A Phase 2, 52 Week, Single Center, Open-Label Study Utilizing Imaging Techniques and Evaluating the Safety and Efficacy of SM04690 Injectable Suspension for the Treatment of Moderately to Severely Symptomatic Knee Osteoarthritis
Phase: PHASE2
Conditions: Knee Osteoarthritis
Sponsor: Biosplice Therapeutics, Inc.

 
A Phase 2, 52 Week, Single Center, Open-Label Study 
Utilizing Imaging Techniques and Evaluating the Safety and 
Efficacy of SM04690 Injectable Suspension for the 
Treatment of Moderately to Severely Symptomatic Knee 
Osteoarthritis 
 
Study Number: SM04690-OA-08 (NCT03706521) 
IND Sponsor: Samumed, LLC 
Investigational Product: SM04690 Injectable Suspension 
Version Number:  Amendment 02 Version 00 
Date: 26 September 2018 
 
 
Original Protocol Date: 31 August 2017 
Amendment 01 Version 00: 14 December 2017 
 
 
 
 
 
 
 
 
 
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. 
 
 

ii 
 
SPONSOR SIGNATURE PAGE 
 
A Phase 2, 52 Week, Single Center, Open-Label Study Utilizing Imaging Techniques and 
Evaluating the Safety and Efficacy of SM04690 Injectable Suspension for the Treatment of 
Moderately to Severely Symptomatic Knee Osteoarthritis 
 
Protocol Number: 
SM04690-OA-08 AM02V00 
Date:  
 
26 September 2018 
Name & Title 
Signature 
 
Date 
 
Yusuf Yazici, MD 
Chief Medical Officer  
Document has been electronically signed. Please see the 
final page of the viewable rendition for electronic 
signature(s). 
 
Ismail Simsek, MD 
Associate Medical Director 
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final page of the viewable rendition for electronic 
signature(s). 
 
 
Anita DiFrancesco 
Vice President, Clinical 
Development 
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final page of the viewable rendition for electronic 
signature(s). 
 
 
Christopher Swearingen, PhD 
Vice President, Clinical 
Outcomes and Analytics 
Document has been electronically signed. Please see the 
final page of the viewable rendition for electronic 
signature(s). 
 
 
Hutch Humphreys 
Director, Regulatory Affairs 
Document has been electronically signed. Please see the 
final page of the viewable rendition for electronic 
signature(s). 
 
 
 
Samumed commits to satisfying the requirements of the ICH-GCP Guidelines regarding the 
responsibilities of the Sponsor, the US Code of Federal Regulations 21 CFR Parts 50, 54, 56, 312, and 
314, and Good Clinical Practice Guidelines, as applicable. 
 

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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ................................................................................................ II 
TABLE OF CONTENTS ............................................................................................................. 1 
LIST OF ABBREVIATIONS ...................................................................................................... 6 
STATEMENT OF COMPLIANCE ............................................................................................ 9 
PROTOCOL SUMMARY ......................................................................................................... 10 
SCHEMATIC OF STUDY DESIGN ........................................................................................ 17 
1. 
KEY ROLES ....................................................................................................................... 18 
2. 
INTRODUCTION: BACKGROUND INFORMATION & SCIENTIFIC 
RATIONALE .............................................................................................................................. 18 
2.1 
BACKGROUND INFORMATION ........................................................................................ 18 
2.2 
RATIONALE .................................................................................................................... 19 
2.3 
POTENTIAL RISKS AND BENEFITS................................................................................... 19 
2.3.1 Known Potential Risks .............................................................................................. 19 
STUDY MEDICATION SM04690 ................................................................................................. 19 
RISKS OF INJECTION ................................................................................................................... 20 
RISKS OF TOPICAL ANESTHETICS ............................................................................................... 20 
BLOOD SAMPLING...................................................................................................................... 20 
KNEE RADIOGRAPH ................................................................................................................... 20 
MAGNETIC RESONANCE IMAGING (MRI) SCANS ....................................................................... 20 
2.3.2 Known Potential Benefits ......................................................................................... 20 
3. 
OBJECTIVES AND PURPOSE ........................................................................................ 21 
4. 
STUDY DESIGN AND ENDPOINTS ............................................................................... 21 
4.1 
DESCRIPTION OF THE STUDY DESIGN ............................................................................. 21 
SUBJECT RE-SCREENING ............................................................................................................ 22 
4.2 
STUDY ENDPOINTS ......................................................................................................... 22 
4.2.1 Primary Endpoints .................................................................................................... 22 
4.2.2 Secondary Endpoints ................................................................................................ 22 
5. 
STUDY ENROLLMENT AND WITHDRAWAL ........................................................... 23 
5.1 
PARTICIPANT INCLUSION CRITERIA ............................................................................... 23 
5.2 
PARTICIPANT EXCLUSION CRITERIA .............................................................................. 24 
5.3 
LIFESTYLE GUIDELINES ................................................................................................. 26 
5.3.1 Contraception ............................................................................................................ 26 
Women of Child Bearing Potential (WOCBP) ..................................................................... 26 
Men of Child Bearing Potential (MOCBP) .......................................................................... 27 

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5.4 
STRATEGIES FOR RECRUITMENT AND RETENTION ......................................................... 27 
5.5 
PARTICIPANT WITHDRAWAL OR TERMINATION ............................................................. 27 
5.5.1 Reasons for Withdrawal or Termination................................................................... 27 
5.5.2 Handling of Participant Withdrawals or Termination .............................................. 28 
5.6 
PREMATURE TERMINATION OR SUSPENSION OF STUDY ................................................. 28 
6. 
STUDY AGENT .................................................................................................................. 28 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION ............................................................. 28 
6.1.1 Acquisition ................................................................................................................ 28 
6.1.2 Formulation, Appearance, Packaging, and Labeling ................................................ 28 
6.1.3 Product Storage and Stability.................................................................................... 29 
6.1.4 Preparation ................................................................................................................ 29 
6.1.5 Dosing and Administration ....................................................................................... 29 
6.1.6 Route of Administration ........................................................................................... 29 
6.1.7 Starting Dose and Dose Escalation Schedule ........................................................... 30 
6.1.8 Dose Adjustments/Modifications/Delays ................................................................. 30 
6.1.9 Duration of Therapy .................................................................................................. 30 
6.1.10 Tracking of Dose....................................................................................................... 30 
6.1.11 Device Specific Considerations ................................................................................ 30 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES ............................................................ 30 
7. 
STUDY PROCEDURES AND SCHEDULE .................................................................... 31 
7.1 
STUDY PROCEDURES/EVALUATIONS .............................................................................. 31 
7.1.1 Study Specific Procedures ........................................................................................ 31 
COLLECTION OF ADVERSE EVENTS DATA .................................................................................. 31 
MEDICAL HISTORY .................................................................................................................... 31 
PHYSICAL EXAMINATION ........................................................................................................... 32 
KNEE EXAMINATION .................................................................................................................. 32 
VITAL SIGNS .............................................................................................................................. 32 
HEIGHT AND WEIGHT ................................................................................................................ 32 
RADIOGRAPH OF THE KNEE JOINTS ............................................................................................ 32 
MAGNETIC RESONANCE IMAGING (MRI) OF THE KNEE JOINTS ................................................. 33 
WIDESPREAD PAIN INDEX AND SYMPTOM SEVERITY (WPI&SS) FORM .................................... 33 
PAIN NUMERIC RATING SCALE (NRS) ....................................................................................... 33 
WESTERN ONTARIO AND MCMASTER UNIVERSITIES ARTHRITIS INDEX (WOMAC) ................ 34 
PATIENT GLOBAL ASSESSMENT OF DISEASE ACTIVITY ............................................................. 34 
7.1.2 Standard of Care Study Procedures .......................................................................... 34 
7.2 
LABORATORY PROCEDURES/EVALUATIONS ................................................................... 34 
7.2.1 Clinical Laboratory Evaluations ............................................................................... 34 
7.2.2 Other Assays or Procedures ...................................................................................... 35 
PREGNANCY TEST ...................................................................................................................... 35 
DRUG TEST ................................................................................................................................ 35 
7.2.3 Specimen Preparation, Handling, and Storage ......................................................... 35 

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7.2.4 Specimen Shipment .................................................................................................. 36 
7.3 
STUDY SCHEDULE .......................................................................................................... 36 
7.3.1 Screening................................................................................................................... 36 
SCREENING VISIT ....................................................................................................................... 36 
7.3.2 Enrollment................................................................................................................. 37 
DAY 1 37 
7.3.3 Follow-up .................................................................................................................. 37 
WEEK 4 ...................................................................................................................................... 37 
WEEK 13 .................................................................................................................................... 37 
WEEK 26 .................................................................................................................................... 38 
WEEK 39 .................................................................................................................................... 38 
7.3.4 Final Study Visit ....................................................................................................... 39 
WEEK 52 END OF STUDY (EOS) ................................................................................................ 39 
7.3.5 Early Termination Visit ............................................................................................ 39 
7.3.6 Schedule of Events Table .......................................................................................... 40 
7.4 
JUSTIFICATION FOR SENSITIVE PROCEDURES ................................................................. 42 
7.5 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES ................................. 42 
7.5.1 Precautionary Medications, Treatments, and Procedures ......................................... 42 
7.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES ...................................... 42 
7.7 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES ................................. 43 
7.8 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES ............................................. 43 
7.9 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE ....................................... 43 
8. 
ASSESSMENT OF SAFETY ............................................................................................. 43 
8.1 
SPECIFICATION OF SAFETY PARAMETERS ...................................................................... 43 
8.1.1 Definition of Adverse Events (AEs) ......................................................................... 43 
8.1.2 Definition of Serious Adverse Events (SAE) ........................................................... 44 
8.1.3 Definition of Unanticipated Problems (UP) ............................................................. 44 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT ...................................................................... 44 
8.2.1 Severity of Event....................................................................................................... 44 
8.2.2 Relationship to Study Agent ..................................................................................... 45 
8.2.3 Expectedness ............................................................................................................. 45 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP ................. 45 
8.4 
REPORTING PROCEDURES .............................................................................................. 46 
8.4.1 Adverse Event Reporting .......................................................................................... 46 
8.4.2 Serious Adverse Event Reporting ............................................................................. 46 
8.4.3 Unanticipated Problem Reporting............................................................................. 46 
8.4.4 Events of Special Interest.......................................................................................... 47 
8.4.5 Reporting of Pregnancy ............................................................................................ 47 

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8.5 
STUDY HALTING RULES ................................................................................................. 47 
8.6 
SAFETY OVERSIGHT ....................................................................................................... 47 
9. 
CLINICAL MONITORING .............................................................................................. 47 
10. 
STATISTICAL CONSIDERATIONS .......................................................................... 48 
10.1 
STATISTICAL AND ANALYTICAL PLANS ......................................................................... 48 
10.2 
STATISTICAL HYPOTHESES ............................................................................................ 48 
10.3 
ANALYSIS DATASETS ..................................................................................................... 48 
10.4 
DESCRIPTION OF STATISTICAL METHODS ...................................................................... 48 
10.4.1 General Approach ..................................................................................................... 48 
10.4.2 Analysis of the Primary Endpoint(s)......................................................................... 48 
10.4.3 Analysis of the Secondary Endpoint(s)..................................................................... 49 
10.4.4 Safety Analyses ......................................................................................................... 49 
10.4.5 Baseline Descriptive Statistics .................................................................................. 49 
10.4.6 Planned Interim Analyses ......................................................................................... 49 
10.4.6.1 Safety Review .............................................................................................. 50 
10.4.6.2 Efficacy Review ........................................................................................... 50 
10.4.7 Exploratory Analyses ................................................................................................ 50 
10.4.8 Additional Sub-Group Analyses ............................................................................... 50 
10.5 
SAMPLE SIZE .................................................................................................................. 50 
10.6 
MEASURES TO MINIMIZE BIAS ....................................................................................... 50 
10.6.1 Blinding Procedures .................................................................................................. 50 
10.6.2 Evaluation of Success of Blinding ............................................................................ 50 
10.6.3 Breaking the Study Blind/Participant Code .............................................................. 50 
11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .... 50 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL ............................................ 51 
13. 
ETHICS/PROTECTION OF HUMAN SUBJECTS ................................................... 51 
13.1 
ETHICAL STANDARD ...................................................................................................... 51 
13.2 
INSTITUTIONAL REVIEW BOARD .................................................................................... 51 
13.3 
INFORMED CONSENT PROCESS ....................................................................................... 52 
13.3.1 Consent/Assent and Other Informational Documents Provided to Participants ....... 52 
13.3.2 Consent Procedures and Documentation .................................................................. 52 
13.4 
PARTICIPANT AND DATA CONFIDENTIALITY .................................................................. 52 
13.4.1 Research Use of Stored Human Samples, Specimens, or Data ................................ 53 

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13.5 
FUTURE USE OF STORED SPECIMENS ............................................................................. 53 
14. 
DATA HANDLING AND RECORD KEEPING ......................................................... 53 
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES ........................................... 53 
14.2 
STUDY RECORDS RETENTION ........................................................................................ 53 
14.3 
PROTOCOL DEVIATIONS ................................................................................................. 54 
14.4 
PUBLICATION AND DATA SHARING POLICY ................................................................... 54 
15. 
STUDY ADMINISTRATION ....................................................................................... 55 
15.1 
STUDY LEADERSHIP ....................................................................................................... 55 
16. 
LITERATURE REFERENCES .................................................................................... 56 
APPENDIX .................................................................................................................................. 57 
APPENDIX 1. 
GUIDANCE FOR INDUSTRY: TOXICITY SCALE FOR HEALTHY 
ADULT AND ADOLESCENT VOLUNTEERS ENROLLED IN PREVENTIVE 
VACCINE TRIALS .................................................................................................................... 57 
APPENDIX 2. 
PROHIBITED CONCOMITANT MEDICATIONS AND 
PROCEDURES (SUPPLEMENT) ............................................................................................ 60 
APPENDIX 3. 
AMENDMENT ........................................................................................... 62 
AMENDMENT 02 VERSION 00 SUMMARY OF CHANGES............................................. 62 
AMENDMENT 01 VERSION 00 SUMMARY OF CHANGES............................................. 66 
 
 
 

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LIST OF ABBREVIATIONS 
 
Abbreviation 
Term 
3D-SPGR 
Three-dimensional spoiled gradient recalled 
ACR 
American College of Rheumatology 
AE  
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
CFR 
Code of Federal Regulations 
CRF 
Case report form 
DLT 
Dose-limiting toxicity 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EOS 
End of study 
ETF 
Early termination 
FAS 
Full Analysis Set 
FDA 
(US) Food and Drug Administration 
GAG 
Glycosaminoglycan 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
IA 
Intra-articular 
IB 
Investigator Brochure 

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Abbreviation 
Term 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization  
IND 
Investigational new drug 
IP 
Investigational product 
IQRMP 
Integrated Quality and Risk Management Plan 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
JSW 
Joint space width 
KL 
Kellgren-Lawrence 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mJSW 
Medial joint space width 
mL 
Milliliter 
mm 
Millimeter 
MOCBP 
Men of childbearing potential 
MRI 
Magnetic resonance imaging 
mSv 
Millisievert 
NCS 
Not clinically significant 
NRS 
Numeric rating scale 
NSAID 
Nonsteroidal anti-inflammatory drug 
OA 
Osteoarthritis 
PA 
Posterior-anterior 
PPAS 
Per-protocol Analysis Set 
PRO 
Patient reported outcome  
PRP 
Platelet-rich plasma 
RBC 
Red blood cell 
SAE 
Serious adverse event 

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Abbreviation 
Term 
SAP 
Statistical analysis plan 
SAS 
Safety Analysis Set 
SOP 
Standard operating procedure 
SS 
Symptom Severity 
SSQ 
Symptom Severity Question  
ULN 
Upper limit of the normal range 
UP 
Unanticipated problem 
US 
United States 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
WOMAC 
Western Ontario and McMaster Universities Arthritis Index 
WORMS 
Whole Organ MRI Scoring 
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, Single Center, Open-Label Study Utilizing Imaging 
Techniques and Evaluating the Safety and Efficacy of SM04690 
Injectable Suspension for the Treatment of Moderately to Severely 
Symptomatic Knee Osteoarthritis 
Protocol Number 
SM04690-OA-08 
Protocol Date 
26 September 2018 
Protocol Version 
AM02V00 
I have read and understand the protocol and agree to implement the study in accordance with the 
procedures set forth in the protocol and in accordance with the Sponsor's guidelines, all 
applicable government regulations, and the International Conference on Harmonization Good 
Clinical Practice Guidelines E6 (ICH-GCP). 
I will obtain Institutional Review Board/Ethics Committee (IRB/EC) approval of the protocol 
and Informed Consent Form prior to enrollment of subjects in the study. I understand that any 
modifications to the protocol made during the course of the study must first be approved by the 
IRB/EC prior to implementation except when such modification is made to remove an immediate 
hazard to the subject. 
I will ensure that a fully executed IRB/EC-approved Informed Consent Form is obtained from 
each subject prior to initiation of any study procedures.  
I will allow the Sponsor, Samumed, LLC and its agents, as well as the United States (US) Food 
and Drug Administration (FDA) and other regulatory agencies, to inspect study facilities and 
pertinent records at reasonable times and in a reasonable manner, ensuring subject 
confidentiality. If I am notified that this study is to be inspected by a regulatory agency, I will 
notify the Sponsor as soon as possible thereafter (no later than 48 hours). 
This protocol contains information that is proprietary to Samumed, LLC. The information 
contained herein is provided for the purpose of conducting a clinical trial for Samumed, LLC. 
The contents of this protocol may only be disclosed to study personnel under my supervision and 
to my IRB/EC. The contents of this protocol may not be disclosed to any other parties (unless 
such disclosure is required by government regulations or laws) without the prior written approval 
of Samumed, LLC. 
 
__________________________________________ 
_______________________ 
Investigator’s Signature 
 
 
 
 
Date 
 
__________________________________________ 
 
Investigator’s Printed Name 
 
 

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PROTOCOL SUMMARY 
Title: 
A Phase 2, 52 Week, Single Center, Open-Label Study Utilizing Imaging 
Techniques and Evaluating the Safety and Efficacy of SM04690 Injectable 
Suspension for the Treatment of Moderately to Severely Symptomatic 
Knee Osteoarthritis 
Objectives: 
 
Primary: 
Evaluate the efficacy of SM04690 Injectable Suspension for the treatment 
of knee osteoarthritis (OA) via magnetic resonance imaging (MRI) 
Secondary: 
1. Evaluate the efficacy of SM04690 Injectable Suspension for the 
treatment of knee OA as assessed by patient reported outcomes 
(PROs)  
2. Evaluate the efficacy of SM04690 Injectable Suspension for the 
treatment of knee OA via radiographs  
3. Evaluate the safety and tolerability of SM04690 Injectable 
Suspension  
Endpoints: 
Primary: 
1. Change from baseline in cartilage thickness in the target knee as 
measured by three-dimensional spoiled gradient recalled (3D-
SPGR) pulse sequence MRI at Week 26 
2. Change from baseline in cartilage volume in the target knee as 
measured by 3D-SPGR pulse sequence MRI at Week 26 
3. Change from baseline in cartilage quality in the target knee 
determined by the increase or decrease in proteoglycan and 
glycosaminoglycan (GAG) content and hydration as measured by 
T1rho and T2 mapping pulse sequence MRI at Week 26 
Secondary: 
1. Change from baseline in cartilage thickness in the target knee as 
measured by 3D-SPGR pulse sequence MRI at Weeks 13 and 52 
2. Change from baseline in cartilage volume in the target knee as 
measured by 3D-SPGR pulse sequence MRI at Weeks 13 and 52 
3. Change from baseline in cartilage quality in the target knee by the 
increase or decrease in proteoglycan and GAG content and 
hydration as measured by T1rho and T2 mapping pulse sequence 
MRI at Weeks 13 and 52 
4. Change from baseline in total Whole Organ MRI Scoring 
(WORMS) in the target knee at Weeks 13, 26, and 52 
5. Change from baseline OA pain in the target knee as assessed by 
Western Ontario and McMaster Universities Arthritis Index 
(WOMAC) pain subscore at Weeks 13, 26, and 52 

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6. Change from baseline OA function in the target knee as assessed 
by WOMAC physical function subscore at Weeks 13, 26, and 52 
7. Change from baseline symptoms of OA in the target knee as 
assessed by WOMAC total score at Weeks 13, 26, and 52 
8. Change from baseline OA disease activity as assessed by Patient 
Global Assessment at Weeks 13, 26, and 52 
9. Change from baseline in medial joint space width (mJSW) as 
documented by radiograph of the target knee at Weeks 26 and 52 
10. Change from baseline in cartilage thickness in the non-target knee 
as measured by 3D-SPGR pulse sequence MRI at Weeks 13, 26, 
and 52 
11. Change from baseline in cartilage volume in the non-target knee as 
measured by 3D-SPGR pulse sequence MRI at Weeks 13, 26, and 
52 
12. Change from baseline in cartilage quality in the non-target knee 
determined by the increase or decrease in proteoglycan and GAG 
content and hydration as measured by T1rho and T2 mapping pulse 
sequence MRI at Weeks 13, 26, and 52 
13. Change from baseline in total WORMS in the non-target knee at 
Weeks 13, 26, and 52 
14. Change from baseline in mJSW as documented by radiograph of 
the non-target knee at Weeks 26 and 52 
15. Incidence and severity of adverse events (AEs) throughout the trial 
 
Methodology: 
This study will be a single center, open-label study of SM04690 injected 
into the target knee joint of moderately to severely symptomatic 
osteoarthritis subjects. 
Fifteen subjects will be enrolled and receive a dose of 0.07 milligram (mg) 
SM04690 per 2 milliliter (mL) injection. Subjects will participate in a 
screening period of a minimum of 7 days and up to 14 days, and a 52-week 
follow-up period. Clinic visits will be scheduled at the Screening Visit, 
Day 1, and Weeks 4, 13, 26, 39, and 52 [End of Study (EOS) / Early 
Termination (ET)].  
Inclusion/ 
Exclusion 
Criteria: 
Criteria for Inclusion: 
1. Males and females between 40 and 80 years of age, inclusive, in 
general good health 
2. Ambulatory (single assistive devices such as canes allowed if 
needed less than 50% of the time, subjects requiring a walker are 
excluded) 
3. Diagnosis of femorotibial OA in the target knee by standard 
American College of Rheumatology (ACR) criteria at the 
Screening Visit (clinical AND radiographic criteria); OA of the 
knee is not to be secondary to any rheumatologic conditions (e.g., 

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rheumatoid arthritis) 
4. Pain compatible with OA of the knee(s) for at least 26 weeks prior 
to the Screening Visit 
5. Primary source of pain throughout the body is due to OA in the 
target knee  
6. Daily OA knee pain diary average Numeric Rating Scale (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. Baseline mJSW by radiograph between 2 and 4 mm, inclusive, in 
the target knee at the Screening Visit as assessed by independent 
central readers  
11. Total WOMAC score of 96-192 (out of 240) for the target knee at 
Day 1 regardless of if the subject is on symptomatic oral treatment  
12. Negative drug test for amphetamine, methamphetamine, 
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 the Screening Visit  
13. Subjects with depression or anxiety must be clinically stable for 12 
weeks prior to the Screening Visit and, if on treatment for 
depression or anxiety, be on 12 weeks of stable therapy  
14. Full understanding of the requirements of the study and willingness 
to comply with all study visits and assessments 
15. Subjects must have read and understood the informed consent 
form, and must have signed it prior to any study-related procedure 
being performed 
16. Subject’s Screening Visit must occur while enrollment into the 
study is open 
Criteria for Exclusion: 
1. Women who are pregnant, lactating, or have a positive pregnancy 
test result at the Screening Visit 
2. Women of childbearing potential who are sexually active, and who 
are not willing to use an acceptable method of birth control (as per 
Section 5.3.1 of the protocol) during the study period 

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3. Men of childbearing potential who are sexually active and have a 
partner who is capable of becoming pregnant, neither of whom are 
agreeable to using an acceptable method of birth control (as per 
Section 5.3.1 of the protocol) during the study period 
4. Body mass index (BMI) > 40 
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 the 
Screening Visit according to the Kellgren-Lawrence (KL) grading 
of knee OA as assessed by independent central readers 
8. Previous treatment with SM04690 
9. Subjects who have previously failed screening on this protocol and 
fail to meet re-screening criteria  
10. Any surgery (e.g., arthroscopy) in either knee within 26 weeks 
prior to the Screening Visit 
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 the Screening Visit 
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 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 

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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. Any diagnosed psychiatric condition that includes, but is not 
limited to, a history of mania, bipolar disorder, psychotic disorder, 
schizophrenia, schizoaffective disorder, major depressive disorder, 
or generalized anxiety disorder 
19. Participation in a clinical research trial that included the receipt of 
an investigational product or any experimental therapeutic 
procedure, or an observational research trial related to osteoarthritis 
within 8 weeks prior to to the Screening Visit, or planned 
participation in any such trial; the last date of participation in the 
trial, not the last date of receipt of investigational product, must be 
at least 8 weeks prior to the Screening Visit 
20. 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 the Screening Visit; treatment of 
the target knee with intra-articular glucocorticoids greater than 12 
weeks prior to the Screening Visit is allowed 
21. Treatment with systemic glucocorticoids greater than 10 mg 
prednisone or the equivalent per day within 4 weeks prior to the 
Screening Visit 
22. Effusion of the target knee clinically requiring aspiration within 12 
weeks prior to the Screening Visit 
23. Use of electrotherapy, acupuncture, and/or chiropractic treatments 
for knee OA within 4 weeks prior to the Screening Visit (refer to 
Appendix 2) 
24. Any known active infections, including urinary tract infection, 
upper respiratory tract infection, sinusitis, suspicion of intra-
articular infection, hepatitis B or hepatitis C infection, and/or 
infections that may compromise the immune system such as human 
immunodeficiency virus (HIV) at Day 1 
25. Current use, or use within 12 weeks prior to the Screening Visit, of 
centrally acting analgesics (refer to Appendix 2) w 
26. Current use, or use within 12 weeks prior to the Screening Visit, of 
anticonvulsants (refer to Appendix 2)   
27. Subjects requiring the usage of opioids >1x per week within 12 
weeks prior to the Screening Visit 
28. Topical local anesthetic agents (gels, creams, or patches such as the 

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Lidoderm patch) used for the treatment of knee OA within 7 days 
of the Screening Visit  
29. Any chronic condition that has not been well controlled or subjects 
with a chronic condition who have not maintained a stable 
therapeutic regimen of a prescription therapy in the opinion of the 
investigator. In addition, subjects with an HbA1c >9 at the 
Screening Visit will be excluded. 
30. If on nonsteroidal anti-inflammatory drugs (NSAIDs) for the 
treatment of OA pain, subjects who have not maintained a stable 
regimen in the opinion of the Investigator at the Screening Visit 
31. Any contraindications for performing MRI  
32. Subjects who have a current or pending disability claim, workers’ 
compensation, or litigation(s) that may compromise response to 
treatment  
33. Subjects who are immediate family members (spouse, parent, child, 
or sibling; biological or legally adopted) of personnel directly 
affiliated with the study at any investigative site, or are directly 
affiliated with the study at any investigative site  
34. Subjects employed by Samumed, LLC, or any of its affiliates or 
development partners (that is, an employee, temporary contract 
worker, or designee) responsible for the conduct of the study 
Population: 
Approximately 15 subjects with moderately to severely symptomatic knee 
OA 
Phase: 
2 
Number of Sites 
enrolling 
participants: 
This study will be conducted at 1 investigational center 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 18 months 
Estimated date first subject consented: 01 October 2018 
Estimated date last subject completed: 01 April 2020 
Participant 
Duration: 
Approximately 52 weeks following a screening period of 7 to 14 days  
 
 

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Criteria for 
evaluation: 
Efficacy: 
Efficacy will be assessed by: 
• Cartilage volume and thickness as measured by MRI (3D-SPGR 
pulse sequences) 
• Cartilage quality as measured by MRI (T1rho and T2 mapping 
pulse sequences) 
• Total WORMS 
• WOMAC total score as well as WOMAC pain and physical 
function subscores for the target knee 
• Patient Global Assessment  
• Medial JSW as evaluated by radiograph 
 
Safety: 
The overall safety and tolerability of SM04690 will be assessed by 
the incidence, seriousness, severity, and relationship of AEs and 
clinically significant changes in clinical laboratory measures and vital 
signs.  
 
 
 
 

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SCHEMATIC OF STUDY DESIGN 
 
 
 

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1. 
KEY ROLES 
Medical monitor 
Naina Rastalsky, MD - Study Physician  
Samumed, LLC 
9381 Judicial Dr. 
San Diego, CA 92121 
(858) 371-3874 
naina@samumed.com 
Regulatory specialist 
Hutch Humphreys – Director, Regulatory Affairs 
Samumed, LLC 
9381 Judicial Dr. 
San Diego, CA 92121 
(858) 926-2960 
hutch@samumed.com 
Biostatistician 
Christopher Swearingen, PhD – Vice President, Clinical Outcomes 
and Analytics  
Samumed, LLC 
9381 Judicial Dr. 
San Diego, CA 92121 
(858) 926-2952 
chris@samumed.com 
Data manager 
Todd Smith, PMP – Vice President, Clinical Data Management 
Samumed, LLC 
9381 Judicial Dr. 
San Diego, CA 92121 
(858) 926-2924 
todd@samumed.com 
Central radiology reader 
Medical Metrics, Inc. (MMI) 
2121 Sage Road, Suite 300 
Houston, Texas 77056 
(713) 850-7500 
Central laboratory 
ACM Global Central Laboratory 
160 Elmgrove Park 
Rochester, NY 14624 
(800) 525-5227 
2. 
INTRODUCTION: BACKGROUND INFORMATION & SCIENTIFIC 
RATIONALE  
2.1 
BACKGROUND INFORMATION  
Osteoarthritis (OA) is the most common form of arthritis and the major cause of activity 
limitation and physical disability in older people. Today, 35 million people (13% of the US 
population) are 65 and older, and more than half of them have radiological evidence of OA in at 
least 1 joint. By 2030, 20% of Americans (about 70 million people) will have passed their 65th 
birthday and will be at risk for OA (Nevitt, Felson et al. 2006). 
Therapies available to treat OA are limited. Most current treatments are designed only to relieve 
pain and reduce or prevent the disability caused by bone and cartilage degeneration. Drug 
therapies target the symptoms but not the cause of this disease; no treatment inhibits or reverses 

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the degenerative structural changes that are responsible for its progression (Nevitt, Felson et al. 
2006). 
Samumed, LLC (Samumed) is developing SM04690 for the treatment of OA. SM04690 is a 
small molecule inhibitor of the Wnt pathway.  
SM04690 has been tested in a number of appropriate nonclinical and clinical studies. The results 
of those studies are included in the Investigator Brochure (IB). 
2.2 
RATIONALE  
Osteoarthritis is the most common form of arthritis and chronic joint disorder in humans 
(Dougados & 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 & Hochberg 
2011). OA is a leading cause of physical disability in the US (Lawrence, Felson et al. 2008).  
The Wnt pathway plays a central role in the initiation and progression of OA pathology and is 
crucial in normal joint metabolism (Hochberg, Altman et al. 2012). Wnt is a major regulator of 
joint development and is involved in the formation of bone, cartilage, and synovium. The 
transcription of Wnt target genes causes an increase in catabolic processes during the 
development of OA, and increased Wnt signaling may contribute to cartilage loss (Gelse, Ekici 
et al. 2012). Polymorphisms in genes involved in Wnt signaling are associated with an increased 
susceptibility to OA development (Wu, Huang et al. 2012). Established research suggests that 
modulation of Wnt signaling is an attractive target for treatment of OA. 
In order to address the need for effective pharmaceutical agents to treat OA, Samumed has used 
structure-based drug design to synthesize a small molecule inhibitor of the Wnt pathway, 
SM04690, as a potential OA therapeutic to be administered in the form of a local injection in the 
affected joint. 
This phase 2 study, SM04690-OA-08, is a single center, open-label study of SM04690 Injectable 
Suspension injected into the target knee joint of moderately to severely symptomatic OA 
subjects at a single dose of 0.07 mg SM04690 per 2 mL injection. A consistent change in joint 
space width as measured by radiograph was observed in this dose group in both a phase 1 study 
(SM04690-OA-01) and a phase 2 study (SM04690-OA-02). Therefore, the 0.07 mg SM04690 
dose was selected for further investigation in this study. 
2.3 
POTENTIAL RISKS AND BENEFITS  
2.3.1 
KNOWN POTENTIAL RISKS  
Study Medication SM04690 
The study drug SM04690 and procedures have risks and discomforts. The study drug SM04690 
modulates the Wnt pathway. Refer to the IB for the known potential risks associated with 
SM04690.  

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Risks of Injection 
Risks associated with knee joint injection include bleeding, bruising, infection, pain at the 
injection site, swelling of the knee, and/or injury to knee joint. 
Risks of Topical Anesthetics 
Reactions to the topical anesthetic drug that may be applied to the subjects’ skin are rare and 
may consist of cutaneous lesions (patches of skin that contrast with surrounding skin due to 
differences in texture, thickness, and color), or urticaria (red, raised itchy bumps). In addition to 
the local reactions, systemic reactions, although much rarer than the local ones, can be seen and 
include edema, bradycardia, dizziness, drowsiness, paresthesia, nausea, vomiting, or 
anaphylactoid reactions (generalized itching and hives, swelling, wheezing and difficulty 
breathing, fainting, and/or other allergy symptoms). 
Blood Sampling 
There is some risk of pain or local bruising and infection at the site where blood is drawn for 
laboratory tests. There is also a small risk of a fainting episode, which can occur as a reaction to 
donating blood. 
Knee Radiograph 
This study involves radiation exposure from a total of 3 radiographs of the subjects’ knees on 3 
different days, each approximately 6 months apart. As part of everyday living, everyone is 
exposed to a small amount of background radiation that comes from soil, rocks, outer space, and 
within the body itself. The radiation dose for all knee X-rays that the subject will receive in this 
study is expected to be approximately 0.015 millisievert (mSv) and is approximately equivalent 
to 1 day’s dose from background radiation. The risk from this dose is small. This radiation 
exposure may not be necessary for the subjects’ medical care, but it is necessary to obtain the 
research information desired. 
Magnetic Resonance Imaging (MRI) Scans 
MRI contains no radiation. There have been no reported side effects from the magnetic fields and 
radio waves. The strong magnetic fields created during an MRI can cause heart pacemakers and 
other implants to not work as well. It can also cause a piece of metal inside the body to move or 
shift. For safety reasons, subjects are not to bring anything that contains metal into the scanner 
room. Receiving an MRI scan requires being positioned in a tunnel-shaped chamber. There is a 
risk of experiencing symptoms of claustrophobia (for example, a panic attack), due to the 
narrowness of the chamber. This procedure may not be necessary for the subjects’ medical care, 
but it is necessary to obtain the research information desired. 
2.3.2 
KNOWN POTENTIAL BENEFITS  
Taking part in this study may or may not provide any benefit to the subject. Information from 
this study may help doctors learn more about treatments for OA and this information may help 
future subjects, even if it may not help the subjects in this study. 
 
 

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3. 
OBJECTIVES AND PURPOSE 
The purpose of this study is to evaluate the safety and efficacy of SM04690 injected in the target 
knee joint of moderately to severely symptomatic OA subjects. 
Primary objective: 
Evaluate the efficacy of SM04690 Injectable Suspension for the treatment of knee osteoarthritis 
(OA) via magnetic resonance imaging (MRI) 
Secondary objectives: 
1. Evaluate the efficacy of SM04690 Injectable Suspension for the treatment of knee OA as 
assessed by patient reported outcomes (PROs) 
2. Evaluate the efficacy of SM04690 Injectable Suspension for the treatment of knee OA 
via radiographs 
3. Evaluate the safety and tolerability of SM04690 Injectable Suspension  
4. 
STUDY DESIGN AND ENDPOINTS 
4.1 
DESCRIPTION OF THE STUDY DESIGN 
This study is a single center, open-label study of SM04690 injected into the target knee joint of 
moderately to severely symptomatic OA subjects. 
Approximately 15 subjects will be enrolled and receive a dose of 0.07 mg SM04690 per 2 mL 
injection. Subjects will participate in a screening period of a minimum of 7 days and up to 14 
days and a 52-week follow-up period. Clinic visits will be scheduled at the Screening Visit, Day 
1, and Weeks 4, 13, 26, 39, and 52 (EOS)/ET. Specific timing of protocol procedures is 
described in the Schedule of Events Table (Section 7.3.6).  
This study will be conducted at 1 investigational center in the US.  
In this study, subjects will be required to complete a paper diary during the screening period to 
capture daily pain NRS (for target knee and non-target knee OA pain). 
A Widespread Pain Index and Symptom Severity (WPI&SS) assessment will be administered at 
Day 1. WOMAC and Patient Global Assessments will be performed at Day 1, and Weeks 4, 13, 
26, 39, and 52 (EOS)/ET.  
In addition, general medical evaluations including physical examination, knee examination, and 
recording of vital signs will be performed at the Screening Visit, Day 1, and Weeks 4 (excluding 
physical examination), 13, 26, 39, and 52 (EOS)/ET. Height will be measured at the Screening 
Visit and weight will be measured at the Screening Visit and Week 52 (EOS)/ET. Clinical 
laboratory evaluations will be performed at the Screening Visit and Weeks 4, 13, 26, 39, and 52 
(EOS)/ET. Radiographic imaging of the knees will be performed at the Screening Visit and 
Weeks 26, and 52 (EOS)/ET. MRI scans of the knees will be performed at the Screening Visit 
and Weeks 13, 26, and 52 (EOS)/ET.  
Recording of signs and symptoms of study medication intolerability and AE reporting will start 
following the injection of the study medication and continue until the subject completes Week 52 
(EOS)/ET. All AEs, whether volunteered, elicited, or noted during examination, will be recorded 
throughout the study. 

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Subject Re-Screening 
Subjects are allowed to be re-screened once for this protocol. 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 and MRI (if taken at 
previous screen), must be performed at re-screen; no results or data, except for the knee 
radiograph and MRI, may be used from the previous screen. Target knee selection may not be 
changed at re-screen.  
4.2 
STUDY ENDPOINTS 
4.2.1 
PRIMARY ENDPOINTS 
1. Change from baseline in cartilage thickness in the target knee as measured by three-
dimensional spoiled gradient recalled (3D-SPGR) pulse sequence MRI at Week 26 
2. Change from baseline in cartilage volume in the target knee as measured by 3D-SPGR 
pulse sequence MRI at Week 26 
3. Change from baseline in cartilage quality in the target knee determined by the increase or 
decrease in proteoglycan and glycosaminoglycan (GAG) content and hydration as 
measured by T1rho and T2 mapping pulse sequence MRI at Week 26 
4.2.2 
SECONDARY ENDPOINTS 
1. Change from baseline in cartilage thickness in the target knee as measured by 3D-SPGR 
pulse sequence MRI at Weeks 13 and 52 
2. Change from baseline in cartilage volume in the target knee as measured by 3D-SPGR 
pulse sequence MRI at Weeks 13 and 52 
3. Change from baseline in cartilage quality in the target knee by the increase or decrease in 
proteoglycan and GAG content and hydration as measured by T1rho and T2 mapping 
pulse sequence MRI at Weeks 13 and 52 
4. Change from baseline in total Whole Organ MRI Scoring (WORMS) in the target knee at 
Weeks 13, 26, and 52 
5. Change from baseline OA pain in the target knee as assessed by Western Ontario and 
McMaster Universities Arthritis Index (WOMAC) pain subscore at Weeks 13, 26, and 52 
6. Change from baseline OA function in the target knee as assessed by WOMAC physical 
function subscore at Weeks 13, 26, and 52 
7. Change from baseline symptoms of OA in the target knee as assessed by WOMAC total 
score at Weeks 13, 26, and 52 

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8. Change from baseline OA disease activity as assessed by Patient Global Assessment at 
Weeks 13, 26, and 52 
9. Change from baseline in medial joint space width (mJSW) as documented by radiograph 
of the target knee at Weeks 26 and 52 
10. Change from baseline in cartilage thickness in the non-target knee as measured by 3D-
SPGR pulse sequence MRI at Weeks 13, 26, and 52 
11. Change from baseline in cartilage volume in the non-target knee as measured by 3D-
SPGR pulse sequence MRI at Weeks 13, 26, and 52 
12. Change from baseline in cartilage quality in the non-target knee determined by the 
increase or decrease in proteoglycan and GAG content and hydration as measured by 
T1rho and T2 mapping pulse sequence MRI at Weeks 13, 26, and 52 
13. Change from baseline in total WORMS in the non-target knee at Weeks 13, 26, and 52 
14. Change from baseline in mJSW as documented by radiograph of the non-target knee at 
Weeks 26 and 52 
15. Incidence and severity of AEs throughout the trial 
5. 
STUDY ENROLLMENT AND WITHDRAWAL 
Eligibility of subjects will be determined by the following inclusion and exclusion criteria. 
Subjects should meet all the inclusion criteria and none of the exclusion criteria. 
5.1 
PARTICIPANT INCLUSION CRITERIA 
In order to be eligible for the study, subjects must fulfill all of the following criteria: 
1. Males and females between 40 and 80 years of age, inclusive, in general good health 
2. Ambulatory (single assistive devices such as canes allowed if needed less than 50% of 
the time, subjects requiring a walker are excluded) 
3. Diagnosis of femorotibial OA in the target knee by standard American College of 
Rheumatology (ACR) criteria at the Screening Visit (clinical AND radiographic criteria); 
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 the Screening Visit 
5. Primary source of pain throughout the body is due to OA in the target knee  
6. Daily OA knee pain diary average Numeric Rating Scale (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. Baseline mJSW by radiograph between 2 and 4 mm, inclusive, in the target knee at the 
Screening Visit as assessed by independent central readers  
11. Total WOMAC score of 96-192 (out of 240) for the target knee at Day 1 regardless of if 

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the subject is on symptomatic oral treatment  
12. Negative drug test for amphetamine, methamphetamine, 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 the Screening Visit  
13. Subjects with depression or anxiety must be clinically stable for 12 weeks prior to the 
Screening Visit and, if on treatment for depression or anxiety, be on 12 weeks of stable 
therapy  
14. Full understanding of the requirements of the study and willingness to comply with all 
study visits and assessments 
15. Subjects must have read and understood the informed consent form, and must have 
signed it prior to any study-related procedure being performed 
16. Subject’s Screening Visit must occur while enrollment into the study is open 
5.2 
PARTICIPANT EXCLUSION CRITERIA 
Any potential subject who meets one or more of the following criteria will not be included in this 
study: 
Criteria for Exclusion: 
1. Women who are pregnant, lactating, or have a positive pregnancy test result at the 
Screening Visit 
2. Women of childbearing potential who are sexually active, and who are not willing to use 
an acceptable method of birth control (as per Section 5.3.1 of the protocol) during the 
study period 
3. Men of childbearing potential who are sexually active and have a partner who is capable 
of becoming pregnant, neither of whom are agreeable to using an acceptable method of 
birth control (as per Section 5.3.1 of the protocol) during the study period 
4. Body mass index (BMI) > 40 
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 the Screening Visit according 
to the Kellgren-Lawrence (KL) grading of knee OA as assessed by independent central 
readers 
8. Previous treatment with SM04690 
9. Subjects who have previously failed screening on this protocol and fail to meet re-
screening criteria  
10. Any surgery (e.g., arthroscopy) in either knee within 26 weeks prior to the Screening 
Visit 

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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 the Screening Visit 
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 
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. Any diagnosed psychiatric condition that includes, but is not limited to, a history of 
mania, bipolar disorder, psychotic disorder, schizophrenia, schizoaffective disorder, 
major depressive disorder, or generalized anxiety disorder 
19. Participation in a clinical research trial that included the receipt of an investigational 
product or any experimental therapeutic procedure, or an observational research trial 
related to osteoarthritis within 8 weeks prior to the Screening Visit, or planned 
participation in any such trial; the last date of participation in the trial, not the last date of 
receipt of investigational product, must be at least 8 weeks prior to the Screening Visit 
20. 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 the Screening Visit; treatment of the target 
knee with intra-articular glucocorticoids greater than 12 weeks prior to the Screening 
Visit is allowed 
21. Treatment with systemic glucocorticoids greater than 10 mg prednisone or the equivalent 
per day within 4 weeks prior to the Screening Visit 
22. Effusion of the target knee clinically requiring aspiration within 12 weeks prior to the 
Screening Visit 
23. Use of electrotherapy, acupuncture, and/or chiropractic treatments for knee OA within 4 
weeks prior to the Screening Visit (refer to Appendix 2) 
24. Any known active infections, including urinary tract infection, upper respiratory tract 
infection, sinusitis, suspicion of intra-articular infection, hepatitis B or hepatitis C 
infection, and/or infections that may compromise the immune system such as human 

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immunodeficiency virus (HIV) at Day 1 
25. Current use, or use within 12 weeks prior to the Screening Visit, of centrally acting 
analgesics (refer to Appendix 2) w 
26. Current use, or use within 12 weeks prior to the Screening Visit, of anticonvulsants (refer 
to Appendix 2)   
27. Subjects requiring the usage of opioids >1x per week within 12 weeks prior to the 
Screening Visit 
28. Topical local anesthetic agents (gels, creams, or patches such as the Lidoderm patch) 
used for the treatment of knee OA within 7 days of the Screening Visit  
29. Any chronic condition that has not been well controlled or subjects with a chronic 
condition who have not maintained a stable therapeutic regimen of a prescription therapy 
in the opinion of the investigator. In addition, subjects with an HbA1c >9 at the 
Screening Visit will be excluded. 
30. If on nonsteroidal anti-inflammatory drugs (NSAIDs) for the treatment of OA pain, 
subjects who have not maintained a stable regimen in the opinion of the Investigator at 
the Screening Visit 
31. Any contraindications for performing MRI  
32. Subjects who have a current or pending disability claim, workers’ compensation, or 
litigation(s) that may compromise response to treatment  
33. Subjects who are immediate family members (spouse, parent, child, or sibling; biological 
or legally adopted) of personnel directly affiliated with the study at any investigative site, 
or are directly affiliated with the study at any investigative site  
34. Subjects employed by Samumed, LLC, or any of its affiliates or development partners 
(that is, an employee, temporary contract worker, or designee) responsible for the 
conduct of the study 
5.3 
LIFESTYLE GUIDELINES 
5.3.1 
CONTRACEPTION  
WOMEN OF CHILD BEARING POTENTIAL (WOCBP) 
Women of childbearing potential refers to women who are not post-menopausal (defined as 12 
months with no menses without an alternative medical cause) or permanently surgically sterile 
(includes hysterectomy, bilateral salpingectomy, and bilateral oophorectomy, but NOT tubal 
ligation). 
From the Screening Visit until Week 52 (EOS)/ET, sexually active WOCBP must agree to use an 
acceptable form of contraception as defined by this protocol: 
1. Intrauterine device 
2. Implantable rod 
3. Established hormonal contraceptive methods in combination with a barrier method. This 
includes injectable, oral, patch, and vaginal ring hormonal contraception. Females who 
are using hormonal contraceptives must have had consistent use of the same hormonal 

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contraceptive product for at least 4 weeks prior to dosing and must continue to use the 
same contraceptive during the study. Barrier methods include male or female condom, 
diaphragm with spermicide, sponge with spermicide, or cervical cap with spermicide. 
4. Bilateral tubal occlusion 
5. Male partner who had a vasectomy provided that the partner is the sole sexual partner of 
the WOCBP, and that the vasectomized partner has received medical assessment of the 
success of the surgical procedure or had the vasectomy greater than 6 months prior to the 
screening visit 
6. Abstinence 
MEN OF CHILD BEARING POTENTIAL (MOCBP) 
Men are considered of childbearing potential unless permanently sterile by bilateral orchiectomy. 
From the screening visit until the end of Week 52 (EOS)/ET, MOCBP who are sexually active 
with a female partner who is of childbearing potential must agree to use one of the following 
acceptable forms of contraception as defined by this protocol: 
1. Use of a condom for males who have had a vasectomy > 6 months ago or demonstrated 
success of the surgical procedure 
2. Use of a condom for MOCBP without a vasectomy or vasectomy within 6 months prior 
to the screening visit and no demonstrated success of the surgical procedure. In addition, 
their female partner(s), if any, must be of non-childbearing potential (surgically sterile or 
postmenopausal) or instructed to use an acceptable form of birth control. Acceptable 
methods of birth control include 
• intrauterine device (IUD) 
• implantable rod 
• bilateral tubal occlusion 
• hormonal contraceptive (injectable, oral, patch, vaginal ring) used consistently for at 
least 4 weeks prior to study inclusion of the MOCBP 
3. Abstinence 
5.4 
STRATEGIES FOR RECRUITMENT AND RETENTION 
A detailed recruitment and retention plan will be maintained by the Sponsor.  
5.5 
PARTICIPANT WITHDRAWAL OR TERMINATION 
5.5.1 
REASONS FOR WITHDRAWAL OR TERMINATION 
As the study treatment requires only one injection, best efforts will be made to encourage 
subjects to attend all follow-up visits. Subjects will be informed that they are free to withdraw 
from the study at any time and for any reason. A premature discontinuation from study will 
occur when a subject who signed informed consent ceases participation in this study, regardless 
of circumstances, prior to completion of the defined study period. Subjects can be prematurely 
discontinued from the study for one of the following reasons:  

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• AE 
• Lost to follow-up after a minimum of 3 attempts have been made to contact the 
subject, including sending a registered letter 
• Withdrawal by subject 
• Subject non-compliance 
• Investigator decision 
• Study terminated by Sponsor 
• Site terminated by Sponsor 
• Request by regulatory authority 
• Death 
5.5.2 
HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 
In case of premature discontinuation of study participation, Week 52 (EOS)/ET procedures 
should be conducted within 14 days of discontinuation for any subject who discontinues after the 
Day 1 visit, if possible. The date the subject is withdrawn from the study and the reason for the 
discontinuation should be recorded on the electronic case report form (eCRF). The Investigator 
or designee must complete all applicable eCRF pages for subjects who discontinue from the 
study prematurely.  
Replacement of subjects who withdraw or discontinue prematurely is not allowed. 
5.6 
PREMATURE TERMINATION OR SUSPENSION OF STUDY 
The Investigator and the Institutional Review Board/Ethics Committee (IRB/EC) reserve the 
right to prematurely terminate the study in the interest of subject safety and welfare. The Sponsor 
reserves the right to prematurely terminate the study at any time for administrative or safety 
reasons. Written notification, documenting the reason for study suspension or termination, will 
be provided by the suspending or terminating party to the Investigator, Sponsor, and regulatory 
authorities as appropriate. If the study is prematurely terminated or suspended, the Investigator 
will promptly inform the IRB and will provide the reason(s) for the termination or suspension.  
6. 
STUDY AGENT 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION 
6.1.1 
ACQUISITION 
Samumed will be responsible for the manufacturing, labeling, packaging, distribution, 
reconciliation, and destruction of study medication product and vehicle product related to the 
study. 
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 

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phosphate buffered saline. SM04690 drug product is supplied as 2.4 mL of formulated 
suspension in a 3 mL Type I glass vial. A separate 3 mL Type I glass vial contains 2.4 mL of 
vehicle to be used as a diluent. SM04690 vehicle product contains 0.5% carboxymethylcellulose 
sodium and 0.05% polysorbate 80 in pH 7.4 phosphate buffered saline. 
SM04690 and vehicle are manufactured by PrimaPharma, Inc. (San Diego, CA) and will be 
supplied as single-use injections. SM04690 and vehicle will be supplied to the study pharmacist 
and labeled according to the applicable local and country regulations. For dispensing, dose 
preparation, and labeling instructions, refer to the Pharmacy Manual. 
6.1.3 
PRODUCT STORAGE AND STABILITY 
The study medication and vehicle must be stored at the appropriate temperature (15-30°C or 
59-86°F) and in a restricted area with limited access. Temperature excursions are allowed 
between 2-60°C (36-140°F) for a time period not to exceed a cumulative of 72 hours.  
6.1.4 
PREPARATION 
Each dose will be prepared by taking a known volume of SM04690 drug product and adding to a 
vehicle (diluent) vial, mixing well to re-suspend the product, then injecting 2 mL intra-articularly 
into the target knee. Refer to the Pharmacy Manual for detailed instructions on study medication 
preparation.  
6.1.5 
DOSING AND ADMINISTRATION 
SM04690 will be administered in the following dosage strength:  
• SM04690 0.07 mg in 2 mL Injectable Suspension 
The injectable investigational product is to be administered by the Investigator as a 1-time single 
injection into the target knee joint. Only 1 knee will be treated for each subject in this study. 
Although not required, the injection may be guided by ultrasound if it is the standard practice of 
the Investigator. The injection can be done either through lateral or medial approach, based on 
the standard practice of the Investigator or the knee examination of the subject.  
Only topical anesthetic (absolutely no invasive anesthetic) is allowed for the study injections. 
Topical anesthetic, if used, may not be combined with the study medication prior to injection. 
The 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 is a suspension, prior 
aspiration of synovial fluid into the syringe containing the injectate should be avoided in order 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) 
in order to confirm correct needle placement, this will have to be done with a separate empty 
sterile syringe and the injectate volume subsequently injected via syringe exchange.  
6.1.6 
ROUTE OF ADMINISTRATION 
The injectable investigational product is to be administered as a single intra-articular injection 
into the target knee joint once at Day 1. 

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6.1.7 
STARTING DOSE AND DOSE ESCALATION SCHEDULE 
Not applicable to this study.  
6.1.8 
DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS 
No modification in the specified dose concentration or the volume (2 mL) of the study 
medication injected into the target knee joint will be allowed. 
6.1.9 
DURATION OF THERAPY 
The injectable investigational product is to be administered as a single intra-articular injection 
into the target knee joint once at Day 1. 
6.1.10 
TRACKING OF DOSE 
Not applicable to this study. 
6.1.11 
DEVICE SPECIFIC CONSIDERATIONS 
Not applicable to this study. 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES 
All used and unused study medication and vehicle vials received must be returned and accounted 
for. All injections prepared and dispensed must also be logged. The log includes the following: 
• Subject number and initials 
• Date that study medication was prepared/injected 
• Quantity dispensed (active vial, vehicle vial) 
• Quantity returned/used (active vial, vehicle vial) 
All study medication and vehicle prepared and dispensed by the Investigator and/or designee will 
be inventoried and accounted for throughout the study. The Investigator and/or designee must 
maintain an accurate, up-to-date dispensing log for all study medications supplied by the 
Sponsor. Study medication and vehicle dispensed for all subjects must be recorded on the drug 
accountability forms. The study medication dispensing log and remaining drug inventory will be 
reviewed by the Sponsor-designated clinical monitor. 
The study medications supplied for this study are for use only in subjects properly consented into 
this protocol. Used and unused study medications must be kept in a secure location physically 
separated from standard clinic or office drug supplies, and with access limited to the Investigator 
and/or designee. Procedures for Investigator return or destruction of used and unused vials of the 
study medication will be provided in the Pharmacy Manual.   

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7. 
STUDY PROCEDURES AND SCHEDULE 
7.1 
STUDY PROCEDURES/EVALUATIONS 
7.1.1 
STUDY SPECIFIC PROCEDURES  
Collection of Adverse Events Data 
Data regarding AEs will be collected in this study. AEs are events that occur during the 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 Week 52 (EOS) or ET. 
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 
“Guidance for Industry: Toxicity Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Trials” (Appendix 1), causal relationship to study medication, outcome, and 
any treatment given.  
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. 
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. Serious adverse 
events that are not resolved or stabilized during this time period will be followed until resolution 
or stabilization. 
Medical History 
A medical history will be obtained at the Screening Visit and Day 1 with a follow-up at Week 52 
(EOS)/ET. Medical history at the Screening Visit 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 nonsymptomatic 
medical history that could become symptomatic while on the study. Review of medical history at 
the Week 52 (EOS)/ET visit will only be to capture End Dates of any ongoing medical history 
collected at screening. 

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Physical Examination  
A general physical examination will be conducted at the Screening Visit, Day 1, and Weeks 13, 
26, 39, and 52 (EOS)/ET. Results of the physical examination will be noted in the source 
documents. Any clinically significant finding noted prior to study medication injection should be 
recorded as medical history. If it is found after study medication injection, it should be reported 
as an AE.  
Knee Examination 
A knee examination of both knees will be conducted at the Screening Visit, Day 1, and Weeks 4, 
13, 26, 39, and 52 (EOS)/ET. Results of the knee examination will be noted in the source 
documents. Any clinically significant finding noted prior to study medication injection should be 
recorded as medical history. If it is found after study medication injection, it should be reported 
as an AE.  
Presence of bilateral knee OA will be recorded in the eCRF at the Screening Visit. If the subject 
has OA in both knees, the site is to establish the target knee as the knee with greater pain at the 
Screening Visit based on the subject’s evaluation and the Investigator’s clinical judgment. 
Misalignment of both knees will be assessed by the Investigator during the knee examination at 
the Screening Visit. In the opinion of the Investigator, subjects with significant and clinically 
evident misalignment in either knee that would impact subject function must be excluded from 
the study. 
Vital Signs 
Vital signs will be measured by a qualified staff member at the Screening Visit, Day 1, and 
Weeks 4, 13, 26, 39, and 52 (EOS)/ET. 
At each time point, the following vital signs will be measured: 
• Body temperature 
• Pulse rate 
• Respiration rate 
• Blood pressure (systolic and diastolic) after the subject rests (sitting or supine) for at 
least 5 minutes; same resting position should be used for all blood pressure 
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 the Screening Visit only. Weight measurements will be 
taken at the Screening Visit and Week 52 (EOS)/ET. 
Radiograph of the Knee Joints 
Radiograph of the knee joints will be taken at the Screening Visit, and at Weeks 26 and 52 
(EOS)/ET.  

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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 inclusion/exclusion criteria and 
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.   
Magnetic Resonance Imaging (MRI) of the Knee Joints 
Magnetic resonance imaging scans of the knee joints will be taken at the Screening Visit and 
Weeks 13, 26, and 52 (EOS)/ET.  
Detailed instructions for obtaining and managing the MRI images will be provided to the site 
prior to the initiation of subject enrollment. MRI assessments on the knee joints will include, but 
are not limited to, measurement of cartilage quality by T1rho and T2 mapping pulse sequence 
MRI, measurement of cartilage volume and thickness by 3D-SPGR pulse sequence MRI, and 
WORMS.  
The MRI scans will be submitted to the site’s radiologist(s) for qualitative and quantitative 
interpretation.  
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 (SSQs) (Clauw 
2014). A WPI&SS assessment will be completed by the subject at Day 1 on paper.  
Upon completion of the WPI&SS assessment, the subject will sign/initial and date the source 
document to indicate that the assessments are reported accurately. 
The WPI&SS assessment sheets will be provided by the Sponsor and may not be reproduced. 
Pain Numeric Rating Scale (NRS) 
The pain NRS is an 11-point scale (0-10) for subject self-reporting of average knee pain in the 
last 24 hours. A pain NRS for each knee will be completed daily by the subject during the 
screening period from the Screening Visit until Day 1 to assess the subject’s daily OA knee pain 
diary average for the 7 days immediately preceding Day 1 and to determine subject eligibility. 
During the screening period, daily pain NRS assessments will be completed remotely by subjects 

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on the paper diary. It is recommended that subjects complete the diary in the evening. Subjects 
need to bring in their paper diary on Day 1. Subject eligibility and paper diary compliance for 
daily pain NRS and daily OA knee pain diary average for each knee from Day -7 to Day -1 will 
be reviewed at Day 1 prior to enrollment to determine subject eligibility. 
The paper diary will be provided by the Sponsor and may not be reproduced. 
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. WOMAC questionnaires will be completed at 
Day 1 prior to study medication injection. WOMAC questionnaire completion will be reviewed 
at Day 1 prior to enrollment to determine subject eligibility. After Day 1, WOMAC assessments 
will be completed at Weeks 4, 13, 26, 39, and 52 (EOS)/ET.  
Upon completion of the WOMAC, both the subject and the study staff member will sign/initial 
and date the source document to indicate that the activity and pain assessments are reported 
accurately.  
The WOMAC questionnaires will be provided by the Sponsor and may not be reproduced. 
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 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 at Day 1 
prior to study medication injection and at Weeks 4, 13, 26, 39, and 52 (EOS)/ET.  
Upon completion of the Patient Global Assessment, both the subject and the study staff member 
will sign/initial and date the source document to indicate that the activity assessments are 
reported accurately. The study staff member will record the Patient Global Assessment score in 
the eCRF.  
The Patient Global Assessment of Disease Activity questionnaires will be provided by the 
Sponsor and may not be reproduced.  
7.1.2 
STANDARD OF CARE STUDY PROCEDURES  
All Investigators are to provide appropriate care to their subjects as they deem necessary, 
however, additional standard of care study procedures are not required by this protocol. 
7.2 
LABORATORY PROCEDURES/EVALUATIONS 
7.2.1 
CLINICAL LABORATORY EVALUATIONS  
Non-fasting samples for clinical laboratory analysis by ACM Global Central Laboratory will be 
collected by a qualified staff member at the Screening Visit and Weeks 4, 13, 26, 39, and 52 
(EOS)/ET. At a minimum, the following tests will be conducted: 
 

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• 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 the Screening Visit. 
Urine microscopy will be performed if urinalysis urine protein, leukocyte esterase (WBC 
esterase), occult blood, or nitrite values are out of range, or if the Investigator deems that the 
microscopy is clinically warranted. 
The Investigator or the Investigator’s designee must review the results of each subject’s 
Screening Visit clinical laboratory test results prior to the Day 1 visit. The subject must not be 
enrolled on Day 1 if any of the Screening Visit results are outside the normal range for the 
laboratory AND, in the opinion of the Investigator, are clinically significant.  
The results of the clinical laboratory tests will be reported on the laboratory’s standard reports. 
The Investigator must review all laboratory reports in a timely manner, noting “not clinically 
significant” (NCS) or comment on the clinical significance of any result that is outside the 
normal range for the laboratory or has a toxicity grade of 1 or greater, then date and initial the 
report. The Investigator must report all laboratory results that are BOTH outside the normal 
range for the laboratory or have a toxicity grade of 1 or greater AND, in the opinion of the 
Investigator, are clinically significant. If any abnormal, clinically significant laboratory measure 
is found prior to study medication injection, the subject is to be excluded. If it is found after 
study medication injection, it should be reported as an AE. 
7.2.2 
OTHER ASSAYS OR PROCEDURES 
Pregnancy Test 
A serum-based pregnancy test will be performed on female subjects at the Screening Visit. 
Results from the pregnancy test will be utilized to determine subject eligibility. A urine-based 
pregnancy test will be performed at the Screening Visit, Weeks 13, 26, and 52 (EOS) / ET. A 
negative urine pregnancy test must be confirmed prior to performing radiographs and MRI scans. 
Drug Test 
A urine sample for drug testing will be collected at the Screening Visit. The urine drug test will 
include: amphetamine, methamphetamine, 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. 
7.2.3 
SPECIMEN PREPARATION, HANDLING, AND STORAGE 
Refer to the Laboratory Manual for ACM Global Laboratory.  

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7.2.4 
SPECIMEN SHIPMENT 
Refer to the Laboratory Manual for ACM Global Laboratory. 
7.3 
STUDY SCHEDULE 
7.3.1 
SCREENING 
Screening Visit 
The Investigator or designee must explain the nature of the study protocol and associated risks to 
the potential study participant. The potential participant must be allowed to review the study 
information and to ask questions before being asked to sign and date the informed consent form. 
Written informed consent must be provided, signed, and dated by the potential study participant 
prior to initiation of any screening evaluations or other study-related procedures. The signature, 
date, and the name of the individual at the site who obtained the informed consent will be 
recorded. After written informed consent is obtained, the subject will be assigned a subject 
number.  
The following procedures and assessments will be performed 7-14 days prior to Day 1. A 
negative urine pregnancy test must be confirmed prior to performing radiographs and MRI scans. 
• Documentation of demographic information, including date of birth, gender, race, and 
ethnicity 
• Documentation of current and past medical history including assistive device usage, 
documentation of current medications, and review of prior medication excluded by 
the protocol 
• Physical examination, including knee examination of both knees and selection of 
target knee 
• Vital signs measurements (pulse, blood pressure, respiration rate, and temperature) 
• Height and weight measurements 
• Venipuncture and collection of samples for clinical laboratory tests 
• Pregnancy tests (serum-based and urine-based) 
• Urine drug test  
• Radiograph – bilateral in weight-bearing fixed flexion position, posterior-anterior 
(PA) view X-ray 
• MRI scans 
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.  
Starting on the day of the Screening Visit, after the site visit, subjects will begin completion of 
daily pain NRS assessments remotely on a paper diary. It is recommended that subjects complete 
the diary in the evening. Subjects need to bring in their paper diary on Day 1.  

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7.3.2 
ENROLLMENT 
Day 1 
This visit must occur within 7 to 14 days of the Screening Visit. 
The following procedures and assessments will be performed at Day 1 prior to study medication 
injection: 
• Review and/or documentation of current and past medical history, documentation of 
current medications, and review of prior medication excluded by the protocol 
• Physical examination, including knee examination of both knees 
• Vital signs measurements (pulse, blood pressure, respiration rate, and temperature) 
• Review of pain NRS paper diary compliance and daily OA knee pain diary average 
for each knee from Day -7 to Day -1 
• WOMAC  
Results from these evaluations will be compared with inclusion/exclusion criteria to determine 
subject eligibility. 
Patient Global Assessment and WPI&SS assessment will also be performed prior to enrollment; 
however, results from these assessments do not determine eligibility. 
The following procedures and assessments will be performed at Day 1 following enrollment: 
• Intra-articular study medication injection 
• Collection of AE and concomitant procedures/medication data 
7.3.3 
FOLLOW-UP  
Week 4 
The Week 4 visit should occur on Day 29 with a window of ± 3 days.  
The following procedures and assessments will be performed at Week 4:  
• Collection of AE and concomitant procedures/medication data 
• Knee examination of both knees  
• Vital signs measurements (pulse, blood pressure, respiration rate, and temperature) 
• Venipuncture and collection of samples for clinical laboratory tests 
• WOMAC  
• Patient Global Assessment 
Week 13  
The Week 13 visit should occur on Day 92 with a window of ± 7 days.  
The following procedures and assessments will be performed at Week 13. A negative pregnancy 
test must be confirmed prior to performing radiographs and MRI scans. 

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• Collection of AE and concomitant procedures/medication data 
• Physical examination, including knee examination of both knees  
• Vital signs measurements (pulse, blood pressure, respiration rate, and temperature) 
• Venipuncture and collection of samples for clinical laboratory tests 
• Patient Global Assessment  
• WOMAC 
• Pregnancy test (urine-based) 
• MRI scans 
Week 26 
The Week 26 visit should occur on Day 183 with a window of ± 7 days.  
The following procedures and assessments will be performed at Week 26. A negative pregnancy 
test must be confirmed prior to performing radiographs and MRI scans 
• Collection of AE and concomitant procedures/medication data 
• Physical examination, including knee examination of both knees  
• Vital signs measurements (pulse, blood pressure, respiration rate, and temperature) 
• Venipuncture and collection of samples for clinical laboratory tests 
• Patient Global Assessment  
• WOMAC 
• Pregnancy test (urine-based) 
• Radiograph – bilateral in weight-bearing fixed flexion position, posterior-anterior 
(PA) view X-ray 
• MRI scans 
Week 39 
The Week 39 visit should occur on Day 274 with a window of ± 7 days.  
The following procedures and assessments will be performed at Week 39: 
• Collection of AE and concomitant procedures/medication data 
• Physical examination, including knee examination of both knees  
• Vital signs measurements (pulse, blood pressure, respiration rate, and temperature) 
• Venipuncture and collection of samples for clinical laboratory tests 
• Patient Global Assessment  
• WOMAC 

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7.3.4 
FINAL STUDY VISIT 
Week 52 End of Study (EOS) 
This final study visit should occur on Day 365 with a window of ± 7 days. 
The following procedures and assessments will be performed at Week 52 (EOS). A negative 
pregnancy test must be confirmed prior to performing radiographs and MRI scans 
• Collection of AE and concomitant procedures/therapies/medication data 
• Review of medical history 
• Vital signs measurements (pulse, blood pressure, respiration rate, and temperature) 
• Physical examination, including knee examination of both knees 
• Weight measurement 
• Venipuncture and collection of samples for clinical laboratory tests 
• Pregnancy test (urine-based) 
• Radiograph – bilateral in weight-bearing fixed flexion position, posterior-anterior 
(PA) view X-ray 
• Patient Global Assessment 
• WOMAC 
• MRI scans 
7.3.5 
EARLY TERMINATION VISIT 
If possible, the following procedures and assessments should be performed within 14 days of 
subject premature withdrawal or termination. A negative pregnancy test must be confirmed prior 
to performing radiographs and MRI scans 
• Collection of AE and concomitant procedures/therapies/medication data 
• Review of medical history 
• Vital signs measurements (pulse, blood pressure, respiration rate, and temperature) 
• Physical examination, including knee examination of both knees 
• Weight measurement 
• Venipuncture and collection of samples for clinical laboratory tests 
• Pregnancy test (urine-based) 
• Radiograph – bilateral in weight-bearing fixed flexion position, posterior-anterior 
(PA) view X-ray 
• Patient Global Assessment 
• WOMAC 
• MRI scans 

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7.3.6 
SCHEDULE OF EVENTS TABLE 
 
Procedure 
Screening 
Visita  
(Days -14 
to -7) 
Day 1b 
Week 4  
(Day 29 ± 
3 days) 
Week 13 
(Day 92 ± 
7 days) 
Week 26 
(Day 183 
± 7 days) 
Week 39 
(Day 274 
± 7 days) 
Week 52 
(EOS) (Day 
365 ± 7 
days) / ET 
Informed consent 
X 
 
 
 
 
 
 
Inclusion & exclusion 
criteria 
X 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
Xc 
Current and prior 
procedures/medications 
X 
X 
 
 
 
 
 
Pregnancy testd 
X 
 
 
X 
X 
 
X 
Radiograph 
X 
 
 
 
X 
 
X 
MRI 
X 
 
 
X 
X 
 
X 
Physical examination 
X 
X 
 
X 
X 
X 
X 
Knee examination 
X 
X 
X 
X 
X 
X 
X 
Selection of target knee 
X 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory 
sampling 
X 
 
X 
X 
X 
X 
X 
Urine drug test 
X 
 
 
 
 
 
 
WPI&SS 
 
X 
 
 
 
 
 
Pain NRSe, f 
 
X 
(Review) 
 
 
 
 
 
WOMAC 
 
X  
X 
X 
X 
X 
X 
Patient Global 
Assessment 
 
X 
X 
X 
X 
X 
X 
Intra-articular injection 
 
X 
 
 
 
 
 
AEs and concomitant 
procedures/medications 
 
X 
X 
X 
X 
X 
X 
 
a The screening period is a minimum of 7 days and a maximum of 14 days. 
b At Day 1, all procedures should be performed prior to study medication injection except for collection of AEs and 
any medication data that occurs post injection. 
c Review medical history to capture End Date(s), if applicable, of any ongoing medical history(ies) collected at 
screening. 
d Both a serum- and urine-based pregnancy test will be performed on female subjects at the Screening Visit; a urine-
based pregnancy test only will be performed at Weeks 13, 26 , and 52 (EOS) / ET. A negative urine pregnancy test 
must be confirmed prior to performing radiographs and MRI scans. 

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e Paper diary compliance for daily pain NRS and daily OA knee pain diary average for each knee from Day -7 to Day -
1 will be reviewed at Day 1 prior to enrollment to determine subject eligibility.  
f Pain NRS should be completed daily starting the day of the Screening Visit until Day -1. Subjects will complete the 
paper diary remotely. It is recommended that subjects complete the diary in the evening.  
 

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7.4 
JUSTIFICATION FOR SENSITIVE PROCEDURES 
Not applicable for this study. 
7.5 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES  
Details regarding the name, indication, route of administration, dose, and frequency of all 
medications taken within 30 days prior to the Screening Visit through Week 52 (EOS)/ET will 
be recorded in the 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. 
7.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES  
Prohibited Concomitant Medications and Procedures: 
• Any intra-articular injection, including glucocorticoids, hyaluronic acid derivatives, 
PRP, stem cell therapies, or other agents with therapeutic intent, into either knee is 
prohibited while the subject is on study; intra-articular injection of glucocorticoids, 
hyaluronic acid derivatives, PRP, stem cells, or other therapeutic agents into joints 
other than the knee is allowed. 
• The following medications are prohibited while the subject is on study: 
− Opioids; short-term use of opioids as part of anesthesia or procedural sedation 
during the study period is permitted 
− Centrally acting analgesics (e.g., duloxetine) (refer to Appendix 2)  
− Other anticonvulsants not listed in Appendix 2  
− 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, methamphetamine, buprenorphine, cocaine, methadone, 
opiates, PCP, propoxyphene, barbiturates, benzodiazepine, methaqualone, and 
tricyclic antidepressants  
• Electrotherapy (refer to Appendix 2), acupuncture, and/or chiropractic treatments for 
knee OA are prohibited while the subject is on study. 
• Any new formalized (i.e., prescribed by a medical professional) physical therapy 
exercise programs for knee OA are prohibited while the subject is on study; 
continuation of formalized physical therapy exercise programs that are already in 
progress at the time of screening are allowed. 

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• Elective surgery, including arthroscopy, is prohibited while the subject is on the 
study. Non-surgical invasive procedures conducted for a diagnostic or therapeutic 
purpose that are scheduled during the study period are not prohibited. Examples 
include, but are not limited to: endoscopy, colonoscopy, bronchoscopy, cystoscopy, 
radiologic procedures such as coronary artery catheterization with or without 
intervention, and non-surgical cosmetic procedures such as Botox or other cosmetic 
injections. 
• Subjects are prohibited from participating in any other clinical research trial that 
includes the receipt of an investigational product or any experimental therapeutic 
procedure. Subjects are also prohibited from participating in any observational 
research trial related to osteoarthritis while on study. 
The Investigator should notify the Samumed Medical Monitor immediately if any prohibited 
therapies are required to ensure subject safety.  
7.7 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES  
Not applicable to this study. 
7.8 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES  
Not applicable to this study. 
7.9 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE  
Not applicable to this study. 
8. 
ASSESSMENT OF SAFETY 
8.1 
SPECIFICATION OF SAFETY PARAMETERS 
Safety assessments include physical examinations, vital signs, clinical laboratory tests, 
solicitation of AEs and concomitant medications, and general medical evaluations.  
8.1.1 
DEFINITION OF ADVERSE EVENTS (AEs) 
AEs in the eCRF will be classified according to the most recent US FDA definitions and in a 
manner consistent with ICH guidelines. As such the following definitions will be used: 
An 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 

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Sponsor to the original terms entered on the eCRF, using the Medical Dictionary for Regulatory 
Activities (MedDRA).   
8.1.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
According to the ICH Guidelines for Good Clinical Practice (E6), an SAE is any untoward 
medical occurrence during the course of a clinical investigation that is characterized by 1 or 
more of the following: 
• Results in death 
• Is life threatening 
• Requires 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 
abuse would be other examples of important medical events.  
“Inpatient hospitalization” is clarified as hospitalization lasting ≥24 hours. All SAE information 
must be recorded on the SAE form approved by the Sponsor. Additional follow-up information 
(e.g., test results, autopsy, and discharge summary) may be requested to supplement the SAE 
report form and can be attached as de-identified records. 
8.1.3 
DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
An unanticipated problem is defined as, in general, any incident, experience, or outcome that 
meets all of the following criteria:  
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the participant 
population being studied;  
• 
Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and  
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized.  
8.2 
CLASSIFICATION OF AN ADVERSE EVENT 
8.2.1 
SEVERITY OF EVENT 
The Investigator will assess AEs for severity utilizing the “Guidance for Industry: Toxicity Scale 

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for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Trials”. This 
toxicity scale is presented in Appendix 1. Laboratory values not listed on the toxicity scale will 
be assessed for severity by the clinical Investigator. 
8.2.2 
RELATIONSHIP TO STUDY AGENT 
The relationship of the study treatment to 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 investigational product 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 or product not associated with the investigational 
product 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 investigational product or study injection (i.e., there are no 
facts [evidence] or arguments to suggest a causal relationship). 
3.  Possibly Related 
The AE is possibly related if (1) the investigational product or the study injection and AE are 
considered reasonably related in time and (2) the AE could be explained by causes other than 
exposure to the investigational product or administration of the study injection. 
4.  Probably Related 
Exposure to the investigational product or administration of the study injection and AE are 
probably related if (1) the investigational product or study injection and AE are considered 
reasonably related in time and (2) the investigational product or study injection is more likely 
than other causes to be responsible for the AE or is the most likely cause of the AE. 
8.2.3 
EXPECTEDNESS  
The Sponsor will be responsible for determining whether an AE/SAE is expected or unexpected. 
An AE/SAE will be considered unexpected if the nature, severity, or frequency of the event is 
not consistent with the risk information previously described for the study agent in the IB or is 
not listed in the IB at the specificity or severity that has been observed.  
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-
UP 
The reporting period for AEs starts after the injection of study medication on Day 1 and ends 
after the final study visit. 
AEs must be followed until resolution by the Investigator. Resolution is defined as the return to 
baseline status or stabilization of the condition with the expectation that it will remain chronic. 
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 

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ongoing at the subject’s last visit will be followed for a maximum of 30 days. SAEs that are not 
resolved or stabilized during this time period will be followed until resolution or stabilization. 
8.4 
REPORTING PROCEDURES 
8.4.1 
ADVERSE EVENT REPORTING  
The Investigator is responsible for reporting AEs to the Sponsor and IRB according to the 
protocol as well as 21 CFR Parts 50, 56, and 312. The Investigator is responsible for ensuring 
accurate AE information is reviewed and recorded in the subject source and the AE eCRF in a 
timely manner. The Sponsor is responsible for submitting reports of AEs associated with the use 
of study medication that are both serious and unexpected to the FDA according to 21 CFR 
312.32. All Investigators participating in ongoing studies with the study medication will receive 
copies of these reports from the Sponsor for prompt submission to their IRB/EC according to 
their institution’s requirements.  
8.4.2 
SERIOUS ADVERSE EVENT REPORTING  
The Investigator is responsible for reporting SAEs to the Sponsor and IRB according to 21 CFR 
Parts 50, 56, and 312. The Investigator and Samumed will manage SAEs according to the study 
document “Guidelines for the Management of Serious Adverse Events (SAEs) and Pregnancies”. 
All SAEs must be reported as described in the study manual by the Investigator, Study 
Coordinator, other designated study personnel, or Clinical Research Associate within 24 hours of 
notification of the SAE. The Investigator or designee should submit the SAE report to the 
Samumed Study SAE email address: sae@samumed.com or FAX: +1 858 408 4470. Follow-up 
information must be detailed in a follow-up SAE report and reported to the Samumed Study SAE 
email address or fax number as it becomes available. The Investigator also must report all SAEs 
promptly to the appropriate IRB/EC as required by the institution. Sponsor contact information 
for questions regarding SAE reporting is provided in Table 1. 
Table 1: 
Sponsor Contact Information for Questions on SAE Reporting 
Primary Contact 
Alternative Contact 
Medical Monitor: Naina Rastalsky, MD 
Clinical Project Manager, Clinical Development: 
Ashley Gantt 
Office Tel:  
(858) 371-3874 
Office Tel:  
(858) 371-3880 
Cellular:  
(858) 926-8490 
Cellular:  
(858) 232-3426 
Email:  
naina@samumed.com 
Email:  
ashleyg@samumed.com 
8.4.3 
UNANTICIPATED PROBLEM REPORTING  
Incidents or events that meet the criteria for unanticipated problem require the creation and 
completion of an UP report. It is the site Investigator’s responsibility to report UPs to their IRB 
and to the Sponsor. The UP report will include the following information:  

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• 
Protocol identifying information: protocol title and number, Investigator’s name, and the 
IRB project number;  
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP; and 
• 
A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP.  
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline:  
• 
UPs that are SAEs will be reported to the IRB and to the Sponsor within 24 hours of the 
Investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and to the Sponsor within the IRB-required 
reporting timeframe.  
• 
All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures) and IRB within the timeframe specified by the 
institution procedures and IRB.   
8.4.4 
EVENTS OF SPECIAL INTEREST  
Not applicable to this study. 
8.4.5 
REPORTING OF PREGNANCY  
Although pregnancy is not a formal SAE, if a study participant or the partner of a study 
participant becomes pregnant while the study participant is on study, the pregnancy is to be 
reported via SAE reporting procedures. The Investigator and Samumed will manage reporting of 
pregnancies according to the study document “Guidelines for the Management of Serious 
Adverse Events (SAEs) and Pregnancies”. 
8.5 
STUDY HALTING RULES  
Not applicable to this study. 
8.6 
SAFETY OVERSIGHT 
Clinical safety oversight will be performed by centralized review conducted by Medical 
Monitors per the Medical Monitoring Plan. In addition, on-site review will be conducted by 
Clinical Research Associates. 
9. 
CLINICAL MONITORING 
All aspects of the study will be monitored by the Sponsor or the Sponsor’s designees with 
respect to current Good Clinical Practice (GCP) and Standard Operating Procedures (SOPs) for 
compliance with applicable government regulations. It is the responsibility of the Investigator to 
provide all study records, including eCRFs and source documents among other records, for 
review and inspection by the clinical monitor. 
Clinical monitoring will be performed per the Clinical Monitoring Plan. Clinical monitors will 

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periodically evaluate the progress of the study, including the verification of appropriate consent 
form procedures and the verification of the accuracy and completeness of eCRFs. Clinical 
monitors will also ensure that all protocol requirements, applicable US FDA regulations, other 
regulatory requirements, and the Investigator’s obligations are being fulfilled. 
The accuracy of the data will be verified by reviewing the documents described in Section 11. 
10. 
STATISTICAL CONSIDERATIONS  
10.1 
STATISTICAL AND ANALYTICAL PLANS 
This section describes the planned statistical analyses in general terms. A complete description of 
the statistical analyses will be specified in a statistical analysis plan (SAP), finalized prior to 
database lock.   
10.2 
STATISTICAL HYPOTHESES 
No formal hypotheses are being tested in this study. 
10.3 
ANALYSIS DATASETS 
Full Analysis Set (FAS): All subjects who receive a study injection. The FAS is used to 
describe the analysis set which is as complete as possible and as close as possible to the intent-
to-treat ideal of including all subjects. 
Per-Protocol Analysis Set (PPAS): FAS subjects who complete the study and did not have any 
major protocol deviations. 
Safety Analysis Set (SAS): All subjects who receive a study injection. 
10.4 
 DESCRIPTION OF STATISTICAL METHODS 
10.4.1 
GENERAL APPROACH 
For continuous variables, the number of subjects in the analysis, mean, standard deviation, 
median, minimum, and maximum will be reported. All categorical endpoints will be summarized 
using frequencies and percentages. 
10.4.2 
ANALYSIS OF THE PRIMARY ENDPOINT(S) 
Analysis of covariance (ANCOVA) will be used to estimate change from baseline in cartilage 
volume and thickness as measured by 3D-SPGR pulse sequence MRI as well as change from 
baseline in cartilage quality as determined by proteoglycan levels and GAG content hydration as 
measured by T1rho and T2 mapping pulse sequence MRI. The models will be evaluated at Week 
26 and adjusted for baseline value. Unadjusted 95% confidence intervals and P values will be 
reported. 
Change from baseline in all primary endpoints will be summarized with descriptive statistics. 

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10.4.3 
ANALYSIS OF THE SECONDARY ENDPOINT(S) 
Imaging assessments of the target knee will be used to evaluate cartilage volume, thickness, and 
quality (as determined by proteoglycan levels and GAG content hydration) at Weeks 13 and 52 
as well as mJSW at Weeks 26 and 52. Imaging assessments of the non-target knee will be used 
to evaluate cartilage volume, thickness, and quality (as determined by proteoglycan levels and 
GAG content hydration) at Weeks 13, 26, and 52 as well as mJSW at Weeks 26 and 52. 
Total WORMS of the target knee and non-target knee will be summarized with means and 
standard deviations, as well as percentages of maximum possible score at Weeks 13, 26 and 52.  
WOMAC total score, WOMAC pain subscore, WOMAC function subscore, and Patient Global 
Assessment of the target knee will be assessed at Weeks 13, 26, and 52. Change from baseline 
will be summarized with descriptive statistics. 
ANCOVA will be used to estimate change from baseline in all secondary endpoints. The models 
will be adjusted for baseline value and unadjusted 95% confidence intervals and P values will be 
reported.  
The number and percent of subjects experiencing AEs will be summarized by seriousness, 
severity, and relationship for all subjects who receive the study injection. 
10.4.4 
SAFETY ANALYSES 
Safety analyses will be performed on subjects who receive a study injection. Safety assessments 
include physical examinations, vital signs, clinical laboratory tests, solicitation of AEs and 
concomitant medications, and general medical evaluations. No formal statistical analyses are 
planned. Safety will be evaluated based on the incidence, seriousness, severity, and relationship 
of AEs and by changes in clinical laboratory parameters and vital signs, relative to baseline. 
10.4.5 
BASELINE DESCRIPTIVE STATISTICS 
Baseline is defined as the last value recorded for any given parameter prior to study medication 
injection. In the case of questionnaires, all items collected from the last timepoint prior to study 
medication injection will be collectively flagged as baseline.  
Descriptive statistics will be provided for age, weight, height, BMI, and WPI&SS assessments at 
baseline, while frequencies and percentages will be provided for sex, race, ethnicity, KL grade, 
and the presence of bilateral OA. 
10.4.6 
PLANNED INTERIM ANALYSES  
Not applicable to this study.  

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10.4.6.1 
SAFETY REVIEW 
Medical monitoring of study safety assessment data will be performed during periodic safety 
reviews detailed in the Medical Monitoring Plan. 
10.4.6.2 
EFFICACY REVIEW 
Not applicable to this study.  
10.4.7 
EXPLORATORY ANALYSES 
Not applicable to this study. 
10.4.8 
ADDITIONAL SUB-GROUP ANALYSES 
Not applicable to this study. 
10.5 
SAMPLE SIZE 
A sample size of 15 subjects is selected for this exploratory study in order to have approximately 
12 subjects complete the study. This sample size is based upon accepted statistical practice 
(Julious 2005). 
10.6 
MEASURES TO MINIMIZE BIAS 
10.6.1 
BLINDING PROCEDURES 
This is an open-label study. Not applicable to this study. 
10.6.2 
EVALUATION OF SUCCESS OF BLINDING  
Not applicable to this study.  
10.6.3 
BREAKING THE STUDY BLIND/PARTICIPANT CODE 
Not applicable to this study. 
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. The source documents should include detailed notes on the following: 

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• The oral and written communication with the subject regarding the study (including 
the risks and benefits of the study); the date and time of informed consent(s) must be 
recorded in the source documentation 
• The subject’s medical and disease history before participation in the study 
• The subject’s basic identifying information, such as subject number, that links the 
subject’s source documents with the eCRFs 
• The results of all diagnostic tests performed, diagnoses made, therapy provided, and 
any other data on the condition of the subject 
• All 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) 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL 
This study will be organized, performed, and reported in compliance with the protocol, SOPs, 
site/Investigator training, and applicable regulations and guidelines. Clinical Investigator sites 
will be trained at individual, on-site, Site Initiation Visits. All aspects of the study will be 
monitored carefully by the Sponsor’s designees with respect to current GCP and SOPs for 
compliance with applicable government regulations. It is the responsibility of the Investigator to 
provide all study records, including CRFs and source documents, among other records, for 
review and inspection by the clinical monitor. 
The Integrated Quality and Risk Management Plan (IQRMP) details the trial specific quality 
management plans to indicate how risks are mitigated and data quality is addressed in the clinical 
trial.  
13. 
ETHICS/PROTECTION OF HUMAN SUBJECTS  
13.1 
ETHICAL STANDARD  
The study will be conducted in accordance with the Declaration of Helsinki (1964), including all 
amendments up to and including the Brazil revision (2013). The Investigator will ensure that this 
study is conducted in full conformity with Regulations for the Protection of Human Subjects of 
Research set forth in US 21 CFR Parts 50 and 56 and/or the ICH E6. 
13.2 
INSTITUTIONAL REVIEW BOARD  
The Investigator agrees to provide the IRB/EC with all appropriate material, including a copy of 
the informed consent form (ICF). The study will not be initiated until the Investigator obtains 
written approval of the research plan and the ICF from the appropriate IRB/EC and copies of 
these documents are received by the Sponsor. Appropriate reports on the progress of this study 
will be made by the Investigator to the IRB/EC and Sponsor in accordance with applicable 
government regulations and in agreement with the policies established by the Sponsor and the 

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IRB/EC. Any amendment to the protocol will require review and approval by the IRB before the 
changes are implemented to the study. All changes to the consent form will be IRB approved; a 
determination will be made regarding whether previously consented participants need to be re-
consented. The Sponsor ensures that the IRB/EC complies with the requirements set forth in US 
21 CFR Part 56.  
13.3 
INFORMED CONSENT PROCESS  
13.3.1 
CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS 
PROVIDED TO PARTICIPANTS 
Consent forms describing in detail the study procedures and risks will be given to the potential 
participant and written documentation of informed consent is required prior to starting any 
screening evaluations or other study-related procedures.   
13.3.2 
CONSENT PROCEDURES AND DOCUMENTATION 
The informed consent and consent process should be in accordance with the current Declaration 
of Helsinki, ICH, GCP, federal, state, and local regulations. The Investigator or designee must 
explain the nature of the study protocol and associated risks to the potential study participant. 
The potential participant must be allowed to review the study information and to ask questions 
before being asked to sign and date the ICF. Written informed consent must be provided (signed 
and dated) by the potential study participant prior to initiation of any screening evaluations or 
other study-related procedures. A copy of the ICF will be given to the participants for their 
records. The signature, date, and the name of the individual at the site who obtained the informed 
consent will be recorded.  
13.4 
PARTICIPANT AND DATA CONFIDENTIALITY  
The Investigator(s) and the Sponsor or its authorized representative will preserve the 
confidentiality of all subjects participating in a study, in accordance with current GCP, federal, 
state, and local regulations, including, to the extent applicable, the Health Insurance Portability 
and Accountability Act of 1996 (“HIPAA”). 
In order to maintain subject confidentiality, all eCRFs, study reports, and communications 
relating to the study will identify subjects by initials and assigned subject numbers; subjects 
should not be identified by name. If a subject name appears on any document, it must be 
obliterated before a copy of the document is supplied to the Sponsor or its authorized 
representative. Study findings stored on a computer will be stored in accordance with federal, 
state, and local data protection laws. Subjects will be told that representatives of the Sponsor, its 
authorized representative, IRB or EC, or regulatory authorities may inspect their medical records 
to verify the information collected, and that all personal information will be held in strict 
confidence and in accordance with applicable data protection laws. The Investigator or designee 
will maintain a personal subject identification list (subject numbers with the corresponding 
subject names) to make it possible for records to be identified.  
Clinical information will not be released without written permission from the subject, except as 
necessary for monitoring by the IRB/EC, the FDA, or the study Sponsor.  

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Any information, inventions, or discoveries (whether patentable or not), innovations, 
suggestions, ideas, and reports made or developed by the Investigator(s) as a result of conducting 
this study shall be promptly disclosed to the Sponsor and shall be the sole property of the 
Sponsor. The Investigator agrees, upon the Sponsor’s request and at the Sponsor's expense, to 
execute such documents and to take such other actions, as the Sponsor deems necessary or 
appropriate, to obtain patents in the Sponsor’s name covering any of the foregoing. 
13.4.1 
RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS, OR DATA 
Not applicable to this study. 
13.5 
FUTURE USE OF STORED SPECIMENS  
Not applicable to this study. 
14. 
DATA HANDLING AND RECORD KEEPING  
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
As defined by ICH guidelines, the CRF is a printed, optical, or electronic document designed to 
record all 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 (EDC) system fully compliant with regulatory expectations for 
software developers and service providers within the global regulatory environment, including 
but not limited to ICH E6 and US 21 CFR Parts 312, 812, and 11. Data to be transferred external 
to Rave may include imaging results. 
Data collection on the eCRF will follow the instructions described in the eCRF Completion 
Guidelines. The Investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the eCRF. The Investigator or designee as identified on Form FDA 1572 
will sign the completed eCRF to attest to its accuracy, authenticity, and completeness. Copies of 
the completed eCRFs will be retained by each investigational center as well as Samumed. 
Clinical Data Management activities will be conducted by Samumed as described in the study-
specific Data Management Plan. 
14.2 
STUDY RECORDS RETENTION  
During this study, an Investigator is required to prepare and maintain adequate and accurate case 
histories designed to record all observations and other data pertinent to the investigation on each 
individual treated with the IP or entered as a control in the investigation. CRFs will be provided 
for each subject by the Sponsor. Data reported on the eCRFs and derived from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
completed eCRFs must be promptly reviewed, and electronically signed and dated in EDC by a 
qualified physician who is an Investigator on the study once all data is considered final. During 
this study, the Investigator must retain copies of eCRFs (or electronic files), and source 

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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. 
14.3 
PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol requirements. The 
noncompliance may be either on the part of the subject, the Investigator, or the study site staff. 
As a result of deviations, corrective actions are to be developed by the site and implemented 
promptly. Protocol deviations must be sent to the site IRB per their guidelines. The site PI/study 
staff is responsible for knowing and adhering to their IRB requirements.  
Refer to the current version of Samumed SOP-300-13 Protocol Deviations for Sponsor 
procedures related to protocol deviations. 
14.4 
PUBLICATION AND DATA SHARING POLICY 
The Sponsor encourages the scientific publication of data from clinical research studies. 
Investigators, however, may not present or publish partial or complete study results individually 
without the participation of the Sponsor. The Investigator(s) and the Sponsor may propose 
appropriate scientific manuscripts or abstracts from the study data. All proposed publications 
must be reviewed and commented on by the Sponsor before submission for publication. The 
detailed procedures for the review of publications are set out in the Clinical Trial Agreement 
entered into with the Sponsor in connection with this study. These procedures are in place to 
ensure coordination of study data publication and adequate review of data for publication against 
the validated study database for accuracy. Names of all Investigators and Sponsor representatives 
responsible for designing the study and analyzing the results will be included in the 
publication(s). 

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15. 
STUDY ADMINISTRATION 
15.1 
STUDY LEADERSHIP 
The study will be led and conducted by Samumed, LLC.  
 
 

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16. 
LITERATURE REFERENCES  
Clauw, D. J. (2014). Fibromyalgia: a clinical review. JAMA, 311(15), 1547-1555. 
doi:10.1001/jama.2014.3266 
 
Dougados, M. & Hochberg, M. C. (2011). Management of osteoarthritis. In M. C. Hochberg, A. 
J. Silman, J. S. Smolen, M. E. Weinblatt, & M. H. Weisman (Eds.), Rheumatology (5th 
Edition ed., pp. 1793-1799). PA, USA: Elsevier. 
 
Gelse, K., Ekici, A. B., Cipa, F., Swoboda, B., Carl, H. D., Olk, A., et al. (2012). Molecular 
differentiation between osteophytic and articular cartilage--clues for a transient and 
permanent chondrocyte phenotype. Osteoarthritis Cartilage, 20(2), 162-171. 
doi:10.1016/j.joca.2011.12.004 
 
Hochberg, M. C., Altman, R. D., April, K. T., Benkhalti, M., Guyatt, G., McGowan, J., et al. 
(2012). American College of Rheumatology 2012 recommendations for the use of 
nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and 
knee. Arthritis Care Res (Hoboken), 64(4), 465-474.  
 
Julious, S. A. (2005). Sample size of 12 per group rule of thumb for a pilot study. 
Pharmaceutical Statistics, 4(4), 287-291. doi:10.1002/pst.185 
 
Lawrence, R. C., Felson, D. T., Helmick, C. G., Arnold, L. M., Choi, H., Deyo, R. A., et al. 
(2008). Estimates of the prevalence of arthritis and other rheumatic conditions in the 
United States. Part II. Arthritis Rheum, 58(1), 26-35. doi:10.1002/art.23176 
 
Nevitt, M. C., Felson, D. T. & Lester, G. (2006). A Knee Health Study. "The Osteoarthritis 
Initiative.".  
 
Wu, L., Huang, X., Li, L., Huang, H., Xu, R. & Luyten, W. (2012). Insights on biology and 
pathology of HIF-1alpha/-2alpha, TGFbeta/BMP, Wnt/beta-catenin, and NF-kappaB 
pathways in osteoarthritis. Curr Pharm Des, 18(22), 3293-3312.  
 
 
 

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

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

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

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

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Excluded and prohibited centrally acting analgesics include, but are not limited to, the following: 
Gabapentin (Neurontin, Horizant, Gaberone, Gralise, Fusepaq Fanatrex) 
Pregabalin (Lyrica) 
Carbamazepine (Tegretol, Carbatrol, Epitol, Equetrol) 
Duloxetine (Cymbalta, Irenka) 
Milnacipran (Savella) 
Tramadol (Ultram, Ryzolt, Conzip, Rybix ODT, Fusepaq Synapryn) 
Tapentadol (Nucynta) 
Orphenadrine Citrate (Norflex, Orfro, Orphenate, Mio-Rel, Antiflex) 
Amitriptyline (Elavil, Vanatrip) 
Clomipramine (Anafranil) 
Nortriptyline (Aventyl, Pamelor) 
Desipramine (Norpramin) 
Imipramine (Tofranil) 
Doxepin (Prudoxin, Sinequan, Zonalon, Silenor) 
Ketamine (Ketalar) 
Sodium Oxybate (Xyrem, GHB) 
Other non-listed anticonvulsants are also prohibited 
 
Excluded and prohibited electrotherapy treatments include, but are not limited to, the following: 
Diathermy 
TENS 
NMES 
Interferential therapy 
Shortwave therapy 
Iontophoresis 
LASER 
Ultrasound 

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Appendix 3. 
Amendment 
AMENDMENT 02 VERSION 00 SUMMARY OF CHANGES 
Study Title: 
A Phase 2, 52 Week, Single Center, Open-Label Study Utilizing 
Imaging Techniques and Evaluating the Safety and Efficacy of 
SM04690 Injectable Suspension for the Treatment of Moderately to 
Severely Symptomatic Knee Osteoarthritis 
Purpose: 
The purpose of this amendment is to add pregnancy tests to visits at 
Screening and Weeks 13, 26, and 52; update language regarding 
contraception and AEs; and refine exclusion criteria. 
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 all previous and current 
protocol versions 
Added a confidentiality disclaimer to the 
Title Page. 
Title Page 
Change was made to correct an 
oversight 
Protocol date and version have been 
updated as applicable. 
All 
Change was made to reflect 
current protocol amendment 
Added Ismail Simsek as a signatory 
Signature Page 
Change was made to comply with 
sponsor SOP 
Updated titles for Ismail Simsek and 
Christopher Swearingen 
Signature Page and Key 
Roles 
Change was made for 
administrative reasons 
Changed to Naina Rastalsky as Medical 
Monitor 
Key Roles, Section 8.4.2 
Change was made for 
administrative reasons 
Updated list of abbreviations 
List of Abbreviations 
Change was made for accuracy 
Changed terminology from treatment-
emergent adverse events (AEs) to adverse 
events (AEs) 
Throughout 
Change was made to align current 
protocol with sponsor SOP 
Changed terminology from “contralateral 
knee” to “non-target knee” to describe 
knee that does not receive injection 
Throughout 
Change was made to more 
precisely describe procedures 
Updated dates of study duration 
Protocol Summary 
Change was made to reflect 
estimated time of study 
Added information to Inclusion Criteria 
#2: “Ambulatory (single assistive devices 
such as canes allowed if needed less than 
50% of the time, subjects requiring a 
walker are excluded)” 
Protocol Summary, Section 
5.2 
Change was made to better define 
ambulatory 
Added information to Inclusion Criteria 
#11: “Negative drug test for opioids and 
drugs of abuse, except alcohol and 
marijuana, amphetamine, 
methamphetamine, buprenorphine, 
cocaine, methadone, opiates, 
Protocol Summary, Section 
5.2 
Change was made to better define 
drugs of abuse 

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Change 
Sections Affected 
Rationale 
phencyclidine (PCP), propoxyphene, 
barbiturates, benzodiazepine, 
methaqualone, and tricyclic 
antidepressants, except if any such drugs 
are clinically indicated and allowed by the 
protocol, at the Screening Visit” 
Updated Exclusion Criteria 1-3 regarding 
pregnancy and birth control 
Protocol Summary, Section 
5.2 
Change was made to provide 
clarity to our criteria  
Changed Exclusion Criteria #4 from >35 
BMI to >40 BMI  
Protocol Summary, Section 
5.2 
Change was made to allow more 
subjects to meet criteria 
Modified Exclusion Criteria #8: “Previous 
randomization enrollment into a Samumed 
clinical trial investigating SM04690” 
Protocol Summary, Section 
5.2 
Change was made to refine criteria 
Changed Exclusion Criterion #10:  
Any planned surgery scheduled during… 
Protocol Summary, Section 
5.2 
Change was made to refine 
exclusion criteria 
Removed Exclusion Criteria #19: 
Treatment with systemic glucocorticoids 
greater than 10 mg prednisone or the 
equivalent per day within 4 weeks prior to 
the Screening Visit 
Protocol Summary, Section 
5.2 
Change was made because this 
Exclusion Criteria was redundant 
with later Exclusion Criteria 
regarding glucocorticoids 
Modified Exclusion Criteria #24 (#25 in 
previous Amendment): “Chronic use (i.e., 
regular and consistent use ≥ 3 days per 
week for ≥ 12 weeks) Current use, or use 
within 12 weeks prior to the Screening 
Visit, of centrally acting analgesics (e.g., 
duloxetine and tramadol) (refer to 
Appendix 2) within 12 weeks prior to the 
Screening Visit” 
Protocol Summary, Section 
5.2 
Change was made to refine 
Exclusion Criteria 
Modified Exclusion Criteria #25 (#26 in 
previous Amendment): “Chronic use (i.e., 
regular and consistent use ≥ 3 days per 
week for ≥ 12 weeks) Current use, or use 
within 12 weeks prior to the Screening 
Visit, of anticonvulsants not listed in (refer 
to Appendix 2) within 12 weeks prior to 
the Screening Visit, unless used for seizure 
or migraine prophylaxis” 
Protocol Summary, Section 
5.2 
Change was made to refine 
Exclusion Criteria 
Modified Exclusion Criterion #32 (#31 in 
this Amendment): Subjects employed by 
Samumed, LLC, or any of its affiliates or 
development partners (that is, an 
employee, temporary contract worker, or 
designee) responsible for the conduct of 
the study, or who are immediate family 
members (spouse, parent, child, or sibling; 
biological or legally adopted) of said 
employees responsible for the conduct of 
the study 
Protocol Summary, Section 
5.2 
Deleted section was repeated 
verbatim in an earlier Exclusion 
Criterion 
Updated dates and information for clinical 
trials OA-04 and OA-05 
Section 2.3 
Change was made to provide most 
recent information  

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Change 
Sections Affected 
Rationale 
Updated date for allergic reactions to study 
medication 
Section 2.3.1 
Change was made to provide most 
recent information 
Defined women and men of childbearing 
age and modified language for 
contraception for women and men 
Section 5.3.1 
Change was made to clarify rules 
regarding contraception for 
subjects 
Changed language regarding 
administration of medication by 
Investigator 
Section 6.1.5 
Change was made to provide 
better guidance to Investigators for 
proper injections 
The following was added: “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.” 
Section 7.1.1 
Change was made to provide 
guidance for study personnel 
Added the following to description of knee 
radiographs: “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.” 
Section 7.1.1 
Section was added to ensure that 
patient information was handled 
properly by study personnel. 
Changed measure of Patient Global 
Assessment of Disease Activity from a 
100 mm visual analog scale to an 11-point 
numerical rating scale 
Section 7.1.1 
Change was made for more 
accurate assessments 
Modified language for clinical laboratory 
tests: “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)” 
Section 7.2.1 
Change was made to provide 
clarity to investigators 

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Added a urine-based pregnancy test at 
Screening and Weeks 13, 26, and 52 
(EOS) / ET. Added language that 
pregnancy tests must be negative prior to 
performing radiography and MRI 
Sections 7.2.2, 7.3.3, 7.3.4 
Change was requested by study 
site for subject safety 
Added information to the informed 
consent process at the screening visit. 
Section 7.3.1 
Change was made to ensure 
compliance with sponsor and 
government regulations 
Modified Day 1 description: “The 
following procedures and assessments will 
be performed at Day 1 prior to enrollment 
study medication injection” 
Section 7.3.2 
Change was made to avoid 
confusion with the timing of 
enrollment 
Changed window for Week 39 visit from ± 
3 days to ± 7 days 
Sections 7.3.3 and 7.3.6 
Change was made to correct an 
error 
Changed description of prohibited 
medication: “Other anticonvulsants not 
listed in Appendix 2 are also prohibited 
unless used for seizure or migraine 
prophylaxis” 
Section 7.6 
Change was made to align with 
Exclusion Criteria 
Changed description of prohibited 
proecures: “Planned or elective surgery…” 
Section 7.6 
Change was made to align with 
Exclusion Criteria 
Added the following to definition of 
Adverse Events: “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.” 
Section 8.1.1 
Change was made to better define 
adverse events 
Changed one of the definitions of SAEs:  
Requires nonscheduled (not routine or 
planned) subject inpatient hospitalization 
or prolongation of existing hospitalization 
for ≥ 24 hours and admission to the 
hospital …“Inpatient hospitalization” is 
clarified as hospitalization lasting ≥24 
hours. 
Section 8.1.2 
Change was made to align with the 
FDA’s definitions of SAEs and 
with Sponsor’s AE SOP 
Removed the phrase “(or placebo)” from 
the definition of adverse events (AEs). 
Section 8.2.2 
Change was made to avoid 
confusion since this study does not 
have a placebo. 
Modified language for AE reporting: “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 8.3 
Change was made to provide 
better guidance to investigators 
Added Ashley Gantt as Clinical Project 
Manager 
Section 8.4.2 
Change was made for 
administrative reasons 
Removed paragraph relating to centralized 
data monitoring 
Section 9 
Removed because trial is a single-
center study 

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Changed title of Intent-to-Treat (ITT) 
Analysis Set to Full Analysis Set (FAS).  
Section 10.3 
Change was made for clarity 
Refined description of consent procedures 
Section 13.3.2 
Change was made to ensure better 
compliance with sponsor SOPs 
and government regulations 
Minor grammatical and formatting edits 
Throughout 
Changes were made for 
consistency.  
 
AMENDMENT 01 VERSION 00 SUMMARY OF CHANGES 
Study Title: 
A Phase 2, 52 Week, Single Center, Open-Label Study Utilizing 
Imaging Techniques and Evaluating the Safety and Efficacy of 
SM04690 Injectable Suspension for the Treatment of Moderately to 
Severely Symptomatic Knee Osteoarthritis 
Purpose: 
The purpose of this amendment is to refine and clarify the study 
design. Primary changes include removal of MRI at Week 39, removal 
of electronic diaries, removal of NRS as an endpoint assessment tool 
in the study, and addition of exploratory endpoints related to the 
contralateral (non-target) knee.  
Summary of Changes: The table below provides a list of changes and their rationale 
Change 
Sections Affected 
Rationale 
Protocol Amendment 01 Version 00 has 
been added on the title page. 
Title Page 
Change was made to capture the 
dates of all previous and current 
protocol versions 
Protocol date and version have been 
updated as applicable. 
All 
Change was made to reflect 
current protocol amendment 
Updated list of abbreviations 
List of Abbreviations 
Change was made for accuracy 
The primary objective was updated: 1. 
Evaluate the clinical efficacy of SM04690 
Injectable Suspension for the treatment of 
knee osteoarthritis (OA) via magnetic 
resonance imaging (MRI) 
Protocol Summary 
Section 3 
Change was made for accuracy 
The following secondary objectives were 
updated: 2. Evaluate the clinical efficacy 
of SM04690 Injectable Suspension for the 
treatment of knee OA as assessed by 
patient reported outcomes (PROs). 3. 
Evaluate the clinical efficacy of SM04690 
Injectable Suspension for the treatment of 
knee OA via radiograph 
Protocol Summary 
Section 3 
Change was made for accuracy 
The following secondary endpoints were 
updated/added to the study: 1.Change from 
baseline in cartilage volume and thickness 
Protocol Summary 
Section 4.2.2 
Section 10.4.3 
Change was made for accuracy 

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in the target knee as measured by 3D-
SPGR pulse sequence MRI at Weeks 13, 
39, and 52. 2. Change from baseline in 
cartilage quality in the target knee by the 
increase or decrease in proteoglycan and 
GAG content and hydration as measured 
by T1rho and T2 mapping pulse sequence 
MRI at Weeks 13, 39, and 52. 3. Change 
from baseline in total Whole Organ MRI 
Scoring (WORMS) in the target knee at 
Weeks 13, 26, and 52.  
The following exploratory endpoints were 
added to the study:  1. Change from 
baseline in cartilage volume and thickness 
in the contralateral knee as measured by 
3D-SPGR pulse sequence MRI at Weeks 
13, 26, and 52. 2. Change from baseline in 
cartilage quality in the contralateral knee 
determined by the increase or decrease in 
proteoglycan and GAG content and 
hydration as measured by T1rho and T2 
mapping pulse sequence MRI at Weeks 
13, 26, and 52. 3. Change from baseline in 
total WORMS in the contralateral knee at 
Weeks 13, 26, and 52. 4. Change from 
baseline in medial joint space width (JSW) 
as documented by radiograph of the 
contralateral knee at Weeks 26 and 52 
Protocol Summary 
Section 4.2 
Section 10.4 
Change was made for accuracy 
Daily pain NRS (except during the 
screening period) was removed from the 
study. 
Protocol Summary 
Schematic of Study Design 
Section 7.1.1 
Section 7.3.2 
Section 7.3.6 
Section 10.4.2 
Change was made to refine study 
design 
The following secondary endpoints were 
removed from the study: 4. Change from 
baseline OA pain in the target knee as 
assessed by the weekly averages of daily 
pain numeric rating score (NRS) at Weeks 
4, 13, 26, 39, and 52. 5. Change from 
baseline OA pain in the contralateral knee 
as assessed by the weekly averages of 
daily pain NRS at Weeks 4, 13, 26, 39, and 
52.  
Protocol Summary 
Section 4.2.2 
Change was made to align with 
pain NRS removal from the study  
The following exclusion criteria were 
updated 25. Chronic use (i.e., regular and 
consistent use ≥ 3 days per week for ≥ 12 
weeks) of centrally acting analgesics (e.g., 
duloxetine and tramadol) (refer to 
Appendix 2) within 12 weeks prior to the 
Screening Visit. 26. Chronic use (i.e., 
Protocol Summary 
Section 5.2 
Change was made to refine study 
design  

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regular and consistent use ≥ 3 days per 
week for ≥ 12 weeks) of anticonvulsants 
not listed in Appendix 2 within 12 weeks 
prior to the Screening Visit, unless used 
for seizure or migraine prophylaxis 
Estimated date first subject consented was 
updated to January 2018 (previously 
November 2017). 
Estimated date last subject completed was 
updated to May (previously July) 
Protocol Summary 
Change was made for accuracy  
Total WORMS analysis was added to the 
study 
Protocol Summary 
Section 7.1.1 
Section 10.4.3 
Change was made to refine study 
design 
MRI was removed from Week 39 Follow-
up Visit. 
Protocol Summary 
Schematic of Study Design 
Section 4.1 
Section 4.2.2 
Section 7.1.1 
Section 7.3.3 
Section 7.3.6 
Section 10.4.3 
Change was made to refine study 
design 
Study information for OA-04 and OA-05 
were updated 
Section 2.2 
Change was made for accuracy  
Electronic Diary/Training/Return of 
devices were removed from the study 
Schematic of Study Design 
Section 1 
Section 4.1 
Section 7.1.1 
Section 7.3.1 
Section 7.3.2 
Section 7.3.4 
Section 7.3.5 
Section 7.3.6 
Section 11 
Section 14.1 
Change was made to refine study 
design 
The pain NRS diary and study 
questionnaires for WOMAC and PGA are 
to be completed on paper (previously on 
electronic devices)  
Section 4.1 
Section 7.1.1 
Section 7.3.1 
Section 7.3.2 
Section 7.3.6 
Change was made to refine study 
design 
The following inclusion criteria was 
removed from the study: 11. Willingness 
to use an electronic diary on a daily basis 
in the evening for the screening period and 
52 week study duration.  
Protocol Summary 
Section 5.1 
Change was made to align with 
electronic diary removal from the 
study 

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Windows for Follow-up Visits where 
MRIs will be performed were expanded to 
±7 days (previously ±3 days). 
Section 7.3.3 
Section 7.3.6 
Change was made to refine study 
design