Clinical trial NCT03691974
Conditions: Osteoarthritis, Knee Osteoarthritis, Hip
Sponsor: Regeneron Pharmaceuticals
Start date: 2018-10-15; Completion date: 2021-01-07
Enrollment: 180 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study is to evaluate the effect of fasinumab compared to placebo on peripheral nerves in participants with pain due to Osteoarthritis (OA) of the hip or knee.

The secondary objectives of the study are to:

* Evaluate the efficacy of fasinumab compared to placebo in participants with pain due to OA of the hip or knee
* Evaluate the safety and tolerability of fasinumab compared to placebo in participants with pain due to OA of the hip or knee
* Characterize the concentrations of fasinumab in serum in participants with pain due to OA of the hip or knee
* Evaluate the immunogenicity of fasinumab in participants with pain due to OA of the hip or knee.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Fasinumab intervention 2: Placebo
Intervention descriptions: intervention 1: Subcutaneous (SC) every four weeks (Q4W) intervention 2: Subcutaneous (SC) every four weeks (Q4W)

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
R475-OA-1758 Amendment 2 
Regeneron Pharmaceuticals, Inc. 
Page 1 of 83 
CONFIDENTIAL 
IND: Number:  103245 
EudraCT: 2017-004921-33 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to 
Evaluate the Effects of Fasinumab on Peripheral Nerve Function in Patients 
with Pain due to Osteoarthritis of the Hip or Knee  
Compound: 
Fasinumab 
Clinical Phase: 
2 
Protocol Number: 
R475-OA-1758 
Protocol Version: 
R475-OA-1758 Amendment 2 
Amendment 2 Date of Issue: 
See appended electronic signature page 
Amendment 1 Date of Issue: 
16 Jul 2018 
Original Date of Issue 
20 Feb 2018 
Medical/Study Director: 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
 
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NCT03691974


Clinical Study Protocol 
 
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Regeneron Pharmaceuticals, Inc. 
 
Page 2 of 83 
CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 2 
The purpose of this amendment is to revise the criterion for detecting a change in nerve conduction 
velocity that would be considered not to be within established parameters, in order to reduce 
false-positive findings.  Additional minor changes have been made to improve clarity.  The 
following table outlines the changes made to the protocol and the affected sections: 
Change and Rationale 
Sections Changed 
Main Change: 
The criterion for detection of a change in nerve 
conduction velocity has been revised from a deficit of 
5 m/second to a deficit of >12% relative to the baseline 
value.  This update was made to allow the measurement 
of change from baseline to be relative to the patient’s 
size (eg, height and length of limb) and, thus, decrease 
the potential of obtaining false-positive findings due to 
varying patient size.  Procedures for monitoring 
peripheral sensory adverse events of special interest 
have been updated accordingly. 
Section 9.6.1.3 Peripheral Sensory Adverse Events 
Other Changes: 
Time frames have been added to the safety endpoints for 
clarity. 
Clinical Study Protocol Synopsis, Endpoints 
Section 4.3 Additional Safety Endpoints 
Text has been updated to align with current best 
practices (ie, updated protocol template text) 
Clinical Study Protocol Synopsis, Endpoints  
Section 4.5 Anti-Drug Antibody Variables 
Section 10.3.4 Anti-Drug Antibody Analysis Set 
Section 10.4.6 Analysis of Anti-Drug Antibody Data 
Section 14.5 Clinical Study Data Transparency (section 
added) 
An additional reason for permanent discontinuation of 
study drug has been added, as follows:  
‘Per protocol repeated nerve conduction test that 
confirms results are not within the established 
parameters for peroneal, sural, or ulnar nerves, as per 
central reader assessment and the neurologist’s 
evaluation that confirms the diagnosis of peripheral 
neuropathy.’ 
Section 7.3.2.1 Reasons for Permanent Discontinuation 
of Study Drug 
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CONFIDENTIAL 
Minor edits were also made to this section. 
A statement has been added to clarify that patient-
reported outcome measures should be completed before 
all other assessments. 
Table 1 Schedule of Events 
Section 8.1.1 Footnotes for the Schedule of Events 
Table 1, Footnote #22 
Section 8.2.2.1 
Western 
Ontario 
and 
McMaster 
Universities Osteoarthritis Index 
Section 8.2.3.3 Survey of Autonomic Symptoms 
Section 8.2.4.4 Joint Pain Questionnaire 
Methotrexate has been added to the list of prohibited 
immunosuppressants. 
Section 7.7.1 Prohibited Medications 
The scale used to assess the WOMAC index has been 
revised to the numerical rating scale (previously 
incorrectly cited as the Likert scale). 
Section 8.2.2.1 
Western 
Ontario 
and 
McMaster 
Universities Osteoarthritis Index 
RAVE Medidata Imaging System has been added to the 
list of electronic systems used in the study.  This is an 
electronic platform used to upload nerve conduction test 
wave forms for central reader review. 
Section 11.2 Electronic Systems 
Other edits have been made throughout the document to 
improve clarity or correct minor errors. 
Clinical Study Protocol Synopsis, Study Design 
List of Abbreviations and Definition of Terms 
Section 5.1.1 Screening and Pre-Randomization 
Section 5.1.2 Rescreening 
Section 6.2.2 Exclusion Criteria, #7 
Section 7.1 Investigational and Reference Treatments 
Section 7.3.2.2 Reasons for Temporary Discontinuation 
of Study Drug 
Table 1 Schedule of Events 
Section 8.1.1 Footnotes for the Schedule of Events 
Table 1, Footnote #8, Footnote #19 
Section 8.2.3.1 Nerve Conduction 
Section 8.2.4.8 Laboratory Testing 
Section 10.4.5 Analysis of Drug Concentration Data 
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Amendment 1 
The purpose of this amendment is to change the fasinumab 3 mg Q4W dose regimen to a 1 mg 
Q4W dose regimen because the 3 mg Q4W dose regimen is no longer being evaluated in the 
osteoarthritis (OA) pain program.  The 1 mg Q4W dose regimen is now the highest dose being 
evaluated in this patient population. Additional changes have been made to improve study outcome 
measures and for clarity. The following table outlines the changes made to the protocol and the 
affected sections: 
Change and Rationale 
Sections Changed 
The 3 mg Q4W dose regimen has been removed and 
replaced with a 1 mg Q4W dose regimen.  
Clinical Study Protocol Synopsis, Study Design, 
Treatments, Statistical Plan 
Section 1 Introduction 
Section 3.1.2 Rationale for Dose Selection 
Section 5.1.3 Randomization 
Section 5.1.4 Treatment Period 
Section 7.1 Investigational and Reference Treatments 
Section 7.5 Method of Treatment Assignment 
Section 10.2 Justification of Sample Size 
The phone visit at week 1 has been changed to a site visit 
in order to obtain a more complete pharmacokinetic 
profile.  
Table 1 Schedule of Events 
The exclusion criterion regarding carpal tunnel 
syndrome has been updated to include additional 
conditions that could interfere with the assessment of the 
primary endpoint.  Specifically, “Signs or symptoms of 
carpal tunnel syndrome within 6 months of the screening 
visit” has been updated to “History or presence of signs 
or symptoms of compression neuropathy, including 
carpal tunnel syndrome or sciatica.”  
Section 6.2.2 Exclusion Criteria, #4 
Text has been added to clarify that the results of the 
nerve conduction assessment must be obtained before 
randomization can occur.  
Clinical Study Protocol Synopsis, Study Design 
Section 5.1.1 Screening and Pre-Randomization 
Table 1 Schedule of Events 
Section 8.1.1 Footnotes for the Schedule of Events, 
Table 1 Footnote #8 
Drugs included in the urine drug test have been listed in 
the Laboratory Testing section 
Section 8.2.4.8 Laboratory Testing 
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Additional text has been added, edited or deleted in 
order to improve clarity of the protocol, to make minor 
corrections, to be consistent across fasinumab program, 
or to align with current Regeneron best practices. 
Clinical Study Protocol Synopsis, Safety Endpoints 
List of Abbreviations and Definitions of Terms 
Section 4.3 Additional Safety Endpoints 
Section 5.1.1 Screening and Pre-Randomization 
Section 5.1.2 Rescreening 
Section 6.2.2 Exclusion Criteria, #7 
Section 7.4.2 Local Injection Site Reactions 
Section 7.7.1 Prohibited Medications 
Section 7.7.2 Permitted Medications and Procedures 
Table 1, Schedule of Events 
Section 8.1.1 Footnotes for the Schedule of Events 
Table 1, Footnote #4 
Section 8.2.1.8 Diary Training 
Section 8.2.1.9 Patient Education Brochures 
Section 8.2.4.7 Procedures to be Performed Only in the 
Event of a Joint Replacement Surgery 
Section 9.4.3 Other Events that Require Accelerated 
Reporting to Sponsor 
Section 9.6.1.1 Adjudicated Arthropathy 
Section 9.6.1.3 Peripheral Sensory Adverse Events 
Section 10.3.3 Pharmacokinetic Analysis Set 
Section 10.4.3 Efficacy Analysis 
Section 10.4.5 Analysis of Drug Concentration Data 
Section 11.2 Electronic Systems  
Section 12.1 Monitoring of Study Sites 
 
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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................18 
1. 
INTRODUCTION ......................................................................................................20 
2. 
STUDY OBJECTIVES ..............................................................................................23 
2.1. 
Primary Objective .......................................................................................................23 
2.2. 
Secondary Objectives .................................................................................................23 
3. 
RATIONALE .............................................................................................................24 
3.1. 
Rationale .....................................................................................................................24 
3.1.1. 
Rationale for Study Design .........................................................................................24 
3.1.2. 
Rationale for Dose Selection ......................................................................................24 
4. 
STUDY VARIABLES................................................................................................25 
4.1. 
Demographic and Baseline Characteristics ................................................................25 
4.2. 
Primary and Secondary Endpoints..............................................................................25 
4.2.1. 
Primary Endpoints ......................................................................................................25 
4.2.2. 
Secondary Endpoints ..................................................................................................25 
4.3. 
Additional Safety Endpoints .......................................................................................25 
4.4. 
Pharmacokinetic Variables .........................................................................................26 
4.5. 
Anti-Drug Antibody Variables ...................................................................................26 
5. 
STUDY DESIGN .......................................................................................................26 
5.1. 
Study Description and Duration .................................................................................26 
5.1.1. 
Screening and Pre-Randomization .............................................................................26 
5.1.2. 
Rescreening .................................................................................................................27 
5.1.3. 
Randomization ............................................................................................................28 
5.1.4. 
Treatment Period ........................................................................................................28 
5.1.5. 
Follow-up Period ........................................................................................................28 
5.1.6. 
End of Study Phone Contact and Additional Imaging ................................................28 
5.1.7. 
Study Stopping Rules .................................................................................................28 
5.1.8. 
End of Study Definition ..............................................................................................29 
5.2. 
Planned Interim Analysis ............................................................................................29 
5.3. 
Study Committees .......................................................................................................29 
5.3.1. 
Independent Data Monitoring Committee ..................................................................29 
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5.3.2. 
Arthropathy Adjudication Committee ........................................................................29 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............29 
6.1. 
Number of Patients Planned .......................................................................................29 
6.2. 
Study Population .........................................................................................................30 
6.2.1. 
Inclusion Criteria ........................................................................................................30 
6.2.2. 
Exclusion Criteria .......................................................................................................31 
6.3. 
Premature Withdrawal from the Study .......................................................................34 
6.4. 
Replacement of Patients .............................................................................................35 
7. 
STUDY TREATMENTS............................................................................................35 
7.1. 
Investigational and Reference Treatments ..................................................................35 
7.2. 
Rescue Treatment .......................................................................................................35 
7.3. 
Dose Modification and Study Treatment Discontinuation Rules ...............................36 
7.3.1. 
Dose Modification ......................................................................................................36 
7.3.2. 
Study Drug Discontinuation .......................................................................................36 
7.3.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................36 
7.3.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................38 
7.4. 
Management of Acute Reactions ................................................................................38 
7.4.1. 
Systemic Injection Reactions ......................................................................................38 
7.4.2. 
Local Injection Site Reactions ....................................................................................38 
7.5. 
Method of Treatment Assignment ..............................................................................38 
7.5.1. 
Blinding ......................................................................................................................38 
7.5.2. 
Emergency Unblinding ...............................................................................................39 
7.5.3. 
Unblinding for Regulatory Reporting Purposes .........................................................39 
7.6. 
Treatment Logistics and Accountability .....................................................................39 
7.6.1. 
Packaging, Labeling, and Storage ..............................................................................39 
7.6.2. 
Supply and Disposition of Treatments .......................................................................39 
7.6.3. 
Treatment Accountability ...........................................................................................40 
7.6.4. 
Treatment Compliance ................................................................................................40 
7.7. 
Concomitant Medications and Procedures .................................................................40 
7.7.1. 
Prohibited Medications ...............................................................................................40 
7.7.2. 
Permitted Medications and Procedures ......................................................................41 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................41 
8.1. 
Schedule of Events .....................................................................................................41 
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8.1.1. 
Footnotes for the Schedule of Events Table 1 ............................................................45 
8.1.2. 
Footnotes for Table 2 - Follow-up Period for Patients Undergoing Joint 
Replacement Surgery ..................................................................................................47 
8.1.3. 
Early Termination Visit ..............................................................................................48 
8.1.4. 
Unscheduled Visits .....................................................................................................48 
8.2. 
Study Procedures ........................................................................................................48 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................48 
8.2.1.1. 
Main Study Informed Consent ....................................................................................48 
8.2.1.2. 
Genomics Sub-study Informed Consent .....................................................................48 
8.2.1.3. 
Medical History ..........................................................................................................48 
8.2.1.4. 
Medication History .....................................................................................................48 
8.2.1.5. 
Demographics .............................................................................................................49 
8.2.1.6. 
Determination of Osteoarthritis ..................................................................................49 
8.2.1.7. 
Assessment of Childbearing Potential ........................................................................49 
8.2.1.8. 
Diary Training ............................................................................................................50 
8.2.1.9. 
Patient Education Brochures.......................................................................................50 
8.2.2. 
Patient-Completed Assessments and Efficacy Procedures .........................................50 
8.2.2.1. 
Western Ontario and McMaster Universities Osteoarthritis Index ............................50 
8.2.3. 
Neurological Assessments ..........................................................................................50 
8.2.3.1. 
Nerve Conduction .......................................................................................................50 
8.2.3.2. 
Neurological Examination (Full) ................................................................................51 
8.2.3.3. 
Survey of Autonomic Symptoms ................................................................................51 
8.2.3.4. 
Orthostatic Blood Pressure Assessment and Heart Rate ............................................51 
8.2.4. 
Safety Procedures .......................................................................................................52 
8.2.4.1. 
Vital Signs ..................................................................................................................52 
8.2.4.2. 
Electrocardiogram .......................................................................................................52 
8.2.4.3. 
Physical Examination and Body Weight ....................................................................52 
8.2.4.4. 
Joint Pain Questionnaire .............................................................................................52 
8.2.4.5. 
Imaging .......................................................................................................................52 
8.2.4.6. 
End of Study Phone Contact and Additional Imaging ................................................53 
8.2.4.7. 
Procedures to be Performed Only in the Event of a Joint Replacement 
Surgery ........................................................................................................................53 
8.2.4.8. 
Laboratory Testing ......................................................................................................54 
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8.2.4.9. 
Injection Site Evaluations ...........................................................................................56 
8.2.5. 
Pharmacokinetic and Anti-Drug Antibody Procedures ..............................................56 
8.2.5.1. 
Drug Concentration Measurements and Samples .......................................................56 
8.2.5.2. 
Anti-Drug Antibody Measurements and Samples ......................................................56 
8.2.6. 
Research Samples .......................................................................................................56 
8.2.6.1. 
Biomarkers ..................................................................................................................56 
8.2.6.2. 
Future Biomedical Research .......................................................................................57 
8.2.6.3. 
Genomics Sub-study - Optional..................................................................................57 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................58 
9.1. 
Obligations of Investigator .........................................................................................58 
9.2. 
Obligations of Sponsor ...............................................................................................58 
9.3. 
Definitions ..................................................................................................................58 
9.3.1. 
Adverse Event .............................................................................................................58 
9.3.2. 
Serious Adverse Event ................................................................................................58 
9.3.3. 
Adverse Events of Special Interest .............................................................................59 
9.4. 
Recording and Reporting Adverse Events ..................................................................59 
9.4.1. 
Adverse Events ...........................................................................................................59 
9.4.2. 
Serious Adverse Events ..............................................................................................59 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor ...................................60 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................61 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results .............................61 
9.4.6. 
Follow-up ....................................................................................................................61 
9.5. 
Evaluation of Severity and Causality .........................................................................61 
9.5.1. 
Evaluation of Severity ................................................................................................61 
9.5.2. 
Evaluation of Causality ...............................................................................................62 
9.6. 
Safety Monitoring .......................................................................................................64 
9.6.1. 
Monitoring Adverse Events of Special Interest ..........................................................64 
9.6.1.1. 
Adjudicated Arthropathy ............................................................................................64 
9.6.1.2. 
Sympathetic Nervous System Dysfunction ................................................................65 
9.6.1.3. 
Peripheral Sensory Adverse Events ............................................................................66 
9.6.1.4. 
Joint Replacement Surgery .........................................................................................66 
9.7. 
Investigator Alert Notification ....................................................................................67 
10. 
STATISTICAL PLAN................................................................................................67 
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10.1. 
Statistical Hypothesis ..................................................................................................67 
10.2. 
Justification of Sample Size........................................................................................67 
10.3. 
Analysis Sets ...............................................................................................................68 
10.3.1. 
Efficacy Analysis Set ..................................................................................................68 
10.3.2. 
Safety Analysis Set .....................................................................................................68 
10.3.3. 
Pharmacokinetic Analysis Set ....................................................................................68 
10.3.4. 
Anti-Drug Antibody Analysis Set ..............................................................................68 
10.4. 
Statistical Methods ......................................................................................................68 
10.4.1. 
Patient Disposition ......................................................................................................68 
10.4.2. 
Demography and Baseline Characteristics .................................................................68 
10.4.3. 
Efficacy Analysis ........................................................................................................69 
10.4.4. 
Safety Analysis ...........................................................................................................69 
10.4.4.1. 
Primary Safety Analysis .............................................................................................69 
10.4.4.2. 
Adverse Events ...........................................................................................................70 
10.4.4.3. 
Other Safety ................................................................................................................70 
10.4.4.4. 
Treatment Exposure ....................................................................................................71 
10.4.4.5. 
Treatment Compliance ................................................................................................71 
10.4.5. 
Analysis of Drug Concentration Data .........................................................................71 
10.4.6. 
Analysis of Anti-Drug Antibody Data ........................................................................71 
10.5. 
Interim Analysis ..........................................................................................................72 
10.6. 
Additional Statistical Data Handling Conventions .....................................................72 
10.7. 
Statistical Considerations Surrounding the Premature Termination of a Study .........72 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS .....................................73 
11.1. 
Data Management .......................................................................................................73 
11.2. 
Electronic Systems ......................................................................................................73 
12. 
STUDY MONITORING ............................................................................................73 
12.1. 
Monitoring of Study Sites ...........................................................................................73 
12.2. 
Source Document Requirements ................................................................................73 
12.3. 
Case Report Form Requirements ................................................................................74 
13. 
AUDITS AND INSPECTIONS .................................................................................74 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................75 
14.1. 
Good Clinical Practice Statement ...............................................................................75 
14.2. 
Informed Consent .......................................................................................................75 
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14.3. 
Patient Confidentiality and Data Protection ...............................................................75 
14.4. 
Institutional Review Board/Ethics Committee ...........................................................76 
14.5. 
Clinical Study Data Transparency ..............................................................................76 
15. 
PROTOCOL AMENDMENTS ..................................................................................76 
16. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................76 
16.1. 
Premature Termination of the Study ...........................................................................76 
16.2. 
Close-out of a Site ......................................................................................................76 
17. 
STUDY DOCUMENTATION ...................................................................................77 
17.1. 
Certification of Accuracy of Data ...............................................................................77 
17.2. 
Retention of Records ..................................................................................................77 
18. 
DATA QUALITY ASSURANCE ..............................................................................77 
19. 
CONFIDENTIALITY ................................................................................................78 
20. 
FINANCING AND INSURANCE .............................................................................78 
21. 
PUBLICATION POLICY ..........................................................................................78 
22. 
REFERENCES ...........................................................................................................79 
23. 
INVESTIGATOR’S AGREEMENT ..........................................................................82 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................83 
 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................42 
Table 2: 
Follow-up Period for Patients Undergoing Joint Replacement Surgery on 
Study ...........................................................................................................................47 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................26 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to 
Evaluate the Effects of Fasinumab on Peripheral Nerve Function in Patients 
with Pain Due to Osteoarthritis of the Hip or Knee 
Site Locations 
 
Principal Investigator 
To be determined. 
Objectives 
Primary Objective 
The primary objective of the study is to evaluate the effect of fasinumab 
compared to placebo on peripheral nerves in patients with pain due to 
osteoarthritis (OA) of the hip or knee.  
Secondary Objectives 
The secondary objectives of the study are:  
 
To evaluate the efficacy of fasinumab compared to placebo in 
patients with pain due to OA of the hip or knee  
 
To evaluate the safety and tolerability of fasinumab compared to 
placebo in patients with pain due to OA of the hip or knee 
 
To characterize the concentrations of fasinumab in serum in 
patients with pain due to OA of the hip or knee  
 
To evaluate the immunogenicity of fasinumab in patients with pain 
due to OA of the hip or knee 
Study Design 
This is a phase 2, randomized, double-blind, placebo-controlled, multicenter 
study designed to evaluate the neurological safety of fasinumab compared 
to placebo in patients with pain due to OA of the hip or knee.  In addition, 
the safety, efficacy, pharmacokinetics (PK), and immunogenicity of 
fasinumab compared to placebo will be assessed. 
The study duration will be approximately 64 weeks starting at 
randomization (day 1). The study consists of a screening period of up to 30 
days, a 7 to 10 day pre-randomization period (7 days with a +3 day window), 
a 16-week treatment period (with the last every 4 week [Q4W] dose of study 
drug administered at week 12), a 20-week follow-up period, and a final 
phone contact approximately 52 weeks after the last dose of study drug is 
administered. 
Screening and Pre-Randomization 
Prior to randomization, patients will undergo screening procedures, 
including X-ray of the shoulders, hips, and knees. Magnetic resonance 
imaging (MRI) of the index and contralateral joints must be performed at 
screening and the results assessed by the central imaging vendor. In 
addition, an MRI will be performed on any knee or hip joint with a Kellgren-
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Lawrence (K-L) score of ≥3. Randomization visits cannot occur until there 
is confirmation from the central imaging vendor that there are no 
exclusionary findings on the X-rays and any required MRIs.  
Prior to randomization, patients will also undergo nerve conduction 
assessments.  Patients must complete all other inclusion/exclusion 
assessments before undergoing the nerve conduction assessments.  
Randomization cannot occur until there is confirmation from the central 
reader assessment that the results are within the established parameters. 
During the screening period, patients may continue to take their current 
treatment regimen for OA pain.  
Patients eligible for the study will complete a pre-randomization period. The 
pre-randomization visit will be 7 to 10 days before the randomization visit. 
During this period, patients will discontinue and/or undergo a washout of 
their current pain medications for OA.  All pain medication, except for the 
study-provided rescue medication (acetaminophen/paracetamol), will be 
discontinued. 
Randomization 
On day 1 (baseline), approximately 180 patients will be randomized in a 1:1 
ratio to fasinumab 1 mg subcutaneous (SC) Q4W or fasinumab-matching 
placebo SC Q4W. Randomization will be stratified according to the affected 
index joint (hip or knee) and the K-L score (2 to 3, or 4) at the screening 
visit.  
Treatment 
During the treatment period (day 1 through week 16), patients will be 
permitted to use only study-provided acetaminophen/paracetamol as rescue 
medication. Patients will record their use of acetaminophen/paracetamol in 
a diary.  
Neurological, efficacy and safety assessments will be performed during the 
treatment period.  
Follow-up 
Follow-up of patients will continue for an additional 20 weeks after the last 
treatment period visit. Neurological, efficacy, and safety assessments will 
be performed during this period.  
If a patient must undergo joint replacement (JR) surgery during the follow-
up period, he or she will be asked to complete pre-operative imaging and to 
undergo post-surgery follow-up. 
End of study Phone Contact 
A phone contact questionnaire will be conducted at approximately 52 weeks 
after administration of the last dose of study drug to document patient status 
with regard to JR surgery (if patient underwent, is scheduled for, or is on a 
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wait list for JR surgery).  Patients who had an adjudicated arthropathy (AA) 
will have an MRI performed of the affected joint(s). 
Study Duration 
The duration of the study is up to 64 weeks, excluding the screening and 
pre-randomization periods. Patients who discontinue study drug will be 
requested to return for all scheduled study visits and to complete all planned 
assessments, including phone contacts. 
End of Study Definition 
The end of study is defined as the last phone contact of the last patient in 
this study. 
Population 
 
 
Sample Size: 
Enrollment of approximately 180 patients is planned for this study 
(approximately 90 patients per treatment group) 
 
Target Population: 
Men and women who are at least 18 years of age at the time of study entry 
with a clinical diagnosis at the screening visit of OA of the knee or hip, 
based on the American College of Rheumatology criteria, and with 
radiologic evidence of OA (K-L score ≥2) at the index joint.  
Treatments 
 
 
Study Drug 
 
Dose/Route/Schedule: 
Fasinumab 
1 mg SC Q4W 
 
Study Drug Placebo 
 
Route/Schedule: 
Fasinumab-matching placebo  
SC Q4W 
 
Rescue Treatment: 
Starting at pre-randomization to the end of the 16-week treatment period, 
acetaminophen/paracetamol is the only study-provided rescue medication. 
In the event of inadequate pain relief for OA or in the event of other pain 
(eg, 
headache) 
or 
fever, 
1 
to 
2 
tablets/capsules 
of 
acetaminophen/paracetamol may be taken no less than 4 hours apart as 
needed according to the local standard of care.  
Endpoints 
 
 
Primary: 
The primary endpoints of the study are: 
 
Change from baseline to week 16 in peroneal motor nerve 
conduction velocity 
 
Change from baseline to week 16 in peroneal motor nerve action 
potential amplitude 
 
Change from baseline to week 16 in sural sensory nerve conduction 
velocity 
 
Change from baseline to week 16 in sural sensory nerve action 
potential amplitude 
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 
Change from baseline to week 16 in ulnar sensory nerve 
conduction velocity 
 
Change from baseline to week 16 in ulnar sensory nerve action 
potential amplitude 
 
Secondary: 
The secondary endpoints of the study are: 
 
Change from baseline to week 16 in Western Ontario and 
McMaster Universities Osteoarthritis Index (WOMAC) pain 
subscale score 
 
Change from baseline to week 16 in WOMAC physical function 
subscale score 
 
Safety: 
Additional safety endpoints in this study include:  
 
Incidence of AA (as confirmed by an independent adjudication 
committee) through week 36 
 
Incidence of destructive arthropathy (DA) (as confirmed by an 
independent adjudication committee) through week 36 
 
Incidence of treatment-emergent adverse event (TEAEs) through 
week 16 
 
Incidence of sympathetic nervous system (SNS) dysfunction (as 
diagnosed after consultation with an appropriate specialist, such as 
a neurologist and/or cardiologist) through week 36 
 
Incidence of peripheral sensory adverse events (AEs) that require 
a neurology or other specialty consultation through week 36 
 
Incidence of all-cause JR surgeries through week 36  
 
Incidence of JRs at telephone survey approximately 52 weeks after 
last dose of study drug 
 
Pharmacokinetic 
 
variable: 
The PK variable is the concentration of functional fasinumab in serum 
samples collected at specified time points. 
 
Anti-drug antibody 
 
variables: 
Anti-drug antibody (ADA) variables include status (positive or negative), 
titer, and time point/visit. 
Procedures and Assessments 
At the screening visit, patients will provide informed consent, medical 
history, and medication history.  Determination of the K-L score of the knee 
or hip will be performed to establish a diagnosis of OA based on the 
American College of Rheumatology criteria using a K-L score cutoff of ≥2.  
Patients will be assessed for childbearing potential. 
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Peripheral nerve function will be assessed by measuring nerve conduction 
velocities and evoked amplitudes of the peroneal motor, sural sensory and 
ulnar sensory nerves. 
Additional safety assessments will be performed at each study visit and upon 
occurrence of any joint AEs.  Potential events of AA will be monitored via 
clinical signs and symptoms of worsening joint pain during the study and 
adjudication of pre-operative imaging for patients who undergo JR during 
the conduct of the study.  Potential events of SNS dysfunction will be 
monitored throughout the study through physical examination, AE 
reporting, assessment of orthostatic hypotension, and the Survey of 
Autonomic Symptoms.  
Efficacy will be assessed using WOMAC pain and physical function 
subscale scores. 
Approximately 52 weeks after administration of the last study dose, a phone 
contact questionnaire will be conducted to document patient status with 
regard to JR surgery (if patient underwent, is scheduled for, or is on a wait 
list for JR surgery). Patients who had an AA will have an MRI performed of 
the affected joint(s). 
Statistical Plan 
Statistical Hypothesis  
No formal hypothesis testing will be performed on nerve conduction 
measures. The treatment difference between fasinumab and placebo in the 
change from baseline to week 16 in nerve conduction measures will be 
estimated and presented descriptively along with 95% confidence intervals. 
Justification of Sample Size 
Approximately 180 patients will be randomized in a 1:1 ratio to fasinumab 
1 mg Q4W or placebo. With this sample size, the precision of the estimated 
treatment difference between fasinumab and placebo at week 16 in nerve 
conduction velocity is no more than 1.21 m/s with a 95% confidence level, 
assuming a standard deviation (SD) of 3.6 m/s. This sample size provides 
similar precision for the estimated treatment difference in nerve conduction 
amplitude assuming a SD of 3.6 μV. Assuming a 2-sided alpha level of 0.05 
and a 15% dropout rate up to week 16, an enrollment of 90 patients per group 
will provide at least 80% power to detect an effect size of 0.46 in the 
WOMAC pain and physical function subscale scores (ie, absolute treatment 
difference of 1.1 between fasinumab and placebo with an SD of 2.4). The 
assumed treatment difference and SD are based on results from study 
R475-PN-1227.  
Statistical Methods 
For continuous variables, descriptive statistics will include the following 
information:  the number of patients reflected in the calculation (n), mean, 
median, standard deviation, minimum, Q1, Q3, and maximum. 
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For categorical or ordinal data, frequencies and percentages will be 
displayed for each category. 
Safety data including nerve conduction measures, TEAEs and treatment-
emergent adverse events of special interest (AESIs), vital signs, physical 
exams, laboratory tests, electrocardiograms (ECGs), and ADA formation 
will be listed and summarized by treatment group. The nerve conduction 
variables will be analyzed using a mixed-effect model repeated measure 
(MMRM) approach based on the safety analysis set (SAF). The least-
squares mean estimates for the mean change from baseline to week 16, as 
well as the differences of the estimates between fasinumab and placebo, with 
their corresponding standard errors and associated 95% confidence 
intervals, will be provided descriptively. 
The efficacy variables will be analyzed using multiple imputation approach 
with MMRM based on the full analysis set (FAS) with adjustment for 
missing data due to lack of efficacy or AEs assuming the scores would on 
average return to baseline values. 
For analysis of categorical variables, eg, proportions of patients with ≥30% 
improvement in the WOMAC pain subscale scores at week 16, the Cochran 
Mantel Haenszel approach stratified by the randomization strata will be used 
with missing data considered as non-response. 
Summaries of serum concentrations of functional fasinumab will be 
presented by nominal time point. Plots of individual concentration over time 
will be presented by actual day. Plots of mean or median concentrations of 
functional fasinumab will be presented by nominal day. No formal statistical 
analysis will be performed. 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
5-ASA 
5-aminosalicylic acid 
AA 
Adjudicated arthropathy 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
bpm 
Beats per minute  
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DA 
Destructive arthropathy  
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
ESR 
Erythrocyte sedimentation rate 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
IWRS 
Interactive web response system 
JR 
Joint replacement 
K-L 
Kellgren-Lawrence 
MedDRA 
Medical Dictionary for Regulatory Activities 
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MMRM 
Mixed-effect Model for Repeated Measures 
MRI  
Magnetic Resonance Imaging 
NGF 
Nerve growth factor 
NSAID 
Nonsteroidal anti-inflammatory drug 
OA 
Osteoarthritis 
PCSV 
Potentially clinically significant value 
PK 
Pharmacokinetic 
PT 
Preferred term 
QRS 
Complex of Q, R, and S waves on an electrocardiogram 
Q4W 
Every 4 weeks 
Q8W 
Every 8 weeks 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SD 
Standard deviation 
SNS 
Sympathetic Nervous System 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TBL 
Total bilirubin  
TEAE 
Treatment-emergent adverse event 
TJR 
Total joint replacement 
TrkA 
Tyrosine kinase type 1  
ULN 
Upper limit of normal 
WBC 
White blood cell 
WOCBP 
Woman of child-bearing potential  
WOMAC 
Western Ontario and McMaster Universities Osteoarthritis Index 
 
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1. 
INTRODUCTION  
Chronic musculoskeletal pain affects a large proportion of the global population. A significant 
cause of chronic musculoskeletal pain is due to osteoarthritis (OA). Osteoarthritis is a progressive, 
chronic disease caused by the breakdown and loss of cartilage of the joints, which leads to pain in 
the hips, knees, hands, feet, and spine. It is characterized by focal areas of loss of articular cartilage 
in synovial joints accompanied by subchondral bone changes, osteophyte formation at the joint 
margins, thickening of the joint capsule and mild synovitis. Symptoms and disability increase with 
increasing age. The prevalence of OA in patients aged 65 and older is 60% in men and 70% in 
women, and is continually rising (Sarzi-Puttini 2005). 
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the mainstay of treatment in patients with 
mild-to-moderate OA. The efficacy of NSAIDs is well documented, albeit modest, but their use is 
associated with a number of risks (Bingham 2007, Bjordal 2004, Makarowski 2002, 
Silverstein 2000). The risks associated with long-term therapy with NSAIDs in particular, have 
been well characterized and include gastrointestinal bleeding and increased risk of cardiovascular 
events (Lanas 2011, Trelle 2011). Nonsteroidal anti-inflammatory drugs have limited efficacy in 
many OA patients; those with advanced OA typically try several NSAIDs and must often escalate 
to other therapies such as opioids.  
Treatment guidelines for OA suggest that opioids may be used in OA only if management with 
NSAIDs is ineffective, intolerable, or otherwise contraindicated. However, the use of opioids is 
limited by central nervous system effects, nausea and vomiting, constipation, and potential for 
abuse and dependence. In addition, opioid use may be associated with both acute and chronic side 
effects, including drowsiness, dizziness, gastrointestinal intolerability, motor imbalance, 
respiratory depression, and even death. Opioid use must be closely monitored in patients who are 
vulnerable or potentially vulnerable to abuse or addiction. Moreover, there is no evidence to 
support superiority of opioids over other available pain medications. While the efficacy of opioids 
in treating pain over a short duration is supported by research data, long-term efficacy has not been 
evaluated.  
Thus, there remains an unmet medical need for alternative treatment options to opioids that have 
a more effective analgesic effect, particularly since there are a significant number of patients who 
are intolerant to or do not get adequate pain relief from the currently available treatment options. 
Inadequate pain relief has a profound impact on the quality of life for millions of people worldwide 
with an associated substantial cost to society, including healthcare cost (Salmon 2016) and loss of 
productivity (Dibonaventura 2011). 
Neurotrophins are a family of peptide growth factors that play a role in the development, 
differentiation, survival, and death of neuronal and non-neuronal cells (Chao 2006). Nerve growth 
factor (NGF) was the first neurotrophin to be identified, and its role in the development and 
survival of both peripheral and central neurons during the development of the nervous system is 
well characterized (Crowley 1994, Smeyne 1994). In the adult, NGF is not required as a survival 
factor but acts as a pain mediator that sensitizes neurons (Pezet 2006). Nerve growth factor activity 
is mediated through 2 different membrane-bound receptors, the high-affinity tyrosine kinase type 
1 (TrkA) and the low-affinity p75 neurotrophin receptors.  
By acting upstream of several relevant molecular pathways, the NGF/TrkA system appears to play 
a major role in the control of pain. Administration of NGF has been shown to provoke pain in both 
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rodents (Lewin 1994) and humans (McArthur 2000), while NGF antagonists have been shown to 
prevent hyperalgesia and allodynia in animal models of neuropathic and chronic inflammatory 
pain (Ramer 1999). Humans with mutations in TrkA (hereditary sensory and autonomic 
neuropathy IV) or NGF (hereditary sensory and autonomic neuropathy V) have been identified 
with a loss of deep pain perception (Einarsdottir 2004, Indo 1996). In addition, NGF is known to 
be elevated in the synovial fluid of patients with rheumatoid arthritis and other types of arthritis 
(Aloe 1992, Halliday 1998), and to be up-regulated in injured and inflamed tissues in conditions 
such as cystitis, prostatitis, and chronic headache (Lowe 1997, Miller 2002, Sarchielli 2001). 
Fasinumab (also known as REGN475) is a fully-human high-affinity monoclonal antibody 
directed against NGF. By selectively blocking NGF, fasinumab has the potential to be effective in 
modulating NGF-associated pain without some of the adverse side effects of other analgesic 
medications, such as opioids and NSAIDs. Following an evaluation of the safety and tolerability 
of the antibody in a single-ascending-dose first-in-human study (study R475-PN-0817), a 
proof-of-concept study evaluating the effect of fasinumab on pain in 217 patients with OA of the 
knee was completed (study R475-PN-0901, see current version of the Fasinumab Investigator’s 
Brochure). Three intravenous (IV) doses of fasinumab were evaluated (0.03, 0.1, 0.3 mg/kg every 
8 weeks [Q8W]). All 3 doses, compared with placebo, were associated with statistically significant 
improvement in pain as evaluated by walking knee pain, the Western Ontario and McMaster 
Universities Osteoarthritis Index (WOMAC), and the Patient’s Global Impression of Change 
questionnaire. Additionally, another study (R475-PN-1227) in patients with OA revealed 
significant efficacy in the WOMAC pain subscale score for each of the doses of fasinumab 
evaluated (1 mg, 3 mg, 6 mg, and 9 mg given every 4 weeks [Q4W]) compared with placebo (see 
current version of the Investigator’s Brochure). Results from recent clinical studies with other anti-
NGF antibodies, tanezumab (Pfizer) and fulranumab (Janssen), also support the role of NGF in 
pain modulation in patients with pain due to OA of the knee and hip (Brown 2012, Hefti 2006, 
Lane 2010) and in patients with chronic low back pain (Katz 2011, Kivitz 2013).  
In all clinical studies completed to date, fasinumab was generally well tolerated. Arthralgia, joint 
swelling, peripheral edema, hypoesthesia, and myalgia were more frequently reported in 
fasinumab-treated patients than in placebo-treated patients. In neurological evaluations, 
abnormalities in vibration sense were more frequent in the fasinumab patients than in the placebo 
patients. These adverse events (AEs) or physical examination abnormalities associated with 
fasinumab were generally mild to moderate in intensity and were transient (see current version of 
the Investigator’s Brochure).   
Data from studies of tanezumab and fulranumab indicated that these molecules were associated 
with an increased risk of destructive arthropathy (DA), a unique clinical form of rapidly 
progressive arthropathy over and above that seen in the normal progression of osteoarthritis.  
Analyses of the tanezumab data by its sponsor, defined by anatomic pathological criteria on 
specimens obtained on joint replacement (JR), revealed that the risk of DA increases with 
tanezumab dose and is further increased with the concomitant use of chronic NSAIDs (>90 days) 
(Lane 2010). Most cases of DA occurred in joints with a documented history of OA. 
Based on the potential risk of DA identified in tanezumab and fulranumab, the US Food and Drug 
Administration (FDA) placed the class of anti-NGF antibodies on clinical hold in 2010. Following 
a review of anti-NGF antibody clinical data in March 2012, the FDA determined that clinical 
studies of anti-NGF therapies could resume if mitigation strategies were implemented to minimize 
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the risk of DA. To address concerns about potential events of DA, a risk-mitigation approach is 
also being implemented for all fasinumab studies, as outlined in Section 9.6.1.1.  This approach 
includes sensitive, prospective, and rigorous radiologic screening and monitoring for select 
changes in joint structure. Patients who develop these changes, which are referred to throughout 
this document as adjudicated arthropathy (AA), are required to discontinue study therapy.  
Since the removal of the FDA clinical hold, Regeneron Pharmaceuticals, Inc, (Regeneron) has 
conducted or initiated several clinical studies of fasinumab. In all clinical studies to date, 
fasinumab was associated with a low rate of discontinuations due to AEs. Patients treated with 
fasinumab generally had more frequent events than did placebo-treated patients of arthralgia, joint 
swelling, peripheral edema, altered peripheral sensation (eg, paresthesia, dysesthesia), and 
myalgia. 
In the phase 2/3 study of fasinumab in patients with pain due to OA of the knee or hip (R475-PN-
1227), 26 AA events occurred in 24 patients. There was an increase in AA events that appeared to 
be related to greater fasinumab dose. Although these events were milder than the severe DA events 
presented at the 2012 FDA Arthritis Advisory Committee, in consideration of the lack of an 
observed dose response for efficacy in OA, the risk-benefit ratio was deemed unfavorable for the 
fasinumab 6 mg Q4W and 9 mg Q4W doses in patients with OA in comparison to the other 
fasinumab doses that were studied (ie, 1 mg Q4W and 3 mg Q4W).  The dose regimens that were 
being evaluated in the phase 3 studies for OA pain in the knee or hip included 1 mg Q8W, 
1 mg Q4W, 3 mg Q4W, and 6 mg Q8W.  In April 2018, the independent Data Monitoring 
Committee (DMC) recommended discontinuing 6 mg Q8W and 3 mg Q4W (expected to have 
similar exposure to 6 mg Q8W) based on a review of unblinded data in study R475-PN-1523.  
Subsequently, a small Regeneron team reviewed the data and agreed with this recommendation.  
The DMC noted imbalances in clinically relevant AEs including time to total joint replacement, 
peripheral edema, arthralgia and a trend towards early fractures.  The phase 3 program for OA pain 
in the hip or knee will continue to evaluate fasinumab 1 mg with the highest dose regimen of 1 mg 
Q4W, which is supported by the independent DMC as having a favorable benefit-risk profile. 
In 2012, studies of other anti-NGF monoclonal antibodies identified adverse changes in the 
sympathetic nervous system (SNS) of mature animals of several species (rat and non-human 
primate).  These effects included a reversible decrease in neuron volume. To date, no statistically 
significant or consistent effects of fasinumab on the SNS have been detected in animal studies with 
up to 6 months of treatment. Fasinumab has sub-picomolar affinity for human NGF (0.35pM).  
Fasinumab has little or no affinity for other neurotrophin family members, showing no detectable 
binding to either brain-derived neurotrophic factor (BDNF) or neurotrophin 3 (NT-3). At high 
concentrations, fasinumab shows low affinity binding to neurotrophin 4 (NT-4) (344nM).  
Fasinumab’s high specificity for NGF could potentially limit its nervous system impact relative to 
other anti-NGF antibodies with less specificity. Some populations of neurons, such as 
proprioceptive neurons and some visceral neurons, preferentially express TrkC as their 
neurotrophin receptor. The only neurotrophin that can activate TrkC is NT-3, so blocking NT-3 
could compromise the integrity of these populations of neurons. NT-3 appears to have functional 
benefit in adult organisms. For instance, NT-3 has been shown to be neuroprotective for 
proprioceptive neurons using nerve conduction studies in adult rats (Liu 2011). NT-3 has also 
shown efficacy against constipation in adult patients, and is therefore thought to play a role in 
bowel motility (Parkman 2003). Based on the potential risk of SNS toxicity associated with other 
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anti-NGF monoclonal antibodies in animal studies, a risk mitigation approach is being 
implemented for all fasinumab studies, as outlined in Section 9.6.1.2. 
Fasinumab is currently being evaluated in 3 ongoing phase 3 studies in OA patients. Study 
R475-PN-1523 is designed to assess the long-term safety and efficacy of multiple doses of 
fasinumab compared to placebo in patients with pain due to OA of the hip or knee. Study 
R475-OA-1611 is designed to compare the efficacy and safety of fasinumab to placebo and to 
naproxen, a standard-of-care NSAID for moderate-to-severe pain due to OA of the hip or knee. 
Study R475-OA-1688 is designed to compare the efficacy and safety of fasinumab to placebo, and 
to a pooled NSAID arm (celecoxib or diclofenac, which are additional standard-of-care NSAIDs 
for moderate-to-severe pain due to OA of the hip or knee). 
The phase 2 study described here is designed to evaluate the neurological safety of fasinumab 
compared to placebo on nerve impulse transmission in motor and sensory nerves. Potential SNS 
symptoms will be monitored using the Survey of Autonomic Symptoms and through assessments 
of orthostatic hypotension. 
Additional background information on the study drug and development program may be found in 
the current version of the Investigator’s Brochure.  A benefit-risk statement for fasinumab is also 
provided in the Investigator’s Brochure. 
2. 
STUDY OBJECTIVES  
2.1. 
Primary Objective 
The primary objective of the study is to evaluate the effect of fasinumab compared to placebo on 
peripheral nerves in patients with pain due to OA of the hip or knee.  
2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
 To evaluate the efficacy of fasinumab compared to placebo in patients with pain due to 
OA of the hip or knee  
 To evaluate the safety and tolerability of fasinumab compared to placebo in patients 
with pain due to OA of the hip or knee 
 To characterize the concentrations of fasinumab in serum in patients with pain due to 
OA of the hip or knee  
 To evaluate the immunogenicity of fasinumab in patients with pain due to OA of the 
hip or knee 
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3. 
RATIONALE  
3.1. 
Rationale  
3.1.1. 
Rationale for Study Design 
The present study is a randomized, double-blind, placebo-controlled, multicenter study to evaluate 
the neurological safety and efficacy of fasinumab in patients with OA of the knee or hip who have 
a history of inadequate pain relief for their OA pain from acetaminophen/paracetamol, and a 
history of intolerance to or inadequate pain relief from oral NSAIDS and opioids (or are unwilling 
to take opioids) for OA pain management. This study will evaluate the neurological safety of 
fasinumab compared to placebo in OA patients treated for up to 16 weeks by measuring nerve 
conduction velocities and evoked amplitudes of the peroneal, ulnar, and sural nerves. This study 
will also provide additional safety, tolerability, efficacy, pharmacokinetic (PK), and 
immunogenicity data for fasinumab.  
The target study population was chosen because they currently have unmet medical needs with 
respect to unacceptable pain control, in spite of the availability of current analgesic treatment 
options. The study will be conducted with appropriate eligibility criteria to exclude patients who 
may be at risk for events of joint damage and SNS effects. Furthermore, specific questionnaires 
and physical examinations will be employed to monitor for any events of arthralgia, worsening 
joint pain, altered peripheral sensation, AA, and SNS effects. All patients included in the study 
will have regular study visits and receive diagnostic procedures (ie, X-rays, magnetic resonance 
imaging [MRI]) to evaluate their ongoing OA.  Adverse event monitoring will be ongoing 
throughout the trial.  
The inclusion of a placebo treatment group is important to accurately determine the neurological 
safety, overall safety, and efficacy of fasinumab and to more accurately estimate the risk of AEs, 
including the adverse events of special interest (AESI) of AA, SNS dysfunction, and altered 
peripheral sensation. Rescue medication (paracetamol/acetaminophen) will be made available for 
any patient with breakthrough pain. Therefore, the use of a placebo group is justified, as 
placebo-treated patients will not be placed at significant risk. Patients and investigators can choose 
to end participation at any time. 
The patients will be stratified by the affected index joint (hip or knee) and by Kellgren-Lawrence 
(K-L) score (2 to 3, or 4) of the index joint at screening to enable analysis of efficacy and safety. 
The use of a K-L stratification scheme ensures that there is an equal distribution of patients with 
the most severe OA at baseline across the treatment groups. 
3.1.2. 
Rationale for Dose Selection  
In this study, patients will be randomized to receive fixed-dose, subcutaneous (SC) injections of 
1 mg fasinumab Q4W or placebo Q4W.  The 1 mg Q4W dose regimen is the highest dose regimen 
(exposure) under evaluation in the fasinumab phase 3 OA pain program.  This dose regimen is 
anticipated to have a favorable benefit-risk profile in patients with OA pain. 
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4. 
STUDY VARIABLES  
4.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height, etc.), 
disease characteristics including medical and surgical history, and medication history for each 
patient.  
4.2. 
Primary and Secondary Endpoints 
4.2.1. 
Primary Endpoints 
The primary endpoints of the study are: 
 Change from baseline to week 16 in peroneal motor nerve conduction velocity 
 Change from baseline to week 16 in peroneal motor nerve action potential amplitude 
 Change from baseline to week 16 in sural sensory nerve conduction velocity 
 Change from baseline to week 16 in sural sensory nerve action potential amplitude 
 Change from baseline to week 16 in ulnar sensory nerve conduction velocity 
 Change from baseline to week 16 in ulnar sensory nerve action potential amplitude 
4.2.2. 
Secondary Endpoints 
The secondary endpoints of the study are: 
 Change from baseline to week 16 in WOMAC pain subscale score 
 Change from baseline to week 16 in WOMAC physical function subscale score 
4.3. 
Additional Safety Endpoints 
Additional safety endpoints in this study include:  
 Incidence of AA (as confirmed by an independent adjudication committee) through 
week 36 
 Incidence of DA (as confirmed by an independent adjudication committee) through 
week 36 
 Incidence of treatment-emergent adverse event (TEAEs) through week 16 
 Incidence of SNS dysfunction (as diagnosed after consultation with an appropriate 
specialist, such as a neurologist and/or cardiologist) through week 36 
 Incidence of peripheral sensory AEs that require a neurology or other specialty 
consultation through week 36 
 Incidence of all-cause joint replacement (JR) surgeries week 36  
 Incidence of JRs at telephone survey approximately 52 weeks after last dose of study 
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4.4. 
Pharmacokinetic Variables 
The PK variable is the concentration of functional fasinumab in serum samples collected at each 
time point.  Samples in this study will be collected using a sparse sampling schedule.  These 
sampling time points are specified in Table 1. 
4.5. 
Anti-Drug Antibody Variables 
Anti-drug antibody (ADA) variables include status (positive or negative), titer, and time 
point/visit.  Samples in this study will be collected at the visits specified in Table 1. 
5. 
STUDY DESIGN  
5.1. 
Study Description and Duration 
This is a phase 2, randomized, double-blind, placebo-controlled, multicenter study designed to 
evaluate the neurological safety of fasinumab compared to placebo in patients with pain due to OA 
of the hip or knee.   
The study duration will be approximately 64 weeks starting at randomization (day 1). The study 
consists of a screening period of up to 30 days, a 7- to 10-day pre-randomization period (7 days 
with a +3 day window), a 16-week treatment period (with the last Q4W dose of study drug 
administered at week 12), a 20-week follow-up period, and a final phone contact approximately 
52 weeks after the last dose of study drug is administered (Figure 1).  
Figure 1: 
Study Flow Diagram 
Screening and 
Pre-randomization 
Treatment 
Follow-up 
EOS Phone 
Contact 
Up to 40 days 
Day 1 to Week 16 
Week 17 to 36 
Up to Week 64 
 
Randomization 
 
End of 
Treatment  
End of 
Follow-up 
 
 
 
 
 
Screening 
Pre-randomization 
 
 
 
 
Up to 30 days 
7 to 10 days 
Baseline  
Day 1 
 
Week 16 
Week 36 
Week 64 
 
EOS- End of study 
5.1.1. 
Screening and Pre-Randomization 
Prior to randomization, patients will undergo screening procedures, including X-ray of the 
shoulders, hips, and knees. Magnetic resonance imaging of the index and contralateral joints must 
be performed at screening and the results assessed by the central imaging vendor. In addition, an 
MRI will be performed on any knee or hip joint with a K-L score of ≥3. Randomization visits 
cannot occur until there is confirmation from the central imaging vendor that there are no 
exclusionary findings on the X-rays and any required MRIs.  
Prior to randomization, patients will also undergo nerve conduction assessments.  Patients must 
complete all other inclusion/exclusion assessments before undergoing the nerve conduction 
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assessments.  Randomization cannot occur until there is confirmation from the central reader 
assessment that the results are within the established parameters. 
During the screening period, patients may continue to take their current treatment regimen for OA 
pain.  
Patients eligible for the study will complete a pre-randomization period, during which all pain 
medication, except for the study-provided rescue medication (acetaminophen/paracetamol), will 
be discontinued.  The pre-randomization visit will be 7 to 10 days (7 days with a +3 day window) 
before the randomization visit. Patients will discontinue and/or undergo a washout of their current 
pain medications for OA during the pre-randomization period. As needed, during this pre-
randomization period, patients may take acetaminophen/paracetamol for pain relief according to 
the regional standard-of-care (see Section 7.2 for details).  Acetaminophen/paracetamol must not 
be taken within 24 hours prior to the randomization visit. 
5.1.2. 
Rescreening 
Retesting during the Screening and Pre-Randomization Periods 
An assessment that fails to meet eligibility criteria may be repeated once within the screening or 
pre-randomization period when approved by the sponsor or designated Medical Monitor under 
either of the following conditions: 1) The failure is believed by the investigator to be due to a 
condition that would resolve or could be treated; or 2) A laboratory value that minimally exceeds 
the cut-off value and is not clinically relevant. Only the assessments that did not meet the eligibility 
criteria require repetition, if done within the screening period or pre-randomization period.  
Patients may not repeat any assessments if they did not meet the WOMAC criteria, if they had 
orthostatic hypotension (defined in Section 8.2.3.4), or if the nerve conduction test showed results 
not within the established parameters as per central reader assessment during the screening or 
pre-randomization visit. 
Rescreening after Screen Failure 
Rescreening can be completed for patients who fail to meet the screening visit window 
requirements or who are unable to complete all imaging assessments within the specified screening 
period.  Patients who are rescreened after the pre-randomization window must be declared screen 
failures, be registered in the interactive web response system (IWRS) as a new patient with a new 
identification number, and then repeat all screening procedures, with the exception of imaging 
assessments. Any imaging assessments would need to be repeated only if they were taken more 
than 60 days from completion of the previous screening X-rays and MRI assessments. Patients 
cannot rescreen if they have screen failed due to not meeting the WOMAC criteria, if they have 
orthostatic hypotension (defined in Section 8.2.3.4), or if the nerve conduction test showed results 
not within the established parameters as per central reader assessment during the screening or pre-
randomization visit. 
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5.1.3. 
Randomization 
On day 1 (baseline), approximately 180 patients will be randomized in a 1:1 ratio to the following 
treatment groups: 
 Fasinumab 1 mg SC Q4W 
 Fasinumab-matching placebo SC Q4W 
Patients will receive treatment as described in Section 7.1. Randomization will be stratified 
according to the affected index joint (hip or knee) and the K-L score (2 to 3, or 4) at the screening 
visit.  
5.1.4. 
Treatment Period 
During the treatment period (day 1 through week 16), patients will be permitted to use only 
study-provided acetaminophen/paracetamol as rescue medication.  Patients will record their use of 
acetaminophen/paracetamol in a diary. Patients should discontinue use of acetaminophen/ 
paracetamol at least 24 hours prior to the start of each study visit in order to minimize the 
confounding effects of the rescue medication on efficacy measurements.  
Neurological, efficacy, and safety assessments will be performed during the treatment period, as 
outlined in Table 1.  
If a patient must undergo JR surgery during the treatment period, he or she will be asked to 
complete pre-operative imaging and to undergo post-surgery follow-up, as outlined in Table 2. 
5.1.5. 
Follow-up Period 
Follow-up of patients will continue for an additional 20 weeks after the last treatment period visit. 
Patients will have 2 study visits during the follow-up period (week 26 and week 36). Neurological, 
efficacy and safety assessments will be performed during the follow-up period, as outlined in 
Table 1.  
Patients will be directed not to take concomitant medications that contain NSAIDs (oral or topical, 
except up to 150 mg/day of aspirin, which is permitted for cardiac prophylaxis) until at least 
16 weeks after the last study drug injection. 
If a patient must undergo JR surgery during the follow-up period, he or she will be asked to 
complete pre-operative imaging and to undergo post-surgery follow-up, as outlined in Table 2. 
5.1.6. 
End of Study Phone Contact and Additional Imaging 
Phone contact will be made approximately 52 weeks after administration of the last dose of 
fasinumab or placebo to document patient status with regard to JR surgery (if patient underwent, 
is scheduled for, or is on a wait list for JR surgery). Additionally, patients who had an AA 
confirmed during the study will have an MRI performed of the AA joint(s). If the AA joint(s) have 
undergone JR, an X-ray may be substituted for an MRI.  
5.1.7. 
Study Stopping Rules 
An independent Data Monitoring Committee (DMC) will monitor unblinded data on an ongoing 
basis to assess the risk/benefit profile of fasinumab. Based on these reviews, in the context of the 
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totality of evidence, if the DMC has significant concerns at any time regarding a meaningful 
imbalance between treatment groups in joint-related AEs, SNS dysfunction, neurosensory 
disturbances, or any other safety issues, the DMC may make a recommendation to temporarily 
halt, alter, or terminate:  
 individual dose groups within the study or across studies 
 the full study (screening, randomization, dosing of study drug) 
 the fasinumab program  
for additional review and communication to regulatory authorities.  Based on the outcome of the 
review and discussions with the appropriate regulatory authorities, the study may be suspended, 
restarted, or terminated. 
Formal program wide statistical study stopping criteria for clinical studies involving fasinumab 
may be added to the DMC charter as deemed necessary by the sponsor, DMC and/or Health 
Authorities.  
5.1.8. 
End of Study Definition 
The end of study is defined as the last phone contact of the last patient in this study. 
5.2. 
Planned Interim Analysis  
An interim analysis may be performed in order to provide peripheral nerve safety data for 
regulatory purposes. 
5.3. 
Study Committees  
5.3.1. 
Independent Data Monitoring Committee 
An independent DMC will meet periodically to review unblinded data as the study progresses, and 
based on the findings, will make recommendations to the sponsors about the conduct of the study. 
The DMC will comprise independent statistical and medical experts. Further details will be defined 
in the DMC charter. Additional safety monitoring will occur on an ongoing basis by the Regeneron 
Safety Team. 
5.3.2. 
Arthropathy Adjudication Committee 
An independent, expert, blinded adjudication committee composed of radiologists trained in 
musculoskeletal imaging will adjudicate all potential joint AEs of AA (defined in Section 9.6.1.1) 
as well as pre-operative images in patients undergoing JR.   
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
6.1. 
Number of Patients Planned 
The study will enroll approximately 180 patients at about 30 global sites. Each treatment group 
(fasinumab and fasinumab-matching placebo) will enroll approximately 90 patients.  
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6.2. 
Study Population  
Eligible patients for this study consist of men and women who are at least 18 years of age at the 
time of study entry with a clinical diagnosis at the screening visit of OA of the knee or hip, based 
on the American College of Rheumatology criteria, and with radiologic evidence of OA (K-L score 
≥2) at the index joint.  
6.2.1. 
Inclusion Criteria  
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Male and female patients ≥18 years of age at screening visit 
2. Provide signed informed consent signed by study patient or legally acceptable 
representative 
3. Body mass index ≤39 at screening visit 
4. A clinical diagnosis of OA of the knee or hip based on the American College of 
Rheumatology criteria with radiologic evidence of OA (K-L score ≥2 for the index joint) 
at the screening visit, with the following definitions: 
 The index joint is defined as the joint with OA under evaluation for this study 
 A joint previously treated with JR surgery cannot be the index joint 
 A joint previously surgically modified within the past year cannot be the index joint 
(with the exception of cruciate ligament reconstruction surgery, patellar fracture repair 
surgery, or meniscal repair) 
 If a patient has a K-L score of ≥2 at more than 1 knee or hip joint, the index joint is the 
joint with the greatest WOMAC pain subscore at the screening visit 
 If 2 or more knee or hip joints have a K-L score of ≥2 and the same WOMAC pain 
subscore, the index joint is the joint with the greater K-L score 
 If 2 or more joints have a K-L score of ≥2, the same WOMAC pain subscores, and the 
same K-L scores, then the investigator may choose 1 of these joints as the index joint 
5. Moderate-to-severe pain in the index joint defined as a WOMAC average pain subscale 
score of ≥4 at both the screening and randomization visits 
6. Willing to discontinue current pain medications and to adhere to study requirements for 
rescue treatments (paracetamol/acetaminophen to be taken as needed with a maximum 
daily dose of 2500 mg [countries where 500 mg strength tablets/capsules are available] or 
2600 mg [countries where 325 mg strength tablets/capsules are available])  
7. A history of at least 12 weeks of analgesics use for pain due to OA of the knee or hip, as 
defined by: 
a. Inadequate pain relief from acetaminophen/paracetamol AND 
b. Intolerance to or inadequate pain relief from at least 1 oral NSAID AND 
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c. Intolerance to or inadequate pain relief from opioid or tramadol therapy, unwillingness 
to take opioid or tramadol therapy for a medically acceptable reason, or lack of access 
to an opioid or to tramadol  
8. A history of regular use of analgesic medications for OA pain (defined as an average of 4 
days per week over the 4 weeks prior to the screening visit), including oral NSAIDs, 
selective cyclooxygenase 2 inhibitors, opioids, paracetamol/acetaminophen, or 
combinations thereof 
9. Consent to allow all radiographs and medical/surgical/hospitalization records of care 
received elsewhere prior to and during the study period to be shared with the investigator 
10. Willing to maintain current activity and exercise levels throughout the study 
11. Willing and able to comply with clinic visits and study-related procedures and willing to 
provide follow-up information related to any JR surgery that occurs within the period of 
time covered by their intended participation in the study 
12. Able to understand and complete study-related questionnaires 
6.2.2. 
Exclusion Criteria  
A patient who meets any of the following criteria will be excluded from the study: 
1. History or presence at the screening visit of non-OA inflammatory joint disease (eg, 
rheumatoid arthritis, lupus erythematosus, psoriatic arthritis, pseudo-gout, gout, 
spondyloarthropathy, polymyalgia rheumatica, joint infections within the past 5 years), 
Paget's disease of the spine, pelvis or femur, neuropathic disorders, multiple sclerosis, 
fibromyalgia, tumors or infections of the spinal cord, or renal osteodystrophy 
2. History or presence on imaging of arthropathy (osteonecrosis, subchondral insufficiency 
fracture, rapidly progressive OA type 1 or type 2), stress fracture, recent stress fracture, 
neuropathic joint arthropathy, hip dislocation (prosthetic hip dislocation is eligible), knee 
dislocation (patella dislocation is eligible), congenital hip dysplasia with degenerative joint 
disease, extensive subchondral cysts, evidence of bone fragmentation or collapse, or 
primary metastatic tumor with the exception of chondromas or pathologic fractures during 
the screening period 
3. Trauma to the index joint within 3 months prior to the screening visit 
4. History or presence of signs or symptoms of compression neuropathy, including carpal 
tunnel syndrome or sciatica 
5. Patient is not a candidate for MRI 
6. Is scheduled for a JR surgery to be performed during the study period or who would be 
unwilling or unable to undergo JR surgery if one eventually became necessary 
7. Patients with nerve conduction results (for the peroneal, sural, and ulnar nerves) that are 
outside of the established parameters, based on standards detailed in the study manual and 
according to the eligibility report provided by the central reader 
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8. Patients receiving, or who plan to receive, interventions, devices, or medications that alter 
nerve conduction or are contraindicated in patients undergoing nerve conduction studies 
(eg, edema, tarsal tunnel syndrome) 
9. History or presence at the screening visit of autonomic neuropathy, diabetic neuropathy, or 
other peripheral neuropathy, including reflex sympathetic dystrophy and complex regional 
pain syndrome 
10. History or diagnosis of chronic autonomic failure syndrome including pure autonomic 
failure, multiple system atrophy (Shy-Drager syndrome) 
11. Known allergy or sensitivity to monoclonal antibodies 
12. Poorly controlled diabetes (defined as any single value of hemoglobin A1c [HbA1c] 
>9.0%) at the screening visit 
13. Known history of human immunodeficiency virus (HIV) infection 
14. Known history of ocular herpes simplex virus, herpes simplex virus pneumonia, or herpes 
simplex virus encephalitis 
15. History of sickle cell disease, including sickle cell anemia and β-thalassemia 
16. Confirmed 
elevated 
screening 
alanine 
aminotransferase 
(ALT) 
or 
aspartate 
aminotransferase (AST) ≥2.5 times the upper limit of normal (ULN) 
17. Resting heart rate of <50 beats per minute (bpm) or >100 bpm (by vital sign assessment or 
as captured during electrocardiogram [ECG] assessment) at the screening or randomization 
visits 
18. History or presence of 2nd or 3rd degree heart block, 1st degree heart block with abnormal 
QRS complex, or bifascicular block by ECG assessment at the screening visit  
19. History or presence of orthostatic hypotension, as defined in Section 8.2.3.4, at the 
screening, pre-randomization, or randomization visits  
20. History of poorly controlled hypertension, as defined by:  
a. Systolic blood pressure ≥180 mm Hg or diastolic blood pressure ≥110 mm Hg at the 
screening visit 
b. Systolic blood pressure of 160 mm Hg to 179 mm Hg or diastolic blood pressure of 
100 mm Hg to 109 mm Hg at the screening visit, AND a history of end-organ damage 
(including history of left ventricular hypertrophy, heart failure, angina, myocardial 
infraction, stroke, transient ischemic attack, peripheral arterial disease and moderate to 
advanced retinopathy [hemorrhages or exudates, papilledema]) 
21. Congestive heart failure with New York Heart Classification of stage III or IV 
(Dolgin 1994) 
22. Transient ischemic attack or cerebrovascular accident within the past 12 months prior to 
the screening visit, or myocardial infarction, or acute coronary syndromes within the past 
6 months prior to the screening visit 
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23. Significant concomitant illness including, but not limited to, psychiatric, cardiac, renal, 
hepatic, neurological, endocrinological, metabolic, or lymphatic disease that, in the opinion 
of the investigator, would adversely affect the patient’s participation in the study 
24. New major illness diagnosed within 2 months prior to the screening visit 
25. Known history of infection with hepatitis B virus. Patients with a history of hepatitis B are 
eligible if there is documentation of a negative test for hepatitis B surface antigen and a 
positive test for antibodies to the hepatitis B virus surface antigen  
26. Known history of infection with the hepatitis C virus. Patients with a history of hepatitis C 
are eligible if there is documentation of a negative hepatitis C virus RNA test  
27. History or presence of malignancy within the last 5 years prior to screening, except patients 
who have been treated successfully with no recurrence for >1 year of basal cell or 
squamous cell carcinoma of the skin or in-situ cervical cancer 
28. History of hospital admission for depression or suicide attempt within 5 years or active, 
severe major depression at screening 
29. Use of systemic (ie, oral or intramuscular) corticosteroid within 30 days prior to the 
screening visit. Intra-articular corticosteroids in the index joint within 12 weeks prior to 
the screening visit, or to any other joint within 30 days prior to the screening visit (topical, 
intra-nasal, and inhaled corticosteroids are permitted) 
30. Use of a monoamine reuptake inhibitor, tricyclic antidepressants, selective serotonin 
reuptake inhibitors and serotonin norepinephrine reuptake inhibitors for treatment of pain 
within 4 weeks prior to the screening visit 
31. Has 
positive 
urine 
drug 
test 
results 
during 
screening 
(eg, 
amphetamines/methamphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, 
and opiates), unless in the opinion of the investigator, the positive test results may be due 
to the patient’s current permitted medications 
32. History of (within 5 years prior to the screening visit) or current alcoholism, alcohol abuse, 
substance abuse, or abuse of prescription pain medication 
33. History of cannabis use for the treatment of pain within the past 6 months prior to the 
screening visit 
34. Ongoing participation in a clinical research study evaluating another investigational drug 
or having received another investigational product within 30 days or 5 half-lives of the 
screening visit, whichever is longer  
35. Exposure to an anti-NGF antibody prior to the screening visit or known sensitivity or 
intolerance to anti-NGF antibodies or participation in a clinical trial evaluating anti-NGF 
antibodies 
36. Member of the clinical site study team and/or his/her immediate family, unless prior 
approval granted by the sponsor 
37. Pregnant or breastfeeding women 
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38. Women of childbearing potential who have a positive pregnancy test result or do not have 
their pregnancy test result at baseline 
39. Women of childbearing potential* who are unwilling to practice highly effective 
contraception prior to start of the first treatment, during the study, and for at least 20 weeks 
after the last dose.  Highly effective contraceptive measures include: 
a. stable use of combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, 
injectable, implantable) associated with inhibition of ovulation initiated 2 or more 
menstrual cycles prior to screening  
b. intrauterine device (IUD); intrauterine hormone-releasing system (IUS)  
c. bilateral tubal ligation  
d. vasectomized partner  
e. and or sexual abstinence†‡ 
* Postmenopausal women must be amenorrheic for at least 12 months (without an alternative 
medical cause) in order not to be considered of childbearing potential.  Pregnancy testing 
and contraception are not required for women with documented complete hysterectomy or 
tubal ligation. 
† Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatments.  The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject. 
‡ Periodic abstinence (calendar, symptothermal, and post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not 
acceptable methods of contraception.  Female condom and male condom should not be 
used together. 
Note: HIV and/or hepatitis testing will be performed on a country-by-country basis, according to 
local guidelines if required by regulatory authorities or ethics boards. 
6.3. 
Premature Withdrawal from the Study 
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and/or sponsor have the right to withdraw a patient from the study if it is no longer 
in the interest of the patient to continue in the study, or if the patient’s continuation in the study 
places the scientific outcome of the study at risk (eg, if a patient does not or cannot follow study 
procedures). An excessive rate of withdrawals would render the study uninterpretable; therefore, 
unnecessary withdrawal of patients should be avoided.  
Patients who are withdrawn prematurely from the study will be asked to complete the early 
termination visit, as described in Section 8.1.3. 
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 7.3.2.  
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6.4. 
Replacement of Patients 
Patients prematurely withdrawn from the study or study drug will not be replaced.   
7. 
STUDY TREATMENTS  
7.1. 
Investigational and Reference Treatments 
Fasinumab drug product is supplied for this study in the following concentrations: 
 Fasinumab 2 mg/mL:  Each 1 mL single-use pre-filled syringe delivers 0.5 mL of 
2 mg/mL solution to provide a 1 mg dose of study drug 
 Fasinumab-matching placebo:  Each 1 mL single use pre-filled syringe delivers 0.5 mL 
of placebo solution. 
All patients will receive SC injections of fasinumab or fasinumab-matching placebo. Patients will 
be randomized to 2 treatment groups in a 1:1 ratio to receive either fasinumab 1 mg SC Q4W or 
fasinumab-matching placebo SC Q4W. All SC injections will be in the abdomen, thigh, or upper 
arm. Instructions for dose preparation and study drug administration are provided in the pharmacy 
manual. Patients will be observed in the clinic for approximately 1 hour after study drug is 
administered.  
Doses of study drug must be given within ±7 days from the scheduled dose date. If the window is 
missed, the dose should not be administered. The next dose should be administered at the next 
scheduled dosing date.  
7.2. 
Rescue Treatment  
Starting at pre-randomization to the end of the 16-week treatment period, study-provided 
acetaminophen/paracetamol is the only allowed rescue medication. In the event of inadequate pain 
relief for OA or in the event of other pain (eg, headache) or fever, 1 to 2 tablets/capsules of 
study-provided acetaminophen/paracetamol may be taken no less than 4 hours apart as needed 
according to the local standard of care. The maximum allowed daily dose during the treatment and 
follow up periods is 2500 mg (500 mg x 5 tablets/capsules) in countries where 500 mg strength 
tablets/capsules are available or 2600 mg (325 mg x 8 tablets/capsules) in countries where 325 mg 
strength tablets/capsules are available (eg, North America). Where 500 mg strength 
tablets/capsules are available, the highest individual single dose is 1 gram. Where 325 mg 
tablets/capsules are available, the highest individual single dose is 650 mg.  
In order to prevent severe liver damage, patients should be cautioned to avoid consumption of 
alcoholic beverages while on paracetamol/acetaminophen. Patients should also be cautioned not 
to take rescue medication at intervals of fewer than 4 hours and to take no more than the maximum 
allowable single dose (1 to 2 tablets/capsules) or maximum allowable total daily dose.  
Acetaminophen/paracetamol must not be taken within 24 hours prior to scheduled study visits 
during the treatment period in order to minimize the confounding effects of rescue medication on 
efficacy assessment measures. Use of acetaminophen/paracetamol as study-provided rescue 
medication 
during 
the 
treatment 
period 
will 
be 
reported 
daily 
using 
diaries. 
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Acetaminophen/paracetamol accountability will be conducted at each study site visit starting at 
the baseline visit and continuing through the week 16 visit.  
During the treatment period, acetaminophen/paracetamol will be sourced by the study sites and 
reimbursed by the sponsor unless country-specific regulations and customs require a different 
approach. 
During the 20-week follow-up period, if acetaminophen/paracetamol is used, dosing instructions 
will be the same as during the treatment period including the maximum allowed daily dose. Use 
of acetaminophen/paracetamol will be captured as a concomitant medication during the follow-up 
period.  
7.3. 
Dose Modification and Study Treatment Discontinuation Rules 
7.3.1. 
Dose Modification 
Study drug dose modification for an individual patient is not allowed. 
7.3.2. 
Study Drug Discontinuation 
Study drug may be temporarily or permanently discontinued due to medical need, as determined 
by the investigator, medical monitor, or the sponsor and according to the study stopping rules 
(Section 5.1.7).  
Patients who permanently discontinue from study drug will be encouraged to remain in the study 
and to complete all study assessments. Patients who agree and thus do not withdraw from the study 
will be asked to return to the clinic for all remaining study visits per Table 1. 
Patients who permanently discontinue from study drug and who opt to withdraw from the study 
will be asked to complete an early termination visit (Section 8.1.3). 
Patients who discontinue from study drug prior to study completion due to an AA (see 
Section 9.6.1.1) should return to the clinic for all remaining study visits per the visit schedule.  
In the event that a patient must undergo JR surgery during the treatment or follow-up periods, 
he/she will be discontinued from study drug and asked to return to the study site for a pre-operative 
visit and for follow-up safety evaluations 4 and 20 weeks after surgery (as described in 
Section 8.2.4.7). Pre-operative imaging (X-rays and/or MRI) will be obtained and submitted to the 
independent adjudication committee for review to exclude or confirm the presence of an AA event. 
Instructions for the submission process are provided in the study manual.  
7.3.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
Study drug dosing will be permanently stopped in the event of: 
 A patient developing clinically significant peripheral sensory or motor neurologic 
events confirmed by a neurologist’s examination and graded by the neurologist as at 
least moderate peripheral neuropathy limiting activities of daily living, ie, grade ≥2 
according to Common Terminology Criteria for Adverse Events (CTCAE) v.4; study 
sites should use CTCAE v.4 criteria throughout the study for consistency  
 Evidence of pregnancy 
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 A patient developing signs and symptoms indicative of carpal tunnel syndrome 
 Continued 
noncompliance 
with 
protocol-defined 
maximum 
acetaminophen/ 
paracetamol use (with a maximum daily dose of 2500 mg [countries where 500 mg 
strength tablets/capsules are available] or 2600 mg [countries where 325 mg strength 
tablets/capsules are available]) during the treatment and follow-up periods, after 
appropriate counseling 
 Continued noncompliance with the protocol, including usage of NSAIDs or other 
medications or non-pharmacologic treatments that are not permitted in the study, after 
appropriate counseling 
 JR surgery 
 AESI: 
 Adjudicated arthropathy, as described in Section 9.6.1.1. 
 Sympathetic nervous system dysfunction, as described in Section 9.6.1.2.  
 Per protocol repeated nerve conduction test that confirms results are not within the 
established parameters for peroneal, sural, or ulnar nerves, as per central reader 
assessment and the neurologist’s evaluation that confirms the diagnosis of peripheral 
neuropathy. 
 Hepatotoxicity.  Study drug should be discontinued if the following are observed: 
1. Total bilirubin (TBL) >2x ULN or international normalized ratio (INR) >1.5, and 
2. ALT or AST >3x ULN, and 
3. No other cause for 1 and 2 is readily apparent 
Other causes of ALT, AST, and TBL elevations may include alcoholic hepatitis, 
autoimmune hepatitis, non-alcoholic hepatitis, heritable diseases (Gilbert's Syndrome), 
heart failure, and viral hepatitis. 
NOTE: Study drug may be withheld in patients who do not meet criteria for permanently 
discontinuing study drug, until an alternative cause for drug-induced liver injury can be 
determined. The patient may be re-challenged if an alternative cause for elevated liver 
function tests is found and the liver function tests return to baseline, but only after 
discussion with the sponsor. 
 Systemic hypersensitivity reaction deemed by the investigator to be related to study 
drug 
 Any other medical need, as determined by the investigator 
 Sponsor decision 
 Patient withdraws consent 
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7.3.2.2. 
Reasons for Temporary Discontinuation of Study Drug 
Study drug may be temporarily discontinued due to medical need, as determined by the 
investigator. Study drug will be temporarily withheld while awaiting imaging adjudication for 
worsening joint pain or when routine imaging suggests AA and prompts the need for additional 
imaging (see Section 9.6.1.1), for patients who are determined to have orthostatic hypotension or 
determined to have new or worsening symptoms suggestive of SNS dysfunction while awaiting 
evaluation by a specialist (see Section 9.6.1.2), or for patients with symptoms of peripheral 
neuropathy while awaiting evaluation by a specialist and/or results of a nerve conduction test (see 
Section 9.6.1.3).  
Study drug should not be re-started until the next study visit, unless imaging, nerve conduction 
test results, or neurology evaluation results are available within the current visit window and 
confirm that study drug may be restarted.  
7.4. 
Management of Acute Reactions  
7.4.1. 
Systemic Injection Reactions 
Emergency equipment and medication for the treatment of systemic reactions must be available 
for immediate use. All systemic injection reactions must be reported as AEs (as defined in 
Section 9.3.1) and graded using the grading scales as instructed in Section 9.5.1.  
Acute systemic reactions following SC injection of study drug should be treated using clinical 
judgment to determine the appropriate response according to typical clinical practice. 
7.4.2. 
Local Injection Site Reactions 
Local injection site reactions must be reported as AEs and graded according to Section 9.5.1. 
7.5. 
Method of Treatment Assignment  
Approximately 180 patients will be randomized in a 1:1 ratio to receive fasinumab (1 mg SC 
Q4W) or fasinumab-matching placebo (Q4W) according to a central randomization scheme 
provided by an IWRS to the designated study pharmacist (or qualified designee). Randomization 
will be stratified according to the affected index joint (hip or knee) and the K-L score (2 to 3, or 
4) at the screening visit.  
7.5.1. 
Blinding 
Study patients, the principal investigators, and study site personnel will remain blinded to all 
randomization assignments throughout the study. The Regeneron study team and contract research 
organization (CRO) personnel who are in regular contact with the study site will remain blinded 
to all patient randomization assignments. 
Blinded study drug kits coded with a drug numbering system will be used.  In order to maintain 
the blind, lists linking these codes with product lot numbers will not be accessible to individuals 
involved in study conduct. 
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Anti-drug antibody results will not be communicated to the sites before the end of the study, and 
the sponsor operational team will not have access to results associated with patient identification 
until after the final database lock. 
Selected individuals not involved in the conduct of the study may have access to unblinded data 
as needed for safety review or other data review. No study personnel involved in the day-to-day 
conduct of the study will have access to unblinded data before the database is locked for this study.  
7.5.2. 
Emergency Unblinding 
Unblinding of treatment assignment for a patient may be necessary due to a medical emergency or 
any other significant medical event (eg, pregnancy). 
If unblinding is required: 
 Only the investigator will make the decision to unblind the treatment assignment  
 Only the affected patients will be unblinded  
 The designated study pharmacist(s)/designee at the study site will provide the treatment 
assignment to the investigator. If there is no study pharmacist, the investigator for the 
site will unblind the patient 
 The investigator will notify Regeneron and/or designee as soon as possible after 
unblinding the patient 
Treatment assignment is not to be provided to site personnel, other than the unblinded study 
pharmacist (when applicable), at any time during the conduct of the study, except in the case of a 
true emergency.  In the event that there is no study pharmacist, the individual at the site fulfilling 
that role will be the only unblinded member of the site personnel. 
7.5.3. 
Unblinding for Regulatory Reporting Purposes 
Treatment assignments for certain patients may be unblinded to Pharmacovigilance and Risk 
Management personnel for the purpose of regulatory reporting of Suspected Unexpected Serious 
Adverse Reactions (SUSARs).  
7.6. 
Treatment Logistics and Accountability 
7.6.1. 
Packaging, Labeling, and Storage 
A medication numbering system will be used to label blinded investigational study drug. Lists 
linking medication numbers with product lot numbers will be maintained by the groups (or 
companies) responsible for study drug packaging. In order to maintain the blind, these lists will 
not be accessible to individuals involved in study conduct. 
Study drug will be stored at the site at a temperature of 2ºC to 8ºC. Storage instructions will be 
provided in the pharmacy manual.  
7.6.2. 
Supply and Disposition of Treatments  
Study drug will be shipped at a temperature of 2ºC to 8ºC to the investigator or designee at regular 
intervals or as needed during the study. At specified time points during the study (eg, interim site 
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monitoring visits), at the site close-out visit, and following drug reconciliation and documentation 
by the site monitor, all used drug will be destroyed at site while unused drug will be returned to 
the sponsor or designee. Refer to pharmacy manual for details. 
7.6.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all used and unused study drug. These records should 
contain the dates, quantity, and study drug that is: 
 dispensed to each patient, 
 returned from each patient (if applicable),  
 disposed of at the site, or returned to the sponsor or designee. 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
7.6.4. 
Treatment Compliance 
All study drug compliance records must be kept current and made available for inspection by the 
sponsor and regulatory agency inspectors. 
7.7. 
Concomitant Medications and Procedures 
Any treatment administered and/or procedures performed from screening to the end of the follow-
up period will be considered concomitant medication and/or procedures, respectively.  This 
includes medications and/or procedures that were started before the study and are ongoing during 
the study. 
7.7.1. 
Prohibited Medications  
Patients will be required to discontinue all non-study pain medication (oral or topical; except up 
to 150 mg/day of aspirin/aminosalicylic acid [5-ASA], which is permitted for cardiac prophylaxis, 
per local guidelines), starting at the pre-randomization visit and through the treatment period. 
Opioid analgesic medications (including tramadol) are prohibited through the week 16 study visit.  
Patients will be directed not to take concomitant medications that contain NSAIDs (oral or topical, 
except up to 150 mg/day of aspirin, which is permitted for cardiac prophylaxis) until at least 
16 weeks after the last study drug injection. A list of medications containing NSAIDs will be 
provided in the study reference manual and in a reference card given to patients.  
Other excluded medications during the treatment period include: 
 Any other investigational agent 
 Medical or regular recreational use of marijuana 
 Chondroitin sulfate  
 Glucosamine   
 Hyaluronic Acid Intra-articular Injections  
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 Muscle relaxants including cyclobenzaprine, carisoprodol, orphenadrine, tizanidine 
(see Section 7.7.2 for permitted muscle relaxants) 
 Corticosteroids (topical, intranasal, and inhaled formulations are permitted), 
adrenocorticotropic hormone 
 Cyclosporine, methotrexate, mycophenolate mofetil, tacrolimus 
 Azathioprine, sulfasalazine, hydroxychloroquine 
 IL-6 or IL-6 receptor antagonists 
 Abatacept, ustekinumab  
 Tumor necrosis factor antagonists 
 IL-1 inhibitors, including diacerein  
 Apremilast, and tofacitinib  
7.7.2. 
Permitted Medications and Procedures  
Patients receiving chronic medication therapy must be on a stable dose of such medication for at 
least the 30 days prior to the screening visit. Monoamine reuptake inhibitors, tricyclic 
antidepressants, selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake 
inhibitors are permitted for non-pain-related treatment.  Patients must be on therapy for at least 
8 consecutive weeks and on a stable dose for at least 4 weeks prior to the screening visit and 
throughout the planned duration of the patient’s participation in the study. 
Low-dose aspirin/5-ASA (up to 150 mg/day) for cardiac prophylaxis is permitted. 
Acetaminophen/paracetamol taken acutely for treatment of non-OA pain is permitted, however, 
the total daily dosage limits cannot be exceeded regardless of the reason for 
acetaminophen/paracetamol use.  During the pre-randomization and treatment periods, 
acetaminophen/paracetamol use will be captured in the diary; use for relief of pain other than pain 
due to OA will be reported in the diary as "other".  During the screening and follow-up periods, 
acetaminophen/paracetamol taken for any reason should be reported as concomitant medication. 
Topical steroids are permitted.  
Muscle relaxants, such as Skelaxin® (metaxalone) and others, are permitted.  Prohibited muscle 
relaxants are listed in Section 7.7.1.  
Physical therapies (such as transcutaneous electrical nerve stimulation and acupuncture) are 
permitted during the trial, provided that patients have been on a stable regimen for at least 4 weeks 
prior to entering into the trial and that they expect to maintain this regimen during the trial. 
Joint replacement is a permitted procedure during the study (see Section 8.2.4.7 for procedures to 
be followed in the event of JR). 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
8.1. 
Schedule of Events 
Study assessments and procedures are presented by study period and visit in Table 1. 
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Table 1: 
Schedule of Events 
 
Screening/Pre-
randomization 
Treatment Period 
Follow-up Period 
EOS 
Study Week 
Screen 
Pre-
rand 
 
Baseline 
 
Wk 1 
 
Wk 2 
 
Wk 4 
 
Wk 8 
 
Wk 12 
EOT  
Wk 16 
ET1/ 
JR 
Pre-
Op  
 
Wk 26 
 
Wk 36 
ET1 
/JR 
Pre-
Op 
 
Wk 64 
Study Day 
Up to 30 
Days 
7 to 10 
Days 
1 
8 
15 
29 
57 
85 
113 
183 
253 
449 
Visit Window (days) 
 
 
 
±1 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Visit/Phone Contact 
Number 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
Phone 
1 
Screening/Baseline: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion2 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Main study informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genomics sub-study 
informed consent3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary instructions 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Training on pain 
reporting /patient 
education brochures 4 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
MRI for index joint, 
contralateral joint & any 
hip or knee with K-L ≥3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discontinue non-study 
pain medications 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug SC injection5 
 
 
X 
 
 
X 
X 
X 
 
 
 
 
 
 
Dispense to home 
paracetamol/ 
acetaminophen 
 
X 
X 
 
 
X 
X 
X 
 
 
 
 
 
 
Paracetamol/ 
acetaminophen 
accountability 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Record rescue 
medication use in diary6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Concomitant therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient-Completed Assessments/Efficacy: 
 
 
 
 
 
 
 
 
 
 
 
 
WOMAC7, 22 
X7 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Screening/Pre-
randomization 
Treatment Period 
Follow-up Period 
EOS 
Study Week 
Screen 
Pre-
rand 
 
Baseline 
 
Wk 1 
 
Wk 2 
 
Wk 4 
 
Wk 8 
 
Wk 12 
EOT  
Wk 16 
ET1/ 
JR 
Pre-
Op  
 
Wk 26 
 
Wk 36 
ET1 
/JR 
Pre-
Op 
 
Wk 64 
Study Day 
Up to 30 
Days 
7 to 10 
Days 
1 
8 
15 
29 
57 
85 
113 
183 
253 
449 
Visit Window (days) 
 
 
 
±1 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Visit/Phone Contact 
Number 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
Phone 
1 
Neurological 
Assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nerve conduction 
X8 
 
 
 
 
 
X 
 
X 
X9 
 
X 
X9 
 
Neurological 
examination (full) 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Survey of autonomic 
symptoms22 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Orthostatic blood 
pressure assessment and 
heart rate 10,11 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Safety: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs11 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Electrocardiogram 
X 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
Physical examination 
and weight 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
 
Joint pain questionnaire22  
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Event-triggered 
imaging12 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
--------------------------------------------------------------------------------------------------------------------------------------------------------------- 
 
SC injection site 
evaluation 
 
 
X 
 
 
X 
X 
X 
 
 
 
 
 
 
Bilateral X-rays (knee, 
hip, shoulder) 
X13 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
 
Pre-op questionnaire (JR 
follow-up)14 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
MRI affected joint(s) - 
AA patients only15 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
End of study phone 
contact16 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Laboratory Testing: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug test17 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology17 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Blood chemistry17 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
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Screening/Pre-
randomization 
Treatment Period 
Follow-up Period 
EOS 
Study Week 
Screen 
Pre-
rand 
 
Baseline 
 
Wk 1 
 
Wk 2 
 
Wk 4 
 
Wk 8 
 
Wk 12 
EOT  
Wk 16 
ET1/ 
JR 
Pre-
Op  
 
Wk 26 
 
Wk 36 
ET1 
/JR 
Pre-
Op 
 
Wk 64 
Study Day 
Up to 30 
Days 
7 to 10 
Days 
1 
8 
15 
29 
57 
85 
113 
183 
253 
449 
Visit Window (days) 
 
 
 
±1 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Visit/Phone Contact 
Number 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
Phone 
1 
Urinalysis and urine 
electrolytes17 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
ESR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c17 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH and estradiol17,18 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (for 
WOCBP)19 
X - 
Serum 
 
X - 
Urine 
 
 
X - 
Urine 
X - 
Urine 
X - 
Urine 
X - 
Urine 
X – 
Urine 
X - 
Urine 
X – 
Urine 
X – 
Urine 
 
PK, Antibody, and Research Samples: 
 
 
 
 
 
 
 
 
 
 
 
 
PK sample20 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
ADA samples20 
 
 
X 
 
 
 
 
 
X 
X 
 
X 
X 
 
Genomics sub-study 
sample (optional)3 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
hs-CRP sample20,21 
 
 
X 
 
 
X 
 
 
X 
X 
 
X 
X 
 
Research serum/plasma 
sample20,21 
 
 
X 
 
 
X 
 
 
X 
X 
 
X 
X 
 
AA: Adjudicated arthropathy 
JR: Joint replacement 
ADA: Anti-drug antibody 
MRI: Magnetic resonance imaging 
EOS: End of study 
PK: Pharmacokinetic 
EOT: End of treatment 
Pre-op: Pre-operative 
ESR: Erythrocyte sedimentation rate 
Pre-rand: Pre-randomization 
ET: Early termination 
SC: Subcutaneous 
FSH: Follicle stimulating hormone 
Wk: Week 
HbA1c: Glycated hemoglobin 
WOCBP: Women of childbearing potential 
hs-CRP: high-sensitivity C-reactive Protein 
WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index 
 
 
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8.1.1. 
Footnotes for the Schedule of Events Table 1 
1. Patients who discontinue study drug will be encouraged to follow the visit schedule throughout the entire study. If a patient 
chooses to end study participation he/she will be asked to return to the study site as soon as possible for an early termination 
visit. Imaging assessments need to be repeated if it has been >30 days since the joints were last imaged. If it has been ≤30 days 
since imaging assessments were completed, imaging assessments may be completed at the discretion of the investigator. 
2. HIV and/or hepatitis testing will be performed on a country-by-country basis, according to local guidelines if required by 
regulatory authorities or ethics boards.  Patients must complete all other inclusion/exclusion assessments before undergoing the 
nerve conduction assessments. 
3. Only for patients who provide written informed consent for the optional genomics sub-study.  The sample should be collected at 
the day 1 (baseline/randomization) visit, but may be collected at any visit during the study after a patient has been randomized. 
4. At the screening and pre-randomization visits, study staff will review the “Participating in a Research Study: What You Need to 
Know” brochure and the “Reporting Your Pain” brochure with patients to ensure they understand what a clinical study is and 
how to report their pain accurately. At subsequent visits, patients will be asked to review the ‘Reporting Your Pain’ brochure 
themselves.  At any time during the conduct of the study, patients may require retraining by study staff. 
5. Study drug administration will be the last procedure at each dosing visit, and will be administered after all laboratory, PK, ADA, 
and research samples have been collected and all study related activities have been performed. Patients will be observed in the 
clinic for approximately 1 hour after SC study drug is administered. 
6. Use of study-provided rescue medication will be recorded daily using diaries. Acetaminophen/paracetamol use will be reported 
from pre-randomization visit to week 16. 
7. The WOMAC pain sub-scale will be evaluated for both knees and both hip joints at the screening visit only. Then, the WOMAC 
Full Survey will be completed only for the index joint at the subsequent visits. 
8. Nerve conduction can be performed during screening or pre-randomization. Patients must complete all other inclusion/exclusion 
assessments before undergoing the nerve conduction assessments. Randomization cannot occur until there is confirmation from 
the central reader assessment that the results are within the established parameters.  
9. Nerve conduction assessments should be performed at the early termination visit if it has been >2 weeks since the last nerve 
conduction assessment. 
10. Blood pressure measurements to assess for orthostatic hypotension may be discontinued following regulatory approval if the 
safety database does not reveal an imbalance for the fasinumab-treated patients.  
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11. If the pulse is less than 45 bpm at any visit, an ECG with rhythm strip will be obtained and sent to the central reader to confirm 
the heart rate and rhythm. 
12. Imaging (X-ray and/or MRI) will be performed at the investigator’s discretion on any joint with worsening or exacerbation of 
pain beyond the fluctuations in pain typical for that patient’s OA. This imaging will be submitted to the adjudication committee 
for review.  
13. If screening radiographs are inconclusive for potential joint related findings, an MRI must be performed.  Confirmation from the 
central reader that there are no exclusionary findings on the MRI must be received before a patient can be randomized.  
14. In the event that a patient must undergo JR surgery during the study, the patient must complete the pre-operative visit (early 
termination assessments, as applicable) and the procedures outlined in the schedule of events for JR follow-up. This will include 
a Knee Society Score questionnaire for knee replacements or Harris Hip Score questionnaire for hip replacements.  The 
pre-operative visit must be completed before the JR surgery. Pre-operative images will be submitted to the adjudication 
committee for review. 
15. If the AA joint(s) has undergone JR, an X-ray may be substituted for an MRI. 
16. The purpose of this phone contact is to ask the patient if he/she has had or is scheduled (or on a waiting list) to have JR surgery. 
Pre-operative images will be submitted to the central reader for adjudication, if available. 
17. Samples will be analyzed by the central laboratory and results will be evaluated by the investigator. 
18. Assessment of follicle-stimulating hormone (FSH) and estradiol levels are only to be performed if assessment of postmenopausal 
status is required (ie, for female patients ≤59 years of age). 
19. In the event of a positive urine pregnancy test result, the patient must have a serum pregnancy test with a negative result in order 
to continue study drug. If the serum pregnancy test is positive, the patient must be withdrawn from study drug and should be 
asked to return to the clinic for all remaining study visits per the visit schedule. 
20. Collection of samples for PK, ADA, and research are mandatory at the time points specified above.  In addition, PK, ADA, and 
research samples may be drawn at any scheduled visit or unscheduled visit if a patient experiences a treatment-related safety 
TEAE.  Samples should be collected prior to study drug administration on study drug dosing days. 
21. Biomarker samples should be collected after the patients have been fasting overnight or for 8 hours (in the event of an afternoon 
visit). 
22. Patient-reported outcome measures should be completed before any clinical assessments. 
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Table 2: 
Follow-up Period for Patients Undergoing Joint Replacement Surgery on Study 
 
Post-Operative  
Long-Term 
Follow-up Study Day (Visit Window)1 
Follow-up Visit 1 
4 weeks after joint replacement surgery 
Follow-up Visit 2 
20 weeks after joint replacement surgery 
Follow-up Day 29 (±5) 
Follow-up Day 140 (±7) 
Treatment: 
 
Concomitant medications and therapy 
X 
X 
Safety: 
 
Adverse events 
-------------------------------------------------------------- 
Vital signs 
X 
X 
Orthostatic blood pressure2 
X 
X 
Physical examination with joint examination 
X 
X 
Medical history related to the joint replacement 
X 
X 
Joint pain questionnaire 
X 
X 
Post-operative questionnaire3 
X 
X 
Bilateral X-rays (shoulders, hips, knees)4 
X5 
X 
Event-triggered imaging6 
X 
X 
8.1.2. 
Footnotes for Table 2 - Follow-up Period for Patients Undergoing Joint Replacement Surgery 
1. All available information for patients who undergo JR surgery must be collected, including placement of the prosthesis, healing 
of the surgical wound and the results of the histopathologic examination. 
2. If it is not possible to obtain orthostatic blood pressure following JR then blood pressure and pulse should be recorded. 
3. A Knee Society Score questionnaire for knee replacements or Harris Hip Score questionnaire for hip replacements. 
4. In the event of more than 1 JR, imaging assessments should be repeated if it has been >60 days since the joints were last imaged. 
If it has been ≤60 days since imaging assessments were completed, imaging assessments may be completed at the discretion of 
the investigator. An MRI may be requested by the imaging vendor after review of the X-rays. 
5. Imaging will be done at week 4 if not done pre-operatively. 
6. Imaging may be performed on any joint following a report of clinically significant worsening or exacerbation of pain in that 
joint. 
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8.1.3. 
Early Termination Visit 
Patients who are withdrawn from study drug early should be encouraged to continue in the study 
and complete all other study assessments without receiving study drug. If a patient decides to 
completely withdraw from the study, every attempt should be made to have the patient complete 
an early termination visit (as outlined in Table 1). Imaging assessments need to be repeated if it 
has been >30 days since the joints were last imaged. If it has been ≤30 days since imaging 
assessments were completed, imaging assessments may be completed at the discretion of the 
investigator. 
8.1.4. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule.  Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for any 
other reason, as warranted. 
8.2. 
Study Procedures 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed at the screening visit for the sole purpose of 
determining study eligibility or characterizing the baseline population:  
8.2.1.1. 
Main Study Informed Consent 
All patients must sign and date the Institutional Review Board (IRB)/Ethics Committee 
(EC)-approved written informed consent form (ICF) before study procedures are performed, per 
Section 14.2. 
8.2.1.2. 
Genomics Sub-study Informed Consent 
Patients who are willing to participate in the Genomics Sub-study, which is optional, will sign the 
consent form prior to the collection of samples. Samples for DNA extraction should be collected 
on day 1/baseline (pre-dose), but may be collected at any study visit. 
8.2.1.3. 
Medical History 
The investigator or designee will take a complete medical history that includes information on 
concurrent medical conditions and the severity for each condition that has not resolved. This 
history will include a patient’s history of surgical procedures. 
8.2.1.4. 
Medication History 
The investigator or designee will query patients on the medication(s) they have taken. This 
includes medication taken for their pain due to OA (medication history), including information on 
their ability to tolerate the medication, and will record the information on an electronic case report 
form (eCRF) for this purpose.  
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8.2.1.5. 
Demographics 
A patient’s demographic characteristics will be recorded, including age, height, weight, gender, 
race, and ethnicity.  
8.2.1.6. 
Determination of Osteoarthritis 
Diagnosis of OA of the knee or hip will be based on the American College of Rheumatology 
criteria with radiologic evidence of OA (K-L score ≥2). 
In addition, diagnosis of OA of the hip and knee will use the following criteria: 
Hip 
The American College of Rheumatology clinical and radiographic criteria for the diagnosis of OA 
of the hip (Altman 1991) should be used to confirm a diagnosis of OA of the hip, as applicable, at 
screening. The criteria consist of the following combinations: 
 Hip pain, and 
 At least 2 of the following 3 features: 
 Erythrocyte sedimentation rate (ESR) <20 mm/hour 
 Radiographic femoral or acetabular osteophytes  
 Radiographic joint space narrowing (superior, axial, and/or medial) 
Additional information is provided in the study reference manual. 
Knee 
The American College of Rheumatology clinical and radiographic criteria for the diagnosis of OA 
of the knee (Altman 1986) should be used to confirm a diagnosis of OA of the knee, as applicable, 
at screening.  The criteria consist of the following combinations: 
 Knee pain 
 Osteophytes on radiograph 
 At least 1 of the following 3 features: 
 Age >50 years 
 Stiffness <30 minutes 
 Crepitus 
Additional information is provided in the study reference manual.  
8.2.1.7. 
Assessment of Childbearing Potential 
Each female patient should be evaluated for childbearing potential.  
Women will be considered to be of childbearing potential unless they are postmenopausal, or have 
had a tubal ligation, a bilateral oophorectomy, bilateral salpingectomy, or complete hysterectomy. 
For women ≥60 years of age, postmenopausal is defined as at least 12 continuous months of 
spontaneous amenorrhea. In women ≤59 years of age, postmenopausal is defined as at least 
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12 continuous months of spontaneous amenorrhea, with serum FSH levels >40 IU/L 
(>40 mIU/mL) and serum estradiol levels <5 ng/dL (<184 pmol/L) (Section 8.2.4.8). 
8.2.1.8. 
Diary Training 
At the screening and pre-randomization visits, patients will be trained on the use of the diary to 
report their daily acetaminophen/paracetamol use for OA and other non-OA-related reasons. 
Retraining should occur as needed throughout the conduct of the study. 
8.2.1.9. 
Patient Education Brochures 
At the screening and pre-randomization visits, study staff will review the “Participating in a 
Research Study: What You Need to Know” brochure and the “Reporting Your Pain” brochure 
with patients to ensure they understand what a clinical study is and how to report their pain 
accurately. At subsequent visits, patients will be asked to review the ‘Reporting Your Pain’ 
brochure themselves.  At any time during the conduct of the study, patients may require retraining 
by study staff. 
8.2.2. 
Patient-Completed Assessments and Efficacy Procedures  
8.2.2.1. 
Western Ontario and McMaster Universities Osteoarthritis Index 
The WOMAC index is used to assess patients with OA of the hip or knee using 24 parameters and 
reported using a numerical rating scale. This index can be used to monitor the course of a disease 
or to determine effectiveness of study drugs. The WOMAC pain sub-scale will be evaluated for 
both knees and both hip joints at the screening visit. Then, patients will complete the WOMAC 
Full Survey on the index joint at the subsequent visits, as indicated in Table 1. If possible, the 
assessment should be administered and entered by the same person throughout the study. 
The WOMAC index is a patient-reported outcome measure and should be completed along with 
other patient-reported outcome measures, but before any clinical assessments. 
A copy of WOMAC assessments will be provided in the study reference manual. 
8.2.3. 
Neurological Assessments 
8.2.3.1. 
Nerve Conduction 
Nerve conduction velocities and evoked amplitudes of the peroneal motor, sural sensory and ulnar 
sensory nerves will be assessed at the time points indicated in Table 1. Motor nerve conduction is 
evaluated by electrical stimulation of the nerve and recording the compound muscle action 
potential from surface electrodes overlying a muscle supplied by the nerve (Mallik 2005). Sensory 
nerve conduction is evaluated by electrically stimulating sensory fibers and recording the nerve 
action potential at a point further along that nerve (Mallik 2005). Data will be interpreted by a 
central reader. Complete guidance on how to perform the nerve conduction assessments and how 
to report the findings is provided in the study reference manual. 
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8.2.3.2. 
Neurological Examination (Full) 
A full neurological examination will be performed at the time points indicated in Table 1.  
Neurological findings at baseline that are not exclusionary should be recorded in the medical 
history. Findings at subsequent visits will be assessed by the investigator to determine if these 
should be recorded as an AE. 
The neurological examination will cover the following domains: motor, sensory, cranial nerves, 
reflexes, and coordination/balance and assessment for presence/absence of signs of carpal tunnel 
syndrome and may be conducted by any clinician at the site qualified to do so. Whenever possible, 
the same clinician who conducts the baseline neurological examination should continue to conduct 
the examinations on a given patient. The investigator may refer patients with persistent or 
worsening neurologic symptoms for a neurologic consultation, if clinically indicated. Additional 
neurologic assessments may include other tests as deemed clinically necessary in the judgement 
of the neurologist.  
Complete guidance on how to conduct the full neurologic examination is provided in the study 
reference manual. 
8.2.3.3. 
Survey of Autonomic Symptoms 
The survey of autonomic symptoms will be completed by the patient at the time points indicated 
in Table 1. The completed survey will be reviewed for signs and symptoms of autonomic 
dysfunction by the investigator/medical designee at each visit prior to study drug injection at the 
time points indicated in Table 1. If possible, the assessment should be completed by the same 
person throughout the study.  A patient report of having experienced symptoms of autonomic 
dysfunction will serve as a tool to prompt further evaluations as deemed necessary by the 
investigator or medical designee.  
Survey of Autonomic Symptoms is a patient-reported outcome measure and should be completed 
along with other patient-reported outcome measures, but before any clinical assessments. 
A copy of the survey is provided in the study reference manual. 
8.2.3.4. 
Orthostatic Blood Pressure Assessment and Heart Rate 
An assessment of orthostatic blood pressure will be conducted at the time points indicated in 
Table 1. The assessments should be conducted as per the instructions in the study manual. A patient 
will be determined to have orthostatic hypotension if any of the following criteria are met: 
If the supine systolic blood pressure is <160 mm Hg, a decrease in either the 1 or 3 minute standing 
systolic blood pressure of ≥20 mm Hg or a decrease in the standing diastolic blood pressure of ≥10 
mm Hg from the supine systolic or diastolic blood pressure, respectively 
OR 
If the supine systolic blood pressure is ≥160 mm Hg, a decrease in either the 1 or 3 minute standing 
systolic blood pressure of ≥30 mm Hg or a decrease in the standing diastolic blood pressure of ≥15 
mm Hg from the supine systolic or diastolic blood pressure, respectively 
OR 
An increase in either the 1 or 3 minute standing heart rate of ≥30 bpm from the supine heart rate 
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OR 
The patient is unable to stand for either one of the standing blood pressure measurements due to 
dizziness or lightheadedness 
If the initial assessment for orthostatic hypotension is consistent with the above definition, the 
supine and standing blood pressures and/or pulse should be repeated as outlined above, up to 
2 more times. 
Refer to Section 9.6.1.2 for details on referral to specialists and reporting. 
8.2.4. 
Safety Procedures  
8.2.4.1. 
Vital Signs 
Vital signs, including body temperature and respiratory rate, will be collected pre-dose at time 
points according to Table 1. Blood pressure and heart rate will be collected as part of the orthostatic 
hypotension assessments. If at any visit after the randomization visit the pulse is less than 45 bpm, 
an ECG with rhythm strip will be obtained to confirm the heart rate and rhythm. 
8.2.4.2. 
Electrocardiogram 
A standard 12-lead ECG will be performed at the time points indicated in Table 1, with the patient 
in the supine position for approximately 5 minutes and prior to blood samples being drawn. Heart 
rate will be recorded from the ventricular rate, and the PR, QRS, and the QT and QTc intervals 
will be recorded. The ECG data will be read by a central reading center. Detailed procedures will 
be provided in a separate manual provided by the central reading center.  
8.2.4.3. 
Physical Examination and Body Weight 
A thorough and complete physical examination will be performed at time points according to 
Table 1. Body weight will also be measured.  Care should be taken to examine and assess any 
abnormalities that may be present, as indicated by the patient’s medical history.  
8.2.4.4. 
Joint Pain Questionnaire 
A joint pain questionnaire will be completed by the patient at the time points indicated in Table 1. 
For each knee, hip, and shoulder joint, the patient will be prompted to indicate if he or she has 
experienced pain. A patient report of having experienced pain will serve as a tool to prompt further 
evaluations as deemed necessary by the investigator. 
Joint Pain Questionnaire is a patient-reported outcome measure and should be completed along 
with other patient-reported outcome measures, but before any clinical assessments. 
A copy of the assessment is provided in the study reference manual. 
8.2.4.5. 
Imaging 
Radiographs of the large joints (knees, hips, and shoulders) will be taken using a standard approach 
at the time points indicated in Table 1.  An MRI of the index and contralateral joints must be 
performed at screening. Magnetic resonance imaging will also be performed on any hip or knee 
joint with a K˗L score of ≥3.  Radiographs and an MRI must be performed on any joint following 
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a report of clinically significant worsening or exacerbation of pain in that joint. An X˗ray and an 
MRI should also be performed pre-operatively if a patient is to have a JR during the study. Event 
based and pre-operative images will be submitted for adjudication. Detailed procedures will be 
provided in a separate manual provided by the central imaging center.  Radiograph or MRI will be 
sent to a central reader, where the images will be digitized.  
Radiographs 
Weight-bearing (standing) posterior-anterior radiographs of both knees in the semi-flexed 
position, and anterior-posterior radiographs of both hips and both shoulders, will be conducted at 
these visits.  Additional instructions for positioning of joints are provided in the study reference 
manual. 
Radiographs of the knees, hips, and shoulders will be sent to a central reader and evaluated to 
confirm no evidence of AA such as rapidly progressive osteoarthritis type 1 or 2, subchondral 
insufficiency fracture, or osteonecrosis. 
MRI 
During screening, MRIs of the index and contralateral joints as well as joints with a K-L score ≥3 
will be sent to a central reader to confirm that there is no evidence of exclusionary features.  
Confirmation that there are no exclusionary findings on MRI must be received before a patient can 
be randomized. An MRI of any joint will be considered if radiographs taken after randomization 
suggest the presence of an abnormal process inconsistent with normal progression of OA, as 
determined by the investigator or central reader. 
At the end of study phone contact, patients who had an AA will have an MRI performed of the 
affected joint(s). If the affect joint has undergone JR, an X-ray may be substituted for an MRI. 
Refer to the supplemental imaging manuals for data collection and management procedures. 
8.2.4.6. 
End of Study Phone Contact and Additional Imaging 
An end of study phone contact will be conducted at 52 weeks following the last dose of study drug. 
Patients will be asked whether they underwent JR surgery following the last in-clinic visit of the 
follow-up period or whether they are scheduled (or on a waiting list) for JR surgery.  Patients who 
had JR surgery will also be asked to submit pre-operative imaging (X-ray and MRI, if available) 
for adjudication. Patients who had an AA will have an MRI performed of the affected joint(s). If 
the affected joint has undergone JR, an X-ray may be substituted for an MRI.  
8.2.4.7. 
Procedures to be Performed Only in the Event of a Joint Replacement Surgery  
In the event that a patient must undergo JR surgery during the treatment or follow-up periods, the 
patient will be discontinued from study drug and asked to return for a pre-operative visit. The pre-
operative visit should be completed before JR surgery if possible, and pre-operative images will 
be submitted to the adjudication committee for review.  Following the JR surgery, the patient will 
complete follow-up safety evaluations at 4 weeks and 20 weeks after surgery (see Table 2). 
In the event that the pre-operative visit is not performed, standard-of-care pre-operative images of 
the joint with JR must be obtained and submitted to the central imaging vendor's adjudication 
committee for review. Imaging of all other joints per the pre-operative visit procedures will be 
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done post-operatively at the first JR follow-up study visit (4 weeks after surgery) if not done before 
surgery.  
All available medical history/information for patients who undergo JR surgery must be collected, 
including the results of histopathologic examination. 
Full details of these assessments are provided in the study reference manual. 
Knee Society Score 
The Knee Society Score is an investigator-completed questionnaire that is used to objectively 
measure a patient’s ability to function before and after total knee arthroplasty (Insall 1989). If 
possible, the assessment should be completed by the same person throughout the study. 
Harris Hip Score 
The Harris Hip Score is an investigator-completed questionnaire that is used to objectively 
measure a patient’s ability to function before and after total hip arthroplasty (Harris 1969). If 
possible, the assessment should be completed by the same person throughout the study. 
8.2.4.8. 
Laboratory Testing 
The central laboratory will analyze all screening and on-study laboratory samples for blood 
chemistry, hematology, HbA1c, urine analysis, urine drug tests, and serum pregnancy tests.  Urine 
pregnancy and ESR testing will be done at the site using kits provided by the central laboratory. 
Regeneron or its designee will be responsible for fasinumab PK, anti-fasinumab antibody, 
biomarker development, and pharmacogenetic sample assessments; the central laboratory will ship 
the samples to Regeneron or a specialty laboratory depending on the assessment. 
All samples will be collected before study drug administration.  Missed tests should be reported in 
the source documents and in the eCRF, as appropriate.  Central laboratory kits will be provided 
for sample collection and shipment.  Detailed instructions for blood sample collection are in the 
laboratory manual provided to study sites. 
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Samples for laboratory testing will be collected at time points according to Table 1. Tests will 
include: 
Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin 
Potassium 
Creatinine 
Phosphorus 
Chloride 
Blood urea nitrogen 
Uric acid 
Carbon dioxide 
Aspartate aminotransferase (AST) 
Creatine phosphokinase 
Calcium 
Alanine aminotransferase (ALT) 
 
Glucose 
Alkaline phosphatase 
 
Albumin 
Lactate dehydrogenase 
 
Hematology 
Hemoglobin 
Differential: 
Hematocrit 
Neutrophils 
Red blood cells (RBCs) 
Lymphocytes 
White blood cells (WBCs) 
Monocytes 
Red cell indices 
Basophils 
Platelet count 
Eosinophils 
Urinalysis 
Color 
Glucose 
RBC 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBC 
Yeast 
Urine Electrolytes 
Creatinine 
 
 
Phosphorus 
 
 
Other Laboratory Tests 
Serum and urine samples for pregnancy testing will be collected from women of childbearing 
potential (WOCBP) (as defined in Section 8.2.1.7) at time points according to Table 1. At dosing 
study visits, urine pregnancy testing will be done before the study drug is administered. In the 
event of a positive urine pregnancy test result, the patient should have a serum pregnancy test with 
a negative result in order to continue study drug. If the serum pregnancy test is positive, the patient 
should be withdrawn from study drug and should be asked to return to the clinic for all remaining 
study visits per the visit schedule (see Table 1). 
To assess postmenopausal status for women ≤59 years of age, serum samples to test for FSH levels 
and estradiol levels will be collected for analysis at the central laboratory according to 
Section 8.2.1.7. 
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Samples will be collected for HbA1c and ESR testing at time points according to Table 1. 
Urine drug testing will be performed at screening and includes amphetamines/methamphetamines, 
barbiturates, benzodiazepines, cannabinoids, cocaine, and opiates. 
Blood samples for study drug PK and ADA assessment (Section 8.2.5) will also be collected. 
Abnormal Laboratory Values and Laboratory Adverse Events 
All laboratory values must be reviewed by the investigator or authorized designee. 
Significantly abnormal test results that occur after start of treatment must be repeated to confirm 
the nature and degree of the abnormality. When necessary, appropriate ancillary investigations 
should be initiated. If the abnormality fails to resolve or cannot be explained by events or 
conditions unrelated to the study medication or its administration, the medical monitor must be 
consulted. 
The clinical significance of an abnormal test value, within the context of the disease under study, 
must be determined by the investigator. 
Criteria for reporting laboratory values as an AE are provided in Section 9.4.5. Evaluation of 
severity of laboratory abnormalities will be assessed according to the scale outlined in 
Section 9.5.1. 
8.2.4.9. 
Injection Site Evaluations 
An injection site evaluation should be conducted following the injection at each dosing visit, 
according to Table 1.  
8.2.5. 
Pharmacokinetic and Anti-Drug Antibody Procedures 
8.2.5.1. 
Drug Concentration Measurements and Samples 
Samples for drug concentration will be collected at time points listed in Table 1. Detailed 
instructions for blood sample collection are included in the laboratory manual provided to study 
sites. 
Any unused samples may be used for exploratory biomarker research. 
8.2.5.2. 
Anti-Drug Antibody Measurements and Samples 
Samples for ADA assessment will be collected at time points listed in Table 1. Detailed 
instructions for blood sample collection are included in the laboratory manual provided to study 
sites. 
Any unused samples may be used for exploratory biomarker research. 
8.2.6. 
Research Samples 
8.2.6.1. 
Biomarkers 
Serum and plasma samples will be collected at time points according to Table 1. These samples 
may be used to measure biomarkers related to inflammation, collagen and bone turnover, OA pain 
and NGF and may include CTX-I, osteocalcin, high-sensitivity C-reactive protein and matrix 
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metalloprotein generated collagen fragments (CIM, C3M).  Samples may be used to study other 
markers of collagen and bone turnover, OA and pain.  If necessary, samples may also be used to 
identify markers associated with AEs. 
8.2.6.2. 
Future Biomedical Research 
Unused research samples, as well as unused PK and ADA samples, will be stored for up to 15 years 
after the final date of the database lock. The unused samples may be utilized for future biomedical 
research of OA and other diseases. No additional samples will be collected for future biomedical 
research. After 15 years, any remaining samples will be destroyed. 
8.2.6.3. 
Genomics Sub-study - Optional 
Patients who agree to participate in the genomics sub-study will be required to sign a separate 
genomics sub-study ICF before collection of the samples. Patients are not required to participate 
in the genomics sub-study in order to enroll in the primary study. Samples for DNA extraction 
should be collected on day 1/baseline (pre-dose), but may be collected at any study visit.  
DNA samples for the genomics sub-study will be double-coded as defined by the International 
Council for Harmonisation (ICH) guideline E15. Sub-study samples will be stored for up to 15 
years after the final date of the database lock and may be used for research purposes. The purpose 
of the genomic analyses is to identify genomic associations with collagen and bone turnover, OA, 
pain, and response to fasinumab.  In addition, associations between genomic variants and 
prognosis or progression of OA as well as other diseases may also be studied.  These data may be 
used or combined with data collected from other studies to identify and validate genomic markers 
related to the study drug or other diseases.  Analyses may include sequence determination or single 
nucleotide polymorphism studies of candidate genes and surrounding genomic regions.  Other 
methods, including whole-exome sequencing, whole-genome sequencing, and DNA copy number 
variation may also be performed.  The list of methods may be expanded to include novel 
methodology that may be developed during the course of this study or sample storage period. 
The results of these future biomedical research analyses will not be presented in the clinical study 
report. 
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9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
9.1. 
Obligations of Investigator 
The investigator must promptly report to the IRB or EC all unanticipated problems involving risks 
to patients, according to local regulations. This may include death from any cause and all serious 
adverse events (SAEs) related to the use of the study drug.  It is recommended that all SAEs be 
reported to the IRB or EC according to local regulations. 
9.2. 
Obligations of Sponsor 
During the course of the study, the sponsor will report in an expedited manner all SAEs that are 
both unexpected and at least reasonably related to the study drug (SUSAR), to the health 
authorities, EC/IRBs as appropriate, and to the investigators (in a blinded manner).  
Any AE not listed as an expected event in the Reference Safety Information section of the 
Investigator’s Brochure will be considered unexpected. Any worsening of or new onset of 
symptoms related to OA that occur during the screening period prior to study drug administration 
will be considered expected. 
In addition, the sponsor will report all other SAEs to the health authorities, according to local 
regulations. 
At the completion of the study, the sponsor will report all safety observations made during the 
conduct of the trial in the clinical study report to health authorities and ECs/IRBs as appropriate.  
9.3. 
Definitions 
9.3.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug which may or 
may not have a causal relationship with the study drug. Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease which is temporally 
associated with the use of a study drug, whether or not considered related to the study drug. 
An AE also includes any worsening (ie, any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug. 
9.3.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death – includes all deaths, even those that appear to be completely unrelated 
to study drug (eg, a car accident in which a patient is a passenger). 
 Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event.  This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
 Requires in-patient hospitalization or prolongation of existing hospitalization.  
In-patient hospitalization is defined as admission to a hospital or an emergency room 
for longer than 24 hours.  Prolongation of existing hospitalization is defined as a 
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hospital stay that is longer than was originally anticipated for the event, or is prolonged 
due to the development of a new AE as determined by the investigator or treating 
physician. 
 Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions). 
 Is a congenital anomaly/birth defect 
 Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent one of the other serious outcomes listed above.  
Examples of these include intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse. 
Criteria for reporting SAEs must be followed for these events. See Section 9.4 for more 
information on recording and reporting SAEs. 
9.3.3. 
Adverse Events of Special Interest 
An AESI (serious or non-serious) is one of scientific and medical concern specific to the sponsor’s 
product or program, for which ongoing monitoring and rapid communication by the investigator 
to the sponsor can be appropriate.  Such an event might warrant further investigation in order to 
characterize and understand it.  Depending on the nature of the event, rapid communication by the 
trial sponsor to other parties (eg, regulators) might also be warranted (Section 9.4.3). 
9.4. 
Recording and Reporting Adverse Events  
9.4.1. 
Adverse Events 
The investigator (or designee) will record all AEs that occur from the time the informed consent 
is signed until the end of the follow-up period (week 36)/early termination visit. Refer to the study 
reference manual for the procedures to be followed. 
Information on follow-up for AEs is provided in Section 9.4.6. Laboratory, vital signs, or ECG 
abnormalities are to be recorded as AEs as outlined in Section 9.4.5. 
9.4.2. 
Serious Adverse Events 
All SAEs, regardless of assessment of causal relationship to study drug, must be reported to the 
sponsor (or designee) within 24 hours. Refer to the study reference manual for the procedure to be 
followed. 
Information not available at the time of the initial report must be documented in a follow-up report. 
Substantiating data such as relevant hospital or medical records and diagnostic test reports may 
also be requested. 
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In the event the investigator is informed of an SAE after the patient completes the follow-up period 
(week 36)/early termination visit, the following will apply: 
 SAE with an onset within 30 days of the end of the follow-up (week 36)/early 
termination visit - the SAE will be reported to the sponsor.  The investigator should 
make every effort to obtain follow-up information on the outcome until the event is 
considered chronic and/or stable. 
 SAE with an onset day greater than 30 days from the end of follow-up period 
(week 36)/early termination visit - only SAEs deemed by the investigator to be 
drug-related will be reported to the sponsor. The investigator should make every effort 
to obtain follow-up information on the outcome of a drug-related SAE until the event 
is considered chronic and/or stable. 
 SAE reported by the patient at the end of the study phone call and deemed by the 
investigator to be drug-related will be reported to the sponsor. The investigator should 
make every effort to obtain follow-up information on the outcome of a drug-related 
SAE until the event is considered chronic and/or stable. 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of learning 
of the event: 
Symptomatic Overdose of Study Drug: 
Accidental or intentional overdose of at least 2 times 
the intended dose of study drug within the intended therapeutic window, if 
associated with an AE 
Pregnancy: 
Although pregnancy is not considered an AE, it is the responsibility of the 
investigator to report to the sponsor (or designee), within 24 hours of identification, 
any pregnancy occurring in a female study patient during the study or within 20 
weeks of the last dose of study drug. Any complication of pregnancy affecting a 
female study patient and/or fetus and/or newborn that meets the SAE criteria must 
be reported as an SAE. Outcome for all pregnancies should be reported to the 
sponsor. 
Adverse Events of Special Interest: 
All AESI, serious and non-serious, must be reported 
within 24 hours of identification using the same reporting process as for SAE 
reporting per Section 9.4.2. Monitoring of AESIs is described in Section 9.6.1.  
Adverse events of special interest for this study include the following: 
 Adjudicated arthropathy (as confirmed by adjudication)  
 Joint replacement surgery (refer to Section 9.6.1.4 for when to report as an 
AESI) 
 Sympathetic nervous system dysfunction (as diagnosed after consultation 
with an appropriate specialist, such as a neurologist and/or cardiologist) 
 Peripheral sensory AEs that require a neurology or other specialty 
consultation 
Refer to the study manual for the procedures to be followed. 
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9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study 
All AEs that lead to a patient’s withdrawal from the study must be reported to the sponsor’s 
Medical/Study Director within 30 days. 
Refer to the study reference manual for the procedures to be followed. 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results 
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE include: 
 the test result is associated with accompanying symptoms, and/or 
 the test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
 the test result leads to a change in dosing (outside of protocol-stipulated dose 
adjustments), discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy 
Contact the Medical/Study Director in the event the investigator feels that an abnormal test finding 
should be reported as an AE, although it does not meet any of the above criteria. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an 
AE. Any abnormal test result that is determined to be an error does not require reporting as an AE.  
Evaluation of severity of laboratory abnormalities will be assessed according to the scale outlined 
in Section 9.5.1.  
9.4.6. 
Follow-up 
Adverse event information will be collected until the patient’s last study visit. 
Serious adverse event information will be collected until the event is considered chronic and/or 
stable. 
9.5. 
Evaluation of Severity and Causality 
9.5.1. 
Evaluation of Severity 
The severity of AEs will be graded according to the following scale: 
 Mild:  Does not interfere in a significant manner with the patient normal functioning 
level.  It may be an annoyance. Prescription drugs are not ordinarily needed for relief 
of symptoms, but may be given because of personality of the patient. 
 Moderate:  Produces some impairment of functioning but is not hazardous to health. 
It is uncomfortable or an embarrassment. Treatment for symptom may be needed. 
 Severe:  Produces significant impairment of functioning or incapacitation and is a 
definite hazard to the subject’s health. Treatment for symptom may be given and/or 
patient hospitalized. 
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
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Injection Site Reactions 
The severity of injection site reactions will be graded according to the following scale (semi-colon 
indicates “or” within description of grade): 
 Mild:  Pain that does not interfere with activity; mild discomfort to touch; <5 cm of 
erythema or induration that does not interfere with activity. 
 Moderate:  Pain that requires repeated use of non-narcotic pain reliever >24 hours or 
interferes with activity; discomfort with movement; 5.1 cm to 10 cm erythema or 
induration or induration that interferes with activity. 
 Severe:  Pain that requires any use of narcotic pain reliever or that prevents daily 
activity; significant discomfort at rest; >10 cm erythema or induration; prevents daily 
activity; requires emergency room visit or hospitalization; necrosis or exfoliative 
dermatitis. 
9.5.2. 
Evaluation of Causality  
Relationship of Adverse Events to Study Drug: 
The relationship of AEs to study drug will be assessed by the "blinded" investigator, and will be a 
clinical decision based on all available information. The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by the study drug? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by the study 
drug. 
Related: 
There is a reasonable possibility that the event may have been caused by the study 
drug. 
The investigator should justify the causality assessment of each SAE. 
A list of factors to consider when assessing the relationship of AEs to study drug is provided below.  
Please note that this list is not exhaustive. 
Is there a reasonable possibility that the event may have been caused by the study drug? 
No: 
 due to external causes such as environmental factors or other treatment(s) being 
administered 
 due to the patient’s disease state or clinical condition 
 do not follow a reasonable temporal sequence following the time of administration of 
the dose of study drug 
 do not reappear or worsen when dosing with study drug is resumed 
Yes: 
 could not be explained by environmental factors or other treatment(s) being 
administered 
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 could not be explained by the patient’s disease state or clinical condition 
 follow a reasonable temporal sequence following the time of administration of the dose 
of study drug  
 resolve or improve after discontinuation of study drug  
 reappear or worsen when dosing with study drug  
 are known or suspected to be a response to the study drug based upon preclinical data 
or prior clinical data 
Relationship of Adverse Events to Study Conduct 
The relationship of AEs to study conduct will be assessed by the "blinded" investigator, and will 
be a clinical decision based on all available information.  The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by study conduct? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by study 
conduct. 
Related: 
There is a reasonable possibility that the event may have been caused by study 
conduct. 
The investigator should justify the causality assessment of each SAE. 
A list of factors to consider when assessing the relationship of AEs to study conduct is provided 
below. Please note that the list if not exhaustive. 
Is there a reasonable possibility that the event may have been caused by the study conduct? 
Is there a reasonable possibility that the event may have been caused by the study conduct? 
No: 
 due to external causes such as environmental factors or other treatment(s) being 
administered 
 due to the patient’s disease state or clinical condition 
 do not follow a reasonable temporal sequence following the course of the study 
 do not reappear or worsen when dosing with study participation is resumed 
Yes: 
 could not be explained by environmental factors or other treatment(s) being 
administered 
 could not be explained by the patient’s disease state or clinical condition 
 follow a reasonable temporal sequence following the course of the study 
 resolve or improve after discontinuation from study participation. 
 reappear or worsen when study participation is resumed 
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9.6. 
Safety Monitoring 
The investigator will monitor the safety of study patient at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP). Any questions or 
concerns should be discussed with the sponsor in a timely fashion. The sponsor will monitor the 
safety data from across all study sites. The Medical/Study Director will have primary responsibility 
for the emerging safety profile of the compound, but will be supported by other departments 
(eg, Pharmacovigilance and Risk Management; Biostatistics and Data Management). Safety 
monitoring will be performed on an ongoing basis (eg, individual review of SAEs) and on a 
periodic cumulative aggregate basis. 
9.6.1. 
Monitoring Adverse Events of Special Interest 
9.6.1.1. 
Adjudicated Arthropathy 
Adjudicated arthropathy is an umbrella term that encompasses the following conditions: 
 Rapidly progressive OA type 1 and 2 
 Subchondral insufficiency fractures 
 Primary osteonecrosis 
In addition, adjudicated arthropathies will be evaluated to determine if they meet destructive 
arthropathy criteria. 
Potential events of AA will be monitored via clinical signs and symptoms of worsening joint pain 
during the course of the study (eg, by applying adverse experiences, the joint pain questionnaire 
and imaging) as well as scheduled imaging and pre-operative imaging, if a patient requires a JR 
during the study. 
Clinically significant worsening of joint pain during the course of this study is characterized as a 
worsening of pain in any joint that occurs in spite of treatment with analgesics, is in the opinion of 
the investigator inconsistent with the normal fluctuation of pain or progression of OA, and is at 
least 2 weeks duration (or less than 2 weeks if deemed clinically significant at the discretion of the 
investigator). 
If a patient reports an increase in pain as described above, study drug administration will be 
withheld while imaging of the affected joint, as well as any additional imaging deemed appropriate 
to understand the cause of the worsening pain, is performed (Section 8.2.4.5). A decision to 
perform imaging after patient reported of worsening of joint pain will be documented in the 
respective CRF page. Images, along with any other radiographic evaluation, will be submitted to 
the arthropathy adjudication committee for review (Section 5.3.2). The investigator may consider 
aspiration of synovial fluid for further analysis such as cell count and crystal analysis.  
If routine imaging suggests the presence of one of the types of AA, study drug administration will 
be withheld. Any additional imaging deemed appropriate will be obtained. The images, along with 
results of any other radiographic evaluation, will be submitted to the Adjudication Committee for 
review (Section 5.3.2).  
If the adjudication does not confirm the presence of AA, according to the adjudication criteria, 
study drug may be restarted. 
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Study drug dosing will be permanently discontinued for patients with findings that suggest AA; 
the patients will be referred for orthopedic consultation. If presence of AA is confirmed by the 
Adjudication Committee, the case must be reported as an AESI (Section 9.3.3 and Section 9.4.3).  
Any patient whose study drug is discontinued due to an AA should be encouraged to return to the 
clinic for all remaining study visits. If JR surgery is warranted, prior to the scheduled JR, the 
patient should complete the pre-operative study visit and, after the JR, should complete the week 
4 and week 20 post-operative study visits (Table 2).  Pre-operative images, along with any other 
radiographic evaluation will be submitted to the arthropathy adjudication committee for review 
(Section 5.3.2). 
Details of data collection for adjudication of events will be provided in the adjudication charter. 
9.6.1.2. 
Sympathetic Nervous System Dysfunction 
Sympathetic nervous system dysfunction will be monitored throughout the study through physical 
examination, AE reporting, assessment of orthostatic hypotension, and the Survey of Autonomic 
Symptoms (Section 8.2.3.3). New onset or worsening of signs and symptoms of autonomic 
dysfunction will be evaluated by the investigator.  Sympathetic nervous system dysfunction will 
only be diagnosed after consultation with an appropriate specialist, such as a neurologist and/or 
cardiologist. 
In cases in which new or worsening symptoms consistent with SNS dysfunction are moderate to 
severe or are clinically significant and do not resolve or return to baseline in 2 weeks (or less at 
the discretion of the investigator), study drug will be withheld and the patient will be referred to a 
specialist. If the evaluation by the appropriate specialist does not suggest SNS dysfunction, study 
drug may be restarted. If the specialist’s evaluation does reveal SNS dysfunction then study drug 
will be permanently discontinued and the case reported as an AESI (Section 9.4.3). 
Orthostatic hypotension may be a manifestation of SNS dysfunction. If a patient is determined to 
have orthostatic hypotension, study drug should be withheld and the AE should be entered in the 
CRF. The following procedures should be followed: 
 If the patient is symptomatic and a clinical explanation for orthostatic hypotension is 
identified (such as a new medication or dehydration due to exercise or illness or 
excessive heat exposure), study drug will be withheld, and the patient should return to 
the study site for an unscheduled visit in 1 to 10 days for an unscheduled assessment 
of orthostatic hypotension. 
 If the orthostatic hypotension has resolved, study drug may be restarted. 
 If the orthostatic hypotension has not resolved, then study drug will be withheld, 
and the patient will be referred to a specialist (neurologist or a cardiologist) for 
evaluation of sympathetic nervous system dysfunction. 
 If the specialist’s evaluation does not reveal new onset SNS dysfunction, 
including symptoms of bradycardia (lightheadedness), orthostatic 
hypotension (lightheadedness on standing), syncope, absence of sweating 
in conditions where sweating would be expected, or if the specialist’s 
evaluation identifies an alternative cause, such as initiation of a new 
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medication known to cause orthostasis, then study drug may be given at the 
next visit. 
 If the specialist’s evaluation does reveal SNS dysfunction, then study drug 
will be permanently discontinued and the case reported as an AESI 
(Section 9.4.3). 
 If the patient has asymptomatic orthostatic hypotension, study drug will be withheld, 
and the patient should return to the study site for an unscheduled visit in 1 to 10 days 
for an unscheduled assessment of orthostatic hypotension. 
 If the unscheduled assessment does not reveal orthostatic hypotension then study 
drug may be continued. 
 If the unscheduled assessment demonstrates orthostatic hypotension then study 
drug will continue to be withheld until the patient has been evaluated by a specialist 
(neurologist or a cardiologist) for evidence of SNS dysfunction. 
 If the specialist’s evaluation does not reveal new SNS dysfunction including 
symptoms of bradycardia (lightheadedness), orthostatic hypotension 
(lightheadedness on standing), syncope, absence of sweating in conditions 
where sweating would be expected, or if the specialist’s evaluation 
identifies an alternative cause such as initiation of a new medication known 
to cause orthostasis, then study drug may be restarted. 
 If the specialist’s evaluation does reveal SNS dysfunction then study drug 
will be permanently discontinued and the case reported as an AESI 
(Section 9.4.3). 
9.6.1.3. 
Peripheral Sensory Adverse Events 
Altered peripheral sensation (eg, paraesthesia and hypoaesthesia) is an important identified risk 
with fasinumab (see Investigator’s Brochure) and other anti-NGF compounds. Any peripheral 
sensory AE that, per the investigator’s judgment, requires a neurology or other specialty 
consultation must be reported as an AESI. If any peripheral sensory event persists for 2 months, 
the patient must be referred for a neurology or other specialty consultation and the event must be 
reported as an AESI. Refer to the study manual for further details related to reporting of peripheral 
sensory neuropathy AEs. 
If the repeated per-protocol nerve conduction test performed on the regions of the peroneal, sural, 
or ulnar nerves at any post-baseline visit shows a difference from baseline of >12% (based on 
central reader assessment), the patient will be referred for a neurology evaluation.  If the 
neurologist’s evaluation confirms the diagnosis of peripheral neuropathy, the study drug will be 
permanently discontinued.  Refer to the study manual for further details related to reporting of 
results of nerve conduction tests. 
9.6.1.4. 
Joint Replacement Surgery 
Any elective JR surgery planned before completion of the ICF would be part of the exclusion 
criteria and would not be considered an AE. 
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After signing of the ICF, report JR surgery as an AESI if the JR surgery is an elective event that is 
not associated with a new/worsening AE. 
Do not report JR surgery as an AE/AESI if the JR surgery is for the treatment of a new or worsening 
AE. In this case, the new or worsening AE should be the reported AE/AESI term. 
An end of study phone contact will be conducted approximately 52 weeks following the last dose 
of study drug to evaluate the number of patients who have undergone or are scheduled for JR 
surgery as described in Section 8.2.4.7. 
9.7. 
Investigator Alert Notification 
Regeneron (or designee) will inform all investigators participating in this clinical trial, as well as 
in any other clinical trial using the same investigational drug, of any SAE that meets the relevant 
requirements for expedited reporting (an AE that is serious, unexpected based on the Investigator’s 
Brochure or this protocol, and has a reasonable suspected causal relationship to the 
medicinal/study drug). 
10. 
STATISTICAL PLAN  
This section provides the basis for the statistical analysis plan (SAP) for the study.  The SAP may 
be revised during the study to accommodate amendments to the clinical study protocol and to make 
changes to adapt to unexpected issues in study execution and data that may affect the planned 
analyses.  The final SAP will be issued before the database is locked. 
Analysis variables are listed in Section 4. 
10.1. 
Statistical Hypothesis 
No formal hypothesis testing will be performed on nerve conduction measures. The treatment 
difference between fasinumab and placebo in the change from baseline to week 16 in nerve 
conduction measures will be estimated and presented descriptively along with 95% confidence 
intervals. 
10.2. 
Justification of Sample Size 
Approximately 180 patients will be randomized in a 1:1 ratio to fasinumab 1 mg Q4W or placebo.  
With this sample size, the precision of the estimated treatment difference between fasinumab and 
placebo at week 16 in nerve conduction velocity is no more than 1.21 m/s with a 95% confidence 
level, assuming a standard deviation (SD) of 3.6 m/s. This sample size provides similar precision 
for the estimated treatment difference in nerve conduction amplitude assuming an SD of 3.6 μV. 
The assumed SDs are estimated based on the nerve conduction results from Arezzo 2008. 
Assuming a 2-sided alpha level of 0.05 and a 15% dropout rate up to week 16, an enrollment of 
90 patients per group will provide at least 80% power to detect an effect size of 0.46 in the 
WOMAC pain and physical function subscale scores (ie, absolute treatment difference of 1.1 
between fasinumab and placebo with an SD of 2.4). The assumed treatment difference and SD are 
based on results from study R475-PN-1227.  
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10.3. 
Analysis Sets  
10.3.1. 
Efficacy Analysis Set 
The full analysis set (FAS) includes all randomized patients and is based on the treatment allocated 
(as randomized).  Efficacy endpoints will be analyzed using the FAS. 
10.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized patients who received any study drug; it is 
based on the treatment received (as treated).  Treatment compliance/administration and all clinical 
safety variables will be analyzed using the SAF. 
10.3.3. 
Pharmacokinetic Analysis Set 
The PK analysis set includes all treated patients who received any study drug and who had at least 
1 non-missing drug concentration result following the first dose of study drug. 
10.3.4. 
Anti-Drug Antibody Analysis Set 
The ADA analysis set includes all treated patients who had at least 1 qualified (non-missing) post-
dose ADA result following the first dose of study drug. 
10.4. 
Statistical Methods  
For continuous variables, descriptive statistics will include the following information:  the number 
of patients reflected in the calculation (n), mean, median, SD, minimum, Q1, Q3, and maximum.   
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
10.4.1. 
Patient Disposition 
The following will be provided: 
 The total number of screened patients:  met the inclusion criteria regarding the target 
indication and signed the ICF 
 The total number of randomized patients:  received a randomization number 
 The total number of patients in each analysis set  
 The total number of patients who discontinued the study, and the reasons for 
discontinuation 
 A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized 
 A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation 
10.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group, 
and by all patients combined.   
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10.4.3. 
Efficacy Analysis 
The efficacy variables will be analyzed using multiple imputation approach with mixed-effect 
model for repeated measure (MMRM) based on the FAS with adjustment for missing data due to 
lack of efficacy or AEs assuming the scores would on average return to baseline values. The 
imputed data for patients discontinued from study drug due to lack of efficacy or AEs will be 
centered at the mean baseline value.  The missing data for patients discontinued from treatment 
due to other reasons will be imputed under missing-at-random assumption. 
Missing data will be imputed 50 times to generate 50 complete data sets. Each imputed data set 
will be analyzed using the MMRM with terms for baseline score corresponding to the efficacy 
variable being analyzed, randomization strata (K-L category [2 to 3, or 4] and index joint [knee, 
hip]), treatment, visit, and treatment-by-visit interaction. The MMRM will be performed with an 
unstructured covariance matrix to model the within-patient errors. Denominator degrees of 
freedom will be estimated using Kenward-Roger’s approximation. The results from the 50 
analyses will be combined using Rubin’s formulae. The least-squares mean estimates for the mean 
change from baseline to week 16, as well as the difference of the estimates between fasinumab and 
placebo with their corresponding standard errors and associated 95% confidence intervals, will be 
provided.  
For analysis of categorical variables, eg, proportions of patients with ≥30% improvement in the 
WOMAC pain subscale scores at week 16, the Cochran Mantel Haenszel approach stratified by 
the randomization strata will be used with missing data considered as non-response. 
10.4.4. 
Safety Analysis 
Safety data including nerve conduction measures, TEAEs and treatment emergent AESIs, vital 
signs, physical exams, laboratory tests, ECGs, and ADA formation will be listed and summarized 
by treatment group. 
Thresholds for potentially clinically significant values (PCSVs) in laboratory parameters and vital 
signs will be defined by the sponsor and be in effect at the time of final SAP approval. 
The time interval to detect any AEs, including AESIs, is between the first dose of double-blinded 
study drug injection and the week 36 visit, as well as study drug-related SAEs occurring between 
the week 36 visit and the end of study. 
For safety variables, 3 observation periods are defined: 
 The pretreatment period is defined as the time from signing the ICF to before the first 
dose of study drug. 
 The treatment period is defined as the day from first dose of study drug through the day 
of last dose (week 12) + 4 weeks. 
 The follow-up period is defined from the end of on-treatment period to the week 36 
visit. 
10.4.4.1. Primary Safety Analysis 
The variables for the evaluation of peripheral nerve function are the change from baseline to week 
16 in the amplitude and velocity from the 3 individual nerve conduction tests. 
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The nerve conduction variables will be analyzed using an MMRM approach based on the safety 
analysis set. The model will include baseline value, randomization strata, treatment, visit, and 
treatment-by-visit interaction.  The least-squares mean estimates for the mean change from 
baseline to week 16, as well as the differences of the estimates between fasinumab and placebo, 
with their corresponding standard errors and associated 95% confidence intervals, will be provided 
descriptively. Missing data due to no response or outside of test detection limit will be imputed 
using the first percentile of all non-missing values for that measurement prior to the MMRM 
analysis. Additional analysis based on observed data with no imputation may also be performed. 
Sensitivity analysis may be performed with data from all patients including data collected after 
discontinuing treatment up to week 16.  
10.4.4.2. Adverse Events 
Definitions 
Treatment-emergent adverse events are defined as those that are not present at baseline or represent 
the exacerbation of a pre-existing condition during the on-treatment period. 
Analysis 
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®).  Coding will be to lowest level terms.  The 
verbatim text, the preferred term (PT), and the primary system organ class (SOC) will be listed. 
Post-treatment AEs and all AEs during the study will be summarized similarly as TEAEs. 
Summaries of all TEAEs by treatment group will include: 
 The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
 TEAEs by severity (according to the grading scale outlined in Section 9.5.1), 
presented by SOC and PT 
 TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
 Treatment-emergent AESIs (defined with a PT or a prespecified grouping) 
Deaths and other SAEs will be listed and summarized by treatment group. 
Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized by treatment group. 
In addition, AESIs will be reported according to the adjudicated diagnosis.  Imaging data related 
to AA including change from baseline in joint space width will be summarized. 
10.4.4.3. Other Safety 
Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiration rate) will be summarized by 
baseline and change from baseline to each scheduled assessment time with descriptive statistics. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics. 
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Number and percentage of patients with a PCSV at any post randomization time point will be 
summarized for each clinical laboratory test.  
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
Listings will be provided with flags indicating the out of laboratory range values. 
10.4.4.4. Treatment Exposure 
Because of the half-life of the biologic being studied, the duration of fasinumab exposure during 
the study will be presented by treatment group and calculated as: 
(Date of last administration of study drug - date of the first study drug administration after 
randomization) + 28 
The number and percentage of patients randomized and exposed to double-blind study drug will 
be presented by specific time period for each treatment group.   
10.4.4.5. Treatment Compliance 
Overall treatment compliance is defined as the actual dose of injection compared to the prescribed 
dose of treatment during the treatment period up to treatment discontinuation.  It is calculated 
according to the following formula: 
100* Total actual injection dose taken/Prescribed injection dose. 
The total number of actual doses of fasinumab will be summarized. 
10.4.5. 
Analysis of Drug Concentration Data 
Summaries of concentrations of functional fasinumab in serum will be presented descriptively by 
nominal time. Plots of individual concentration over time will be presented by actual day. Plots of 
mean or median concentrations of functional fasinumab will be presented by nominal day or week.  
No formal statistical analysis will be performed. 
10.4.6. 
Analysis of Anti-Drug Antibody Data 
Immunogenicity will be characterized by the ADA response observed: 
 Treatment-emergent ADA response – defined as any post-dose positive ADA assay 
response when the baseline results are negative  
 Treatment-boosted ADA response – defined as any post-dose positive ADA assay 
response that is 9-fold over baseline titer levels when baseline is positive in the ADA 
assay 
 Maximum ADA titer values 
 Low (titer <1,000) 
 Moderate (1,000≤ titer ≤10,000) 
 High (titer >10,000) 
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Listings of ADA positivity and titers presented by patient, time point, and dose group will be 
provided. Incidence of treatment-emergent ADA response will be assessed as absolute occurrence 
(N) and percent of patients (%), grouped by study cohorts. 
The influence of ADAs on drug concentrations will be evaluated.  Assessment of impact of ADAs 
on safety and efficacy may be provided. 
10.5. 
Interim Analysis  
An interim analysis may be performed after 50% patients have completed the 16-week treatment 
period in order to assess peripheral nerve safety data for regulatory purposes. 
10.6. 
Additional Statistical Data Handling Conventions 
The following analysis and data conventions will be followed: 
General rules for handling missing data:  
 Rules for handling missing data for efficacy assessments due to missing individual item 
data will follow each questionnaire’s instrument manual. 
 If the start date of an AE or concomitant medication is incomplete or missing, it will 
be assumed to have occurred on or after the intake of study medication, except if an 
incomplete date (eg, month and year) clearly indicates that the event started prior to 
treatment.  If the partial date indicates the same month or year of the intake of study 
medication date, then the start date by the study medication intake date will be imputed; 
otherwise, the missing day or month by the first day or the first month will be imputed.  
 No imputations for missing laboratory data, ECG data, vital sign data, or physical 
examination data will be made. 
Visit windows: 
 Assessments taken outside of protocol allowable windows will be displayed according 
to the CRF assessment recorded by the investigator. 
Unscheduled assessments: 
 Extra assessments (laboratory data or vital signs associated with nonprotocol clinical 
visits or obtained in the course of investigating or managing AEs) will be included in 
listings, but not summaries.  If more than 1 laboratory value is available for a given 
visit, the first observation will be used in summaries and all observations will be 
presented in listings. 
10.7. 
Statistical Considerations Surrounding the Premature Termination 
of a Study 
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized.  Investigator and sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 16.1. 
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11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
11.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation, cleaning, correcting, releasing) will be maintained and stored at Regeneron. 
A medical coding plan will specify the processes and the dictionary used for coding. All data 
coding (eg, AEs, baseline findings, medication, medical history, surgical history) will be done 
using internationally recognized and accepted dictionaries. 
The eCRF data for this study will be collected with an electronic data capture (EDC) tool, Rave 
Medidata. 
11.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
 IWRS system – randomization and study drug supply 
 Rave Medidata EDC system – clinical data capture 
 Statistical Analysis System – statistical review and analysis 
 Argus - pharmacovigilance and clinical safety software system for the collection and 
reporting of SAEs and AESIs 
 Electronic Clinical Outcome Assessment systems – collected patient-reported or 
patient clinical assessment results 
 RAVE Medidata Imaging System - electronic platform used to upload nerve 
conduction test wave forms for central reader review 
12. 
STUDY MONITORING  
12.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, CRO monitor) will visit each site prior to enrollment of 
the first patient, and periodically during the study. 
The investigator must allow study-related monitoring. 
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements. 
12.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). 
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The investigator must keep all source documents on file with the CRF (throughout this protocol, 
CRF refers to either a paper CRF or an electronic CRF). Case report forms and source documents 
must be available at all times for inspection by authorized representatives of the sponsor and 
regulatory authorities. 
12.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic CRFs within 
the EDC system by trained site personnel. All required CRFs must be completed for each patient 
enrolled in the study. After review of the clinical data for each patient, the investigator must 
provide an electronic signature. A copy of each patient CRF casebook is to be retained by the 
investigator as part of the study record and must be available at all times for inspection by 
authorized representatives of the sponsor and regulatory authorities. 
The investigator must ensure the accuracy, completeness, and timeliness of the data reported to 
the sponsor in the CRFs.  
Corrections to the CRF will be entered in the CRF by the investigator or an authorized designee.  
All changes, including date and person performing corrections, will be available via the audit trail, 
which is part of the EDC system. For corrections made via data queries, a reason for any alteration 
must be provided. 
13. 
AUDITS AND INSPECTIONS  
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities.  Should this occur, the investigator is responsible for: 
 Informing the sponsor of a planned inspection by the authorities as soon as notification 
is received, and authorizing the sponsor’s participation in the inspection 
 Providing access to all necessary facilities, study data, and documents for the inspection 
or audit 
 Communicating any information arising from inspection by the regulatory authorities 
to the sponsor immediately 
 Taking all appropriate measures requested by the sponsor to resolve the problems found 
during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, CRFs, 
medical records, correspondence, ICFs, IRB or EC files, documentation of certification and quality 
control of supporting laboratories, and records relevant to the study maintained in any supporting 
pharmacy facilities.  Conditions of study material storage are also subject to inspection.  In 
addition, representatives of the sponsor may observe the conduct of any aspect of the clinical study 
or its supporting activities both within and outside of the investigator's institution. 
In all instances, the confidentiality of the data must be respected. 
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14. 
ETHICAL AND REGULATORY CONSIDERATIONS  
14.1. 
Good Clinical Practice Statement  
It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory 
requirements. 
14.2. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB or EC.  A copy of the IRB- or EC-approved ICF and 
documentation of approval must be provided to the sponsor before study drug will be shipped to 
the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient prior to his/her participation in the study and after the 
aims, methods, objectives, and potential hazards of the study have been explained to the patient in 
language that he/she can understand.  The ICF should be signed and dated by the patient and by 
the investigator or authorized designee who reviewed the ICF with the patient. 
 Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF 
 Patients who can understand but who can neither write nor read will have the ICF read 
to them in presence of an impartial witness, who will sign and date the ICF to confirm 
that informed consent was given 
The original ICF must be retained by the investigator as part of the patient's study record, and a 
copy of the signed ICF must be given to the patient. 
If new safety information results in significant changes in the risk/benefit assessment, the ICF must 
be reviewed and updated appropriately.  All study patients must be informed of the new 
information and provide their written consent if they wish to continue in the study. The original 
signed revised ICF must be maintained in the patient’s study record and a copy must be given to 
the patient. 
14.3. 
Patient Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained. Patients should be identified by their patient identification number, 
only, on CRFs or other documents submitted to the sponsor. Documents that will not be submitted 
to the sponsor (eg, signed ICF) must be kept in strict confidence. 
The patient's identifiers and investigator's personal data, which may be included in the sponsor 
database, will be treated in compliance with all applicable laws and regulations. The sponsor shall 
take all appropriate measures to safeguard and prevent access to this data by any unauthorized 
third party. 
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14.4. 
Institutional Review Board/Ethics Committee  
An appropriately constituted IRB or EC, as described in ICH guidelines for GCP, must review and 
approve: 
 The protocol, ICF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
 Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patients, in 
which case the IRB or EC should be informed as soon as possible  
 Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
In addition, the IRB or EC should be informed of any event likely to affect the safety of patients 
or the continued conduct of the clinical study. 
A copy of the IRB- or EC-approval letter with a current list of the IRB or EC members and their 
functions must be received by the sponsor prior to shipment of drug supplies to the investigator.  
The approval letter should include the study number and title, the documents reviewed, and the 
date of the review. 
Records of the IRB or EC review and approval of all study documents (including approval of 
ongoing studies) must be kept on file by the investigator. 
14.5. 
Clinical Study Data Transparency 
Final study results will be published on a public clinical trial website according to applicable local 
guidelines and regulations.  Treatment codes will be disseminated to each investigation site 
thereafter. 
15. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an IRB- or 
EC-approved amendment. Regulatory approval will also be obtained where required by local 
regulations. 
16. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
16.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely. Reasons may include efficacy, safety, 
or futility, among others. Should the sponsor decide to terminate the study, the investigator(s) will 
be notified in writing. 
16.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
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Investigator’s Decision 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at least 
30 days’ notice.  The final decision should be made through mutual agreement with the sponsor.  
Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing.  
Reasons may include the following, among others:  
 The investigator has received all items and information necessary to perform the study, 
but has not enrolled any patient within a reasonable period of time 
 The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines  
 The total number of patients required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB or EC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection of 
the patients’ interests. 
17. 
STUDY DOCUMENTATION 
17.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the eCRF must be signed 
electronically by the investigator. This signed declaration accompanies each set of patient final 
eCRF that will be provided to the sponsor. 
17.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of CRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
regulatory authorities.  The investigator must obtain written approval from the sponsor before 
discarding or destroying any essential study documents during the retention period following study 
completion or discontinuation.  Records must be destroyed in a manner that ensures 
confidentiality. 
If the investigator's personal situation is such that archiving can no longer be ensured, the 
investigator must inform the sponsor (written notification) and the relevant records will be 
transferred to a mutually agreed-upon destination.  
18. 
DATA QUALITY ASSURANCE  
In accordance with ICH E6, the sponsor is responsible for quality assurance to ensure that the 
study is conducted and the data generated, recorded, and reported in compliance with the protocol, 
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GCP, and any applicable regulatory requirement(s).  The planned quality assurance and quality 
control procedures for the study are summarized.  
Data Management 
The sponsor is responsible for the data management of this study including quality checking of the 
data (Section 11.1). 
Study Monitoring 
The investigator must allow study-related monitoring, IRB/EC review, audits, and inspections 
from relevant health regulatory authorities, and provide direct access to source data documents 
(Section 12.1, Section 12.2, and Section 13). 
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements (Section 12.1). 
All patient data collected during the study will be recorded on paper or electronic CRF unless the 
data are transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator 
is responsible for affirming that data entries in the CRF are accurate and correct by electronically 
signing a declaration that accompanies each set of patient final CRF (Section 12.3, Section 17.1).  
Study Documentation 
The investigator must maintain accurate documentation (source data) that supports the information 
entered in the CRF (Section 12.2).  
The investigator will retain all records and documents, including signed ICFs, pertaining to the 
conduct of this study for at least 15 years after study completion, unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor (Section 17.2).  
19. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
20. 
FINANCING AND INSURANCE  
Financing and insurance information is provided as a separate agreement. 
21. 
PUBLICATION POLICY  
The publication policy is provided as a separate agreement. 
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23. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol, entitled “A Randomized, Double-Blind, Placebo-Controlled, 
Multicenter Study to Evaluate the Effects of Fasinumab on Peripheral Nerve Function in Patients 
with Pain due to Osteoarthritis of the Knee or Hip,” dated as noted in the appended signature page, 
and agree to abide by all provisions set forth therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, state, 
or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor or a partnership 
in which the sponsor is involved.  I will immediately disclose it in writing to the sponsor if any 
person who is involved in the study is debarred, or if any proceeding for debarment is pending, or, 
to the best of my knowledge, threatened. 
This document contains confidential information of the sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the Institutional Review Board or Ethics 
Committee.  I agree to ensure that this information will not be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of the sponsor. 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
 
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SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Medical/Study Director, Regulatory Representative, Clinical Study Team Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the conduct of the study. 
Study Title: 
A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to 
Evaluate the Effects of Fasinumab on Peripheral Nerve Function in Patients 
with Pain Due to Osteoarthritis of the Hip or Knee  
Protocol Number: 
R475-OA-1758 
Protocol Version: 
R475-OA-1758 Amendment 2 
 
See appended electronic signature page 
Sponsor’s Responsible Medical/Study Director 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Liaison 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Team Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
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Signature Page for VV-RIM-00063020 v2.0
Signature Page for VV-RIM-00063020 v2.0 Approved
ESig Approval
00
ESig Approval
-2019 17:04:45 GMT+0000
ESig Approval
-2019 17:53:27 GMT+0000
ESig Approval
19 19:09:00 GMT+0000
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SAP_001.pdf: 
Global Development 
Biostatistics and Data Management 
CONFIDENTIAL 
Page 1 of 66 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
28MAY2020 
STATISTICAL ANALYSIS PLAN 
VERSION: FINAL 
Clinical Study Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled, 
Multicenter Study to Evaluate the Effects of 
Fasinumab on Peripheral Nerve Function in Patients 
with Pain due to Osteoarthritis of the Hip or Knee 
Compound: 
Fasinumab 
Protocol Number: 
R475-OA-1758 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician (SB): 
 
Clinical Trial Manager (CTM): 
 
Medical Director (MD): 
 
Version/Date: 
Original Statistical Analysis Plan/ 28MAY2020
VV-RIM-00113088-1.0 Approved - 04 Jun 2020 GMT-5:00
NCT03691974


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R475-OA-1758 
Statistical Analysis Plan 
Date: 28MAY2020 
 
CONFIDENTIAL 
Page 2 of 66 
The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
 
See appended electronic signature page 
Study Biostatistician 
 
 
See appended electronic signature page 
Study Pharmacokinetics 
 
 
See appended electronic signature page 
Study Bioanalytical Sciences 
 
See appended electronic signature page 
Study Medical Director 
 
See appended electronic signature page 
Project Biostatistician
 
See appended electronic signature page 
Head of BDM or designee
 
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Protocol: R475-OA-1758 
Statistical Analysis Plan 
Date: 28MAY2020 
 
CONFIDENTIAL 
Page 3 of 66 
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................5 
LIST OF FIGURES .........................................................................................................................6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................7 
1. 
OVERVIEW .................................................................................................................9 
1.1. 
Background/Rationale ..................................................................................................9 
1.2. 
Study Objectives ...........................................................................................................9 
1.2.1. 
Primary Objectives .......................................................................................................9 
1.2.2. 
Secondary Objectives ...................................................................................................9 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol ................................10 
1.2.4. 
Revision History for SAP Amendments .....................................................................10 
2. 
INVESTIGATION PLAN ..........................................................................................11 
2.1. 
Study Design and Randomization ..............................................................................11 
2.2. 
Sample Size and Power Considerations .....................................................................11 
2.3. 
Study Plan ...................................................................................................................12 
3. 
ANALYSIS POPULATIONS ....................................................................................13 
3.1. 
Full Analysis Set .........................................................................................................13 
3.2. 
Safety Analysis Set .....................................................................................................13 
3.3. 
Pharmacokinetic Analysis Set ....................................................................................13 
3.4. 
Anti-Drug Antibody Analysis Set ..............................................................................13 
4. 
ANALYSIS VARIABLES .........................................................................................14 
4.1. 
Demographic and Baseline Characteristics ................................................................14 
4.2. 
Medical History ..........................................................................................................14 
4.3. 
Prior/Concomitant Medications and Procedures, Prohibited Medications .................15 
4.4. 
Prohibited Medication ................................................................................................15 
4.5. 
Efficacy Variables ......................................................................................................16 
4.6. 
Safety Variables ..........................................................................................................16 
4.6.1. 
Primary Safety Variables ............................................................................................17 
4.6.2. 
Additional Safety Variables ........................................................................................17 
4.6.3. 
Adverse Events and Serious Adverse Events .............................................................17 
4.6.4. 
Adverse Events of Special Interest .............................................................................18 
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Protocol: R475-OA-1758 
Statistical Analysis Plan 
Date: 28MAY2020 
 
CONFIDENTIAL 
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4.6.5. 
Laboratory Safety Variables .......................................................................................18 
4.6.6. 
Vital Signs ..................................................................................................................19 
4.6.7. 
Orthostatic Hypotension .............................................................................................19 
4.6.8. 
12-Lead Electrocardiography .....................................................................................20 
4.6.9. 
Physical and Neurological Examination Variables ....................................................20 
4.6.10. 
Biomarker variables ....................................................................................................20 
4.6.11. 
Other Safety Variables ................................................................................................20 
4.7. 
Pharmacokinetic Variables .........................................................................................21 
4.8. 
Anti-Drug Antibody Variables ...................................................................................22 
5. 
STATISTICAL METHODS .......................................................................................23 
5.1. 
Demographics and Baseline Characteristics ...............................................................23 
5.2. 
Medical History ..........................................................................................................23 
5.3. 
Prior/Concomitant Medications ..................................................................................23 
5.4. 
Prohibited Medications ...............................................................................................24 
5.5. 
Subject Disposition .....................................................................................................24 
5.5.1. 
Screening Disposition .................................................................................................25 
5.5.2. 
Treatment and Study Disposition ...............................................................................25 
5.6. 
Extent of Study Treatment Exposure and Compliance ...............................................26 
5.6.1. 
Treatment Compliance ................................................................................................26 
5.6.2. 
Treatment Exposure ....................................................................................................26 
5.6.3. 
Length of Study Observation/Participation ................................................................27 
5.6.4. 
Protocol Deviations ....................................................................................................27 
5.7. 
Analysis of Efficacy Data ...........................................................................................27 
5.7.1. 
Efficacy Analysis ........................................................................................................27 
5.7.2. 
Subgroup Analysis ......................................................................................................29 
5.7.3. 
Analysis of Other Efficacy Variables .........................................................................30 
5.8. 
Analysis of Safety Data ..............................................................................................30 
5.8.1. 
Primary Safety Analysis .............................................................................................31 
5.8.2. 
Adverse Events ...........................................................................................................32 
5.8.3. 
Adverse Events of Special Interest .............................................................................34 
5.8.4. 
Clinical Laboratory Measurements.............................................................................35 
5.8.5. 
Analysis of Vital Signs ...............................................................................................35 
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Protocol: R475-OA-1758 
Statistical Analysis Plan 
Date: 28MAY2020 
 
CONFIDENTIAL 
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5.8.6. 
Analysis of 12-Lead Electrocardiography ..................................................................36 
5.8.7. 
Physical and Neurological Examinations ...................................................................36 
5.8.8. 
Joint Pain Questionnaire .............................................................................................36 
5.8.9. 
Analysis of Other Safety Variables ............................................................................36 
5.9. 
Analysis of Pharmacokinetics and Drug Concentration Data ....................................37 
5.10. 
Analysis of Immunogenicity Data ..............................................................................37 
5.10.1. 
Analysis of Anti-Drug Antibody Data ........................................................................37 
5.10.2. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................39 
5.10.2.1. 
Immunogenicity and Exposure ...................................................................................39 
5.10.2.2. 
Immunogenicity and Safety and Efficacy ...................................................................39 
6. 
DATA CONVENTIONS ............................................................................................41 
6.1. 
Definition of Baseline for Variables ...........................................................................41 
6.2. 
Data Handling Conventions for Efficacy Data ...........................................................41 
6.3. 
Data Handling Convention for Repeat Data ...............................................................41 
6.4. 
Data Handling Convention for Missing Data .............................................................42 
6.5. 
Visit Windows ............................................................................................................44 
6.6. 
Nerve Conduct Test Analysis Windows .....................................................................45 
6.7. 
Unscheduled Assessments ..........................................................................................45 
7. 
INTERIM ANALYSES ..............................................................................................47 
8. 
SOFTWARE ...............................................................................................................48 
9. 
REFERENCES ...........................................................................................................49 
10. 
APPENDIX.................................................................................................................50 
10.1. 
Schedule of Events .....................................................................................................50 
10.2. 
Reference for Criteria for Treatment-Emergent Potentially Clinically 
Significant Values (PCSV) .........................................................................................56 
10.3. 
OMERACT-OARSI set of responder criteria .............................................................66 
 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................50 
Table 2: 
Follow-up Period for Patients Undergoing Joint Replacement Surgery on 
Study ...........................................................................................................................55 
Table 3: 
Criteria for Treatment-Emergent Potentially Clinically Significant Values 
(PCSV) ........................................................................................................................56 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R475-OA-1758 
Statistical Analysis Plan 
Date: 28MAY2020 
 
CONFIDENTIAL 
Page 6 of 66 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................11 
 
 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R475-OA-1758 
Statistical Analysis Plan 
Date: 28MAY2020 
 
CONFIDENTIAL 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
5-ASA 
5-aminosalicylic acid 
AA 
Adjudicated arthropathy 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
Cmax 
Maximum observed drug concentration 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
Ctrough 
Concentration measured at the end of a dosing interval at steady 
state (taken directly before next administration) 
DA  
Destructive arthropathy 
ECG 
Electrocardiogram 
EOS 
End of study 
EOT 
End of treatment 
ESR 
 
Erythrocyte sedimentation rate 
ET 
Early termination 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
HbA1c 
Glycated hemoglobin 
hs-CRP 
High-sensitivity C-reactive protein 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
JR 
Joint replacement 
K-L 
Kellgren-Lawrence  
LLN 
Lower limit of normal 
LLOQ 
Lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
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Protocol: R475-OA-1758 
Statistical Analysis Plan 
Date: 28MAY2020 
 
CONFIDENTIAL 
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MMRM 
Mixed-effect model repeated measure 
MRI 
Magnetic resonance imaging 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
OA 
Osteoarthritis 
OMERACT-OARSI 
Osteoarthritis Research Society International Standing Committee 
for Clinical Trials Response Criteria Initiative and The Outcome 
Measure in Rheumatology 
PCSA 
Potentially clinically significant abnormalities 
PCSV 
Potentially clinically significant value 
PK 
Pharmacokinetic 
PT 
Preferred term 
Q4W 
Every 4 weeks 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SD 
Standard deviation 
SNS 
Sympathetic Nervous System 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WHODD 
WHO Drug Dictionary 
WOCBP 
Women of childbearing potential 
WOMAC 
Western Ontario and McMaster Universities Osteoarthritis Index 
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Protocol: R475-OA-1758 
Statistical Analysis Plan 
Date: 28MAY2020 
CONFIDENTIAL 
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1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study results 
by pre-specifying the statistical approaches for the analysis of study data prior to database lock. 
The SAP is intended to be a comprehensive and detailed description of the strategy and statistical 
methods to be used in the analysis of data for study R475-OA-1758. 
This plan may be revised during the study to accommodate protocol amendments and/or to make 
changes to adapt to unexpected issues in study execution and/or data that affect planned 
analyses. These revisions will be based on blinded review of the study and data, and a final plan 
will be issued prior to the first step database lock and before unblinding of the study. 
1.1. 
Background/Rationale 
This is a phase 2, randomized, double-blind, placebo-controlled, multicenter study designed to 
evaluate the neurological safety and efficacy of fasinumab compared to placebo in patients with 
pain due to Osteoarthritis (OA) of the hip or knee who have a history of inadequate pain relief 
for their OA pain from acetaminophen/paracetamol and a history of intolerance to or inadequate 
pain relief from oral Non-steroidal anti-inflammatory drugs (NSAIDs) and opioids (or are 
unwilling to take opioids) for OA pain management. This study will evaluate the neurological 
safety of fasinumab compared to placebo in OA patients treated for up to 16 weeks by measuring 
nerve conduction velocities and evoked amplitudes of the peroneal, ulnar, and sural nerves. This 
study will also provide additional safety, tolerability, efficacy, pharmacokinetic (PK), and 
immunogenicity data for fasinumab. 
The target study population was chosen because they currently have unmet medical needs with 
respect to unacceptable pain control, in spite of the availability of current analgesic treatment 
options. 
1.2. 
Study Objectives 
1.2.1. 
Primary Objectives 
The primary objective of the study is to evaluate the effect of fasinumab compared to placebo on 
peripheral nerves in patients with pain due to OA of the hip or knee. 
1.2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To evaluate the efficacy of fasinumab compared to placebo in patients with pain due 
to OA of the hip or knee  
• To evaluate the safety and tolerability of fasinumab compared to placebo in patients 
with pain due to OA of the hip or knee 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R475-OA-1758 
Statistical Analysis Plan 
Date: 28MAY2020 
CONFIDENTIAL 
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• To characterize the concentrations of fasinumab in serum in patients with pain due to 
OA of the hip or knee  
• To evaluate the immunogenicity of fasinumab in patients with pain due to OA of the 
hip or knee 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol 
This SAP is based on Protocol R475-OA-1758 Amendment 2. 
1.2.4. 
Revision History for SAP Amendments 
N/A.  
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Protocol: R475-OA-1758 
Statistical Analysis Plan 
Date: 28MAY2020 
CONFIDENTIAL 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
This is a Phase 2, randomized, double-blind, placebo-controlled, multicenter study designed to 
evaluate the neurological safety of fasinumab compared to placebo in patients with pain due to 
OA of the hip or knee. In addition, the safety, efficacy, PK, and immunogenicity of fasinumab 
compared to placebo will be assessed. 
The study duration will be approximately 64 weeks starting at randomization (day 1). The study 
consists of a screening period of up to 30 days (Screening Period), followed by a 7 to 10 day pre-
randomization period (Pre-Randomization Period), a 16-week randomized, double-blind, 
placebo-controlled treatment period (Treatment Period), a 20-week follow-up period, and an end 
of study (EOS) phone contact at 52 weeks following the last dose of study drug. See Figure 1 for 
the Study Flow Diagram. 
Figure 1: 
Study Flow Diagram 
 
Approximately 180 patients (90 patients per treatment group) will be recruited and randomized 
in a 1:1 ratio to the following treatment groups: 
• Fasinumab 1 mg Subcutaneous (SC) Q4W 
• Fasinumab-matching placebo SC Q4W 
Randomization is stratified by the affected index joint (hip or knee) and by the Kellgren-
Lawrence (K-L) score (2 to 3, or 4) at the screening visit. 
2.2. 
Sample Size and Power Considerations 
Approximately 180 patients will be randomized in a 1:1 ratio to fasinumab 1 mg Q4W or 
placebo. With this sample size, the precision of the estimated treatment difference between 
fasinumab and placebo at week 16 in nerve conduction velocity is no more than 1.21 m/s with a 
95% confidence level, assuming a standard deviation (SD) of 3.6 m/s. This sample size provides 
similar precision for the estimated treatment difference in nerve conduction amplitude assuming 
Screening and 
Pre-randomization 
Treatment 
Follow-up 
EOS Phone 
Contact 
Up to 40 days 
Day 1 to Week 16 
Week 17 to 36 
Up to Week 64 
 
Randomization 
 
End of 
Treatment  
End of 
Follow-up 
 
 
 
 
 
Screening 
Pre-randomization 
 
 
 
 
Up to 30 days 
7 to 10 days 
Baseline  
Day 1 
 
Week 16 
Week 36 
Week 64 
 
EOS- End of study 
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Protocol: R475-OA-1758 
Statistical Analysis Plan 
Date: 28MAY2020 
CONFIDENTIAL 
Page 12 of 66 
a SD of 3.6 μV. Assuming a 2-sided alpha level of 0.05 and a 15% dropout rate up to week 16, 
an enrollment of 90 patients per group will provide at least 80% power to detect an effect size of 
0.46 in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain 
and physical function subscale scores (ie, absolute treatment difference of 1.1 between 
fasinumab and placebo with an SD of 2.4). The assumed treatment difference and SD are based 
on results from study R475-PN-1227. 
2.3. 
Study Plan 
The Schedule of Events table is presented in Appendix 10.1. 
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Protocol: R475-OA-1758 
Statistical Analysis Plan 
Date: 28MAY2020 
CONFIDENTIAL 
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3. 
ANALYSIS POPULATIONS  
In accordance with guidance from the International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (ICH, 1998), the following population of analysis will be 
used for all statistical analysis: 
3.1. 
Full Analysis Set 
The full analysis set (FAS) includes all randomized patients and is based on the treatment 
allocated (as randomized). Efficacy endpoints will be analyzed using the FAS. 
3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized patients who received any study drug; it is 
based on the treatment received (as treated). Treatment compliance/administration and all 
clinical safety variables will be analyzed using the SAF. 
3.3. 
Pharmacokinetic Analysis Set 
The PK analysis set includes all treated patients who received any study drug and who had at 
least 1 non-missing drug concentration result following the first dose of study drug. 
3.4. 
Anti-Drug Antibody Analysis Set 
The anti-drug antibody (ADA) analysis set includes all treated patients who received any study 
drug and had at least 1 qualified (non-missing) ADA result following the first dose of study drug. 
Patients will be analyzed according to the treatment actually received. 
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Protocol: R475-OA-1758 
Statistical Analysis Plan 
Date: 28MAY2020 
CONFIDENTIAL 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (e.g., age, sex, race, ethnicity, weight, 
height, etc.), disease characteristics including index joint, K-L score, WOMAC pain subscale 
score at screening, medical history, and medication history for each patient. 
The following demographic and baseline characteristic variables will be summarized by 
treatment group: 
• Age at screening (years) 
• Age category (<65, 65-74, >=75 years) 
• Sex (Male, Female) 
• Race (American Indian/Alaskan Native, Asian, Black/African American, Native 
Hawaiian/Other Pacific Islander, White, and Other) 
• Ethnicity (Hispanic/Latino: Yes, No, Not Reported, and Unknown) 
• Baseline Weight (kg) 
• Baseline Height (cm) 
• Baseline Body mass index (BMI) calculated from weight and height 
• Index Joint (Knee or Hip) per IWRS 
• K-L score (2, 3, 4) for the Index Joint 
• K-L score for all Knees and Hips and severity for shoulders 
• WOMAC pain score of the index joint at screening 
• Duration of OA at baseline 
• History of analgesic intolerance and inadequate pain relief 
• Baseline nerve conduction variables measures 
4.2. 
Medical History  
Medical history will be coded to a Preferred Term (PT) and associated primary System Organ 
Class (SOC) according to the latest available version of Medical Dictionary for Regulatory 
Activities (MedDRA®). 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R475-OA-1758 
Statistical Analysis Plan 
Date: 28MAY2020 
CONFIDENTIAL 
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4.3. 
Prior/Concomitant Medications and Procedures, Prohibited 
Medications 
Medications/Procedures will be recorded from the day of informed consent until the end of 
follow-up period. Medications will be coded to the Anatomical Therapeutic Chemical (ATC) 
level 2 (therapeutic main group) and ATC level 4 (chemical/therapeutic subgroup), according to 
the latest available version of WHO Drug Dictionary (WHODD). Patients will be counted once 
in all ATC categories linked to the medication. 
Medication/Procedure Classifications 
Prior medications/procedures are defined as medications/procedures starting prior to the first 
dose of study drug. 
Concomitant medications/procedures are defined as medications/procedures starting prior to or 
during treatment period (as defined in Section 5.8) and ending during or after the treatment 
period. 
Post treatment medications/procedures are medications/procedures starting after the treatment 
period (as defined in Section 5.8). 
4.4. 
Prohibited Medication 
Patients will be required to discontinue all non-study pain medication (oral or topical; except up 
to 150 mg/day of aspirin/5-aminosalicylic acid [5-ASA], which is permitted for cardiac 
prophylaxis, per local guidelines), starting at the pre-randomization visit and through the 
treatment period. 
Opioid analgesic medications (including tramadol) are prohibited through the week 16 study 
visit. Patients will be directed not to take concomitant medications that contain NSAIDs (oral or 
topical, except up to 150 mg/day of aspirin, which is permitted for cardiac prophylaxis) until at 
least 16 weeks after the last study drug injection. 
Other prohibited medications during the treatment period include: 
• Any other investigational agent 
• Medical or regular recreational use of marijuana 
• Chondroitin sulfate  
• Glucosamine  
• Hyaluronic Acid Intra-articular Injections 
• Muscle relaxants including cyclobenzaprine, carisoprodol, orphenadrine, tizanidine 
(see protocol Section 7.7.2 for permitted muscle relaxants) 
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Protocol: R475-OA-1758 
Statistical Analysis Plan 
Date: 28MAY2020 
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• Corticosteroids (topical, intranasal, and inhaled formulations are permitted), 
adrenocorticotropic hormone 
• Cyclosporine, methotrexate, mycophenolate mofetil, tacrolimus 
• Azathioprine, sulfasalazine, hydroxychloroquine 
• Interleukin -6 or interleukin-6 receptor antagonists 
• Abatacept, ustekinumab  
• Tumor necrosis factor antagonists 
• IL-1 inhibitors, including diacerein  
• Apremilast, and tofacitinib 
The following variables will be summarized for prohibited medications: 
• Number and percentage of patients using at least one prohibited medication during 
the treatment period 
• Number and percentage of patients using at least one prohibited medication during 
the follow-up period  
• Number and percentage of patients with at least one prohibited NSAID use during the 
treatment period 
• Number of days patients used prohibited medications during the treatment period 
• Number of days patients used prohibited NSAID during the treatment period 
4.5. 
Efficacy Variables 
The efficacy endpoints are the secondary endpoints of the study: 
• Change from baseline to week 16 in WOMAC pain subscale score 
• Change from baseline to week 16 in WOMAC physical function subscale score 
4.6. 
Safety Variables 
Patient safety will be assessed through the collection of nerve conduction measures (described in 
protocol Section 8.2.3.1), reported adverse events (AEs), clinical laboratory data, vital signs, 
Electrocardiogram (ECG), Survey of Autonomic Symptoms Questionnaire, neurological exams 
and physical exams. Unless otherwise noted, the baseline value is defined as the last available 
value before the first dose of study drug. 
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Protocol: R475-OA-1758 
Statistical Analysis Plan 
Date: 28MAY2020 
CONFIDENTIAL 
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4.6.1. 
Primary Safety Variables 
The primary endpoints of the study are: 
• Change from baseline to week 16 in peroneal motor nerve conduction velocity 
• Change from baseline to week 16 in peroneal motor nerve action potential amplitude 
• Change from baseline to week 16 in sural sensory nerve conduction velocity 
• Change from baseline to week 16 in sural sensory nerve action potential amplitude 
• Change from baseline to week 16 in ulnar sensory nerve conduction velocity 
• Change from baseline to week 16 in ulnar sensory nerve action potential amplitude 
4.6.2. 
Additional Safety Variables 
Additional safety endpoints in this study include:  
• Incidence of Adjudicated arthropathy (AA, as confirmed by an independent 
adjudication committee) through week 36 
• Incidence of Destructive arthropathy (DA, as confirmed by an independent 
adjudication committee) through week 36 
• Incidence of treatment-emergent adverse event (TEAEs) through week 16 
• Incidence of SNS dysfunction (as diagnosed after consultation with an appropriate 
specialist, such as a neurologist and/or cardiologist) through week 36 
• Incidence of peripheral sensory AEs that require a neurology or other specialty 
consultation through week 36 
• Incidence of all-cause JR surgeries week 36  
• Incidence of JRs at telephone survey approximately 52 weeks after last dose of study 
drug 
4.6.3. 
Adverse Events and Serious Adverse Events 
Adverse events (AE) and Serious Adverse Events (SAE) will be collected from the time of 
informed consent signature and then at each visit until the end of follow-up period. All AEs are 
to be coded to a PT and associated primary SOC according to the MedDRA® (the latest current 
available version). 
An AE is any untoward medical occurrence in a patient administered a study drug which may or 
may not have a causal relationship with the study drug. Therefore, an AE is any unfavorable and 
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Protocol: R475-OA-1758 
Statistical Analysis Plan 
Date: 28MAY2020 
CONFIDENTIAL 
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unintended sign (including abnormal laboratory finding), symptom, or disease which is 
temporally associated with the use of a study drug, whether or not considered related to the study 
drug. An AE also includes any worsening (ie, any clinically significant change in frequency 
and/or intensity) of a pre-existing condition that is temporally associated with the use of the 
study drug. 
A SAE is an AE that is classified as serious according to the criteria specified in the protocol. 
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE include:  
• the test result is associated with accompanying symptoms, and/or 
• the test result requires diagnostic testing and medical/surgical intervention, and/or 
• the test result leads to a change in dosing (outside of protocol-stipulated dose 
adjustments), discontinuation from study, significant additional concomitant drug 
treatment, or other therapy. 
4.6.4. 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) are AEs (serious or non-serious) required to be 
monitored, documented, and managed in a pre-specified manner as described in the protocol. In 
this study, the AESI are listed below (as provided in the protocol): 
• Adjudicated Arthropathy (as confirmed by adjudication) selected using an eCRF specific 
tick box on the AE page. 
• Sympathetic nervous system dysfunction (as diagnosed after consultation with an 
appropriate specialist, such as a neurologist and/or a cardiologist) selected using an eCRF 
specific tick box on the AE page. 
• Peripheral sensory AEs that require a neurology or other specialty consultation selected 
using an eCRF specific tick box on the AE page. 
• Joint replacement surgery (defined as elective joint replacement surgery not due to new or 
worsening AE) using eCRF specific tick box on the AE page. 
4.6.5. 
Laboratory Safety Variables 
The clinical laboratory data consists of serum chemistry, hematology, urinalysis and urine 
electrolytes. Samples for laboratory testing will be collected at the time points specified in the 
Schedule of Events (Appendix 10.1).  
Clinical laboratory values will be in standard international (SI) units, including associated 
normal ranges provided by the central laboratory, and grouped by function in summary tables. 
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Protocol: R475-OA-1758 
Statistical Analysis Plan 
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Clinical laboratory values in conventional (US) units will also be available in the database, with 
associated normal ranges.  
Both actual test values and “change from baseline” values (defined as the post-baseline value 
minus the baseline value) will be used in central lab result summaries. Potentially clinically 
significant values (PCSV) ranges will be applied to central lab test values as applicable (see 
Appendix 10.2 for PCSV definitions).  
4.6.6. 
Vital Signs 
The following vital signs parameters will be collected according to the Schedule of Events in 
Appendix 10.1:  
• Body temperature (oC) 
• Supine/standing systolic and diastolic blood pressures (mmHg) and pulse (bpm) 
• Respiratory rate (breaths per minute) 
Both actual values and “change from baseline” values (defined as the post-baseline value minus 
the baseline value) will be used in the result summaries. PCSV ranges will be applied to the vital 
sign parameter values as applicable (see Appendix 10.2 for PCSV definitions). 
4.6.7. 
Orthostatic Hypotension 
A patient will be determined to have orthostatic hypotension if any of the following criteria are 
met: 
• If the supine blood pressure is <160 mmHg systolic, a decrease in either the 1 or 
3 minute standing systolic blood pressure of ≥20 mmHg or a decrease in the standing 
diastolic blood pressure of ≥10 mmHg from the supine systolic or diastolic blood 
pressure 
OR 
• If the supine blood pressure is ≥160 mmHg systolic, a decrease in either the 1 or 
3 minute standing systolic blood pressure of ≥30 mmHg or a decrease in the standing 
diastolic blood pressure of ≥15 mmHg from the supine systolic or diastolic blood 
pressure 
OR 
• An increase in either the 1 or 3 minute standing heart rate of ≥30 bpm from the supine 
heart rate 
OR 
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• The patient is unable to stand for either one of the standing blood pressure 
measurements due to dizziness or lightheadedness 
Confirmed orthostatic hypotension is defined as initial assessment meeting the above orthostatic 
hypotension criteria confirmed by subsequent repeated assessments per protocol. 
4.6.8. 
12-Lead Electrocardiography 
A standard 12-lead ECG will be performed according to the Schedule of Events in 
Appendix 10.1. Heart rate will be recorded from the ventricular rate, and the PR, QRS, and QT, 
QTc intervals, and ECG status (normal, abnormal not clinical significant or abnormal clinical 
significant) will also be recorded.  
QTcF and QTcB are defined as follows:  
QTcF (ms) =QT/RR1/3 and QTcB (ms) =QT/RR1/2, 
where QT is the uncorrected QT interval measured in ms, and RR is 60/HR with HR being the 
heart rate in beats per minute.  
PCSV ranges will be applied to the ECG parameter values as applicable (see Appendix 10.2 for 
PCSV definitions). 
4.6.9. 
Physical and Neurological Examination Variables 
Patients will have a thorough and complete physical examination including an examination of 
the knees, hips, and shoulders performed according to the Schedule of Events in Appendix 10.1. 
The result for each body system is an outcome of normal or abnormal (clinically significant, or 
not clinically significant). Neurological evaluations will cover the following domains: motor, 
sensory, cranial nerves, reflexes and coordination/balance and assessment for presence/absence 
of signs of carpal tunnel syndrome. The results of each specific domains will be described as 
normal or abnormal (clinically significant, or not clinically significant) with the exception of the 
carpal tunnel evaluation which will be described as present/absent. 
4.6.10. 
Biomarker variables 
Biomarker analysis will be described in a separate biomarker SAP. 
4.6.11. 
Other Safety Variables 
Other safety endpoints include: 
• Survey of Autonomic Symptoms questionnaire:  
− The Survey of Autonomic Dysfunction serves as a monitoring tool throughout the 
study to prompt further evaluation of potential events of sympathetic nervous 
system dysfunction, as deemed necessary at the investigator's discretion. The 
survey asks if patients have a symptom, to what extent they are bothered by it. 
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The extent to which symptoms are bothersome are described in 5 categories (not 
at all, a little, some, moderate, a lot). 
− Summaries will include the number and proportion of patients presenting with 
symptoms at scheduled timepoints by degree of bothersomeness. Change from 
baseline in the degree of bothersomeness of each symptom represented will also 
be presented at scheduled timepoints. Change from baseline in the degree of 
bothersomeness will be described as better, same or worse. 
• Joint Pain Questionnaire:  
− Number of subjects with significantly worse joint pain in any joint at each 
scheduled visit 
− Number of subjects with significantly worse joint pain by joint at each scheduled 
visit 
• Joint space width for the affected joints as well as other knee or hip joints at each 
scheduled visit (taken from bilateral x-rays). 
• All-cause JR:  
− Number and percentage of patients with JR (all-cause JRs) 
− Reason for JR (all-cause JRs) 
− Time to JR (all-cause JRs) 
• Adjudicated Arthropathy (AA): 
− Number and percentage of patients with AA 
− Number and percentage of patients meeting Destructive Arthropathy criteria (DA) 
− Subtypes of AA 
− Time to AA 
− Time to DA 
4.7. 
Pharmacokinetic Variables 
The PK variable will be fasinumab concentrations in serum at specified sampling time points. 
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4.8. 
Anti-Drug Antibody Variables 
The immunogenicity variables are ADA status, titer, at each time-point/visit. Serum samples for 
ADA will be collected at the clinic visits specified in Appendix 10.1. 
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5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following information: the 
number of patients reflected in the calculation (n), mean, median, SD, minimum, 1st & 3rd 
quartiles (Q1 & Q3), and maximum. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
Period of Observation - Unless otherwise stated, analysis of all safety and non-safety variables 
captured at multiple visits will be analyzed by the following observation periods: 
• The Pre-Treatment Period is defined as the time from signing the ICF to before the 
first dose of study drug.  
• The On-Treatment Period is defined as the time from the first dose of study drug up 
to 28 days after the last dose of study drug. 
• The Follow-Up/Post-Treatment Period is defined from the end of the On-Treatment 
Period to the date of the follow-up clinic visit (Week 36 visit) or early termination 
date. 
5.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics described in Section 4.1 will be descriptively 
summarized by treatment group and overall for the study based on FAS. 
5.2. 
Medical History 
All reported patient’s medical history and surgical history will be descriptively summarized by 
primary SOC and PT by treatment group and overall for the FAS. The tables will be sorted by 
decreasing frequency of primary SOC in the fasinumab group. Within each primary SOC, PTs 
will be sorted by decreasing frequency in the fasinumab group. 
5.3. 
Prior/Concomitant Medications 
Prior Medications 
All prior medications, dictionary coded by WHO, will be descriptively summarized by treatment 
group based on the FAS. Summaries will present number and percentage of patients for all prior 
medications, by decreasing frequency of the fasinumab group incidence of ATC followed by 
ATC level 2, ATC level 4 and PT. In case of equal frequency across anatomic or therapeutic 
categories, alphabetical order will be used. Patients will be counted once in each ATC category 
(anatomic or therapeutic) linked to the medication but may be counted several times for the same 
medication. 
Concomitant Medications 
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All concomitant medications, dictionary coded by WHO, will be descriptively summarized by 
treatment group based on the SAF. Summaries will present number and percentage of patients 
for the concomitant medication groups described in Section 4.3 for all concomitant medications, 
by decreasing frequency of the fasinumab group incidence of ATC followed by ATC level 2, 
ATC level 4 and PT. In case of equal frequency across anatomic or therapeutic categories, 
alphabetical order will be used. Patients will be counted once in each ATC category (anatomic or 
therapeutic) linked to the medication, hence may be counted several times for the same 
medication. 
The following will be summarized: 
• Prior Medications 
• Concomitant medications 
• Post-treatment medications 
• On-study (Concomitant + Post-Treatment) Medications 
When medication start/end date is missing, the rules for determining whether a medication is 
prior, concomitant, or post-treatment, are specified in Section 6.3. 
5.4. 
Prohibited Medications 
Number and percentage of patients with prohibited medications will be descriptively 
summarized by treatment group based on the SAF. The tables will be sorted by decreasing 
frequency of ATC Level 2, ATC Level 4, and PT in the fasinumab group. 
The number of patients with NSAIDs use during treatment period will be summarized by 
treatment group based on the SAF. 
Total NSAIDs-use days during each treatment period and follow-up period (before AA for 
patients with AA) will be summarized by treatment group for patients in the SAF. Additionally, 
days from last study drug dose to first NSAID dose will be summarized by treatment group for 
patients in the SAF. 
5.5. 
Subject Disposition 
The disposition of patients in the study will be summarized by treatment group and overall for 
FAS. The following will be provided: 
• The total number of screened patients: signed the Informed consent form (ICF) 
• The total number of randomized patients: received a randomization number 
• The total number of patients in each analysis set  
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• The total number of patients who discontinued the study, and the reasons for 
discontinuation 
• The number of patients who completed study treatment, patients who discontinued 
treatment and reason for treatment discontinuation 
• A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized 
• A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation 
• A listing of patients who withdrew from the study, along with reasons for study 
withdrawal 
5.5.1. 
Screening Disposition 
In the summaries below, percentages will be calculated using the number of screened patients as 
the denominator. Summaries will present the overall frequencies (and percentages as applicable) 
for the following: 
• Screened patients (defined as having signed the ICF). 
• Patients randomized (defined in the protocol as having received a randomization 
number). 
• Patients that did not meet the inclusion/exclusion criterion but were randomized (if 
applicable). 
• Patients treated but not randomized (if applicable). 
• Screen Fail patients: broken out by reason for screen failure. 
Additionally, the following listings will be provided (if applicable):  
• Listing of Patients Treated but not Randomized. 
• Listing of Screening Failures and reasons for all screen failing 
5.5.2. 
Treatment and Study Disposition 
Unless otherwise noted, percentages will be calculated using the number of patients in the FAS 
as the denominator. Summaries will present the frequencies (and percentages as applicable) by 
treatment group for the following: 
• Patients randomized (defined as having received a randomization number). This row 
will reflect the grouping based on randomization assignment. 
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• Patients randomized and treated. 
• Patients randomized but not treated. This row will reflect grouping based on 
randomization assignment. 
• Patients who completed study treatment period.  
• Patients who discontinued treatment, and reason for treatment discontinuation. 
• Patients who completed the study.  
• Patients who withdrew from the study, and reason for study withdrawal. 
A Kaplan-Meier plot of time to treatment/study discontinuation by treatment group will be 
provided. 
5.6. 
Extent of Study Treatment Exposure and Compliance  
The analysis population is based on the SAF. 
5.6.1. 
Treatment Compliance  
Overall treatment compliance to the SC study drug injection is defined as the actual number of 
SC injections divided by the expected number of SC injections during the on-treatment period up 
to treatment discontinuation. It is calculated according to the following formula: 
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑎𝑐𝑡𝑢𝑎𝑙 𝑖𝑛𝑗𝑒𝑐𝑡𝑖𝑜𝑛𝑠 𝑜𝑓 𝑠𝑡𝑢𝑑𝑦 𝑑𝑟𝑢𝑔 𝑟𝑒𝑐𝑒𝑖𝑣𝑒𝑑 𝑑𝑢𝑟𝑖𝑛𝑔 𝑡ℎ𝑒 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑒𝑥𝑝𝑠𝑜𝑢𝑟𝑒 𝑝𝑒𝑟𝑖𝑜𝑑
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑝𝑙𝑎𝑛𝑛𝑒𝑑 𝑖𝑛𝑗𝑒𝑐𝑡𝑖𝑜𝑛𝑠 𝑜𝑓 𝑠𝑡𝑢𝑑𝑦 𝑑𝑟𝑢𝑔 𝑑𝑢𝑟𝑖𝑛𝑔 𝑡ℎ𝑒 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑒𝑥𝑝𝑜𝑠𝑢𝑟𝑒 𝑝𝑒𝑟𝑖𝑜𝑑 𝑜𝑛 𝑜𝑟 
 𝑏𝑒𝑓𝑜𝑟𝑒 𝑡ℎ𝑒 𝑡𝑖𝑚𝑒 𝑡ℎ𝑎𝑡 𝑡ℎ𝑒 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 𝑑𝑖𝑠𝑐𝑜𝑛𝑡𝑖𝑛𝑢𝑒𝑑 𝑓𝑟𝑜𝑚 𝑡ℎ𝑒 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑝ℎ𝑎𝑠𝑒 𝑜𝑓 𝑡ℎ𝑒 𝑠𝑡𝑢𝑑𝑦
 𝑥 100 
The total number of SC injections will be summarized by treatment groups via descriptive 
statistics based on the SAF. A summary of the number (and percentage) of patients categorized 
by the number of SC injections received will also be included. 
5.6.2. 
Treatment Exposure 
The treatment exposure to fasinumab and placebo SC doses will be calculated as:  
• (Date of last administration of study drug - date of the first study drug administration 
after randomization) + 28  
The duration of exposure will be summarized for each treatment group by descriptive statistics. 
The number and percentage of patients randomized and exposed to double-blind study drug will 
be presented by specific time periods for each treatment group. The time periods of interest are 
specified as: ≥ 1 day, ≥ 29 days, ≥ 57 days, ≥ 85 days and ≥ 113 days. 
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5.6.3. 
Length of Study Observation/Participation 
The length of the total study observation period (days) will be calculated as: 
• (Date of last study visit [up to End of Follow-up Visit] – date of first study drug 
administration) +1. 
The length of the total study participation (days) will be calculated as: 
• (Date of the last study visit [up to the EOS Phone Call] – date of the first study drug 
administration) + 1 
The lengths of observations and total study participation will be summarized for each treatment 
group by descriptive statistics based on the SAF. 
The number and percentage of patients with observation and participation periods will be 
presented by specific time periods. The time periods of interest are specified as: ≥ 1 day, 
≥ 29 days, ≥ 57 days, ≥ 85 days, ≥ 113 days, ≥ 183 days, ≥ 253 days, ≥ 449 days. 
5.6.4. 
Protocol Deviations 
All important and minor protocol deviations have been collected and reviewed on an ongoing 
basis throughout the study as described in the Protocol Deviation Plan. 
Protocol deviations will be summarized for patients incurring any important deviation by count 
and percentage, and patients incurring each type of important deviation by count and percentage 
for FAS. 
A patient listing of all important and minor protocol deviations will be provided. 
5.7. 
Analysis of Efficacy Data 
5.7.1. 
Efficacy Analysis 
The secondary efficacy endpoints of the study are: 
• Change from baseline to week 16 in WOMAC pain subscale score 
• Change from baseline to week 16 in WOMAC physical function subscale score 
The following hypotheses will be tested:  
• H0,1: There is no treatment difference between fasinumab 1 mg Q4W and placebo in 
WOMAC pain subscale at week 16 
• H0,2: There is no treatment difference between fasinumab 1 mg Q4W and placebo in 
WOMAC physical function subscale at week 16 
 
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For the above hypotheses, the estimand is the difference in means between each fasinumab 1 mg 
Q4W and placebo in the change from baseline to week 16 in the WOMAC pain and physical 
function scores in the FAS, regardless of whether or not prohibited medication had been taken. 
Any data collected after discontinuing treatment will not be used in the main efficacy analysis, 
but used in a treatment policy sensitivity analysis.  
Each of the secondary efficacy variables will be analyzed using a multiple imputation approach 
with mixed-effect model for repeated measure (MMRM) based on the FAS. For patients who 
permanently discontinued treatment due to lack of efficacy, death or AEs, their missing 
WOMAC subscale scores after discontinuation will be imputed with values centered at the mean 
baseline WOMAC subscale score of the treatment group that patient was randomized to. For 
patients who discontinued treatment due to other reasons, their missing WOMAC subscale 
scores after discontinuation will be imputed under missing-at-random assumption using the 
regression method with adjustment for covariates including treatment group, randomization 
strata (K-L category [2 to 3, or 4] and index joint [knee, hip]) and baseline WOMAC subscale 
score. Intermittently missing WOMAC subscale prior to treatment discontinuation will be 
imputed using Markov Chain Monte Carlo method. 
Missing data up to week 16 will be imputed 50 times to generate 50 complete data sets by using 
the SAS procedure PROC MI following the 3 steps below: 
• Step 1: The monotone missing pattern is induced by Markov Chain Monte Carlo 
(MCMC) method in MI procedure using seed number 4751758. 
• Step 2: The missing WOMAC subscale scores at visits subsequent to treatment 
discontinuation will be imputed using the regression method for the monotone pattern 
with seed number 4751758 and adjustment for covariates including treatment groups, 
randomization strata (K-L category [2 to 3, or 4] and index joint [knee, hip), baseline 
WOMAC subscale score and all WOMAC subscale scores at preceding visits. 
• Step 3: For patients who discontinued treatment due to lack of efficacy or AEs, the 
initially missing and now imputed WOMAC subscale scores at visits subsequent to 
treatment discontinuation will be adjusted to be centered at the mean baseline value 
for that treatment group, i.e., final imputed score = imputed score under MAR – 
(mean change from baseline subscale score at the post-baseline time point for the 
treatment group based on patients on treatment with non-missing data at that time 
point).  
Each imputed data set will be analyzed using the MMRM with terms for baseline WOMAC 
subscale score, randomization strata (K-L category [2 to 3, or 4] and index joint [knee, hip]), 
treatment, visit, and treatment-by-visit interaction as fixed effects. Patients will be included as 
random effects. The MMRM will be fitted using the MIXED procedure in Statistical Analysis 
System (SAS) with an unstructured covariance matrix to model the within-patient errors. The 
denominator degrees of freedom will be estimated using Kenward-Roger’s approximation. In the 
event a model cannot be fitted due to the estimation algorithm failing to converge, the covariance 
matrix for within-patient errors will be modeled by an autoregressive 1 structure, followed by a 
compound symmetry structure if convergence is still not achieved for the prior. 
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The results from the 50 analyses will be combined using Rubin’s formulae (PROC 
MIANALYZE). The least squares means estimates for the mean change from baseline to week 
16, as well as the difference of the estimates between fasinumab and placebo will be provided, 
along with the corresponding standard error, p-value and associated 95% confidence interval. 
Similar estimates at other visits will also be presented. 
The null hypotheses will be rejected when the p-values corresponding to the difference in change 
from baseline to week 16 between fasinumab 1 mg Q4W and placebo is less than the available α0 
= 0.05 for both the WOMAC pain subscale score and physical function subscale score.  
For analysis of categorical variables, eg, proportions of patients with ≥30% or ≥50% 
improvement in the WOMAC pain subscale scores at week 16, the percentage of patients who 
are responders based on the Osteoarthritis Research Society International Standing Committee 
for Clinical Trials Response Criteria Initiative and The Outcome Measure in Rheumatology 
(OMERACT-OARSI) responder criteria (Appendix 10.3), the Cochran Mantel Haenszel 
approach stratified by the randomization strata will be used with missing data considered as non-
response. 
No control for multiplicity will be made for these analyses. Tests for comparing fasinumab 
versus placebo will utilize a nominal 2-sided alpha level of 0.05. 
Cumulative distribution of percent change from baseline in WOMAC pain and physical function 
subscale scores will be presented by treatment group. The cumulative distribution plot displays a 
continuous plot of the percent change from baseline on the X-axis and the percent of patients 
experiencing that change on the Y-axis. Different responder definitions can be identified along 
the cumulative distribution curve. 
Sensitivity Analysis 
Sensitivity analyses will be performed to assess the robustness of the results generated for the 
secondary efficacy variables. 
Analysis of Treatment Policy Estimand  
Sensitivity analysis of treatment policy estimand for the secondary endpoints will be performed 
using similar analysis method as the secondary efficacy analysis. The treatment policy estimand 
is the difference in means between each fasinumab and placebo in the change from baseline to 
week 16 in the WOMAC pain and physical function scores in the FAS, regardless of study 
treatment discontinuation prior to week 16 and regardless of whether or not prohibited 
medication had been taken. Hence, data from all patients, including data collected after 
discontinuing treatment up to week 16 will be used in this sensitivity analysis. Missing WOMAC 
subscale scores up to week 16 will be imputed using the same approach as in Section 5.7.1. 
5.7.2. 
Subgroup Analysis 
Descriptive analyses by treatment group will be performed on both raw and change from 
baseline values for each visit for the WOMAC pain subscale score and physical function 
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subscale scores to summarize the treatment effects across subpopulations defined by the 
following baseline characteristics: 
• K-L category [2 to 3, or 4] 
• Index joint [Knee, Hip] 
• Age group [< 65, 65-74, >=75 ] 
• Sex [Male, Female] 
• Weight group [< Median, ≥ Median] 
• BMI group [≤ Median, > Median] 
Forest plots for the subgroup analysis will be provided. 
5.7.3. 
Analysis of Other Efficacy Variables 
Rescue Medications 
The percentage of patients who use rescue medication between baseline and Week 16 will be 
summarized by the treatment group for FAS.  
Number of days patients used rescue medication during the treatment period (Day 1 to Week 1, 
Week 1 to Week 2, Week 2 to Week 4, Week 4 to Week 8, Week 8 to Week 12, Week 12 to 
Week 16 ...) will be summarized descriptively by treatment group. Weekly average amount of 
rescue medication use will be summarized by treatment group. 
For patients taking rescue medication, weekly average usage of rescue medications (measured in 
mg) is calculated as follows: 
= 𝑇𝑜𝑡𝑎𝑙 𝑎𝑚𝑜𝑢𝑡 𝑜𝑓 𝑟𝑒𝑠𝑐𝑢𝑒 𝑚𝑒𝑑𝑖𝑐𝑎𝑡𝑖𝑜𝑛 𝑢𝑠𝑒𝑑 𝑖𝑛 𝑡ℎ𝑒 𝑠𝑝𝑒𝑐𝑖𝑓𝑖𝑒𝑑 𝑤𝑒𝑒𝑘 (𝑖𝑛 𝑚𝑔)
𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑑𝑖𝑎𝑟𝑦 𝑒𝑛𝑡𝑟𝑖𝑒𝑠 𝑖𝑛 𝑡ℎ𝑒 𝑠𝑝𝑒𝑐𝑖𝑓𝑖𝑒𝑑 𝑤𝑒𝑒𝑘
 
Descriptive statistics of the weekly average usage of rescue medications will be presented by 
treatment group based on the FAS. 
5.8. 
Analysis of Safety Data 
The analysis of safety and tolerability will be performed on the SAF, as defined in Section 3.2. 
The safety analysis will be based on the reported AEs and other safety information (nerve 
conduction measures, clinical laboratory evaluations, vital signs and 12-lead ECG). 
Thresholds for Potential Clinically Significant Values (PCSV) in laboratory variables, vital signs 
and ECG are defined in Section 10.3. 
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The summary of safety results will be presented for each treatment group and by visit where 
applicable. 
Day 1 is the first day of study drug, Day -1 is the day before Day 1, and there is no Day 0. 
The time interval to detect any AEs, including AESIs (except JR identified at the 64-week 
telephone follow-up), or abnormalities is between the first dose of study drug dose up to the end 
of the Follow-Up Period (i.e., week 36/Early Termination). Any study drug-related SAEs 
occurring between the end of Follow-Up clinic visit and the EOS will also be included. Data 
collected outside this interval will be excluded from the descriptive statistics and identification of 
abnormalities for laboratory evaluations, ECGs and vital signs. All post-baseline data during the 
interval will be used in the PCSV analysis including scheduled and unscheduled assessments. 
5.8.1. 
Primary Safety Analysis 
The variables for the evaluation of peripheral nerve function are the change from baseline to 
week 16 (based on central reader assessment) in the amplitude and velocity from the 3 individual 
nerve conduction tests.  
The nerve conduction variables will be analyzed using an MMRM approach based on the safety 
analysis set. The model will include baseline value, randomization strata, treatment, visit, and 
treatment-by-visit interaction. The least-squares mean estimates for the mean change from 
baseline to week 16, as well as the differences of the estimates between fasinumab and placebo, 
with their corresponding standard errors and associated 95% confidence intervals, will be 
provided descriptively. 
No imputation will be made for Nerve Conduction values that were missing as a result of 
technical error, were not performed, or performed outside of scheduled visit windows. For 
measurements recorded as physiologically absent ("No Response", meaning outside detection 
sensitivity of the test), nonzero values were imputed using the 1st percentile of all non-missing 
values across all visits, all patients, and all treatment groups. This will be done to impute the low 
end of the range of detectable values while avoiding undue influence by outliers.  
Data collected after discontinuing treatment up to week 16 will be included and used in the 
primary safety analysis. Any unscheduled repeated NCT tests data outside the window described 
in Section 6.6 will not be used in the primary safety analysis, but used in a sensitivity analysis. 
Sensitivity Analysis 
Sensitivity analyses will be performed to assess the robustness of the results generated for the 
primary safety variables. 
Sensitivity analysis for the primary safety endpoints will be performed using similar analysis 
method as the primary safety analysis. For the unscheduled repeated tests at week 8, week 16 and 
week 36, the window described in Section 6.6 won’t be used. Alternatively, the last test value 
prior to the next scheduled visits will be used in this sensitivity analysis. Missing nerve 
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conduction variables up to week 16 will be imputed using the same approach used in the primary 
analysis. 
5.8.2. 
Adverse Events 
All AEs reported in this study will be coded using the currently available version of MedDRA®. 
Coding will be to lowest level terms. The verbatim text, PT, and SOC will be listed.  
• Pre-Treatment Adverse Events are defined as AEs that developed or worsened during 
the pre-treatment period. 
• Treatment-Emergent Adverse Events (TEAE) are defined as AEs that developed or 
worsened during the On-Treatment Period. 
• Post-Treatment Adverse Events are defined as AEs that developed or worsened more 
than 28 days after the last dose of study drug. 
 
Post treatment AEs and all AEs during the study will be summarized similarly as TEAEs. 
Summaries of TEAEs by treatment group will include: 
• Overview of TEAEs, summarizing number of events, summarizing number and 
percentage of patients within the specified category 
− Total number of TEAEs 
− Total number of Serious TEAEs 
− Total number of AESIs 
− Patients with any TEAEs 
− Patients with any Serious TEAEs 
− Patients with any AESIs 
− Patients with any TEAEs leading to death 
− Patients with any TEAEs leading to withdrawal from study 
− Patients with any TEAEs leading to permanent study treatment discontinuation 
• TEAEs by SOC and PT 
− All TEAEs 
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− TEAEs by severity: mild, moderate or severe 
− TEAEs resulting in permanent study treatment discontinuation 
• Treatment-related TEAEs by SOC and PT 
− All treatment-related TEAEs 
• TEAEs by PT 
− All TEAEs 
− TEAEs resulting in permanent study treatment discontinuation 
• Post-treatment AEs by SOC and PT 
− All post-treatment AEs 
− Post-treatment AEs by severity: mild, moderate or severe 
• Serious TEAEs by SOC and PT 
• Post-treatment Serious AEs by SOC and PT 
• All serious AEs on study by SOC and PT 
• Non-serious TEAEs by SOC and PT 
• Post-treatment non-serious AEs by SOC and PT 
• All non-serious AEs on study by SOC and PT 
• All AEs on study by SOC and PT 
− All AEs 
− All AEs by severity: mild, moderate or severe 
• Death 
Counts will be provided according to treatment group for each PT within each SOC. Percentages 
will be calculated using the number of patients in each treatment group using the respective SAF. 
Primary SOCs will be sorted by decreasing frequency in the fasinumab group. Within each 
primary SOC, PTs will be sorted by decreasing frequency in the fasinumab group. For tables 
presenting severity of events, the worst severity will be chosen for patients with multiple 
instances of the same event. 
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A second type of table with counts of each primary SOC in decreasing order of frequency will be 
provided. A third type of table with counts of each PT in decreasing order of frequency will also 
be provided.  
The following listings will be included: 
• AEs leading to death 
• TEAEs leading to permanent discontinuation from study drug (not applicable to post-
treatment AEs) 
• TEAEs leading to withdrawal from study 
• Patients with Serious TEAEs 
• AESIs 
• Deaths 
• All Joint Replacements 
• All AEs 
•  
5.8.3. 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) include adjudicated arthropathies, AEs confirmed as 
SNS dysfunction as well as peripheral neurosensory events and joint replacements meeting pre-
specified AESI criteria. AESIs will be flagged in the database using predefined tick boxes to 
denote the events.  
Summaries of AESI incidence by treatment group will include: 
• Incidence of adjudicated arthropathy events 
• Incidence of adjudicated arthropathies that meet destructive arthropathy criteria 
• Incidence of joint replacements AESI events 
• Incidence of sympathetic nervous system dysfunction AESI events 
• Incidence of peripheral neurosensory AESI events 
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5.8.4. 
Clinical Laboratory Measurements  
Baseline clinical laboratory analytes and change from baseline in clinical laboratory analytes to 
each scheduled assessment time will be summarized with descriptive statistics for each treatment 
group. 
Listings will be provided with flags indicating the out of laboratory range values. 
A Treatment-Emergent PCSV is a laboratory value that was normal or abnormal but not meeting 
PCSV criteria at Screening and Baseline but became abnormal and met PCSV criteria after 
treatment with study drug. Definition of PCSV is listed in Appendix 10.2. Treatment-Emergent 
PCSVs will be summarized by treatment group. 
For hs-CRP and alkaline phosphatase, plots of means and medians of the observed values and 
change from baseline over time will be presented by treatment group. 
For hs-CRP and alkaline phosphatase, subgroup analysis will be performed for the following: 
• Adjudicated Arthropathy category 1 (patients without / with AA)  
• Adjudicated Arthropathy category 2 (patients without AA, patients with RPOA-1, and 
patients with non-RPOA-1 AA) 
• Destructive Arthropathy category (patients without AA, patients with non-DA AA, 
patients with DA) 
The above laboratory summaries will be constructed for the On-Treatment Periods. Lab data 
collected during the Pre-Treatment and Post-Treatment Periods will be displayed in listings. 
5.8.5. 
Analysis of Vital Signs 
Vital signs (temperature, blood pressure, and respiration rate) will be summarized by baseline 
and change from baseline to each scheduled assessment time with descriptive statistics. 
A treatment-emergent PCSV is a vital sign value that was normal or abnormal but not meeting 
PCSV criteria at Screening and Baseline but became abnormal and met PCSV criteria after 
treatment with study drug. Definitions of PCSV is listed in Section 10.3. Treatment-Emergent 
PCSVs will be summarized by treatment group. 
The incidence of confirmed measurements suggesting orthostatic hypotension will also be 
summarized by treatment group. 
The above vital sign summaries will be constructed for the On-Treatment Period. Vital sign data 
collected during the Pre-Treatment and Post-Treatment Periods will be displayed in listings. 
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5.8.6. 
Analysis of 12-Lead Electrocardiography 
ECG parameters (ventricular rate, Heart Rate, PR interval, QRS interval, QT interval and QTc 
interval) will be summarized by baseline and change from baseline to each scheduled assessment 
time. 
A treatment-emergent PCSV is an ECG value that was normal or abnormal but not meeting 
PCSV criteria at Screening and Baseline but became abnormal and met PCSV criteria after 
treatment with study drug. Definitions of PCSV is listed in Section 10.3. Treatment-Emergent 
PCSVs will be summarized by treatment group. 
ECG status (i.e. normal, abnormal not clinical significant or abnormal clinical significant) will be 
reported. Shift tables will be provided to present the post-baseline status according to the 
baseline status (normal or missing/abnormal) by treatment group. 
5.8.7. 
Physical and Neurological Examinations 
The percentage of patients with new-onset clinically significant abnormal physical examinations 
will be summarized by treatment group showing frequency and percentage by body system for 
each period as well as at the end of the period. Similarly summaries will be presented for 
neurological exam findings. These summaries will be constructed for the on-treatment period, 
post-treatment period and overall during the study. 
5.8.8. 
Joint Pain Questionnaire 
The percentage of patients with worse joint pain will be summarized by visit and joint. 
5.8.9. 
Analysis of Other Safety Variables 
Other safety data includes the survey of Autonomic Symptoms, cases of AA and joint 
replacements. 
Adjudicated Arthropathy 
Adjudicated arthropathy events based on imaging data overall and by subtype will be 
summarized by treatment group based on the SAF. Incidence of AA (as confirmed by an 
independent adjudication committee) through week 36 will be summarized by treatment group 
based on the SAF. Time to first AA event will be summarized by Kaplan-Meier method if 
enough number of events occur. Cox regression model will be used for descriptively comparing 
each treatment group to placebo by obtaining hazard ratio estimates along with 95% confidence 
intervals. Swimmer plots depicting the length of the observation window per patient and 
indicating timepoints at which the initial event occurred, worsened and/or changed subtype 
category may be presented by treatment group. 
Incidence of DA (as confirmed by an independent adjudication committee) through week 36 will 
be summarized by treatment group based on the SAF. Time to first DA event will be 
summarized by Kaplan-Meier method if enough number of events occur. Cox regression model 
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will be used for descriptively comparing each treatment group to placebo by obtaining hazard 
ratio estimates along with 95% confidence intervals.  
All-cause joint replacements of any joint will be summarized by treatment group. The number of 
replacements in joints that were positively adjudicated will be summarized by treatment group. 
Joint replacements will also be summarized by KL score of the affected joint at screening.  
In the time to event analyses, Time to first event will be calculated as: (Date of the first event – 
Date of the first dose of study drug +1). Patients without an event will be censored at the last 
visit for AA and DA in the analysis. 
Survey of Autonomic Symptoms 
The number of patients reporting the presence of each symptom/health problem assessed will be 
presented by treatment group at each scheduled visit. The number of symptoms reported and 
total symptom impact score will be presented by treatment group at each scheduled visit. 
All-cause Joint Replacements 
The number and percentage of patients with all-cause joint replacements will be presented by 
treatment group On-Treatment and Post-Treatment Periods based on the SAFs. The number of 
replacements in joints that were positively adjudicated will be summarized by treatment group. 
Joint replacements will also be summarized by KL score of the affected joint at screening. 
Additionally, the number and percentage of patients who reported joint replacements at the End 
of Study Phone Call will be summarized. 
The time to JR is calculated as: 
= (Date of JR – Date of first dose of study drug) + 1 
5.9. 
Analysis of Pharmacokinetics and Drug Concentration Data 
Summaries of concentrations of functional fasinumab will be presented by nominal time point 
and dose. Plots of individual concentration over time will be presented by actual day. Plots of 
mean or median concentration of functional fasinumab will be presented by dose and nominal 
day or week. No formal statistical analysis will be performed. 
5.10. 
Analysis of Immunogenicity Data 
5.10.1. 
Analysis of Anti-Drug Antibody Data 
The immunogenicity variables described in Section 4.8 will be summarized using descriptive 
statistics. Immunogenicity will be characterized by ADA responses and titers observed in 
patients in the ADA analysis set. ADA response categories and titer categories are defined as 
follows: 
ADA response categories 
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• ADA Negative, defined as ADA negative response at all time points, regardless of 
any missing samples. 
• Pre-existing immunoreactivity, defined as either an ADA positive response in the 
ADA assay at baseline with all post first dose ADA results negative, OR a positive 
response at baseline with all post first dose ADA responses less than 9-fold over 
baseline titer levels. 
• Treatment-emergent response, defined as a positive response in the ADA assay post 
first dose when baseline results are negative or missing. The treatment-emergent 
responses will be further characterized as Persistent, Indeterminate or Transient: 
- Persistent Response - Treatment-emergent ADA positive response with two or 
more consecutive ADA positive sampling time points, separated by at least 16-
week period (based on nominal sampling time), with no ADA negative samples 
in between, regardless of any missing samples. 
- Indeterminate Response - Treatment-emergent ADA positive response with only 
the last collected sample positive in the ADA assay, regardless of any missing 
samples. 
- Transient Response - Treatment-emergent ADA positive response that is not 
considered persistent or indeterminate, regardless of any missing samples. 
• Treatment-boosted response, defined as a positive response in the ADA assay post 
first dose that is greater than or equal to 9-fold over baseline titer levels, when 
baseline results are positive. 
Titer categories (Maximum titer values) 
• Low (titer <1,000) 
• Moderate (1,000≤ titer ≤10,000) 
• High (titer >10,000) 
The following analysis will be provided:  
• Number (n) and percent (%) of ADA-negative patients (pre-existing 
immunoreactivity or negative in the fasinumab ADA assay at all time points) by 
treatment groups 
• Number (n) and percent (%) of treatment-emergent ADA positive patients by 
treatment groups and ADA titer categories  
- Number (n) and percent (%) of persistent treatment-emergent ADA positive 
patients  
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- Number (n) and percent (%) of indeterminate treatment-emergent ADA positive 
patients Number (n) and percent (%) of transient treatment-emergent ADA 
positive patients  
- Number (n) and percent (%) of treatment-boosted ADA positive patients by 
treatment groups and ADA titer categories 
Listing of all ADA titer levels will be provided for patients with pre-existing, treatment-emergent 
and treatment-boosted ADA response. 
5.10.2. 
Association of Immunogenicity with Exposure, Safety and Efficacy 
5.10.2.1. Immunogenicity and Exposure 
Potential association between immunogenicity variables and systemic exposure to fasinumab 
will be explored by treatment groups. Plots of fasinumab concentration may be provided for 
analyzing the potential impact of ADA response status and titer on PK. 
5.10.2.2. Immunogenicity and Safety and Efficacy 
Potential association between immunogenicity variables and safety may be explored with a 
primary focus on the following safety events during the TEAE period: 
• Injection site reaction (serious or severe and lasting 24 hours or longer) 
• Hypersensitivity (SMQ: Hypersensitivity [Narrow]) 
• Anaphylactic Reaction (SMQ: Anaphylactic Reaction [Narrow]) 
Potential association between immunogenicity variables and efficacy and safety endpoints may 
be explored (e.g. scatter plot or spaghetti plot). The above-mentioned safety and efficacy 
analyses will be conducted using the following categories:  
• ADA positive patients, that is patients with treatment-emergent or treatment-boosted 
response. 
• ADA negative patients, that is patients with pre-existing immunoreactivity or 
negative in the ADA assay at all time points.  
• Patients with persistent treatment-emergent ADA response.  
• Maximum post-baseline titer in treatment-emergent or treatment-boosted ADA 
positive patients:  
- Low (titer <1,000)  
- Moderate (1,000 ≤ titer ≤ 10,000)  
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- High (titer >10,000) 
 
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis. 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified. When relevant, the number of patients with missing data 
is presented. 
6.1. 
Definition of Baseline for Variables 
Unless otherwise specified, the baseline assessment for all measurements will be the latest 
available valid measurement prior to randomization.  
6.2. 
Data Handling Conventions for Efficacy Data 
Missing data items for questionnaires 
Rules for handling missing data for efficacy assessments due to missing individual item data will 
follow each questionnaire’s instrument manual. WOMAC scores will be computed when one 
pain item, one stiffness item, or at most 3 physical function items are missing. The missing items 
will be imputed by the mean of available items within the same subscale. The scores will be set 
to missing if more items are missing. 
Due to public health measures implemented to address the world-wide COVID-19 pandemic, 
some sites may suspend onsite study visits or patients may opt not to attend. To mitigate data 
loss, patients may be contacted via telephone and the results of their efficacy measures 
transcribed verbally and entered into the eCOA devices. For analysis purposes, this data will be 
treated the same as efficacy data collected in an onsite visit and will be utilized in the efficacy 
analyses. Since all patients already had chance to complete week 16 visit prior to COVID-19 
pandemic, there is no impact to the main efficacy endpoints and primary safety endpoints at 
week 16. 
Data collected through the implementation of new CRFs regarding the impact of the COVID-19 
pandemic (e.g. discontinuation due to COVID-19) on the patients will be summarized including 
missing visits, doses, and reason. 
6.3. 
Data Handling Convention for Repeat Data 
Orthostatic Hypotension data 
This applies specifically to the data handling of repeat measurements in the assessment of 
orthostatic hypotension. Per protocol, if the initial vital assessment for orthostatic hypotension is 
consistent with the definition of orthostatic hypotension, the supine, standing blood pressure or 
pulse should be repeated up to 2 more times. The guideline for the repeat assessments are shown 
below: 
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Initial 
Assessment  
Repeat 
Assessment 1 
Repeat 
Assessment 2 
Does patient 
meet OH 
criteria 
Value to be 
used in the 
analysis 
Does not meet 
OH definition 
N/A 
N/A 
No 
Initial 
Assessment 
Meets OH 
definition - 
repeat 
Does not meet 
definition - 
repeat 
Does not meet 
definition 
No  
N/A 
Meets OH 
definition - 
repeat 
Does not meet 
definition - 
repeat 
Meets OH 
definition 
Yes, AE of OH 
reported 
Repeat 
Assessment 2 
Meets OH 
definition - 
repeat 
Meets OH 
definition 
N/A 
Yes, AE of OH 
reported 
Repeat 
Assessment 1 
Baseline for the assessment of orthostatic hypotension vital assessments uses the last available 
assessment prior to the start of study drug. Measurements post-baseline will not be averaged. 
Rather frequency counts for patients meeting OH criteria for orthostatic hypotension will reflect 
the scenario as shown on the table. 
Patient reported outcomes data 
Should there be duplicate entries for patient reported outcomes data (not including diary data), 
the average of the entries will be used for questionnaires with numerical values such as the 
WOMAC. The worst category will be used in the analysis for questionnaires with categorical 
responses such as the SAS and Joint Pain Questionnaire. 
6.4. 
Data Handling Convention for Missing Data 
Handling of Adverse Event and Injection Site Reaction Severity 
If the severity of a TEAE is missing, it will be classified as “severe” in the frequency tables by 
severity of TEAEs.  
Handling of Adverse Event Relatedness 
If the assessment of relationship of a TEAE to the study drug or study conduct is missing, it will 
be classified as “related”. 
Handling of Adverse Events or Concomitant Medications with missing or partial start 
date/time 
Imputation of AE and Concomitant Missing and Partial start dates: 
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Every effort will be made to collect the start dates of all AEs and concomitant medications. However, 
in the case the start date of an AE or concomitant medication is incomplete or missing, it will be 
assumed to have occurred on or after the first dose of study medication, except if an incomplete date 
(e.g., month and year) clearly indicates that the event started prior to treatment. If the partial date 
indicates the same month or year of the first dose of study medication date, then the start date of the 
first dose will be imputed, otherwise, the missing day or month by the first day or the first month will 
be imputed.  
Imputation of Partial AE and concomitant Medication Partial end dates: 
When only year is present, missing AE/concomitant medication end day and month will be 
imputed to the earlier of (study end date, 31DECYYYY). 
When both month and year are present, missing AE/concomitant medication end date will be 
imputed to the last day of the month. 
There will be no attempt to impute completely missing AE/concomitant medication end dates. 
Events with an end date missing will be assumed to be ongoing at the time of data cut off. 
Missing/Incomplete Medical history dates  
Medical history start dates are used to determine the duration of OA at baseline per eCRF data. 
Completing missing medical history dates will not imputed. Missing month will be imputed to 
January and missing day will be imputed to the first day of the month.  
Handling of Adverse Events classification with missing or partial date/time of first study drug 
administration 
When the date and time of first study drug dose is missing, the date of randomization will be 
used as the start date for classification of AEs. 
When the time of the first study treatment dose is missing, all AEs that occurred on the date of 
the first study drug dose will be considered as TEAEs. 
Handling of missing item data for WOMAC 
WOMAC scores will be computed when one pain, one stiffness, or 1-3 physical function items 
are missing. The missing items will be imputed by the mean of available items within the same 
subscale. The scores will be set to missing if more items are missing. 
Laboratory Safety Variables below lower limit of quantification (LLOQ) 
For central laboratory data below the lower limit of quantification, half of the lower limit value 
(i.e., LLOQ/2) will be used for quantitative analyses. 
Missing laboratory, ECG, vital sign, physical exam, neurological exam 
No imputations for missing laboratory data, ECG data, vital sign data, physical examination, or 
neurological examination data will be made. 
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Handling of Potentially Clinically Significant Abnormalities (PCSA) 
If a patient has a missing baseline value they will be grouped in the category “normal/missing at 
baseline”. 
For PCSAs with 2 conditions, one based on a change from baseline value and the other on a 
threshold value or a normal range, with the first condition being missing, the PCSA will be based 
only on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; eg, for eosinophils the PCSA is >0.5 GIGA/L or >ULN 
if ULN ≥0.5 GIGA/L. When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values. 
Date of first/last injection 
Date of first injection is the first non-missing start date of dosing filled in the ‘SC Study drug 
Injection” CRF module. 
If a patient’s date of the last dose is totally missing or unknown, his/her last visit date in the 
treatment period will be substituted. 
6.5. 
Visit Windows 
By-visit analysis (including laboratory data, vital signs, ECG, ADA) will be summarized by the 
nominal visit number. Assessments taken outside of protocol allowable windows will be 
displayed according to the CRF assessment recorded by the investigator. For assessments 
without a nominal visit number such as Unscheduled, End of treatment (EOT), and EOS 
assessments, a visit number will be assigned based on the actual visit date using the study day 
analysis window based on the targeted visit study day in Table 1 Schedule of Events.  
The following visit windows will be used to map all the visits for eCOA data (including WOMAC, 
Joint Pain Questionnaire and Survey of Autonomic System) and the unscheduled visits, early EOT 
visits, early study termination visits for other data, based on the study day: 
Visit 
No. 
Visit 
Targeted Study 
Days* 
Analysis Window in 
Study Days 
1 
Screening 
Day -30 to Day -11 
≥ -30 and ≤ -11 
2 
Pre-randomization 
Day -10 to -7 
-10 to -1 
3 
Baseline 
1 
≤ 1 
4 
Week 1 
8 
[2, 11] 
5 
Week 2 
15 
[12, 22] 
4 
Week 4 
29 
[23, 43] 
5 
Week 8 
57 
[44, 71] 
6 
Week 12 
85 
[72, 99] 
7 
EOT Week 16 
113 
[100, 148] 
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8 
Week 26 
183 
[149, 218] 
12 
Week 36 
253 
[219, 351] 
13 
Week 64 
449 
≥352 
*Study days are calculated from the first dose of study drug (Day 1). 
If multiple measurements occur within the same visit window, the following rules will be used to 
determine the analysis value:  
• When multiple valid measurements occur within the same visit window, the one 
closest to the target study day will be used in the analysis.  
• When multiple valid measurements occur within equal distance from the target study 
day, the value after the target study day will be used in the analysis.  
Both scheduled and unscheduled measurements will be considered for determining 
abnormal/PCSV values from laboratory, vital sign or ECG as well as the baseline values. 
6.6. 
Nerve Conduct Test Analysis Windows 
Per protocol, if the repeated per-protocol nerve conduction test performed on the regions of the 
peroneal, sural, or ulnar nerves at any post-baseline visit shows a difference from baseline of >12%, 
up to 2 unscheduled tests will be repeated at the same nerve. 
The following visit windows will be used to map the unscheduled visits of the unscheduled NCT 
tests, based on the study day: 
Visit 
Targeted Study Days* 
NCT Analysis Window  
in Study Days 
Screening 
Day -30 to Day -11 
≥ -30 and ≤ -11 
Pre-randomization 
Day -10 to -7 
-10 to -1 
Baseline 
1 
≤ 1 
Week 8 
57 
[29, 85] 
EOT Week 16 
113 
[86, 183] 
Week 36 
253 
≥184 
*Study days are calculated from the first dose of study drug (Day 1). 
If multiple measurements occur within the same visit window, the last one within the window 
will be used in the analysis.  
6.7. 
Unscheduled Assessments 
The determination of baselines and values at the EOT for both efficacy and safety variables will 
be based on scheduled available assessments and unscheduled available assessments. 
Extra assessments (laboratory data or vital signs associated with non-protocol clinical visits or 
obtained in the course of investigating or managing AEs) will be included in listings, but not 
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summaries. If more than 1 laboratory value is available for a given visit, the first observation will 
be used in summaries and all observations will be presented in listings. 
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7. 
INTERIM ANALYSES 
No interim analysis will be performed for primary safety and efficacy endpoints. For the first 
DBL, all patients have had the chance to complete the 16-week treatment period but some 
patients have not completed the 36-week follow-up period. All data up to the first DBL cutoff 
date will be included in the analysis. 
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8. 
SOFTWARE 
All clinical data analyses will be done using SAS Version 9.4 and above. 
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9. 
REFERENCES 
1. ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for 
clinical trials (E9). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
2. Joseph C Arezzo, et.al. (2008, September 16). Efficacy and safety of pregabalin 600 mg/d 
for treating painful diabetic peripheral neuropathy: A double-blind placebo-controlled 
trial. BMC Neurology 2008, 8:33.
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10. 
APPENDIX 
10.1. 
Schedule of Events 
Study assessments and procedures are presented by study period and visit in Table 1. 
Table 1: 
Schedule of Events 
 
Screening/Pre-
randomization 
Treatment Period 
Follow-up Period 
EOS 
Study Week 
Screen 
Pre-
rand 
 
Baseline 
 
Wk 1 
 
Wk 2 
 
Wk 4 
 
Wk 8 
 
Wk 12 
EOT  
Wk 16 
ET1/ 
JR 
Pre-
Op  
 
Wk 26 
 
Wk 36 
ET1 
/JR 
Pre-
Op 
 
Wk 64 
Study Day 
Up to 30 
Days 
7 to 10 
Days 
1 
8 
15 
29 
57 
85 
113 
183 
253 
449 
Visit Window (days) 
 
 
 
±1 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Visit/Phone Contact 
Number 
Visit 1 
Visit 2 
Visit 3 
Visit 
4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
Phone 
1 
Screening/Baseline: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion2 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Main study informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genomics sub-study 
informed consent3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary instructions 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Training on pain 
reporting /patient 
education brochures 4 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
MRI for index joint, 
contralateral joint & any 
hip or knee with K-L ≥3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discontinue non-study 
pain medications 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug SC injection5 
 
 
X 
 
 
X 
X 
X 
 
 
 
 
 
 
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Screening/Pre-
randomization 
Treatment Period 
Follow-up Period 
EOS 
Study Week 
Screen 
Pre-
rand 
 
Baseline 
 
Wk 1 
 
Wk 2 
 
Wk 4 
 
Wk 8 
 
Wk 12 
EOT  
Wk 16 
ET1/ 
JR 
Pre-
Op  
 
Wk 26 
 
Wk 36 
ET1 
/JR 
Pre-
Op 
 
Wk 64 
Study Day 
Up to 30 
Days 
7 to 10 
Days 
1 
8 
15 
29 
57 
85 
113 
183 
253 
449 
Visit Window (days) 
 
 
 
±1 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Visit/Phone Contact 
Number 
Visit 1 
Visit 2 
Visit 3 
Visit 
4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
Phone 
1 
Dispense to home 
paracetamol/ 
acetaminophen 
 
X 
X 
 
 
X 
X 
X 
 
 
 
 
 
 
Paracetamol/ 
acetaminophen 
accountability 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Record rescue 
medication use in diary6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Concomitant therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient-Completed Assessments/Efficacy: 
 
 
 
 
 
 
 
 
 
 
 
 
WOMAC7, 22 
X7 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Neurological 
Assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nerve conduction 
X8 
 
 
 
 
 
X 
 
X 
X9 
 
X 
X9 
 
Neurological 
examination (full) 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Survey of autonomic 
symptoms22 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Orthostatic blood 
pressure assessment and 
heart rate 10,11 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Safety: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs11 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Electrocardiogram 
X 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
Physical examination 
and weight 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
 
Joint pain 
questionnaire22  
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Event-triggered 
imaging12 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
---------------------------------------------------------------------------------------------------------------------------------------------------------------→ 
 
SC injection site 
evaluation 
 
 
X 
 
 
X 
X 
X 
 
 
 
 
 
 
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Screening/Pre-
randomization 
Treatment Period 
Follow-up Period 
EOS 
Study Week 
Screen 
Pre-
rand 
 
Baseline 
 
Wk 1 
 
Wk 2 
 
Wk 4 
 
Wk 8 
 
Wk 12 
EOT  
Wk 16 
ET1/ 
JR 
Pre-
Op  
 
Wk 26 
 
Wk 36 
ET1 
/JR 
Pre-
Op 
 
Wk 64 
Study Day 
Up to 30 
Days 
7 to 10 
Days 
1 
8 
15 
29 
57 
85 
113 
183 
253 
449 
Visit Window (days) 
 
 
 
±1 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Visit/Phone Contact 
Number 
Visit 1 
Visit 2 
Visit 3 
Visit 
4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
Phone 
1 
Bilateral X-rays (knee, 
hip, shoulder) 
X13 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
 
Pre-op questionnaire (JR 
follow-up)14 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
MRI affected joint(s) - 
AA patients only15 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
End of study phone 
contact16 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Laboratory Testing: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug test17 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology17 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Blood chemistry17 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Urinalysis and urine 
electrolytes17 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
ESR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c17 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH and estradiol17,18 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (for 
WOCBP)19 
X - 
Serum 
 
X - 
Urine 
 
 
X - 
Urine 
X - 
Urine 
X - 
Urine 
X - 
Urine 
X – 
Urine 
X - 
Urine 
X – 
Urine 
X – 
Urine 
 
PK, Antibody, and Research Samples: 
 
 
 
 
 
 
 
 
 
 
 
 
PK sample20 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
ADA samples20 
 
 
X 
 
 
 
 
 
X 
X 
 
X 
X 
 
Genomics sub-study 
sample (optional)3 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
hs-CRP sample20,21 
 
 
X 
 
 
X 
 
 
X 
X 
 
X 
X 
 
Research serum/plasma 
sample20,21 
 
 
X 
 
 
X 
 
 
X 
X 
 
X 
X 
 
AA: Adjudicated arthropathy                                                     JR: Joint replacement 
ADA: Anti-drug antibody 
                                                    MRI: Magnetic resonance imaging 
EOS: End of study                                                                     PK: Pharmacokinetic 
EOT: End of treatment 
                                                    Pre-op: Pre-operative 
ESR: Erythrocyte sedimentation rate 
                                    Pre-rand: Pre-randomization 
ET: Early termination 
                                                    SC: Subcutaneous 
FSH: Follicle stimulating hormone 
                                    Wk: Week 
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HbA1c: Glycated hemoglobin 
                                    WOCBP: Women of childbearing potential 
hs-CRP: high-sensitivity C-reactive Protein 
                    WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index 
 
Footnotes for Table 1 - Schedule of Events 
1. Patients who discontinue study drug will be encouraged to follow the visit schedule throughout the entire study. If a patient chooses to end study participation he/she will 
be asked to return to the study site as soon as possible for an Early termination (ET) visit. Imaging assessments need to be repeated if it has been >30 days since the joints 
were last imaged. If it has been ≤30 days since imaging assessments were completed, imaging assessments may be completed at the discretion of the investigator. 
2. HIV and/or hepatitis testing will be performed on a country-by-country basis, according to local guidelines if required by regulatory authorities or ethics boards. Patients 
must complete all other inclusion/exclusion assessments before undergoing the nerve conduction assessments. 
3. Only for patients who provide written informed consent for the optional genomics sub-study. The sample should be collected at the day 1 (baseline/randomization) visit, 
but may be collected at any visit during the study after a patient has been randomized. 
4. At the screening and pre-randomization visits, study staff will review the “Participating in a Research Study: What You Need to Know” brochure and the “Reporting 
Your Pain” brochure with patients to ensure they understand what a clinical study is and how to report their pain accurately. At subsequent visits, patients will be asked 
to review the ‘Reporting Your Pain’ brochure themselves. At any time during the conduct of the study, patients may require retraining by study staff. 
5. Study drug administration will be the last procedure at each dosing visit, and will be administered after all laboratory, PK, ADA, and research samples have been 
collected and all study related activities have been performed. Patients will be observed in the clinic for approximately 1 hour after SC study drug is administered. 
6. Use of study-provided rescue medication will be recorded daily using diaries. Acetaminophen/paracetamol use will be reported from pre-randomization visit to week 16. 
7. The WOMAC pain sub-scale will be evaluated for both knees and both hip joints at the screening visit only. Then, the WOMAC Full Survey will be completed only for 
the index joint at the subsequent visits. 
8. Nerve conduction can be performed during screening or pre-randomization. Patients must complete all other inclusion/exclusion assessments before undergoing the 
nerve conduction assessments. Randomization cannot occur until there is confirmation from the central reader assessment that the results are within the established 
parameters.  
9. Nerve conduction assessments should be performed at the ET visit if it has been >2 weeks since the last nerve conduction assessment. 
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10. Blood pressure measurements to assess for orthostatic hypotension may be discontinued following regulatory approval if the safety database does not reveal an 
imbalance for the fasinumab-treated patients.  
11. If the pulse is less than 45 bpm at any visit, an ECG with rhythm strip will be obtained and sent to the central reader to confirm the heart rate and rhythm. 
12. Imaging (X-ray and/or MRI) will be performed at the investigator’s discretion on any joint with worsening or exacerbation of pain beyond the fluctuations in pain typical 
for that patient’s OA. This imaging will be submitted to the adjudication committee for review.  
13. If screening radiographs are inconclusive for potential joint related findings, an MRI must be performed. Confirmation from the central reader that there are no 
exclusionary findings on the MRI must be received before a patient can be randomized.  
14. In the event that a patient must undergo JR surgery during the study, the patient must complete the pre-operative visit (ET assessments, as applicable) and the procedures 
outlined in the schedule of events for JR follow-up. This will include a Knee Society Score questionnaire for knee replacements or Harris Hip Score questionnaire for hip 
replacements. The pre-operative visit must be completed before the JR surgery. Pre-operative images will be submitted to the adjudication committee for review. 
15. If the AA joint(s) has undergone JR, an X-ray may be substituted for an MRI. 
16. The purpose of this phone contact is to ask the patient if he/she has had or is scheduled (or on a waiting list) to have JR surgery. Pre-operative images will be submitted 
to the central reader for adjudication, if available. 
17. Samples will be analyzed by the central laboratory and results will be evaluated by the investigator. 
18. Assessment of FSH and estradiol levels are only to be performed if assessment of postmenopausal status is required (ie, for female patients ≤59 years of age). 
19. In the event of a positive urine pregnancy test result, the patient must have a serum pregnancy test with a negative result in order to continue study drug. If the serum 
pregnancy test is positive, the patient must be withdrawn from study drug and should be asked to return to the clinic for all remaining study visits per the visit schedule. 
20. Collection of samples for PK, ADA, and research are mandatory at the time points specified above. In addition, PK, ADA, and research samples may be drawn at any 
scheduled visit or unscheduled visit if a patient experiences a treatment-related safety TEAE. Samples should be collected prior to study drug administration on study 
drug dosing days. 
21. Biomarker samples should be collected after the patients have been fasting overnight or for 8 hours (in the event of an afternoon visit). 
22. Patient-reported outcome measures should be completed before any clinical assessments. 
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Table 2: 
Follow-up Period for Patients Undergoing Joint Replacement Surgery on Study 
 
Post-Operative  
Long-Term 
Follow-up Study Day (Visit Window)1 
Follow-up Visit 1 
4 weeks after joint replacement surgery 
Follow-up Visit 2 
20 weeks after joint replacement surgery 
Follow-up Day 29 (±5) 
Follow-up Day 140 (±7) 
Treatment: 
 
Concomitant medications and therapy 
X 
X 
Safety: 
 
Adverse events 
--------------------------------------------------------------→ 
Vital signs 
X 
X 
Orthostatic blood pressure2 
X 
X 
Physical examination with joint examination 
X 
X 
Medical history related to the joint replacement 
X 
X 
Joint pain questionnaire 
X 
X 
Post-operative questionnaire3 
X 
X 
Bilateral X-rays (shoulders, hips, knees)4 
X5 
X 
Event-triggered imaging6 
X 
X 
Footnotes for Table 2 - Follow-up Period for Patients Undergoing Joint Replacement Surgery 
1. 
All available information for patients who undergo JR surgery must be collected, including placement of the prosthesis, healing of the surgical wound and the results of 
the histopathologic examination. 
2. 
If it is not possible to obtain orthostatic blood pressure following JR then blood pressure and pulse should be recorded. 
3. 
A Knee Society Score questionnaire for knee replacements or Harris Hip Score questionnaire for hip replacements. 
4. 
In the event of more than 1 JR, imaging assessments should be repeated if it has been >60 days since the joints were last imaged. If it has been ≤60 days since imaging 
assessments were completed, imaging assessments may be completed at the discretion of the investigator. An MRI may be requested by the imaging vendor after review 
of the X-rays. 
5. 
Imaging will be done at week 4 if not done pre-operatively. 
6. 
Imaging may be performed on any joint following a report of clinically significant worsening or exacerbation of pain in that joint. 
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10.2. 
Reference for Criteria for Treatment-Emergent Potentially Clinically Significant Values (PCSV) 
The PCSV criteria below should be used as a reference; the actual criteria for each study should be determined and agreed to by the 
study team prior to database lock as part of SAP and should be based on the study population, indication, and potential effects of study 
treatment. 
Table 3: 
Criteria for Treatment-Emergent Potentially Clinically Significant Values (PCSV) 
Parameter 
Treatment Emergent PCSV 
Comments 
Clinical Chemistry 
ALT* 
>3 and ≤ 5 ULN and baseline ≤ 3 ULN* 
>5 and ≤ 10 ULN and baseline ≤ 5 ULN 
>10 and ≤ 20 ULN and baseline ≤ 10 ULN 
>20 ULN and baseline ≤ 20 ULN 
Enzyme activity must be expressed in ULN, not in 
IU/L.  
FDA DILI Guidance July 2009. 
Each category is calculated independently. 
* At least one level is required; multiple levels are 
optional for phase 2/3 studies. If it is desirable to get 
the distribution across the different PCSV levels, 
additional shift table on ≤3, >3 to ≤5, >5 to ≤10, >10 
to ≤20, and >20 category for baseline vs. post 
baseline may be provided  
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Parameter 
Treatment Emergent PCSV 
Comments 
AST* 
>3 and ≤ 5 ULN and baseline ≤ 3 ULN* 
>5 and ≤ 10 ULN and baseline ≤ 5 ULN 
>10 and ≤ 20 ULN and baseline ≤ 10 ULN 
>20 ULN and baseline ≤ 20 ULN 
Enzyme activity must be expressed in ULN, not in 
IU/L.  
FDA DILI Guidance July 2009. 
Each category is calculated independently. 
* At least one level is required; multiple levels are 
optional for phase 2/3 studies. If it is desirable to get 
the distribution across the different PCSV levels, 
additional shift table on ≤3, >3 to ≤5, > 5 to ≤10, >10 
to ≤20, and >20 category for baseline vs. 
post baseline may be provided 
Alkaline Phosphatase >1.5 ULN and baseline ≤ 1.5 ULN 
Enzyme activity must be expressed in ULN, not in 
IU/L. 
FDA DILI Guidance July 2009. 
Total Bilirubin* 
>1.5 and ≤ 2 ULN and baseline ≤ 1.5 ULN* 
>2 ULN and baseline ≤ 2.0 ULN 
Must be expressed in ULN, not in µmol/L or mg/L. 
Categories are cumulative. 
FDA DILI Guidance July 2009. 
* At least one level is required; multiple levels are 
optional for phase 2/3 studies. If it is desirable to get 
the distribution of significant level, additional shift 
table on ≤1.5, >1.5 to ≤2.0 and > 2.0 category for 
baseline vs. post baseline may be provided 
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Parameter 
Treatment Emergent PCSV 
Comments 
Conjugated Bilirubin (Direct Bilirubin >35% Total Bilirubin and Total 
Bilirubin >1.5 ULN) and (Direct Bilirubin <=35% Total 
Bilirubin or Total Bilirubin <=1.5 ULN) at baseline 
Conjugated bilirubin dosed on a case-by-case basis. 
ALT/AST and Total 
Bilirubin 
(ALT >3 ULN and TBILI>2 ULN) and baseline (ALT 
<=3 ULN or TBILI <=2 ULN) 
(AST >3 ULN and TBILI>2 ULN) and baseline (AST 
<=3 ULN or TBILI <=2 ULN) 
(ALT >3 ULN and TBILI>1.5 ULN) and baseline (ALT 
<=3 ULN or TBILI <=1.5 ULN) 
(AST >3 ULN and TBILI>1.5 ULN) and baseline (AST 
<=3 ULN or TBILI <=1.5 ULN) 
FDA DILI Guidance July 2009. 
ALT/AST and Total 
Bilirubin and ALP 
(ALT >3 ULN and TBILI>2 ULN and ALP < 2 ULN) 
and baseline (ALT <=3 ULN or TBILI <=2 ULN or 
ALP >=2 ULN) 
(AST>3 ULN and TBILI>2 ULN and ALP < 2 ULN) 
and baseline (AST <=3 ULN or TBILI <=2 ULN or 
ALP >=2 ULN) 
FDA DILI Guidance July 2009. 
 
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Parameter 
Treatment Emergent PCSV 
Comments 
CPK* 
>3 and ≤ 10 ULN and baseline ≤ 3ULN* 
>10 ULN and baseline ≤ 10ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
* At least one level is required; multiple levels are 
optional for phase 2/3 studies. If it is desirable to get 
the distribution of significant level, additional shift 
table on ≤3, >3 to ≤10, and > 10 category for baseline 
vs. post baseline may be provided 
Creatinine 
≥150 μmol/L (Adults) and baseline < 150 μmol/L 
>=30% change from baseline and <100% change from 
baseline 
≥100% change from baseline 
Benichou C., 1994 
3 independent criteria  
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 μmol/L and <=408 μmol/L at baseline 
<120 μmol/L and >= 120 μmol/L at baseline 
Harrison - Principles of internal Medicine 17th Ed., 
2008. 
Two independent criteria 
Blood Urea Nitrogen 
≥17 mmol/L and <17 mmol/L at baseline 
Two independent criteria 
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Parameter 
Treatment Emergent PCSV 
Comments 
Chloride 
Hypochloremia 
Hyperchloremia 
 
<80 mmol/L and baseline ≥ 80 mmol/L  
>115 mmol/L and baseline ≤ 115 mmol/L  
Two independent criteria  
Sodium 
Hyponatremia 
Hypernatremia 
 
≤129 mmol/L and baseline > 129 mmol/L  
≥160 mmol/L and baseline <160 mmol/L  
Two independent criteria 
Potassium 
Hypokalemia 
Hyperkalemia 
 
<3 mmol/L and baseline ≥ 3 mmol/L  
≥5.5 mmol/L and baseline <5.5 mmol/L  
FDA Feb 2005. 
Two independent criteria 
Total Cholesterol 
≥7.74 mmol/L and < 7.74 mmol/L at baseline 
Threshold for therapeutic intervention. 
Triglycerides 
≥4.6 mmol/L and < 4.6 mmol/L at baseline 
Threshold for therapeutic intervention. 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
(≤3.9 mmol/L and <LLN) and (>3.9 mmol/L or 
>=LLN) at baseline 
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) and < 
11.1 mmol/L (unfasted); <7 mmol/L (fasted) at baseline 
 
ADA May 2005. 
ADA Jan 2008. 
HbA1c 
>8% and <= 8% at baseline 
 
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Parameter 
Treatment Emergent PCSV 
Comments 
Albumin 
≤25 g/L and >25 g/L at baseline 
 
hs-CRP 
2 ULN or > 10 mg/L  
(if ULN not provided) 
FDA Sept. 2005 
Hematology 
WBC 
<3.0 Giga/L and >=3.0 Giga/L at baseline (Non-Black);  
<2.0 Giga/L and >=2.0 Giga/L at baseline (Black) 
≥16.0 Giga/L and < 16 Giga/L at baseline 
Increase in WBC: not relevant. 
 
 
To be interpreted only if no differential count 
available. 
Lymphocytes 
>4.0 Giga/L and <= 4.0 Giga/L at baseline 
 
Neutrophils 
<1.5 Giga/L and >=1.5 Giga/L at baseline (Non-Black);  
<1.0 Giga/L and >=1.0 Giga/L at baseline (Black) 
International Consensus meeting on drug-induced 
blood cytopenias, 1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L <= 0.7 Giga/L at baseline 
 
Basophils 
>0.1 Giga/L <= 0.1 Giga/L at baseline 
 
Eosinophils 
(>0.5 Giga/L and >ULN) and (<=0.5 Giga/L or <= ULN 
at baseline) 
Harrison - Principles of internal Medicine 17th Ed., 
2008. 
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Parameter 
Treatment Emergent PCSV 
Comments 
Hemoglobin 
≤115 g/L and > 115 g/L at baseline for male; 
≤95 g/L and> 95 g/L at baseline for Female. 
≥185 g/L and <185 g/L at baseline for Male; 
≥165 g/L and < 165 g/L at baseline for Female 
Decrease from Baseline ≥20 g/L 
Three criteria are independent. 
 
 
Criteria based upon decrease from baseline are more 
relevant than based on absolute value. Other 
categories for decrease from baseline can be used 
(≥30 g/L, ≥40 g/L, ≥50 g/L). 
Hematocrit 
≤0.37 v/v and > 0.37 v/v at baseline for Male; ≤0.32 v/v 
and > 0.32 v/v at baseline forFemale 
≥0.55 v/v and < 0.55 v/v at baseline for Male; ≥0.5 v/v 
and < 0.5 v/v at baseline for Female 
Two Criteria are independent 
RBC 
Female 
<3 Tera/L and baseline ≥3 Tera/L 
≥6 Tera/L and baseline < 6 Tera/L  
Male 
<4 Tera/L and baseline ≥4 Tera/L 
≥7 Tera/L and baseline < 7 Tera/L 
Unless specifically required for particular drug 
development, the analysis is redundant with that of 
Hb. 
Otherwise, consider FDA criteria. 
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Parameter 
Treatment Emergent PCSV 
Comments 
Platelets 
<100 Giga/L and >=100 Giga/L at baseline 
≥700 Giga/L and < 700 Giga/L at baseline 
International Consensus meeting on drug-induced 
blood cytopenias, 1991. 
Two independent criteria 
Urinalysis 
pH 
≤4.6 and > 4.6 at baseline 
≥8 and < 8 at baseline 
Two independent criteria 
Vital signs 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions (including missing) 
except STANDING. 
SBP 
≤95 mmHg and decrease from baseline ≥20mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
                                        VV-RIM-00113088-1.0 Approved - 04 Jun 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
                                                                                                                                 Protocol: R475-OA-1758 
Statistical Analysis Plan                                                                                                                                                                                         Date: 28MAY2020 
CONFIDENTIAL 
Page 64 of 66 
Parameter 
Treatment Emergent PCSV 
Comments 
Orthostatic 
Hypotension 
Su SBP < 160 mmHg - 
SBP St – Su  - 20 mmHg 
DBP St – Su  - 10 mmHg 
Su SBP  160 mmHg - 
SBP St – Su  - 30 mmHg 
DBP St – Su  - 15 mmHg 
 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 
ECG 
Ref.: CPMP 1997 guideline. ICH E14 2005 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline ≥20 bpm 
 
PR 
≥220 ms and increase from baseline ≥20 ms 
 
QRS 
≥120 ms & < 120 ms at baseline 
 
                                        VV-RIM-00113088-1.0 Approved - 04 Jun 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
                                                                                                                                 Protocol: R475-OA-1758 
Statistical Analysis Plan                                                                                                                                                                                         Date: 28MAY2020 
CONFIDENTIAL 
Page 65 of 66 
Parameter 
Treatment Emergent PCSV 
Comments 
QTc 
Absolute values (ms) 
>450 ms and baseline <=450 ms 
>480 ms and baseline <=480 ms 
>500 ms and <= 500 ms at baseline 
 
Increase from baseline 
Increase from baseline 30-60 ms 
Increase from baseline >60 ms 
To be applied to any kind of QT correction formula.  
 
 
 
QTc>60 ms are the PCSA to be identified in 
individual subjects/patients listings. 
 
 
                                        VV-RIM-00113088-1.0 Approved - 04 Jun 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
                                                                                                                                 Protocol: R475-OA-1758 
Statistical Analysis Plan                                                                                                                                                                                         Date: 28MAY2020 
CONFIDENTIAL 
Page 66 of 66 
10.3. 
OMERACT-OARSI set of responder criteria 
 
Note that the criteria in the diagram above are based on standardized score between 0 and 100. For this study, WOMAC pain and 
physical function score are between 0 and 10, so the absolute change required for response is the required change in the diagram 
above divided by 10; PGA is 1, 2, 3, 4 or 5, so the absolute change required for response is at least 1 point. 
                                        VV-RIM-00113088-1.0 Approved - 04 Jun 2020 GMT-5:00


Signature Page for VV-RIM-00113088 v1.0
Signature Page for VV-RIM-00113088 v1.0 Approved
ESig Approval
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ESig Approval
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ESig Approval
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ESig Approval
2020 12:04:53 GMT+0000
ESig Approval
2020 13:01:23 GMT+0000
ESig Approval
20 13:55:06 GMT+0000
                                        VV-RIM-00113088-1.0 Approved - 04 Jun 2020 GMT-5:00