A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Bone Health of Multiple Injections of SM04690 Injected in the Target Knee of Moderately to Severely Symptomatic Osteoarthritis Subjects
Phase: PHASE2
Conditions: Knee Osteoarthritis
Sponsor: Biosplice Therapeutics, Inc.

Protocol SM04690-OA-06  
Samumed, LLC 
 
 
AM04V00 
21 August 2020 
 
Confidential 
 
1 
 
 
A Phase 2, 52-Week, Multicenter, Randomized, Double-
Blind, Placebo-Controlled Study Evaluating the Safety, 
Tolerability, and Efficacy of Two Injections of SM04690 
Injected in the Target Knee Joint of Moderately to Severely 
Symptomatic Osteoarthritis Subjects 
 
Study Number: SM04690-OA-06 
IND Sponsor: Samumed, LLC 
Version Number:  Amendment 04 Version 00 
Date: 21 August 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This document is the sole property of Samumed, LLC. This document and any and all 
information contained herein must be considered and treated as strictly confidential. This 
document shall be used only for the purpose of the disclosure herein provided. No disclosure or 
publication shall be made without the prior written consent of Samumed, LLC. 
Original Protocol Date: 09 May 2018 
Amendment 01 Version 00:  29 June 2018 
Amendment 02 Version 00: 17 May 2019 
Amendment 03 Version 00: 01 August 2019 
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Protocol SM04690-OA-06  
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SPONSOR SIGNATURE PAGE 
A Phase 2, 52-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study 
Evaluating the Safety, Tolerability, and Efficacy of Two Injections of SM04690 Injected in the 
Target Knee Joint of Moderately to Severely Symptomatic Osteoarthritis Subjects 
 
Protocol Number: 
SM04690-OA-06 AM04V00 
Date:  
 
21 August 2020 
Name & Title 
Signature 
 Date 
 
Mark Fineman, PhD 
Sr. Vice President, Clinical 
Development 
Document has been electronically signed. Please see the final 
page of the viewable rendition for electronic signatures. 
Christopher Swearingen, PhD 
Vice President, Clinical 
Outcomes and Analytics  
Document has been electronically signed. Please see the final 
page of the viewable rendition for electronic signatures. 
Ismail Simsek, MD 
Medical Director 
Document has been electronically signed. Please see the final 
page of the viewable rendition for electronic signatures. 
 
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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Protocol SM04690-OA-06  
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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ................................................................................................. 2 
TABLE OF CONTENTS ............................................................................................................. 3 
LIST OF ABBREVIATIONS ...................................................................................................... 7 
STATEMENT OF COMPLIANCE .......................................................................................... 10 
PROTOCOL SUMMARY ......................................................................................................... 11 
SCHEMATIC OF STUDY DESIGN ........................................................................................ 21 
1. 
KEY ROLES ....................................................................................................................... 22 
2. 
INTRODUCTION: BACKGROUND INFORMATION & SCIENTIFIC 
RATIONALE .............................................................................................................................. 23 
 
BACKGROUND INFORMATION ........................................................................................ 23 
 
RATIONALE .................................................................................................................... 23 
 
POTENTIAL RISKS AND BENEFITS................................................................................... 24 
2.3.1 Known Potential Risks .............................................................................................. 24 
2.3.2 Known Potential Benefits ......................................................................................... 25 
3. 
OBJECTIVES AND PURPOSE ........................................................................................ 25 
4. 
STUDY DESIGN AND ENDPOINTS ............................................................................... 26 
 
DESCRIPTION OF THE STUDY DESIGN ............................................................................. 26 
 
STUDY ENDPOINTS ......................................................................................................... 27 
4.2.1 Phase A General Safety Endpoints ........................................................................... 27 
4.2.2 Phase A Bone Imaging Endpoints ............................................................................ 28 
4.2.3 Phase A Efficacy Endpoints...................................................................................... 28 
4.2.4 Phase A Exploratory Biomarker Endpoints .............................................................. 28 
4.2.5 Phase B General Safety Endpoints ........................................................................... 29 
4.2.6 Phase B Bone Imaging Endpoints............................................................................. 29 
4.2.7 Phase B Efficacy Endpoints ...................................................................................... 29 
4.2.8 Phase B Exploratory Biomarker Endpoints .............................................................. 30 
5. 
STUDY ENROLLMENT AND WITHDRAWAL ........................................................... 30 
 
PARTICIPANT INCLUSION CRITERIA ............................................................................... 30 
 
PARTICIPANT EXCLUSION CRITERIA .............................................................................. 31 
 
LIFESTYLE GUIDELINES ................................................................................................. 33 
5.3.1 Contraception ............................................................................................................ 33 
 
STRATEGIES FOR RECRUITMENT AND RETENTION ......................................................... 34 
 
PARTICIPANT WITHDRAWAL OR TERMINATION ............................................................. 34 
5.5.1 Reasons for Withdrawal or Termination................................................................... 34 
5.5.2 Handling of Participant Withdrawals or Termination .............................................. 35 
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PREMATURE TERMINATION OR SUSPENSION OF STUDY ................................................. 35 
6. 
STUDY AGENT .................................................................................................................. 35 
 
STUDY AGENT(S) AND CONTROL DESCRIPTION ............................................................. 35 
6.1.1 Acquisition ................................................................................................................ 35 
6.1.2 Formulation, Appearance, Packaging, and Labeling ................................................ 35 
6.1.3 Product Storage and Stability.................................................................................... 36 
6.1.4 Preparation ................................................................................................................ 36 
6.1.5 Dosing and Administration ....................................................................................... 36 
6.1.6 Route of Administration ........................................................................................... 37 
6.1.7 Starting Dose and Dose Escalation Schedule ........................................................... 37 
6.1.8 Dose Adjustments/Modifications/Delays ................................................................. 37 
6.1.9 Duration of Therapy .................................................................................................. 37 
6.1.10 Tracking of Dose....................................................................................................... 37 
6.1.11 Device Specific Considerations ................................................................................ 37 
 
STUDY AGENT ACCOUNTABILITY PROCEDURES ............................................................ 37 
7. 
STUDY PROCEDURES AND SCHEDULE .................................................................... 38 
 
STUDY PROCEDURES/EVALUATIONS .............................................................................. 38 
7.1.1 Study Specific Procedures ........................................................................................ 38 
7.1.2 Standard of Care Study Procedures .......................................................................... 43 
 
LABORATORY PROCEDURES/EVALUATIONS ................................................................... 43 
7.2.1 Clinical Laboratory Evaluations ............................................................................... 43 
7.2.2 Other Assays or Procedures ...................................................................................... 44 
7.2.3 Specimen Preparation, Handling, and Storage ......................................................... 44 
7.2.4 Specimen Shipment .................................................................................................. 44 
 
STUDY SCHEDULE .......................................................................................................... 44 
7.3.1 Screening................................................................................................................... 44 
7.3.2 Randomization .......................................................................................................... 46 
7.3.3 Follow-Up ................................................................................................................. 46 
7.3.4 Final Study Visit ....................................................................................................... 48 
7.3.5 Extension Phase (Phase B)........................................................................................ 49 
7.3.6 Early Termination Visit ............................................................................................ 50 
7.3.7 Schedule of Events Table .......................................................................................... 51 
7.3.8 Schedule of Electronic Diary and Questionnaire Completion Table ........................ 53 
 
JUSTIFICATION FOR SENSITIVE PROCEDURES ................................................................. 54 
 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES ................................. 54 
7.5.1 Precautionary Medications, Treatments, and Procedures ......................................... 54 
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PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES ...................................... 54 
 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES ................................. 55 
 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES ............................................. 55 
 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE ....................................... 55 
8. 
ASSESSMENT OF SAFETY ............................................................................................. 56 
 
SPECIFICATION OF SAFETY PARAMETERS ...................................................................... 56 
8.1.1 Definition of Adverse Events (AE)........................................................................... 56 
8.1.2 Definition of Serious Adverse Events (SAE) ........................................................... 56 
8.1.3 Definition of Unanticipated Problems (UP) ............................................................. 57 
 
CLASSIFICATION OF AN ADVERSE EVENT ...................................................................... 57 
8.2.1 Severity of Event....................................................................................................... 57 
8.2.2 Relationship to Study Agent ..................................................................................... 58 
8.2.3 Expectedness ............................................................................................................. 58 
 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP ................. 59 
 
REPORTING PROCEDURES .............................................................................................. 59 
8.4.1 Adverse Event Reporting .......................................................................................... 59 
8.4.2 Serious Adverse Event Reporting ............................................................................. 59 
8.4.3 Unanticipated Problem Reporting............................................................................. 60 
8.4.4 Events of Special Interest.......................................................................................... 60 
8.4.5 Reporting of Pregnancy ............................................................................................ 60 
 
STUDY HALTING RULES ................................................................................................. 61 
 
SAFETY OVERSIGHT ....................................................................................................... 61 
9. 
CLINICAL MONITORING .............................................................................................. 61 
10. STATISTICAL CONSIDERATIONS .............................................................................. 61 
 
STATISTICAL AND ANALYTICAL PLANS ......................................................................... 61 
 
STATISTICAL HYPOTHESES ............................................................................................ 61 
 
ANALYSIS DATASETS ..................................................................................................... 61 
 
DESCRIPTION OF STATISTICAL METHODS ...................................................................... 62 
10.4.1 General Approach ..................................................................................................... 62 
10.4.2 Analysis of Phase A General Safety and Bone Imaging Endpoints ......................... 62 
10.4.3 Analysis of Phase A Efficacy and Exploratory Biomarker Endpoints ..................... 62 
10.4.4 Analysis of Phase B Endpoints ................................................................................. 63 
10.4.5 Safety Analyses ......................................................................................................... 63 
10.4.6 Baseline Descriptive Statistics .................................................................................. 63 
10.4.7 Planned Interim Analyses ......................................................................................... 63 
10.4.8 Exploratory Analyses ................................................................................................ 64 
10.4.9 Additional Sub-Group Analyses ............................................................................... 64 
 
SAMPLE SIZE .................................................................................................................. 64 
 
MEASURES TO MINIMIZE BIAS ....................................................................................... 64 
10.6.1 Blinding Procedures .................................................................................................. 64 
10.6.2 Evaluation of Success of Blinding ............................................................................ 65 
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10.6.3 Breaking the Study Blind/Participant Code .............................................................. 65 
11. SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ......... 65 
12. QUALITY ASSURANCE AND QUALITY CONTROL ................................................ 66 
13. ETHICS/PROTECTION OF HUMAN SUBJECTS ....................................................... 66 
 
ETHICAL STANDARD ...................................................................................................... 66 
 
INSTITUTIONAL REVIEW BOARD .................................................................................... 66 
 
INFORMED CONSENT PROCESS ....................................................................................... 67 
13.3.1 Consent/Assent and Other Informational Documents Provided to Participants ....... 67 
13.3.2 Consent Procedures and Documentation .................................................................. 67 
 
PARTICIPANT AND DATA CONFIDENTIALITY .................................................................. 67 
13.4.1 Research Use of Stored Human Samples, Specimens, or Data ................................ 68 
 
FUTURE USE OF STORED SPECIMENS ............................................................................. 68 
14. DATA HANDLING AND RECORD KEEPING ............................................................. 68 
 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES ........................................... 68 
 
STUDY RECORDS RETENTION ........................................................................................ 68 
 
PROTOCOL DEVIATIONS ................................................................................................. 69 
 
PUBLICATION AND DATA SHARING POLICY ................................................................... 69 
15. STUDY ADMINISTRATION ............................................................................................ 69 
 
STUDY LEADERSHIP ....................................................................................................... 70 
16. LITERATURE REFERENCES ........................................................................................ 71 
APPENDIX 1. 
PROHIBITED CONCOMITANT MEDICATIONS AND 
PROCEDURES (SUPPLEMENT) ............................................................................................ 72 
APPENDIX 2. 
AMENDMENTS ......................................................................................... 73 
 
 
 
 
 
 
 
 
 
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LIST OF ABBREVIATIONS 
 
Abbreviation 
Term 
ACR 
American College of Rheumatology 
AE  
Adverse event 
AESEV 
Severity/Intensity Scale for Adverse Events 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
β-CTX 
β-C-terminal telopeptide 
BMD 
Bone mineral density 
BMI 
Body mass index 
BQL 
Below quantitation limit 
CDISC 
Clinical Data Interchange Standards Consortium 
CFR 
Code of Federal Regulations 
COMP 
Cartilage oligomeric matrix protein 
CRF 
Case report form 
CT 
Computed tomography 
DLT 
Dose-limiting toxicity 
DXA 
Dual-energy X-ray absorptiometry 
EC 
Ethics Committee 
eCOA 
Electronic clinical outcomes assessment 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EOSa 
Phase A End of Study 
EOSb 
Phase B End of Study 
ER 
Emergency room 
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Abbreviation 
Term 
ET 
Early termination 
FAS 
Full Analysis Set  
FDA 
(US) Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
IA 
Intra-articular 
IB 
Investigator Brochure 
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 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
mFAS 
Modified Full Analysis Set 
mg 
Milligram 
MI 
Myocardial infarction 
mJSW 
Medial joint space width  
mL 
Milliliter 
mm 
Millimeter 
mSv 
Millisievert 
NCS 
Not clinically significant 
NRS 
Numeric rating scale 
NSAID 
Nonsteroidal anti-inflammatory drug 
OA 
Osteoarthritis 
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Abbreviation 
Term 
PINP 
N-terminal propeptide of procollagen type I 
PA 
Posterior-anterior 
PCP 
Phencyclidine  
PI 
Principal Investigator 
PRO 
Patient reported outcomes  
PRP 
Platelet-rich plasma 
PT 
Preferred term 
qCT 
Quantitative computed tomography 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Safety Analysis Set 
SD 
Standard deviation 
SOP 
Standard operating procedure 
SRC 
Safety Review Committee 
SS 
Symptom Severity 
SSQ2 
Symptom Severity Question 2 
ULN 
Upper limit of the normal range 
UP 
Unanticipated problem 
US 
United States 
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, 52-Week, Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study Evaluating the Safety, Tolerability, and Efficacy of 
Two Injections of SM04690 Injected in the Target Knee Joint of 
Moderately to Severely Symptomatic Osteoarthritis Subjects 
Protocol Number 
SM04690-OA-06 
Protocol Date 
21 August 2020 
Protocol Version 
AM04V00 
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 SM04690-OA-06  
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PROTOCOL SUMMARY 
Title: 
A Phase 2, 52-Week, Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study Evaluating the Safety, Tolerability, and Efficacy of Two 
Injections of SM04690 Injected in the Target Knee Joint of Moderately to 
Severely Symptomatic Osteoarthritis Subjects 
Objectives: 
 
Primary: 
The primary objective of this study is to evaluate the safety and tolerability 
of SM04690 Injectable Suspension administered every 6 months through 
52 weeks for the treatment of knee osteoarthritis (OA). 
Secondary: 
The secondary objectives of this study are: 
1. To evaluate the effectiveness of SM04690 Injectable Suspension 
administered every 6 months through 52 weeks for the treatment of 
knee OA    
2. To evaluate the use of quantitative computed tomography (qCT) to 
assess knee bone mineral density (BMD) 
3. To evaluate the safety, tolerability, and effectiveness of SM04690 
Injectable Suspension from 52 weeks through 104 weeks  
Endpoints: 
Phase A General Safety Endpoints: 
1. Adverse events (AEs), serious adverse events (SAEs), vital signs, 
and clinical laboratory measures through Week 52 
Phase A Bone Imaging Endpoints:  
1. Actual BMD and change from baseline in BMD in the target knee 
as assessed by qCT through Week 52 compared to placebo 
2. Within-subject difference in BMD from baseline through Week 52 
between the target and non-target knee by qCT for SM04690  
3. Within-subject difference in BMD from baseline through Week 52 
between the target and non-target knee by qCT for placebo 
4. Change from baseline in BMD in the spine and hips as assessed by 
dual-energy X-ray absorptiometry (DXA) at Week 24 and 52 
Phase A Efficacy Endpoints:  
1. Characterization of change in OA pain in the target knee as 
measured by the weekly averages of daily pain numeric rating scale 
(NRS) from baseline through Week 52 accounting for repeated 
injections  
2. Characterization of change durability of treatment response in OA 
pain in the target knee as measured by the weekly averages of daily 
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pain NRS through Week 52 elapsed from prior injection to repeat 
injection  
3. Characterization of change in OA function in the target knee as 
measured by WOMAC physical function subscore (WOMAC 
Function) from baseline through Week 52 accounting for repeated 
injections  
4. Characterization of change durability of treatment response in OA 
function in the target knee as measured by WOMAC Function 
through Week 52 elapsed from prior injection to repeat injection  
5. Characterization of change in medial joint space width (mJSW) as 
measured by radiograph of the target knee from baseline through 
Week 52 accounting for repeated injections  
6. Characterization of change durability of treatment response in 
mJSW as measured by radiograph of the target knee through Week 
52 elapsed from prior injection to repeat injection  
7. Characterization of change in OA pain in the target knee as 
measured by WOMAC pain subscore (WOMAC Pain) from 
baseline through Week 52 accounting for repeated injections  
8. Characterization of change durability of treatment response in OA 
pain in the target knee as measured by WOMAC Pain through 
Week 52 elapsed from prior injection to repeat injection  
9. Characterization of change in OA disease activity as measured by 
Patient Global Assessment from baseline through Week 52 
accounting for repeated injections  
10. Characterization of change durability of treatment response in OA 
disease activity as measured by Patient Global Assessment through 
Week 52 elapsed from prior injection to repeat injection  
Phase A Exploratory Biomarker Endpoints:  
1. Change from baseline in serum bone biomarkers (e.g., N-terminal 
propeptide of procollagen type I [PINP] and β-C-terminal 
telopeptide [β-CTX]) and a serum cartilage biomarker (e.g., 
cartilage oligomeric matrix protein [COMP]) through Week 52 
compared to placebo 
 
Phase B General Safety Endpoints: 
1. AEs, SAEs, vital signs, and clinical laboratory measures from 
Week 52 through Week 104 
Phase B Bone Imaging Endpoints:  
1. Actual BMD and change from baseline in BMD in the target knee 
as assessed by qCT through Week 104 compared to placebo 
2. Within-subject difference in BMD from baseline through Week 
104 between the target and non-target knee by qCT for SM04690 
3. Within-subject difference in BMD from baseline through Week 
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104 between the target and non-target knee by qCT for placebo 
4. Change from baseline in BMD in the spine and hips as assessed by 
DXA through Week 104 
Phase B Efficacy Endpoints:  
1. Characterization of change in OA pain in the target knee as 
measured by the weekly averages of daily pain NRS from baseline 
through Week 104 accounting for repeated injections  
2. Characterization of change durability of treatment response in OA 
pain in the target knee as measured by the weekly averages of daily 
pain NRS through Week 104 elapsed from prior injection to repeat 
injection 
3. Characterization of change in OA function in the target knee as 
measured by WOMAC Function from baseline through Week 104 
accounting for repeated injections 
4. Characterization of change durability of treatment response in OA 
function in the target knee as measured by WOMAC Function 
through Week 104 elapsed from prior injection to repeat injection 
5. Characterization of change in mJSW as measured by radiograph of 
the target knee from baseline through Week 104 accounting for 
repeated injections  
6. Characterization of change durability of treatment response in 
mJSW as measured by radiograph of the target knee through Week 
104 elapsed from prior injection to repeat injection  
7. Characterization of change in OA pain in the target knee as 
measured by WOMAC Pain from baseline through Week 104 
accounting for repeated injections 
8. Characterization of change durability of treatment response in OA 
pain in the target knee as measured by WOMAC Pain through 
Week 104 elapsed from prior injection to repeat injection  
9. Characterization of change in OA disease activity as measured by 
Patient Global Assessment from baseline through Week 104 
accounting for repeated injections  
10. Characterization of change durability of treatment response in OA 
disease activity as measured by Patient Global Assessment through 
Week 104 elapsed from prior injection to repeat injection 
 
Phase B Exploratory Biomarker Endpoints:  
1. Change from Week 52 in serum bone biomarkers (e.g., PINP and 
β-CTX) and a serum cartilage biomarker (e.g., COMP) through 
Week 104 
 
Methodology: 
This study will be a multicenter, randomized, double-blind, placebo-
controlled, parallel group study of a single concentration of SM04690 
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injected into the target knee joint of moderately to severely symptomatic 
OA subjects. In this study, “placebo” refers to vehicle product. 
Approximately 100 subjects will be enrolled and randomized at a ratio of 
1:1 (0.07 mg active per 2 mL injection: 2 mL placebo).  
Core Phase (Phase A) 
Subjects will participate in a screening period of a minimum of 10 days 
and up to 19 days and a 52-week evaluation period. Each subject will 
receive an injection on Day 1 and Week 24 (same dose for each injection) 
and will be observed for one year after first injection. Clinic visits will be 
scheduled at Screening Visit 1, Screening Visit 2, Day 1, and Weeks 4, 12, 
24, 36, and 52 [Phase A End of Study (EOSa)] or Early Termination (ET). 
Phase A Study Assessments  
qCT will be performed at Screening Visit 2 and at Weeks 12, 24, 36, and 
52 (EOSa) or ET. DXA will be performed at Screening Visit 2 and at 
Weeks 24 and 52 (EOSa) or ET. Bone and cartilage biomarkers will be 
assessed at Screening Visit 2 and at Weeks 4, 12, 24, 36, and 52 (EOSa) or 
ET. Radiographic images of the knees will be performed at Screening Visit 
1 and at Weeks 24 and 52 (EOSa) or ET.  
Subjects will be required to complete an electronic diary for the following: 
• Daily pain NRS 
• Monthly completion of the WOMAC 
• Monthly completion of Patient Global Assessment  
Extension Phase (Phase B) 
Subjects who complete Phase A will be eligible to enter the extension 
phase, Phase B, for an additional 52 weeks of treatment. Subjects will 
remain on their randomized treatment (SM04690 or placebo) for the 
additional year. Each subject will receive an injection at Week 52 (EOSa) 
and Week 76 with follow-up clinic visits scheduled at Weeks 64, 76, 88, 
and 104 [Phase B End of Study (EOSb)] or ET. 
Primary analysis of Phase A data will be completed after the last subject 
completes Week 52 (EOSa). While the Sponsor will be unblinded to study 
treatment after the Phase A analysis (after the last subject completes Week 
52 [EOSa]), the Investigator and the subject will remain blinded.  
Phase B Study Assessments  
qCT will be performed at Weeks 64, 76, 88, and 104 (EOSb) or ET. DXA 
will be performed at Weeks 76 and 104 (EOSb) or ET. Bone and cartilage 
biomarkers will be assessed at Weeks 64, 76, 88, and 104 (EOSb) or ET. 
Radiographic images of the knees will be performed at Weeks 76 and 104 
(EOSb) or ET. Subjects will be required to complete the following: 
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• Daily pain NRS 
• Monthly completion of the WOMAC  
• 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 
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. WOMAC pain subscore of 20-40 (out of 50) and WOMAC 
physical function subscore of 68-136 (out of 170) for the target 
knee at baseline, regardless of if the subject is on symptomatic oral 
treatment (baseline questionnaire completed during the screening 
period prior to randomization) 
11. Widespread Pain Index (WPI) score of ≤ 4 and a Symptom 
Severity Question 2 (SSQ2) score of ≤ 2 at Screening Visit 1 
12. Willingness to use an electronic diary on a daily basis in the 
evening for the screening period and 104-week study duration 
13. Negative drug test for amphetamine, buprenorphine, cocaine, 
methadone, opiates, phencyclidine (PCP), propoxyphene, 
barbiturates, benzodiazepine, methaqualone, and tricyclic 
antidepressants, except if any such drugs are clinically indicated 
and allowed by the protocol, at Screening Visit 1  
14. Subjects with depression or anxiety must be clinically stable for 12 
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weeks prior to Screening Visit 1 in the opinion of the Investigator 
and, if on treatment for depression or anxiety, be on 12 weeks of 
stable therapy  
15. Full understanding of the requirements of the study and willingness 
to comply with all study visits and assessments 
16. Subjects must have read and understood the Informed Consent 
Form (ICF), and must have signed and dated it prior to any study-
related procedure being performed 
17. Subject’s Screening Visit 1 visit must occur while enrollment into 
the study is open 
18. Subject is able to have a Screening Visit 2 qCT image acquired that 
does not require a re-scan as determined by the central imaging 
vendor 
Criteria for Exclusion: 
1. Pregnant and breastfeeding women, and women who are not post-
menopausal (defined as 12 months with no menses without an 
alternative medical cause) or permanently surgically sterile 
(includes hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy) and have a positive or indeterminate pregnancy 
result at Screening Visit 2 or Day 1 
2. Women who are not post-menopausal or permanently surgically 
sterile, who are sexually active, and who are not willing to use birth 
control (as outlined in Section 5.3.1) during the study period  
3. 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 who are not using birth control as outlined in Section 
5.3.1     
4. Body mass index (BMI) > 35 
5. Partial or complete joint replacement in either knee 
6. Currently requires: 
a. regular use (in the opinion of the Investigator) 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 enrollment in a Samumed clinical trial investigating 
SM04690 
9. Any surgery (e.g., arthroscopy) in either knee within 26 weeks 
prior to Screening Visit 1 
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10. Any bone fracture(s) within 26 weeks prior to Screening Visit 1 
11. Any surgery scheduled 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). 
12. Significant and clinically evident misalignment of either knee that 
would impact subject function, as determined by the Investigator 
13. History of malignancy within the last 5 years; however, subjects 
with prior history of in situ 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 Screening Visit 1 
14. Clinically significant abnormal screening hematology values, blood 
chemistry values, or urinalysis values as determined by the 
Investigator 
15. Any condition, including laboratory findings not included in the 
Screening Visit 2 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 
16. 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 
17. 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 
18. History of mania, bipolar disorder, psychotic disorder, 
schizophrenia, schizoaffective disorder, major depressive disorder, 
or generalized anxiety disorder 
19. Participation in a clinical research trial that included the receipt of 
an investigational product (IP) or any experimental therapeutic 
procedure within 26 weeks prior to Screening Visit 1, or planned 
participation in any such trial 
20. Treatment of the target knee with intra-articular glucocorticoids (e.g., 
methylprednisolone) within 12 weeks prior to Screening Visit 1 
21. Any intra-articular injection into the target knee with a therapeutic 
aim including, but not limited to, viscosupplementation (e.g., 
hyaluronic acid), platelet-rich plasma (PRP), and stem cell 
therapies within 24 weeks prior to Screening Visit 1; treatment of 
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the target knee with intra-articular glucocorticoids greater than 12 
weeks prior to Screening Visit 1 is allowed 
22. Treatment with systemic (oral, intramuscular, or intravenous) 
glucocorticoids greater than 10 mg prednisone or the equivalent per 
day within 4 weeks prior to Screening Visit 1  
23. Effusion of the target knee clinically requiring aspiration within 12 
weeks prior to Screening Visit 1 
24. Use of electrotherapy, acupuncture, and/or chiropractic treatments 
for knee OA within 4 weeks prior to Screening Visit 1 (refer to 
Appendix 1) 
25. 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 
26. Subjects requiring the chronic use (i.e., regular and consistent use 
for ≥ 12 weeks) of centrally acting analgesics (e.g., duloxetine) 
(refer to Appendix 1) within 12 weeks prior to Screening Visit 1  
27. Subjects requiring the chronic use (i.e., regular and consistent use 
for ≥ 12 weeks) of anticonvulsants not listed in Appendix 1 within 
12 weeks prior to Screening Visit 1, unless used for seizure or 
migraine prophylaxis   
28. Subjects requiring the usage of opioids >1x per week within 12 
weeks prior to Screening Visit 1 
29. 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  
30. 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 an HbA1c >9 at Screening 
Visit 2 will be excluded. 
31. 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 
32. Any contraindications for performing DXA scans of the hips or 
spine including but not limited to: 
a. other radiological investigations using contrast media or 
radionuclides within 7 days of Screening Visit 2  
b. weight that precludes scanning at these sites 
33. Subjects who have had a single or bilateral hip replacement 
34. Subjects who have a current or pending disability claim, workers’ 
compensation, or litigation(s) that may compromise response to 
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treatment  
35. 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  
36. 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 
37. Subject has non-evaluable DXA scans of the hips or spine (i.e., 
pins, screws, any surgical implant, fracture, or severe degenerative 
changes in the region of interest), as assessed by the central 
imaging vendor at the time of screening 
Population: 
Approximately 100 subjects with moderately to severely symptomatic 
osteoarthritis of the knee 
Phase: 
2 
Number of Sites 
enrolling 
participants: 
This study will be conducted at approximately 15 investigational centers in 
the United States 
Description of 
Study Agent: 
SM04690 is a small molecule Wnt pathway inhibitor which potentially (a) 
reduces signs and symptoms of knee OA via an anti-inflammatory 
mechanism and (b) inhibits breakdown and enhances formation of 
cartilage through effects on progenitor cells resident in the joint. 
Study Duration: 
Approximately 156 weeks 
Estimated date first subject consented: November 2018 
Estimated date last subject completed: October 2021 
Participant 
Duration: 
Approximately 55 weeks for Phase A and 52 weeks for Phase B 
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Criteria for 
evaluation: 
Efficacy: 
Efficacy will be assessed by: 
• Weekly averages of daily pain NRS (for target knee OA pain) 
• Monthly WOMAC Pain and Function for the target knee 
• Monthly Patient Global Assessment 
• mJSW by radiograph  
Safety: 
The overall safety and tolerability of SM04690 will be assessed by the 
incidence, severity, and relatedness of AEs, SAEs, and clinically 
significant changes in clinical laboratory measures and vital signs, as 
assessed by the Investigator. 
Safety will also be assessed by evaluating BMD in the knee joints by 
qCT and evaluating DXA scans of the spine and hips.  
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SCHEMATIC OF STUDY DESIGN 
DXA = dual-energy X-ray absorptiometry; EOS = End of study; qCT = quantitative computed tomography; S = Screening.   
 
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1. 
KEY ROLES 
Medical monitor 
Ismail Simsek, MD - Medical Director 
Samumed, LLC 
9360 Towne Centre Drive 
San Diego, CA 92121 
(858) 926-2968 
ismail@samumed.com 
Biostatistician 
Christopher Swearingen, PhD – Vice President, Clinical Outcomes 
and Analytics  
Samumed, LLC 
9360 Towne Centre Drive 
San Diego, CA 92121 
(858) 926-2952 
chris@samumed.com 
Central radiology reader 
Medical Metrics, Inc. (MMI) 
2121 Sage Road, Suite 300 
Houston, Texas 77056 
(713) 850-7500 
Central qCT and DXA reader 
Bioclinica 
211 Carnegie Center Drive  
Princeton, NJ 08540  
(877) 632-9432 
Electronic clinical outcomes 
assessment (eCOA) 
YPrime 
263 Great Valley Parkway 
Malvern, PA 19355 
(888) 201-7988 
Central laboratory 
Medpace Central Laboratories 
5365 Medpace Way 
Cincinnati, Ohio 45227 
(800) 749-1737 
 
 
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2. 
INTRODUCTION: BACKGROUND INFORMATION & SCIENTIFIC 
RATIONALE  
 
BACKGROUND INFORMATION  
OA is the most common form of arthritis and the major cause of activity limitation and physical 
disability in older people. Today, 35 million people (13% of the US population) are 65 and older, 
and more than half of them have radiological evidence of OA in at least 1 joint. By 2030, 20% of 
Americans (about 70 million people) will have passed their 65th birthday and will be at risk for 
OA (Nevitt, Felson, and Lester 2006). 
Therapies available to treat OA are limited. Most current treatments are designed only to relieve 
pain and reduce or prevent the disability caused by bone and cartilage degeneration. Drug 
therapies target the symptoms but not the cause of this disease; no treatment inhibits or reverses 
the degenerative structural changes that are responsible for its progression (Nevitt, Felson, and 
Lester 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). 
 
RATIONALE  
OA is the most common form of arthritis and chronic joint disorder in humans (Dougados and 
Hochberg 2011). The exact cause of OA is unknown, but it is associated with aging and normal 
wear on a joint. OA is characterized by the destruction of the articular cartilage, subchondral 
bone alterations, and synovitis. Patients present with pain and stiffness in the joints, with the 
joints becoming more stiff and immobile over time (Dougados and Hochberg 2011). OA is a 
leading cause of physical disability in the 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. 
Based on WOMAC Pain and Function results for the 0.07 mg dose group observed in completed 
clinical studies (SM04690-01 and SM04690-OA-02), the 0.07 mg SM04690 dose was selected 
for further investigation in this study. This phase 2 study, SM04690-OA-06, is a multicenter, 
randomized, double-blind, placebo-controlled, parallel group study of a single concentration of 
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0.07 mg SM04690 per 2 mL injection injected into the target knee joint of moderately to 
severely symptomatic OA subjects at Day 1 and Week 24 (Phase A). Subjects who complete 
Phase A will be eligible to enter the extension phase, Phase B, for an additional 52 weeks of 
treatment. The study is designed to assess the safety and tolerability of repeated SM04690 
injections, focusing not only on AEs but also several assessments of bone density.    
The control to be used in this study is a placebo concurrent control. The placebo consists of a 
vehicle containing all components of the SM04690 injectable suspension with the exception of 
the active ingredient. Vehicle is considered the appropriate control in this study as it allows for 
evaluation of the safety and tolerability of the SM04690 molecule alone through comparison of 
the active and placebo arms. 
 
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. Refer to the IB for the known potential risks associated with 
SM04690. 
Study Placebo 
The placebo injections in this study will be 2 mL of vehicle, which is carboxymethylcellulose 
sodium and polysorbate 80 in phosphate saline buffer. Carboxymethylcellulose sodium and 
polysorbate 80 are inactive substances often used as food or drug excipients. There is a small risk 
of allergic reaction or hypersensitivity to these components.   
Risks of Injection 
Risks associated with knee joint injection include infection and local site reactions such as 
erythema, irritation, and edema. 
Risks of Topical Anesthetics 
Reactions to the topical anesthetic drug that may be applied to the subjects’ skin are rare and 
may consist of cutaneous lesions (patches of skin that contrast with surrounding skin due to 
differences in texture, thickness, and color), or urticaria (red, raised itchy bumps). In addition to 
the local reactions, systemic reactions, although much rarer than the local ones, can be seen and 
include edema, bradycardia, dizziness, drowsiness, paresthesia, nausea, vomiting, or 
anaphylactoid reactions (generalized itching and hives, swelling, wheezing and difficulty 
breathing, fainting, and/or other allergy symptoms). 
Blood Sampling 
There is some risk of pain or local bruising and infection at the site where blood is drawn for 
laboratory tests. There is also a small risk of a fainting episode, which can occur as a reaction to 
giving blood. 
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Radiographs (X-ray) and Dual-Energy X-ray Absorptiometry (DXA)  
This study involves radiation exposure from 5 radiographs and 5 DXA scans of the hips and 
spine, 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 radiographs that the subject will receive in this study is expected 
to be about 0.025 mSv or equivalent to approximately 3 days of background radiation in the US. 
The radiation dose for all DXA scans that the subject will receive in this study is expected to be 
about 0.03 mSv or equivalent to approximately 4 days of background radiation in the US. The 
risks from these doses are small. This radiation exposure may not be necessary for the subjects’ 
medical care, but it is necessary to obtain the research information desired. 
Computed Tomography (CT) Scans  
As part of this study, 9 CT scans will be performed. 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 CT scans that the subject will receive in this 
study is expected to be about 1.8 mSv or equivalent to approximately 7 months of background 
radiation in the US dose from background radiation. The risk from this dose is small but may 
cause a slightly increased risk of cancer over a lifetime. This radiation exposure is not necessary 
for the subject’s medical care but 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, tolerability, and efficacy of two injections 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 evaluate the safety and tolerability of SM04690 
Injectable Suspension administered every 6 months through 52 weeks for the treatment of knee 
OA. 
Secondary objectives: 
 The secondary objectives of this study are: 
1. To evaluate the effectiveness of SM04690 Injectable Suspension administered every 6 
months through 52 weeks for the treatment of knee OA  
2. To evaluate the use of quantitative computed tomography (qCT) to assess knee bone 
mineral density (BMD) 
3. To evaluate the safety, tolerability, and effectiveness of SM04690 Injectable Suspension 
from 52 weeks through 104 weeks 
 
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4. 
STUDY DESIGN AND ENDPOINTS 
 
DESCRIPTION OF THE STUDY DESIGN 
This study is a multicenter, randomized, double-blind, placebo-controlled, parallel group study 
of a single concentration of SM04690 injected into the target knee joint of moderately to 
severely symptomatic OA subjects. In this study, “placebo” refers to vehicle. 
Approximately 100 subjects will be enrolled and randomized at a ratio of 1:1 (0.07 mg active per 
2 mL injection: 2 mL placebo).  
This study will be conducted at approximately 15 investigational centers in the US.  
Core Phase (Phase A) 
Subjects will participate in a screening period of a minimum of 10 days and up to 19 days and a 
52-week evaluation period. Each subject will receive an injection on Day 1 and Week 24 (same 
dose for each injection) and will be observed for one year after first injection. Clinic visits will 
be scheduled at Screening Visit 1, Screening Visit 2, Day 1, and Weeks 4, 12, 24, 36, and 52 
(EOSa) or ET. Specific timing of protocol procedures is described in the Schedule of Events 
Table (Section 7.3.7). Specific timing of electronic diary and questionnaire completion is 
described in the Schedule of Electronic Diary and Questionnaire Completion Table (Section 
7.3.8). 
A Widespread Pain Index and Symptom Severity (WPI&SS) assessment will be administered at 
Screening Visit 1. qCT will be performed at Screening Visit 2 and Weeks 12, 24, 36, and 52 
(EOSa) or ET. DXA will be performed at Screening Visit 2 and Weeks 24 and 52 (EOSa) or ET. 
Bone and cartilage biomarkers will be assessed at Screening Visit 2 and Weeks 4, 12, 24, 36, and 
52 (EOSa) or ET. Radiographic images of the knees will be performed at Screening Visit 1, 
Week 24, and Week 52 (EOSa) or ET.  
Subjects will be required to complete an electronic diary for the following: 
• Daily pain NRS 
• Monthly completion of the WOMAC 
• Monthly completion of Patient Global Assessment 
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 at Weeks 4, 12, 24, 
36, and 52 (EOSa) or ET. Height will be measured at Screening Visit 1 and weight will be 
measured at Screening Visit 1 and at Weeks 24 and 52 (EOSa) or ET. Clinical laboratory 
evaluations will be performed at Screening Visit 2 and at Weeks 4, 12, 24, 36, and 52 (EOSa) or 
ET.  
Extension Phase (Phase B) 
Subjects who complete Phase A will be eligible to enter the extension phase, Phase B, for an 
additional 52 weeks of treatment. Subjects will remain on their randomized treatment (SM04690 
or placebo) for the additional year. Each subject that consents to enter Phase B will receive an 
injection at Week 52 (EOSa) and Week 76 with follow-up clinic visits scheduled at Weeks 64, 
76, 88, and 104 (EOSb) or ET. Specific timing of protocol procedures is described in the 
Schedule of Events Table (Section 7.3.7). Specific timing of electronic diary and questionnaire 
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completion is described in the Schedule of Electronic Diary and Questionnaire Completion Table 
(Section 7.3.8). 
Primary analysis of Phase A data will be completed after the last subject completes Week 52 
(EOSa). While the Sponsor will be unblinded to study treatment after the Phase A analysis (after 
the last subject completes Week 52 [EOSa]), the Investigator and the subject will remain blinded.  
In Phase B, qCT will be performed at Weeks 64, 76, 88, and 104 (EOSb) or ET. DXA will be 
performed at Weeks 76 and 104 (EOSb) or ET. Bone and cartilage biomarkers will be assessed 
at Weeks 64, 76, 88, and 104 (EOSb) or ET. Radiographic images of the knees will be performed 
at Weeks 76 and 104 (EOSb) or ET.  
Subjects will be required to complete the following: 
• Daily pain NRS 
• Monthly completion of the WOMAC  
• Monthly completion of Patient Global Assessment  
Recording of signs and symptoms of study medication intolerability and AE reporting will start 
following the first injection of the study medication and continue until the subjects complete 
their last study visit. All AEs, 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 an acceptable image 
was acquired within the previous 6 weeks), and qCT and DXA (if acceptable images were 
acquired within the previous 3 months), must be performed at re-screen; no results or data, 
except for the knee radiograph, qCT, and DXA, may be used from the previous screen. Target 
knee selection may not be changed at re-screen.  
 
STUDY ENDPOINTS 
4.2.1 PHASE A GENERAL SAFETY ENDPOINTS 
1. Adverse events (AEs), serious adverse events (SAEs), vital signs, and clinical laboratory 
measures through Week 52 
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4.2.2 PHASE A BONE IMAGING ENDPOINTS 
1. Actual BMD and change from baseline in BMD in the target knee as assessed by qCT 
through Week 52 compared to placebo  
2. Within-subject difference in BMD from baseline through Week 52 between the target and 
non-target knee by qCT for SM04690 
3. Within-subject difference in BMD from baseline through Week 52 between the target and 
non-target knee by qCT for placebo  
4. Change from baseline in BMD in the spine and hips as assessed by dual-energy X-ray 
absorptiometry (DXA) at Week 24 and 52 
4.2.3 PHASE A EFFICACY ENDPOINTS 
1. Characterization of change in OA pain in the target knee as measured by the weekly 
averages of daily pain numeric rating scale (NRS) from baseline through Week 52 
accounting for repeated injections  
2. Characterization of change durability of treatment response in OA pain in the target knee 
as measured by the weekly averages of daily pain NRS through Week 52 elapsed from 
prior injection to repeat injection  
3. Characterization of change in OA function in the target knee as measured by WOMAC 
physical function subscore (WOMAC Function) from baseline through Week 52 
accounting for repeated injections  
4. Characterization of change durability of treatment response in OA function in the target 
knee as measured by WOMAC Function through Week 52 elapsed from prior injection to 
repeat injection  
5. Characterization of change in medial joint space width (mJSW) as measured by 
radiograph of the target knee from baseline through Week 52 accounting for repeated 
injections  
6. Characterization of change durability of treatment response in mJSW as measured by 
radiograph of the target knee through Week 52 elapsed from prior injection to repeat 
injection  
7. Characterization of change in OA pain in the target knee as measured by WOMAC pain 
subscore (WOMAC Pain) from baseline through Week 52 accounting for repeated 
injections  
8. Characterization of change durability of treatment response in OA pain in the target knee 
as measured by WOMAC Pain through Week 52 elapsed from prior injection to repeat 
injection  
9. Characterization of change in OA disease activity as measured by Patient Global 
Assessment from baseline through Week 52 accounting for repeated injections  
10. Characterization of change durability of treatment response in OA disease activity as 
measured by Patient Global Assessment through Week 52 elapsed from prior injection to 
repeat injection 
4.2.4 PHASE A EXPLORATORY BIOMARKER ENDPOINTS 
1. Change from baseline in serum bone biomarkers (e.g., N-terminal propeptide of 
procollagen type I [PINP] and β-C-terminal telopeptide [β-CTX]) and a serum cartilage 
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biomarker (e.g., cartilage oligomeric matrix protein [COMP]) through Week 52 
compared to placebo  
4.2.5 PHASE B GENERAL SAFETY ENDPOINTS 
1. AEs, SAEs, vital signs, and clinical laboratory measures from Week 52 through Week 
104 
4.2.6 PHASE B BONE IMAGING ENDPOINTS 
1. Actual BMD and change from baseline in BMD in the target knee as assessed by qCT 
through Week 104 compared to placebo  
2. Within-subject difference in BMD from baseline through Week 104 between the target 
and non-target knee by qCT for SM04690  
3. Within-subject difference in BMD from baseline through Week 104 between the target 
and non-target knee by qCT for placebo  
4. Change from baseline in BMD in the spine and hips as assessed by DXA through Week 
104 
4.2.7 PHASE B EFFICACY ENDPOINTS 
1. Characterization of change in OA pain in the target knee as measured by the weekly 
averages of daily pain NRS from baseline through Week 104 accounting for repeated 
injections  
2. Characterization of change durability of treatment response in OA pain in the target knee 
as measured by the weekly averages of daily pain NRS through Week 104 elapsed from 
prior injection to repeat injection 
3. Characterization of change in OA function in the target knee as measured by WOMAC 
Function from baseline through Week 104 accounting for repeated injections 
4. Characterization of change durability of treatment response in OA function in the target 
knee as measured by WOMAC Function through Week 104 elapsed from prior injection 
to repeat injection 
5. Characterization of change in mJSW as measured by radiograph of the target knee from 
baseline through Week 104 accounting for repeated injections  
6. Characterization of change durability of treatment response in mJSW as measured by 
radiograph of the target knee through Week 104 elapsed from prior injection to repeat 
injection  
7. Characterization of change in OA pain in the target knee as measured by WOMAC Pain 
from baseline through Week 104 accounting for repeated injections 
8. Characterization of change durability of treatment response in OA pain in the target knee 
as measured by WOMAC Pain through Week 104 elapsed from prior injection to repeat 
injection  
9. Characterization of change in OA disease activity as measured by Patient Global 
Assessment from baseline through Week 104 accounting for repeated injections  
10. Characterization of change durability of treatment response in OA disease activity as 
measured by Patient Global Assessment through Week 104 elapsed from prior injection 
to repeat injection   
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4.2.8 PHASE B EXPLORATORY BIOMARKER ENDPOINTS 
1. Change from Week 52 in serum bone biomarkers (e.g., PINP and β-CTX) and a serum 
cartilage biomarker (e.g., COMP) through Week 104 
 
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. 
 
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. WOMAC pain subscore of 20-40 (out of 50) and WOMAC physical function subscore of 
68-136 (out of 170) for the target knee at baseline, regardless of if the subject is on 
symptomatic oral treatment (baseline questionnaire completed during the screening 
period prior to randomization) 
11. Widespread Pain Index (WPI) score of ≤ 4 and a Symptom Severity Question 2 (SSQ2) 
score of ≤ 2 at Screening Visit 1 
12. Willingness to use an electronic diary on a daily basis in the evening for the screening 
period and 104-week study duration 
13. Negative drug test for amphetamine, buprenorphine, cocaine, methadone, opiates, 
phencyclidine (PCP), propoxyphene, barbiturates, benzodiazepine, methaqualone, and 
tricyclic antidepressants, except if any such drugs are clinically indicated and allowed by 
the protocol, at Screening Visit 1.  
14. Subjects with depression or anxiety must be clinically stable for 12 weeks prior to 
Screening Visit 1 in the opinion of the Investigator and, if on treatment for depression or 
anxiety, be on 12 weeks of stable therapy  
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15. Full understanding of the requirements of the study and willingness to comply with all 
study visits and assessments 
16. Subjects must have read and understood the Informed Consent Form (ICF), and must 
have signed and dated it prior to any study-related procedure being performed 
17. Subject’s Screening Visit 1 visit must occur while enrollment into the study is open  
18. Subject is able to have a Screening Visit 2 qCT image acquired that does not require a re-
scan as determined by the central imaging vendor  
 
 
PARTICIPANT EXCLUSION CRITERIA 
Any potential subject who meets one or more of the following criteria will not be included in this 
study: 
1. Pregnant and breastfeeding women, and women who are not post-menopausal (defined as 
12 months with no menses without an alternative medical cause) or permanently 
surgically sterile (includes hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy) and have a positive or indeterminate pregnancy result at Screening Visit 2 
or Day 1 
2. Women who are not post-menopausal or permanently surgically sterile, who are sexually 
active, and who are not willing to use birth control (as outlined in Section 5.3.1) during 
the study period  
3. 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 who are not using birth control 
as outlined in Section 5.3.1     
4. Body mass index (BMI) > 35 
5. Partial or complete joint replacement in either knee 
6. Currently requires: 
a. regular use (in the opinion of the Investigator) 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 enrollment 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 bone fracture(s) within 26 weeks prior to Screening Visit 1 
11. Any surgery scheduled 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). 
12. Significant and clinically evident misalignment of either knee that would impact subject 
function, as determined by the Investigator 
13. History of malignancy within the last 5 years; however, subjects with prior history of in 
situ basal or squamous cell skin cancer are eligible if completely excised. Subjects with 
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other malignancies are eligible if they have been continuously disease free for at least 5 
years prior to Screening Visit 1 
14. Clinically significant abnormal screening hematology values, blood chemistry values, or 
urinalysis values as determined by the Investigator 
15. Any condition, including laboratory findings not included in the Screening Visit 2 
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 
16. 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 
17. 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 
18. History of mania, bipolar disorder, psychotic disorder, schizophrenia, schizoaffective 
disorder, major depressive disorder, or generalized anxiety disorder  
19. Participation in a clinical research trial that included the receipt of an investigational 
product (IP) or any experimental therapeutic procedure within 26 weeks prior to 
Screening Visit 1, or planned participation in any such trial 
20. Treatment of the target knee with intra-articular glucocorticoids (e.g., methylprednisolone) 
within 12 weeks prior to Screening Visit 1 
21. Any intra-articular injection into the target knee with a therapeutic aim including, but not 
limited to, viscosupplementation (e.g., hyaluronic acid), platelet-rich plasma (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 
22. Treatment with systemic (oral, intramuscular, or intravenous) glucocorticoids greater 
than 10 mg prednisone or the equivalent per day within 4 weeks prior to Screening Visit 
1  
23. Effusion of the target knee clinically requiring aspiration within 12 weeks prior to 
Screening Visit 1 
24. Use of electrotherapy, acupuncture, and/or chiropractic treatments for knee OA within 
4 weeks prior to Screening Visit 1 (refer to Appendix 1) 
25. 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 
26. Subjects requiring the chronic use (i.e., regular and consistent use for ≥ 12 weeks) of 
centrally acting analgesics (e.g., duloxetine) (refer to Appendix 1) within 12 weeks prior 
to Screening Visit 1  
27. Subjects requiring the chronic use (i.e., regular and consistent use for ≥ 12 weeks) of 
anticonvulsants not listed in Appendix 1 within 12 weeks prior to Screening Visit 1, 
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unless used for seizure or migraine prophylaxis   
28. Subjects requiring the usage of opioids >1x per week within 12 weeks prior to Screening 
Visit 1 
29. 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  
30. 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 an HbA1c >9 at Screening 
Visit 2 will be excluded. 
31. 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 
32. Any contraindications for performing DXA scans of the hips or spine including but not 
limited to: 
a. other radiological investigations using contrast media or radionuclides within 7 
days of Screening Visit 2  
b. weight that precludes scanning at these sites 
33. Subjects who have had a single or bilateral hip replacement 
34. Subjects who have a current or pending disability claim, workers’ compensation, or 
litigation(s) that may compromise response to treatment  
35. 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  
36. 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 
37. Subject has non-evaluable DXA scans of the hips or spine (i.e., pins, screws, any surgical 
implant, fracture, or severe degenerative changes in the region of interest), as assessed by 
the central imaging vendor at the time of screening 
 
LIFESTYLE GUIDELINES 
5.3.1 CONTRACEPTION  
From Screening Visit 1 until their last study visit, 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. 
Acceptable forms of contraception are: 
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 
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post-menopausal or permanently surgically sterile, or must use another form of birth 
control which includes the following: 
a. Barrier methods of contraception such as a diaphragms or cervical/vault caps 
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. Tubal ligation/occlusion/division  
3. Women who are not post-menopausal or permanently surgically sterile must agree to use 
birth control (as described in #2 above) and be instructed that their male partner(s) must 
use a condom 
Subjects who withdraw from the study after receiving study medication should remain on an 
acceptable form of contraception for 24 weeks after their last study injection. 
 
STRATEGIES FOR RECRUITMENT AND RETENTION 
A detailed recruitment and retention plan will be maintained by the Sponsor.  
 
PARTICIPANT WITHDRAWAL OR TERMINATION 
5.5.1 REASONS FOR WITHDRAWAL OR TERMINATION 
As the study treatment requires two injections in Phase A and two injections in Phase B, best 
efforts will be made to encourage subjects to attend all follow-up visits even if they are 
withdrawn from treatment. Subjects will be informed that they are free to withdraw 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 study medication and/or 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 
• AE 
• Subject non-compliance 
• Request by regulatory authority 
• Study terminated by Sponsor 
The Investigator may withdraw a subject from study medication or the study if, in the 
Investigator’s opinion, it is not in the best interest of the subject to continue with treatment or the 
study. 
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5.5.2 HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 
In case of premature discontinuation of study participation, ET procedures should be conducted 
within 14 days of discontinuation for any subject who 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. 
Subjects who are withdrawn from study medication for safety reasons will continue with all 
planned study visits per protocol, without any further dosing. 
 
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 
 
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 placebo product related to the 
study. 
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 2.5 mL of formulated 
suspension in a ready-to-use 3 mL polypropylene vial. SM04690 placebo product is supplied as 
2.5 mL of formulated vehicle in a ready-to-use 3 mL polypropylene vial. SM04690 placebo 
product contains 0.5% carboxymethylcellulose sodium and 0.05% polysorbate 80 in pH 7.4 
phosphate buffered saline.  
SM04690 drug product and placebo product are manufactured by Catalent Pharma Solutions, 
(Woodstock, IL) and will be supplied as a ready-to-use single-use injection. SM04690 drug 
product and placebo product 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. 
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6.1.3 PRODUCT STORAGE AND STABILITY 
The study medication and placebo 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. Refer to 
the Pharmacy Manual for detailed instructions on how to manage temperature excursions. 
6.1.4 PREPARATION 
Each dose of ready-to-use SM04690 drug product or placebo product should be well mixed (the 
drug product is a suspension) prior to injecting 2 mL intra-articularly into the target knee. Refer 
to the Pharmacy Manual for detailed instructions on study medication preparation.  
6.1.5 DOSING AND ADMINISTRATION 
SM04690 will be administered in the following dosage strengths:  
• SM04690 0.07 mg in 2 mL Injectable Suspension 
• SM04690 0 mg; 2 mL placebo (vehicle) injection only 
The injectable investigational product or placebo is to be administered by the Unblinded 
Investigator as a single injection into the target knee joint once each at Day 1 and Week 24 
(Phase A), and once each at Week 52 (EOSa) and Week 76 (Phase B). The Week 24, 52 (EOSa), 
and 76 injections may occur up to two weeks later than the Week 24, 52 (EOSa), and 76 visits, 
respectively, to allow for resolution of any intercurrent illness (e.g., infection) prior to the 
injection. The Unblinded Investigator must minimize any contact with the subject following the 
injections and may not perform any study assessments throughout the duration of the study. All 
subject contact for the remainder of the study is limited to the Blinded Investigator and other 
appropriate blinded study personnel. 
Only 1 knee will be treated for each subject in this study. The injections can be done either 
through lateral or medial (including superior/suprapatellar, midpatellar and inferior/anterior) 
approaches, based on the standard practice of the Unblinded Investigator or the knee examination 
of the subject. Although not required, the injections may be guided by ultrasound or fluoroscopy 
without contrast if it is the standard practice of the Investigator.  
Only topical anesthetics are allowed prior to study injection. Any local anesthetic injections are 
prohibited.  
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 the total volume 
contained in the syringe is to be injected into the joint space. Because SM04690 drug product is a 
suspension, prior aspiration of synovial fluid into the syringe containing the injectate should be 
avoided to prevent trapping of particles within synovial aspirate/cellular content residues. If it is 
the standard practice of the injector to aspirate a small amount (0.3-0.5 mL) of joint fluid (if 
present) to confirm correct needle placement, this will have to be done with a separate empty 
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sterile syringe and, via syringe exchange, subsequently inject study medication using a new 
syringe.  
6.1.6 ROUTE OF ADMINISTRATION 
The injectable investigational product or placebo is to be administered as a single intra-articular 
injection into the target knee joint once each at Day 1 and Week 24 (Phase A), and once each at 
Week 52 (EOSa) and Week 76 (Phase B). 
6.1.7 STARTING DOSE AND DOSE ESCALATION SCHEDULE 
Not applicable to this study. Each subject will be randomly assigned to active or placebo on 
Day 1. 
6.1.8 DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS 
No modification in the specified dose concentration or the volume (2 mL) of the study 
medication or placebo injected into the target knee joint will be allowed. 
6.1.9 DURATION OF THERAPY 
The injectable investigational product or placebo is to be administered as a single intra-articular 
injection into the target knee joint once each at Day 1 and Week 24 (Phase A), and once each at 
Week 52 (EOSa) and Week 76 (Phase B).  
At the Week 24, 52 (EOSa), and 76 visits, the Investigator should evaluate the subject for 
suitability to receive the study medication injection. The subject should not have any condition, 
including laboratory findings and findings in pre-injection assessments, that, in the opinion of the 
Investigator, constitutes a risk or contraindication for the injection, or that could interfere with 
the study objectives, conduct, or evaluation. The injections may occur up to two weeks later than 
the Week 24, 52 (EOSa), and 76 visits, respectively, to allow for resolution of any intercurrent 
illness (e.g., infection) prior to the injection. If, in the opinion of the Investigator, the subject 
should not receive any of the injections, the subject will discontinue treatment but will continue 
with all planned study visits per protocol.  
6.1.10 TRACKING OF DOSE 
Not applicable to this study. 
6.1.11 DEVICE SPECIFIC CONSIDERATIONS 
Not applicable to this study. 
 
STUDY AGENT ACCOUNTABILITY PROCEDURES 
All used and unused study medication and placebo vials received must be returned and 
accounted for. All injections prepared and dispensed must also be logged. The log includes the 
following: 
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• Subject number and initials 
• Date that study medication was injected 
• Quantity dispensed (active vial, placebo vial) 
• Quantity returned/used (active vial, placebo vial) 
All study medication and vehicle 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 placebo 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 
Unblinded Investigator return or destruction of used and unused vials of the study medication 
and placebo will be provided in the Pharmacy Manual.   
7. 
STUDY PROCEDURES AND SCHEDULE 
 
STUDY PROCEDURES/EVALUATIONS 
7.1.1 STUDY SPECIFIC PROCEDURES  
Collection of Adverse Events Data 
Data regarding AEs will be collected in this study. AEs are events that occur during the 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. AEs will 
be assessed at each study visit from the time of study medication injection on study visit Day 1 
through the subject’s last study visit.  
Each subject will be observed and queried by the Investigator or the Investigator’s designee at 
each study visit for any continuing AEs or new AEs since the previous visit. The subject may be 
asked to return to the site for an unscheduled visit if an AE occurs between study visits, and if, in 
the opinion of the Investigator, the AE requires a study visit for full evaluation. Any AE 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 AE: description of the event, date 
of onset and resolution, etiology, and severity as assessed by the Investigator according to the 
Clinical Data Interchange Standards Consortium (CDISC) Severity/Intensity Scale for Adverse 
Events (AESEV) (Table 1), causal relationship to study medication, outcome, and any treatment 
given.   
In this protocol, signs and symptoms of exacerbation or worsening of target knee OA will be 
captured in the context of efficacy assessments and recorded on specific pages of the eCRF. 
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Anticipated fluctuations or anticipated deterioration (in the opinion of the Investigator) of the 
underlying disease (target knee OA) will not be considered as AEs nor captured on the AE page 
of the eCRF. 
Whenever possible, it is preferable to record a diagnosis as the AE term rather than a series of 
symptoms relating to a diagnosis. Fluctuations of pre-existing conditions, including the disease 
under study, that do not represent a clinically significant exacerbation or worsening, need not be 
considered AEs.  
AEs that are ongoing at a subject’s last visit will be followed for 30 days after administration of 
the last dose of study medication or until resolution, whichever comes first. Resolution is defined 
as the return to baseline status or stabilization of the condition. SAEs that are ongoing at a 
subject’s last visit will be followed until resolution. 
Medical History 
A medical history will be obtained at Screening Visit 1 and Day 1 with a follow-up at Weeks 52 
(EOSa) and 104 (EOSb) or ET to capture End Dates of any ongoing medical history collected at 
screening. 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. Examples of medical conditions and disease states 
that should be considered relevant to the subject’s study participation include history of current 
disease, medical history that confirms the eligibility criteria of the subject, and asymptomatic 
medical history that could become symptomatic while on the study.  
Physical Examination  
A general physical examination will be conducted at all visits except Screening Visit 2. Results 
of the physical examination will be noted in the source documents. Any clinically significant 
finding noted prior to study medication injection should be recorded as medical history. If it is 
found after study medication injection, it should be reported as an AE.  
Knee Examination 
A knee examination of both knees will be conducted at all visits except Screening Visit 2. 
Results of the knee examination will be noted in the source documents. Any clinically significant 
finding noted prior to study medication injection should be recorded as medical history. If it is 
found after study medication injection, it should be reported as an AE.  
Presence of unilateral or bilateral knee OA 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. 
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Vital Signs 
Vital signs will be measured by a qualified staff member at all visits except Screening Visit 2. 
At each time point, the following vital signs will be measured: 
• Body temperature 
• Pulse rate 
• Respiratory rate 
• Blood pressure (systolic and diastolic) after the subject rests (sitting or supine) for at 
least 5 minutes; same resting position should be used for all blood pressure 
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 an AE 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 at Weeks 24, 52 (EOSa), 76, and 104 (EOSb) or ET. 
Radiograph of Knee Joints 
Radiograph of the knee joints will be taken at Screening Visit 1 and at Weeks 24, 52 (EOSa), 76, 
and 104 (EOSb) or 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 at the central imaging vendor 
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. The 
central imaging vendor does not provide medical advice, clinical diagnosis, or treatment 
recommendations. These imaging assessments and quantitative measurements provided to the 
Sponsor do not and shall not constitute a medical diagnosis, treatment recommendation, or 
medical advice, and are not intended to be used as a substitute for the study Investigator's or 
other qualified health care professional's medical diagnosis, treatment, or advice. If any AEs or 
other unusual pathology is noted in the study images, the Sponsor will be notified of the finding 
and will promptly notify the Investigator. The Investigator will then assess the clinical 
significance as well as any follow-up procedures that need to be completed. Clinically significant 
findings that are not part of an existing diagnosis will be recorded as medical history or an AE as 
appropriate.   
Dual-energy X-ray Absorptiometry (DXA) 
Bone density DXA scans of the spine and hips will be taken at Screening Visit 2 and at Weeks 
24, 52 (EOSa), 76, and 104 (EOSb) or ET. The DXA scans should be obtained in the posterior-
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anterior (PA) view. 
Detailed instructions for obtaining and managing the DXA scans will be provided to the 
investigational center prior to the initiation of subject enrollment. 
The DXA scanning will assess changes in BMD of the hips and spine. The DXA scans will be 
submitted to an independent reviewer at the central imaging vendor for interpretation. An 
eligibility report identifying whether subject anatomy can be longitudinally evaluated for the 
Screening Visit 2 DXA and the DXA scan T score and Z scores for each DXA scan will be 
reported to the Investigator. The central imaging vendor does not provide medical advice, 
clinical diagnosis, or treatment recommendations. These imaging assessments and quantitative 
measurements provided to the Sponsor do not and shall not constitute a medical diagnosis, 
treatment recommendation, or medical advice, and are not intended to be used as a substitute for 
the study Investigator’s or other qualified health care professional’s medical diagnosis, 
treatment, or advice. If any AEs or other unusual pathology is noted in the study images, the 
Sponsor will be notified of the finding and will promptly notify the Investigator. The Investigator 
will then assess the clinical significance as well as any follow-up procedures that need to be 
completed. Clinically significant findings that are not part of an existing diagnosis will be 
recorded as medical history or an AE as appropriate. 
Quantitative Computed Tomography (qCT) 
Quantitative computed tomography of both knee joints will be taken at Screening Visit 2 and at 
Weeks 12, 24, 36, 52 (EOSa), 64, 76, 88, and 104 (EOSb) or ET.  
Detailed instructions for obtaining and managing the qCT scans will be provided to the 
investigational center prior to the initiation of subject enrollment. 
The CT scanning will document changes in bone health. The CT scans will be submitted to an 
independent reviewer at the central imaging vendor for interpretation. A quality assessment 
report will be provided to the Investigator by the central imaging vendor to confirm subject 
eligibility. The central imaging vendor does not provide medical advice, clinical diagnosis, or 
treatment recommendations. These imaging assessments and quantitative measurements 
provided to the Sponsor do not and shall not constitute a medical diagnosis, treatment 
recommendation, or medical advice, and are not intended to be used as a substitute for the study 
Investigator's or other qualified health care professional's medical diagnosis, treatment, or 
advice. If any AEs or other unusual pathology is noted in the study images, the Sponsor will be 
notified of the finding and will promptly notify the Investigator. The Investigator will then assess 
the clinical significance as well as any follow-up procedures that need to be completed. 
Clinically significant findings that are not part of an existing diagnosis will be recorded as 
medical history or an AE as appropriate. 
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. The WPI&SS 
assessment used in this study is modified from that described in (Clauw 2014). A WPI&SS 
assessment will be completed by the subject at Screening Visit 1.  
Upon completion of the WPI&SS assessment, the subject will sign/initial and date the source 
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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. 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 the subject’s last study visit. 
Pain Numeric Rating Scale (NRS) 
The pain NRS is an 11-point scale [0-10] for subject self-reporting of their knee pain for that 
day. The NRS will be anchored by descriptors at each end (“No Pain” on the left and “Worst 
Possible Pain” on the right). 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 completed by subjects in the evening (between 5:00 pm and 11:59 pm) 
remotely on their electronic devices for each knee to collect daily knee pain. 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 7.3.8 for a schedule of electronic 
diary and questionnaire completion. 
Subjects will complete the pain NRS on the Sponsor-provided electronic device. Subjects will 
receive notifications reminding them to complete the daily pain NRS assessment.   
Western Ontario and McMaster Universities Arthritis Index (WOMAC) 
The WOMAC is a widely used, proprietary outcome measurement tool used by health 
professionals to evaluate the condition of patients with OA of the knee and hip, including pain, 
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 5 days after their Screening Visit 2 (i.e., 
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, with a window of ± 3 days) 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 7.3.8 for a schedule of electronic diary and 
questionnaire completion. At Weeks 24, 52 (EOSa), and 76, the WOMAC questionnaire must be 
completed prior to the Weeks 24, 52 (EOSa), and 76 study medication injections, respectively. 
Subjects will complete the WOMAC on the Sponsor-provided electronic device. Subjects will 
receive notifications reminding them to complete the monthly WOMAC assessment. 
Patient Global Assessment of Disease Activity 
The Patient Global Assessment is an 11-point (0-10) NRS on which the subjects will rate how 
they feel their target knee OA is, considering all the ways in which their target knee OA may 
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affect them. The NRS will be anchored by descriptors at each end (“Very Good” on the left and 
“Very Bad” on the right). The Patient Global Assessment will be completed by the subject in the 
evening (between 5:00 pm and 11:59 pm) remotely on their electronic devices 5 days after their 
Screening Visit 2 (i.e., Screening Visit 2 + 5 days) or up until the day before the Day 1 visit. 
After Day 1, monthly (every 4 weeks, with a window of ± 3 days) 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 7.3.8 for a schedule of electronic diary and 
questionnaire completion. At Weeks 24, 52 (EOSa), and 76, the Patient Global Assessment must 
be completed prior to the Weeks 24, 52 (EOSa), and 76 study medication injections, 
respectively. 
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.  
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. 
 
LABORATORY PROCEDURES/EVALUATIONS 
7.2.1 CLINICAL LABORATORY EVALUATIONS  
Fasting samples for clinical laboratory analysis by Medpace Central Laboratories will be 
collected by a qualified staff member at Screening Visit 2 and Weeks 4, 12, 24, 36, 52 (EOSa), 
64, 76, 88, and 104 (EOSb) or 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 2. 
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 2 clinical laboratory test results prior to the Day 1 visit. The subject must not be 
randomized on Day 1 if any of the Screening Visit 2 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. 
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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, then date and initial the report. The 
Investigator must report all laboratory results that are BOTH outside the normal range for the 
laboratory AND, in the opinion of the Investigator, are clinically significant. If any abnormal, 
clinically significant laboratory measure is found prior to study medication injection, the subject 
is to be excluded. If it is found after study medication injection, it should be reported as an AE. 
7.2.2 OTHER ASSAYS OR PROCEDURES 
Pregnancy Test 
A serum-based pregnancy test will be performed on female subjects at Screening Visit 2 and a 
urine-based pregnancy test will be performed on female subjects of childbearing potential at Day 
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: amphetamine, buprenorphine, cocaine, methadone, opiates, phencyclidine (PCP), 
propoxyphene, barbiturates, benzodiazepine, methaqualone, and tricyclic antidepressants. 
Results from the drug test will be utilized to determine subject eligibility. 
Biomarkers 
Blood samples for biomarker analysis will be collected by a qualified staff member at Screening 
Visit 2 and Weeks 4, 12, 24, 36, 52 (EOSa), 64, 76, 88, and 104 (EOSb) or ET. 
Biomarkers that will be assessed in serum include, but are not limited to, bone biomarkers (PINP 
and β-CTX), and a cartilage biomarker (COMP).  
7.2.3 SPECIMEN PREPARATION, HANDLING, AND STORAGE 
Refer to the Laboratory Manual for Medpace Central Laboratories.  
7.2.4 SPECIMEN SHIPMENT 
Refer to the Laboratory Manual for Medpace Central Laboratories. 
 
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 
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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.  
The following procedures and assessments will be performed 10-19 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 rate, blood pressure, respiratory rate, and 
temperature) 
• Height and weight measurements 
• 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.  
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 7-16 days (inclusive) 
prior to Day 1. Subjects should fast for 8 hours prior to this visit. 
This visit should occur after confirmation of eligible radiograph and urine drug test report 
results.  
The following procedures and assessments will be performed at Screening Visit 2: 
• qCT of both knees 
• DXA of the spine and hips 
• Venipuncture and collection of samples for clinical laboratory tests and biomarker 
analysis 
• Pregnancy test (serum-based) 
• 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 remotely on their electronic devices in the evening (between 5:00 
pm and 11:59 pm). 
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Note: On Screening Visit 2 + 5 days (or up until the day before the Day 1 visit), subjects will 
complete the WOMAC and Patient Global Assessment, in addition to the pain NRS assessment, 
in the evening (between 5:00 pm and 11:59 pm) remotely on their electronic devices. Refer to 
Section 7.3.8 for a schedule of electronic diary and questionnaire completion. 
7.3.2 RANDOMIZATION 
Day 1 
This visit must occur within 10-19 days of Screening Visit 1.  
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 
• Pregnancy test (urine-based) (for female subjects of childbearing potential) 
• Physical examination, including knee examination of both knees 
• Vital signs measurements (pulse rate, blood pressure, respiratory rate, and 
temperature) 
• Review of pain NRS electronic diary compliance from Screening Visit 2 to Day 1 
• Electronic questionnaire review (WOMAC) 
Results from Screening and Day 1 evaluations will be compared with inclusion/exclusion criteria 
to determine subject eligibility. 
The following procedures and assessments will be performed at Day 1 following randomization: 
• Intra-articular study medication injection (or placebo) 
• Collection of AE and concomitant procedures/medication data 
Note: After the Day 1 site visit, subjects will complete monthly (every 4 weeks, with a window 
of ± 3 days) WOMAC and Patient Global Assessment, and daily pain NRS assessments in the 
evening (between 5:00 pm and 11:59 pm) remotely on their electronic devices. Refer to Section 
7.3.8 for a schedule of electronic diary and questionnaire completion. 
7.3.3 FOLLOW-UP  
Week 4  
The Week 4 visit should occur on Day 29 (with a window of + 3 days). Subjects should fast for 8 
hours prior to this visit. 
The following procedures and assessments will be performed at this visit: 
• Collection of AE and concomitant procedures/medication data 
• Physical examination, including knee examination of both knees  
• Vital signs measurements (pulse rate, blood pressure, respiratory rate, and 
temperature) 
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• Venipuncture and collection of samples for clinical laboratory tests and biomarker 
analysis 
Week 12  
The Week 12 visit should occur on Day 85 (with a window of ± 3 days). Subjects should fast for 
8 hours prior to this visit.  
The following procedures and assessments will be performed at this visit: 
• Collection of AE and concomitant procedures/medication data 
• Physical examination, including knee examination of both knees  
• Vital signs measurements (pulse rate, blood pressure, respiratory rate, and 
temperature) 
• Venipuncture and collection of samples for clinical laboratory tests and biomarker 
analysis 
• qCT of both knees 
Week 24  
The Week 24 visit should occur on Day 169 (with a window of + 3 days). Subjects should fast 
for 8 hours prior to this visit. Prior to study medication injection, the Investigator should evaluate 
the subject for suitability to receive the second injection (refer to Section 6.1.9). The injection 
may occur up to two weeks later than the Week 24 visit to allow for resolution of any 
intercurrent illness (e.g., infection) prior to the injection. The subject should complete all other 
Week 24 assessments and return for an unscheduled visit and injection in the case that they are 
not able to receive the injection at the Week 24 visit. 
The following procedures and assessments will be performed at this visit: 
• Collection of AE and concomitant procedures/medication data 
• Physical examination, including knee examination of both knees  
• Vital signs measurements (pulse rate, blood pressure, respiratory rate, and 
temperature) 
• Weight measurement  
• Venipuncture and collection of samples for clinical laboratory tests and biomarker 
analysis 
• Radiograph – bilateral in weight-bearing fixed flexion position, posterior-anterior 
(PA) view X-ray 
• qCT of both knees 
• DXA of the spine and hips 
• Intra-articular study medication injection (or placebo) 
Note: The Week 24 WOMAC and Patient Global Assessment must have already been completed 
prior to the Week 24 study medication injection. 
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Week 36  
The Week 36 visit should occur on Day 253 (with a window of -3 to + 7 days). Subjects should 
fast for 8 hours prior to this visit. 
The following procedures and assessments will be performed at this visit: 
• Collection of AE and concomitant procedures/medication data 
• Physical examination, including knee examination of both knees  
• Vital signs measurements (pulse rate, blood pressure, respiratory rate, and 
temperature) 
• Venipuncture and collection of samples for clinical laboratory tests and biomarker 
analysis 
• qCT of both knees 
7.3.4 FINAL STUDY VISIT 
Week 52 Phase A End of Study (EOSa) 
This study visit should occur on Day 365 with a window of -3 to + 7 days. Subjects should fast 
for 8 hours prior to this visit. 
The following procedures and assessments will be performed at Week 52 (EOSa): 
• Collection of AE and concomitant procedures/therapies/medication data 
• Review of medical history 
• Vital signs measurements (pulse rate, blood pressure, respiratory rate, and 
temperature) 
• Physical examination, including knee examination of both knees 
• Weight measurement 
• Venipuncture and collection of samples for clinical laboratory tests and biomarker 
analysis 
• Radiograph – bilateral in weight-bearing fixed flexion position, posterior-anterior 
(PA) view X-ray 
• qCT of both knees 
• DXA of the spine and hips 
For subjects who consent to participate in Phase B, prior to study medication injection, the 
Investigator should evaluate the subject for suitability to receive the injection (refer to Section 
6.1.9). The injection may occur up to two weeks later than the Week 52 (EOSa) visit to allow for 
resolution of any intercurrent illness (e.g., infection) prior to the injection. The subject should 
complete all other Week 52 (EOSa) assessments and return for an unscheduled visit and injection 
in the case that they are not able to receive the injection at the Week 52 (EOSa) visit. If the 
subject is determined to be suitable for injection, the subject will receive an intra-articular study 
medication injection (or placebo).  
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Note: The Week 52 (EOSa) WOMAC and Patient Global Assessment must be completed prior to 
the Week 52 (EOSa) study medication injection 
7.3.5 EXTENSION PHASE (PHASE B) 
Week 64 and Week 88 
The Week 64 visit should occur on Day 449 (with a window of +7 days) and the Week 88 visit 
should occur on Day 617 (with a window of + 7 days). Subjects should fast for 8 hours prior to 
these visits.  
The following procedures and assessments will be performed at these visits: 
• Collection of AE and concomitant procedures/medication data 
• Physical examination, including knee examination of both knees  
• Vital signs measurements (pulse rate, blood pressure, respiratory rate, and 
temperature) 
• Venipuncture and collection of samples for clinical laboratory tests and biomarker 
analysis 
• qCT of both knees 
Week 76 
The Week 76 visit should occur on Day 533 (with a window of + 7 days). Subjects should fast 
for 8 hours prior to this visit. Prior to study medication injection, the Investigator should evaluate 
the subject for suitability to receive the injection (refer to Section 6.1.9). The injection may occur 
up to two weeks later than the Week 76 visit to allow for resolution of any intercurrent illness 
(e.g., infection) prior to the injection. The subject should complete all other Week 76 
assessments and return for an unscheduled visit and injection in the case that they are not able to 
receive the injection at the Week 76 visit. 
The following procedures and assessments will be performed at this visit: 
• Collection of AE and concomitant procedures/medication data 
• Physical examination, including knee examination of both knees  
• Vital signs measurements (pulse rate, blood pressure, respiratory rate, and 
temperature) 
• Weight measurement  
• Venipuncture and collection of samples for clinical laboratory tests and biomarker 
analysis 
• Radiograph – bilateral in weight-bearing fixed flexion position, posterior-anterior 
(PA) view X-ray 
• qCT of both knees 
• DXA of the spine and hips 
• Intra-articular study medication injection (or placebo) 
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Note: The Week 76 WOMAC and Patient Global Assessment must be completed prior to the 
Week 76 study medication injection. 
Week 104 Phase B End of Study (EOSb) 
This final study visit should occur on Day 729 with a window of + 7 days. Subjects should fast 
for 8 hours prior to this visit. 
The following procedures and assessments will be performed at Week 104 (EOSb): 
• Collection of AE and concomitant procedures/therapies/medication data 
• Review of medical history 
• Vital signs measurements (pulse rate, blood pressure, respiratory rate, and 
temperature) 
• Physical examination, including knee examination of both knees 
• Weight measurement 
• Venipuncture and collection of samples for clinical laboratory tests and biomarker 
analysis 
• Radiograph – bilateral in weight-bearing fixed flexion position, posterior-anterior 
(PA) view X-ray 
• qCT of both knees 
• DXA of the spine and hips 
7.3.6 EARLY TERMINATION VISIT 
If possible, the following procedures and assessments should be performed within 14 days of 
subject premature withdrawal or termination. Subjects should fast for 8 hours prior to this visit. 
• Collection of AE and concomitant procedures/therapies/medication data 
• Review of medical history 
• Vital signs measurements (pulse rate, blood pressure, respiratory rate, and 
temperature) 
• Physical examination, including knee examination of both knees 
• Weight measurement 
• Venipuncture and collection of samples for clinical laboratory tests and biomarker 
analysis 
• Radiograph – bilateral in weight-bearing fixed flexion position, posterior-anterior 
(PA) view X-ray 
• qCT of both knees 
• DXA of the spine and hips 
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7.3.7 SCHEDULE OF EVENTS TABLE 
 
Procedure 
Phase A 
Phase B 
ET 
Screening Perioda 
(Days -19 to -1) 
Day 
1b 
Week 
4  
(Day 
29  
+3 
days) 
Week 
12  
(Day 
85 
±3 
days) 
Week 
24c  
(Day 
169  
+3 
days) 
Week 
36 
(Day 
253 
-3 to  
+ 7 
days) 
Week 
52c  
(EOSa) 
(Day 
365 
-3 to 
+7 
days)  
Week 
64 
(Day 
449 
+7 
days) 
Week 
76c 
(Day 
533 
+7 
days) 
Week 
88 
(Day 
617 
+7 
days) 
Week 
104 
(EOSb) 
(Day 
729 
+7 
days) 
Screening 
Visit 1 
(Days -19 
to -10)  
Screening 
Visit 2 
(Days -16 
to -7)  
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion & exclusion 
criteria 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
X 
 
 
 
 
Xd 
 
 
 
Xd 
Xd 
Current and prior 
procedures/medications 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
 
 
Xe 
 
 
 
 
 
 
 
 
 
 
Urine drug test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
WPI & SS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Radiograph 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
qCT 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DXA 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
Physical examination 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Knee examination 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Selection of target knee 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
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Procedure 
Phase A 
Phase B 
ET 
Screening Perioda 
(Days -19 to -1) 
Day 
1b 
Week 
4  
(Day 
29  
+3 
days) 
Week 
12  
(Day 
85 
±3 
days) 
Week 
24c  
(Day 
169  
+3 
days) 
Week 
36 
(Day 
253 
-3 to  
+ 7 
days) 
Week 
52c  
(EOSa) 
(Day 
365 
-3 to 
+7 
days)  
Week 
64 
(Day 
449 
+7 
days) 
Week 
76c 
(Day 
533 
+7 
days) 
Week 
88 
(Day 
617 
+7 
days) 
Week 
104 
(EOSb) 
(Day 
729 
+7 
days) 
Screening 
Visit 1 
(Days -19 
to -10)  
Screening 
Visit 2 
(Days -16 
to -7)  
Vital signs 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory 
sampling 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarkersf  
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electronic diary and 
questionnaire training 
 
Xg (eDiary 
device 
provision 
& training) 
 
 
 
 
 
 
 
 
 
 
 
Pain NRS (Review) 
 
 
Xh  
 
 
 
 
 
 
 
 
 
 
WOMAC (Review) 
 
 
Xi  
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Intra-articular injection 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
AEs and concomitant 
procedures/medications 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a The screening period is a minimum of 10 days and a maximum of 19 days and includes Screening Visit 1 and Screening Visit 2; Screening Visit 2 should occur 
at least 3 days after Screening Visit 1, at least 7 days prior to Day 1, and after confirmation of eligible radiograph and urine drug test report results. 
b At Day 1, all procedures should be performed prior to study medication injection except for collection of AE and concomitant procedures/medication data. 
c At Week 24, 52 (EOSa), and 76, all procedures should be performed prior to study medication injection. 
d Review medical history to capture End Date(s), if applicable, of any ongoing medical history(ies) collected at screening. 
e Urine pregnancy test on Day 1 will only be performed on female subjects of childbearing potential. 
f Concentrations of bone and cartilage biomarkers are analyzed in the serum. 
g 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. 
h Electronic diary compliance for daily pain NRS over the screening period will be reviewed at Day 1 prior to randomization to determine subject eligibility. 
i WOMAC questionnaire will be reviewed at Day 1 prior to randomization to determine subject eligibility. 
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7.3.8 SCHEDULE OF ELECTRONIC DIARY AND QUESTIONNAIRE COMPLETION 
TABLE 
 
 
Monthly WOMAC and Patient 
Global Assessment 
Daily pain NRS 
Study Week/Day  
 
(Study Visits are denoted 
with grey shading.) 
 
WOMAC and Patient Global 
Assessment will be completed by 
subjects 5 days after Screening Visit 2 
(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 within a window of ± 3 
days as outlined below; ranges shown 
are inclusive.  
Pain NRS 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. 
  
5 days after Screening 
Visit 2 
Baseline WOMAC and Patient Global 
Assessment questionnaires  
(or up until the day before the  
Day 1 visit) 
Day 1 
  
Starting on the same day of Day 1 
(after the visit), pain NRS assessments 
are to be completed for the target knee 
only. Complete daily.   
Week 4 (Day 29) 
Complete between Day 26 and 32  
Week 8 (Day 57) 
Complete between Day 54 and 60 
Week 12 (Day 85) 
Complete between Day 82 and 88 
 
Week 16 (Day 113) 
Complete between Day 110 and 116 
 
Week 20 (Day 141) 
Complete between Day 138 and 144 
 
Week 24 (Day 169)* 
Complete between Day 166 and 172 
  
Week 28 (Day 197) 
Complete between Day 194 and 200 
 
Week 32 (Day 225) 
Complete between Day 222 and 228 
 
Week 36 (Day 253) 
Complete between Day 250 and 256 
  
Week 40 (Day 281) 
Complete between Day 278 and 284 
 
Week 44 (Day 309) 
Complete between Day 306 and 312 
 
Week 48 (Day 337) 
Complete between Day 334 and 340 
 
Week 52 (Day 365)* 
Complete between Day 362 and 368 
  
Week 56 (Day 393) 
Complete between Day 390 and 396 
 
Week 60 (Day 421) 
Complete between Day 418 and 424 
 
Week 64 (Day 449) 
Complete between Day 446 and 452  
 
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Monthly WOMAC and Patient 
Global Assessment 
Daily pain NRS 
Week 68 (Day 477) 
Complete between Day 474 and 480 
 
Week 72 (Day 505) 
Complete between Day 502 and 508 
 
Week 76 (Day 533)* 
Complete between Day 530 and 536  
 
Week 80 (Day 561) 
Complete between Day 558 and 564 
 
Week 84 (Day 589) 
Complete between Day 586 and 592 
 
Week 88 (Day 617) 
Complete between Day 614 and 620 
 
Week 92 (Day 645) 
Complete between Day 642 and 648 
 
Week 96 (Day 673) 
Complete between Day 670 and 676 
 
Week 100 (Day 701) 
Complete between Day 698 and 704 
 
Week 104 (Day 729) 
Complete between Day 726 and 732 
 
*Note: At Weeks 24, 52 (EOSa), and 76, the WOMAC and Patient Global Assessment must be 
completed prior to the Week 24, 52 (EOSa), and 76 study medication injections, respectively.  
 
 
JUSTIFICATION FOR SENSITIVE PROCEDURES 
Not applicable for this study. 
 
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 the subject’s last visit will 
be recorded in the “Prior and Concomitant Medications” eCRF. “All medications” should 
include prescription, over the counter, supplements, as well as herbal or alternative medications.  
Procedures or non-drug therapies that are ongoing, new, or modified at or after the Screening 
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 an 
AE.  
7.5.1 PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES 
Not applicable to this study. 
 
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: 
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− 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 1)  
− Other anticonvulsants not listed in Appendix 1 are also prohibited unless used for 
seizure or migraine prophylaxis 
− Systemic glucocorticoids greater than 10 mg of prednisone per day or the 
equivalent  
− Drugs screened to assess eligibility, unless clinically indicated and allowed by the 
protocol: amphetamine, buprenorphine, cocaine, methadone, opiates, PCP, 
propoxyphene, barbiturates, benzodiazepine, methaqualone, and tricyclic 
antidepressants  
• Electrotherapy (refer to Appendix 1), 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 
progress at the time of screening are allowed. 
• 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 OA while on study. 
The Investigator should notify the Samumed Medical Monitor immediately if any prohibited 
therapies are required to ensure subject safety.  
 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES  
Not applicable to this study. 
 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES  
Not applicable to this study. 
 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE  
Not applicable to this study. 
 
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8. 
ASSESSMENT OF SAFETY 
 
SPECIFICATION OF SAFETY PARAMETERS 
Safety assessments include physical examinations, vital signs, clinical laboratory tests, collection 
of AEs, SAEs, and concomitant medications, and general medical evaluations.  
8.1.1 DEFINITION OF ADVERSE EVENTS (AE) 
AEs in the eCRF will be classified according to the most recent US FDA definitions and in a 
manner consistent with ICH-GCP guidelines. As such the following definitions will be used: 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with 
the use of an 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 AE term rather than a series of 
symptoms relating to a diagnosis. Fluctuations of pre-existing conditions, including the disease 
under study that does not represent a clinically significant exacerbation or worsening, need not 
be considered AEs. In order to classify AEs and diseases, preferred terms will be assigned by the 
Sponsor to the original terms entered on the eCRF, using the Medical Dictionary for Regulatory 
Activities (MedDRA).   
In this protocol, signs and symptoms of exacerbation or worsening of target knee OA will be 
captured in the context of efficacy assessments and recorded on specific pages of the eCRF or 
electronic diary. Anticipated fluctuations or anticipated deterioration (in the opinion of the 
Investigator) of the underlying disease (target knee OA) will not be considered as AEs nor 
captured on the AE page of the eCRF. 
8.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
According to the ICH 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 inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is an important medical event, defined as an event that does not fit one of the other 
outcomes, but may jeopardize the subject and may require medical or surgical 
intervention (treatment) to prevent one of the other outcomes. Examples include 
allergic bronchospasm (a serious problem with breathing) requiring treatment in an 
emergency room, serious blood dyscrasias (blood disorders), or seizure/convulsion 
that does not result in hospitalization. The development of drug dependence or drug 
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abuse would be other examples of important medical events.  
“Inpatient hospitalization” is clarified as hospitalization lasting ≥24 hours. Admission to the 
hospital or prolongation of hospitalization qualifies as an SAE only if it is the result of an AE. 
All SAE information must be recorded on the SAE form approved by the Sponsor. Additional 
follow-up information (e.g., test results, autopsy, and discharge summary) may be requested to 
supplement the SAE report form and can be attached as de-identified records. 
8.1.3 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
An AE observed during the conduct of a study should be considered an Unanticipated Problem 
(UP) involving risk to human subjects, and be reported to the IRB, only if it was unexpected, 
serious, and would have implications for the conduct of the study (e.g., requiring a significant, 
and usually safety-related, change in the protocol, such as revising inclusion/exclusion criteria or 
including a new monitoring requirement, informed consent, or IB). The occurrence of such an 
event would suggest that the research places study participants or others at a greater risk of harm.  
FDA recommends that there be careful consideration of whether an AE is a UP that must be 
reported to IRBs. In summary, FDA believes that only the following AEs should be considered 
as UPs that must be reported to the IRB:  
• A single occurrence of a serious, unexpected event that is uncommon and strongly 
associated with drug exposure (such as angioedema, agranulocytosis, hepatic injury, or 
Stevens-Johnson syndrome)  
• A single occurrence, or more often a small number of occurrences, of a serious, 
unexpected event that is not commonly associated with drug exposure, but uncommon in 
the study population (e.g., tendon rupture, progressive multifocal leukoencephalopathy)  
• An AE that is described or addressed in the IB, protocol, or informed consent documents, 
but occurs at a specificity or severity that is inconsistent with prior observations  
• An SAE that is described or addressed in the IB, protocol, or informed consent 
documents, but for which the rate of occurrence in the study represents a clinically 
significant increase in the expected rate of occurrence (ordinarily, reporting would only 
be triggered if there were a credible baseline rate for comparison)  
• Any other AE or safety finding (e.g., based on animal or epidemiologic data) that would 
cause the sponsor to modify the IB, study protocol, or informed consent documents, or 
would prompt other action by the IRB to ensure the protection of human subjects  
 
CLASSIFICATION OF AN ADVERSE EVENT 
8.2.1 SEVERITY OF EVENT 
The Investigator will assess AEs for severity utilizing the CDISC AESEV, which classifies AEs 
as mild, moderate, or severe (Table 1). 
 
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Table 1: 
CDISC Definitions of Adverse Event Severity 
CDISC Submission Value 
CDISC Definition 
MILD 
A type of adverse event that is usually transient and may require only 
minimal treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living. 
MODERATE 
A type of adverse event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily 
living, causing discomfort but poses no significant or permanent risk of 
harm to the research participant. 
SEVERE 
A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic 
intervention. 
8.2.2 RELATIONSHIP TO STUDY AGENT 
The relationship of the study treatment to an AE will be determined by the Investigator based on 
the following definitions: 
1.  Not Related 
The AE is not related if (1) exposure to the study medication or administration of the study 
injection has not occurred or (2) the occurrence of the AE is not reasonably related in time or (3) 
the AE is considered related to another event, medical condition, or product not associated with 
the study medication or the study injection. 
2.  Unlikely Related 
The AE is unlikely related if (1) the AE is unlikely related in time or (2) the AE is considered 
unlikely to be related to use of the study medication or study injection (i.e., there are no facts 
[evidence] or arguments to suggest a causal relationship), or the AE is considered possibly 
related to another event, medical condition, or product not associated with the study medication. 
3.  Possibly Related 
The AE is possibly related if (1) the study medication or the study injection and AE are 
considered reasonably related in time and (2) the AE could equally be explained by causes other 
than exposure to the study medication or the study injection. 
4.  Probably Related 
Exposure to study medication or administration of the study injection and AE are probably 
related if (1) the study medication or study injection and AE are considered reasonably related in 
time and (2) the study medication or study injection is more likely than other causes to be 
responsible for the AE or is the most likely cause of the AE. 
8.2.3 EXPECTEDNESS  
The Sponsor will be responsible for determining whether an AE/SAE is expected or unexpected. 
An AE/SAE will be considered unexpected if the nature, severity, or frequency of the event is 
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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.  
 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-
UP 
The reporting period for AEs starts after the injection of study medication on Day 1 and ends 
after the final study visit. 
AEs that are ongoing at a subject’s last visit will be followed for 30 days after administration of 
the last dose of study medication or until resolution, whichever comes first. Resolution is defined 
as the return to baseline status or stabilization of the condition. SAEs that are ongoing at a 
subject’s last visit will be followed until resolution. 
 
REPORTING PROCEDURES 
8.4.1 ADVERSE EVENT REPORTING  
The Investigator is responsible for reporting AEs 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 AE information is reviewed and recorded in the 
subject source and the AE eCRF in a timely manner. The Sponsor is responsible for submitting 
reports of AEs associated with the use of study medication that are both serious and unexpected 
to the FDA according to 21 CFR 312.32. All Investigators participating in ongoing studies with 
the study medication will receive copies of these reports from the Sponsor for prompt submission 
to their IRB/EC according to their institution’s requirements.  
8.4.2 SERIOUS ADVERSE EVENT REPORTING  
The Investigator is responsible for reporting SAEs to the Sponsor and IRB according to 21 CFR 
part 50, part 56, and part 312.  
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 should review the SAE information and sign the SAE 
report, and the Investigator or designee should submit the SAE report to the Samumed Study 
SAE email address: sae@samumed.com or FAX: +1 858 408 4470. Follow-up information must 
be detailed in a follow-up SAE report and reported to the Samumed Study SAE email address or 
fax number as it becomes available. The Investigator also must report all SAEs promptly to the 
appropriate IRB/EC as required by the institution. Sponsor contact information for questions 
regarding SAE reporting is provided in Table 2. 
 
 
 
 
 
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Table 2: 
Sponsor Contact Information for Questions on SAE Reporting 
Primary Contact 
Alternative Contact 
Medical Monitor: Ismail Simsek, MD 
Sr. Manager, Drug Safety and Pharmacovigilance: 
Kathleen Toscano 
Office Tel:  
(858) 926-2968 
Office Tel:  
(858) 371-4057  
Cellular:         (858) 334-5374 
 
Cellular:  
(858) 287-0274 
Email:  
ismail@samumed.com 
Email:  
kathleent@samumed.com 
8.4.3 UNANTICIPATED PROBLEM REPORTING  
Incidents or events that meet the criteria for UP (see Section 8.1.3) require the creation and 
completion of an UP report. It is the site Investigator’s responsibility to report UPs to their IRB 
and to the Sponsor. The UP report will include the following information:  
• Protocol identifying information: protocol title and number, Investigator’s name, and 
the IRB project number;  
• A detailed description of the event, incident, experience, or outcome; and 
• An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP.  
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline:  
• UPs that are SAEs will be reported to the Sponsor and the IRB within 24 hours of the 
Investigator becoming aware of the event on the SAE report form.  
• Any other UP will be reported to the IRB and to the Sponsor within the IRB-required 
reporting timeframe.   
8.4.4 EVENTS OF SPECIAL INTEREST  
Not applicable to this study. 
8.4.5 REPORTING OF PREGNANCY  
If the subject or partner of the subject becomes pregnant, the pregnancy is to be followed until 
the outcome is known. An IRB-approved Pregnant Subject or Pregnant Partner Data Release 
Form should be completed by the subject or the subject’s pregnant partner in order to obtain 
consent to follow the progress of the pregnancy and birth, and the health of the infant.  
Pregnancy is not considered an AE; however, any pregnancy will be collected on a Samumed 
Pregnancy Report Form. Information will be collected for any pregnancy in a female subject or 
the pregnant female partner of a male subject (if consenting), which occurs during the study, 
including perinatal and neonatal outcome. Infants resulting from such pregnancies should be 
followed for a minimum of 12 weeks.   
 
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STUDY HALTING RULES  
Not applicable to this study. 
 
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 
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  
 
STATISTICAL AND ANALYTICAL PLANS 
This section describes the planned statistical analyses in general terms. A complete description of 
Phase A statistical analyses will be specified in a statistical analysis plan (SAP). A second SAP 
will be prepared for Phase B analyses. 
 
STATISTICAL HYPOTHESES 
No formal hypothesis test will be performed in this study. 
 
ANALYSIS DATASETS 
Full Analysis Set (FAS): All subjects who are randomized and receive at least one 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 received injections into the target knee 
both on Day 1 and at Week 24.  
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Per-Protocol Analysis Set (PPAS): mFAS subjects who complete the study and do not have 
any protocol deviations that may impact the evaluation of efficacy outcomes. 
Safety Analysis Set (SAS): All subjects who receive at least one study injection. 
 
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. The principal analysis of the Phase A endpoints will be 
conducted on data extracted from the study database after the last subject completes the Week 52 
(EOSa) visit. 
10.4.2 ANALYSIS OF PHASE A GENERAL SAFETY AND BONE IMAGING 
ENDPOINTS 
The number and percent of subjects experiencing AEs in Phase A will be summarized by 
seriousness, severity, and relationship for each treatment group. 
Change over time in BMD in the target knee as assessed by qCT will be characterized using a 
mixed-effects model for repeated measures (MMRM) in order to estimate change from baseline 
with treatment group, week, treatment×week, and baseline as covariates. The model will be 
evaluated at Week 52. Unadjusted 95% confidence intervals and P values will be reported. The 
model will be estimated assuming an unstructured variance-covariance matrix, allowing the data 
to fully inform the correlation between within-subject observations (Kincaid 2005). 
As a sensitivity analysis, analysis of covariance (ANCOVA) will be used to estimate baseline-
adjusted BMD in the target knee at Weeks 12, 24, 36, and 52. The ratio of baseline-adjusted 
BMD between SM04690 and placebo will be presented with a one-sided 95% confidence 
interval.  
Baseline-adjusted ANCOVA will also be used to analyze the within-subject difference in BMD 
between the target and non-target knee by qCT for SM04690, within-subject difference in BMD 
between the target and non-target knee by qCT for placebo, and change from baseline in BMD of 
the spine and hips by DXA for SM04690 subjects versus placebo. The models will be adjusted 
for baseline and evaluated at Weeks 12, 24, 36, and 52 for qCT and Weeks 24 and 52 for DXA. 
Unadjusted 95% confidence intervals and P values will be reported. 
10.4.3 ANALYSIS OF PHASE A EFFICACY AND EXPLORATORY BIOMARKER 
ENDPOINTS 
Changes in the target knee from baseline in Pain NRS, WOMAC Function, WOMAC Pain, 
mJSW, and Patient Global Assessment will be characterized using MMRM; the models will be 
evaluated through Week 52. All models will use treatment group, week, treatment×week 
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interaction, and baseline values as covariates. Unadjusted 95% confidence intervals and P values 
will be reported. 
For WOMAC, mJSW, and Patient Global Assessment, the model will be estimated assuming an 
unstructured variance-covariance matrix. For Pain NRS, the model will be estimated assuming 
a Toeplitz variance-covariance matrix. The Toeplitz structure is a more generalized form of 
autogressive-1 structure, allowing the data to inform how the correlation between within-subject 
observations decreases over time instead of implicitly defining a uniform decay structure 
(Kincaid 2005). 
To assess response durability, changes in the target knee from Week 24 (i.e., after second 
injection) in Pain NRS, WOMAC Function, WOMAC Pain, mJSW, and Patient Global 
Assessment will be characterized using MMRM; the models will be evaluated through Week 52. 
All models will use treatment group, week, treatment×week interaction, and Week 24 values as 
covariates. Unadjusted 95% confidence intervals and P values will be reported. 
Baseline-adjusted ANCOVA will be used to analyze the change from baseline in serum bone 
biomarkers (e.g. PINP and β-CTX) and a serum cartilage biomarker (e.g., COMP) for SM04690 
subjects versus placebo. The models will be adjusted for baseline and evaluated at Weeks 4, 12, 
24, 36, and 52. Unadjusted 95% confidence intervals and P values will be reported. 
10.4.4 ANALYSIS OF PHASE B ENDPOINTS 
Phase B endpoints will be analyzed in a similar fashion as Phase A endpoints. A separate SAP 
will be prepared for Phase B analyses. 
10.4.5 SAFETY ANALYSES 
Safety analyses will be performed on subjects who receive a study injection (treatment emergent 
adverse events). Safety assessments include imaging, physical examinations, vital signs, clinical 
laboratory tests, collection of AEs, SAEs, and concomitant medications, and general medical 
evaluations. Safety will be evaluated based on the incidence, seriousness, severity, and 
relationship of AEs and SAEs, and by changes in clinical laboratory parameters and vital signs, 
relative to baseline.  
10.4.6 BASELINE DESCRIPTIVE STATISTICS 
Baseline is defined as the last value recorded for any given parameter prior to study medication 
injection at Day 1. If a subject never received a study injection, baseline is defined as the last 
value recorded prior to study termination. 
Baseline descriptive statistics will include age, gender, race, height, weight, BMI, and KL Grade 
10.4.7 PLANNED INTERIM ANALYSES  
This safety study was initially designed as a one-year double-blind study. The protocol was 
amended to add a built-in, one-year single blind extension (Phase B) after the formal, one-year 
core study (Phase A) completes. The primary analysis will be after last subject completes Week 
52 in Phase A and should not be considered an interim analysis.  
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10.4.7.1 
SAFETY REVIEW 
Medical monitoring of study safety assessment data will be performed during periodic safety 
reviews detailed in the Medical Monitoring Plan. 
10.4.7.2 
EFFICACY REVIEW 
Not applicable to this study.  
10.4.8 EXPLORATORY ANALYSES 
Refer to Section 10.4.3.  
10.4.9 ADDITIONAL SUB-GROUP ANALYSES 
Not Applicable.  
 
SAMPLE SIZE 
The sample size for this trial is based upon accepted investigational studies exploring changes in 
bone density.  
Additionally, sample size was also estimated assuming a non-inferiority statistical design. Based 
upon the subchondral BMD data obtained using qCT in SM04690-01, a coefficient of variation 
(CV) of 0.30 was presumed to be shared by both treatment and placebo groups; this presumed 
CV is larger than the observed CVs in SM04690-01. Assuming a Type 1 error of 0.05, 
SM04690-OA-06 will have 81.6% power to estimate a BMD ratio of 0.93 with a one-sided 
confidence interval extending to 0.80 with a sample size of 50 subjects per group. 
 
MEASURES TO MINIMIZE BIAS 
10.6.1 BLINDING PROCEDURES 
Phase A is a double-blind study. Study medication will be provided to the investigational center. 
The investigational center must identify unblinded personnel who are able to prepare and 
perform the injection of study medication and/or placebo. 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 Rave database. Upon randomization of a subject, a 
Dispensation email will be sent from Medidata-Notification@mdsol.com to the designated 
unblinded investigational staff member(s). Subjects will be randomized 1:1 (0.07 mg active per 2 
mL injection : 2 mL placebo) to each treatment group using a permuted block design. Specific 
information regarding the use of Medidata Rave RTSM to store and implement the permuted 
block design will be detailed within the SAP. 
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Primary analysis of Phase A data will be completed after the last subject completes Week 52 
(EOSa). While the Sponsor will be unblinded to study treatment after the Phase A analysis, the 
Investigator and the subject will remain blinded. 
10.6.2 EVALUATION OF SUCCESS OF BLINDING  
Not applicable to this study. 
10.6.3 BREAKING THE STUDY BLIND/PARTICIPANT CODE 
The blind may be broken by a qualified physician who is an Investigator in this study in the 
event of a medical emergency in which knowledge of the identity of the study medication is 
critical to the management of the subject’s immediate course of treatment. Before breaking the 
blind, the Investigator should determine that the information is necessary (i.e., that it will alter 
the subject’s immediate course of treatment).  
If deemed necessary to break the blind for a study subject, the Samumed Medical Monitor is to 
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 Rave 
RTSM and medical records. Instructions on how to unblind treatment assignment will be 
provided to each Investigator and kept within a guidance document at each site. No other blinded 
site users will have access roles to Rave RTSM that will allow treatment assignment unblinding. 
Any subject whose blind has been broken will continue their follow-up visits as per protocol.   
In circumstances when the blind is unintentionally broken at the investigational center, the 
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., eCOA questionnaires). The source documents should include detailed 
notes on the following: 
• The oral and written communication with the subject regarding the study (including 
the risks and benefits of the study); the date of informed consent(s) must be recorded 
in the source documentation 
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• The subject’s medical and disease history before participation in the study 
• The subject’s basic identifying information, such as subject number, that links the 
subject’s source documents with the eCRFs 
• The results of all diagnostic tests performed, diagnoses made, therapy provided, and 
any other data on the condition of the subject 
• All AEs (All AEs 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, eCOA questionnaire 
results are not transferred to eCRFs. 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL 
This study will be organized, performed, and reported in compliance with the protocol, SOPs, 
site/Investigator training, and applicable regulations and guidelines. Clinical Investigator sites 
will be trained at 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, representatives of the Sponsor, and regulatory 
authorities, as needed. 
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  
 
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-GCP E6. 
 
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 
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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.  
 
INFORMED CONSENT PROCESS  
13.3.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED 
TO PARTICIPANTS 
Consent forms describing in detail the study procedures and risks will be given to the potential 
participant and written documentation of informed consent is required prior to starting any 
screening evaluations or other study-related procedures.   
13.3.2 CONSENT PROCEDURES AND DOCUMENTATION 
The 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.  
 
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 or designee 
will maintain a personal subject identification list (subject numbers with the corresponding 
subject names) to make it possible for records to be identified.  
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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. 
 
FUTURE USE OF STORED SPECIMENS  
Not applicable to this study. 
14. 
DATA HANDLING AND RECORD KEEPING  
 
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-GCP E6 and US 21 CFR parts 312, 812, and 11. Data to be transferred 
external to Rave may include eCOA questionnaires, central laboratory data, and imaging results. 
Data collection on the eCRF will follow the instructions described in the eCRF Completion 
Guidelines. The Investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the eCRF. The Investigator or designee as identified on Form FDA 1572 
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. 
 
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 
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qualified physician who is an Investigator on the study once all data is considered final. During 
this study, the Investigator must retain copies of eCRFs (or electronic files), and source 
documents for the maximum period required by (1) applicable regulations and guidelines or 
institution procedures or (2) for the period specified by the Sponsor, whichever is longer. The 
Investigator must contact the Sponsor prior to destroying any records associated with the study. 
The Sponsor will notify the Investigator when the study records are no longer needed. 
In the event the Investigator withdraws from the study (e.g., relocation, retirement), the records 
shall be transferred to a mutually agreed-upon designee (e.g., another Investigator). Notice of 
such transfer will be given in writing to the Sponsor. 
The Investigator must ensure that clinical study records are retained according to national 
regulations, as documented in the Clinical Trial Agreement entered into with the Sponsor in 
connection with this study. For example, US federal laws require that an Investigator maintain all 
study records for the indication under investigation for 2 years following the date of a New Drug 
Application approval or, if no application is filed or if the application is not approved for such 
indication, until 2 years after the investigation is discontinued and the FDA is notified. 
The Sponsor will maintain correspondence with the Investigator after study closeout to ensure 
that study documentation is retained for the appropriate amount of time. Subject files and other 
source data must be kept for the maximum period of time permitted by the hospital, institution, 
or private practice and should be retained in accordance with applicable 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. 
 
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. 
 
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 
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STUDY LEADERSHIP 
The study will be led and conducted by Samumed, LLC.  
 
 
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16. 
LITERATURE REFERENCES  
Clauw DJ. Fibromyalgia: a clinical review. JAMA 2014;311:1547-55. 
Dougados M, and Hochberg MC. 2011. 'Management of osteoarthritis.' in M. C. Hochberg, A. J. 
Silman, J. S. Smolen, M. E. Weinblatt and M. H. Weisman (eds.), Rheumatology (Elsevier: PA, 
USA). 
Gelse K, Ekici AB, Cipa F, Swoboda B, Carl HD, Olk A, Hennig FF, and Klinger P. Molecular 
differentiation between osteophytic and articular cartilage--clues for a transient and permanent 
chondrocyte phenotype. Osteoarthritis Cartilage 2012;20:162-71. 
Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, Mcgowan J, Towheed T, Welch 
V, Wells G, Tugwell P, and American College Of R. 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) 2012;64:465-74. 
Kincaid CM 2005. Guidelines for Selecting the Covariance Structure in Mixed Model Analysis 
In Proceedings of the Thirtieth Annual SAS® Users Group Internation Conference. 
Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, Deyo RA, Gabriel S, Hirsch R, 
Hochberg MC, Hunder GG, Jordan JM, Katz JN, Kremers HM, Wolfe F, and National Arthritis 
Data W. Estimates of the prevalence of arthritis and other rheumatic conditions in the United 
States. Part II. Arthritis Rheum 2008;58:26-35. 
Nevitt MC, Felson DT, and Lester G. A Knee Health Study. "The Osteoarthritis Initiative." 2006. 
Wu L, Huang X, Li L, Huang H, Xu R, and Luyten W. Insights on biology and pathology of 
HIF-1alpha/-2alpha, TGFbeta/BMP, Wnt/beta-catenin, and NF-kappaB pathways in 
osteoarthritis. Curr Pharm Des 2012;18:3293-312. 
 
 
 
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APPENDIX 
Appendix 1. 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) 
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 2. 
Amendments 
 
AMENDMENT 04 VERSION 00 SUMMARY OF CHANGES 
Study Title: 
A Phase 2, 52-Week, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study Evaluating the Safety, Tolerability, and 
Efficacy of Two Injections of SM04690 Injected in the Target Knee 
Joint of Moderately to Severely Symptomatic Osteoarthritis Subjects  
Purpose: 
The purpose of this amendment is to refine the study design and to 
further clarify the primary study phase and the built-in extension phase 
of the protocol.   
Summary of Changes: The table below provides a list of changes and their rationale. 
Change 
Sections Affected 
Rationale 
Protocol Amendment 04 Version 00 has been 
added on the title page. 
Title Page 
Change was made to capture the dates 
of previous and current protocol 
versions 
Protocol date and version have been updated as 
applicable 
All 
Change was made to reflect current 
protocol amendment 
Signatories were removed 
Sponsor Signature 
Page 
Updated to reflect personnel changes 
Study objectives were refined 
Protocol Summary,  
Section 3 
Change was made to refine the study 
design 
Study endpoints were refined and reorganized 
Protocol Summary, 
Section 4.2 
Change was made to refine the study 
design 
Description of the study design was updated  
Protocol Summary, 
Section 4.1 
Change was made to further clarify 
study design 
Key roles were updated, as well as Sponsor 
address 
Section 1 
Change made to reflect personnel 
changes and Sponsor address change 
Language change removing biomarkers from 
Safety endpoints/assessments 
Protocol Summary, 
Section 2.2, Section 
8.1 
Change was made to refine study 
design 
Language describing allowed use of topical 
anesthetics was updated 
Section 6.1.5 
Change was made for clarification 
Language describing the planned Statistical 
Analysis Plans (SAPs) was updated 
Section 10.1 
Change made to clarify plans for the 
SAPs 
Statistical Hypotheses were updated 
Section 10.2 
Change was made to refine the 
planned analyses 
Definition of the Per-Protocol Analysis Set 
(PPAS) was updated 
Section 10.3 
Change was made to refine the 
definition of the PPAS 
Language was updated to reflect changes in the 
study endpoints and timing of planned analyses  
Sections 10.4.1, 
10.4.2, 10.4.3, 10.4.5, 
10.4.6, 10.4.7, 10.4.8, 
10.6.1, and 10.6.3 
Change was made to further clarify 
the study design 
Sample size language updated 
Section 10.5 
Change was made to further refine 
sample size calculations 
The following text was added: “representatives of 
the Sponsor, and regulatory authorities, as 
needed.” 
Section 12 
Change was made for clarification 
Removed “tapentadol (Nucynta)” from the list of 
prohibited concomitant medications 
Appendix 1 
Change made to refine prohibited 
concomitant medications 
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AMENDMENT 03 VERSION 00 SUMMARY OF CHANGES 
Study Title: 
A Phase 2, 52-Week, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study Evaluating the Safety, Tolerability, and 
Efficacy of Two Injections of SM04690 Injected in the Target Knee 
Joint of Moderately to Severely Symptomatic Osteoarthritis Subjects  
Purpose: 
The purpose of this amendment is to refine the study design and add 
an Extension Phase (Phase B) to the study.   
Summary of Changes: The table below provides a list of changes and their rationale 
Change 
Sections Affected 
Rationale 
Protocol Amendment 03 Version 00 has been 
added on the title page. 
Title Page 
Change was made to capture the dates 
of previous and current protocol 
versions 
Protocol date and version have been updated as 
applicable 
All 
Change was made to reflect current 
protocol amendment 
An Extension Phase (Phase B) was added to the 
study. Phase B is an additional 52 weeks of 
treatment. Additional secondary and “other” 
endpoints were added accordingly. 
Protocol Summary, 
Sections 2.2, 3, 4.1, 
6.1.5, 6.1.6, 6.1.9  
Change was made to refine study 
design in order to gather long term 
safety and efficacy data following 
multiple injections of SM04690 
Study endpoints were revised/re-ordered into 
Phase A Primary Endpoints and Phase A 
Secondary Endpoints. Phase B Endpoints were 
added. Description of Statistical Methods was 
updated accordingly. 
Protocol Summary, 
Sections 4.2, 10.2, 
10.3, 10.4 
Change was made to align with 
addition of Phase B and to identify a 
single primary endpoint for alpha-
controlled hypothesis testing. 
Endpoints and study procedures related to serum 
biomarkers were edited to indicate that testing 
includes but is not limited to PINP, β-CTX, and 
COMP. 
Protocol Summary, 
Sections 7.2.2 and 
10.4.3 
Change was made to refine study 
design and allow for additional 
biomarker testing 
Inclusion criterion #12 was edited from “52-week” 
to “104-week” study duration.  
Protocol Summary, 
Section 5.1 
Change was made to align with 
addition of Phase B 
Exclusion criterion #18 was edited to: “History of 
mania, bipolar disorder, psychotic disorder, 
schizophrenia, schizoaffective disorder, major 
depressive disorder, or generalized anxiety 
disorder” 
Protocol Summary, 
Section 5.2 
Change was made to refine exclusion 
criteria 
Exclusion criterion #19 was edited: “…any 
experimental therapeutic procedure for knee OA 
within 26 weeks prior to Screening Visit 1…” is 
excluded. 
Protocol Summary, 
Section 5.2 
Change was made to refine exclusion 
criteria 
Exclusion criterion #22 was edited to clarify 
systemic as “(oral, intramuscular, or intravenous)”.  
Protocol Summary, 
Section 5.2 
Change was made to clarify what 
constitutes systemic glucocorticoids 
Study and participant durations were updated. 
Protocol Summary 
Change was made to reflect addition 
of Phase B 
Schematic of Study Design was updated. 
Schematic of Study 
Design 
Change was made to reflect addition 
of Phase B 
Risks associated with radiographs, qCT, and DXA 
were updated to reflect the additional imaging 
assessments performed in Phase B. 
Section 2.3.1 
Change was made to reflect the new 
number of imaging assessments to be 
performed 
Where applicable, “Week 52 (EOS)/ET” was 
changed to “last study visit” (e.g., guidelines on 
Sections 5.3.1, 7.1.1, 
7.5.1 
Change was made to clarify that these 
instances refer to the subject’s last 
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contraception).  
study visit, whether that be in Phase A 
or Phase B 
Clarification and further guidelines were added to 
Section 5.3.1 Contraception.  
Section 5.3.1 
Changes were made to refine lifestyle 
guidelines pertaining to contraception 
Edits were made to indicate that subjects who are 
withdrawn from study medication for safety 
reasons will continue with all planned study visits 
per protocol. 
Sections 5.5.1, 5.5.2, 
6.1.9 
Change was made to follow subjects 
for safety despite withdrawing from 
study medication 
Further information regarding injections was 
added to Section 6.1.5. 
Section 6.1.5 
Change was made to provide further 
guidance on IA injections 
Study Procedures and Schedule were updated to 
include Phase B assessments and visits. Schedule 
of Events and Schedule of Electronic Diary and 
Questionnaire Completion tables were also 
revised. 
Section 7 
Change was made to reflect addition 
of Phase B 
The following was added to Section 10.1: “A 
second SAP will be prepared for Phase B analyses 
and finalized prior to the Week 104 data lock.” 
Section 10.1 
Change was made to reflect addition 
of Phase B 
The following was added to Section 10.4.6: “If a 
subject never received a study injection, baseline 
is defined as the last value recorded prior to study 
termination.”  
Section 10.4.6 
Addition was made to be consistent 
with other SM04690 studies 
Details in Section 10.4.9 Additional Sub-Group 
Analyses were deleted. 
Section 10.4.9 
Deletion was made to be consistent 
with other SM04690 studies 
The following was added to Section 10.6.3: “After 
the last subject completes Phase A [Screening 
Visit 1 through Week 52 (EOSa)], Phase A study 
visit data will be locked for a 52-week Phase A 
full analysis. While the Sponsor will be unblinded 
to study treatment after this lock, the Investigator 
and the subject will remain blinded.”  
Section 10.6.3 
Addition was made to describe the 
breaking of the blind between Phase A 
and Phase B 
 
 
 
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AMENDMENT 02 VERSION 00 SUMMARY OF CHANGES 
Study Title: 
A Phase 2, 52-Week, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study Evaluating the Safety, Tolerability, and 
Efficacy of Two Injections of SM04690 Injected in the Target Knee 
Joint of Moderately to Severely Symptomatic Osteoarthritis Subjects  
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 
Protocol Amendment 02 Version 00 has been 
added on the title page. 
Title Page 
Change was made to capture the dates 
of previous and current protocol 
versions 
Protocol date and version have been updated as 
applicable 
All 
Change was made to reflect current 
protocol amendment 
Updated titles for Hutch Humphreys and Ismail 
Simsek; added Cristina Damatarca and Mark 
Fineman as signatories and removed Anita 
DiFrancesco 
Sponsor Signature 
Page, Section 1 
Changes were made for administrative 
reasons 
Updated List of Abbreviations 
List of Abbreviations 
Change was made due to new 
abbreviations 
Extended the screening period to 19 days 
(previously 14 days). 
Protocol Summary, 
Sections 4.1 and 7.3 
Change was made to allow sufficient 
time to complete and receive imaging 
reports 
Added “serious adverse events (SAEs), vital signs, 
and clinical laboratory measures for the duration 
of the study” to the safety endpoint. 
Protocol Summary, 
Section 4.2.1 and 
10.4.5 
Change was made to refine the safety 
endpoint 
Removed methamphetamine as tested drug. 
Protocol Summary and 
Sections 5.2, 7.1.1, 
and 7.6 
Drug is included with 
“Amphetamines” in the list of drugs 
Modified inclusion criterion #16: “Subjects must 
have read and understood the informed consent 
form … signed and dated it …” 
Protocol Summary, 
Section 5.1 
Change was made to be consistent 
with documentation requirements 
Added a new inclusion criterion #18: “Subject is 
able to have a Screening Visit 2 qCT image 
acquired that does not require a re-scan as 
determined by the central imaging vendor.” 
Protocol Summary, 
Section 5.1 
Change was made to clarify qCT 
eligibility requirements  
Exclusion criterion #1 was modified to: “Pregnant 
and breastfeeding women, and women who are not 
post-menopausal (defined as 12 months with no 
menses without an alternative medical cause) or 
permanently surgically sterile (includes 
hysterectomy, bilateral salpingectomy, and 
bilateral oophorectomy) and have a positive or 
indeterminate pregnancy result at Screening Visit 
2 or Day 1” 
Protocol Summary, 
Section 5.2 
Change was made to refine exclusion 
criteria 
Exclusion criterion #2 was modified to remove the 
definitions of post-menopausal and permanently 
surgically sterile since they were added to 
exclusion criterion #1. 
Protocol Summary, 
Section 5.2 
Change was made to avoid 
redundancy 
Exclusion criterion #19 was updated to: 
“Participation in a clinical research trial that 
included the receipt of an investigational product 
Protocol Summary, 
Section 5.2 
Change was made to refine exclusion 
criteria and align with other SM04690 
trials 
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(IP) or any experimental therapeutic procedure for 
knee OA within 26 weeks prior to Screening Visit 
1, or planned participation in any such trial” 
Exclusion criterion #32 was modified and 
exclusion criterion #37 was added.  
Protocol Summary, 
Section 5.2 
Change was made to refine exclusion 
criteria related to DXA imaging 
Description of Study Agent was revised. 
Protocol Summary 
Change was made to align with 
current description being used in other 
SM04690 trials 
Study duration was revised to 24 months and the 
estimated date last subject completed was updated 
to August 2020. 
Protocol Summary 
Change was made for accuracy 
Deleted information related to previous and 
ongoing SM04690 clinical trials from the 
Rationale section.   
Section 2.2 
Change was made to simplify the 
Rationale section; pertinent 
information regarding previous 
SM04690 trials is in the IB 
Modified description of risks associated with 
Study Medication SM04690, Study Placebo, and 
Risks of Injection. 
Section 2.3.1 
Change was made to refine 
description and to align protocol with 
current IB. 
An update was made to the allowable windows for 
re-using screening images.  
Section 4.1 
Change was made to refine re-
screening guidance 
“Tubal ligation/occlusion/division” was added as 
an acceptable form of birth control. 
Section 5.3.1 
Change was made to correct a 
previously erroneous omission  
The following was added to Section 6.1.3: “Refer 
to the Pharmacy Manual for detailed instructions 
on how to manage temperature excursions.” 
Section 6.1.3 
Change was made to provide further 
guidance on temperature excursions 
Added following information on blinding: 
“The Unblinded Investigator must minimize any 
contact with the subject following the injections 
and may not perform any study assessments 
throughout the duration of the study. All subject 
contact for the remainder of the study is limited to 
the Blinded Investigator and other appropriate 
blinded study personnel.” 
Section 6.1.5 
Drug product and placebo have 
different appearances; injections 
therefore must be performed by 
unblinded personnel. Change was 
made to remind sites that Unblinded 
Investigators who administer 
injections should not participate in any 
study evaluations. 
Additional information/guidance was added 
regarding the injection by the Unblinded 
Investigator. 
Section 6.1.5 
Change was made to clarify the 
injection process 
Changed scale for collecting AEs from “Guidance 
for Industry: Toxicity Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventative 
Vaccine Trials” to “Clinical Data Interchange 
Standards Consortium (CDISC) Severity/Intensity 
Scale for Adverse Events (AESEV).” 
Sections 7.1.1, 7.2.1, 
8.2.1, and Appendix 1 
The Toxicity Scale is applicable for 
vaccine trials with healthy volunteers, 
whereas this is a Phase 2 trial of a 
non-vaccine drug. 
Further clarification of AEs was provided. 
(“Anticipated fluctuations or anticipated 
deterioration (in the opinion of the Investigator) of 
the underlying disease (target knee OA) will not 
be considered as AEs…”) 
Sections 7.1.1 and 
8.1.18.3 
Changes were made to clarify which 
events should be considered AEs 
Reworded timing of AE reporting to: “AEs that 
are ongoing at a subject’s last visit will be 
followed for 30 days after administration of the 
last dose of study medication or until resolution, 
whichever comes first. Resolution is defined as the 
return to baseline status or stabilization of the 
Sections 7.1.1 and 8.3 
Changes were made to refine 
definitions and timing of collection 
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condition. SAEs that are ongoing at a subject’s last 
visit will be followed until resolution.” 
Minor edits were made in the Medical History 
subsection including adding examples of medical 
conditions and disease states that should be 
considered relevant to the subject’s study 
participation. 
Section 7.1.1 
Edits were made for clarity 
A clarification was made in the Knee Examination 
subsection; presence of unilateral or bilateral knee 
OA will be recorded. 
Section 7.1.1 
Change was made to align with eCRF 
Revised vital sign terminology. 
Sections 7.1.1 and 7.3 
Changes were made to align with 
CDISC standard terminology  
The following was added to the qCT subsection: 
“A quality assessment report will be provided to 
the Investigator by the central imaging vendor to 
confirm subject eligibility.” 
Section 7.1.1 
Change was made for clarification 
Clarified description of assessment: “The 
WPI&SS assessment used in this study is modified 
from that described in (Clauw 2014)” 
Section 7.1.1 
Change was made to indicate that our 
assessment is not the same as that in 
reference 
Added anchor descriptors to Pain NRS and 
corrected the description of the questionnaire.  
Section 7.1.1 
Changes were made to clarify 
procedures and for accuracy 
The following sentence was deleted from the Pain 
NRS subsection: “Increases in pain should only be 
considered AEs if reported by the subject, 
regardless of pain NRS scores.”   
Section 7.1.1 
Change was made to align with the 
updates made to the AE subsection 
(regarding anticipated fluctuations or 
deterioration of the underlying 
disease). 
The urine pregnancy test on Day 1 will only be 
performed on women of childbearing potential. 
Sections 7.2.2, 7.3.2, 
and 7.3.7 
Change was made to align with edit to 
exclusion criterion #1 
The following was deleted from the Day 1 study 
visit: “Subjects with a period of more than 11 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 refine study 
design; subjects need not be screen 
failed since baseline questionnaires do 
not contribute to the primary endpoint. 
Clarified which eCRF page prior and concomitant 
medications will be recorded on. 
Section 7.5 
Addition was made for clarification  
The following was added to definitions of SAEs: 
“Admission to the hospital or prolongation of 
hospitalization qualifies as an SAE only if it is the 
result of an AE.” 
Section 8.1.2 
Change was made to align with 
current ICH definitions of SAEs. 
Descriptions for Unanticipated Problems (UPs) 
changed. 
Sections 8.1.3 and 
8.4.3 
Change was made for clarity and to 
align with current reporting 
guidelines. 
Section 8.2.2 Relationship to Study Agent was 
revised.  
Section 8.2.2 
Changes were made to clarify 
definitions of relatedness to study 
drug 
Removed phrase: 
“The Investigator and Samumed will manage 
SAEs according to the study document 
“Guidelines for the Management of Serious 
Adverse Events (SAEs) and Pregnancies”. 
Section 8.4.2 
Change was made because document 
is no longer used. 
Added following:  
“The Investigator should review the SAE 
Section 8.4.2 
Change was made to clarity reporting 
requirements 
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information and sign the SAE report, and the…” 
Added Kathleen Toscano as Alternative Contact 
for SAE Reporting and to Key Role overseeing 
Drug Safety and Pharmacovigilance 
Section 8.4.2 
Changes were made for administrative 
reasons 
Removed text from UP Reporting: 
1: “A description of any changes to the protocol or 
other corrective actions that have been taken or are 
proposed in response to the UP.”  
2: “All UPs should be reported to appropriate 
institutional officials (as required by an 
institution’s written reporting procedures) and IRB 
within the timeframe specified by the institution 
procedures and IRB.” 
Section 8.4.3 
Changes were made because 1) 
Investigators are not responsible for 
protocol changes, and 2) This 
information was already indicated in 
the section 
Section 8.4.5 Reporting of Pregnancy was revised 
to provide guidance on pregnancy reporting during 
the study.  
Section 8.4.5 
Change was made to clarify 
pregnancy reporting process within 
the protocol 
Section 10.2 Statistical Hypotheses was revised. 
Section 10.2 
Formal hypothesis testing was added 
for clarity given the sample size 
justification 
Further details regarding BMD analysis were 
added to Section 10.3.2 Analysis of Primary 
Endpoint(s). 
Section 10.4.2 
Analysis was clarified in support of 
hypothesis testing. 
Additional sample size justification was added to 
Section 10.4 Sample Size. 
Section 10.5 
Sample size was estimated upon 
request from the regulatory agency. 
Changed e-mail for Medidata notification to sites 
and “Treatment Arm Notification” was changed to 
“Dispensation.” 
Section 10.6.1 
Change was made for administrative 
reasons 
Medidata Balance was revised to Medidata Rave 
RTSM. 
Section 10.6.3 
Change was made for correctness  
Time of informed consent was deleted from 
Section 11.  
Section 11 
Change was made because time is not 
collected on the informed consent 
form 
Deleted the following from Section 14.3 Protocol 
Deviations: “Refer to the current version of 
Samumed SOP-300-013 Protocol Deviations for 
Sponsor procedures related to protocol 
deviations.” 
Section 14.3 
Change was made because this 
information is not applicable to the 
sites 
Updated Section 16 Literature References. 
Section 16 
Change was made to reflect references 
cited in this amendment. 
Removed Appendix 1 (Toxicity Vaccine Scale) 
Appendix 1 
Scale was replaced by CDISC scale 
for AE collection 
Formatting, spelling, and grammar/terminology 
were refined 
Throughout 
Changes were made for clarity and 
presentation 
 
 
 
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AMENDMENT 01 VERSION 00 SUMMARY OF CHANGES 
Study Title: 
A Phase 2, 52-Week, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study Evaluating the Safety, Tolerability, and 
Efficacy of Two Injections of SM04690 Injected in the Target Knee 
Joint of Moderately to Severely Symptomatic Osteoarthritis Subjects  
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 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. 
List of Abbreviations was updated. 
List of Abbreviations 
Change was made for correctness to 
reflect the terms used in the protocol. 
The use of “Treatment-emergent adverse 
events” and “TEAEs” was changed to 
“Adverse events” and “AEs”, 
respectively. 
Summary and throughout 
Change was made to align protocol 
with the EDC and eCRF. 
Wording of primary endpoint 1e was 
modified to “Change in serum bone 
biomarkers (N-terminal propeptides of 
procollagen type I [PINP] and β-C-
terminal telopeptide [β-CTX]) from 
baseline, and change in a serum cartilage 
biomarker (cartilage oligomeric matrix 
protein [COMP]) from baseline at Weeks 
4, 12, 24, 36, and 52”. 
Summary and Section 
4.2.1 
Change was made for clarity. 
Measurement of bone and cartilage 
biomarkers was added at Week 36. 
Summary, Schematic of 
Study Design, Section 4.1, 
Section 4.2.1, Section 
7.2.2, Section 7.3.7, and 
Section 10.4.2  
Change was made to refine study 
design. Biomarkers will be assessed at 
Screening Visit 2 and at Weeks 4, 12, 
24, 36, and 52 (EOS)/ET. 
The following sentence was removed 
from the Methodology section of the 
Protocol Summary: “Comparisons to 
baseline for primary endpoints will be of 
a qualitative nature with no formal 
statistical analysis performed.” 
Summary 
Change was made for accuracy. 
Unadjusted 95% confidence intervals 
and P values will be reported.  
Inclusion criterion #10 was updated to: 
“WOMAC pain subscore of 20-40 (out of 
50) and WOMAC physical function 
subscore of 68-136 (out of 170) for the 
target knee at baseline regardless of if the 
subject is on symptomatic oral treatment 
(baseline questionnaire completed during 
the screening period prior to 
randomization)” 
Summary and Section 5.1 
Change was made to refine study 
design; the inclusion criterion was 
modified to identify required ranges 
for WOMAC pain and physical 
function subscores, instead of 
WOMAC total score. 
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Corrections were made to exclusion 
criteria #1, 15, and 30 to reflect the fact 
that the pregnancy test and clinical 
laboratory evaluations will be performed 
at Screening Visit 2 (not Screening Visit 
1). 
Summary and Section 5.2 
Changes were made for accuracy. 
These tests will be performed at 
Screening Visit 2.  
Exclusion criterion #32 was modified to 
add/clarify exclusionary 
contraindications to DXA scans of the 
hips or spine. 
Summary and Section 5.2 
Changes were made to clarify which 
contraindications should be considered 
exclusionary. 
The address for the Central Laboratory 
was corrected. 
Section 1 
Change was made for correctness.  
Enrollment information was updated for 
ongoing SM04690 clinical trials (to “as 
of 25 May 2018”) and additional 
information and/or edits were made to 
further support or clarify the study 
rationale.  
Section 2.2 
Change was made to provide more 
current information regarding ongoing 
studies and to clarify the study 
rationale.  
The following (and related text) was 
added throughout the protocol: “The 
second injection may occur up to two 
weeks later than the Week 24 visit to 
allow for resolution of any intercurrent 
illness (e.g., infection) prior to the 
injection.” 
Section 6.1.5, Section 
6.1.6, Section 6.1.9, 
Section 7.3.3 
Change was made to refine study 
design. A 2 week window was added 
to allow for resolution of intercurrent 
illness prior to the second IA injection.  
The following was added in Section 6.2: 
“Procedures for unblinded Investigator 
return or destruction of used and unused 
vials…” 
Section 6.2 
Change was made to clarify that these 
procedures would be performed by the 
unblinded Investigator. 
The following clarification was added: 
“AEs that are not serious and are ongoing 
at the subject’s last visit will be followed 
until the study close-out visit, if requested 
by the Sponsor. If not requested, AEs that 
are not serious and are ongoing at the 
subject’s last visit will be followed for a 
maximum of 30 days.” 
Section 7.1.1 and Section 
8.3 
Change was made to clarify how AEs 
that are not serious and are ongoing at 
the subject’s last visit should be 
followed. 
It was clarified that the monthly 
questionnaires for Week 24 should be 
completed prior to the Week 24 study 
medication injection.  
Section 7.1.1, Section 
7.3.3, and Section 7.3.8 
Change was made to clarify the timing 
of Week 24 monthly questionnaires in 
relation to the second study 
medication injection.  
The Patient Global Assessment of 
Disease Activity was changed from a 50 
mm visual analog scale to an 11-point 
NRS, and the description of the 
questionnaire was updated. 
Section 7.1.1 
Change was made to reflect an update 
to the Patient Global Assessment. 
Study visit windows were modified: 
• 
Week 12 now has a window of 
± 3 days 
Section 7.3.3, Section 
7.3.4, and Section 7.3.7 
Change was made to refine study 
design and aid with study logistics. 
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• 
Week 36 and 52 now have a 
window of -3 to +7 days 
The day of the Week 52 visit was 
corrected from 366 to 365. 
Section 7.3.4 and Section 
7.3.7 
Change was made to correct an error. 
Clarifications were made regarding the 
baseline WOMAC and Patient Global 
Assessment questionnaires. “Screening 
Visit 2 + 5 days” was clarified to “5 days 
after Screening Visit 2.” 
Section 7.3.8 
Change was made to avoid confusion 
related to the timing of the baseline 
questionnaires.  
“Biomarker assessments” was added to 
the Specification of Safety Parameters. 
Section 8.1 
Change was made for completeness. 
An additional analysis set was added to 
Section 10.3.  
• 
Modified Full Analysis Set 
(mFAS): FAS subjects who 
received injections into the 
target knee both on Day 1 and at 
Week 24. 
• 
(PPAS was revised to refer to 
mFAS instead of FAS.) 
Section 10.3 
Change was made to refine study 
design. 
The following edits were made: “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 prepare and perform the 
injection of study medication and/or 
placebo.” 
Section 10.6.1 
Change was made for accuracy. There 
is no study medication dilution in this 
study.  
The following was added in Section 13.4: 
“The Investigator or designee will 
maintain a personal subject identification 
list…” 
Section 13.4 
Change was made for accuracy. This 
may be performed by the Investigator 
or his/her designee.  
Minor grammatical edits were made. 
Throughout 
Changes were made for correctness. 
Appendix 3 was added to outline 
amendment revisions.  
Appendix 2 
Change was made to reflect protocol 
amendment.  
 
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Signature Page for VV-TMF-145687 v1.0
Signature Page for VV-TMF-145687 v1.0
Reason for signing: Approved
Name: Ismail Simsek
Role: Medical Director
Date of signature: 21-Aug-2020 21:48:38 GMT+0000
Reason for signing: Approved
Name: Christopher Swearingen
Role: Vice President, Clinical Outcomes and
Analytics
Date of signature: 24-Aug-2020 15:17:20 GMT+0000
Reason for signing: Approved
Name: Mark  Fineman
Role: Vice President, Clinical Development
Date of signature: 24-Aug-2020 15:44:23 GMT+0000
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