. The devices required 
subjects to enter a response for each item before proceeding to the next. 
Subjects were instructed to answer each item with one of 5 standardized Likert responses. Each 
item is assigned a score of 0-4 and a normalized score of 0-100 is calculated. For this study, to 
align with KOOS, 100 represents no difficulty and 0 represents extreme difficulty. 


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5.2.5. 
Patient Global Assessment of Disease Activity 
The patient assessment was a 50 mm visual analog scale (VAS) adapted from the Patient 
Assessment Form © 1999, American College of Rheumatology. Subjects rated how well they 
were doing, considering all the ways in which illness and health conditions may affect them. The 
VAS was anchored by “Very Well” (0) on the left and “Very Poorly” (50) on the right. Subjects 
were prompted to complete the assessment monthly on their electronic device. Scores were 
subsequently scaled to 0-100. 
5.2.6. 
Physician Global Assessment of Disease Activity 
The physician assessment was a 100 mm VAS adapted from the Physician Assessment Form © 
1999, American College of Rheumatology. The investigator rated the subject’s disease activity 
on a paper form on Day 1 and Weeks 4, 12 and 24. The VAS was anchored by “Very Good” (0) 
on the left and “Very Bad” (100) on the right. 
5.2.7. 
Nonsteroidal Anti-Inflammatory Drug Usage 
Subjects were asked “Did you take any medication that is an NSAID in the last 24 hours?” on 
their electronic device daily (between 5:00 pm and 11:59 pm) from Screening Visit 2 through the 
end of the study. If a “yes” or “no” response was provided for at least 4 out of 7 days in a given 
week, a proportion of days with NSAID usage is calculated (days with “yes” response / total 
number of responses). Weeks are defined as Day -7 through Day -1 for baseline, Day 1 through 
Day 7 for Week 1, Day 8 through Day 14 for Week 2, and so on. 
5.2.8. 
Evaluation of Success of Blinding 
Subjects were prompted, “Please indicate which treatment arm you believe you were assigned to 
for this study” on a paper form on Day 1 (post-injection) and on Week 24. The form captured 
responses of “Study drug injection,” “Injection of 2 mL inactive vehicle substance,” “Needle 
insertion into the knee with no vehicle substance injected” and “Do not know”.  
5.2.9. 
Joint Space Width  
Radiograph of the knee joints was taken at Screening Visit 1 and Week 24. Whenever possible, 
the radiographs obtained the posterior-anterior (PA) view according to the Image Review 
Charter. Medial and lateral JSW measurements of the target knee were provided by the vendor, 
Medical Metrics, Inc. (MMI). 
 
6. 
ANALYSIS DATASETS 
6.1. 
Full Analysis Set 
The Full Analysis Set (FAS) includes all subjects who were randomized and received a study 
injection.  


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6.2. 
Modified Full Analysis Set 
The Modified Full Analysis Set (mFAS) includes FAS subjects who received a protocol-
specified injection. Subjects who were administered a treatment that is not prescribed by the 
protocol are excluded from this analysis set. 
6.3. 
Per-Protocol Analysis Set 
The Per-Protocol Analysis Set (PPAS) includes mFAS subjects who completed the study and did 
not have any major protocol deviations (see Section 11). 
6.4. 
Safety Analysis Set 
The Safety Analysis Set (SAS) includes all subjects who received a study injection.  
 
7. 
EFFICACY ANALYSIS 
7.1. 
General Considerations 
Unless otherwise specified, efficacy analyses will be performed on the FAS, mFAS and PPAS. 
For continuous variables within each treatment group, the outcome measure at each visit, as well 
as absolute change (outcome – baseline), will be summarized using descriptive statistics (number 
of subjects, mean, standard deviation, median, minimum and maximum). Categorical variables 
will be summarized with frequency tables. 
Since this study was stratified based upon known clinical phenotypes of OA, all efficacy 
analyses will be completed in three subject populations: 1) subjects with unilateral symptomatic 
OA, 2) subjects with unilateral symptomatic OA and without widespread pain (WPI ≤ 4 and 
SSQ2 ≤ 2), and 3) all subjects. 
Subject-level listings will be provided for each outcome measure.  
7.2. 
ANCOVA Model for Continuous Efficacy Outcomes 
ANCOVA models will be used for all continuous efficacy outcome measures summarized by 
change from baseline in order to test the following four hypotheses: 
H0: (βi – β0) = 0 
HA: (βi – β0) ≠ 0,   where i = 1,2,3,4 
In the statement above, β is the least squares estimate in the change in the continuous efficacy 
outcome from baseline at each timepoint (where β0 is the estimate for vehicle), and i represents 
each of the four SM04690 treatment groups.  
Least squares estimate of difference between each treatment group and placebo in the change in 
the continuous efficacy outcome from baseline at each timepoint, adjusted for baseline value, 
will be reported along with unadjusted 95% confidence intervals and P values. 


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7.3. 
Analysis of Primary Efficacy Endpoints 
The change from baseline in weekly Pain NRS, WOMAC Pain, WOMAC Function and mJSW 
at Week 24 will be analyzed with the ANCOVA model described in Section 7.2. Figures 
displaying the change in outcome over time will be provided for the FAS and mFAS. 
7.4. 
Analysis of Secondary Efficacy Endpoints 
The change from baseline in PTGA at Week 24 will be analyzed with the ANCOVA model 
described in Section 7.2. Figures displaying the change in PTGA over time will be provided for 
the FAS and mFAS. 
7.5. 
Analysis of Exploratory Efficacy Endpoints 
7.5.1. 
Additional Timepoints and Outcome Measures 
The change from baseline in the parameters described below will be analyzed with the 
ANCOVA model described in Section 7.2. 
1. WOMAC Pain at Weeks 4, 8, 12, 16, and 20 
2. WOMAC Function at Weeks 4, 8, 12, 16, and 20 
3. WOMAC Total at Weeks 4, 8, 12, 16, 20, and 24 
4. Weekly Average of Pain NRS at all weeks, except Week 24 
5. PTGA at Weeks 4, 8, 12, 16, and 20 
6. KOOS at Weeks 4, 8, 12, 16, 20, and 24 
7. KOOS-PS at all weeks 
8. PGA at Weeks 4, 12, and 24 
7.5.2. 
Mixed-Effects Model for Repeated Measures 
Change over time in primary and secondary endpoints (weekly Pain NRS, WOMAC Pain, 
WOMAC Function and PTGA) as well as weekly measures (KOOS-PS and NSAID usage) will 
be characterized using mixed-effects models for repeated measures (MMRM). The models will 
estimate change from baseline with treatment, week, treatment×week interaction and baseline 
value as covariates. 
For weekly measured outcomes, MMRM will be estimated assuming a Toeplitz variance-
covariance matrix.  The Toeplitz structure is a more generalized form of autogressive-1 (AR1) 
structure, allowing the data to inform how the correlation between within-subject observations 
decreases over time instead of implicitly defining a uniform decay structure. For monthly 
measured outcomes, MMRM will be estimated assuming an unstructured variance-covariance 
matrix, allowing the data to fully inform the correlation between within-subject observations. 
(Kincaid 2005) 


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7.5.3. 
Subject Perception of Treatment 
The following contingency table will be prepared to evaluate the subjects’ perception of 
treatment received at Day 1 and at Week 24. 
Assignment 
Guess 
Total 
SM04690 (1) 
Vehicle (2) 
Sham (3) 
Don’t Know (4) 
SM04690 (1) 
n11 (P1|1) 
n12 (P2|1) 
n13 (P3|1) 
n14 (P4|1) 
n1. 
Vehicle (2) 
n21 (P1|2) 
n22 (P2|2) 
n23 (P3|2) 
n24 (P4|2) 
n2. 
Sham (3) 
n31 (P1|3) 
n32 (P2|3) 
n33 (P3|3) 
n34 (P4|3) 
n3. 
Total 
n.1 
n.2 
n.3 
n.4 
N 
Pj|i = P(guess j|assigned treatment i) = probability of guessing treatment j when assigned 
treatment i 
Bang’s Blinding Index (BI) (Bang et al. 2010) will be calculated to determine the percentage of 
unblinding that is beyond chance. 
Bang’s BIi = ቀ2
𝑛𝑛𝑖𝑖𝑖𝑖
𝑛𝑛𝑖𝑖1+𝑛𝑛𝑖𝑖2+𝑛𝑛𝑖𝑖3 −1ቁ× ቀ
𝑛𝑛𝑖𝑖1+𝑛𝑛𝑖𝑖2+𝑛𝑛𝑖𝑖3
𝑛𝑛𝑖𝑖1+𝑛𝑛𝑖𝑖2+𝑛𝑛𝑖𝑖3+𝑛𝑛𝑖𝑖4ቁ, 
where BIi = 0 represents random guessing; BIi = 1 represents complete unblinding; 
BIi = –1 represents opposite guessing 
7.5.4. 
Comparison of Vehicle and Sham 
The change from baseline in weekly Pain NRS, WOMAC Pain, WOMAC Function and PTGA at 
Weeks 4, 8, 12, 16, 20 and 24, as well as mJSW at Week 24 will be analyzed with an ANCOVA 
model with the following hypothesis: 
H0: (βvehicle – βsham) = 0 ; HA: (βvehicle – βsham) ≠ 0 
Least squares estimate of difference between vehicle and sham in the change in outcome from 
baseline, adjusted for baseline value, will be reported along with unadjusted 95% confidence 
intervals and P values. 
7.5.5. 
Subgroup Analysis 
Efficacy analyses described in Sections 7.3 and 7.4 will be further analyzed by additional, 
complementary clinical phenotypes of OA not already defined in Section 7.1.  
The additional clinical phenotypes of OA include: 
1. Bilateral Symptomatic OA 
2. WPI ≤ 4 and SSQ2 ≤ 2 
3. WPI > 4 and/or SSQ2 > 2 
4. Unilateral Symptomatic OA with WPI > 4 and/or SSQ2 > 2 
5. Bilateral Symptomatic OA with WPI ≤ 4 and SSQ2 ≤ 2 


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6. Bilateral Symptomatic OA with WPI > 4 and/or SSQ2 > 2 
7.5.6. 
Concordance Analysis 
Logistic regression will be conducted within each treatment group to determine whether 
baseline-adjusted change in mJSW is concordant with response criteria for Pain NRS, WOMAC 
Pain, WOMAC Function, and Patient Global. Response criteria will be patterned after the 
OMERACT-OARSI response criteria (Pham 2003); a responder must have a 50% improvement 
with corresponding 20 point (out of 100) actual scale improvement. Each outcome will be 
modeled individually, and OMERACT-OARSI ‘strict’ responder (response on either WOMAC 
Pain or WOMAC Function) as well as Pain and Function responder (response on both WOMAC 
Pain and WOMAC Function) will also be modeled. Receiver operator characteristic (ROC) 
curves and ROC areas under the curve (AUC) will be provided. 
7.6. 
Dose Selection 
Multiple Comparison Procedure Modelling (MCP-Mod) will be used to estimate SM04690 dose 
response compared to vehicle using the Week 24 baseline-adjusted ANCOVA analysis of the 
primary and secondary outcome measures in the FAS and all three OA phenotypes described in 
Section 7.1. MCP-Mod will use both monotonic (e.g. linear) and non-monotonic (e.g. beta-mod, 
quadratic, emax) models in exploring outcomes’ dose response relationship. 
 
8. 
SAFETY ANALYSIS 
The analysis of safety outcome measures will be performed on the SAS.  
8.1. 
Adverse Events 
All adverse events (AEs) collected in this study are TEAEs. AEs will be presented in summary 
tables depicting the number of AEs and the number and percent of unique subjects experiencing 
each AE within each treatment group. The following summaries will be provided: 
• AEs by seriousness, toxicity grade severity and relationship to study product 
• AEs by MedDRA system organ class and preferred term 
• AEs by preferred term, sorted by prevalence  
Separate subject-level listings will be provided for all serious and non-serious AEs. 
8.2. 
Clinical Laboratory 
All chemistry, hematology and urinalysis results from the central lab will be summarized into 
shift tables as normal, non-clinically significant abnormal, and clinically significant abnormal. 
Assessments of clinical significance for abnormal values were made by the investigator on 
results that were outside of the normal range or had a toxicity grade of 1 or greater. Shift tables 
will compare the number and percent of assessments from each visit to baseline values for each 
treatment group. Abnormal results for each subject will be provided in listings that will include 
assay name, result, normal range and an explanation for clinically significant values. 
Abnormal urine microscopy and manual differential assessments will be listed for each subject. 


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8.3. 
Vital Signs 
Weight, height, body mass index (BMI) and vital signs, including systolic blood pressure, 
diastolic blood pressure, pulse rate, respiratory rate and body temperature, will be summarized 
for each treatment group. A statistical description (number of subjects, mean, standard deviation, 
median, minimum and maximum) of each parameter at baseline will be provided along with the 
change from baseline at each subsequent visit. A subject-level listing will also be provided. 
8.4. 
Concomitant Medications 
The World Health Organization Drug Dictionary (WHODD) will be used to classify prior and 
concomitant medications by Anatomical Main Group (Anatomical Therapeutic Chemical, ATC, 
Level 1), Therapeutic Subgroup (ATC Level 2), and preferred term. Prior and concomitant 
medication usage will be summarized by the number and percentage of subjects receiving each 
medication by treatment group. 
Subject-level listings containing prior and concomitant medications (WHODD coding), and 
procedures and non-drug therapies (MedDRA coding) will be provided.  
8.5. 
Extent of Exposure 
All treated subjects received a single injection. A list of lot numbers used in this study will be 
provided in the clinical study report. 
 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Baseline 
Baseline is defined as the last value recorded for any given parameter prior to study medication 
injection. If a subject never received a study injection, baseline is defined as the last value 
recorded prior to study termination. 
9.2. 
Early Termination 
If a subject discontinues the study, early termination assessments will be performed according to 
the protocol. If these assessments occur within the window of a scheduled visit (+3 days for 
Weeks 4 and 12 and +7 days for Week 24), they will be associated with that visit for the 
purposes of FAS and mFAS analysis.  
9.3. 
Electronic Device Entries 
Section 7.3.7 of the Protocol provides the schedule of electronic diary and questionnaire 
completion. Weeks are defined as Day -7 through Day -1 (day before treatment) for baseline, 
Day 1 (day of treatment) through Day 7 for Week 1, Day 8 through Day 14 for Week 2, and so 
on. If there is more than one response to any parameter during the associated time period (e.g. 
more than one Pain NRS entry in one day or more than one KOOS-PS entry in one week), the 
following steps will be taken in the presented order: 


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1. Weekly or monthly questionnaires that were completed on a day not specified in Section 
7.3.7 of the Protocol (due to device error) will not be considered for analysis 
2. Any response after the initial response will not be considered for analysis 
9.4. 
Handling of Missing Data 
Missing data will not be imputed for the efficacy analyses described in Section 7. A sensitivity 
analysis will be performed using the last observation carried forward (LOCF) approach to impute 
missing assessments at Week 24 for weekly Pain NRS, WOMAC Pain, WOMAC Function and 
PTGA. This will then be followed by the ANCOVA analysis described in Section 7.2. Since 
single imputation is not necessary for the PPAS with complete data, LOCF analysis will be 
performed on the FAS and mFAS, and repeated for the OA phenotypes described in Section 7.1. 
In addition, a second sensitivity analysis for change from baseline in weekly Pain NRS, 
WOMAC Pain, WOMAC Function and PTGA will be conducted using MMRM as outlined in 
Section 7.5.2. 
 
10. 
STUDY SUBJECTS 
10.1. 
Disposition of Subjects 
Subject disposition will be presented in a summary table detailing the number and percentage of 
subjects who were consented, randomized, treated, completed the study or discontinued (e.g. 
screen failure, subject decision, etc.) by treatment group, site and randomization cohort. The 
disposition for individual subjects will be listed along with additional information on 
discontinued subjects. 
10.2. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics, including gender, race, ethnicity, age, weight, height, 
body mass index (BMI), Kellgren-Lawrence (KL) grade, OA laterality, WPI and SSQ2 will be 
presented by treatment group. Continuous variables will be summarized with descriptive 
statistics and categorical variables will be summarized with frequencies and percentages. The 
summaries will be provided for each analysis set and OA phenotype. Subject level listings will 
also be provided. 
10.3. 
Medical History 
Medical history will be collected at screening and reassessed at the Week 24 (EOS) / Early 
Termination visit to record any changes. A summary of reported medical history will be 
provided by system category for each treatment group in the SAS. A subject-level listing will 
provide further information on each event. 


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11. 
PROTOCOL DEVIATIONS 
A protocol deviation is defined as any change, divergence or departure from the study design or 
procedures of a research protocol that is under the Investigator’s control and that has not been 
approved by the site’s Institutional Review Board (IRB). 
Deviations are summarized into one of the following categories: 
• Informed Consent 
• Enrollment 
• Procedures 
• Labs/Specimens 
• Study Visits 
• Source Documentation 
• Investigational Product 
• Diaries, Questionnaires, or Patient Reported Outcomes 
• IXRS (Interactive Response Technologies) 
• Subject Non-Compliance 
• Adverse Events 
Deviations are categorized as major or minor by a cross-functional team according to pre-defined 
criteria established in the Protocol Deviation Classification Guideline. 
• A major deviation is defined as a divergence from the protocol that materially (a) reduces 
the quality or completeness of the data, (b) makes the informed consent inaccurate, or (c) 
impacts a subject’s safety, rights or welfare. 
• A minor deviation is defined as a divergence from the protocol that deviates from the 
procedures and guidelines outlined in the protocol, but is not classified as a major 
deviation (i.e. the deviation does not materially (a) reduce the quality or completeness of 
the data, (b) make the informed consent inaccurate, or (c) impact a subject’s safety, rights 
or welfare). 
Protocol deviations will be summarized by site, category and classification, and listed for each 
subject. 
 
12. 
ANALYSIS SOFTWARE 
All data processing, summarization and analyses will utilize SAS® Version 9.4, equipped with 
Cytel Inc.’s PROC MCPMOD. 
 
 


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13. 
REFERENCES 
Bang, H., Flaherty, S.P., Kolahi, J., Park, J. (2010). “Blinding assessment in clinical trials: A 
review of statistical methods and a proposal of blinding assessment protocol.” Clinical Research 
and Regulatory Affairs 27(2): 42-51. 
Kincaid CD (2005). “Guidelines for Selecting the Covariance Structure in Mixed Model 
Analysis.”  Proceedings of the Thirtieth Annual SAS® Users Group International Conference. 
Paper 198-30. 
KOOSscoring2012.pdf. (2012). Available at: http://www.koos.nu/KOOSscoring2012.pdf 
[Accessed 24 May 2018]. 
Pham, T., D. Van Der Heijde, M. Lassere, R. D. Altman, J. J. Anderson, N. Bellamy, M. 
Hochberg, L. Simon, V. Strand, T. Woodworth, M. Dougados and O. Omeract (2003). "Outcome 
variables for osteoarthritis clinical trials: The OMERACT-OARSI set of responder criteria." J 
Rheumatol 30(7): 1648-1654. 
Ting N., Chen D.-G., Ho S. and Cappelleri J. C. (2017). Phase II Clinical Development of New 
Drugs. Singapore, Springer Singapore.