Clinical trial NCT02536833
Conditions: Osteoarthritis
Keywords: Osteoarthritis Samumed SM04690
Sponsor: Biosplice Therapeutics, Inc.
Start date: 2015-09-09; Completion date: 2017-04-20
Enrollment: 455 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the efficacy, safety, and tolerability of three different strengths of SM04690 injected in the target knee joint of moderately to severely symptomatic osteoarthritis (OA) subjects.

Detailed description:

Arms: arm 1: Single intra-articular injection of SM04690 0.03 mg in 2 mL injectable suspension arm 2: Single intra-articular injection of SM04690 0.07 mg in 2 mL injectable suspension arm 3: Single intra-articular injection of SM04690 0.23 mg in 2 mL injectable suspension arm 4: Single intra-articular injection of SM04690 0 mg in 2 mL phosphate buffered saline
Interventions: intervention 1: SM04690 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
PROTOCOL SM04690-OA-02 
(Amendment 04 Version 00,  October 13, 2016) 
 
 
 
 
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Study Evaluating the Safety, Tolerability, and Efficacy of SM04690 
Injected in the Target Knee Joint of Moderately to Severely 
Symptomatic Osteoarthritis Subjects 
 
 
 
 
NCT02536833 
 
 
 
 
 
 
 
 
 


 
 
SM04690-OA-02 AM04 V00 
Confidential and Proprietary 
 
PROTOCOL SM04690-OA-02 
 
 
Study Title:  
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study Evaluating the Safety, Tolerability, and 
Efficacy of SM04690 Injected in the Target Knee Joint of 
Moderately to Severely Symptomatic Osteoarthritis Subjects 
 
 
Protocol Number:  
 
SM04690-OA-02 
 
Investigational Product: 
 
SM04690 Injectable Suspension  
 
Clinical Phase:  
 
Phase 2 
 
Original Protocol Date: 
 
July 14, 2015  
 
Protocol AM01 V00 Date:   
August 6, 2015 
 
Protocol AM02 V00 Date:   
October 23, 2015 
 
Protocol AM03 V00 Date:  
June 22, 2016 
 
Protocol AM04 V00 Date:  
October 13, 2016 
 
Version: 
 
Amendment 04 Version 00 
 
IND:  
 
 
 
 
 
 
 
 
 
Sponsor: 
Samumed, LLC. 
 
9381 Judicial Dr., Suite 160  
 
San Diego, CA 92121 
 
(858) 926-2900 
 
 
 
Medical Monitor: 
 
 
 
This document is the sole property of Samumed, LLC. This document and any and all information 
contained herein must be considered and treated as strictly confidential. This document shall be 
used only for the purpose of the disclosure herein provided. No disclosure or publication shall be 
made without the prior written consent of Samumed, LLC. 




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PRINCIPAL INVESTIGATOR’S SIGNATURE PAGE 
Study Title 
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Study Evaluating the Safety, Tolerability, and Efficacy of SM04690 
Injected in the Target Knee Joint of Moderately to Severely Symptomatic 
Osteoarthritis Subjects 
Protocol 
Number 
SM04690-OA-02 
Protocol Date 
October 13, 2016 
Protocol Version 
AM04 V00 
I have read and understand the protocol and agree to implement the study in accordance with the 
procedures set forth in the protocol and in accordance with the Sponsor's guidelines, all 
applicable government regulations, and the International Conference on Harmonization Good 
Clinical Practice Guidelines E6 (ICH-GCP). 
I will obtain Institutional Review Board/Ethics Committee (IRB/EC) approval of the protocol 
and Informed Consent Form prior to enrollment of subjects in the study. I understand that any 
modifications to the protocol made during the course of the study must first be approved by the 
IRB/EC prior to implementation except when such modification is made to remove an immediate 
hazard to the subject. 
I will ensure that a fully executed IRB/EC-approved Informed Consent Form is obtained from 
each subject prior to initiation of any study procedures.  
I will allow the Sponsor, Samumed, LLC and its agents, as well as the United States (US) Food 
and Drug Administration (FDA) and other regulatory agencies, to inspect study facilities and 
pertinent records at reasonable times and in a reasonable manner, ensuring subject 
confidentiality. If I am notified that this study is to be inspected by a regulatory agency, I will 
notify the Sponsor as soon as possible thereafter (no later than 48 hours). 
This protocol contains information that is proprietary to Samumed, LLC. The information 
contained herein is provided for the purpose of conducting a clinical trial for Samumed, LLC. 
The contents of this protocol may only be disclosed to study personnel under my supervision and 
to my IRB/EC. The contents of this protocol may not be disclosed to any other parties (unless 
such disclosure is required by government regulations or laws) without the prior written approval 
of Samumed, LLC. 
__________________________________________ 
_______________________ 
Investigator’s Signature  
 
 
 
 
 
 
 
Date 
__________________________________________ 
Investigator’s Printed Name 


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SYNOPSIS 
Name of Sponsor/Company: 
Samumed, LLC 
Name of Investigational Product: 
SM04690 Injectable Suspension  
Name of Active Ingredient: 
SM04690 
Description of Investigational Product: 
SM04690 is a small molecule inhibitor of the Wnt pathway important in driving progenitor cells 
resident in the joint to become chondrocytes, thereby enhancing cartilage formation. SM04690 will be 
supplied as a single-use injectable formulation containing SM04690 suspended in a sodium 
carboxymethylcellulose phosphate buffered saline solution. Dose levels will be concentrations of 0.03, 
0.07 and 0.23 mg per 2 mL injection. 
Title of Study: 
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety, 
Tolerability, and Efficacy of SM04690 Injected in the Target Knee Joint of Moderately to Severely 
Symptomatic Osteoarthritis Subjects 
Study Center(s):  
This study will be conducted at up to 40 investigational centers in the United States 
Study period (years): Approximately 20 months 
Estimated date first subject enrolled: August 2015 
Estimated date last subject completed: April 2017 
Phase of development: 2 
Objectives: 
Primary: 
The primary objective of this study will be to evaluate the change from baseline OA pain in the target 
knee as assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) 
pain subscore at Week 13. 
Secondary: 
•
Evaluate change from baseline OA pain in the target knee as assessed by the WOMAC pain
subscore at Week 26
•
Evaluate change from baseline OA function in the target knee as assessed by the WOMAC
function subscore at Weeks 13 and 26
•
Evaluate change from baseline OA disease activity as assessed by the Patient Global
Assessment at Weeks 13 and 26
•
Evaluate change from baseline in medial joint space width (JSW) as documented by X-
ray of the target knee at Week 26
•
Evaluate the safety and tolerability of SM04690 by monitoring for treatment-emergent
adverse events (TEAEs)
Exploratory: 
•
Evaluate change from baseline in WOMAC total score for the target knee at Weeks 4, 13, 26,
39 and 52


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•
Evaluate change from baseline OA pain in the target knee as assessed by the WOMAC pain
subscore at Weeks 4, 39 and 52
•
Evaluate change from baseline OA function in the target knee as assessed by the WOMAC
function subscore at Weeks 4, 39 and 52
•
Evaluate change from baseline OA disease activity as assessed by the Patient Global
Assessment at Weeks 4, 39 and 52
•
Evaluate change from baseline in medial JSW as documented by X-ray of the target knee at
Week 52
•
Evaluate change from baseline in lateral JSW as documented by X-ray of the target knee at
Weeks 26 and 52
•
Determine the percentage of Outcome Measures in Rheumatology Clinical Trials
(OMERACT)-Osteoarthritis Research Society International (OARSI) responders and “strict”
responders at Weeks 13, 26, and 52
•
Evaluate change from baseline health-related quality of life (HRQOL) as assessed by the 36-
Item Short Form Health Survey (SF-36) at Weeks 4, 13, 26, 39 and 52
•
Evaluate change from baseline OA disease activity as assessed by the Physician Global
Assessment at Weeks 4, 13, 26, 39 and 52
Methodology: 
This study will be a multicenter, randomized, double-blind, placebo-controlled, parallel group study of 
three different strengths of SM04690 injected into the target knee joint of moderately to severely 
symptomatic osteoarthritis subjects. 
Approximately 445 subjects will be enrolled and randomized at a ratio of 1:1:1:1 (0.03 mg active per 2 
mL injection: 0.07 mg active per 2 mL injection: 0.23 mg active per 2 mL injection: placebo). Subjects 
will participate in a screening period of up to 21 days and a 52 week follow-up period. Clinic visits will 
be scheduled at Screening, Treatment Visit Day 1 and Follow-up Weeks 4, 13, 26, 39 and 52 [End of 
study (EOS) or Early Termination (ET)].  An interim analysis will be performed after all subjects have 
completed their Week 26 visit; however, clinical study sites and subjects will remain blinded 
throughout the study. 
Number of subjects (planned): 
Approximately 445 subjects 
Main 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.
Established diagnosis of primary femorotibial OA in the target knee by standard
American College of Rheumatology (ACR) criteria for at least 6 months (clinical AND 
radiographic criteria); if bilateral knee OA is present, the target knee is defined as the knee 
with 
greater 
pain 
at 
screening 
based 
on 
the 
subject’s 
evaluation 
and 
the 
Investigator’s clinical judgment
4.
Radiographic disease Stage 2 or 3 in the target knee according to the Kellgren-Lawrence
grading of knee OA as assessed by independent central readers
5.
Screening pain visual analog scale (VAS) score of 30-80 mm (on a scale of 0-100 mm) for the
target knee while on symptomatic oral treatment at screening (if the subject requires oral
treatment)


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6.
Total WOMAC score of 72-192 (out of 240) for the target knee while on symptomatic oral 
treatment at screening (if the subject requires oral treatment)
7.
Willingness to omit the following for 24 hours prior to all Study Visits, excluding the Screening
Visit:
a.
Pain medications
b.
Medications or supplements for the treatment of OA
c.
Participation in a formalized in-office and/or supervised OA disease program (e.g., a
prescribed patient education program, physiotherapy, etc.)
8.
Full understanding of the requirements of the study and willingness to comply with all study
visits and assessments
9.
Subjects must have read and understood the informed consent form, and must have signed it
prior to any study-related procedure being performed
10. Subject’s Day 1 visit must occur while enrollment into the study is open
Main criteria for exclusion: 
1.
Women who are pregnant or lactating
2.
Women of childbearing potential (i.e., who are not surgically sterile or postmenopausal as
defined by no menstrual periods for 12 consecutive months and no other biological or
physiological cause for amenorrhea can be identified); males who are sexually active and have
a partner who is capable of becoming pregnant, neither of which have had surgery to become
sterilized, who are not using an effective method of birth control (e.g., surgically-implanted
hormonal therapy, intrauterine devices or oral birth control with barrier method)
3.
Body mass index (BMI) >40
4.
Partial or complete joint replacement in the target knee
5.
Previous exposure to SM04690
6.
Major surgery (e.g., interventional arthroscopy) in the target knee within 52 weeks prior to any
study injection
7.
Any planned or elective surgery during the study period
8.
Significant and clinically evident misalignment of the target knee that would impact subject
function, as determined by the Investigator
9.
History of malignancy within the last 5 years; however, subjects with prior history of in situ
cancer or basal or squamous cell skin cancer are eligible. Subjects with other malignancies are
eligible if they have been continuously disease free for at least 5 years prior to any study
injection
10. Clinically significant abnormal Screening Visit hematology values, blood chemistry values,
HbA1c, or urinalysis values as determined by the investigator
11. 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
12. Comorbid conditions that could affect pain assessment of the target knee, including, but not
limited to, inflammatory rheumatic conditions such as rheumatoid arthritis, psoriatic arthritis,
systemic lupus erythematosus, diabetic neuropathy, pseudogout, gout, and fibromyalgia


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13. Other conditions that, in the opinion of the Investigator, could affect pain assessment of the
target knee, including, but not limited to, symptomatic hip osteoarthritis and symptomatic
degenerative disc disease
14. Any diagnosed psychiatric condition that includes, but is not limited to, a history of mania,
bipolar disorder, psychotic disorder, schizophrenia, major depressive disorder, or generalized
anxiety disorder
15. Participation in a clinical research trial that included the receipt of an investigational product or
any experimental therapeutic procedure within 12 weeks prior to any study injection; the last
date of participation in the trial, not the last date of receipt of investigational product, must be at
least 12 weeks prior to Study Visit Day 1
16. Treatment of the target knee with systemic or intra-articular corticosteroids (e.g.,
methylprednisolone) within 8 weeks prior to Study Visit Day 1
17. Viscosupplementation (e.g., hyaluronic acid) in the target knee within 24 weeks prior to Study
Visit Day 1
18. Effusion of the target knee clinically requiring aspiration within 12 weeks prior to Study Visit
Day 1
19. Use of electrotherapy, acupuncture, and/or chiropractic treatments for knee OA within 4 weeks
prior to Study Visit Day 1
20. Any known active infections, including 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)
21. Subjects taking prescription medications for OA who have not maintained a stable therapeutic
regimen for a minimum of 12 weeks prior to Study Visit Day 1
22. Subjects requiring the chronic use (i.e., regular and consistent use for ≥ 12 weeks) of the
medications listed below within 12 weeks prior to Study Visit Day 1.
a.
Opioids, both oral (e.g., tramadol) or transdermal (e.g., fentanyl patches) formulations
b.
Centrally acting analgesics (e.g., duloxetine)
c.
Glucocorticoids (e.g., methylprednisolone) administered by any route, with exception
of inhaled, intranasal, and ophthalmic solutions
23. 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 for a minimum
of 12 weeks prior to Study Visit Day 1. In addition, the following subjects will be excluded:
a.
Subjects with a baseline HbA1c >9
b.
Subjects with uncontrolled hypertension in the opinion of the investigator
c.
Subjects with symptomatic coronary artery disease in the opinion of the investigator
24. Subjects who have a current or pending disability claim, workers’ compensation, or litigation(s)
that may compromise response to treatment
25. Subjects who are immediate family members (spouse, parent, child, or sibling; biological or
legally adopted) of personnel directly affiliated with the study at the investigative site, or are
directly affiliated with the study at the investigative site
26. 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


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Investigational product dosage and mode of administration:  
Three strengths of intra-articularly injected SM04690 suspension will be used in this study: 
•
SM04690 0.03 mg in 2 mL Injectable Suspension
•
SM04690 0.07 mg in 2 mL Injectable Suspension
•
SM04690 0.23 mg in 2 mL Injectable Suspension
The study medication will be prepared by trained study staff and administered as a single intra-articular 
injection. 
Reference therapy dosage and mode of administration:  
The placebo therapy will be an intra-articular injection of 2 mL of phosphate buffered saline (PBS). 
Duration of treatment:  
1 day; single-dose injection 
Duration of subject participation:  
Approximately 52 weeks following a screening period of up to 21 days 
Criteria for evaluation: 
Efficacy: 
Efficacy will be assessed by: 
•
WOMAC pain and function subscores as well as WOMAC total score for the target knee
•
Patient Global Assessment
•
Percentage of OMERACT-OARSI responders and “strict” responders
•
HRQOL as assessed by SF-36
•
Physician Global Assessment
•
JSW as evaluated by X-ray
Safety: 
The overall safety and tolerability of SM04690 will be determined by the incidence, severity and 
relationship of adverse events (AE) and clinically significant changes in clinical laboratory measures 
and vital signs. 
Statistical methods: 
A sample size of approximately 445 subjects will be randomized across four treatment groups 
(0.03 mg active per 2 mL injection: 0.07 mg active per 2 mL injection: 0.23 mg active per 2 
mL injection: placebo) based on a 1:1:1:1 ratio. The sample size for this study was based upon 
accepted statistical practice and not on a formal efficacy hypothesis test and corresponding 
power analysis. 
The Safety Analysis Set will comprise all subjects who were randomized and received 
SM04690 or placebo. The Intent-to-Treat Analysis Set (ITT) will comprise subjects who were 
randomized. The Modified Intent-to-Treat Analysis Set (mITT) will comprise all randomized 
subjects who received a protocol specified dose of SM04690 or placebo. The Per Protocol 
Analysis Set (PP) will comprise ITT subjects who complied with all study procedures and 
evaluations, and did not have major protocol deviations.  
The incidence of AEs and proportion of subjects experiencing AEs will be summarized by 


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seriousness and relatedness to study product for each treatment group; severity of the AEs will 
be assessed by the Investigator according to the “Guidance for Industry: Toxicity Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Trials”. Safety 
summaries will also include listings of clinical laboratory findings, vital signs, and concomitant 
medications. 
Differences in efficacy outcomes between groups will be estimated at time points using 
parametric regression methods adjusting for baseline.  


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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ....................................................................................................2 
PRINCIPAL INVESTIGATOR’S SIGNATURE PAGE ................................................................3 
SYNOPSIS ......................................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................10 
LIST OF TABLES .........................................................................................................................13 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................14 
1. 
INTRODUCTION ......................................................................................................16 
1.1. 
Summary .....................................................................................................................16 
1.2. 
Nonclinical Assessments ............................................................................................16 
1.3. 
Study Rationale ...........................................................................................................16 
2. 
STUDY OBJECTIVES AND PURPOSE ..................................................................17 
2.1. 
Purpose .......................................................................................................................17 
2.2. 
Study Objectives .........................................................................................................17 
3. 
DESCRIPTION OF STUDY DESIGN ......................................................................18 
3.1. 
Study Endpoints ..........................................................................................................19 
3.1.1. 
Primary Endpoints ......................................................................................................19 
3.1.2. 
Secondary Endpoints ..................................................................................................19 
3.1.3. 
Exploratory Endpoints ................................................................................................19 
3.2. 
Measures to Minimize Bias ........................................................................................20 
3.2.1. 
Blinding ......................................................................................................................20 
3.2.2. 
Randomization/Assignment to Investigational Product or Placebo ...........................20 
3.2.3. 
Subject Re-screening ..................................................................................................20 
3.2.4. 
Unblinding During the Study......................................................................................20 
3.3. 
Investigational Product ...............................................................................................21 
3.3.1. 
Rationale for Dosages and Dosing Regimen ..............................................................21 
3.3.2. 
Dosages and Dosing Regimen ....................................................................................22 
3.3.3. 
Dose Modifications .....................................................................................................22 
3.3.4. 
Prior and Concomitant Medications and Procedures ..................................................22 
3.4. 
Duration of Subject Participation ...............................................................................23 
3.5. 
Procedures for Monitoring Subject Compliance ........................................................23 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................23 


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4.1. 
Inclusion Criteria ........................................................................................................24 
4.2. 
Exclusion Criteria .......................................................................................................24 
4.3. 
Strategies for Recruitment and Retention ...................................................................26 
4.4. 
Procedures for Subject Discontinuation from the Study ............................................27 
5. 
CLINICAL ASSESSMENTS .....................................................................................27 
5.1. 
Collection of Adverse Events Data .............................................................................27 
5.2. 
Clinical Laboratory Sampling.....................................................................................27 
5.3. 
Medical History ..........................................................................................................28 
5.4. 
Physical Examination .................................................................................................28 
5.4.1. 
Knee Examination ......................................................................................................29 
5.4.2. 
Vital Signs ..................................................................................................................29 
5.4.3. 
Height and Weight ......................................................................................................29 
5.5. 
Pregnancy Tests ..........................................................................................................29 
5.6. 
X-Ray of Knee Joints ..................................................................................................29 
5.7. 
Widespread Pain Index and Symptom Severity Score ...............................................30 
5.8. 
Western Ontario and McMaster Universities Arthritis Index (WOMAC) .................30 
5.9. 
Pain Visual Analog Scale (VAS) ................................................................................30 
5.10. 
Patient Global Assessment of Disease Activity ..........................................................31 
5.11. 
Physician Global Assessment of Disease Activity .....................................................31 
5.12. 
36-Item Short Form Health Survey (SF-36) ...............................................................31 
5.13. 
Documentation of Prior and Concomitant Medications .............................................31 
6. 
STUDY VISITS (SEE APPENDIX 1) .......................................................................32 
6.1. 
Screening Visit ............................................................................................................32 
6.2. 
Day 1 ...........................................................................................................................33 
6.3. 
Week 4 ........................................................................................................................33 
6.4. 
Week 13 ......................................................................................................................33 
6.5. 
Week 26 ......................................................................................................................34 
6.6. 
Week 39 ......................................................................................................................34 
6.7. 
Week 52 End of Study (EOS)/Early Termination (ET) ..............................................34 
7. 
PREMATURE DISCONTINUATION FROM STUDY............................................35 
8. 
PRODUCT SPECIFICATIONS .................................................................................35 
8.1. 
Description ..................................................................................................................35 


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8.2. 
Formulation, Packaging, and Labeling .......................................................................35 
8.3. 
Preparation of Study Medication ................................................................................35 
8.4. 
Accountability of Study Medications .........................................................................36 
9. 
SAFETY MONITORING AND ADVERSE EVENTS .............................................36 
9.1. 
Treatment-Emergent Adverse Events (TEAEs) .........................................................36 
9.2. 
Serious Adverse Events ..............................................................................................38 
9.2.1. 
Investigator Reporting Requirements for Serious Adverse Events ............................38 
9.2.2. 
Recording of SAEs .....................................................................................................39 
10. 
STATISTICAL CONSIDERATIONS .......................................................................39 
10.1. 
Sample Size Determination ........................................................................................39 
10.2. 
Randomization ............................................................................................................39 
10.3. 
Study Medication Dosing ...........................................................................................39 
10.4. 
Analysis Data Sets ......................................................................................................40 
10.5. 
Data Analyses .............................................................................................................40 
10.5.1. 
Global Parameters .......................................................................................................40 
10.5.2. 
Baseline .......................................................................................................................40 
10.5.3. 
Safety analysis ............................................................................................................40 
10.5.4. 
Interim Analysis ..........................................................................................................40 
10.5.5. 
Efficacy Analysis ........................................................................................................40 
11. 
DATA COLLECTION, STUDY MONITORING, AND DATA 
DISCLOSURE ............................................................................................................41 
11.1. 
Data Collection and Reporting ...................................................................................41 
11.2. 
Study Monitoring ........................................................................................................41 
11.3. 
Records Retention .......................................................................................................42 
11.4. 
Data Disclosure and Subject Confidentiality ..............................................................42 
11.5. 
Policy for Publication and Presentation of Data .........................................................43 
12. 
PROTECTION OF HUMAN SUBJECTS .................................................................43 
12.1. 
Declaration of Helsinki ...............................................................................................43 
12.2. 
Institutional Review Board/Ethics Committee ...........................................................43 
13. 
REFERENCES ...........................................................................................................45 
APPENDIX 1. SCHEDULE OF STUDY PROCEDURES....................................................46 


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APPENDIX 2. GUIDANCE FOR INDUSTRY: TOXICITY SCALE FOR HEALTHY 
ADULT AND ADOLESCENT VOLUNTEERS ENROLLED IN 
PREVENTIVE VACCINE TRIALS ..........................................................................47 
APPENDIX 3. AMENDMENTS ................................................................................................51 
AMENDMENT 04 VERSION 00 SUMMARY OF CHANGES..................................................51 
AMENDMENT 03 VERSION 00 SUMMARY OF CHANGES..................................................52 
AMENDMENT 02 VERSION 00 SUMMARY OF CHANGES..................................................56 
AMENDMENT 01 VERSION 00 SUMMARY OF CHANGES..................................................60 
LIST OF TABLES 
Table 1: 
Sponsor Contact Information for SAE Reporting ......................................................38 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ALP 
Alkaline phosphatase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
CFR 
Code of Federal Regulations 
CRF 
Case report form 
DLT 
Dose-limiting toxicity 
EC 
Ethics Committee 
EOS 
End of study 
FDA 
(US) Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HRQOL 
Health-related Quality of Life 
IB 
Investigator Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
Milliliter 
OA 
Osteoarthritis 
OARSI 
Osteoarthritis Research Society International 
OMERACT 
Outcome Measures in Rheumatology Clinical Trials 
OTC 
Over the counter 
PD 
Pharmacodynamics 


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Abbreviation 
Term 
PI 
Principal investigator 
PK 
Pharmacokinetics 
PP 
Per protocol 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SF-36 
36-Item Short Form Healthy Survey 
SRC 
Safety Review Committee 
SOP 
Standard operating procedure 
US 
United States 
VAS 
Visual Analog Scale 
WBC 
White blood cell 
WOMAC 
Western Ontario and McMaster Universities Arthritis Index 


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1. 
INTRODUCTION 
1.1. 
Summary 
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 et al. 2006). 
Therapies available to treat OA are limited. Most current treatments are designed only to relieve 
pain and reduce or prevent the disability caused by bone and cartilage degeneration. Drug 
therapies target the symptoms but not the cause of this disease; no treatment inhibits or reverses 
the degenerative structural changes that are responsible for its progression (Nevitt et al. 2006). 
Samumed, LLC (Samumed) is developing SM04690 for the treatment of OA. SM04690 is a 
small molecule inhibitor of the Wnt pathway.  
1.2. 
Nonclinical Assessments 
SM04690 has been tested in a number of appropriate nonclinical studies. The results of those 
studies are included in the Investigator Brochure (IB). 
1.3. 
Study Rationale 
Osteoarthritis is the most common form of arthritis and chronic joint disorder in man (Dougados 
and Hochberg 2011). The exact cause of OA is unknown, but it is associated with aging and 
normal wear on a joint. Osteoarthritis is characterized by the destruction of the articular cartilage, 
subchondral bone alterations, and synovitis. Patients present with pain and stiffness in the joints, 
with the joints becoming more stiff and immobile over time (Dougados and Hochberg 2011). 
Osteoarthritis is a leading cause of physical disability in the US (Lawrence et al. 2008).  
The Wnt pathway plays a central role in the initiation and progression of OA pathology and is 
crucial in normal joint metabolism (Hochberg et al. 2012). Wnt is a major regulator of joint 
development and is involved in the formation of bone, cartilage, and synovium. The transcription 
of Wnt target genes causes an increase in catabolic processes during the development of OA, and 
increased Wnt signaling may contribute to cartilage loss (Gelse et al. 2012). Polymorphisms in 
genes involved in Wnt signaling are associated with an increased susceptibility to OA 
development (Wu et al. 2012). Established research suggests that modulation of Wnt signaling is 
an attractive target for treatment of OA. 
In order to address the need for effective pharmaceutical agents to treat OA, Samumed has used 
structure-based drug design to synthesize a small molecule inhibitor of the Wnt pathway, 
SM04690, as a potential OA therapeutic to be administered in the form of a local injection in the 
affected joint. 
SM04690 is currently being tested in a single Phase 1 clinical trial in subjects with moderately to 
severely symptomatic osteoarthritis of the knee. The trial was a placebo-controlled, double-blind, 
dose-escalation study conducted in the US of three concentrations of SM04690 (0.03, 0.07, and 


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0.23 mg per 2 mL injection). In each dose cohort, subjects were randomized to active or vehicle 
at a ratio of 16 active: 4 vehicle. Subject clinic visits occurred on Day 1 and 2 and Weeks 1, 2, 4, 
8, 12, and 24. Each successively higher concentration cohort was enrolled after completion of 
treatment and review of safety data from the previous cohort by a Safety Review Committee. 
The Safety Review Committee was comprised of the Samumed medical monitor, the site 
Investigators, and an independent rheumatologist. As of 07 July 2015, 61 subjects have been 
enrolled in 3 ascending dose cohorts of approximately 20 subjects per cohort. Per protocol, data 
from cohort 1 and 2 were unblinded following the safety review of all subjects enrolled in the 
cohort (observed for a minimum of 12 weeks). Cohort 3 data remains blinded.  
As of 07 July 2015, following dosing in all three cohorts, there have been two dose-limiting 
toxicities (DLTs) and 1 serious adverse event (SAE) reported on the trial. A DLT of increased 
knee pain was reported and met the DLT criteria of increased pain at the target joint of greater 
than 30 mm increase on the pain visual analog scale (VAS); this DLT was due to a procedural 
error and considered unrelated to study drug. A DLT of tachycardia paroxysmal was also 
reported and met the DLT criteria of an AE deemed by the investigator to be a severe or serious 
AE. This DLT also met SAE criteria. The event was a report of tachycardia paroxysmal in a 72 
year old white male, with previous medical history of tachycardia. This event was considered 
unrelated to study drug administration by the reporting investigator. Nevertheless, as the FDA 
requested that all adverse events in this initial OA study be considered related to study drug, this 
event was reported in an expedited manner. No other DLTs or SAEs have been reported. This 
data provided justification to move forward with a Phase 2 dosing trial. 
2.
STUDY OBJECTIVES AND PURPOSE
2.1. 
Purpose 
The purpose of this study is to assess the efficacy, safety, and tolerability of three different 
strengths of SM04690 (0.03 mg, 0.07 mg, and 0.23 mg per 2 mL injection) injected in the target 
knee joint of moderately to severely symptomatic osteoarthritis subjects. 
2.2. 
Study Objectives 
Primary: 
The primary objective of this study will be to evaluate the change from baseline OA pain in the 
target knee as assessed by the Western Ontario and McMaster Universities Osteoarthritis Index 
(WOMAC) pain subscore at Week 13. 
Secondary: 
•
Evaluate change from baseline OA pain in the target knee as assessed by the WOMAC
pain subscore at Week 26
•
Evaluate change from baseline OA function in the target knee as assessed by the
WOMAC function subscore at Weeks 13 and 26
•
Evaluate change from baseline OA disease activity as assessed by the Patient Global
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•
Evaluate change from baseline in medial joint space width (JSW) as documented by X-
ray of the target knee at Week 26
•
Evaluate the safety and tolerability of SM04690 by monitoring for treatment-emergent
adverse events (TEAEs)
Exploratory: 
•
Evaluate change from baseline in WOMAC total score for the target knee at Weeks 4, 13,
26, 39 and 52
•
Evaluate change from baseline OA pain in the target knee as assessed by the WOMAC
pain subscore at Weeks 4, 39 and 52
•
Evaluate change from baseline OA function in the target knee as assessed by the
WOMAC function subscore at Weeks 4, 39 and 52
•
Evaluate change from baseline OA disease activity as assessed by the Patient Global
Assessment at Weeks 4, 39 and 52
•
Evaluate change from baseline in medial JSW as documented by X-ray of the target knee
at Week 52
•
Evaluate change from baseline in lateral JSW as documented by X-ray of the target knee
at Weeks 26 and 52
•
Determine the percentage of Outcome Measures in Rheumatology Clinical Trials
(OMERACT)-Osteoarthritis Research Society International (OARSI) responders and
“strict” responders at Weeks 13, 26, and 52
•
Evaluate change from baseline health-related quality of life (HRQOL) as assessed by the
36-Item Short Form Health Survey (SF-36) at Weeks 4, 13, 26, 39 and 52
•
Evaluate change from baseline OA disease activity as assessed by the Physician Global
Assessment at Weeks 4, 13, 26, 39 and 52
3.
DESCRIPTION OF STUDY DESIGN
This study will be a multicenter, randomized, double-blind, placebo-controlled, parallel group 
study of three different strengths of SM04690 injected into the target knee joint of moderately to 
severely symptomatic osteoarthritis subjects. 
Approximately 445 subjects will be enrolled and randomized at a ratio of 1:1:1:1 (0.03 mg active 
per 2 mL injection: 0.07 mg active per 2 mL injection: 0.23 mg active per 2 mL injection: 
placebo). Subjects will participate in a screening period of up to 21 days and a 52 week follow-
up period. Clinic visits will be scheduled at Screening, Treatment Visit Day 1 and Follow-up 
Weeks 4, 13, 26, 39 and 52 [End of study (EOS) or Early Termination (ET)]. 
The study schedule is as follows: 
•
Day -21 to -1: Screening Visit
•
Day 1: Treatment visit
•
Week 4: Follow-up visit
•
Week 13: Follow-up visit
•
Week 26: Follow-up visit


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•
Week 39: Follow-up visit
•
Week 52: End of Study (EOS) or Early Termination (ET): Follow-up visit
Specific timing of protocol procedures are described in Appendix 1. 
This study will be conducted at up to 40 investigational centers in the US. Potential subjects will 
attend a Screening Visit and participate in a screening period of no longer than 21 days.   
In this study, general medical evaluations and recording of vital signs will be performed at all 
visits. A pain VAS will be administered at the Screening Visit. X-ray imaging of the target knee 
joint will be performed at screening and at Weeks 26 and 52 (EOS)/Early Termination. A 
Widespread Pain Index and Symptom Severity Score assessment will be conducted at the 
Screening Visit only. Physical examinations will be performed at the Screening Visit (including 
knee examination), Day 1, Week 13, Week 26, Week 39 and Week 52 (EOS)/Early Termination. 
Clinical laboratory evaluations will be performed at the Screening Visit, Week 13, Week 26, 
Week 39 and Week 52 (EOS)/Early Termination. The subject will complete the WOMAC 
questionnaire, Patient Global Assessment, and SF-36 at all visits; the investigator or designated 
study staff will complete the Physician Global Assessment at all visits. Recording of signs and 
symptoms of study medication intolerability and adverse event reporting will start following the 
injection of the study medication and continue until the subject completes follow-up visit Week 
52 (EOS)/Early Termination. All AEs, whether volunteered, elicited, or noted during 
examination, will be recorded throughout the study. 
An interim analysis will be performed after all subjects have completed their Week 26 visit; 
however clinical study sites and subjects will remain blinded throughout the study. 
3.1. 
Study Endpoints 
3.1.1. 
Primary Endpoints 
The efficacy of treatment with SM04690 Injectable Suspension will be assessed by evaluating 
changes from baseline WOMAC pain subscore for the target knee at Week 13. 
3.1.2. 
Secondary Endpoints 
Efficacy will be assessed by evaluating changes from baseline WOMAC pain (Week 26) and 
function (Weeks 13 and 26) subscores and Patient Global Assessment at Weeks 13 and 26, as 
well as by evaluating change in JSW as evaluated by X-ray at Week 26.  
Safety assessments will be performed on all subjects who are administered study treatments. 
Safety assessments include vital signs, clinical laboratory sampling, solicitation of adverse 
events and concomitant medications, as well as general medical evaluations.  
Safety analyses will be conducted on data collected from all subjects who are administered study 
treatment. 
3.1.3. 
Exploratory Endpoints 
Exploratory efficacy will be assessed by evaluating changes from baseline WOMAC total score, 
HRQOL as assessed by SF-36, and Physician Global Assessment at all timepoints, as well as by 


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evaluating the percentage of OMERACT-OARSI responders and “strict” responders at Weeks 
13, 26, and 52 (Pham et al. 2003) and change in lateral JSW as evaluated by X-ray at Week 26 
and 52 and medial JSW at Week 52. Additionally, efficacy will be assessed by evaluating 
changes from baseline WOMAC pain and function subscores and Patient Global Assessment at 
Weeks 4, 39, and 52. 
3.2. 
Measures to Minimize Bias 
3.2.1. 
Blinding 
This is a double-blind study. Study medication will be provided to the investigational center. The 
investigational center must identify unblinded personnel who will be responsible for preparing 
the appropriate dilution of the study medication and who are able to perform the injection of 
study medication and/or placebo. Study personnel administering or preparing study medication 
and reference therapy must minimize any contact with the subject following the injection and 
may not perform any study assessments throughout the duration of the study. On study visit Day 
1, subjects will be randomized via the Medidata database.  
3.2.2. 
Randomization/Assignment to Investigational Product or Placebo 
Subjects will be assigned a subject number at their Screening Visit. Eligible subjects will be 
randomized at their study visit Day 1 to a blinded treatment code within the randomization 
schema. To be eligible for randomization, the subject must fulfill the following requirements: 
•
Meet all study inclusion criteria and none of the exclusion criteria
•
Have acceptable Screening clinical laboratory test results
•
Have signed the Informed Consent form
•
Comply with the study instructions
3.2.3. 
Subject Re-screening 
Subjects are allowed to be re-screened once. Re-screens are limited to subjects who did not meet 
inclusion/exclusion criteria due to a transient reason. Transient refers to self-limiting and 
predictably resolving conditions or acute events (e.g., seasonal allergies, 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).  
Subjects who failed any entry criteria in 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 must be performed at re-screen; no results or data may be 
used from the previous screen.  
3.2.4. 
Unblinding During the Study 
The blind may be broken by a qualified physician who is an Investigator in this study in the 


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event of a medical emergency in which knowledge of the identity of the study medication is 
critical to the management of the subject’s immediate course of treatment. Before breaking the 
blind, the Investigator should determine that the information is necessary (i.e., that it will alter 
the subject’s immediate course of treatment).  
If deemed necessary to break the blind for a study subject, the Samumed Medical Monitor is to 
be contacted to obtain concurrence. If it is not possible to contact the Medical Monitor 
beforehand, he or she should be contacted as soon as possible after breaking the blind for a 
subject. Details regarding the emergency unblinding will be documented in Medidata Balance 
and medical records. Instructions on how to unblind treatment assignment will be provided to 
each Investigator and kept within a guidance document at each site. No other site users will have 
access roles to Balance that will allow treatment assignment unblinding. 
Any subject whose blind has been broken will continue their follow-up visits as per protocol. 
An interim analysis will be performed after all subjects have completed their Week 26 visit; 
however clinical study sites and subjects will remain blinded throughout the study. Only the 
study sponsor will be unblinded at this time. 
3.3. 
Investigational Product 
3.3.1. 
Rationale for Dosages and Dosing Regimen 
A phase 1 clinical trial was conducted to assess the safety, tolerability, pharmacokinetics (PK), 
and pharmacodynamics (PD) of a SM04690 formulation at 3 different dose-level concentrations 
(0.03, 0.07, and 0.23 mg per 2 mL injection) injected into the intra-articular space of the OA-
affected target knee. The initial dose level of SM04690 (0.03 mg) was based on the mammalian 
species most sensitive to SM04690 in 8-week toxicology studies (the approximate residence time 
of the drug) in accordance with US Food and Drug Administration (FDA) guidelines. Preclinical 
studies to date have not demonstrated toxicity or systemic exposure at the biologically 
efficacious dose, so doses were selected that bracketed the projected biologically efficacious 
dose based on preclinical studies, hence resulting in the escalation sequence of 0.03, 0.07, and 
0.23 mg per 2 mL injection. 
As of 07 July 2015, 61 subjects have been enrolled in 3 ascending dose cohorts of approximately 
20 subjects per cohort. Per protocol, data from cohort 1 and 2 were unblinded following the 
safety review of all subjects enrolled in the cohort (observed for a minimum of 12 weeks). 
Cohort 3 data remains blinded. 
A total of 28/61 subjects have reported 68 treatment emergent adverse events (TEAEs) with 35 
preferred terms. The system organ class (SOC) most reported was ‘Musculoskeletal and 
connective tissue disorders’ with 11/61 subjects reporting 19 TEAEs of 5 preferred terms.   
As of 07 July 2015, following dosing in all three cohorts, there have been two dose-limiting 
toxicities (DLTs) and 1 serious adverse event (SAE) reported on the trial. A DLT of increased 
knee pain was reported and met the DLT criteria of increased pain at the target joint of greater 
than 30 mm increase on the pain VAS; this DLT was due to a procedural error and considered 
unrelated to study drug. A DLT of tachycardia paroxysmal was also reported and met the DLT 
criteria of an AE deemed by the investigator to be a severe or serious AE. This DLT also met 


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SAE criteria. The event was a report of tachycardia paroxysmal in a 72 year old white male, with 
previous medical history of tachycardia. This event was considered unrelated to study drug 
administration by the reporting investigator. Nevertheless, as the FDA requested that all adverse 
events in this initial OA study be considered related to study drug, this event was reported in an 
expedited manner. No other DLTs or SAEs have been reported. 
Overall, the data suggest that, at the strengths under evaluation (0.03 mg per 2 mL injection, 0.07 
mg per 2 mL injection, and 0.23 mg per 2 mL injection), this Phase 2 clinical trial with SM04690 
has the therapeutic potential to safely treat individuals with moderately to severely symptomatic 
osteoarthritis of the knee. 
3.3.2. 
Dosages and Dosing Regimen 
SM04690 will be administered in the following dosage strengths: 
•
SM04690 0.03 mg in 2 mL Injectable Suspension
•
SM04690 0.07 mg in 2 mL Injectable Suspension
•
SM04690 0.23 mg in 2 mL Injectable Suspension
•
SM04690 0 mg; placebo (PBS) injection only
Each subject will be randomly assigned to a dose at Study Visit Day 1. The injectable 
investigational product or the placebo (PBS) is to be administered as a 1-time single injection 
into the target knee joint. Only 1 knee will be treated for each subject in this study.  
Only topical anesthetic (absolutely no invasive anesthetic) is allowed for the study injections. 
Anesthetic is also not allowed to be combined with the study medication for injection. 
3.3.3. 
Dose Modifications 
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. 
3.3.4. 
Prior and Concomitant Medications and Procedures 
Prior medications are defined as medications that were taken within 30 days prior to study 
injection on Day 1. Concomitant medications are defined as medications taken any time after 
study injection on Day 1 until follow-up visit Week 52 (EOS)/Early Termination. All prior and 
new or modified concomitant therapy used during the study must be recorded on the “Prior and 
Concomitant Medications” page of the eCRF. 
Procedures that are ongoing, new, or modified at or post-Day 1 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 
adverse event (AE).  
Subjects will be encouraged to remain on a stable dose of any allowed medications throughout 
the study. The use of aspirin (325 mg/day) for thrombosis prophylaxis is permitted. 
Prohibited Concomitant Medications and Procedures: 


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•
Subjects must not take any pain medication or medications/supplements for the
treatment of OA within 24 hours prior to their scheduled visit, excluding the
Screening Visit. This includes both OTC and prescription pain medications.
•
Subjects must not participate in a formalized in-office and/or supervised OA disease
program (e.g., a prescribed patient education program, physiotherapy, etc.) within 24
hours prior to their scheduled visit, excluding the Screening Visit.
•
Intra-articular injection of steroids (glucocorticoids/corticosteroids), hyaluronic acid
derivatives, or other agents with therapeutic intent into either knee is prohibited while
the study subject is on study; intra-articular injection of steroids, hyaluronic acid
derivatives, or other therapeutic agents into joints other than the knee are allowed.
•
The following medications are prohibited while the subject is on study:
− Opioids, both oral (e.g., tramadol) or transdermal (e.g., fentanyl patches)
formulations 
− Centrally acting analgesics (e.g., duloxetine)
− Glucocorticoids (also referred to as steroids or corticosteroids such as
methylprednisolone,) administered by any route, with exception of inhaled, 
intranasal or ophthalmic application, or intra-articular injection of a non-knee 
joint. 
•
Electrotherapy and acupuncture for knee OA are prohibited while the subject is on
study.
•
Chiropractic adjustments of the knee are prohibited while the subject is on the study.
•
Planned or elective surgery, including arthroscopy, is prohibited while the subject is
on the study.
At each visit, excluding the Screening Visit, the study coordinator will ask the subject to confirm 
that no pain medications and medications/supplements for the treatment of OA were taken within 
the last 24 hours. The Investigator should notify the Samumed Medical Monitor immediately if 
any prohibited therapies are required to ensure subject safety. 
3.4. 
Duration of Subject Participation 
The duration of study participation for each subject is anticipated to be up to 55 weeks. This 
duration includes the Screening Visit during a screening period of up to 21 days, a 1-day 
treatment period occurring at Day 1, and a 52-week follow-up period.  
3.5. 
Procedures for Monitoring Subject Compliance 
Subjects will return to the clinic for scheduled visits as specified in Appendix 1. Subjects who do 
not comply with the visit schedule may be discontinued from the study. 
4.
SELECTION AND WITHDRAWAL OF SUBJECTS


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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. 
4.1. 
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.
Established diagnosis of primary femorotibial OA in the target knee by standard
American College of Rheumatology (ACR) criteria for at least 6 months (clinical AND
radiographic criteria); if bilateral knee OA is present, the target knee is defined as the
knee with greater pain at screening based on the subject’s evaluation and the
Investigator’s clinical judgment
4.
Radiographic disease Stage 2 or 3 in the target knee according to the Kellgren-Lawrence
grading of knee OA as assessed by independent central readers
5.
Screening pain visual analog scale (VAS) score of 30-80 mm (on a scale of 0-100 mm)
for the target knee while on symptomatic oral treatment at screening (if the subject
requires oral treatment)
6.
Total WOMAC score of 72-192 (out of 240) for the target knee while on symptomatic
oral treatment at screening (if the subject requires oral treatment)
7.
Willingness to omit the following for 24 hours prior to all Study Visits, excluding the
Screening Visit:
a.
Pain medications
b. Medications or supplements for the treatment of OA
c.
Participation in a formalized in-office and/or supervised OA disease program
(e.g., a prescribed patient education program, physiotherapy, etc.)
8.
Full understanding of the requirements of the study and willingness to comply with all
study visits and assessments
9.
Subjects must have read and understood the informed consent form, and must have
signed it prior to any study-related procedure being performed
10. Subject’s Day 1 visit must occur while enrollment into the study is open
4.2. 
Exclusion Criteria 
Any potential subject who meets one or more of the following criteria will not be included in this 
study: 
1.
Women who are pregnant or lactating
2.
Women of childbearing potential (i.e., who are not surgically sterile or postmenopausal
as defined by no menstrual periods for 12 consecutive months and no other biological or


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physiological cause for amenorrhea can be identified); males who are sexually active and 
have a partner who is capable of becoming pregnant, neither of which have had surgery 
to become sterilized, who are not using an effective method of birth control (e.g., 
surgically-implanted hormonal therapy, intrauterine devices or oral birth control with 
barrier method)    
3.
Body mass index (BMI) >40
4.
Partial or complete joint replacement in the target knee
5.
Previous exposure to SM04690
6.
Major surgery (e.g., interventional arthroscopy) in the target knee within 52 weeks prior
to any study injection
7.
Any planned or elective surgery during the study period
8.
Significant and clinically evident misalignment of the target knee that would impact
subject function, as determined by the Investigator
9.
History of malignancy within the last 5 years; however, subjects with prior history of in
situ cancer or basal or squamous cell skin cancer are eligible. Subjects with other
malignancies are eligible if they have been continuously disease free for at least 5 years
prior to any study injection
10. Clinically significant abnormal Screening Visit hematology values, blood chemistry
values, HbA1c, or urinalysis values as determined by the investigator
11. 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
12. Comorbid conditions that could affect pain assessment of the target knee, including, but
not limited to, inflammatory rheumatic conditions such as rheumatoid arthritis, psoriatic
arthritis, systemic lupus erythematosus, diabetic neuropathy, pseudogout, gout, and
fibromyalgia
13. Other conditions that, in the opinion of the Investigator, could affect pain assessment of
the target knee, including, but not limited to, symptomatic hip osteoarthritis and
symptomatic degenerative disc disease
14. Any diagnosed psychiatric condition that includes, but is not limited to, a history of
mania, bipolar disorder, psychotic disorder, schizophrenia, major depressive disorder, or
generalized anxiety disorder
15. Participation in a clinical research trial that included the receipt of an investigational
product or any experimental therapeutic procedure within 12 weeks prior to any study
injection; the last date of participation in the trial, not the last date of receipt of
investigational product, must be at least 12 weeks prior to Study Visit Day 1
16. Treatment of the target knee with systemic or intra-articular corticosteroids (e.g.,
methylprednisolone) within 8 weeks prior to Study Visit Day 1


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17. Viscosupplementation (e.g., hyaluronic acid) in the target knee within 24 weeks prior to 
Study Visit Day 1  
18. Effusion of the target knee clinically requiring aspiration within 12 weeks prior to Study 
Visit Day 1 
19. Use of electrotherapy, acupuncture, and/or chiropractic treatments for knee OA within 
4 weeks prior to Study Visit Day 1 
20. Any known active infections, including 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) 
21. Subjects taking prescription medications for OA who have not maintained a stable 
therapeutic regimen for a minimum of 12 weeks prior to Study Visit Day 1  
22. Subjects requiring the chronic use (i.e., regular and consistent use for ≥ 12 weeks) of the 
medications listed below within 12 weeks prior to Study Visit Day 1: 
a. Opioids, both oral (e.g., tramadol) or transdermal (e.g., fentanyl patches) 
formulations 
b. Centrally acting analgesics (e.g., duloxetine) 
c. Glucocorticoids (e.g., methylprednisolone) administered by any route, with 
exception of inhaled, intranasal, and ophthalmic solutions 
23. 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 
for a minimum of 12 weeks prior to Study Visit Day 1. In addition, the following subjects 
will be excluded: 
a. Subjects with a baseline HbA1c >9 
b. Subjects with uncontrolled hypertension in the opinion of the investigator 
c. Subjects with symptomatic coronary artery disease in the opinion of the 
investigator 
24. Subjects who have a current or pending disability claim, workers’ compensation, or 
litigation(s) that may compromise response to treatment  
25. Subjects who are immediate family members (spouse, parent, child, or sibling; biological 
or legally adopted) of personnel directly affiliated with the study at the investigative site, 
or are directly affiliated with the study at the investigative site  
26. 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 
4.3. 
 Strategies for Recruitment and Retention  
The Investigator is responsible for retention of study subjects at the study site. Specific training 
regarding retention of study subjects will be provided by the Sponsor to all sites after all subjects 
have completed the Week 26 visit. This training will include strategies that the sites should 


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employ to maintain best efforts for subject retention. The Sponsor is responsible for tracking 
participation to ensure proper retention of study subjects and will work with the site(s) to 
develop a site-specific action plan if needed. 
4.4. 
Procedures for Subject Discontinuation from the Study 
As the study treatment requires only a single injection, best efforts will be made to encourage 
subjects to attend all follow-up visits. Nevertheless, subjects will be informed that they are free 
to withdraw from the study at any time and for any reason.  
The Investigator may remove a subject from the study if, in the Investigator's opinion, it is not in 
the best interest of the subject to continue in the study; refer to Section 7 for further details. 
Notification of discontinuation will immediately be made to the Sponsor’s medical monitor. In 
case of premature discontinuation of study participation, efforts will be made to perform all final 
study day [Week 52 (EOS)/Early Termination] assessments within 14 days of subject 
discontinuation. The date the subject is withdrawn from the study and the reason for 
discontinuation will be recorded on the subject’s case report form (CRF).  
The study may be discontinued at the discretion of the Investigator or the Sponsor. 
5.
CLINICAL ASSESSMENTS
5.1. 
Collection of Adverse Events Data
Data regarding treatment-emergent adverse events (TEAEs) will be collected in this study. 
TEAEs are events that occur during the course of the study that are not present prior to Day 1 
study medication injection, or, if present at the time of study medication injection, have 
worsened in severity during the course of the study. Adverse events will be assessed at each 
study visit from the time of study medication injection on study visit Day 1 through Week 52 
(EOS)/Early Termination.  
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 will 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 adverse event: description of the 
event, date of onset and resolution, 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 2), causal relationship to study medication, outcome, and 
any treatment given. 
Adverse events 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. 
5.2. 
Clinical Laboratory Sampling 
Non-fasting samples for clinical laboratory analysis will be collected by a qualified staff member 


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at the Screening Visit and follow-up visit Weeks 13, 26, 39, and 52 (EOS)/Early Termination. At 
a minimum, the following tests will be conducted: 
•
Chemistry panel: Albumin, alkaline phosphatase (ALP), alanine aminotransferase
(ALT), aspartate aminotransferase (AST), blood urea nitrogen, bicarbonate, calcium
(corrected total), chloride, creatinine, glucose, lactate dehydrogenase (LDH),
potassium, sodium, bilirubin (total)
•
Hematology: Hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell
(WBC) count with differential, and platelet count
•
Urinalysis: Clarity, specific gravity, pH, protein, glucose, ketones, nitrite, leukocytes,
and occult blood
A urine-based pregnancy test will be performed on female subjects at the Screening Visit and at 
study visit Day 1, prior to study medication injection. 
An HbA1c test will be performed on all subjects at the Screening Visit. 
Urine microscopy will be performed if urinalysis values are out of range and 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 
randomized on Day 1 if any of the Screening Visit results are outside the normal range for the 
laboratory AND, in the opinion of the Investigator, are clinically significant.  
The results of the clinical laboratory tests will be reported on the laboratory’s standard reports. 
The Investigator must review all laboratory reports in a timely manner, noting “not clinically 
significant” (NCS) or comment on the clinical significance (clinically significant: yes/no) of any 
result that is outside the normal range for the laboratory or has a toxicity grade of 1 or greater, 
then date and initial the report. The Investigator must report all laboratory results that are BOTH 
outside the normal range for the laboratory or has a toxicity grade of 1 or greater AND, in the 
opinion of the Investigator, are clinically significant. If any abnormal, clinically significant 
laboratory measure is found prior to study medication injection, the subject is to be excluded. If 
it is found after study medication injection, it should be reported as an AE (see Section 9). 
5.3. 
Medical History 
A medical history will be obtained at screening with a follow-up at end of study or Early 
Termination. Medical history will include demographic data (e.g., age, race/ethnicity). In 
addition, medical information will also be recorded, including all (1) medical conditions and 
disease states that require current or ongoing therapy and (2) other medical conditions and 
disease states that, in the opinion of the Investigator, are relevant to the subject’s study 
participation. Review of medical history at the Week 52 (EOS)/Early Termination visit will only 
be to capture End Dates of any ongoing medical history collected at screening. 
5.4. 
Physical Examination 
A general physical examination will be conducted at the Screening Visit, Day 1, and Weeks 13, 
26, 39, and 52 (EOS)/Early Termination. Results of the physical examination will be noted in the 


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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 (see Section 9). 
5.4.1. 
Knee Examination 
A knee examination will be conducted at the Screening Visit. Results of the knee examination 
will be noted in the source documents. Presence of bilateral knee OA (yes/no) will be recorded in 
the eCRF. If the subject has osteoarthritis in both knees, the site is to establish the target knee as 
the knee with greater pain at screening based on the subject’s evaluation and the Investigator’s 
clinical judgment. 
Misalignment of the target knee will be assessed by the Investigator during the knee examination 
at the Screening Visit. Presence of significant misalignment of the target knee (yes/no) will be 
recorded in the eCRF. In the opinion of the Investigator, subjects with significant and clinically 
evident misalignment of the target knee that would impact subject function must be excluded 
from the study. 
5.4.2. 
Vital Signs 
Vital signs will be measured by a qualified staff member at all visits. 
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 sits for at least 5 minutes 
Any measurement that is, in the opinion of the Investigator, abnormal AND clinically significant 
must be recorded as medical history if found prior to study medication injection or as an AE if 
found after study medication injection (see Section 9). 
5.4.3. 
Height and Weight 
Height measurements will be taken at the Screening Visit only. Weight measurements will be 
taken at the Screening Visit and follow-up visit Week 52 (EOS)/Early Termination. 
5.5. 
Pregnancy Tests 
A urine-based pregnancy test will be performed on female subjects at the Screening Visit and at 
study visit Day 1, prior to study medication injection.  
5.6. 
X-Ray of Knee Joints 
X-ray of the knee joints will be taken during the screening period and follow-up visit Weeks 26 
and 52 (EOS)/Early Termination. The screening X-ray is to be taken within 21 days before study 
visit Day 1 and must be taken according to the guidance provided by the independent radiologist. 
Detailed instructions for obtaining and managing the X-rays will be provided to the 


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investigational center prior to the initiation of subject enrollment. The intent (and included in the 
Image Review Charter – Image Acquisition guidelines) is that X-rays should be obtained in the 
posterior-anterior (PA) view, whenever possible. The Image Acquisition Protocol allows for 
anteroposterior (AP) view when PA view X-ray cannot be acquired.  
All radiographs will be submitted to an independent radiologist who will document disease stage 
according to the Kellgren-Lawrence grading scale for compliance with enrollment criteria, as 
well as joint space width for efficacy assessments. 
5.7. 
Widespread Pain Index and Symptom Severity Score 
A Widespread Pain Index and Symptom Severity Score assessment will be performed at the 
Screening Visit only. This assessment consists of a set of questionnaires that determine a 
subject’s areas of pain or tenderness and the severity of specified symptoms (Clauw 2014).  
Upon completion of the Widespread Pain Index and Symptom Severity Score assessment, both 
the subject and the study staff member will sign/initial and date the source document to indicate 
that the assessments are reported accurately. 
The Widespread Pain Index and Symptom Severity Score assessment sheets will be provided by 
the Sponsor and may not be reproduced. 
5.8. 
Western Ontario and McMaster Universities Arthritis Index 
(WOMAC) 
The subject will complete the WOMAC Version NR3.1 questionnaire at all visits; at the Day 1 
visit, the subject will complete the questionnaire prior to study injection. 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 the joints.  
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. 
5.9. 
Pain Visual Analog Scale (VAS) 
A pain VAS for the target knee will be administered at the Screening Visit. The VAS is a 
psychometric response scale. The subject will be asked on a 100 mm scale to rate their knee 
arthritis pain from “No pain” (left anchor) to “Pain as bad as it could be” (right anchor), 
considering the last 48 hours. 
Upon completion of the pain VAS, both the subject and the study staff member will sign/initial 
and date the source document to indicate that the pain assessment is reported accurately. The 
study staff member will record the pain VAS score in the eCRF. The score is determined by 


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measuring the distance (mm) between the “No pain” anchor and the subject’s mark, providing a 
range of scores from 0 to 100. 
The VAS questionnaires will be provided by the Sponsor and may not be reproduced. 
5.10. 
Patient Global Assessment of Disease Activity 
The Patient Global Assessment will be performed at all visits; at the Day 1 visit, the subject will 
complete the assessment prior to study injection. The Patient Global Assessment will be a 100 
mm VAS scale on which the subject will rate how well they are doing, considering all the ways 
in which illness and health conditions may affect him/her. The VAS scale will be anchored by 
descriptors at each end (“Very Well” on the left and “Very Poorly” on the right). 
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 score is determined by measuring the distance (mm) between the “Very Well” 
anchor and the subject’s mark, providing a range of scores from 0 to 100. 
The Patient Global Assessment of Disease Activity questionnaires will be provided by the 
Sponsor and may not be reproduced. 
5.11. 
Physician Global Assessment of Disease Activity 
The Physician Global Assessment will be performed at all visits; at the Day 1 visit, the 
assessment will be performed prior to study injection. The Physician Global Assessment will be 
a 100 mm VAS scale on which the investigator will rate the subject’s disease activity 
independent of the patient’s self-assessment. The VAS scale will be anchored by descriptors at 
each end (“Very Good” on the left and “Very Bad” on the right). 
The investigator completing the Physician Global Assessment must sign/initial and date the 
source document to indicate that the assessment is reported accurately. A study staff member 
will record the Physician Global Assessment score in the eCRF. The score is determined by 
measuring the distance (mm) between the “Very Good” anchor and the Investigator’s mark, 
providing a range of scores from 0 to 100. 
The Physician Global Assessment of Disease Activity questionnaires will be provided by the 
Sponsor and may not be reproduced. 
5.12. 
36-Item Short Form Health Survey (SF-36) 
The SF-36 will be administered at all visits; at the Day 1 visit, the assessment will be performed 
prior to study injection. The SF-36 is a widely-used questionnaire which relies upon subject self-
reporting and measures the subject’s health-related quality of life. 
Upon completion of the SF-36, both the subject and the study staff member will sign/initial and 
date the source document to indicate that the quality of life assessments are reported accurately. 
The SF-36 questionnaires will be provided by the Sponsor and may not be reproduced. 
5.13. 
Documentation of Prior and Concomitant Medications 


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Details regarding the name, indication, route of administration, dose, and frequency of all 
medications taken within 30 days prior to study injection on Day 1 will be recorded in the eCRF. 
Details regarding the name, indication, route of administration, dose, and frequency of all 
medications taken after study injection will be recorded in the eCRF at study visit Day 1, Week 
4, 13, 26, 39, and 52 (EOS)/Early Termination. “All medications” should include prescription, 
over the counter, supplements, as well as herbal or alternative medications. 
 
6. 
STUDY VISITS (SEE APPENDIX 1) 
The following procedures are to be performed at each study visit.  
6.1. 
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 the informed consent form. Written 
informed consent must be provided by the potential study participant prior to initiation of any 
screening evaluations or other study-related procedures. The signature, date, and the name of the 
individual at the site who obtained the informed consent will be recorded in the subject’s source 
record. After written informed consent is obtained, the subject will be assigned a subject number.  
The following procedures and assessments will be performed within 21 days prior to study visit 
Day 1: 
• Documentation of demographic information, including date of birth, gender, race, and 
ethnicity 
• 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 
• Vital signs measurements (pulse, blood pressure, respiration rate, and temperature) 
• Height and weight measurements 
• Venipuncture and collection of samples for clinical laboratory tests 
• Pregnancy test (urine-based) 
• X-ray – bilateral in weight bearing fixed flexion position, posterior-anterior view 
• Widespread Pain Index and Symptom Severity Score assessment 
• WOMAC and pain VAS assessments 
• Patient Global Assessment and Physician Global Assessment 
• SF-36 
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. 


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6.2. 
Day 1 
This visit must occur within 21 days of the Screening Visit. 
The following procedures and assessments will be performed at Day 1 prior to randomization: 
• Physical examination 
• Vital signs measurements (pulse, blood pressure, respiration rate, and temperature) 
• Pregnancy test (urine-based) 
Results from these evaluations will be compared with inclusion/exclusion criteria to determine 
subject eligibility. 
The following procedures and assessments are also to be performed prior to randomization; 
however, results from the following evaluations do not determine eligibility. 
• WOMAC assessment, Patient Global Assessment, and Physician Global Assessment 
• SF-36 
The following procedures and assessments will be performed at Day 1 following randomization: 
• Intra-articular study medication injection (or placebo) 
• Collection of AE and concomitant medication data 
6.3. 
Week 4 
This follow-up visit should occur 28 days after study medication injection with a window of 
± 3 days.  
The following procedures and assessments will be performed at follow-up visit Week 4: 
• Collection of AE and concomitant medication data 
• Vital signs measurements (pulse, blood pressure, respiration rate, and temperature) 
• WOMAC assessment, Patient Global Assessment, and Physician Global Assessment 
• SF-36 
6.4. 
Week 13 
This follow-up visit should occur 91 days after study medication injection with a window of 
± 3 days.  
The following procedures and assessments will be performed at follow-up visit Week 13: 
• Collection of AE and concomitant medication data 
• Vital signs measurements (pulse, blood pressure, respiration rate, and temperature) 
• Physical examination 
• Venipuncture and collection of samples for clinical laboratory tests 
• WOMAC assessment, Patient Global Assessment, and Physician Global Assessment 


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•
SF-36
6.5. 
Week 26
This follow-up visit should occur 182 days after study medication injection with a window of 
- 10 days.  
The following procedures and assessments will be performed at follow-up visit Week 26: 
•
Collection of AE and concomitant medication data
•
Vital signs measurements (pulse, blood pressure, respiration rate, and temperature)
•
Physical examination
•
Venipuncture and collection of samples for clinical laboratory tests
•
WOMAC assessment, Patient Global Assessment, and Physician Global Assessment
•
SF-36
•
X-ray – bilateral in weight bearing fixed flexion position, posterior-anterior view
6.6. 
Week 39
This follow-up visit should occur 273 days after study medication injection with a window of 
± 3 days.  
The following procedures and assessments will be performed at follow-up visit Week 39: 
•
Collection of AE and concomitant medication data
•
Vital signs measurements (pulse, blood pressure, respiration rate, and temperature)
•
Physical examination
•
Venipuncture and collection of samples for clinical laboratory tests
•
WOMAC assessment, Patient Global Assessment, and Physician Global Assessment
•
SF-36
6.7. 
Week 52 End of Study (EOS)/Early Termination (ET)
This follow-up visit should occur 365 days after study medication injection with a window of 
± 7 days, or within 14 days of subject premature discontinuation. 
The following procedures and assessments will be performed at follow-up visit Week 52 
(EOS)/Early Termination: 
•
Collection of AE and concomitant medication data
•
Physical examination
•
Review of medical history
•
Vital signs measurements (pulse, blood pressure, respiration rate, and temperature)
•
Weight measurement
•
Venipuncture and collection of samples for clinical laboratory tests


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•
WOMAC assessment, Patient Global Assessment, and Physician Global Assessment
•
SF-36
•
X-ray– bilateral in weight bearing fixed flexion position, posterior-anterior view
7.
PREMATURE DISCONTINUATION FROM STUDY
As the study treatment requires only a single injection, best efforts will be made to encourage 
subjects to attend all follow-up visits. A premature discontinuation from study will occur when a 
subject who signed informed consent ceases participation in this study, regardless of 
circumstances, prior to completion of the defined study period. Subjects can be prematurely 
discontinued from the study for one of the following reasons:  
•
Death
•
Lost to follow-up after a minimum of 2 attempts have been made to contact the
subject, including sending a registered letter
•
Subject withdraws consent
The reason for the discontinuation should be recorded on the eCRF. The Investigator or designee 
must complete all applicable eCRF pages for subjects who discontinue from the study 
prematurely. Week 52 (EOS)/Early Termination procedures should be conducted within 14 days 
of discontinuation for any subject who discontinues after study injection on Day 1. 
The principal 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 
reasons. 
8.
PRODUCT SPECIFICATIONS
8.1. 
Description
SM04690 drug substance is an off-white powder. SM04690 drug product is a sterile suspension 
in diluent containing 0.5% carboxymethylcellulose sodium and 0.05% polysorbate 80 in pH 7.4 
phosphate buffered saline. SM04690 drug product is 2 mL in a 3 mL Type I glass vial. A 
separate 3 mL Type I glass vial contains 2 mL of vehicle to be used as a diluent. The placebo 
will be phosphate buffered saline and is provided in a different container.  
8.2. 
Formulation, Packaging, and Labeling 
SM04690 and vehicle will be supplied as single-use injections. SM04690, vehicle, and placebo 
will be supplied to the study pharmacist and labeled according to the applicable local and 
country regulations. For dispensing and labeling instructions, refer to the Pharmacy Manual. 
8.3. 
Preparation of Study Medication 
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. Each placebo will be prepared by taking a known volume of PBS and adding to a 


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saline vial, mixing well, and then injecting 2 mL intra-articularly. Refer to the Pharmacy Manual 
for detailed instructions on study medication preparation.  
8.4. 
Accountability of Study Medications 
All study medication 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, PBS vial, and saline vial) 
• Quantity returned (active vial, vehicle vial, PBS vial, and saline vial) 
All study medication received, prepared, and dispensed by the unblinded Investigator and/or 
unblinded designee will be inventoried and accounted for throughout the study. The study 
medication 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 72 hours and only during study medication shipment. The 
unblinded Investigator and/or unblinded designee must maintain an accurate, up-to-date 
dispensing log for all study medications supplied by the Sponsor. Study medication dispensed for 
all subjects must be recorded on the drug accountability forms. The study medication dispensing 
log and remaining drug inventory will be reviewed by the Sponsor-designated unblinded clinical 
monitor. 
The study medication supplied for this study is for use only in subjects properly consented and 
enrolled into this protocol. Used and unused study medications must be kept in a secure, blinded 
location physically separated from standard clinic or office drug supplies and with access limited 
to the unblinded Investigator and/or unblinded designee. 
9. 
SAFETY MONITORING AND ADVERSE EVENTS 
9.1. 
Treatment-Emergent Adverse Events (TEAEs) 
Data regarding TEAEs will be collected in this study. TEAEs are events that are not present prior 
to study medication injection or, if present prior to study medication injection, have worsened in 
severity. 
The reporting period for AEs starts after the injection of study medication on Day 1 and ends 
after the final study visit. 
Definition of Adverse Events: 
Adverse events in the eCRF will be classified according to the most recent US FDA definitions 
and in a manner consistent with ICH guidelines. As such the following definitions will be used: 
An adverse event (AE) is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational (medicinal) product (IP) or other protocol-imposed 
intervention, regardless of attribution. An AE may include intercurrent illnesses or injuries that 
represent an exacerbation (increase in frequency, severity, or specificity) of preexisting 
conditions (e.g., worsening of asthma).  


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The Investigator must report all laboratory results that are BOTH outside the normal range for 
the laboratory or has a toxicity grade of 1 or greater AND, in the opinion of the Investigator, are 
clinically significant. If any abnormal, clinically significant laboratory measure is found after 
informed consent but 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.  
Whenever possible, it is preferable to record a diagnosis as the AE term rather than a series of 
symptoms relating to a diagnosis. In order to classify AEs and diseases, preferred terms will be 
assigned by the Sponsor to the original terms entered on the eCRF, using the Medical Dictionary 
for Regulatory Activities (MedDRA).  
The Investigator will assess AEs for severity utilizing the “Guidance for Industry: Toxicity Scale 
for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Trials”. This 
toxicity scale is presented in Appendix 2. Laboratory values not listed on the toxicity scale will 
be assessed for severity by the clinical Investigator. 
All adverse events that occur during this trial will be considered related to the study treatment. 
For future planning and informational purposes, the investigator opinion regarding the 
relatedness of the adverse event is to be collected for all adverse events. All adverse events that 
occur within the trial will continue to be reported to all regulatory authorities as well as 
summarized in the final clinical study report as related to study medication. The Investigator will 
determine the relationship of an AE to study treatment and will record it on the source 
documents and eCRF using the categories defined below.  
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 placebo) 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 placebo) 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 placebo) 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 placebo) 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 placebo) or administration of the study 
injection. 
4.  Probably Related 
Exposure to the investigational product (or placebo) or administration of the study injection and 
AE are probably related if (1) the investigational product (or placebo) or study injection and AE 
are considered reasonably related in time and (2) the investigational product (or placebo) or 


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study injection is more likely than other causes to be responsible for the AE or is the most likely 
cause of the AE. 
Adverse events must be followed until resolution by the PI. Resolution is defined as the return to 
baseline status or stabilization of the condition with the expectation that it will remain chronic. 
Adverse events 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. 
9.2. 
Serious Adverse Events 
According to the ICH Guidelines for Good Clinical Practice (E6), an SAE is any untoward 
medical occurrence during the course of a clinical investigation that is characterized by 1 or 
more of the following: 
• Results in death 
• Is life threatening 
• Requires nonscheduled (not routine or planned) subject hospitalization or 
prolongation of existing hospitalization for ≥ 24 hours and admission to the hospital 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is an important medical event, defined as an event that does not fit one of the other 
outcomes, but may jeopardize the subject and may require medical or surgical 
intervention (treatment) to prevent one of the other outcomes. Examples include 
allergic bronchospasm (a serious problem with breathing) requiring treatment in an 
emergency room, serious blood dyscrasias (blood disorders), or seizure/convulsion 
that does not result in hospitalization. The development of drug dependence or drug 
abuse would be other examples of important medical events. 
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 the SAE reporting process. 
9.2.1. 
Investigator Reporting Requirements for Serious Adverse Events 
All SAEs must be reported as described in the study manual at sae@samumed.com or by FAX 
by the Investigator, study coordinator, other designated study personnel, or clinical research 
associate within 24 hours of notification of the SAE. Follow-up information must be reported to 
the medical monitor 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 SAE reporting if needed is provided in Table 1. 
 
Table 1: 
Sponsor Contact Information for SAE Reporting 
Primary Contact 
Alternative Contact 


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Medical Monitor: 
 
Vice President of Clinical Development: 
 
 
Office Tel:  
 
Office Tel:  
 
Office Fax:  
 
Office Fax:  
 
Cellular: 
 
Cellular: 
 
Email: 
 
Email: 
 
9.2.2. 
Recording of SAEs 
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. 
10.
STATISTICAL CONSIDERATIONS
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 
completion of the study. The study assesses the efficacy, safety, and tolerability of SM04690. 
Approximately 445 subjects will be enrolled and randomized in this study. 
10.1. 
Sample Size Determination 
A sample size of approximately 445 randomized subjects is selected for this exploratory study. 
The sample size for this study was based upon accepted statistical practice (Piantadosi 1997).  
10.2. 
Randomization 
Subjects will be randomized 1:1:1:1 (0.03 mg active per 2 mL injection: 0.07 mg active per 2 mL 
injection: 0.23 mg active per 2 mL injection: placebo) to each dose group using a permuted block 
design stratified by each site. Specific information regarding the use of Medidata Balance to 
store and implement the permuted block design will be detailed within the statistical analysis 
plan. 
10.3. 
Study Medication Dosing 
Three strengths of SM04690 injectable suspension and placebo will be used in this study: 
•
SM04690 0.03 mg in 2 mL Injectable Suspension
•
SM04690 0.07 mg in 2 mL Injectable Suspension
•
SM04690 0.23 mg in 2 mL Injectable Suspension
•
SM04690 0 mg; placebo (PBS) injection only


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10.4. 
Analysis Data Sets 
Intent-to-Treat (ITT) Analysis Set: All subjects who were randomized (SM04690 or placebo). 
Modified Intent-to-Treat (mITT) Analysis Set: ITT subjects who received a protocol specified 
dose of SM04690 or placebo, analyzed as treated. Subjects incorrectly receiving doses not 
prescribed by the protocol are excluded from this analysis set. 
Per-Protocol Analysis Set: ITT subjects who complied with all study procedures and 
evaluations, and did not have any major protocol deviations  
Safety Analysis Set: Subjects who were randomized and received SM04690 or placebo will be 
included in the safety analyses.  
10.5. 
Data Analyses 
10.5.1. 
Global Parameters 
For all analyses detailed here, the following global parameters will be used. For continuous 
variables, number of subjects in the analysis, mean, standard deviation (SD), median, minimum, 
and maximum will be reported. All categorical endpoints will be summarized using frequencies 
and percentages. 
10.5.2. 
Baseline 
For comparisons with baseline within each analysis population, baseline is defined as the last 
value recorded for any given parameter prior to study medication injection at Day 1. 
10.5.3. 
Safety analysis 
Safety assessments will be performed on all subjects who were randomized and received the 
study medication injection (SM04690 or placebo). 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, severity, and seriousness of treatment-emergent AEs 
and by changes in clinical laboratory parameters and vital signs, relative to baseline. 
10.5.4. 
Interim Analysis 
An interim analysis will be performed after all subjects have completed their Week 26 visit; 
however clinical study sites and subjects will remain blinded throughout the study. The aim of 
this interim analysis is to assess safety and efficacy objectives at Weeks 13 and 26. No trial 
adaptation(s) will be made based upon these results. 
10.5.5. 
Efficacy Analysis 
Efficacy analysis will be performed on the ITT, mITT, and PP Analysis Sets. Change in primary 
and secondary efficacy endpoints from baseline will be estimated at specified time points using 
parametric analysis of covariance (ANCOVA) models. Formal hypothesis testing between 
treatment groups will be conducted using a strategy to control the familywise error rate; the error 
rate strategy is detailed in the study’s SAP. 


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Exploratory efficacy analysis will be performed on the ITT, mITT, and PP analysis sets. Change 
in WOMAC total, WOMAC pain subscore, WOMAC function subscore, Patient Global 
Assessment, Physician Global Assessment, JSW and HRQOL from baseline will be estimated at 
specified time points using parametric analysis of covariance (ANCOVA) models. Logistic 
regression will be used to analyze the proportion of OARSI responders within each treatment 
group compared to placebo at specified time points. Exploratory subgroup analyses may also be 
performed. 
11. 
DATA COLLECTION, STUDY MONITORING, AND DATA 
DISCLOSURE 
11.1. 
Data Collection and Reporting 
The Investigator must maintain required records for all study subjects. Data for this study will be 
recorded in the subject's source document 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: 
• The oral and written communication with the subject regarding the study treatment 
(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 
• The subject’s exposure to study medication  
• All AEs 
• The subject’s exposure to any concomitant therapy (including start and stop dates, 
route of administration, and dosage) 
11.2. 
Study 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. 
All eCRFs will be 100% source verified against corresponding source documentation (e.g., 


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office and clinical laboratory records) for each subject. Clinical monitors will periodically 
evaluate the progress of the study, including the verification of appropriate consent form 
procedures, review of drug accountability and preparation procedures, adherence to dosing 
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. 
11.3. 
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 investigational product or entered as a control in the investigation. 
Case report forms 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, signed, and 
dated by a qualified physician who is an Investigator on the study. During this study, the 
Investigator must retain study medication (investigational product and placebo) disposition 
records, copies of eCRFs (or electronic files), and source documents for the maximum period 
required by (1) applicable regulations and guidelines or institution procedures or (2) for the 
period specified by the Sponsor, whichever is longer. The Investigator must contact the Sponsor 
prior to destroying any records associated with the study. 
The Sponsor will notify the Investigator when the study records are no longer needed. 
In the event the Investigator withdraws from the study (e.g., relocation, retirement), the records 
shall be transferred to a mutually agreed-upon designee (e.g., another Investigator). Notice of 
such transfer will be given in writing to the Sponsor. 
The Investigator must ensure that clinical study records are retained according to national 
regulations, as documented in the Clinical Trial Agreement entered into with the Sponsor in 
connection with this study. For example, US federal laws require that an Investigator maintain all 
study records for the indication under investigation for 2 years following the date of a New Drug 
Application approval or, if no application is filed or if the application is not approved for such 
indication, until 2 years after the investigation is discontinued and the FDA is notified. 
The Sponsor will maintain correspondence with the Investigator after study closeout to ensure 
that study documentation is retained for the appropriate amount of time. Subject files and other 
source data must be kept for the maximum period of time permitted by the hospital, institution, 
or private practice and should be retained in accordance with applicable legislation. The 
Investigator must inform the Sponsor immediately if any documents are to be destroyed, to be 
transferred to a different facility, or to be transferred to a different owner. 
11.4. 
Data Disclosure and Subject Confidentiality 
The Investigator(s) and the Sponsor or its authorized representative will preserve the 
confidentiality of all subjects participating in a study, in accordance with GCP, federal, state, and 
local regulations, including, to the extent applicable, the Health Insurance Portability and 
Accountability Act of 1996 (“HIPAA”). 


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In order to maintain subject confidentiality, all eCRFs, study reports, and communications 
relating to the study will identify subjects by initials and assigned subject numbers; subjects 
should not be identified by name. If a subject name appears on any document, it must be 
obliterated before a copy of the document is supplied to the Sponsor or its authorized 
representative. Study findings stored on a computer will be stored in accordance with federal, 
state, and local data protection laws. Subjects will be told that representatives of the Sponsor, its 
authorized representative, IRB or EC, or regulatory authorities may inspect their medical records 
to verify the information collected, and that all personal information will be held in strict 
confidence and in accordance with applicable data protection laws. The Investigator will 
maintain a personal subject identification list (subject numbers with the corresponding subject 
names) to make it possible for records to be identified.  
Clinical information will not be released without written permission from the subject, except as 
necessary for monitoring by the IRB/EC, the FDA, or the study Sponsor.  
Any information, inventions, or discoveries (whether patentable or not), innovations, 
suggestions, ideas, and reports made or developed by the Investigator(s) as a result of conducting 
this study shall be promptly disclosed to the Sponsor and shall be the sole property of the 
Sponsor. The Investigator agrees, upon the Sponsor’s request and at the Sponsor's expense, to 
execute such documents and to take such other actions, as the Sponsor deems necessary or 
appropriate, to obtain patents in the Sponsor’s name covering any of the foregoing. 
11.5. 
Policy for Publication and Presentation of Data 
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 PI(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). 
12.
PROTECTION OF HUMAN SUBJECTS
12.1. 
Declaration of Helsinki 
The study will be conducted in accordance with the Declaration of Helsinki (1964), including all 
amendments up to and including the South Africa revision (2008). 
12.2. 
Institutional Review Board/Ethics Committee 
The Investigator agrees to provide the IRB/EC with all appropriate material, including a copy of 
the informed consent form (ICF). The study will not be initiated until the Investigator obtains 


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written approval of the research plan and the ICF from the appropriate IRB/EC and copies of 
these documents are received by the Sponsor. Appropriate reports on the progress of this study 
will be made by the Investigator to the IRB/EC and Sponsor in accordance with applicable 
government regulations and in agreement with the policies established by the Sponsor and the 
IRB/EC. The Sponsor ensures that the IRB/EC complies with the requirements set forth in US 
21 Code of Federal Regulations Part 56.  


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13.
REFERENCES
Clauw, D. J. (2014). "Fibromyalgia: a clinical review." JAMA 311(15): 1547-1555. 
Dmitrienko, A., R. B. D'Agostino, Sr. and M. F. Huque (2013). "Key multiplicity issues in 
clinical drug development." Stat Med 32(7): 1079-1111. 
Dougados, M. and M. C. Hochberg (2011). Management of osteoarthritis. Rheumatology. M. C. 
Hochberg, A. J. Silman, J. S. Smolen, M. E. Weinblatt and M. H. Weisman. PA, USA, Elsevier: 
1793-1799. 
Gelse, K., A. B. Ekici, F. Cipa, B. Swoboda, H. D. Carl, A. Olk, F. F. Hennig and P. Klinger 
(2012). "Molecular differentiation between osteophytic and articular cartilage--clues for a 
transient and permanent chondrocyte phenotype." Osteoarthritis Cartilage 20(2): 162-171. 
Hochberg, M. C., R. D. Altman, K. T. April, M. Benkhalti, G. Guyatt, J. McGowan, T. Towheed, 
V. Welch, G. Wells, P. Tugwell and R. American College of (2012). "American College of 
Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic 
therapies in osteoarthritis of the hand, hip, and knee." Arthritis Care Res (Hoboken) 64(4): 465-
474. 
Lawrence, R. C., D. T. Felson, C. G. Helmick, L. M. Arnold, H. Choi, R. A. Deyo, S. Gabriel, R. 
Hirsch, M. C. Hochberg, G. G. Hunder, J. M. Jordan, J. N. Katz, H. M. Kremers, F. Wolfe and 
W. National Arthritis Data (2008). "Estimates of the prevalence of arthritis and other rheumatic 
conditions in the United States. Part II." Arthritis Rheum 58(1): 26-35. 
Nevitt, M. C., D. T. Felson and G. Lester (2006). " A Knee Health Study." "The Osteoarthritis 
Initiative.". 
Pham, T., D. Van Der Heijde, M. Lassere, R. D. Altman, J. J. Anderson, N. Bellamy, M. 
Hochberg, L. Simon, V. Strand, T. Woodworth, M. Dougados and O. Omeract (2003). "Outcome 
variables for osteoarthritis clinical trials: The OMERACT-OARSI set of responder criteria." J 
Rheumatol 30(7): 1648-1654. 
Piantadosi, S. (1997). Clinical Trials: A Methodologic Perspective. New York, Wiley-
Interscience. 
Wu, L., X. Huang, L. Li, H. Huang, R. Xu and W. Luyten (2012). "Insights on biology and 
pathology of HIF-1alpha/-2alpha, TGFbeta/BMP, Wnt/beta-catenin, and NF-kappaB pathways in 
osteoarthritis." Curr Pharm Des 18(22): 3293-3312. 


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APPENDIX 1. SCHEDULE OF STUDY PROCEDURES 
Procedure 
Screen 
(Days    
-21 to -1) 
Day 1a 
Week 4 
(Day 29 
± 3 days) 
Week 13 
(Day 92 
± 3 days) 
Week 26 
(Day 183 
-10 days) 
Week 39 
(Day 274 
± 3 days) 
Week 
52(EOS) 
(Day 366 
± 7 days) 
/ ET 
Informed consent 
X 
Inclusion & exclusion 
criteria 
X 
X 
Demographics 
X 
Medical history 
X 
Xb 
Pregnancy test 
X 
X 
X-ray 
X 
X 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
Knee examination 
X 
Height 
X 
Weight 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory 
sampling 
X 
X 
X 
X 
X 
Widespread Pain Index 
and Symptom Severity 
Score Assessment 
X 
Pain VAS 
X 
Intra-articular injection 
X 
Randomization 
X 
WOMAC 
X 
X 
X 
X 
X 
X 
X 
Patient Global 
Assessment 
X 
X 
X 
X 
X 
X 
X 
Physician Global 
Assessment 
X 
X 
X 
X 
X 
X 
X 
SF-36 
X 
X 
X 
X 
X 
X 
X 
AEs and concomitant 
procedures/medications 
X 
X 
X 
X 
X 
X 
Abbreviations: ACR, American College of Rheumatology; VAS, Visual Analog Scale; WOMAC, Western Ontario 
and McMaster Universities Arthritis Index; SF-36, 36-Item Short Form Healthy Survey; AEs, Adverse Events.
a At Study Visit Day 1, all procedures should be performed prior to study medication injection except for collection 
of AE and concomitant procedures/medication data.  
b Review medical history to capture End Date(s), if applicable, of any ongoing medical history(ies) collected at 
screening.  


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APPENDIX 2. 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.
** The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the 


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


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APPENDIX 3. AMENDMENTS 
 
AMENDMENT 04 VERSION 00 SUMMARY OF CHANGES 
Study Title: 
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study Evaluating the Safety, Tolerability, and Efficacy of 
SM04690 Injected in the Target Knee Joint of Moderately to Severely 
Symptomatic Osteoarthritis Subjects 
Purpose: 
The purpose of this amendment is to address FDA comments received 
during the Type C Meeting and to provide additional information 
regarding subject retention 
Summary of Changes: The table below provides a list of changes and their rationale 
Change 
Sections Affected 
Rationale 
“Protocol AM04 V00 Date” 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 
The study objectives were modified 
and now include exploratory 
objectives in addition to the primary 
and secondary objectives.   
Synopsis and 
Section 2.2   
Change was made to align with 
Statistical Analysis Plan and to 
address FDA comments 
Study endpoints were updated and 
Section 3.1.3 Exploratory Endpoints 
was added to reflect modification of 
study objectives described above. 
Section 3.1  
Changes were made to align with 
Statistical Analysis Plan and to 
address FDA comments  
A new Section 4.3 Strategies for 
Recruitment and Retention was 
added.  
Section 4.3  
Information was added as it was 
deemed that Investigator 
considerations for retention of 
subjects will be important due to 
the duration of the study 
Section 10.5.5 Efficacy Analysis was 
updated to reflect modification of 
study objectives described above.  
Section 10.5.5  
Changes were made to align with 
Statistical Analysis Plan and to 
address FDA comments 
 
 
 
 


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Amendment 04 Version 00 
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October 13, 2016 
 
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AMENDMENT 03 VERSION 00 SUMMARY OF CHANGES 
Study Title: 
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study Evaluating the Safety, Tolerability, and Efficacy of 
SM04690 Injected in the Target Knee Joint of Moderately to Severely 
Symptomatic Osteoarthritis Subjects 
Purpose: 
The purpose of this amendment is to update the timing of the planned 
interim analysis and Week 26 visit window, and to provide 
clarification to protocol language in areas noted below 
Summary of Changes: The table below provides a list of changes and their rationale 
Change 
Sections Affected 
Rationale 
“Protocol AM03 V00 Date” 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 
On Sponsor Signature page, John 
Hood has been removed as a 
signatory and Anita DiFrancesco’s 
title has been updated to “Vice 
President, Clinical Development.”  
Sponsor Signature Page 
Change was made to reflect 
personnel and title change, 
respectively 
The date of last subject completed has 
been changed from December 2016 
to April 2017 and the duration of 
study was updated to 20 months 
accordingly.  
Synopsis 
Change was made to align with 
new estimate of last subject 
completed date 
Interim analysis will now be 
performed at Week 26 (previously 
Week 13). 
Synopsis, Section 3, 
Section 3.2.4, 
and Section 10.5.4   
Change was made to refine study 
design 
The Per-Protocol Analysis Set 
definition was modified: ITT subjects 
who complied with all study 
procedures and evaluations, and did 
not have any major protocol 
deviations that may affect efficacy 
outcomes.    
Synopsis and 
Section 10.4  
Change was made for consistency 
to match Sponsor definition 
A new analysis data set was added to 
the synopsis and Section 10.4: 
Modified Intent-to-Treat (mITT) 
Analysis Set: ITT subjects who 
received a protocol-specified dose of 
SM04690 or placebo, analyzed as 
treated. Subjects incorrectly receiving 
doses not prescribed by the protocol 
Synopsis, Section 10.4, 
and Section 10.5.5  
Change was made for consistency 
as this analysis set was used in 
SM04690-OA-01  


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Change 
Sections Affected 
Rationale 
are excluded from this analysis set. 
The following line was deleted from 
the Statistical Methods section of the 
synopsis: “If statistical assumptions 
supporting parametric regression 
methods cannot be supported, rank-
based or semi-parametric methods 
may be used.” 
Synopsis 
Change was made to align with 
Statistical Analysis Plan 
In Section 3. Description of Study 
Design, the following correction was 
made: “; the physician investigator or 
designated study staff will complete 
the Physician Global Assessment…” 
Section 3  
Change was made to align with 
updated Physician Global site 
signatory wording 
Aspirin at a dose of 325 mg/day 
(instead of one to two 81 mg 
doses/day) is allowed for thrombosis 
prophylaxis. 
Section 3.3.4  
Change was made to conform to 
common clinical practice for 
thrombosis prophylaxis 
IA injection of other agents with 
therapeutic intent into either knee was 
added as a prohibited concomitant 
medication and procedure. IA 
injection of other therapeutic agents 
into joints other than the knee are 
allowed. 
Section 3.3.4  
Change was made to refine 
prohibited concomitant 
medications and procedures 
IA injection of glucocorticoids (also 
referred to as steroids or 
corticosteroids such as 
methylprednisolone) in a non-knee 
joint is allowed. 
Section 3.3.4  
Change was made to refine 
prohibited concomitant 
medications and procedures 
A review of medical history has been 
added to the end of study visit. 
Review of medical history at the 
Week 52 (EOS)/Early Termination 
visit will only be to capture End 
Dates of any ongoing medical history 
collected at screening. 
Section 5.3, Section 6.7, 
and Appendix 1  
Review of medical history was 
added to track any status changes 
A clarification has been added 
regarding X-ray view: “The intent 
(and included in the Image Review 
Charter – Image Acquisition 
guidelines) is that X-rays should be 
obtained in the posterior-anterior 
(PA) view, whenever possible. The 
Image Acquisition Protocol allows 
for anteroposterior (AP) view when 
Section 5.6 and 
Section 6  
Clarification was added to align 
with the Image Acquisition 
Protocol 


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Change 
Sections Affected 
Rationale 
PA view X-ray cannot be acquired.” 
The Week 26 visit window was 
changed from ±3 days to -10 days. 
Section 6.5 and 
Appendix 1  
Change was made to refine study 
design 
The following was added to Section 
9.1: “The Investigator must report all 
laboratory results that are BOTH 
outside the normal range for the 
laboratory or has a toxicity grade of 1 
or greater AND, in the opinion of the 
Investigator, are clinically 
significant.” 
Section 9.1  
Change was made for consistency 
with wording in Section 5.2 
A pregnancy is not to be reported as 
an SAE but via the SAE reporting 
process. 
Section 9.2  
Change was made for consistency 
with SM04690-OA-02-SAE-
Reporting-Guidelines-2015aug28 
The SAE reporting process and 
contact information were updated. 
Section 9.2.1  
Change was made for consistency 
with SM04690-OA-02-SAE-
Reporting-Guidelines-2015aug28 
The following was deleted from 
Section 10: “The general analytical 
approach for all endpoints will be 
descriptive in nature, providing a 
summary and estimate of the safety 
and efficacy profile of SM04690. No 
formal statistical hypothesis testing 
will be conducted in this study. All 
summaries will present the data by 
dose group.”   
Section 10  
Change was made to align with 
Statistical Analysis Plan 
Section 10.1 Sample Size 
Determination was revised with the 
following deletion: “…the sample 
size for this study was based upon 
accepted statistical practice and not 
on a formal efficacy hypothesis test 
and corresponding power analysis 
(Piantadosi 1997). However, based 
upon this sample size, a treatment 
response rate of 45% can be 
estimated with a confidence  interval 
width of 10 percentage points.” 
Section 10.1  
Change was made to simplify and 
clarify sample size determination 
The Safety Analysis Set definition 
was modified: Subjects who were 
randomized and received SM04690 
or placebo will be included in the 
safety analyses. This population is 
identical to the ITT Population 
Section 10.4 
Change was made for accuracy 


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Change 
Sections Affected 
Rationale 
The following was added to Section 
10.5.4: “The aim of this interim 
analysis is to assess safety and 
efficacy objectives at Weeks 13 and 
26. No trial adaptation(s) will be 
made based upon these results.” 
Section 10.5.4  
Change was made to clarify the 
aim of the interim analysis 
The following was deleted from 
Section 10.5.5: “If parametric 
assumptions fail to be supported, 
rank-based or non-parametric 
methods may be used. The goal of 
this primary efficacy analysis is to 
provide a precise estimate of 
treatment effect.” 
Section 10.5.5  
Change was made to align with 
Statistical Analysis Plan 
 
 
 


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AMENDMENT 02 VERSION 00 SUMMARY OF CHANGES 
Study Title: 
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study Evaluating the Safety, Tolerability, and Efficacy of 
SM04690 Injected in the Target Knee Joint of Moderately to Severely 
Symptomatic Osteoarthritis Subjects 
Purpose: 
The purpose of this amendment is to refine the study design and 
protocol procedures; several amendments were made in response to 
FDA feedback, as noted below 
Summary of Changes: The table below provides a list of changes and their rationale 
Change 
Sections Affected 
Rationale 
“Protocol AM02 V00 Date” 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 
The screening period was expanded 
to 21 days (originally 14 days). 
Synopsis, Section 3, 
Section 3.4, Section 5.6, 
Section 6.1, Section 6.2, 
Appendix 1  
Change was made to refine study 
design 
Inclusion criteria #5 and 6 were 
clarified; “while on symptomatic oral 
treatment” applies to subjects who 
require oral treatment.  
Synopsis and 
Section 4.1 
Change was made for clarification 
Inclusion criteria #1 was updated to: 
“Males and females between 40 and 
7580 years of age, inclusive, in 
general good health” 
Synopsis and 
Section 4.1 
Change was made to refine study 
design 
“Months” were converted to “weeks” 
in the exclusion criteria for 
consistency.  
Synopsis and 
Section 4.2 
Change was made for consistency 
In exclusion criteria #8, significant 
and clinically evident misalignment 
of the target knee was clarified as 
“that would impact subject function.” 
Synopsis and 
Section 4.2 
Change was made for clarification 
Exclusion criteria #10 was revised to: 
“Clinically significant abnormal 
Screening Visit hematology values, 
blood chemistry values, HbA1c, or 
urinalysis values  as determined by 
the investigator” 
Synopsis and 
Section 4.2 
Change was made to refine study 
design 
A clarification was added to 
exclusion criteria #11; ‘laboratory 
Synopsis and 
Section 4.2 
Change was made for clarification 


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Change 
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findings’ refers to those “not included 
in the Screening Visit laboratory 
tests.” 
Exclusion criteria #18 was updated to 
“effusion of the target knee clinically 
requiring aspiration…” 
Synopsis and 
Section 4.2 
Change was made to refine study 
design 
Chiropractic treatments and 
clarification of “knee OA” were 
added to exclusion criteria #19. 
Synopsis and 
Section 4.2 
Change was made to refine study 
design 
In exclusion criteria #22, “chronic” 
was clarified to be “regular and 
consistent use for ≥3 months.” 
Synopsis and 
Section 4.2 
Change was made for clarification 
Exclusion criteria #22c was revised 
to: “Glucocorticoids (e.g., 
methylprednisolone) administered by 
any route, with exception of inhaled, 
intranasal, and ophthalmic solution. 
Synopsis and 
Section 4.2 
Change was made to refine study 
design 
In exclusion criteria #23, exclusion of 
subjects with uncontrolled 
hypertension and/or symptomatic 
coronary artery disease is to be “in 
the opinion of the investigator.” 
Synopsis and 
Section 4.2 
Change was made to refine study 
design 
Section 3.2.3 Subject Re-screening 
was added to allow subjects to be re-
screened once. 
Section 3.2.3  
Change was made to refine study 
design 
In Section 3.3.3, the clarification was 
made that procedures that are 
ongoing, new, or modified at or post-
Day 1 must be recorded on the 
“Procedures and Non-Drug 
Therapies” page of the eCRF. 
Section 3.3.4 
Change was made for clarification 
Prohibited Concomitant Medications 
and Procedures were clarified:  
• 
“Intra-articular injections of 
steroids or hyaluronic acid 
derivatives into joints other than 
the knee are allowed. 
• 
Electrotherapy, acupuncture, and 
chiropractic adjustments of the 
knee are prohibited.  
Section 3.3.4  
Change was made for clarification 
Section 5.2 was updated and Section 
5.5 Pregnancy Tests was added. 
Pregnancy tests will be performed on 
Section 5.2, Section 5.5, 
Section 6.1, Section 6.2, 
and Appendix 1   
Change was made per FDA request  


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Change 
Sections Affected 
Rationale 
female subjects at screening and on 
Day 1 prior to study medication 
injection.  
Section 5.4.1 Knee Examination was 
updated to align with exclusion 
criteria #8. 
Section 5.4.1  
Change was made for accuracy 
Section 5.6 X-Ray of Knee Joints was 
revised to reflect the bilateral view of 
the x-ray as well as to correctly 
describe assessments being 
performed with the radiographs. 
Section 5.6  
Change was made for accuracy 
Only one view is required for the 
knee X-ray (bilateral in weight 
bearing fixed flexion position, 
anteroposterior view).  
Section 6.1, Section 6.5, 
and Section 6.7 
Change was made to align with 
vendor requirements 
Clarification was added to Section 6.2 
regarding which procedures will be 
evaluated for subject eligibility. 
Section 6.2  
Change was made for clarification 
Temperature correction and excursion 
clarification was added to Section 
8.4: “The study medication 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 72 hours 
and only during study medication 
shipment.” 
Section 8.4  
Change was made for accuracy 
In Section 9.1, the following 
correction was made: “Definition of 
Adverse Events and Adverse Drug 
Reactions” 
Section 9.1 
Change was made for accuracy  
Per FDA request, all AEs that occur 
during the trial will be considered 
related to study treatment. 
Investigator opinion regarding 
relatedness will still be collected for 
future planning and informational 
purposes.  
Section 9.1  
Change was made per FDA request 
In Section 10.5.5, reference to 
gatekeeping was removed to align 
with the SAP. 
Section 10.5.5  
Change was made to align with 
SAP 


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Change 
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Rationale 
“Week 52(EOS) or ET” was revised 
to “Week 52 (EOS)/Early 
Termination” to align with study 
database. 
Throughout 
Change was made for accuracy 
Grammar and punctuation corrections 
were made throughout. 
Throughout 
Changes were made to correct 
minor errors 
 
 
 
 
 
 


Protocol SM04690-OA-02 
 
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October 13, 2016 
 
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AMENDMENT 01 VERSION 00 SUMMARY OF CHANGES 
Study Title: 
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study Evaluating the Safety, Tolerability, and Efficacy of 
SM04690 Injected in the Target Knee Joint of Moderately to Severely 
Symptomatic Osteoarthritis Subjects 
Purpose: 
The purpose of this amendment is to refine the study design and 
protocol procedures 
Summary of Changes: The table below provides a list of changes and their rationale 
Change 
Sections Affected 
Rationale 
“Protocol AM01 V00 Date” 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 
Inclusion criteria #5 was revised to: 
“Screening pain visual analog scale 
(VAS) score of 40 30-80 mm” 
Synopsis and 
Section 4.1 
Change was made to refine study 
design 
Inclusion criteria #6 was revised to: 
“Total WOMAC score of 36–77  72-
192 (out of 96240) for the target knee 
while on symptomatic oral treatment 
at screening” 
Synopsis and 
Section 4.1  
Change was made to reflect 
updated scaling of WOMAC 
scores 
Exclusion criteria #8 was revised to: 
“Significant and clinically evident 
misalignment of the target knee, as 
assessed by centrally read radiograph 
[as determined by Investigator]” 
Synopsis and 
Section 4.2 
Change was made to refine study 
design 
Exclusion criteria #12 was revised to: 
“Comorbid conditions that, in the 
opinion of the Investigator, could 
affect pain assessment of the target 
knee…” 
Synopsis and 
Section 4.2 
Change was made to refine study 
design 
Symptomatic hip osteoarthritis and 
symptomatic degenerative disc 
disease were moved from exclusion 
criteria #12 to a new exclusion 
criteria #13. 
Synopsis and 
Section 4.2 
Change was made to refine study 
design 
Exclusion criteria #21 was revised to: 
“Subjects taking [prescription] 
medications or supplements for OA 
who have not maintained a stable 
therapeutic regimen for a minimum of 
Synopsis and 
Section 4.2 
Change was made to refine study 
design 


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Rationale 
3 months prior to Study Visit Day 1 
Exclusion criteria #22 and Section 
3.3.4 was revised to include: 
a. Opioids, both oral (e.g., tramadol)
or transdermal (e.g., fentanyl
patches) formulations
b. Centrally acting analgesics (e.g.,
duloxetine)
c. Glucocorticoids (e.g.,
methylprednisolone)
administered by any route, with
exception of intranasal and
ophthalmic solutions
Synopsis, Section 3.3.4, 
and Section 4.2  
Change was made for clarity and to 
refine study design 
Exclusion criteria #23a was revised 
to: “Subjects with diabetes who have 
a baseline HbA1c >9” 
Synopsis and 
Section 4.2 
Change was made to refine study 
design 
Updates were made to the Phase 1 
clinical trial description in Section 1.3 
Study Rationale and Section 3.3.1 
Rationale for Dosages and Dosing 
Regimen. 
Section 1.3 and 
Section 3.3.1   
Change was made to align with 
Investigator Brochure 
The modified 2010 ACR 
Fibromyalgia Diagnostic Criteria 
assessment was replaced with the 
Widespread Pain Index and Symptom 
Severity Score assessment in Section 
3 Description of Study Design. 
Section 3 
Change was made to correct an 
error; the modified 2010 ACR 
Fibromyalgia Diagnostic Criteria 
will not be used at the Screening 
Visit.  
The following change was made in 
Section 3.2.1: “…subjects will be 
randomized via the Medidata Balance 
database.” 
Section 3.2.1 
Change was made to avoid 
confusion 
In Section 3.2.2, an additional 
requirement was added in order for a 
subject to be eligible for 
randomization; the subject must have 
signed the Informed Consent form. 
Section 3.2.2 
Change was made for clarity 
The following was added to Section 
3.3.2 Dosages and Dosing Regimen: 
“Only topical anesthetic (absolutely 
no invasive anesthetic) is allowed for 
the study injections. Anesthetic is 
also not allowed to be combined with 
the study medication for injection” 
Section 3.3.2 
Change was made to refine 
protocol procedures 


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“An HbA1c test will be performed on 
all subjects at the Screening Visit” 
was added to Section 5.2. 
Section 5.2 
Change was made for clarity 
In Section 5.2 and 9.1, the following 
correction was made: “If any 
abnormal, clinically significant 
laboratory measure is found prior to 
study medication injection, [the 
subject is to be excluded.]” 
Section 5.2 and 
Section 9.1  
Change was made for consistency 
with exclusion criteria 
Section 5.4.1 Knee Examination was 
updated with information regarding 
assessment of misalignment of the 
target knee. 
Section 5.4.1 
Change was made for clarity 
In Section 5.5 X-ray of Target Knee 
Joint, the clarification was made that 
the X-ray taken during the screening 
period “must be taken according to 
the guidance provided by the 
independent radiologist.” 
Section 5.5 
Change was made for clarity 
All questionnaires will be provided 
by the sponsor and may not be 
reproduced. 
Section 5.7, Section 5.8, 
Section 5.9, 
Section 5.10, 
Section 5.11, and 
Section 5.12  
Change was made to refine 
protocol procedures 
Updates were made to Sections 5.8, 
5.9, and 5.10 to align with 
questionnaires to be used in the study: 
-No numbers will be included with 
the anchor descriptors.  
-Scoring instructions for the site staff 
were added. 
Section 5.9, 
Section 5.10, and 
Section 5.11 
Changes were made for 
consistency and clarity 
The 2 views of the target knee joint 
X-ray are to be the lateral and 
anteroposterior views. 
Section 6.1, Section 6.5, 
and Section 6.7  
Change was made for clarity 
Placebo preparation instructions were 
added to Section 8.3 Preparation of 
Study Medication. 
Section 8.3 
Change was made to refine 
protocol procedures 
 “Quantity dispensed” and “Quantity 
returned” applies to active vials, 
vehicle vials, PBS vials, and saline 
vials. 
Section 8.4 
Change was made for clarity 
Clarifications were made to Section 
8.4 Accountability of Study 
Section 8.4 
Change was made for clarity 


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Medications; unblinded PI and/or 
designee are responsible for study 
medication accountability. 
The Systemic Illness row was added 
to Table A1: Tables for Clinical 
Abnormalities.  
Appendix 2 
Change was made to align with 
Guidance for Industry: Toxicity 
Grading Scale for Healthy Adult 
and Adolescent Volunteers 
Enrolled in Preventive Vaccine 
Clinical Trials 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN SM04690-OA-02 
(Version 1.0,  October 14, 2016) 
 
 
 
 
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Study Evaluating the Safety, Tolerability, and Efficacy of SM04690 
Injected in the Target Knee Joint of Moderately to Severely 
Symptomatic Osteoarthritis Subjects 
 
 
 
 
NCT02536833 
 
 
 
 
 
 
 
 
 


 
 
SM04690-OA-02 SAP V0.1 
 
Confidential 
Page 1 of 19 
 
 
 
STATISTICAL ANALYSIS PLAN SM04690-OA-02 
 
 
 
Study Title:  
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study Evaluating the Safety, Tolerability, and Efficacy 
of SM04690 Injected in the Target Knee Joint of Moderately to 
Severely Symptomatic Osteoarthritis Subjects 
 
 
Protocol Number:  
SM04690-OA-02 
 
Protocol Version: 
Amendment 04, October 13, 2016 
 
SAP Version: 
1.0 
 
Investigational Product: 
SM04690 Injectable Suspension  
 
Clinical Phase:  
Phase 2 
 
 
 
 
Sponsor: 
Samumed, LLC.  
 
9381 Judicial Dr., Suite 160  
 
San Diego, CA 92121 
 
(858) 926-2900 
 
 
 
 
 
 
 
 
 
 
This document is the sole property of Samumed, LLC. This document and any and all information 
contained herein must be considered and treated as strictly confidential. This document shall be 
used only for the purpose of the disclosure herein provided. No disclosure or publication shall be 
made without the prior written consent of Samumed, LLC. 




Protocol SM04690-OA-02 
 
SAP Version 1.0 
Samumed, LLC  
 
 October 14, 2016 
 
Confidential 
 
Page 3 of 19 
 
TABLE OF CONTENTS 
SAP SIGNATURE PAGE ...............................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
1. 
INTRODUCTION AND OBSERVATIONS ...............................................................5 
1.1. 
Primary Objectives .......................................................................................................5 
1.2. 
Secondary Objectives ...................................................................................................5 
1.3. 
Exploratory Objectives .................................................................................................5 
2. 
STUDY DESIGN .........................................................................................................6 
2.1. 
Sample Size ..................................................................................................................6 
2.2. 
Randomization ..............................................................................................................7 
2.3. 
Study Medication Dosing .............................................................................................7 
3. 
STUDY OUTCOME MEASURES ..............................................................................8 
3.1. 
Safety Outcome Measures ............................................................................................8 
3.2. 
Efficacy Outcome Measures .........................................................................................8 
3.2.1. 
Western Ontario and McMaster Universities Arthritis (WOMAC) Index ...................8 
3.2.2. 
OMERACT-OARSI Response .....................................................................................8 
3.2.3. 
Patient Global Assessment of Disease Activity ............................................................9 
3.2.4. 
Physician Global Assessment of Disease Activity .......................................................9 
3.2.5. 
Joint Space Width (JSW) ..............................................................................................9 
3.2.6. 
Health-Related Quality of Life .....................................................................................9 
4. 
ANALYSIS SETS ......................................................................................................10 
4.1. 
Intent-to-Treat Analysis Set ........................................................................................10 
4.2. 
Modified Intent-to-Treat Analysis Set ........................................................................10 
4.3. 
Per Protocol Analysis Set ...........................................................................................10 
4.4. 
Safety Analysis Set .....................................................................................................10 
5. 
STATISTICAL CONSIDERATIONS .......................................................................10 
5.1. 
Interim Analysis ..........................................................................................................10 
5.2. 
Handling of Missing Data ...........................................................................................11 
5.2.1. 
Tipping Point Analysis ...............................................................................................11 
5.3. 
Baseline .......................................................................................................................12 
5.4. 
Early Termination .......................................................................................................12 
6. 
STUDY SUBJECTS ...................................................................................................12 


Protocol SM04690-OA-02 
 
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6.1. 
Disposition of Subjects ...............................................................................................12 
6.2. 
Demographic and Baseline Characteristics ................................................................12 
6.3. 
Medical History ..........................................................................................................13 
6.4. 
Protocol Deviations ....................................................................................................13 
7. 
SAFETY EVALUATION ..........................................................................................13 
7.1. 
Treatment-Emergent Adverse Events .........................................................................14 
7.2. 
Clinical Laboratory .....................................................................................................14 
7.3. 
Vital Signs ..................................................................................................................14 
7.4. 
Concomitant Medications ...........................................................................................14 
8. 
EFFICACY EVALUATION ......................................................................................14 
8.1. 
General Considerations ...............................................................................................15 
8.1.1. 
ANCOVA Model for Continuous Efficacy Outcomes ...............................................15 
8.1.2. 
Logistic Regression Model for Binary Efficacy Outcomes ........................................15 
8.2. 
Interim Analysis of Efficacy Outcomes .....................................................................16 
8.2.1. 
Familywise Error Rate Control ...................................................................................16 
8.2.2. 
Subgroup Analysis ......................................................................................................17 
8.3. 
Final Analysis of Efficacy Outcomes .........................................................................18 
9. 
ANALYSIS SOFTWARE ..........................................................................................18 
10. 
REFERENCES ...........................................................................................................19 
 


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1. 
INTRODUCTION AND OBSERVATIONS 
Osteoarthritis (OA) is the most common form of arthritis that causes degenerative structural 
change and results in pain and decreased mobility. Samumed, LLC is developing SM04690, a 
small molecule inhibitor of the Wnt pathway, for the treatment of OA. The purpose of this study 
is to assess the efficacy, safety and tolerability of three different strengths of SM04690 
administered by intra-articular injection into the target knee joint of moderately to severely 
symptomatic OA subjects. 
 
1.1. 
Primary Objectives 
The primary objective of this study will be to evaluate the change from baseline OA pain in the 
target knee as assessed by the Western Ontario and McMaster Universities Osteoarthritis Index 
(WOMAC) pain subscore at Week 13. 
1.2. 
Secondary Objectives 
The secondary objectives of this study include: 
 Evaluate change from baseline OA pain in the target knee as assessed by the WOMAC 
pain subscore at Week 26 
 Evaluate change from baseline OA function in the target knee as assessed by the 
WOMAC function subscore at Weeks 13 and 26 
 Evaluate change from baseline OA disease activity as assessed by the Patient Global 
Assessment at Weeks 13 and 26 
 Evaluate change from baseline in medial joint space width (JSW) as documented by X-
ray of the target knee at Week 26  
 Evaluate the safety and tolerability of SM04690 by monitoring for treatment-emergent 
adverse events (TEAEs) 
 
1.3. 
Exploratory Objectives 
Additional exploratory objectives of this study include: 
 Evaluate change from baseline in WOMAC total score for the target knee at Weeks 4, 13, 
26, 39 and 52 
 Evaluate change from baseline OA pain in the target knee as assessed by the WOMAC 
pain subscore at Weeks 4, 39 and 52 
 Evaluate change from baseline OA function in the target knee as assessed by the 
WOMAC function subscore at Weeks 4, 39 and 52 
 Evaluate change from baseline OA disease activity as assessed by the Patient Global 
Assessment at Weeks 4, 39 and 52 
 Evaluate change from baseline in medial JSW as documented by X-ray of the target knee 
at Week 52  
 Evaluate change from baseline in lateral JSW as documented by X-ray of the target knee 
at Weeks 26 and 52 


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 Determine the percentage of Outcome Measures in Rheumatology Clinical Trials 
(OMERACT)-Osteoarthritis Research Society International (OARSI) responders and 
“strict” responders at Weeks 4, 13, 26, 39 and 52 
 Evaluate change from baseline health-related quality of life (HRQOL) as assessed by the 
36-Item Short Form Health Survey (SF-36) at Weeks 4, 13, 26, 39 and 52 
 Evaluate change from baseline OA disease activity as assessed by the Physician Global 
Assessment at Weeks 4, 13, 26, 39 and 52 
 
2. 
STUDY DESIGN 
This study will be a multicenter, randomized, double-blind, placebo-controlled, parallel group 
study of three different strengths of SM04690 injected into the target knee joint of moderately to 
severely symptomatic osteoarthritis subjects. 
 
2.1. 
Sample Size 
A sample size of approximately 445 subjects will be randomized at a ratio of 1:1:1:1 (0.03 mg 
active per 2 mL injection : 0.07 mg active per 2 mL injection : 0.23 mg active per 2 mL 
injection : placebo). The sample size for this study was based upon accepted statistical practice to 
establish an acceptable level of precision with respect to treatment effect estimation (Piantadosi 
1997). 
To explore possible power expected from this study design, an analysis of covariance regression 
model was simulated via a Monte Carlo simulation of 1000 replicates. The simulation model 
estimated a change in WOMAC Pain from baseline comparison between SM04690 and placebo 
adjusting for baseline WOMAC Pain. The following assumptions were made for the power 
simulation: 
 Sample size of 100 subjects per group, 
 Type 1 error rate of 5%,  
 WOMAC Pain Baseline average is 11 points [scale 0-20] with a standard deviation of 3, 
 WOMAC Pain Baseline is the same for both treatment and placebo groups, 
 Treatment change from baseline is -5.8 points, leading to a final score of 5.2 points 
[scale 0-20] 
 Historical placebo change from baseline is -3.5 points, leading to a final score of 7.5 
points [scale 0-20] 
 Final pain score has standard deviation of 4 and is the same for both treatment and 
placebo groups, and 
 Correlation between baseline and final pain score is 0.1. 
The WOMAC Pain subscore parameters were based upon observed data from the 0.07 mg group 
in SM04690-01. Based upon these assumptions, SM04690-OA-02 is estimated to have 95.8% 
power. 


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A simulation model for WOMAC Function was also estimated. The following assumptions were 
made for the power simulation: 
 Sample size of 100 subjects per group, 
 Type 1 error rate of 5%,  
 WOMAC Function Baseline average is 39 points [scale 0-68] with a standard deviation 
of 11, 
 WOMAC Function Baseline is the same for both treatment and placebo groups, 
 Treatment change from baseline is -19.5 points, leading to a final score of 19.5 points 
[scale 0-68] 
 Historical placebo change from baseline is -13.5 points, leading to a final score of 25.5 
points [scale 0-68] 
 Final function score has standard deviation of 15 and is the same for both treatment and 
placebo groups, and 
 Correlation between baseline and final function score is 0.1. 
The WOMAC Function subscore parameters were also based upon observed data from the 0.07 
mg group in SM04690-01. Based upon these assumptions, SM04690-OA-02 is estimated to have 
78.5% power.  
No prior data exist for Patient Global Assessment in SM04690-01; no formal power analysis is 
possible at this time.   
 
2.2. 
Randomization 
Subjects will be randomized 1:1:1:1 (0.03 mg active per 2 mL injection : 0.07 mg active per 2 
mL injection : 0.23 mg active per 2 mL injection : placebo) to each dose group using Medidata 
Balance with a permuted block design stratified by study site. A block size of 8 has been selected 
for this study. 
 
2.3. 
Study Medication Dosing 
Three strengths of SM04690 injectable suspension and placebo will be used in this study: 
 SM04690 0.03 mg in 2-mL Injectable Suspension 
 SM04690 0.07 mg in 2-mL Injectable Suspension 
 SM04690 0.23 mg in 2-mL Injectable Suspension 
 SM04690 0 mg in 2-mL Injectable Suspension; placebo (phosphate buffered saline) 
 


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3. 
STUDY OUTCOME MEASURES 
 
3.1. 
Safety Outcome Measures 
TEAEs will be presented in summary tables and categorized by seriousness and toxicity severity 
grade. While all TEAEs will be considered as related to study product, the investigator’s 
assessment of relatedness will be analyzed for informational purposes. TEAEs will also be 
summarized according to MedDRA dictionary terms, including system organ class and preferred 
term.  
 
3.2. 
Efficacy Outcome Measures 
Knee pain and function will be assessed by the subject using the WOMAC Index. Disease 
activity will be assessed by the Patient Global Assessment of Disease Activity and the Physician 
Global Assessment of Disease Activity. Overall HRQOL will be assessed with the SF-36 
questionnaire which provides scores for eight scales (physical functioning, role-physical, bodily 
pain, general health, vitality, social functioning, role-emotional, mental health) and two summary 
measures (physical health, mental health). JSW will be assessed with X-Ray imaging of the 
target knee at Week 26 and 52. 
 
3.2.1. 
Western Ontario and McMaster Universities Arthritis (WOMAC) Index  
The WOMAC NRS3.1 instrument is a patient reported outcome measure to assess the symptoms 
of OA. Subjects will be asked to complete the WOMAC instrument based on their symptoms in 
the target knee. 
The WOMAC consists of 24 questions in three domains: physical function (17 questions), pain 
(5 questions) and stiffness (2 questions). The response for each question in the NRS format 
ranges from 0 to 10. Each domain subscore as well as a total score are calculated by adding 
together the numerical responses. Subsequently, the WOMAC NRS3.1 ranges from 0 to 240 total 
points.  
If any response is missing, the score for that domain (i.e. physical function, pain, or stiffness) as 
well as the WOMAC Total score will not be able to be calculated.  
 
3.2.2. 
OMERACT-OARSI Response 
The OMERACT-OARSI response (Pham et al. 2003) is defined as follows: 
A. High improvement from baseline in pain or function greater than or equal to 50% and 
absolute change of at least 20 points [scaled on a 0-100 range], OR 
B. Improvement from baseline in at least two of the following  
o pain greater than or equal to 20% and absolute change of at least 10 [scaled on a 
0-100 range] 


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o function greater than or equal to 20% and absolute change of at least 10 [scaled 
on a 0-100 range] 
o Patient Global Assessment greater than or equal to 20% and absolute change of at 
least 10 [scaled on a 0-100 range] 
Additionally, the OMERACT-OARSI “strict” response is defined by any response satisfying the 
above condition A only.  
Both OMERACT-OARSI response and OMERACT-OARSI “strict” response are efficacy 
outcome measures in this study. WOMAC Pain and WOMAC Function subscores will be 
utilized and scaled appropriately to calculate the OMERACT-OARSI response.  
 
3.2.3. 
Patient Global Assessment of Disease Activity 
The patient assessment will be a 100 mm VAS scale adapted from the Patient Assessment Form 
© 1999, American College of Rheumatology. The subject will rate how well they are doing, 
considering all the ways in which illness and health conditions may affect him/her. The VAS 
scale will be anchored by “Very Well” on the left and “Very Poorly” on the right.  
 
3.2.4. 
Physician Global Assessment of Disease Activity 
The physician assessment will be a 100 mm VAS scale adapted from the Physician Assessment 
Form © 1999, American College of Rheumatology The investigator will rate the subject’s 
disease activity. The VAS scale will be anchored by “Very Good” on the left and “Very Bad” on 
the right. 
 
3.2.5. 
Joint Space Width (JSW) 
JSW in the target knee will be assessed by radiograph. A radiograph may be repeated if the 
image quality of the original radiograph is deemed unsatisfactory by the imaging vendor, 
Medical Metrics, Inc. (MMI), according to Image Review Charter. The radiograph with the best 
image quality (where applicable) will be used for analysis as long as it was taken within the visit 
window. If two or more radiographs for the same study visit are assessed as having the same 
image quality, the earliest radiograph will be considered for that visit. Medial and lateral joint 
space width measurements will be provided by the vendor. 
 
3.2.6. 
Health-Related Quality of Life 
Overall HRQOL will be assessed with the SF-36 Version 2 questionnaire which consists of 36 
questions that are asked of the subject. The subject’s responses will be used to calculate norm-
based scores for eight scales (physical functioning, role-physical, bodily pain, general health, 
vitality, social functioning, role-emotional, mental health) and two component summary 
measures (physical health, mental health). Scoring software provided by the SF-36 vendor, 
Optum, will be utilized to calculate the standardized scores. 


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4. 
ANALYSIS SETS 
 
4.1. 
Intent-to-Treat Analysis Set 
The Intent-to-Treat (ITT) Analysis Set includes all subjects who were randomized. 
 
4.2. 
Modified Intent-to-Treat Analysis Set 
The Modified Intent-to-Treat (mITT) Analysis Set includes all ITT subjects who received a 
protocol specified dose of SM04690 or placebo, analyzed as treated. Subjects incorrectly 
receiving doses not prescribed by the protocol are excluded from this analysis set. 
 
4.3. 
Per Protocol Analysis Set 
The Per Protocol (PP) Analysis Set includes all ITT subjects who complied with all study 
procedures and evaluations and did not have major protocol deviations. 
 
4.4. 
Safety Analysis Set 
The Safety Analysis Set includes all subjects who were exposed to study product.  
 
5. 
STATISTICAL CONSIDERATIONS 
 
5.1. 
Interim Analysis 
By definition, “[a]n interim analysis is any analysis intended to compare treatment arms with 
respect to efficacy or safety at any time prior to formal completion of a trial” (ICH E9 Guidance 
1999). Analysis of the specified efficacy endpoints (Section 8.2) will be conducted after all 
subjects complete the Week 26 visit but prior to the formal completion of the trial at 52 weeks. 
Thus, by definition, these efficacy analyses will be described as an interim analysis. However, no 
trial adaptation(s) will be made based upon the results of the interim analysis.  
The datasets supporting this analysis will be validated from a snapshot of the raw study database.  
Source data verification of the raw data supporting the interim analysis as well as query 
resolution will be completed before unblinding for the interim analysis. All available data 
supporting the Week 26 JSW analysis (i.e. radiographs) will be measured by the imaging vendor 
and included in the snapshot dataset prior to unblinding for the interim analysis. In addition, all 
available safety events occurring up to and including the Week 26 visit will also be included in 
the snapshot dataset prior to unblinding and summarized in the interim analysis report.  
All available data in support of the interim analysis will be dated and sequestered from the final 
analytical databases. Any changes made to the sequestered data in the raw database after the 
interim analysis that impacts any outcome within the interim efficacy analysis will be 
summarized in the clinical study report.  


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5.2. 
Handling of Missing Data 
Multiple imputation will be utilized for the primary and secondary analyses. Missing data will be 
imputed based upon the observed data for each outcome under the missing at random (MAR) 
assumption following the paradigm first developed by Rubin (Schafer 1999). The imputation 
will adjust for the outcome’s baseline data in a regression model with data imputed 
independently for each timepoint; any missing baseline data will also be imputed. A total of 10 
imputation datasets will be created and analyzed based upon accepted convention (Schafer 
1999). Error estimates of the multiple imputation itself as well as an overall summary of the 
efficacy analysis will be averaged across the 10 imputed datasets based upon Rubin’s paradigm.  
Specifically, let Q denote the imputed mean of an efficacy outcome Y subject to missing data at a 
given timepoint, where the estimate of that mean for any ith imputation would be defined as 
function of both observed and missing data such that 
𝑄(𝑖)
̂ =  𝐸(𝑄(𝑖)|𝑌𝑜𝑏𝑠𝑒𝑟𝑣𝑒𝑑, 𝑌𝑚𝑖𝑠𝑠𝑖𝑛𝑔
(𝑖)
, 𝑌𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒, 𝐼(𝐺𝑟𝑜𝑢𝑝)), 𝑖= 1, … , 10. 
After all 10 datasets have been imputed, the overall estimate of Q is a simple average defined as 
𝑄̅ =
∑
𝑄(𝑖)
̂
10
𝑖=1
10
 . 
For this analysis using 10 imputed datasets, the variance of 𝑄̅ is defined as  
𝑉𝑎𝑟(𝑄̅) = 1.1𝐵+ 𝑈̅ 
where B is the between imputation variance and U is the within imputation variance: 
𝐵= 1
9 ∑(𝑄(𝑖)
̂ −𝑄̅)
2
10
𝑖=1
; 
𝑈̅ =
∑
𝑈(𝑖)
10
𝑖=1
10
. 
Imputations will be performed with a seed of 201610141. 
 
5.2.1. 
Tipping Point Analysis 
 
The MI paradigm, as proposed by Rubin, does not require nor assume any specific assumption 
about the nature of the missing data. Further, imputations can be (theoretically) created under 
any assumption of missing mechanism.  A sensitivity analysis will be conducted using the 
tipping point approach to evaluate the robustness of the primary analysis with multiple 
imputation under the MAR assumption. With the tipping point approach, several additional 
multiple imputation datasets are created, each departing slightly from the original assumptions 
used in the primary analyses. The intended result is to establish a certain point in which the new 
shifted imputations have “tipped”, or overturned, the original conclusions from the primary 
analysis (i.e. a statistically significant result is now not statistically significant). The magnitude 
of the shift required to tip the analysis are then evaluated for plausibility; an implausible shift 
will lead to the conclusion that the multiple imputation analysis is robust to the departure from 
MAR assumption. 


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Tipping point analysis will be conducted only for the dose group(s) that is/are statistically 
significant under the MAR assumption. Based on the SM04690 Phase I study, the placebo 
change in WOMAC pain from baseline was observed at -3.5 points. When scaled to the NRS 
format, this translates to a -8.75 reduction in WOMAC pain. The primary analysis will be 
reassessed by shifting the mean change in WOMAC pain in the treatment group by intervals of 
+0.5 until the historical placebo threshold of -8.75 (or the placebo response observed in 
SM04690-OA-02, whichever is more conservative) is reached and/or surpassed. Intervals of +0.1 
may further be explored in order to determine a more precise shift parameter for the tipping 
point. An implausible shift parameter is defined as one that results in the magnitude of change in 
WOMAC pain in the treatment group to equal or worse than historical (or SM04690-OA-02, 
again whichever is more conservative) placebo change. 
Imputations for the tipping point analysis will be performed with a seed of 201610142. 
 
5.3. 
Baseline 
Baseline is defined as the last value recorded for any given parameter prior to study medication 
injection. However, for radiographs used to evaluate JSW, baseline is defined as the assessment 
prior to study medication injection with the best image quality as determined by the imaging 
vendor, where applicable. If two or more radiographs are assessed with the same image quality, 
the earliest radiograph will be considered for baseline. 
 
5.4. 
Early Termination 
If a subject discontinues the study, early termination assessments will be performed according to 
the protocol. If these assessments occur within the window of a scheduled visit (±3 days for 
Weeks 4, 13 and 39 and -10 days for Week 26), they will be associated with that visit for the 
purposes of ITT and mITT analysis. All other visits will be considered missing data and treated 
as described in section 5.2. 
 
6. 
STUDY SUBJECTS 
 
6.1. 
Disposition of Subjects 
Subject disposition will be presented in a summary table detailing the number and percentage of 
subjects who were consented, randomized, treated, completed the study or discontinued (e.g. 
screen failure, subject decision, etc.) by treatment group and site. The disposition for individual 
subjects will be listed along with additional information on discontinued subjects. 
 
6.2. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics, including gender, race, ethnicity, age, weight, height, 
body mass index (BMI), Kellgren-Lawrence (KL) grade, presence of bilateral OA and 


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Widespread Pain Index (WPI) score will be summarized by treatment group and listed for 
individual subjects. 
6.3. 
Medical History 
Medical history will be collected at screening and reassessed at the Week 52 (EOS) / Early 
Termination visit to record any changes. A summary of reported medical history will be 
provided by system category for each treatment group. A subject-level listing will provide 
further information on each event. 
 
6.4. 
Protocol Deviations 
For SM04690-OA-02, a protocol deviation is defined as any change, divergence or departure 
from the study design or procedures of a research protocol that is under the Investigator’s control 
and that has not been approved by the site’s Institutional Review Board. 
Deviations are summarized into one of the following categories: 
 Those who were randomized to the study even though they did not satisfy the eligibility 
criteria 
 Those who developed withdrawal criteria during the study but were not withdrawn 
 Those who received the wrong treatment or incorrect dose 
 Those who received an excluded concomitant treatment 
 Those who missed or received an incorrect protocol procedure 
Deviations are categorized as major or minor. 
 A major deviation is defined as a divergence from the protocol that materially (a) reduces 
the quality or completeness of the data, (b) makes the informed consent inaccurate, or (c) 
impacts a subject’s safety, rights or welfare. 
 A minor deviation is defined as a divergence from the protocol that deviates from the 
procedures and guidelines outlined in the protocol, but is not classified as a major 
deviation (i.e. the deviation does not materially (a) reduce the quality or completeness of 
the data, (b) make the informed consent inaccurate, or (c) impact a subject’s safety, rights 
or welfare). 
Protocol deviations will be summarized by site, category and classification, and listed for each 
subject. 
 
7. 
SAFETY EVALUATION 
The analysis of safety outcome measures will be performed on the Safety Analysis Set. The 
interim report will include all available safety information up to and including Week 26. The 
final report will include a cumulative assessment safety. 
 


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7.1. 
Treatment-Emergent Adverse Events 
TEAEs will be presented in an overview summary table depicting the number and percent of 
subjects in each treatment group experiencing TEAEs by seriousness and toxicity grade severity. 
While all TEAEs will be considered as related to study product, the investigator’s assessment of 
relatedness will be included in the summary table for informational purposes. TEAEs will also 
be summarized by MedDRA system organ class and preferred term, including the number of 
TEAEs and the number and percent of unique subjects experiencing each TEAE. 
Separate subject-level listings will be provided for all serious and non-serious TEAEs. 
 
7.2. 
Clinical Laboratory 
All chemistry, hematology and urinalysis results from the central lab will be summarized into 
shift tables as normal, non-clinically significant abnormal and clinically significant abnormal. 
Assessments of clinical significance for abnormal values will be made by the investigator on 
results that are outside of the normal range or have a toxicity grade of 1 or greater. The shift 
tables will compare the number and percent of assessments from each visit to baseline values for 
each treatment group. Abnormal results for each subject will be provided in listings that will 
include assay name, result, normal range and an explanation for clinically significant values. 
Abnormal urine microscopy and manual differential assessments will be listed for each subject. 
 
7.3. 
Vital Signs 
Weight and vital signs, including systolic blood pressure, diastolic blood pressure, pulse rate, 
respiratory rate and body temperature, will be summarized for each treatment group. A statistical 
description of each parameter at baseline will be provided along with the change from baseline at 
each subsequent visit. A subject-level listing will also be provided. 
 
7.4. 
Concomitant Medications 
The World Health Organization Drug Dictionary (WHODD) will be used to classify prior and 
concomitant medications by Anatomical Main Group (Anatomical Therapeutic Chemical, ATC, 
Level 1), Therapeutic Subgroup (ATC Level 2), and preferred term. Prior and concomitant 
medication usage will be summarized by the number and percentage of subjects receiving each 
medication by treatment group. 
Subject-level listings containing prior and concomitant medications (WHODD coding), and 
procedures and non-drug therapies (MedDRA coding) will be provided. 
 
8. 
EFFICACY EVALUATION 
All efficacy analysis will be performed on the ITT analysis set in support of regulatory 
requirements. Efficacy analysis will also be performed on the mITT and PP Analysis Sets.  
 


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8.1. 
General Considerations 
For continuous variables within each treatment group, the outcome measure at each visit, as well 
as absolute change (outcome – baseline), will be summarized using descriptive statistics. 
Categorical variables will be summarized with frequency tables. 
Subject-level listings will be provided for each outcome measure in the final analysis report.  
 
8.1.1. 
ANCOVA Model for Continuous Efficacy Outcomes 
ANCOVA models will be used for all continuous efficacy outcome measures summarized by 
change from baseline in order to test the following three hypotheses: 
H0: (βi – β0) = 0 
HA: (βi – β0) ≠ 0,   where i = 1,2,3 
In the statement above, β is the least squares estimate in the change in the continuous efficacy 
outcome from baseline at each timepoint (where β0 is the estimate for placebo), and i represents 
each of the three SM04690 treatment groups.  
Least squares estimate of difference between each treatment group and placebo in the change in 
the continuous efficacy outcome from baseline at each timepoint, adjusted for baseline value, 
will be reported along with unadjusted 95% confidence intervals and P values. 
Continuous efficacy measures to be analyzed by the ANCOVA model include: 
 WOMAC Pain 
 WOMAC Function 
 WOMAC Total 
 Patient Global Assessment 
 Physician Global Assessment 
 Medial and Lateral Joint Space Width 
 SF-36 
8.1.2. 
Logistic Regression Model for Binary Efficacy Outcomes 
Logistic regression will be used to analyze the proportion of positive responses within each 
treatment group compared to placebo at each timepoint for all binary efficacy outcomes. Odds 
ratios as well as unadjusted 95% confidence intervals and P values will be presented. 
Binary efficacy measures to be analyzed by logistic regression include: 
 OMERACT-OARSI “strict” response 
 OMERACT-OARSI response 
 


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8.2. 
Interim Analysis of Efficacy Outcomes 
Analysis of all endpoints in support of the primary and secondary objectives will be conducted 
after all subjects complete the Week 26 visit but prior to the formal completion of the trial at 52 
weeks. 
This will include: 
 Evaluate change from baseline OA pain in the target knee as assessed by the WOMAC 
pain subscore at Weeks 13 and 26  
 Evaluate change from baseline OA function in the target knee as assessed by the 
WOMAC function subscore at Weeks 13 and 26  
 Evaluate change from baseline OA disease activity as assessed by the Patient Global 
Assessment at Weeks 13 and 26 
 Evaluate change from baseline in medial joint space width (JSW) as documented by X-
ray of the target knee at Week 26 
 
Additionally, endpoints in support of exploratory objectives will also be analyzed, including:  
 Evaluate change from baseline OA pain in the target knee as assessed by the WOMAC 
pain subscore at Week 4  
 Evaluate change from baseline OA function in the target knee as assessed by the 
WOMAC function subscore at Week 4 
 Evaluate change from baseline in WOMAC total score for the target knee at Weeks 4, 13 
and 26  
 Evaluate change from baseline OA disease activity as assessed by the Patient Global 
Assessment at Week 4 
 Evaluate change from baseline in lateral JSW as documented by X-ray of the target knee 
at Week 26 
 Determine the percentage of Outcome Measures in Rheumatology Clinical Trials 
(OMERACT)-Osteoarthritis Research Society International (OARSI) responders and 
“strict” responders at Weeks 4, 13 and 26 
 Evaluate change from baseline OA disease activity as assessed by the Physician Global 
Assessment at Weeks 4, 13 and 26 
 
8.2.1. 
Familywise Error Rate Control  
The familywise error rate for the interim efficacy analyses will be controlled in the strong sense 
using the closed, fixed sequence testing method (Dmitrienko et al 2010). All hypothesis tests will 
be evaluated in the pre-specified sequential order that matches clinical inference from prior 
SM04690 studies regarding the relative therapeutic benefit of each dose. If a test fails to meet the 


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critical value of α = 0.05, all subsequent tests will not be evaluated for the interim efficacy 
analysis and only be considered as exploratory analysis. 
 
For this study, the pre-specified, fixed hypothesis hierarchy is:  
H1. 
Change in WOMAC Pain at Week 13, 0.07 mg SM04690 vs Placebo 
H2. 
Change in WOMAC Pain at Week 13, 0.03 mg SM04690 vs Placebo 
H3. 
Change in WOMAC Pain at Week 13, 0.23 mg SM04690 vs Placebo 
H4. 
Change in WOMAC Function at Week 13, 0.07 mg SM04690 vs Placebo 
H5. 
Change in WOMAC Function at Week 13, 0.03 mg SM04690 vs Placebo 
H6. 
Change in medial JSW at Week 26, 0.07 mg SM04690 vs Placebo 
H7. 
Change in medial JSW at Week 26, 0.03 mg SM04690 vs Placebo 
H8. 
Change in WOMAC Function at Week 13, 0.23 mg SM04690 vs Placebo 
H9. 
Change in medial JSW at Week 26, 0.23 mg SM04690 vs Placebo 
H10. Change in Patient Global Assessment at Week 13, 0.07 mg SM04690 vs Placebo 
H11. Change in Patient Global Assessment at Week 13, 0.03 mg SM04690 vs Placebo 
H12. Change in Patient Global Assessment at Week 13, 0.23 mg SM04690 vs Placebo 
H13. Change in WOMAC Pain at Week 26, 0.07 mg SM04690 vs Placebo 
H14. Change in WOMAC Pain at Week 26, 0.03 mg SM04690 vs Placebo 
H15. Change in WOMAC Function at Week 26, 0.07 mg SM04690 vs Placebo 
H16. Change in WOMAC Function at Week 26, 0.03 mg SM04690 vs Placebo 
H17. Change in WOMAC Pain at Week 26, 0.23 mg SM04690 vs Placebo 
H18. Change in WOMAC Function at Week 26, 0.23 mg SM04690 vs Placebo 
H19. Change in Patient Global Assessment at Week 26, 0.07 mg SM04690 vs Placebo 
H20. Change in Patient Global Assessment at Week 26, 0.03 mg SM04690 vs Placebo 
H21. Change in Patient Global Assessment at Week 26, 0.23 mg SM04690 vs Placebo 
 
8.2.2. 
Subgroup Analysis 
The primary and secondary efficacy analysis described above will be further explored by the 
following covariates: 
 KL Grade 2 vs. KL Grade 3 
 Age Groups: age < 65, 65 ≤ age < 75, age ≥ 75 
 BMI Groups: BMI < 30, 30 ≤ BMI < 35, BMI ≥ 35 
 Bilateral knee vs. unilateral knee OA 


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 WPI: WPI < 13, WPI ≥ 13 
 
Each covariate will be added to the original ANCOVA model along with a term for the 
interaction between treatment group and the covariate at Week 13 for WOMAC pain, WOMAC 
function and Patient Global, and Week 26 for medial JSW. The significance of each interaction 
term will be determined using a likelihood ratio test that compares the original model to the 
model with the interaction. If the significance level of the interaction is P < 0.10 at Week 13 for 
WOMAC pain, WOMAC function and Patient Global, and Week 26 for medial JSW, the 
interaction model will be evaluated at those timepoints as well as subsequent timepoints. 
 
8.3. 
Final Analysis of Efficacy Outcomes 
Interim efficacy analyses will not be repeated but will be included in the final report. Any 
changes to the data that was sequestered and analyzed for interim will be summarized and 
explained. In addition, the following objectives will be explored: 
 Evaluate change from baseline in WOMAC total score for the target knee at Weeks 39 
and 52  
 Evaluate change from baseline OA function in the target knee as assessed by the 
WOMAC function subscore at Weeks 39 and 52 
 Evaluate change from baseline OA in the target knee as assessed by the WOMAC Total 
at Weeks at Weeks 39 and 52 
 Evaluate change from baseline OA disease activity as assessed by the Patient Global 
Assessment at Weeks 39 and 52 
 Evaluate change from baseline in medial and lateral JSW as documented by X-ray of the 
target knee at Week 52 
 Determine the percentage of Outcome Measures in Rheumatology Clinical Trials 
(OMERACT)-Osteoarthritis Research Society International (OARSI) responders and 
“strict” responders at Weeks 39 and 52 
 Evaluate change from baseline OA disease activity as assessed by the Physician Global 
Assessment at Weeks 39 and 52 
 Evaluate change from baseline health-related quality of life (HRQOL) as assessed by the 
36-Item Short Form Health Survey (SF-36) at Weeks 4, 13, 26, 39 and 52 
 
 
9. 
ANALYSIS SOFTWARE 
All data processing, summarization and analyses will utilize SAS® Version 9.4. QualityMetric 
Health Outcomes Scoring Software 4.5 will be used to score SF-36 questionnaires. 
 
 


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10. 
REFERENCES 
Dmitrienko, A., A. C. Tamhane, and F. Bretz. (2010). Multiple testing problems in 
pharmaceutical statistics. Boca Raton, Chapman & Hall.  
ICH E9 Guidance. (1999). "ICH Harmonised Tripartite Guideline. Statistical principles for 
clinical trials. International Conference on Harmonisation E9 Expert Working Group." Stat Med 
18(15): 1905-1942. 
 
Pham, T., D. Van Der Heijde, M. Lassere, R. D. Altman, J. J. Anderson, N. Bellamy, M. 
Hochberg, L. Simon, V. Strand, T. Woodworth, M. Dougados and O. Omeract (2003). "Outcome 
variables for osteoarthritis clinical trials: The OMERACT-OARSI set of responder criteria." J 
Rheumatol 30(7): 1648-1654. 
 
Piantadosi, S. (1997). Clinical Trials: A Methodologic Perspective. New York, Wiley-
Interscience. 
 
Schafer, JL. (1999) “Multiple imputation: a primer.” Stat Methods Med Res 8: 3-15.