Clinical trial NCT03304379
Conditions: Osteoarthritis, Knee Osteoarthritis, Hip
Sponsor: Regeneron Pharmaceuticals
Start date: 2017-10-26; Completion date: 2020-11-09
Enrollment: 1650 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study is to evaluate the efficacy of fasinumab compared to placebo, when administered for up to 24 weeks in patients with pain due to osteoarthritis (OA) of the knee or hip.

The secondary objectives of the study are:

* To evaluate the efficacy of fasinumab compared to non-steroidal anti-inflammatory drugs (NSAID)s, when administered for up to 24 weeks in patients with pain due to OA of the knee or hip
* To assess the safety and tolerability of fasinumab compared to placebo and compared to NSAIDs, when administered for up to 24 weeks in patients with pain due to OA of the knee or hip

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: Fasinumab intervention 2: Diclofenac intervention 3: Celecoxib intervention 4: Matching placebo
Intervention descriptions: intervention 1: Solution for injection in pre-filled syringe intervention 2: NSAID active comparator (capsule) intervention 3: NSAID active comparator (capsule) intervention 4: Fasinumab-matching placebo (solution for injection in pre-filled syringe); NSAID-matching placebo (capsule)

Protocol documents:
Prot_000.pdf: 
IND Number: 103245 
EudraCT: 2017-001702-15 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A PHASE 3 RANDOMIZED, DOUBLE-BLIND, MULTI-DOSE, PLACEBO 
AND NSAID-CONTROLLED STUDY TO EVALUATE THE EFFICACY 
AND SAFETY OF FASINUMAB IN PATIENTS WITH PAIN DUE TO 
OSTEOARTHRITIS OF THE KNEE OR HIP 
Compound: 
Fasinumab 
Study Name: 
FACT OA2  
Clinical Phase: 
3 
Protocol Number: 
R475-OA-1688 
Protocol Version: 
R475-OA-1688 Amendment 4 
Amendment 4 Date of Issue: 
See appended electronic signature page 
Amendment 3 Global Date of Issue: 
24 May 2018 
Amendment 2 CA Date of Issue: 
19 Mar 2018 
Amendment 2 Date of Issue: 
12 Mar 2018 
Amendment 1 Date of Issue: 
17 Aug 2017 
Original Date of Issue: 
09 Jun 2017 
Scientific/Medical Monitor: 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
 
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NCT03304379


Clinical Study Protocol 
R475-OA-1688 Amendment 4 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 2 of 93 
CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 4 
The purpose of this amendment is to update the exclusion criteria to improve patient safety. 
Additional changes have been made to improve clarity, ensure consistency across the fasinumab 
program, and to make minor corrections. The following table outlines the changes made to the 
protocol and the rationale: 
Change and Rationale 
Sections Changed 
Main changes to improve patient safety: 
The exclusion criterion #22 regarding adverse cardiac events 
within the past 12 months prior to the screening visit has been 
updated to exclude patients with a history of adverse cardiac 
events, per Ethics Committee request.  In addition, acute 
coronary syndrome has been removed from this criterion 
because this is covered by exclusion criterion #10. 
Section 6.2.2 Exclusion Criteria, #22 
 
In exclusion criterion #10 regarding NSAID use, the general 
statement regarding the use of concomitant medications for 
which NSAIDs are contraindicated has been removed.  Specific 
medications that are not to be taken concomitantly with NSAIDs 
are listed in the prohibited medications section. In addition, 
patients with conditions requiring use of anti-platelet therapy has 
been added to this criterion. 
Section 6.2.2 Exclusion Criteria, #10 
A new exclusion criterion has been added to exclude patients at 
the highest risk of renal complications due to NSAID use, as 
follows: 
‘Patients taking concomitant ACE inhibitors/ARBs and 
diuretics, or presence of an estimated glomerular filtration rate 
(GFR) <30 mL/minute/1.73m2’ 
Section 6.2.2 Exclusion Criteria, #40 
The reasons for permanent discontinuation of study drug have 
been updated to ensure that patients enrolled under an earlier 
version of the protocol are immediately discontinued from study 
drug and moved to the follow up period if they meet either of the 
updated exclusion criteria described above, or are taking the 
newly added prohibited medications described above 
(combination therapy of diuretics with either an ACE inhibitor 
or ARB). 
Section 7.3.2.1 Reasons for Permanent 
Discontinuation of Study Drug 
All other changes: 
The rescreening text has been updated for clarity and to be 
consistent across the fasinumab program 
Section 5.1.2 Rescreening 
The sample size has been revised from 2700 patients to 
approximately 1620 patients due to the discontinuation of the 
3 mg Q4W and 6 mg Q8W dose regimens. 
Clinical Study Protocol Synopsis: Population 
Section 6.1 Number of Patients Planned 
Clarified that fasinumab and fasinumab-matching placebo are 
referred to as ‘SC study drug’ and that NSAIDs (diclofenac and 
celecoxib) and NSAID-matching placebo are referred to as ‘oral 
study drug’. 
Throughout the document 
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Change and Rationale 
Sections Changed 
The rescue medication (acetaminophen/paracetamol) text has 
been updated to be consistent across the fasinumab program: 
 
Clarified that acetaminophen/paracetamol may be taken 
for inadequate pain relief for OA and for other 
acceptable reasons (eg, headache, fever);  
 
Added text to clarify the dosing instructions;  
 
Added text to caution against consumption of alcoholic 
beverages while on acetaminophen/paracetamol 
Clinical Study Protocol Synopsis: Rescue 
Treatment 
Section 7.2 Rescue Medication  
Section 7.7.2 Permitted Medications and 
Procedures   
The section on Prohibited Medications and Procedures has been 
updated: 
 
To include methotrexate, which should be used with 
caution in patients taking NSAIDs and because 
methotrexate clearance can be decreased with concurrent 
NSAIDs, leading to potential increases in methotrexate 
levels; 
 
To include anticoagulants and anti-platelet therapy (eg, 
warfarin, heparins, factor Xa inhibitors, thrombin 
inhibitors, aspirin/5-aminosalicylic acid (aspirin/5-ASA) 
>150 mg daily, clopidogrel), which should be used with 
caution in patients taking NSAIDs; 
 
To include recreational use of marijuana in addition to 
medical marijuana, as both have the potential to impact 
efficacy assessments; 
 
To include combination therapy of diuretics with either an 
ACE inhibitor or angiotensin receptor blocker (ARB); 
 
To clarify that cyclobenzaprine, carisoprodol, orphenadrine 
and tizanidine are muscle relaxants 
 
To make minor corrections   
Section 7.7.1 Prohibited Medications 
Text has been added or updated to align with current Regeneron 
best practices 
Section 7.4.2 Local Injection Site Reactions 
Section 7.5.2 Emergency Unblinding 
Section 12.1 Monitoring of Study Sites 
Changes have been made to the Schedule of Events table and 
footnotes for clarity, to make minor corrections, and for 
consistency across the fasinumab program: 
 
Added a separate row to the Schedule of Events table 
for high-sensitivity C-reactive protein  
 
Clarified that the Early Termination/Joint Replacement 
(ET/JR) visit is also the pre-operative visit for patients 
who undergo JR. 
 
Added event-triggered imaging to the follow-up period 
and Early Termination Visit during the follow-up 
period in the Schedule of Events Table 
 
Removed the footnote from the erythrocyte 
sedimentation rate (ESR) row of the Schedule of Events 
table that states the ESR sample will be analyzed by the 
central laboratory (ESR samples will be analyzed 
locally using kits provided by the central lab, see row 
below) 
Table 1 Schedule of Events 
Section 8.1.1 Footnotes for Schedule of 
Events Table, footnote #2 
Section 8.1.1 Footnotes for Schedule of 
Events Table, footnote #4 
Section 8.1.1 Footnotes for Schedule of 
Events Table, footnote #6 
Section 8.1.1 Footnotes for Schedule of 
Events Table, footnote 8 
Section 8.1.1 Footnotes for Schedule of 
Events Table, footnote #19 
 
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CONFIDENTIAL 
Change and Rationale 
Sections Changed 
 
Clarified in footnote #4 that patients will review a 
“Participating in a Research Study: What You Need to 
Know” brochure and a “Reporting Your Pain’ brochure 
at the screening and pre-randomization visits 
 
Added a urine pregnancy test at week 28  
 
Added a footnote to state that HIV and/or hepatitis 
testing with be performed on a country-by-country 
basis, according to local guidelines if required by 
regulatory authorities or ethics boards 
 
Clarified that walking index joint pain NRS scores are 
recorded by the patient at home and not onsite at the 
pre-randomization visit 
The laboratory Testing text has been corrected to state that ESR 
testing will be performed at the site using kits provided by the 
central laboratory 
Drugs included in the urine drug test have been listed. 
Section 8.2.3.11 Laboratory Testing 
Corrected the text describing the Healthcare Resource 
Utilization Questionnaire to state that the sites (not the patients) 
will complete the questionnaire. 
Section 8.2.2.7 Healthcare Resource 
Utilization Questionnaire 
The efficacy analyses in the Statistical Plan have been updated 
to be consistent across the fasinumab program 
Clinical Study Protocol Synopsis: Statistical 
Plan 
Section 10.1 Statistical Hypothesis 
Section 10.4.3.1 Primary Efficacy Analysis 
Section 10.4.3.2 Secondary Efficacy Analysis 
Section 10.5 Additional Statistical Data 
Handling Conventions 
 
Section 10.4.4.4 Treatment Compliance 
REGN475 has been removed from the compound name on the 
title page and it has been clarified in the Introduction that 
fasinumab is also known as REGN475 (for consistency across 
the fasinumab program) 
Title Page 
Section 1 Introduction 
Minor edits have been made to the text throughout the document 
for clarity, to delete redundant text, to make minor corrections, 
and to ensure consistency across the fasinumab program.  
Clinical Study Protocol Synopsis: Objectives, 
Study Design, Endpoints 
List of Abbreviations and Definitions of 
Terms 
Section 1 Introduction  
Section 2.1 Primary Objective 
Section 2.2  Secondary Objective(s) 
Section 2.3  Exploratory Objectives 
Section 3.2.1 Rationale for Study Design 
Section 3.2.2 Rationale for Dose Selection 
Section 4.3 Safety Endpoints 
Section 5.1 Study Description and Duration 
Section 5.1.1 Screening and Pre-
Randomization 
Section 5.1.5 Follow-up Period 
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Change and Rationale 
Sections Changed 
Section 6.2.1 Inclusion Criteria, #6 
Section 6.2.1 Inclusion Criteria, #8 
Section 6.2.1 Inclusion Criteria, #9 
Section 6.2.2 Exclusion Criteria, #29 
Section 7.1 Investigational and Reference 
Treatments 
Section 7.3.2.1 Reasons for Permanent 
Discontinuation of Study Drug 
Section 7.3.2.2 Reasons for Temporary 
Discontinuation of Study Drug 
Section 7.4.1 Acute Injection Reactions 
(header deleted) 
Section 7.5 Method of Treatment Assignment 
Section 7.7.1 Prohibited Medications 
Section 7.7.2 Permitted Medications and 
Procedures  
Table 1 Schedule of Events 
Section 8.1.3 Early Termination Visit 
Section 8.2.1.8  Instructions for Use of Diary 
(section added) 
Section 8.2.1.9  Patient Education Brochures 
(section added) 
Section 8.2.2.3 Walking Index Joint Pain 
Numeric Rating Score 
Section 8.2.2.4 Work Productivity and 
Activity Impairment 
Section 8.2.2.8 Treatment Satisfaction 
Questionnaire for Medication 
Section 8.2.3.1 Vital Signs 
Section 8.2.3.10 Procedures to be Performed 
Only in the Event of Joint Replacement 
Section 8.2.3.11 Laboratory Testing 
Section 8.2.4.1 Drug Concentration 
Measurements and Samples 
Section 9.4.3 Other Events that Require 
Accelerated Reporting 
Section 9.6.1.1 Adjudicated Arthropathy  
Section 9.6.1.3 Peripheral Sensory Adverse 
Events 
Section 11.2  Electronic Systems 
Section 12.1 Monitoring of Study Sites 
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CONFIDENTIAL 
Amendment 3 Global 
The primary purpose of this amendment was to incorporate an urgent safety measure, which 
requires discontinuing the 3 mg every 4 weeks (Q4W) and 6 mg every 8 weeks (Q8W) dose 
regimens. The recommendation by the independent Data Monitoring Committee (DMC) to 
discontinue these dose regimens was made following a review of unblinded data from an ongoing 
study in the fasinumab phase 3 osteoarthritis program (R475-PN-1523) and was based on an 
imbalance in clinically relevant adverse events including time to total joint replacement, peripheral 
edema, arthralgia and a trend towards early fractures in the 6 mg Q8W group.  Based on the 
independent DMC review, study of lower dose levels (eg, 1 mg Q4W) may continue to be 
evaluated in this population. With this amendment, patients randomized to the 3 mg Q4W or 6 mg 
Q8W dose regimens will be permanently discontinued from study drug but encouraged to 
otherwise complete all remaining study visits and study procedures in the follow up period and the 
end of study phone call.   
Amendment 2CA (obsolete) 
The purpose of this amendment was to incorporate health authority feedback.  This amendment 
was not implemented. 
Amendment 2 (obsolete) 
The purpose of this amendment was to incorporate Ethics Committee feedback, to make edits for 
clarity and to ensure consistency across the program, and to make minor corrections. This 
amendment was not implemented. 
Amendment 1 
The purpose of this amendment was to incorporate health authority feedback, to make minor edits 
to the text to improve clarity, remove redundant text and to correct typos. 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................14 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................20 
1. 
INTRODUCTION ......................................................................................................23 
2. 
STUDY OBJECTIVES ..............................................................................................26 
2.1. 
Primary Objective .......................................................................................................26 
2.2. 
Secondary Objective(s) ...............................................................................................26 
2.3. 
Exploratory Objectives ...............................................................................................26 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................26 
3.1. 
Hypothesis ..................................................................................................................26 
3.2. 
Rationale .....................................................................................................................27 
3.2.1. 
Rationale for Study Design .........................................................................................27 
3.2.2. 
Rationale for Dose Selection ......................................................................................28 
4. 
STUDY VARIABLES................................................................................................29 
4.1. 
Demographic and Baseline Characteristics ................................................................29 
4.2. 
Primary and Secondary Endpoints..............................................................................29 
4.2.1. 
Primary Endpoint ........................................................................................................29 
4.2.2. 
Secondary Endpoints ..................................................................................................29 
4.2.3. 
Exploratory Endpoints ................................................................................................30 
4.3. 
Safety Endpoints .........................................................................................................30 
4.4. 
Pharmacokinetic Variables .........................................................................................30 
4.5. 
Anti-Drug Antibody Variables ...................................................................................30 
5. 
STUDY DESIGN .......................................................................................................31 
5.1. 
Study Description and Duration .................................................................................31 
5.1.1. 
Screening and Pre-Randomization .............................................................................31 
5.1.2. 
Rescreening .................................................................................................................32 
5.1.3. 
Randomization ............................................................................................................32 
5.1.4. 
Treatment Period ........................................................................................................32 
5.1.5. 
Follow-up Period ........................................................................................................33 
5.1.6. 
End of Study Phone Contact .......................................................................................33 
5.1.7. 
Study Stopping Rules .................................................................................................33 
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5.1.8. 
End of Study Definition ..............................................................................................33 
5.2. 
Planned Interim Analysis ............................................................................................34 
5.3. 
Study Committees .......................................................................................................34 
5.3.1. 
Independent Data Monitoring Committee ..................................................................34 
5.3.2. 
Arthropathy Adjudication Committee ........................................................................34 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............34 
6.1. 
Number of Patients Planned .......................................................................................34 
6.2. 
Study Population .........................................................................................................34 
6.2.1. 
Inclusion Criteria ........................................................................................................34 
6.2.2. 
Exclusion Criteria .......................................................................................................36 
6.3. 
Premature Withdrawal from the Study .......................................................................39 
6.4. 
Replacement of Patients .............................................................................................39 
7. 
STUDY TREATMENTS............................................................................................40 
7.1. 
Investigational and Reference Treatments ..................................................................40 
7.2. 
Rescue Treatment .......................................................................................................40 
7.3. 
Dose Modification and Study Treatment Discontinuation Rules ...............................41 
7.3.1. 
Dose Modification ......................................................................................................41 
7.3.2. 
Study Drug Discontinuation .......................................................................................41 
7.3.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................42 
7.3.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................43 
7.4. 
Management of Acute Reactions ................................................................................44 
7.4.1. 
Systemic Injection Reactions ......................................................................................44 
7.4.2. 
Local Injection Site Reactions ....................................................................................44 
7.5. 
Method of Treatment Assignment ..............................................................................44 
7.5.1. 
Blinding ......................................................................................................................44 
7.5.2. 
Emergency Unblinding ...............................................................................................45 
7.5.3. 
Unblinding for Regulatory Reporting Purposes .........................................................45 
7.6. 
Treatment Logistics and Accountability .....................................................................45 
7.6.1. 
Packaging, Labeling, and Storage ..............................................................................45 
7.6.2. 
Supply and Disposition of Treatments .......................................................................46 
7.6.3. 
Treatment Accountability ...........................................................................................46 
7.6.4. 
Treatment Compliance ................................................................................................46 
7.7. 
Concomitant Medications and Procedures .................................................................46 
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7.7.1. 
Prohibited Medications ...............................................................................................46 
7.7.2. 
Permitted Medications and Procedures ......................................................................47 
8. 
SCHEDULE OF EVENTS AND PROCEDURES ....................................................48 
8.1. 
Schedule of Events .....................................................................................................48 
8.1.1. 
Footnotes for the Schedule of Events Table ...............................................................54 
8.1.2. 
Footnotes for Table 2 - Follow-up Period for Patients Undergoing Joint 
Replacement Surgery ..................................................................................................56 
8.1.3. 
Early Termination Visit ..............................................................................................57 
8.1.4. 
Unscheduled Visits .....................................................................................................57 
8.2. 
Study Procedures ........................................................................................................57 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................57 
8.2.1.1. 
Informed Consent .......................................................................................................57 
8.2.1.2. 
Medical History ..........................................................................................................57 
8.2.1.3. 
Medication History .....................................................................................................57 
8.2.1.4. 
Demographics .............................................................................................................57 
8.2.1.5. 
Determination of Osteoarthritis ..................................................................................57 
8.2.1.6. 
Assessment of Childbearing Potential ........................................................................58 
8.2.1.7. 
Assessment of Peripheral or Central Pain ..................................................................58 
8.2.1.8. 
Instructions for Use of Diary ......................................................................................59 
8.2.1.9. 
Patient Education Brochures.......................................................................................59 
8.2.2. 
Efficacy Procedures ....................................................................................................59 
8.2.2.1. 
Western Ontario and McMaster Universities Osteoarthritis Index ............................59 
8.2.2.2. 
Patient Global Assessment of Osteoarthritis ..............................................................59 
8.2.2.3. 
Walking Index Joint Pain Numeric Rating Score .......................................................59 
8.2.2.4. 
Work Productivity and Activity Impairment ..............................................................59 
8.2.2.5. 
36-Item Short Form Medical Outcomes Study Questionnaire Version 2 ...................60 
8.2.2.6. 
EuroQoL 5 Dimensions 5 Level Questionnaire..........................................................60 
8.2.2.7. 
Healthcare Resource Utilization Questionnaire ..........................................................60 
8.2.2.8. 
Treatment Satisfaction Questionnaire for Medication ................................................60 
8.2.3. 
Safety Procedures .......................................................................................................61 
8.2.3.1. 
Vital Signs ..................................................................................................................61 
8.2.3.2. 
Physical Examination .................................................................................................61 
8.2.3.3. 
Assessment of Orthostatic Blood Pressure and Heart Rate ........................................61 
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8.2.3.4. 
Joint Pain Questionnaire .............................................................................................61 
8.2.3.5. 
Survey of Autonomic Symptoms ................................................................................62 
8.2.3.6. 
Neurologic Examination .............................................................................................62 
8.2.3.7. 
Imaging .......................................................................................................................62 
8.2.3.8. 
Electrocardiogram .......................................................................................................63 
8.2.3.9. 
End of Study Phone Contact .......................................................................................63 
8.2.3.10. 
Procedures to be Performed Only in the Event of a Joint Replacement 
Surgery ........................................................................................................................63 
8.2.3.11. 
Laboratory Testing ......................................................................................................64 
8.2.3.12. 
Injection Site Evaluations ...........................................................................................65 
8.2.4. 
Pharmacokinetic and Anti-Drug Antibody Procedures ..............................................66 
8.2.4.1. 
Drug Concentration Measurements and Samples .......................................................66 
8.2.4.2. 
Anti-Drug Antibody Measurements and Samples ......................................................66 
8.2.5. 
Research Samples .......................................................................................................66 
8.2.5.1. 
Biomarkers ..................................................................................................................66 
8.2.5.2. 
Future Biomedical Research .......................................................................................66 
8.2.6. 
Genomics Sub-study – Optional .................................................................................66 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................67 
9.1. 
Obligations of Investigator .........................................................................................67 
9.2. 
Obligations of Sponsor ...............................................................................................67 
9.3. 
Definitions ..................................................................................................................67 
9.3.1. 
Adverse Event .............................................................................................................67 
9.3.2. 
Serious Adverse Event ................................................................................................67 
9.3.3. 
Adverse Events of Special Interest .............................................................................68 
9.4. 
Recording and Reporting Adverse Events ..................................................................68 
9.4.1. 
Adverse Events ...........................................................................................................68 
9.4.2. 
Serious Adverse Events ..............................................................................................69 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor ...................................69 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................70 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results .............................70 
9.4.6. 
Follow-up ....................................................................................................................70 
9.5. 
Evaluation of Severity and Causality .........................................................................70 
9.5.1. 
Evaluation of Severity ................................................................................................70 
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9.5.2. 
Evaluation of Causality ...............................................................................................71 
9.6. 
Safety Monitoring .......................................................................................................73 
9.6.1. 
Monitoring Adverse Events of Special Interest ..........................................................73 
9.6.1.1. 
Adjudicated Arthropathy ............................................................................................73 
9.6.1.2. 
Sympathetic Nervous System Dysfunction ................................................................74 
9.6.1.3. 
Peripheral Sensory Adverse Events ............................................................................75 
9.6.1.4. 
Joint Replacement Surgery .........................................................................................76 
9.7. 
Investigator Alert Notification ....................................................................................76 
10. 
STATISTICAL PLAN................................................................................................76 
10.1. 
Statistical Hypothesis ..................................................................................................76 
10.2. 
Justification of Sample Size........................................................................................77 
10.3. 
Analysis Sets ...............................................................................................................77 
10.3.1. 
Efficacy Analysis Sets ................................................................................................77 
10.3.2. 
Safety Analysis Set .....................................................................................................77 
10.3.3. 
Per-Protocol Set ..........................................................................................................78 
10.3.4. 
Pharmacokinetic Analysis Set ....................................................................................78 
10.3.5. 
Anti-Drug Antibody Analysis Set ..............................................................................78 
10.4. 
Statistical Methods ......................................................................................................78 
10.4.1. 
Patient Disposition ......................................................................................................78 
10.4.2. 
Demography and Baseline Characteristics .................................................................78 
10.4.3. 
Efficacy Analyses .......................................................................................................79 
10.4.3.1. 
Primary Efficacy Analysis ..........................................................................................79 
10.4.3.2. 
Secondary Efficacy Analysis ......................................................................................79 
10.4.4. 
Safety Analysis ...........................................................................................................80 
10.4.4.1. 
Adverse Events ...........................................................................................................80 
10.4.4.2. 
Other Safety ................................................................................................................81 
10.4.4.3. 
Treatment Exposure ....................................................................................................81 
10.4.4.4. 
Treatment Compliance ................................................................................................81 
10.4.5. 
Analysis of Drug Concentration Data .........................................................................82 
10.4.6. 
Analysis of Anti-Drug Antibody Data ........................................................................82 
10.5. 
Additional Statistical Data Handling Conventions .....................................................82 
10.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .........83 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS .....................................83 
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11.1. 
Data Management .......................................................................................................83 
11.2. 
Electronic Systems ......................................................................................................83 
12. 
STUDY MONITORING ............................................................................................83 
12.1. 
Monitoring of Study Sites ...........................................................................................83 
12.2. 
Source Document Requirements ................................................................................84 
12.3. 
Case Report Form Requirements ................................................................................84 
13. 
AUDITS AND INSPECTIONS .................................................................................84 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................85 
14.1. 
Good Clinical Practice Statement ...............................................................................85 
14.2. 
Informed Consent .......................................................................................................85 
14.3. 
Patients Confidentiality and Data Protection ..............................................................85 
14.4. 
Institutional Review Board/Ethics Committee ...........................................................86 
15. 
PROTOCOL AMENDMENTS ..................................................................................86 
16. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................86 
16.1. 
Premature Termination of the Study ...........................................................................86 
16.2. 
Close-out of a Site ......................................................................................................86 
17. 
STUDY DOCUMENTATION ...................................................................................87 
17.1. 
Certification of Accuracy of Data ...............................................................................87 
17.2. 
Retention of Records ..................................................................................................87 
18. 
DATA QUALITY ASSURANCE ..............................................................................87 
19. 
CONFIDENTIALITY ................................................................................................88 
20. 
FINANCING AND INSURANCE .............................................................................88 
21. 
PUBLICATION POLICY ..........................................................................................88 
22. 
REFERENCES ...........................................................................................................89 
23. 
INVESTIGATOR’S AGREEMENT ..........................................................................92 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................93 
 
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LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................49 
Table 2: 
Follow-up Period for Patients Undergoing Joint Replacement Surgery on 
Study ...........................................................................................................................56 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................31 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Phase 3 Randomized, Double-Blind, Multi-Dose, Placebo And 
NSAID-Controlled Study To Evaluate The Efficacy And Safety Of 
Fasinumab In Patients With Pain Due To Osteoarthritis Of The Knee Or Hip 
Site Location(s) 
 
Principal Investigator 
To be determined 
Objective(s) 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of fasinumab 
compared to placebo, when administered for up to 24 weeks in patients with 
pain due to osteoarthritis (OA) of the knee or hip. 
Secondary Objective(s) 
The secondary objectives of the study are: 
 To evaluate the efficacy of fasinumab compared to non-steroidal 
anti-inflammatory drugs (NSAID)s, when administered for up to 
24 weeks in patients with pain due to OA of the knee or hip 
 To assess the safety and tolerability of fasinumab compared to placebo 
and compared to NSAIDs, when administered for up to 24 weeks in 
patients with pain due to OA of the knee or hip  
 To characterize the concentrations of fasinumab over time when 
administered for up to 24 weeks in patients with pain due to OA of the 
knee or hip 
 To evaluate the immunogenicity of fasinumab administered for up to 
24 weeks in patients with pain due to OA of the knee or hip  
Exploratory Objectives 
 To evaluate patient-reported outcome measures in patients with pain 
due to OA of the knee or hip treated for up to 24 weeks with fasinumab 
compared to placebo and compared to NSAIDs 
 To evaluate the use of rescue medication in patients with pain due to 
OA of the knee or hip treated for up to 24 weeks with fasinumab 
compared to placebo and compared to NSAIDs 
Study Design 
This study is a randomized, double-blind, placebo- and NSAID-controlled 
study designed to evaluate the efficacy and safety of fasinumab in patients 
with OA of the knee or hip who have a history of inadequate pain relief with 
acetaminophen/paracetamol and a history of intolerance to or inadequate 
pain relief with opioids (or are unwilling to take opioids or have lack of 
access to opioids). The study consists of a screening period of up to 30 days, 
a 7 to 10 day pre-randomization/washout period (7 days with a +3 day 
window), a 24-week treatment period, a 20-week follow-up period, and a 
final phone call approximately 52 weeks after the last subcutaneous (SC) 
dose of study drug. 
 
Screening and Pre-Randomization 
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Prior to randomization, patients will undergo screening procedures, 
including X-ray of the shoulders, hips, and knees, and magnetic resonance 
imaging (MRI) of the index and contralateral joints must be performed and 
assessed by the central imaging vendor.  In addition, any knee or hip joint 
with a K-L score of ≥3 will have MRI completed during the screening 
period.  During the screening period, all patients will continue to take their 
current treatment regimen for OA pain, which must include use of an oral 
NSAID on a regular basis, defined as approximately 4 days per week over 
the last 4 weeks. 
Patients eligible for the study will complete a pre-randomization period. The 
pre-randomization visit will be 7 to 10 days before randomization. During 
the pre-randomization visit patients will discontinue and/or undergo a 
washout of their standard-of-care pain medications for OA.  All pain 
medications, 
except 
for 
the 
study-provided 
rescue 
medication 
(acetaminophen/paracetamol), will be discontinued. 
Randomization 
Patients will be randomized on day 1 (baseline) in a 2:1:1:1 ratio to receive 
1 of the following: 
 
Fasinumab 1 mg SC Q4W 
 
Diclofenac 75 mg oral, twice daily 
 
Celecoxib 200 mg oral once daily 
 
Placebo 
Randomization will be stratified according to the affected index joint (hip 
or knee), the K-L score (2 to 3, or 4) at the screening visit, and geographical 
region. 
Treatment 
During the treatment period (day 1 through week 24), patients will be 
permitted to use only acetaminophen/paracetamol as rescue medication.  
Patients will record their use of acetaminophen/paracetamol in a diary. 
The study visits during the treatment period will include 1 phone visit on 
day 15 (±3 day). 
Safety and efficacy assessments will be performed and potential events of 
adjudicated arthropathy (AA) and sympathetic nervous system dysfunction 
will be monitored. 
Follow-up 
After the end of treatment, follow-up of patients will continue for an 
additional 20 weeks after the last visit.  Safety and efficacy assessments will 
be performed similarly to those of the treatment period. 
If a patient must undergo joint replacement (JR) surgery during the study, 
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 SC study drug 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). 
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Study Duration 
The duration of the study is up to 72 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. 
Population 
 
 
Sample Size: 
The sample size has been revised from 2700 patients in the previous 
amendments to approximately 1620 patients in amendment 4 due to the 
discontinuation of fasinumab 3 mg Q4W and 6 mg Q8W dose regimens.  
There will be approximately 600 patients randomized to the fasinumab 1 mg 
SC Q4W group, 300 patients randomized to the each of the NSAID groups, 
and 300 patients randomized to the placebo group (a total of 1500 patients).  
In addition, approximately 60 patients each were enrolled in the fasinumab 
3 mg SC Q4W and 6 mg SC Q8W groups under earlier versions of the 
protocol before dosing was discontinued in these treatment groups. 
 
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. 
Treatment(s) 
 
 
SC Study Drug 
 
Dose/Route/Schedule: 
Fasinumab 
1 mg SC every 4 weeks (Q4W). 
 
Oral Study Drug 
 
Dose/Route/Schedule: 
Celecoxib (200 mg oral once daily) 
Diclofenac (75 mg oral twice daily) 
 
SC Study Drug Placebo 
 
Route/Schedule: 
Fasinumab placebo  
SC Q4W 
 
Oral Study Drug 
  
Placebo  
 
Route/Schedule: 
NSAID placebo (oral, see below for schedule). 
 
 
Patients will receive study drug and reference treatments as follow to 
maintain the study blind: 
 
Fasinumab 1 mg SC Q4W and NSAID-matching placebo oral, twice 
daily 
 
Fasinumab-matching placebo SC Q4W and diclofenac 75 mg oral, 
twice daily 
 
Fasinumab-matching placebo SC Q4W, celecoxib 200 mg oral once 
daily, and NSAID-matching placebo oral once daily 
 
Fasinumab-matching placebo SC Q4W and NSAID-matching placebo 
oral, twice daily 
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Rescue Treatment: 
During the 24-week treatment period, acetaminophen/paracetamol will be 
the only study-provided rescue medication.  In the event that pain relief for 
OA pain is inadequate, 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 local standard of care.  The 
maximum 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. 
Endpoint(s) 
 
 
Primary: 
The co-primary endpoints are: 
1. Change in the Western Ontario and McMaster Universities 
Osteoarthritis Index (WOMAC) pain subscale scores from baseline 
to week 24 in patients treated with fasinumab compared to patients 
treated with placebo. 
2. Change in the WOMAC physical function subscale scores from 
baseline to week 24 in patients treated with fasinumab compared 
to patients treated with placebo. 
 
Secondary: 
The key secondary endpoints of the study are: 
1. Change from baseline to week 24 in Patient Global Assessment 
(PGA) in patients treated with fasinumab compared to patients 
treated with placebo 
2. Percentage of patients treated with fasinumab, compared to 
patients treated with placebo, who had a response at week 24, with 
response defined as an improvement by ≥30% in WOMAC pain 
sub scale score 
3. Change from baseline to week 24 in WOMAC pain subscale scores 
in patients treated with fasinumab compared to patients treated 
with NSAIDs (pooled celecoxib and diclofenac arms) 
4. Change from baseline to week 24 in WOMAC physical function 
subscale scores in patients treated with fasinumab compared to 
patients treated with NSAIDs (pooled celecoxib and diclofenac 
arms) 
5. Change from baseline to week 24 in PGA score in patients treated 
with fasinumab compared to patients treated with NSAIDs (pooled 
celecoxib and diclofenac arms) 
Safety: 
The safety endpoints in this study are: 
1. Incidence of AA (as confirmed by independent adjudication) 
2. Incidence of destructive arthropathy (DA) (as confirmed by 
independent adjudication)  
3. Incidence of TEAEs  
4. Incidence of sympathetic nervous system dysfunction (as 
diagnosed after consultation with an appropriate specialist, such as 
a neurologist and/or cardiologist) 
5. Incidence of peripheral sensory AEs that require a neurology or 
other specialty consultation 
6. Incidence of all-cause JRs through week 24 and through the 
follow-up period (week 44) 
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7. Incidence of JR at telephone survey 52 weeks after completion of 
study drug 
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 and complete a 
self-reported assessment of peripheral or central pain. 
Efficacy will be assessed by the change from baseline in the WOMAC pain 
and physical function subscale scores, the PGA, the Numeric Rating Scale 
of the average walking index joint pain, the EuroQoL 5 Dimensions 5 Level 
Questionnaire, the 36-item Short Form Survey, the Healthcare Resource 
Utilization 
Questionnaire, 
the 
Work 
Productivity 
and 
Activity 
Impairment-Osteoarthritis, and the Treatment Satisfaction Questionnaire for 
Medication.  The WOMAC total and stiffness scores will also be evaluated. 
Safety assessments will be performed at each study visit during treatment 
period and upon occurrence of any joint adverse events (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 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. 
Approximately 52 weeks after administration of the last dose of SC study 
drug, 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 
There are 6 hypotheses for the primary and key secondary endpoints.  The 
primary treatment comparison for the WOMAC pain and physical function 
subscale scores will be declared superior only if the comparisons are 
significant for both WOMAC pain and physical function subscale scores.  A 
sequentially rejective multiple test procedure will be applied to control for 
multiplicity and to maintain study-wise Type I error rate at two-sided 0.05 
level for the hypotheses (Hi, i=1,…, 6 for fasinumab 1 mg Q4W) for the 
primary and key secondary endpoints. 
Justification of Sample Size 
Assuming a 2-sided alpha level 0.05 and a 20% dropout rate up to week 24, 
an enrollment of 600 patients in the fasinumab 1 mg SC Q4W group and 
300 patients in the placebo group will provide at least 99% 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 a SD of 2.4). The assumed treatment difference and SD are 
based on results from study R475-PN-1227.  The sample size will provide 
99% power to detect an effect size of 0.36 in PGA (ie, absolute treatment 
difference of 0.4 with a SD of 1.1, R475-PN-1227). 
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Assuming a 2-sided alpha level 0.05 and a 20% dropout rate up to week 24, 
an enrollment of 600 patients per arm in the fasinumab 1 mg SC Q4W group 
and pooled NSAIDs group will provide approximately 92% power to detect 
an effect size of 0.22 in the WOMAC pain subscale (ie, absolute treatment 
difference of 0.51 with a SD of 2.3).  The sample size will provide 
95% power to detect an effect size of 0.24 in WOMAC physical function 
subscale (ie, absolute treatment difference of 0.50 with a SD of 2.1) and 
79% power to detect an effect size of 0.18 in PGA (ie, absolute treatment 
difference of 0.18 with a SD of 1.0). 
Statistical Methods 
Baseline demographic disease characteristics, including medical history and 
exposure to study drug, will be summarized by treatment group using 
descriptive statistics.  Continuous variables will be summarized with mean, 
median, standard deviation, minimum, and maximum.  For categorical or 
ordinal data, frequencies and percentages will be displayed for each 
category. 
The primary 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 adverse 
events assuming the WOMAC scores would on average return to baseline 
values. The imputed data for patients discontinued from the study treatment 
due to lack of efficacy or AEs will be centered at the mean baseline value. 
The missing data for patients who discontinued treatment due to other 
reasons will be imputed under missing-at-random assumption. Sensitivity 
analysis using tipping point approach with multiple imputation will be 
performed to assess the robustness of the results due to data that may be 
missing not-at-random. 
For analysis of continuous secondary endpoints, the analysis method will be 
the same as that used for the primary variables.  For analysis of categorical 
variables in secondary endpoints, eg, proportions of patients with ≥30% 
improvement in the WOMAC pain subscale scores at week 24, the Cochran 
Mantel Haenszel approach stratified by the randomization strata will be used 
with missing data considered as non-response. 
Safety 
data 
including 
treatment-emergent 
adverse 
events 
and 
treatment-emergent adverse events of special interest, vital signs, physical 
examinations, laboratory tests, electrocardiograms, and anti-drug antibody 
formation will be listed and summarized by treatment group. 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
5-ASA 
5-aminosalicylic acid 
AA 
Adjudicated arthropathy 
ACE 
Angiotensin-converting enzyme 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ARB 
Angiotensin receptor blocker 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
bpm 
Beats per minute  
Cmax 
Maximal concentration 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
Ctrough 
Trough concentrations 
CTCAE 
Common Terminology Criteria for Adverse Events 
DA 
Destructive arthropathy 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EOS 
End of study 
EOT 
End of treatment 
EQ-5D-5L 
EuroQoL 5 Dimensions 5 Level Questionnaire 
ESR 
Erythrocyte sedimentation rate 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
HbA1c 
Hemoglobin A1c 
HCRU 
Healthcare Resource Utilization 
hs-CRP 
High-sensitivity C-reactive Protein 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
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IV 
Intravenous 
IWRS 
Interactive web response system 
JR 
Joint replacement 
K-L 
Kellgren-Lawrence 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect Model for Repeated Measures 
MRI  
Magnetic Resonance Imaging 
NGF 
Nerve growth factor 
NRS 
Numeric Rating Scale 
NSAID 
Non-steroidal anti-inflammatory drug 
OA 
Osteoarthritis 
PGA 
Patient Global Assessment 
PK 
Pharmacokinetic 
PPS 
Per protocol set  
Pre-op 
Pre-operative 
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 Software 
SC 
Subcutaneous 
SD 
Standard deviation 
SF-36 
36-item Short Form Medical Outcomes Study Questionnaire Version 2 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TBL 
Total bilirubin  
TEAE 
Treatment-emergent adverse event 
TrkA 
Tyrosine kinase type 1  
TSQM 
Treatment Satisfaction Questionnaire for Medication 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
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WOCBP 
Woman of child-bearing potential  
WOMAC 
Western Ontario and McMaster Universities Osteoarthritis Index 
WPAI-OA 
Work Productivity and Activity Impairment-Osteoarthritis 
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1. 
INTRODUCTION  
Chronic musculoskeletal pain affects a large portion 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 continually rising (Sarzi-Puttini 2005). 
Non-steroidal 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 (GI) bleeding and increased risk of 
cardiovascular events (Lanas 2011) (Trelle 2011).  Non-steroidal anti-inflammatory drugs have 
limited efficacy in many OA patients; those with advanced OA typically try several NSAIDs and 
must often move 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 (American College of 
Rheumatology Subcommittee on Osteoarthritis Guidelines 2000).  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 are 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 (Smith 2016), 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. 
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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 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 edition of 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 three 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, the R475-PN-1227 study 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 edition 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 demonstrated 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. 
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Based on the potential risk of DA identified in tanezumab and fulranumab, the United States (US) 
Food and Drug Administration (FDA) placed this 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 are implemented 
to minimize 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 for select changes in 
joint structure.  The 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 has conducted or initiated several clinical 
trials of fasinumab. In all clinical studies to date, fasinumab was associated with a low rate of 
discontinuations due to adverse events. 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 2012, studies of other anti-NGF monoclonal antibodies (mAbs) identified adverse changes in 
the sympathetic nervous system of mature animals of several species (rat and non-human primate).  
These effects include a reversible decrease in neuron volume.  To date, no statistically significant 
or consistent effects of fasinumab on the sympathetic nervous system have been detected in animal 
studies with up to 6-months of treatment.  Nonetheless, based on the potential risk of sympathetic 
nervous system toxicity associated with these other anti-NGF mAbs in animal studies, a risk 
mitigation approach is being implemented for all fasinumab studies, as outlined in Section 9.6.1.2. 
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 benefit-risk 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 an on-going study in the 
fasinumab phase 3 OA program (R475-PN-1523). Subsequently a small Regeneron team reviewed 
the data and agreed with this recommendation.  The DMC noted imbalances in clinically relevant 
adverse events 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.  
Fasinumab is currently being evaluated in 2 phase 3 studies in patients with pain due to OA. Study 
R475-PN-1523 is currently ongoing and is designed to assess the long-term safety and efficacy of 
multiple doses of fasinumab compared to placebo in patients with 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.  
The phase 3 study described here, R475-OA-1688, is designed to compare the efficacy and safety 
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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). 
Additional background information on fasinumab and the development program can be found in 
the current edition of the Investigator’s Brochure. 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of fasinumab compared to placebo, 
when administered for up to 24 weeks in patients with pain due to OA of the knee or hip. 
2.2. 
Secondary Objective(s) 
The secondary objectives of the study are: 
 To evaluate the efficacy of fasinumab compared to NSAIDs, when administered for up 
to 24 weeks in patients with pain due to OA of the knee or hip 
 To assess the safety and tolerability of fasinumab compared to placebo and compared 
to NSAIDs, when administered for up to 24 weeks in patients with pain due to OA of 
the knee or hip  
 To characterize the concentrations of fasinumab over time when administered for up to 
24 weeks in patients with pain due to OA of the knee or hip 
 To evaluate the immunogenicity of fasinumab administered for up to 24 weeks in 
patients with pain due to OA of the knee or hip  
2.3. 
Exploratory Objectives 
 To evaluate patient-reported outcome measures in patients with pain due to OA of the 
knee or hip treated for up to 24 weeks with fasinumab compared to placebo and 
compared to NSAIDs  
 To evaluate the use of rescue medication in patients with pain due to OA of the knee 
or hip treated for up to 24 weeks with fasinumab compared to placebo and compared 
to NSAIDs  
3. 
HYPOTHESIS AND RATIONALE  
3.1. 
Hypothesis 
Based on results from previous clinical studies of fasinumab in patients with OA, fasinumab is 
expected to provide effective pain relief based on an improvement in the WOMAC pain sub-scale 
score and improved functionality based on the WOMAC physical function sub-scale. 
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3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
The present study is a randomized, double-blind, placebo- and NSAID-controlled study to evaluate 
the efficacy and safety of fasinumab in patients with OA of the knee or hip who have a history of 
inadequate pain relief from acetaminophen/paracetamol and a history of intolerance to or 
inadequate pain relief from opioids (or are unwilling to take opioids) for OA pain management. 
This study will compare the efficacy and safety of fasinumab to placebo and to a pooled NSAID 
group of celecoxib or diclofenac, which are members of the class of NSAID medications 
commonly used for moderate-to-severe pain due to OA. 
The target study population was chosen because they currently have unmet medical needs with 
respect to incomplete pain control, in spite of the availability of NSAIDs.  This study will provide 
efficacy and safety data for OA patients exposed for up to 24 weeks to fasinumab, a pooled NSAID 
comparator group (celecoxib or diclofenac), or placebo.  The study will be conducted with 
appropriate eligibility criteria to exclude patients who may be at risk for events of joint damage 
and sympathetic nervous system effects. 
Rescue medication (acetaminophen/paracetamol) will be made available for any patient with 
breakthrough pain.  Specific questionnaires and physical examinations will be employed to 
monitor for any events of arthralgia, worsening joint pain, altered peripheral sensation, AA, and 
sympathetic nervous system effects. 
This study will enroll patients who have failed or are intolerant to opioids and have failed 
acetaminophen/paracetamol.  As there are currently a limited number of therapeutic options 
available, enrollment of this study population supports equipoise with respect to randomization of 
patients to fasinumab or to placebo. 
The inclusion of a placebo treatment group is important to accurately determine the efficacy of 
fasinumab. Non-steroidal anti-inflammatory drugs are the most common medications used to treat 
pain due to OA. Therefore, comparison of fasinumab to the NSAIDs treatment group will aid in 
determining the efficacy of fasinumab compared to a frequently used and effective standard of 
care class of medications for OA, but that have associated clinically significant AEs.  As celecoxib 
and diclofenac are commonly used and highly effective NSAIDs (Ong 2007), they have been 
selected as comparator drugs for this study. As a widely studied, standard of care therapy for OA, 
NSAIDs will serve as an effective calibrator to best understand the potential therapeutic benefit of 
fasinumab in this study population.  
Inclusion of both the placebo group and the active treatment comparator group will be important 
to accurately estimate the risk of AEs, including the AEs of special interest of adjudicated 
arthropathy and sympathetic nervous system dysfunction. 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. A patient or investigator can choose to end participation at any time. Patients 
will have access to rescue medication, as appropriate. Therefore, the use of a placebo group is 
justified, as placebo-treated patients will not be placed at significant risk. 
The patients will be stratified by the affected index joint (hip or knee), by Kellgren-Lawrence 
(K-L) score (2 to 3, or 4), and by geographic region to enable analysis of efficacy and safety.  The 
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K-L stratification scheme is used here to ensure that at baseline there is an equal distribution of 
patients with the most severe OA at baseline across the dosing groups. 
3.2.2. 
Rationale for Dose Selection 
Previous versions of this protocol randomized patients to receive fixed-dose, subcutaneous (SC) 
injections of 1 mg of fasinumab Q4W, 3 mg fasinumab Q4W, 6 mg fasinumab every 8 weeks 
(Q8W with alternating placebo injections at the monthly visits where fasinumab will not be given, 
to maintain the blind), celecoxib active comparator, diclofenac active comparator, or matching 
placebo. Based on April 2018 recommendations from an independent Data Monitoring Committee 
(DMC) that reviewed unblinded data from a different ongoing phase 3 study of fasinumab 
(R475-PN-1523), the decision was made to discontinue further evaluation of fasinumab at 3 mg 
Q4W or 6 mg Q8W in the phase 3 program. This recommendation was based on an imbalance in 
clinically relevant adverse events including time to total joint replacement, peripheral edema, 
arthralgia and a trend towards fractures.  Under amendment 3 global, all patients previously 
randomized to 3 mg Q4W or 6 mg Q8W under an earlier version of the protocol were discontinued 
from study drug but encouraged to otherwise continue all protocol visits and study procedures in 
the follow-up period and the end of study phone call. 
Clinical trial data, including PK data, that support selection of these fasinumab doses include those 
from the phase 1 studies in healthy volunteers (R475-PN-0817 and TDU-11480), the R475-PN-
0901 phase 2 proof-of-concept study in patients with pain due to OA of the knee, the R475-PN-
1227 phase 2/3 study in patients with OA of the hip or knee, and the R475-PN-0908 single-dose, 
proof-of-concept study in patients with sciatic pain.  
Single SC doses of fasinumab of up to 30 mg were well-tolerated in healthy male and female 
subjects in the TDU-11480 study.  All single IV doses of fasinumab in the R475-PN-0817 study 
in healthy male and female subjects were generally well tolerated at all but the highest IV dose 
(1 mg/kg).  The occurrence of neurosensory AEs, which were transient and non-severe, led to the 
decision to refrain from escalating above the 1 mg/kg IV dose and instead, to expand enrollment 
of the 1 mg/kg IV cohort. 
In the R475-PN-0901 phase 2 proof-of-concept study of fasinumab in patients with pain due to 
OA of the knee, multiple IV doses of up to 0.3 mg/kg administered Q8W demonstrated efficacy 
with regard to pain relief and were well tolerated in Caucasian subjects.  All 3 doses of fasinumab 
(0.03 mg/kg, 0.1 mg/kg, and 0.3 mg/kg IV Q8W) were associated with greater improvement 
compared with placebo in walking index knee pain, standardized total WOMAC score, WOMAC 
subscales (pain, function, and stiffness) and Patient’s Global Impression of Change.  However, it 
was noted that pain relief had the slowest onset with the lowest (0.03 mg/kg) dose. 
In the R475-PN-1227 phase 2/3 study of fasinumab in patients with pain due to OA of the hip or 
knee, all SC doses (1 mg, 3 mg, 6 mg, and 9 mg Q4W) demonstrated efficacy in pain relief and 
physical function measures, based upon WOMAC pain and physical function scales assessed after 
16 weeks of treatment. Considering the relative lack of an observed dose response for efficacy and 
the increased risk of AA with both the 9 mg and 6 mg Q4W doses, the latter doses are no longer 
being studied. Neuromuscular AEs, such as arthralgia and paresthesia, were reported more 
frequently in fasinumab treated patients than in placebo-treated patients, though these events were 
typically mild or moderate in intensity. The efficacy and safety data from the 1 mg and 3 mg Q4W 
dose regimens in R475-PN-1227 supported the previous dose selection of 1 mg and 3 mg Q4W 
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and 6 mg Q8W in the present study. Now, with the removal of the 3 mg Q4W and 6 mg Q8W dose 
regimens due to emerging safety information, the 1 mg Q4W dose regimen will continue to be 
evaluated in this study and is deemed to have a favorable benefit-risk profile. 
All randomized patients in this study will receive an orally administered NSAID or matching 
NSAID placebo.  The dose of diclofenac will be 75 mg twice daily.  The dose of celecoxib will be 
200 mg once daily.  These NSAID doses reflect the recommendations in the US label for treatment 
of pain associated with OA. In order to preserve the blind, patients randomized to celecoxib will 
receive celecoxib 200 mg once daily in the morning and a matching celecoxib placebo in the 
afternoon. Patients randomized to matching NSAID placebo will receive the placebo twice daily.  
All NSAIDs and matching NSAID placebo will be over-encapsulated to preserve the blind. 
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 Endpoint 
The co-primary endpoints are: 
1. Change in the WOMAC pain subscale scores from baseline to week 24 in patients treated 
with fasinumab compared to patients treated with placebo. 
2. Change in the WOMAC physical function subscale scores from baseline to week 24 in 
patients treated with fasinumab compared to patients treated with placebo. 
4.2.2. 
Secondary Endpoints 
The key secondary endpoints of the study are: 
1. Change from baseline to week 24 in Patient Global Assessment (PGA) in patients treated 
with fasinumab compared to patients treated with placebo 
2. Percentage of patients treated with fasinumab, compared to patients treated with placebo, 
who had a response at week 24, with response defined as an improvement by ≥30% in 
WOMAC pain sub scale score 
3. Change from baseline to week 24 in WOMAC pain subscale scores in patients treated with 
fasinumab compared to patients treated with NSAIDs (pooled celecoxib and diclofenac 
arms) 
4. Change from baseline to week 24 in WOMAC physical function subscale scores in patients 
treated with fasinumab compared to patients treated with NSAIDs (pooled celecoxib and 
diclofenac arms) 
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5. Change from baseline to week 24 in PGA score in patients treated with fasinumab 
compared to patients treated with NSAIDs (pooled celecoxib and diclofenac arms) 
4.2.3. 
Exploratory Endpoints 
Exploratory endpoints will be defined in the Statistical Analysis Plan. 
4.3. 
Safety Endpoints 
The safety endpoints in this study are: 
 Incidence of AA (as confirmed by independent adjudication) 
 Incidence of DA (as confirmed by independent adjudication)  
 Incidence of TEAEs  
 Incidence of sympathetic nervous system dysfunction (as diagnosed after consultation 
with an appropriate specialist, such as a neurologist and/or cardiologist) 
 Incidence of peripheral sensory AEs that require a neurology or other specialty 
consultation 
 Incidence of all-cause JRs through week 24 and through the follow-up period 
(week 44) 
 Incidence of JR at telephone survey 52 weeks after completion of study drug 
4.4. 
Pharmacokinetic Variables 
The PK variables will consist of fasinumab concentrations in samples collected at time points 
specified in Table 1. 
4.5. 
Anti-Drug Antibody Variables 
Anti-drug antibody (ADA) variables include status (positive or negative) and titer as follows:  
 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 or greater over baseline titer levels when baseline is positive in 
the ADA assay  
 Titer values 
 Titer category 
 Low (titer <1,000) 
 Moderate (1,000≤ titer ≤10,000) 
 High (titer >10,000)  
 Neutralizing ADA for samples that are positive in the ADA assay 
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5. 
STUDY DESIGN 
5.1. 
Study Description and Duration 
This study is a randomized, double-blind, placebo- and NSAID-controlled study designed to 
evaluate the efficacy and safety of fasinumab in patients with OA of the knee or hip who have a 
history of inadequate pain relief with acetaminophen/paracetamol and a history of intolerance to 
or inadequate pain relief with opioids (or are unwilling to take opioids or have lack of access to 
opioids). The study consists of a screening period of up to 30 days, a 7 to 10 day 
pre-randomization/washout period (7 days with a +3 day window), a 24-week treatment period 
(with the last Q4W dose of study drug administered at week 20), a 20-week follow-up period, and 
a final phone call approximately 52 weeks after the last SC dose of study drug (Figure 1). 
Figure 1: 
Study Flow Diagram 
Screening & Pre-randomization 
Treatment 
Follow-Up 
EOS-Phone 
Contact 
Up to 40 Days 
Day 1 to Week 24 
Week 25 to 44 
Up to Week 72 
 
Randomization 
 
End of 
Treatment  
End of 
Follow up 
 
 
 
 
 
Screening 
Pre-randomization  
 
 
 
 
Up to 30 Days  
 
7 to 10 Days 
Baseline  
Day 1 
 
Week 24 
Week 44 
Week 72 
 
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 joint 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. During the screening period, all 
patients will continue to take their current treatment regimen for OA pain, which must include use 
of an oral NSAID on a regular basis, defined as approximately 4 days per week over the last 
4 weeks. 
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 randomization.  Patients will discontinue and/or undergo a washout of, their standard-of-
care pain medications for OA during the pre-randomization period.  As needed, 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. 
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5.1.2. 
Rescreening 
Re-testing During Screening or Pre-randomization 
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 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 do not meet the WOMAC criteria or have orthostatic 
hypotension (defined in Section 8.2.3.3) during the screening or pre-randomization visit. 
Rescreening Due to 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 or have 
orthostatic hypotension (defined in Section 8.2.3.3) during the screening or pre-randomization 
visit. 
5.1.3. 
Randomization 
Patients will be randomized on day 1 (baseline) to 1 of the following treatment groups: 
 Fasinumab 1 mg SC Q4W and NSAID-matching placebo oral, twice daily 
 Fasinumab-matching placebo SC Q4W and diclofenac 75 mg oral, twice daily 
 Fasinumab-matching placebo SC Q4W, celecoxib 200 mg oral once daily, and NSAID-
matching placebo oral once daily 
 Fasinumab-matching placebo SC Q4W and NSAID-matching placebo oral, twice daily 
Patients will receive treatment as described in Section 7.1.  The method of treatment assignment 
is described in Section 7.5. 
5.1.4. 
Treatment Period 
During the treatment period (day 1 through week 24), patients will be permitted to use only 
acetaminophen/paracetamol as rescue medication. The study visits during the treatment period will 
include 1 phone visit on day 15 (±3 days). 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 study visits in order to minimize the confounding 
effects of the rescue medication on efficacy measurements.  
Efficacy will be assessed by the change from baseline in the WOMAC pain and physical function 
subscale scores, the PGA, the Numeric Rating Scale (NRS) of the average walking index joint 
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pain, the Work Productivity and Activity Impairment-Osteoarthritis (WPAI-OA), the 36-item 
Short Form Survey (SF-36), the EuroQoL 5 Dimensions 5 Level Questionnaire (EQ-5D-5L), the 
Healthcare Resource Utilization (HCRU) questionnaire, and the Treatment Satisfaction 
Questionnaire for Medication (TSQM).  The WOMAC total and stiffness scores will also be 
evaluated. 
Safety assessments will be performed at each study visit during treatment period, as outlined in 
Table 1. 
5.1.5. 
Follow-up Period 
After the end of treatment, follow up of patients will continue for an additional 20 weeks after the 
last treatment period visit.  Safety and efficacy assessments will be performed according to the 
schedule outlined in Table 1.  
If a patient must undergo JR surgery during the study, 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 
A phone contact questionnaire will be conducted at approximately 52 weeks after administration 
of the last dose of fasinumab or fasinumab-matching 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). 
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. 
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 
totality of evidence, if the DMC has significant concerns at any time regarding a meaningful 
imbalance between treatment groups in joint-related AEs, sympathetic nervous system 
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 for the last patient.  
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5.2. 
Planned Interim Analysis  
No interim analysis of efficacy is planned for this study. The primary efficacy analysis may be 
conducted when 24 week data are available for all randomized patients. No alpha adjustment is 
necessary, as the week 24 efficacy analysis will be the final primary analysis for efficacy.  The 
results will not be disclosed to any site-facing personnel or to any personnel directly involved with 
the conduct of the study. 
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 sponsor about the conduct of the study.  
The DMC will be comprised of 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, 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 sample size for this study has been revised from 2700 patients in the previous amendments to 
approximately 1620 patients in amendment 4 due to the discontinuation of fasinumab 3 mg Q4W 
and 6 mg Q8W dose regimens.  There will be approximately 600 patients randomized to the 
fasinumab 1 mg SC Q4W group, 300 patients randomized to the each of the NSAID groups, and 
300 patients randomized to the placebo group (a total of 1500 patients).  In addition, 
approximately, 60 patients each were enrolled in the fasinumab 3 mg SC Q4W and 6 mg SC Q8W 
groups prior to the implementation of the urgent safety measure to discontinue these doses. 
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, at least 18 years of age, at screening 
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2. Provide signed informed consent 
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 (acetaminophen/paracetamol 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 analgesic 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 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. Currently using a stable dose of NSAID, defined as using oral NSAIDs at regularly 
prescribed doses for approximately 4 days per week over the last 4 weeks (patients who 
are screen failures prior to the randomization visit but who met the NSAID use criterion at 
screening would still meet this criterion if they are eligible for rescreening) 
9. Willing to continue a stable dose of oral NSAID during the screening period, defined as 
using NSAIDs for approximately 4 days per week 
10. Willing to discontinue glucosamine sulfate and chondroitin sulfate treatments during the 
24 weeks of treatment 
11. Stable treatment with glucosamine sulfate and chondroitin sulfate treatments must be 
stopped during the pre-randomization period 
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12. 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 
13. Willing to maintain current activity and exercise levels throughout the study 
14. 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 
15. 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. Non-compliance with the NRS recording during the pre-randomization period (4 or more 
consecutive missed diary entries) 
2. 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 
3. 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 
4. Trauma to the index joint within 3 months prior to the screening visit 
5. Signs or symptoms of carpal tunnel syndrome within 6 months of screening 
6. Patient is not a candidate for MRI 
7. 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 
8. History or presence at the screening visit of autonomic neuropathy, diabetic neuropathy, or 
other peripheral neuropathy, including reflex sympathetic dystrophy  
9. History or diagnosis of chronic autonomic failure syndrome including pure autonomic 
failure, multiple system atrophy (Shy-Drager syndrome) 
10. History of NSAID intolerance, or existence of a medical condition that is high risk for 
NSAID-associated complications (eg, high risk of gastrointestinal bleed, previous ulcer, 
condition requiring the use of anti-coagulants or anti-platelet therapy, or acute coronary 
syndrome)  
11. Known allergy or sensitivity to doxycycline or related compounds, or monoclonal 
antibodies or sulfa drugs. 
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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 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 8.2.3.2, 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 NY Heart Classification of stage III or IV (Dolgin 1994)  
22. History of peripheral vascular disease, transient ischemic attack, cerebrovascular accident, 
myocardial infarction, unstable angina, or documented atherosclerotic cardiovascular 
disease 
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 
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28. History of hospital admission for depression or suicide attempt within 5 years or active, 
severe major depression at screening 
29. Use of systemic, eg, IV, oral or intramuscular corticosteroids 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, 
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 
37. Pregnant or breastfeeding women 
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 the start of the first treatment, during the study, and for at least 
20 weeks after the last dose. Highly effective contraceptive measures include 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; intrauterine device; intrauterine hormone-releasing system; bilateral 
tubal ligation; vasectomized partner; and or sexual abstinence†, ‡. 
*Postmenopausal women must be amenorrheic for at least 12 months in order not to be 
considered of childbearing potential.  Pregnancy testing and contraception are not required 
for women with documented 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 
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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, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method are not 
acceptable methods of contraception.  Female condom and male condom should not be 
used together. 
40. Patients taking concomitant angiotensin-converting enzyme (ACE) inhibitors/angiotensin 
receptor blockers (ARBs) and diuretics, or presence of an estimated glomerular filtration 
rate (GFR) <30 mL/minute/1.73m2* 
*GFR is calculated using the Modification of Diet in Renal Disease Study (MDRD) 
equation, as follows: 
GFR = 175 x (Standardized SCr)-1.154 x (age)-0.203 (x 0.742 if female) x (1.212 if African 
American) 
GFR is expressed in mL/min/1.73m2 
SCr is serum creatinine expressed in mg/dL 
Age is expressed in years 
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 study 
assessments, as described in Section 8.1.3. 
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 7.3.2. 
6.4. 
Replacement of Patients 
Patients prematurely discontinued from the study or study drug will not be replaced. 
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7. 
STUDY TREATMENTS  
7.1. 
Investigational and Reference Treatments 
Study drug in this study includes fasinumab, NSAID (diclofenac or celecoxib), and their matching 
placebo.  Fasinumab and its matching placebo are SC study drug. NSAID (diclofenac or celeoxib) 
and its matching placebo are oral study drug. 
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 a 
2 mg/mL solution (1 mg dose) of study drug 
 Fasinumab-matching placebo: Each 1 mL single use pre-filled syringe delivers 0.5 mL 
of placebo solution 
 Celecoxib (200 mg capsules), diclofenac (75 mg capsules) and NSAID-matching 
placebo capsules will be provided by the sponsor. All NSAIDs and NSAID-matching 
placebo will be over-encapsulated to preserve the blind. 
Patients will be randomized 2:1:1:1 to receive 1 of the following treatment regimens: 
 Fasinumab 1 mg SC Q4W and NSAID-matching placebo oral, twice daily 
 Fasinumab-matching placebo SC Q4W and diclofenac 75 mg oral, twice daily 
 Fasinumab-matching placebo SC Q4W, celecoxib 200 mg oral once daily, and NSAID-
matching placebo oral once daily 
 Fasinumab-matching placebo SC Q4W and NSAID-matching placebo oral, twice daily 
All patients will receive SC injections of fasinumab or fasinumab-matching placebo.  All SC 
injections will be in the abdomen, thigh or upper arm.  Patients will be observed in the clinic for 
approximately 1 hour after study drug is administered. Patients randomized to earlier versions of 
the protocol with 3 mg SC Q4W or 6 mg SC Q8W fasinumab must be discontinued from study 
drug for the remainder of the study and will move directly into the follow-up period. 
NSAIDs or NSAID-matching placebo will be administered orally.  A proton pump inhibitor or 
other gastric protective medication may be prescribed if deemed medically necessary by the 
investigator or sub-investigator. 
Doses of SC study drug must be given within ±7 days from the scheduled dose date.  If the window 
is missed, the SC dose of fasinumab or fasinumab-matching placebo should not be administered, 
however, the oral dose of NSAID or NSAID-matching placebo should be dispensed.  The next SC 
dose of fasinumab or fasinumab-matching placebo should be administered at the next scheduled 
dosing date. 
Detailed instructions for study drug dose administration are provided in the pharmacy manual. 
7.2. 
Rescue Treatment  
During the 24-week treatment period, acetaminophen/paracetamol will be the only study-provided 
rescue medication.  In the event that pain relief for OA pain is inadequate, or in the event of other 
pain (eg, headache) or fever, 1 to 2 tablets/capsules of acetaminophen/paracetamol may be taken 
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no less than 4 hours apart, as needed, according to local standard of care.  The maximum 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 acetaminophen/paracetamol. 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 assessments. Use of acetaminophen/paracetamol as study-provided rescue medication 
during the treatment period will be reported daily by patients using diaries. During the treatment 
period, the acetaminophen/paracetamol will be sourced by the study sites and dispensed to the 
patient at each visit where SC study drug is administered. Acetaminophen/paracetamol 
accountability will be conducted at each study visit starting at the baseline visit and continuing 
through the week 24 visit.  
During the 20-week follow-up period, acetaminophen/paracetamol will not be provided by the 
sites to the patients.  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 
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.  
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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 (as described in Section 8.2.3.10).  Preoperative imaging 
(X-ray and MRI) will be obtained and submitted to the independent adjudication committee for 
review to ensure that an AA event is not in occurrence.  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 any of the following: 
 A patient who is currently enrolled under an earlier version of this protocol must be 
immediately discontinued from study drug, undergo all end of treatment visit 
assessments and move directly into the 20-week safety follow-up period under this 
version of the protocol, if they meet any of the following conditions that were excluded 
after re-evaluating the safety profile of NSAIDs: 
a) They have a known medical history (at any time) of peripheral vascular disease, 
transient ischemic attack, cerebrovascular accident, myocardial infarction, unstable 
angina, or documented atherosclerotic cardiovascular disease; or 
b) They have a known GFR <30 mL/minute/1.73 m2 or, 
c) They are currently taking combination therapy of a diuretic with either an ACE 
inhibitor or ARB (Note: Patients may remain in the study if they are willing and 
able to change their antihypertensive regimen such that they are no longer on a 
combination of a diuretic with either an angiotensin-converting enzyme (ACE) 
inhibitor or angiotensin receptor blocker (ARB) 
 A patient who was randomized under an earlier version of the protocol to 3 mg SC 
Q4W or 6 mg SC Q8W fasinumab 
 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 
 A patient developing new or worsening signs and symptoms indicative of carpal tunnel 
syndrome 
 Continued 
non-compliance 
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 non-compliance with the protocol, including usage of NSAIDs that are not 
permitted in the study, after appropriate counseling 
 Joint replacement surgery 
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 Adverse events of special interest (AESIs) of: 
- 
Adjudicated arthropathy, as described in Section 9.6.1.1 
- 
Sympathetic nervous system dysfunction, as described in Section 9.6.1.2 
 Hepatotoxicity.  Study drug should be discontinued if the following are observed: 
1. Total bilirubin (TBL) >2x ULN or international normalized ratio >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 
 Gastrointestinal bleeding, acute coronary syndrome 
 Any other medical need, as determined by the investigator  
 Sponsor decision 
 Patient decision  
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. Subcutaneous study drug (fasinumab or fasinumab-matching placebo) will be 
temporarily withheld while awaiting imaging adjudication for worsening joint pain or when 
routine imaging suggests adjudicated arthropathy and prompts the need for additional imaging (see 
Section 9.6.1.1), or for patients who are determined to have orthostatic hypotension or determined 
to have new or worsening symptoms suggestive of sympathetic nervous system dysfunction while 
awaiting evaluation by a specialist (see Section 9.6.1.2). Patients may continue to take NSAID or 
NSAID-matching placebo during this time. Subcutaneous study drug (fasinumab or 
fasinumab-matching placebo) should not be re-started until the next study visit unless 
imaging/evaluation results are available within the current visit window. If oral study drug is 
temporarily discontinued by the investigator, patients may continue to take SC study drug during 
this time. 
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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 for injections performed at the study site.  All 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 injection of SC 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 grade according to Section 9.5.1. 
7.5. 
Method of Treatment Assignment  
Approximately 1500 patients will be randomized in a 2:1:1:1 ratio to receive fasinumab 
(1 mg Q4W), diclofenac, celecoxib, or placebo 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), the K-L score (2 to 3, or 4) at 
the screening visit, and geographical region. 
Prior to amendment 3 global (urgent safety measure), approximately 60 patients each were 
enrolled in the fasinumab 3 mg Q4W and 6 mg Q8W groups.  However, dosing of these patients 
was discontinued, as recommended by the independent DMC in April 2018. Overall, a total of 
approximately 1620 patients are planned for this study. 
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 medical director, study 
monitor, and any other Regeneron 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. 
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. 
No study personnel involved in the day-to-day conduct of the study will have access to unblinded 
data before the final database is locked for this study. 
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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  
Blinded supplies will be packaged in the following configuration and distributed to sites by 
Regeneron. 
1. One prefilled syringe of investigational SC study drug (Fasinumab or Placebo) per carton 
2. Two bottles containing 35 capsules of NSAIDs or NSAID-matching placebo per carton. 
Diclofenac carton will consist of two bottles of Diclofenac 75 mg capsules. Celecoxib carton will 
consist of one bottle of Celecoxib 200 mg capsules and one bottle of NSAID-matching placebo 
capsules.  NSAID-matching placebo carton will consist of two bottles of NSAID-matching placebo 
capsules. 
A drug numbering system will be used to label blinded study drug.  Lists linking drug 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. 
Subcutaneous study drug will be stored at the site at a temperature of 2ºC to 8ºC, while oral study 
drug will be stored at 20ºC to 25ºC; storage instructions will be provided in the pharmacy manual. 
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7.6.2. 
Supply and Disposition of Treatments  
Subcutaneous and oral study drug will be shipped to the investigator or designee at regular 
intervals or as needed during the study.  At specified time points during the study (eg, interim site 
monitoring visits), at the site close-out visit, and following drug reconciliation and documentation 
by the site monitor, all unopened fasinumab and fasinumab-matching placebo will be returned to 
the sponsor or designee for destruction; opened fasinumab and fasinumab-matching placebo can 
be destroyed at the site; opened and unopened diclofenac, celecoxib and NSAID-matching placebo 
will be returned to the sponsor or designee for destruction.  
7.6.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug.  These records 
should contain the dates, quantity, and study drug that is: 
 dispensed to each patient, 
 returned from each patient (if applicable), 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 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/5-aminosalicyclic acid [5-ASA], which is permitted for cardiac 
prophylaxis, per local guidelines) and opioid analgesic medications, starting at the 
pre-randomization visit and through the treatment period. 
Opioid analgesic medications (including tramadol) are prohibited through the week 24 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/5-ASA, which is permitted for cardiac prophylaxis) until at 
least 16 weeks after the last SC study drug injection.  A list of medications containing NSAIDs 
will be provided in the study reference manual and a reference card given to the patients. 
Other excluded medications during the treatment period include: 
 Any other investigational agent 
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 Medical or regular recreational use of marijuana 
 Chondroitin sulfate 
 Glucosamine  
 Hyaluronic acid intra-articular injections 
 Anticoagulants and antiplatelets (eg, warfarin, heparins, factor Xa inhibitors, thrombin 
inhibitors, aspirin/5-ASA >150 mg daily, clopidogrel) 
 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 
 Interleukin-6 or interleukin-6 receptor antagonists 
 Abatacept, ustekinumab  
 Tumor necrosis factor antagonists 
 IL-1 inhibitors, including diacerein 
 Apremilast, and tofacitinib  
 Combination therapy of diuretics with either an ACE inhibitor or ARB 
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. 
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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. 
8. 
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 Period1 
EOS 
Study Week (wk) 
Visit (V)/Phone 
 
Screen 
V 1 
Pre- 
rand 
V 2 
 
Baseline 
V 3 
 
Wk 2 
Phone 1 
 
Wk 4 
V 4 
 
Wk 8 
V 5 
 
Wk 12 
V 6 
 
Wk 16 
V 7 
 
Wk 20 
V 8 
EOT 
Wk 24 
V 9 
ET1/ 
JR 
Pre-
Op 
Visit 
 
Wk 28 
V 10 
 
Wk 44 
V 11 
ET1/ 
JR 
Pre-
Op 
Visit 
 
Wk 72 
Phone 2 
Study Day 
Up to 
30 
Days 
7 to 10 
Days 
1 
15 
29 
57 
85 
113 
141 
169 
197 
309 
505 
Window (days) 
 
 
 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Screening/Baseline: 
Inclusion/ 
Exclusion2 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Main study 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genomics Sub-
study Informed 
Consent3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI for index 
joint, contralateral 
joint & any hip or 
knee with K-L ≥3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Instructions for use 
of diary 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Training on pain 
reporting/patient 
education  
brochures4 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment: 
SC study drug 
injection5 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Dispense oral 
study drug 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
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Screening/ 
Pre-
randomization  
Treatment Period 
Follow-up Period1 
EOS 
Study Week (wk) 
Visit (V)/Phone 
 
Screen 
V 1 
Pre- 
rand 
V 2 
 
Baseline 
V 3 
 
Wk 2 
Phone 1 
 
Wk 4 
V 4 
 
Wk 8 
V 5 
 
Wk 12 
V 6 
 
Wk 16 
V 7 
 
Wk 20 
V 8 
EOT 
Wk 24 
V 9 
ET1/ 
JR 
Pre-
Op 
Visit 
 
Wk 28 
V 10 
 
Wk 44 
V 11 
ET1/ 
JR 
Pre-
Op 
Visit 
 
Wk 72 
Phone 2 
Study Day 
Up to 
30 
Days 
7 to 10 
Days 
1 
15 
29 
57 
85 
113 
141 
169 
197 
309 
505 
Window (days) 
 
 
 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Oral study drug 
accountability  
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Dispense to home 
acetaminophen/ 
paracetamol 
 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Acetaminophen/ 
paracetamol 
accountability 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Record rescue 
medication use in 
patient diary6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Concomitant 
therapies 
(medications and 
procedures) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Efficacy: 
WOMAC7 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PGA 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
NRS8 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
WPAI-OA 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
SF-36 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
 
EQ-5D-5L  
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Central vs. 
peripheral pain 
Questionnaire 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HCRU 
X 
 
 
 
 
 
X 
 
 
X 
X 
 
 
 
 
TSQM 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
 
 
 
 
Safety: 
Weight 
X 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
 
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Screening/ 
Pre-
randomization  
Treatment Period 
Follow-up Period1 
EOS 
Study Week (wk) 
Visit (V)/Phone 
 
Screen 
V 1 
Pre- 
rand 
V 2 
 
Baseline 
V 3 
 
Wk 2 
Phone 1 
 
Wk 4 
V 4 
 
Wk 8 
V 5 
 
Wk 12 
V 6 
 
Wk 16 
V 7 
 
Wk 20 
V 8 
EOT 
Wk 24 
V 9 
ET1/ 
JR 
Pre-
Op 
Visit 
 
Wk 28 
V 10 
 
Wk 44 
V 11 
ET1/ 
JR 
Pre-
Op 
Visit 
 
Wk 72 
Phone 2 
Study Day 
Up to 
30 
Days 
7 to 10 
Days 
1 
15 
29 
57 
85 
113 
141 
169 
197 
309 
505 
Window (days) 
 
 
 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Vital Signs9 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical 
Examination 
X 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
 
Orthostatic blood 
pressure and heart 
rate assessment9,10 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Joint pain 
questionnaire 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Survey of 
Autonomic 
Symptoms 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Neurologic 
examination 
X 
Full 
 
X 
Brief 
 
X 
Brief 
X 
Brief 
X 
Brief 
X 
Brief 
X 
Brief 
X 
Full 
X 
Full 
X 
Brief 
X 
Full 
X 
Full 
 
Adverse events 
----------------------------------------------------------------------------------------------------------------------------------------------------------------------> 
 
Injection site 
evaluation 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Bilateral X-rays 
(knee, hip, 
shoulder) 
X11 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
X 
 
Event-triggered 
imaging12 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pre-op 
questionnaire (JR 
follow-up)13 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Electrocardiogram  
X 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
EOS phone 
contact14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
MRI of affected 
joint(s) for AA 
patients only15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
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Screening/ 
Pre-
randomization  
Treatment Period 
Follow-up Period1 
EOS 
Study Week (wk) 
Visit (V)/Phone 
 
Screen 
V 1 
Pre- 
rand 
V 2 
 
Baseline 
V 3 
 
Wk 2 
Phone 1 
 
Wk 4 
V 4 
 
Wk 8 
V 5 
 
Wk 12 
V 6 
 
Wk 16 
V 7 
 
Wk 20 
V 8 
EOT 
Wk 24 
V 9 
ET1/ 
JR 
Pre-
Op 
Visit 
 
Wk 28 
V 10 
 
Wk 44 
V 11 
ET1/ 
JR 
Pre-
Op 
Visit 
 
Wk 72 
Phone 2 
Study Day 
Up to 
30 
Days 
7 to 10 
Days 
1 
15 
29 
57 
85 
113 
141 
169 
197 
309 
505 
Window (days) 
 
 
 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Laboratory Testing: 
Hematology16 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
X 
X 
 
Blood Chemistry16 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
X 
X 
 
ESR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hb1AC16 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH and 
estradiol16,17 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
(WOCBP)18 
X 
Serum 
 
X 
Urine 
 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
 
Urinalysis and 
urine electrolytes16 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
X 
X 
 
Urine drug test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK ADA and Research Samples: 
ADA sample19 
 
 
X 
 
 
 
 
X 
 
X 
X 
 
X 
X 
 
PK sample19 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
 
hs-CRP sample19,20 
 
 
X 
 
X 
 
 
X 
 
X 
X 
 
X 
X 
 
Research 
serum/plasma 
sample19, 20 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
 
Genomic sub-study 
sample (optional)3 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
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AA: Adjudicated arthropathy 
NRS: Numeric Rating Scale (for walking index joint pain) 
ADA: Anti-drug antibody 
PGA: Patient Global Assessment 
EOS: End of study 
PK: Pharmacokinetic 
EOT: End of treatment 
Pre-Op: Pre-Operative  
EQ-5D-5L: EuroQoL 5 Dimensions 5 Level Questionnaire 
Pre-rand: Pre-randomization 
ESR: Erythrocyte sedimentation rate 
SC: Subcutaneous 
ET: Early termination 
SF-36: 36-item Short Form Medical Outcomes Study Questionnaire Version 2 
FSH: Follicle stimulating hormone 
TSQM: Treatment Satisfaction Questionnaire for Medication 
HbA1c: Hemoglobin A1c 
Visit: V 
HCRU: Healthcare Resource Utilization 
Week: Wk 
Hs-CRP: High-sensitivity C-reactive Protein 
WOCBP: Women of child-bearing potential 
JR: Joint replacement 
WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index 
K-L: Kellgren-Lawrence 
WPAI-OA: Work Productivity and Activity Impairment-Osteoarthritis 
MRI: Magnetic resonance imaging 
 
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8.1.1. 
Footnotes for the Schedule of Events Table 
1. Patients who discontinue study medication before week 24 will be encouraged to follow 
the visit schedule through the remainder of the study. If a patient chooses to end study 
participation, he or she will be asked to return to the clinic 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 
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. Subcutaneous study drug administration will be the last procedure at each dosing visit, and 
will be done after all laboratory, PK, ADA and research samples have been collected and 
all study assessments 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 24. 
7. Patients will complete the WOMAC pain subscale for both hips and knees at the screening 
visit. Then, the WOMAC Full Survey will be completed only for the index joint at 
subsequent visits. 
8. Walking index joint pain NRS score will be recorded by the patient each day using their 
diary, starting during the pre-randomization period through week 24. Walking index joint 
pain NRS score will be recorded by the patient at the site at the week 24 visit. 
9. If the pulse is less than 45 bpm, an ECG with rhythm strip will be obtained to confirm the 
heart rate and rhythm. 
10. Blood pressure measurements to assess orthostatic hypotension may be discontinued 
following regulatory approval if the safety database does not reveal an imbalance for the 
fasinumab treated patients. 
11. 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. 
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12. Imaging (X-ray and possibly 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. In the event that a patient must undergo joint arthroplasty during the study, the patient will 
complete the pre-operative JR study visit (Table 1) and the procedures outlined in the 
schedule of events for joint arthroplasty follow-up (Table 2).  The pre-operative 
questionnaire would be the Knee Society for knee replacements and the Harris Hip Score 
questionnaire for hip replacements.  The pre-operative visit should be completed before 
joint arthroplasty if at all possible.  Pre-operative imaging will be performed and submitted 
to the adjudication committee. 
14. The purpose of this phone contact is to ask the patient if they have had or are scheduled (or 
on a waiting list) to have a JR.  Pre-operative images will be submitted to the central reader 
for adjudication, if available. 
15. If the affected joint has undergone JR an X-ray may be substituted for an MRI. 
16. Samples will be analyzed by the central laboratory and results evaluated by the 
investigator. 
17. Only to be performed if postmenopausal status has to be assessed for female patients who 
are ≤59 years of age. 
18. 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 participation.  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. 
19. Collection of samples for PK, ADA, high sensitivity C-reactive protein (hs-CRP) and 
research are mandatory at the time points specified above. In addition, PK, ADA, hs-CRP 
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 SC 
study drug administration on SC study drug dosing days. 
20. Research samples should be collected after the patients have been fasting overnight or for 
8 hours (in the event of an afternoon visit). 
 
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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 permanently 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 consent 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 for the sole purpose of determining study eligibility 
or characterizing the baseline population: 
8.2.1.1. 
Informed Consent 
All patients must sign and date the Institutional Review Board (IRB)/ Ethics Committee 
(EC)-approved written informed consent form (ICF) before any study procedures are performed, 
per Section 14.2. 
8.2.1.2. 
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. 
8.2.1.3. 
Medication History 
The investigator or designee will record information on a patient’s medication history, including 
any history of intolerance to NSAIDs. 
8.2.1.4. 
Demographics 
A patient’s demographic characteristics will be recorded, including age, height, weight, gender, 
race, and ethnicity. 
8.2.1.5. 
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: 
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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. 
8.2.1.6. 
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 
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). 
8.2.1.7. 
Assessment of Peripheral or Central Pain 
Patients will complete a self-reported survey to evaluate the peripheral versus central nature of 
their pain at time points indicated in Table 1. 
A copy of the survey is provided in the study reference manual.  
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8.2.1.8. 
Instructions for Use of Diary 
At the pre-randomization and baseline visits, patients will be instructed on the use of the NRS for 
scoring their walking index joint pain. Patients will be trained on the use of the diary to report their 
walking index joint pain NRS score and their daily acetaminophen/paracetamol use for OA and 
other non-OA-related reason. Retraining should occur as needed throughout the conduct of the 
study. 
8.2.1.9. 
Patient Education Brochures 
At the pre-randomization and baseline 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. 
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 Likert scale.  This index can be used to monitor the course of a disease or to 
determine effectiveness of study drugs.  Patients will complete the WOMAC Full Survey at the 
time points indicated in Table 1.  If possible, the assessment should be administered and entered 
by the same person throughout the study. 
A copy of WOMAC assessments will be provided in the study reference manual. 
8.2.2.2. 
Patient Global Assessment of Osteoarthritis 
The Patient Global Assessment of OA is a patient-rated assessment of their current disease state 
on a 5-point Likert scale (1 = very good; 2 = good; 3 = fair; 4 = poor; and 5 = very poor).  Patients 
will complete the assessment scale at the time points indicated in Table 1. 
A copy of the assessment is provided in the study reference manual. 
8.2.2.3. 
Walking Index Joint Pain Numeric Rating Score 
Walking index joint pain intensity (scored using the NRS) will be reported by the patient each day 
in his or her diary, starting during the pre-randomization period through week 24. Once initial 
eligibility criteria are confirmed during the screening period, the investigator or designee will 
review the NRS with the patient at the baseline visit. 
A copy of the assessment is provided in the study reference manual. 
8.2.2.4. 
Work Productivity and Activity Impairment 
The work productivity and activity impairment-osteoarthritis questionnaire is a validated measure 
of impairments in work and daily activities (Reilly 1993) (Zhang 2010). Patients will complete the 
questionnaire at time points indicated in Table 1. 
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A copy of the assessment is provided in the study reference manual. 
8.2.2.5. 
36-Item Short Form Medical Outcomes Study Questionnaire Version 2  
The SF-36 version 2 standard is a health status measure with a 4-week recall period.  The SF-36 
measures eight concepts: physical functioning, role limitations due to physical health, bodily pain, 
general health perceptions, vitality, social functioning, role limitations due to emotional problems, 
and general mental health.  Two summary measures of physical and mental health are constructed 
from the eight scales.  Patients will complete the questionnaire at time points indicated in Table 1.  
Higher scores on the scales and summary measures indicate better health status. 
A copy of the assessment is provided in the study reference manual  
8.2.2.6. 
EuroQoL 5 Dimensions 5 Level Questionnaire  
The EQ-5D-5L is a standardized measure of health status developed by the EuroQoL Group to 
provide a simple, generic measure of health for clinical and economic appraisal.  The EQ-5D-5L, 
as a measure of health-related quality of life, defines health in terms of 5 dimensions: mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression.  
Each dimension has 5 ordinal levels of severity: “no problems” (1), “slight problems” (2), 
“moderate problems” (3), “severe problems” (4), and “unable to” (5).  Overall health state is 
defined as a 5-digit number.  Health states defined by the 5-dimensional classification can be 
converted into corresponding index scores that quantify health status, which ranges from <0 for 
states worse than dead to 1 (full health), anchoring dead at 0.  Patients will complete the 
questionnaire at time points indicated in Table 1. 
A copy of the assessment is provided in the study reference manual.  
8.2.2.7. 
Healthcare Resource Utilization Questionnaire 
The HCRU questionnaire is a tool designed to capture, over a preceding three-month period, 
healthcare utilization events that are not collected as part of the safety assessments in the current 
study. Examples of these types of events include a patient's use of walking aid, emergency room 
visits, and unscheduled physician office visits.  Sites will complete the questionnaire at time points 
indicated in Table 1.  The overall healthcare resource use will be computed based on responses to 
the healthcare resource utilization questionnaire as well as any hospital visits that are captured in 
the safety database. 
A copy of the assessment is provided in the study reference manual.  
8.2.2.8. 
Treatment Satisfaction Questionnaire for Medication 
The TSQM questionnaire is a standardized instrument to assess patients' satisfaction with 
medication.  The questionnaire provides scores on 4 domains – side effects, effectiveness, 
convenience, and global satisfaction.   Patients will complete the TSQM at time points indicated 
in Table 1. 
A copy of the assessment is provided in the study reference manual. 
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8.2.3. 
Safety Procedures  
8.2.3.1. 
Vital Signs 
Vital signs, including body temperature and respiratory rate, will be collected predose 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. 
8.2.3.2. 
Physical Examination 
A thorough and complete physical examination will be performed at time points according to 
Table 1.  Care should be taken to examine and assess any abnormalities that may be present, as 
indicated by the patient’s medical history.  Measurements of patient height and weight should be 
recorded at the time points indicated in Table 1. 
8.2.3.3. 
Assessment of Orthostatic Blood Pressure 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 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, respectively 
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, respectively 
OR 
An increase in either the 1 or 3 minute standing heart rate of ≥30 bpm from the supine heart rate 
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. 
8.2.3.4. 
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. 
A copy of the assessment is provided in the study reference manual. 
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8.2.3.5. 
Survey of Autonomic Symptoms 
Signs and symptoms of autonomic dysfunction will be assessed by the investigator at 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. 
A copy of the survey is provided in the study reference manual. 
8.2.3.6. 
Neurologic Examination 
A full or a brief 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 will include nerve conduction studies and other tests as deemed clinically 
necessary in the judgement of the neurologist. 
Complete guidance on how to conduct the full and the brief neurologic examination is provided in 
the study reference manual. 
8.2.3.7. 
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 joint must be 
performed at screening. MRIs will also be performed on any hip or knee joint with a K˗L score of 
≥3.  Radiographs and possibly an MRI will be performed on any joint following 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 
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During screening, MRIs of the index and contralateral joint 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 an exclusionary feature. 
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 affected 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. 
8.2.3.8. 
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. 
8.2.3.9. 
End of Study Phone Contact 
An end of study phone contact will be conducted at 52 weeks following the last dose of SC 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. 
8.2.3.10. 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 
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 placement of prosthesis, healing of the surgical wound and the results of histopathologic 
examination. 
Full details of these assessments are provided in the study reference manual. 
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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.  
8.2.3.11. 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 assessments, 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 SC 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. 
Samples for laboratory testing will be collected at visits 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 
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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 (as defined in Section 8.2.1.6) at time points according to Table 1.  At each study visit 
during the treatment period, 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 participation.  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 8.2.1.6. 
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 fasinumab PK and ADA assessment (Section 8.2.4) 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 tests 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. 
8.2.3.12. Injection Site Evaluations 
An injection site evaluation should be conducted following the injection at each dosing visit, 
according to Table 1. 
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8.2.4. 
Pharmacokinetic and Anti-Drug Antibody Procedures 
8.2.4.1. 
Drug Concentration Measurements and Samples 
Samples for fasinumab 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. 
8.2.4.2. 
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. 
8.2.5. 
Research Samples 
8.2.5.1. 
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, hs-CRP, and matrix 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 adverse events. 
8.2.5.2. 
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. 
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 (predose), but may be collected at any study visit. 
DNA samples for the genomics sub-study will be de-identified 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 
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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. 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
9.1. 
Obligations of Investigator 
The investigator must promptly report to the IRB/EC all unanticipated problems involving risks to 
patient.  This includes death from any cause and all SAEs related to the use of the study drug.  It 
is recommended that all SAEs be reported to the IRB/EC, regardless of assessed causality. 
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, IRBs/ECs as appropriate, and to the investigators.  
Any AE not listed as an expected event in the Investigator’s Brochure or in this protocol will be 
considered as unexpected.  Any worsening of or new onset of symptoms related to OA, which 
occur during the screening/washout period prior to study drug administration will be considered 
expected. 
In addition, the sponsor will report in an expedited manner all SAEs that are expected and at least 
reasonably related to the study drug 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 IRBs/ECs 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). 
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 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 
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. 
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). 
Adverse events of special interest are described in 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 44).  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. 
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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. 
In the event the investigator is informed of an SAE after the patient completes the follow-up period 
(week 44)/early termination visit, the following will apply: 
 SAE with an onset within 30 days of the end of the follow-up period (week 44)/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 the follow-up period (week 
44)/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 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 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 are: 
 Adjudicated arthropathy (as confirmed by adjudication)  
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 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. 
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 monitor 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 monitor 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: 
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 Mild:  Does not interfere in a significant manner with the patient’s 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 patient’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. 
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: 
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 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 
 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 
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 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 
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 monitor 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, AAs will be evaluated to determine if they meet the criteria for destructive arthropathy. 
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 joint 
replacement during the study. 
Clinically significant worsening of joint pain during the course of this study is defined 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 8.2.3.7).  A decision to 
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perform imaging after patient reported worsening of joint pain will be documented in the 
respective case report form (CRF) page. Images, along with any other radiographic evaluation, 
will be submitted to the 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.  
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, 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.  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 (Section 8.2.3.10, Table 2).  Pre-operative images, along with any other radiographic 
evaluation will be submitted to the 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 8.2.3.5).  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 where new or worsening symptoms consistent with sympathetic nervous system 
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 sympathetic nervous system dysfunction, study drug may be restarted. If the specialist’s 
evaluation does reveal sympathetic nervous system dysfunction then study drug will be 
permanently discontinued and the case will be reported as an AESI (Section 9.4.3). 
Orthostatic hypotension may be a manifestation of sympathetic nervous system 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. 
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 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 sympathetic nervous 
system 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 given 
at the next visit. 
 If the specialist’s evaluation does reveal sympathetic nervous system 
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 sympathetic nervous system 
dysfunction.  
 If the specialist’s evaluation does not reveal new sympathetic nervous 
system 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 sympathetic nervous system 
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 (Section 9.4.3). 
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9.6.1.4. 
Joint Replacement Surgery 
An end of study phone contact will be conducted at 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 8.2.3.9. Any elective JR surgery planned before completion of the ICF would 
be part of the exclusion criteria and would not be considered an AE. 
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. 
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 
There are 6 hypotheses for the primary and key secondary endpoints.  The primary treatment 
comparison for the WOMAC pain and physical function subscale scores is declared superior only 
if the comparisons are significant for both WOMAC pain and physical function subscale scores.  
The sequentially rejective multiple test procedure (Bretz 2009) will be applied to control for 
multiplicity and to maintain study-wise Type I error rate at two-sided 0.05 level for the hypotheses 
(Hi, i=1,…, 6 for fasinumab 1 mg Q4W) for the primary and key secondary endpoints.  The 
primary hypothesis will be tested at 0.05 level.  If the primary hypothesis is rejected, the alpha 
level will be reallocated to other hypotheses according to the pre-specified procedure.  The testing 
will stop when no hypothesis can be rejected at any step.  Details will be provided a priori in the 
SAP. 
 H1: There is no treatment difference between fasinumab 1 mg Q4W and placebo in 
WOMAC pain or physical function subscale scores at week 24 versus there is treatment 
difference in WOMAC pain and physical function subscale scores at week 24 
 H2: There is no treatment difference between fasinumab 1 mg Q4W and placebo in 
Patient Global Assessment score at week 24 versus there is treatment difference in 
Patient Global Assessment score at week 24 
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 H3: There is no treatment difference between fasinumab 1 mg Q4W and placebo in the 
proportion of patients with ≥30% improvement in the WOMAC pain subscale scores 
at week 24 versus there is treatment difference in proportion of patients with ≥30% 
improvement in WOMAC pain at week 24 
 H4: There is no treatment difference between fasinumab 1 mg Q4W and NSAIDs in the 
WOMAC pain subscale scores at week 24 versus there is treatment difference in 
WOMAC pain subscale scores at week 24 
 H5: There is no treatment difference between fasinumab 1 mg Q4W and NSAIDs in the 
WOMAC physical function subscale scores at week 24 versus there is treatment 
difference in WOMAC physical function subscale scores at week 24 
 H6: There is no treatment difference between fasinumab 1 mg Q4W and NSAIDs in 
Patient Global Assessment score at week 24 versus there is treatment difference in 
Patient Global Assessment score at week 24 
10.2. 
Justification of Sample Size 
Assuming a 2-sided alpha level 0.05 and a 20% dropout rate up to week 24, an enrollment of 
600 patients in the fasinumab 1 mg Q4W group and 300 patients in the placebo group will provide 
at least 99% 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 a SD 
of 2.4).  The assumed treatment difference and standard deviation (SD) are based on results from 
study R475-PN-1227. The sample size will provide 99% power to detect an effect size of 0.36 in 
PGA (ie, absolute treatment difference of 0.4 with a SD of 1.1, R475-PN-1227). 
Assuming a 2-sided alpha level 0.05 and a 20% dropout rate up to week 24, an enrollment of 
600 patients in the fasinumab 1 mg Q4W group and the pooled NSAIDs group will provide 
approximately 92% power to detect an effect size of 0.22 in the WOMAC pain subscale 
(ie, absolute treatment difference of 0.51 with a SD of 2.3, [Schnitzer 2015]).  The sample size 
will provide 95% power to detect an effect size of 0.24 in WOMAC physical function subscale 
(ie, absolute treatment difference of 0.50 with a SD of 2.1, [Schnitzer 2015]), and 79% power to 
detect an effect size of 0.18 in PGA (ie, absolute treatment difference of 0.18 with a SD of 1.0 
[Ekman 2014]). 
10.3. 
Analysis Sets  
10.3.1. 
Efficacy Analysis Sets 
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 including patients 
randomized to fasinumab 1 mg Q4W, NSAIDs, and placebo. Efficacy data from patients 
randomized to fasinumab 3 mg Q4W or 6 mg Q8W will not be included in the analysis, but will 
be summarized descriptively in separate tables. 
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 
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safety variables will be analyzed using the SAF including patients randomized to fasinumab 1 mg 
Q4W, NSAIDs, and placebo. Safety data from patients randomized to fasinumab 3 mg Q4W or 6 
mg Q8W will not be included in the main safety analysis summaries, but will be summarized in 
separate tables. 
10.3.3. 
Per-Protocol Set 
The per protocol set (PPS) will include all randomized patients who complete the 24-week 
treatment period and who do not have to be excluded due to major protocol deviations.  The PPS 
will be used to perform sensitivity analyses for the primary and selected secondary endpoints. 
10.3.4. 
Pharmacokinetic Analysis Set 
The PK analysis population includes all treated patients who received any study drug and who had 
at least 1 non-missing drug concentration result following the first study dose. 
10.3.5. 
Anti-Drug Antibody Analysis Set 
The ADA analysis population includes all treated patients who had at least 1 non-missing ADA 
result following the first study dose. 
10.4. 
Statistical Methods  
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 
Baseline demographic, disease characteristics including medical history, and exposure to study 
drug will be summarized descriptively by treatment group using descriptive statistics.  Continuous 
variables will be summarized with mean, median, SD, minimum, and maximum.  For categorical 
or ordinal data, frequencies and percentages will be displayed for each category. 
Details of the statistical methods will be provided in the SAP. 
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10.4.3. 
Efficacy Analyses 
10.4.3.1. Primary Efficacy Analysis 
The primary 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 WOMAC scores would on average return to 
baseline values. Data collected after discontinuing treatment up to week 24 will not be used in the 
primary efficacy analysis, but used in a treatment policy sensitivity analysis. The imputed data for 
patients discontinued from the study treatment due to lack of efficacy or AEs will be centered at 
the mean baseline value. The missing data for patients who discontinued 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 complete 
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], index joint 
[knee, hip], and geographical region), treatment (fasinumab 1 mg Q4W, NSAIDs or placebo), visit 
and treatment-by-visit interaction.  The MMRM will be performed using the MIXED procedure 
in Statistical Analysis System (SAS) 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 (PROC 
MIANALYZE). The least-squares mean estimates for the mean change from baseline to week 24, 
as well as the differences of the estimates between fasinumab 1 mg Q4W and placebo, and between 
fasinumab 1 mg Q4W and pooled NSAIDs group, with their corresponding standard errors, p 
values and associated 95% confidence intervals, will be provided.    
Sensitivity analysis of treatment policy estimand for the co-primary endpoints will be performed 
using a similar analysis method as the primary efficacy analysis, including data collected after 
discontinuing treatment up to week 24. Sensitivity analysis using tipping point approach with 
multiple imputation will be performed to assess the robustness of the results due to data that may 
be missing not-at-random. Multiple imputation will be based on monotone missing data structure 
of the change from baseline score using regression method. Monotone missing data structure will 
be achieved using Markov Chain Monte Carlo method. After each imputation, a fasinumab 
patient's imputed data will subtract k (eg, 20%, 40%, 100%) times the treatment effect at each 
corresponding time point. By progressively increasing coefficient k, the sensitivity analysis will 
explore the tipping point, ie, the upper bound on the critical value of coefficient k at which 
conclusion from the primary analysis will be overturned (p>0.05). Sensitivity analyses using PPS 
will also be performed for the primary and selected secondary endpoints. 
10.4.3.2. Secondary Efficacy Analysis 
For analysis of continuous secondary endpoints, the analysis method will be the same as that used 
for the primary variables.  For analysis of categorical variables in secondary endpoints, eg, 
proportions of patients with ≥30% improvement in the WOMAC pain subscale scores at week 24, 
the Cochran Mantel Haenszel approach stratified by the randomization strata (K-L category [2 to 
3, or 4], index joint [knee, hip], and geographical region) will be used with missing data considered 
as non-response. 
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10.4.4. 
Safety Analysis 
Safety data including TEAEs and treatment emergent AESIs, vital signs, physical examinations, 
laboratory tests, ECGs, and ADA formation will be listed and summarized by treatment group. 
Thresholds for potentially clinically significant values 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 collect any AEs, including AESIs, is between the first dose of double-blinded 
study drug injection and the week 44 visit, as well as study drug-related SAEs occurring between 
the week 44 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 of the first dose of study drug through to the 
day of the last dose of study drug (week 20) + 4 weeks. 
 The follow-up period is defined as from the end of the on-treatment period (week 24) 
to the week 44 visit. 
10.4.4.1. Adverse Events 
Definitions 
Treatment-emergent AEs 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.  
The focus of AE reporting in the clinical study report will be on TEAEs.  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 pre-specified 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. 
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10.4.4.2. Other Safety 
Vital Signs and Electrocardiograms 
Vital signs (temperature, pulse, blood pressure, and respiration rate) and ECGs (heart rate, ECG 
intervals) will be summarized by baseline and change from baseline to each scheduled assessment 
time with descriptive statistics. Potentially clinically significant values at any post-randomization 
time point will be summarized for each vital sign and ECG parameter. 
Physical Examinations 
The percentage of patients with abnormal physical examinations will be summarized. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics. 
Potentially clinically significant values 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. 
10.4.4.3. 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.  The time periods of interest will be 
specified in the SAP. 
10.4.4.4. Treatment Compliance 
Overall treatment compliance to study drug injection is defined as the actual dose of injection 
compared to the prescribed dose of treatment during the treatment phase up to treatment 
discontinuation.  It is calculated according to the following formula: 
100* Total actual injection dose taken/ Planned injection dose. 
The total number of actual doses of fasinumab will be summarized. 
Overall treatment compliance to oral study drug is defined as the actual oral dose taken compared 
to the prescribed dose of treatment during the treatment phase up to treatment discontinuation.  It 
is calculated according to the following formula: 
100* Total actual oral dose taken/ Planned oral dose. 
The total number of actual doses of oral study drug will be summarized. 
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10.4.5. 
Analysis of Drug Concentration Data 
Summaries of the mean concentrations of functional fasinumab will be presented by nominal time 
point and dose. Individual patient concentration data will be provided by actual time. Plots of 
individual concentration will be presented by actual day (linear and log scales). Plots of mean or 
median concentration of functional fasinumab will be presented by nominal time (linear and log 
scales). 
No formal statistical analysis will be performed. 
10.4.6. 
Analysis of Anti-Drug Antibody Data 
Listings of ADA positivity and titers presented by patient, time point, and dose group will be 
provided.  Prevalence of treatment-emergent and treatment-boosted 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. 
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 drug, 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 
drug date, then the start date by the study drug 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 non-protocol-specified 
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. 
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10.6. 
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. 
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 CRF 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, study drug supply 
 Rave Medidata EDC system – clinical data capture 
 SAS – statistical review and analysis 
 Argus - pharmacovigilance and clinical safety software system – collection and 
reporting of SAEs and AESIs 
 Electronic Clinical Outcome Assessment systems – collect patient-reported or patient 
clinical assessments results 
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 
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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). 
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 [eCRF]).  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 eCRFs 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. 
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. 
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In all instances, the confidentiality of the data must be respected. 
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. 
Patients 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. 
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The patient’s 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. 
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 patient, 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/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. 
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. Where required per local legislation, regulatory authority approval will 
also be sought. 
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’/subjects’ 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 
eCRFs 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 consult with the sponsor before discarding or 
destroying any essential study documents 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 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 eCRF 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: A phase 3 randomized, double-blind, multi-dose, placebo and 
NSAID-controlled study to evaluate the efficacy and safety of fasinumab in patients with pain due 
to osteoarthritis of the knee or hip, 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 
(Scientific/Medical Monitor, 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 Phase 3 Randomized, Double-blind, Multi-dose, Placebo and 
NSAID-controlled Study to Evaluate the Efficacy and Safety of 
Fasinumab in Patients with Pain Due to Osteoarthritis of the 
Knee or Hip 
Protocol Number: 
R475-OA-1688  
Protocol Version: 
R475-OA-1688 Amendment 4 
 
 
See appended electronic signature page 
Sponsor’s Responsible Scientific/Medical Monitor 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Representative 
 
 
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-00048600 v1.0
Signature Page for VV-RIM-00048600 v1.0 Approved
Approval
2018 11:30:22 GMT+0000
Approval
2018 12:50:08 GMT+0000
Approval
00
Approval
8 16:32:04 GMT+0000
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SAP_001.pdf: 
Global Clinical Development and Regulatory 
Affairs 
Biostatistics and Data Management 
CONFIDENTIAL 
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Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 
STATISTICAL ANALYSIS PLAN 
VERSION: FINAL
A PHASE 3 RANDOMIZED, DOUBLE-BLIND, MULTI-DOSE, PLACEBO AND NSAID-
CONTROLLED STUDY TO EVALUATE THE EFFICACY AND SAFETY OF 
FASINUMAB IN PATIENTS WITH PAIN DUE TO OSTEOARTHRITIS OF THE KNEE 
OR HIP 
Compound: 
REGN475 (fasinumab) 
Protocol Number: 
R475-OA-1688 
Clinical Phase:  
Phase 3 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician:  
Clinical Trial Manager: 
 
Study Medical Director: 
 
Version/Date:  
Original Statistical Analysis Plan / 08April 2020 
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NCT03304379


Regeneron Pharmaceuticals, Inc. 
Protocol: R475-OA-1688 
Statistical Analysis Plan 
Date: 08Apr2020 
 
CONFIDENTIAL 
Page 2 of 68 
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-1688 
Statistical Analysis Plan 
Date: 08Apr2020 
 
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TABLE OF CONTENTS 
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. 
Exploratory Objectives ...............................................................................................10 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol ................................10 
1.2.5. 
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. 
The Full Analysis Set (FAS) .......................................................................................13 
3.2. 
The Modified Full Analysis Set (FAS) .......................................................................13 
3.3. 
The Per Protocol Set (PPS) .........................................................................................13 
3.4. 
The Safety Analysis Set (SAF) ...................................................................................13 
3.5. 
The Urgent Safety Measure Set (USMS) ...................................................................14 
3.6. 
The Pharmacokinetic (PK) Analysis Set ....................................................................14 
3.7. 
The Anti-Drug Antibody Analysis (ADA) Set ...........................................................14 
3.8. 
The Neutralizing Antibody (Nab) Analysis Set ..........................................................14 
4. 
ANALYSIS VARIABLES .........................................................................................15 
4.1. 
Demographic and Baseline Characteristics ................................................................15 
4.2. 
Medical History ..........................................................................................................15 
4.3. 
Prior and Concomitant Medications and Procedures ..................................................15 
4.4. 
Prohibited Medications ...............................................................................................16 
4.5. 
Efficacy Variable ........................................................................................................17 
4.5.1. 
Primary Efficacy Variable(s) ......................................................................................17 
4.5.2. 
Secondary Efficacy Variable(s) ..................................................................................17 
4.5.3. 
Exploratory Variable(s) ..............................................................................................17 
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4.6. 
Safety Variables ..........................................................................................................18 
4.6.1. 
Adverse Events and Serious Adverse Events .............................................................18 
4.6.2. 
Adverse Events of Special Interest .............................................................................19 
4.6.3. 
Laboratory Safety Variables .......................................................................................19 
4.6.4. 
Vital Signs ..................................................................................................................19 
4.6.5. 
Orthostatic Hypotension .............................................................................................20 
4.6.6. 
12-Lead Electrocardiography (ECG) ..........................................................................20 
4.6.7. 
Physical and Neurological Examination Variables ....................................................20 
4.6.8. 
Other Safety Variables ................................................................................................21 
4.7. 
Pharmacokinetic Variables .........................................................................................22 
4.8. 
Immunogenicity Variables ..........................................................................................22 
4.9. 
Quality-of-Life Variables ...........................................................................................22 
4.10. 
Health Economic 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 .................................................................................................24 
5.5.2. 
Treatment and Study Disposition ...............................................................................25 
5.6. 
Extent of Study Treatment Exposure and Compliance ...............................................25 
5.6.1. 
Measurement of Compliance ......................................................................................25 
5.6.2. 
Exposure to Study Drugs ............................................................................................26 
5.6.3. 
Length of Study Observation ......................................................................................26 
5.7. 
Analyses of Efficacy Variables ..................................................................................26 
5.7.1. 
Analysis of Primary Efficacy Variable(s) ...................................................................27 
5.7.2. 
Subgroup analysis: ......................................................................................................30 
5.7.3. 
Analysis of Secondary Efficacy Variables .................................................................30 
5.7.4. 
Adjustment for Multiple Comparison .........................................................................31 
5.7.5. 
Analysis of Other Efficacy Variables .........................................................................32 
5.7.6. 
Analysis of Quality-of-Life and Health Economic Variables ....................................33 
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5.8. 
Analysis of Safety Data ..............................................................................................34 
5.8.1. 
Adverse Events ...........................................................................................................34 
5.8.2. 
Analysis of Adverse Events of Special Interest ..........................................................36 
5.8.3. 
Clinical Laboratory Measurements.............................................................................36 
5.8.4. 
Analysis of Vital Signs ...............................................................................................37 
5.8.5. 
Analysis of 12-Lead ECG ...........................................................................................37 
5.8.6. 
Physical and Neurological Examinations ...................................................................38 
5.8.7. 
Analysis of Other Safety Variables ............................................................................38 
5.9. 
Analysis of Pharmacokinetic Data ..............................................................................39 
5.10. 
Analysis of Immunogenicity Data ..............................................................................39 
5.10.1. 
Analysis of ADA Data ................................................................................................39 
5.10.2. 
Analysis of Neutralizing Antibody (NAb) Data .........................................................40 
5.10.3. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................41 
5.10.3.1. 
Immunogenicity and Safety and Efficacy ...................................................................41 
6. 
DATA CONVENTIONS ............................................................................................42 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................42 
6.2. 
Data Handling Convention for Efficacy Variables .....................................................42 
6.2.1. 
Data Handling Convention for Efficacy Variables due to COVID-19 
Pandemic .....................................................................................................................42 
6.3. 
Data Handling Convention for Repeat Measurements ...............................................42 
6.4. 
Data Handling Convention for Missing Data .............................................................43 
6.5. 
Visit Windows ............................................................................................................45 
6.6. 
Unscheduled Assessments ..........................................................................................46 
6.7. 
Pooling of Centers for Statistical Analyses ................................................................46 
6.8. 
Statistical Technical Issues .........................................................................................46 
7. 
INTERIM ANALYSIS ...............................................................................................47 
8. 
SOFTWARE ...............................................................................................................48 
9. 
REFERENCES ...........................................................................................................49 
10. 
APPENDIX.................................................................................................................50 
10.1. 
Summary of Statistical Analyses ................................................................................50 
10.2. 
Schedule of Time and Events .....................................................................................54 
10.3. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................62 
10.4. 
Protocol Deviations Excluding Patients from the PPS ...............................................67 
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Protocol: R475-OA-1688 
Statistical Analysis Plan 
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10.5. 
OMERACT – OARSI RESPONDER CRITERIA .....................................................68 
 
LIST OF TABLES 
Table 1: 
Analysis Windows ......................................................................................................45 
Table 2: 
Schedule of Events .....................................................................................................54 
Table 3: 
Follow-up Period for Patients Undergoing Joint Replacement Surgery on 
Study ...........................................................................................................................61 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................11 
 
 
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Protocol: R475-OA-1688 
Statistical Analysis Plan 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AA 
Adjudicated Arthropathy 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
CI 
Confidence Interval 
DA 
Destructive Arthropathy 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EQ-5D 
EuroQol Group Questionnaire 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IVRS 
Interactive Voice Response System 
JR 
Joint replacement 
K-L 
Kellgren-Lawrence 
LS 
Least Squares 
MedDRA® 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect model for repeated measures 
MRI 
Magnetic resonance imaging 
NGF 
Nerve growth factor 
NRS 
Numeric Rating Scale 
NSAIDs 
Nonsteroidal anti-inflammatory drugs 
OA 
Osteoarthritis 
OMERCAT-
OARSI 
Osteoarthritis Research Society International Standing Committee for 
Clinical Trials Response Criteria Initiative and The Outcome Measure 
in Rheumatology 
PCSV 
Potentially clinically significant value 
PK 
Pharmacokinetic 
PPS 
Per protocol set 
PT 
Preferred term 
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Statistical Analysis Plan 
Date: 08Apr2020 
 
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Q4 
Every 4 (weeks) 
Q8 
Every 8 (weeks) 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
RPOA 
Rapidly Progressive Osteo-Arthritis 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Software 
SC 
Subcutaneous 
SD 
Standard deviation 
SF-36 
Short Form (36) Health Survey 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TJR 
Total joint replacement 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WOMAC 
Western Ontario and McMaster Osteoarthritis Index 
 
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Protocol: R475-OA-1688 
Statistical Analysis Plan 
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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 R475-OA-1688 study. 
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 data lock and before code breaking. 
1.1. 
Background/Rationale 
This randomized, double-blind, placebo- and NSAID-controlled study is designed to evaluate the 
efficacy and safety of fasinumab in patients with OA of the knee or hip who have a history of 
inadequate pain relief from acetaminophen/paracetamol and a history of intolerance to or 
inadequate pain relief from opioids (or are unwilling to and/or lack access to take opioids) for 
OA pain management. This study will compare the efficacy and safety of fasinumab to placebo 
and to a pooled NSAID group of celecoxib or diclofenac, which are members of the class of 
NSAID medications commonly used for moderate-to-severe pain due to OA. 
The target study population was chosen because they currently have unmet medical needs with 
respect to incomplete pain control, despite the availability of NSAIDs i.e. they have failed or are 
intolerant to opioids and have failed acetaminophen/paracetamol and thus provides equipoise 
with regards to randomization of patients to fasinumab or placebo. Patients were also required to 
be on a stable dose of NSAID, defined as oral NSAID use at regularly prescribed doses for 
approximately 4 days per week over the last 4 weeks prior to the start of the screening period.  
This study will provide efficacy and safety data for OA patients exposed for up to 24 weeks to 
fasinumab, a pooled NSAID comparator group (celecoxib or diclofenac), or placebo. 
1.2. 
Study Objectives  
1.2.1. 
Primary Objectives 
The primary objective of the study is to evaluate the efficacy of fasinumab compared to placebo, 
when administered for up to 24 weeks in patients with pain due to OA of the knee or hip. 
1.2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
 To evaluate the efficacy of fasinumab compared to NSAIDs, when administered for up to 
24 weeks in patients with pain due to OA of the knee or hip 
 To assess the safety and tolerability of fasinumab compared to placebo and compared to 
NSAIDs, when administered for up to 24 weeks in patients with pain due to OA of the knee 
or hip  
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 To characterize the concentrations of fasinumab over time when administered for up to 24 
weeks in patients with pain due to OA of the knee or hip 
 To evaluate the immunogenicity of fasinumab administered for up to 24 weeks in patients 
with pain due to OA of the knee or hip 
1.2.3. 
Exploratory Objectives 
 To evaluate patient-reported outcome measures in patients with pain due to OA of the knee 
or hip treated for up to 24 weeks with fasinumab compared to placebo and compared to 
NSAIDs 
 To evaluate the use of rescue medication in patients with pain due to OA of the knee or hip 
treated for up to 24 weeks with fasinumab compared to placebo and compared to NSAIDs  
1.2.4. 
Modifications from the Statistical Section in the Final Protocol 
This SAP is based on Protocol R475-OA-1688 Amendment 4. The following were modified or 
were not specified in the protocol but are being clarified/added in this SAP: 
 The Per-protocol set (PPS) was updated to exclude patients with relevant protocol 
deviations rather than major protocol deviations as stated in the protocol since not all 
major/important protocol deviations will lead to removal of patients from the PPS.  
 The Urgent Safety Measure Set (USMS) was explicitly defined in this SAP since the 
protocol intimates that USM patients will not be included as part of the full analysis 
set (FAS).  
 The Neutralizing Anti-Body (Nab) Set was included to support the ADA analysis that 
is planned to be performed.  
 Subgroup analyses for the change from baseline in WOMAC pain subscale and 
physical function subscale scores at week 24 by flare status. Flare patients are defined 
as patients who experience a ≥ 1 point increase in WOMAC pain scores from the 
Screening to the Baseline Visit. 
 Analyses for the percentage of patients who had improvements of ≥ 50% and ≥ 70% 
in the WOMAC pain subscale scores at week 24  
 Analyses for the percentage of patients who had improvements of ≥30%, ≥ 50% and 
≥ 70% in the WOMAC physical function subscale scores at week 24  
 Analyses for the percentage of patients who met the OMERACT-OARSI criterion at 
week 24. The OMERACT-OARSI criterion are described in Appendix Section 10.5 
of this SAP. 
 Analyses for additional exploratory endpoints of change in WOMAC pain and 
physical function subscale scores from baseline to the average score across Weeks 12, 
16, 20 and 24.  
1.2.5. 
Revision History for SAP Amendments 
None. 
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Statistical Analysis Plan 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
This study is a randomized, double-blind, placebo- and NSAID-controlled study designed to 
evaluate the efficacy and safety of fasinumab in patients with OA of the knee or hip who have a 
history of inadequate pain relief with acetaminophen/paracetamol and a history of intolerance to 
or inadequate pain relief with opioids (or are unwilling to take opioids or have lack of access to 
opioids). The study consists of a screening period of up to 30 days, a 7 to 10 day 
pre-randomization/washout period (7 days with a +3 day window), a 24-week treatment period 
(with the last Q4W dose of study drug administered at week 20), a 20-week follow-up period, 
and a final phone call approximately 52 weeks after the last SC dose of study drug (Figure 1). 
Figure 1: 
Study Flow Diagram 
Screening & Pre-randomization 
Treatment 
Follow-Up 
EOS-Phone 
Contact 
Up to 40 Days 
Day 1 to Week 24 
Week 25 to 44 
Up to Week 72 
 
Randomization 
 
End of 
Treatment  
End of 
Follow up 
 
 
 
 
 
Screening 
Pre-randomization  
 
 
 
 
Up to 30 Days  
 
7 to 10 Days 
Baseline  
Day 1 
 
Week 24 
Week 44 
Week 72 
 
EOS- End of study 
Patients will be randomized on day 1 (baseline) to one of the following treatment groups: 
 Fasinumab 1 mg SC Q4W and NSAID-matching placebo oral, twice daily 
 Fasinumab-matching placebo SC Q4W and diclofenac 75 mg oral, twice daily and 
NSAID matching placebo oral once daily 
 Fasinumab-matching placebo SC Q4W, celecoxib 200 mg oral once daily, and 
NSAID-matching placebo oral once daily 
 Fasinumab-matching placebo SC Q4W and NSAID-matching placebo oral, twice 
daily 
Randomization will be stratified according to the affected index joint (hip or knee), the K-L 
score (2 to 3, or 4) at the screening visit, and geographical region (Asia/Pacific, Europe and 
North America). 
2.2. 
Sample Size and Power Considerations 
Assuming a 2-sided alpha level of 0.05 and a 20% dropout rate up to week 24, an enrollment of 
600 patients in the fasinumab 1 mg Q4W group and 300 patients in the placebo group will 
provide at least 99% power to detect an effect size of 0.46 in the WOMAC pain and physical 
function subscale scores (i.e., absolute treatment difference of 1.1 between fasinumab and 
placebo with a SD of 2.4). The assumed treatment difference and standard deviation (SD) are 
based on results from study R475-PN-1227. The sample size will provide 99% power to detect 
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Statistical Analysis Plan 
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an effect size of 0.36 in PGA (i.e., absolute treatment difference of 0.4 with a SD of 1.1, 
R475-PN-1227). 
Assuming a 2-sided alpha level 0.05 and a 20% dropout rate up to week 24, an enrollment of 
600 patients in the fasinumab 1 mg Q4W group and the pooled NSAIDs group will provide 
approximately 92% power to detect an effect size of 0.22 in the WOMAC pain subscale 
(i.e., absolute treatment difference of 0.51 with a SD of 2.3, [Schnitzer 2015]). The sample size 
will provide 95% power to detect an effect size of 0.24 in WOMAC physical function subscale 
(i.e., absolute treatment difference of 0.50 with a SD of 2.1, [Schnitzer 2015]), and 79% power to 
detect an effect size of 0.18 in PGA (i.e., absolute treatment difference of 0.18 with a SD of 1.0 
[Ekman 2014]). 
The sample size has been revised from 2700 patients in the previous amendments to 
approximately 1620 patients in amendment 4 due to the discontinuation of fasinumab 3 mg Q4W 
and 6 mg Q8W dose regimens. There will be approximately 600 patients randomized to the 
fasinumab 1 mg SC Q4W group, 300 patients randomized to the each of the NSAID groups, and 
300 patients randomized to the placebo group (a total of 1500 patients). In addition, 
approximately 60 patients each were enrolled in the fasinumab 3 mg SC Q4W and 6 mg SC 
Q8W groups under earlier versions of the protocol before dosing was discontinued in these 
treatment groups. 
2.3. 
Study Plan 
Study assessments and procedures are presented by study period and visit in Section 10.2, 
Table 2. 
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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 populations of analysis will 
be used for all statistical analysis: 
3.1. 
The Full Analysis Set (FAS) 
The full analysis set (FAS) includes all randomized patients excluding patients affected by the 
urgent safety measure (i.e. patients randomized to the 3 mg Q4W or 6 mg Q8W doses) and is 
based on the treatment allocated (as randomized). Efficacy endpoints will be analyzed using the 
FAS including patients randomized to fasinumab 1 mg Q4W, NSAIDs, and placebo.  
Efficacy data from patients randomized to fasinumab 3 mg Q4W or 6 mg Q8W will not be 
included in the analysis, but will be summarized descriptively in separate tables. 
3.2. 
The Modified Full Analysis Set (FAS) 
The modified full analysis set (mFAS) includes all randomized patients in the FAS but excludes 
patients from four sites (
) for which there were potential 
concerns regarding data quality. The co-primary endpoints and selected secondary endpoints 
may be evaluated in the mFAS as a sensitivity analysis.  
3.3. 
The Per Protocol Set (PPS) 
The per protocol set (PPS) will include all randomized patients from the FAS who complete the 
24-week treatment period and who do not have to be excluded due to relevant protocol 
deviations. The PPS will be used to perform sensitivity analyses for the primary and selected 
secondary endpoints.  
Section 10.4 contains the list of protocol violations which lead to exclusion from the PPS and 
corresponding PDID.  
3.4. 
The Safety Analysis Set (SAF) 
The safety analysis set (SAF) includes all randomized patients from the FAS 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 
including patients randomized to fasinumab 1 mg Q4W, NSAIDs, and placebo.  
Determination of ‘as-treated’ will be performed in the following stepwise manner: 
 If a patient receives at least one dose of fasinumab, ‘as treated’ implies the patients 
data will be analyzed under the fasinumab arm.  
 If a patient receives no doses of fasinumab and was ever dispensed NSAIDs, ‘as 
treated’ implies the patients’ data will be analyzed under the NSAID arm.  
 If a patient receives no doses of either fasinumab or NSAID, the patients data will be 
analyzed under the placebo arm.  
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Safety data from patients randomized to fasinumab 3 mg Q4W or 6 mg Q8W will not be 
included in the main safety analysis summaries, but will be summarized in separate tables. 
3.5. 
The Urgent Safety Measure Set (USMS) 
The USMS will include all patients randomized to fasinumab 3 mg Q4W or 6 mg Q8W and is 
based on the treatment allocated (as randomized). The USMS will be utilized for all analyses of 
data collected from its included patients. 
3.6. 
The Pharmacokinetic (PK) Analysis Set 
The PK analysis population includes all treated patients who received any study drug and who 
had at least 1 non-missing drug concentration result following the first study dose. Patients will 
be analyzed according to the treatment actually received (as treated). 
3.7. 
The Anti-Drug Antibody Analysis (ADA) Set 
The ADA analysis set includes all patients who received any study drug and had at least 1 non-
missing ADA result following the first dose of study drug. Patients will be analyzed according to 
the treatment actually received.  
3.8. 
The Neutralizing Antibody (Nab) Analysis Set  
The neutralizing antibody (NAb) analysis set includes all patients who received any study drug 
and who are negative in the ADA assay or with at least 1 non-missing result in the NAb assay 
following first dose of the study drug. Patients who are ADA negative are set to negative in the 
NAb analysis set. Patients will be analyzed according to the treatment actually received. 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
The following demographic and baseline variables will be summarized:  
 Age at screening (year) 
 Age group (< 65, 65-74, >=75) 
 Sex (Male, Female) 
 Race (White, Black/African American, 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 
 Geographic Region (North America, Europe, and Asia Pacific/South Africa) 
 Index Joint (Knee or Hip) per IWRS 
 Kellgren-Lawrence score (2, 3, 4) per IWRS for index joint 
 Kellgren-Lawrence 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 
4.2. 
Medical History 
Medical history will be recorded at screening and 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®).  
4.3. 
Prior and Concomitant Medications and Procedures 
Medications/Procedures will be recorded from the day of informed consent until the end of 
Follow-up Clinic Visit at Week 44 or the early termination visit.  
Medications will be coded to the 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. 
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Concomitant medications/procedures are defined as medications/procedures starting prior to or 
during the On-Treatment Period (as defined in Section 5.8) and ending during or after the On-
Treatment Period. 
Post-Treatment medications/procedures are medications/procedures starting after the On-
Treatment Period.  
4.4. 
Prohibited Medications 
Opioid analgesic medications (including tramadol) are prohibited through the week 24 study 
visit. NSAIDs (oral or topical, except up to 150 mg/day of aspirin/5-ASA, which is permitted for 
cardiac prophylaxis) are prohibited until at least 16 weeks after the last SC 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 
 Anticoagulants and antiplatelets (e.g., warfarin, heparins, factor Xa inhibitors, 
thrombin inhibitors, aspirin/5-ASA >150 mg daily, clopidogrel) 
 Muscle relaxants including cyclobenzaprine, carisoprodol, orphenadrine, tizanidine 
(see protocol 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 
 Interleukin-6 or interleukin-6 receptor antagonists 
 Abatacept, ustekinumab  
 Tumor necrosis factor antagonists 
 IL-1 inhibitors, including diacerein 
 Apremilast, and tofacitinib  
 Combination therapy of diuretics with either an ACE inhibitor or ARB 
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.  
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 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 Variable 
4.5.1. 
Primary Efficacy Variable(s) 
The co-primary endpoint in the study are:  
1. Change in the WOMAC pain subscale scores from baseline to week 24 in patients treated 
with fasinumab compared to patients treated with placebo. 
2. Change in the WOMAC physical function subscale scores from baseline to week 24 in 
patients treated with fasinumab compared to patients treated with placebo. 
4.5.2. 
Secondary Efficacy Variable(s) 
The key secondary endpoints in the study are:  
1. Change from baseline to week 24 in Patient Global Assessment (PGA) in patients treated 
with fasinumab compared to patients treated with placebo 
2. Percentage of patients treated with fasinumab, compared to patients treated with placebo, 
who had a response at week 24, with response defined as an improvement by ≥30% in 
WOMAC pain sub scale score 
3. Change from baseline to week 24 in WOMAC pain subscale scores in patients treated 
with fasinumab compared to patients treated with NSAIDs (pooled celecoxib and 
diclofenac arms) 
4. Change from baseline to week 24 in WOMAC physical function subscale scores in 
patients treated with fasinumab compared to patients treated with NSAIDs (pooled 
celecoxib and diclofenac arms) 
5. Change from baseline to week 24 in PGA score in patients treated with fasinumab 
compared to patients treated with NSAIDs (pooled celecoxib and diclofenac arms) 
4.5.3. 
Exploratory Variable(s) 
The exploratory endpoints in the study are 
 Change from baseline to week 24 in patient-reported outcome measures in patients 
with pain due to OA of the knee or hip treated for up to 24 weeks with fasinumab 
compared to placebo 
 Change from baseline to week 24 in patient-reported outcome measures in patients 
with pain due to OA of the knee or hip treated for up to 24 weeks with fasinumab 
compared to NSAIDs (pooled celecoxib and diclofenac arms) 
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 The proportion of patients taking rescue medication, number of days on rescue 
medication, and weekly average use of rescue medication from baseline to week 24 in 
patients with pain due to OA of the knee or hip treated for up to 24 weeks with 
fasinumab compared to placebo 
 The proportion of patients taking rescue medication, number of days on rescue 
medication, and weekly average use of rescue medication from baseline to week 24 in 
patients with pain due to OA of the knee or hip treated for up to 24 weeks with 
fasinumab compared to NSAIDs (pooled celecoxib and diclofenac arms) 
 Change in WOMAC pain subscale scores from baseline to the average score across 
Weeks 12, 16, 20 and 24 with fasinumab compared to placebo 
 Change in WOMAC physical function subscale from baseline to the average score 
across Weeks 12, 16, 20 and 24 with fasinumab compared to placebo 
4.6. 
Safety Variables 
Patient safety will be assessed through the collection of reported adverse events (AEs), clinical 
laboratory data, vital signs, electrocardiogram (ECG), survey of autonomic symptoms 
questionnaire, neurological and physical examinations and imaging. Unless otherwise noted, the 
baseline value is defined as the last available value before the first administration of study drug.  
4.6.1. 
Adverse Events and Serious Adverse Events 
Adverse events and serious adverse events will be collected from the time of informed consent 
signature and until the end of the follow-up period (week 44). All adverse events are to be coded 
to a “Preferred Term (PT)” and associated primary “System Organ Class (SOC)” according to 
the Medical Dictionary for Regulatory Activities (MedDRA, the latest current available version). 
An Adverse Event is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
A Serious Adverse Event is an adverse event (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.  
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4.6.2. 
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.  
4.6.3. 
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 10.2).  
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. 
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 10.3 for PCSV definitions).  
4.6.4. 
Vital Signs 
The following vital signs parameters will be collected according to the Schedule of Events in 
Section 10.2: 
 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. Potentially clinically significant values 
(PCSV) ranges will be applied to the vital sign parameter values as applicable (see 
Appendix 10.3 for PCSV definitions). 
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4.6.5. 
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 
 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 or if initial 
assessment met the above orthostatic hypotension criteria yet repeated assessments were not 
performed. 
4.6.6. 
12-Lead Electrocardiography (ECG) 
A standard 12-lead ECG will be performed according to the Schedule of Events in 
Appendix 10.2.  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.  
Potentially clinically significant values (PCSV) ranges will be applied to the ECG parameter 
values as applicable (see Appendix 10.3 for PCSV definitions). 
4.6.7. 
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 10.2. 
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, 
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sensory, cranial nerves, reflexes and coordination/balance and assessment for presence/absence 
of signs of carpal tunnel syndrome.  
The results of each specific domain 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. 
4.6.8. 
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. 
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:  
 The Joint Pain Questionnaire serves as a monitoring tool that prompts further 
evaluations of joints, as deemed necessary by the investigator.  
 Summaries will include :  
- 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 index joints as well as other knee or hip joints at each 
scheduled visit (taken from bilateral x-rays) 
 All-cause Joint replacements: 
 Number and percentage of patients with joint replacement (all-cause joint 
replacements) 
 Reason for joint replacement (all cause joint replacements) 
 Time to joint replacement (all cause Joint replacements) 
 Adjudicated Arthropathy (AA): 
 Number and percentage of patients with AA 
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 Number and percentage of patients meeting Destructive Arthropathy criteria (DA) 
 Subtypes of AA 
 Time to AA 
 Time to DA 
4.7. 
Pharmacokinetic Variables  
The pharmacokinetic variable is the concentration of fasinumab in serum at the time points 
specified in Table 1 of the protocol. 
4.8. 
Immunogenicity Variables  
The immunogenicity variables are ADA status, titer, NAb status, at each time-point/visit. Serum 
samples for ADA will be collected at the clinic visits specified in Appendix 10.2. 
4.9. 
Quality-of-Life Variables 
The following patient reported quality-of-life outcome measures will be summarized: 
 Change from baseline by visit in the SF-36 subscale scores including physical 
functioning, role-physical, bodily pain, general health, vitality, social functioning, 
role-emotional, mental health, physical component score, and mental component 
score 
 Change from baseline by visit in the EQ-5D-5L VAS and utility index scores. The 
EQ-5D-5L utility index will be calculated using UK time-trade-off value set which 
maps each health state to an index score that quantify health status 
 Change from baseline by visit in the TSQM domain scores including effectiveness, 
side effects, convenience and global satisfaction score 
4.10. 
Health Economic Variables 
The following patient reported health economic outcome measures will be summarized: 
 HealthCare Resource Utilization (HCRU) including total and type of usage and 
hospitalizations 
 Change from baseline by visit in the WPAI-OA item and sub scores including 
absenteeism, presenteeism, work productivity loss and activity impairment 
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5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, median, standard deviation, minimum & maximum and 1st 
& 3rd quartiles (Q1 & Q3). 
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 44 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 the FAS. 
5.2. 
Medical History 
All reported patient’s medical history and surgical history will be presented showing patient 
counts (percentages) by primary SOC and PT by treatment group and overall for the study based 
on the SAF.  The tables will be sorted by decreasing frequency of primary SOC in the overall 
group.  Within each primary SOC, PTs will be sorted by decreasing frequency in the overall 
group. 
5.3. 
Prior/Concomitant Medications 
Summaries will present patient counts (and percentages) for all medications, dictionary coded by 
WHO, by decreasing frequency of the overall group incidence (or fasinumab 1mg Q4W group 
incidence in tables where the overall is not presented) of ATC followed by ATC level 2, ATC 
level 4 and preferred term.  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. 
The following will be summarized: 
 All prior medications will be summarized by treatment group and overall, based on 
the SAF. 
 All concomitant medications taken during the On-Treatment Period will be 
summarized by treatment group based on the SAF. 
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 All Post-treatment medications taken during the Post-Treatment period will be 
summarized by treatment group based on the subset of patients in the SAF. 
5.4. 
Prohibited Medications 
Prohibited Medications 
Summaries of prohibited medications will present patient counts (and percentages) for all 
prohibited medications, dictionary coded by WHO, by decreasing frequency of the overall group 
incidence (or fasinumab 1mg Q4W group incidence in tables where the overall is not presented) 
of ATC followed by ATC level 2, ATC level 4 and preferred term.  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. 
Number and percentage of patients with prohibited medications will be descriptively 
summarized by treatment group, and combined fasinumab group based on the SAF.  
The number of patients with prohibited NSAID use during the on-treatment period will be 
summarized by treatment group. Total prohibited NSAIDs-use days during the treatment period 
and follow-up (before AA for patients with AA) will be summarized by treatment group. 
Additionally, days from last study drug dose to first NSAID dose will be summarized. 
5.5. 
Subject Disposition 
The disposition of patients in the study will be summarized by treatment group and overall based 
on the FAS. 
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. 
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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. 
 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 
5.6.1. 
Measurement of Compliance 
SC Study Drug Injection 
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 treatment compliance to the SC study drug injection will be summarized by treatment 
groups via descriptive statistics based on the SAF. 
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. 
Oral NSAID Study Drug 
Overall treatment compliance to oral NSAID study drug is defined as the total oral dose actually 
taken divided by the expected total oral dose of treatment during the treatment exposure period 
up to patient discontinuation from the treatment phase.  It is calculated according to the 
following formula based on the NSAID/Placebo Dispensing/Accountability eCRF: 
∑
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑝𝑖𝑙𝑙𝑠 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑−𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑝𝑖𝑙𝑙𝑠 𝑟𝑒𝑡𝑢𝑟𝑛𝑒𝑑)
𝑎𝑙𝑙 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑣𝑖𝑠𝑖𝑡𝑠(
(𝑑𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑑𝑜𝑠𝑒 𝑜𝑓 𝑜𝑟𝑎𝑙 𝑠𝑡𝑢𝑑𝑦 𝑑𝑟𝑢𝑔−𝑑𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 𝑜𝑓 𝑜𝑟𝑎𝑙 𝑠𝑡𝑢𝑑𝑦 𝑑𝑟𝑢𝑔+ 1) ∗2  𝑥 100 
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Overall treatment compliance to oral study drug during the On-Treatment Period will be 
summarized descriptively by treatment group based on the SAF. 
5.6.2. 
Exposure to Study Drugs 
The duration of treatment exposure to fasinumab and placebo SC doses will be calculated as: 
= (Date of last SC injection of study drug in the on-treatment period – date of the first SC 
injection of study drug administration in the on-treatment period) + 28 
The duration of treatment exposure to oral study drug will be calculated as: 
= (Date of last dose of oral study drug in the on-treatment period – date of first dose of oral 
study drug in the on-treatment period) + 1 
The duration of exposure will be summarized by treatment group using descriptive statistics 
based on the SAF. 
The number and percentage of patients exposed to study drug will be presented by specific time 
period for each treatment group based on the SAF.  The time periods of interest are specified as: 
≥ 1 day, ≥ 29 days, ≥ 57 days, ≥ 85 days, ≥ 113 days, ≥ 141 days, ≥ 169 days. 
5.6.3. 
Length of Study Observation 
The length of study observation will be calculated as: 
= (Date of the last study visit[up to the End of Follow-up Clinic Visit] – date of the first 
study drug administration) + 1 
The length of total study participation will be calculated as: 
= (Date of the last study visit[up to the End of study phone call] – date of the first study drug 
administration) + 1 
The lengths of study observation and total study participation will be summarized by treatment 
group using descriptive statistics based on the SAF. 
The number and percentage of patients with observation and participation periods will be 
presented by treatment group based on the SAF. The time periods of interest are specified as: ≥ 1 
day, ≥ 29 days, ≥ 57 days, ≥ 85 days, ≥ 113 days, ≥ 141 days, ≥ 169 days, ≥ 197 days, ≥ 225 
days, ≥ 253 days, ≥ 281 days, ≥ 309 days). 
5.7. 
Analyses of Efficacy Variables 
Unless stated otherwise, all efficacy analyses will be based on the FAS.  Confidence intervals 
will be constructed with level of confidence equal to 95%.  With the exception of analyses based 
on the PPS, models including stratifying variables will utilize the value of these variables as 
captured in the IWRS system. 
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5.7.1. 
Analysis of Primary Efficacy Variable(s) 
The co-primary efficacy variables are: 
1. Change in the WOMAC pain subscale scores from baseline to week 24 
2. Change in the WOMAC physical function subscale score from baseline to week 24 
The following hypotheses will be tested:  
 H1: There is no treatment difference between fasinumab 1 mg Q4W and placebo in 
WOMAC pain or physical function subscale at week 24 versus there is treatment 
difference in WOMAC pain and physical function subscale score at week 24 
For H1, the estimand is the difference in means between the fasinumab 1 mg Q4W dose+ 
protocol-defined rescue medication and placebo+ protocol-defined rescue medication in the 
change from baseline to week 24 in the WOMAC pain and physical function scores in the FAS, 
regardless of whether or not rescue medication or prohibited medication had been taken.  Any 
data collected after discontinuing treatment will not be used in the primary efficacy analysis, but 
used in a treatment policy sensitivity analysis. 
The co-primary efficacy variables will be analyzed separately using a multiple imputation 
approach with a mixed-effect model for repeated measures (MMRM) based on the FAS.  For 
patients who discontinued treatment due to lack of efficacy or AEs or deaths, 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 the patient was randomized to.  For 
patients who discontinued treatment due to other reasons including discontinuation because of 
public health measures implemented in response to COVID-19, their missing WOMAC subscale 
scores after discontinuation will be imputed under the 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], index joint [knee, hip], and geographical region [Other, 
Europe, North America]) and baseline WOMAC subscale score. Intermittently missing 
WOMAC subscale scores prior to treatment discontinuation will be imputed using the Markov 
Chain Monte Carlo method. 
Missing data up to week 24 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 4751688. Any score imputed 
outside the range of the WOMAC subscale score of 0-10 will be truncated to the 
nearest permissible value on the WOMAC scale according to the following 
algorithm:  
 If the imputed score > 10, then the final imputed score will be 10. 
 If the imputed score < 0, then the final imputed score will be 0. 
 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 4751688 and adjustment for covariates including treatment groups, 
randomization strata (K-L category [2 to 3, or 4], index joint [knee, hip], and 
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geographical region [Other, Europe, North America]), baseline WOMAC subscale 
score and all WOMAC subscale scores at preceding visits. Scores that are imputed 
outside the range of the WOMAC subscale will be truncated in the same manner as in 
step 1.  As the regression method imputes missing data sequentially by visits, the 
truncation will be implemented after each visit iteration. 
 Step 3: For patients who permanently discontinued study treatment due to lack of 
efficacy, death 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., imputed score =initial 
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). Scores that are adjusted to outside the range of the 
WOMAC subscale will be truncated in the same manner as in step 1. 
Each imputed data set will be analyzed using a MMRM with terms for baseline WOMAC 
subscale score, randomization strata (K-L category [2 to 3, or 4], index joint [knee, hip], and 
geographical region [Other, Europe, North America]), treatment, visit, and treatment-by-visit 
interaction.  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 fit 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. 
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 
24, as well as the difference of these 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 hypothesis for H1, will be rejected when the p-values corresponding to the difference in 
change from baseline to week 24 between fasinumab 1 mg Q4W and placebo is less than the 
available α0 (see Section 5.7.4) for both the WOMAC pain subscale score and physical function 
subscale score. 
Sensitivity analysis:  
Three sensitivity analyses will be performed to assess the robustness of the results generated for 
the primary efficacy analysis. 
Analysis of Treatment Policy Estimand 
Sensitivity analysis of the treatment policy estimand for the co-primary endpoints will be 
performed using similar analysis methods as the primary efficacy analysis.  The treatment policy 
estimand is the difference in means between each fasinumab dose+ protocol-defined rescue 
medication and placebo+ protocol-defined rescue medication in the change from baseline to 
week 24 in the WOMAC pain and physical function scores based on the FAS, regardless of 
study treatment discontinuation prior to week 24 and regardless of whether or not rescue 
medication or prohibited medication had been taken.  Hence, data from all patients, including 
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data collected after discontinuing treatment up to week 24 will be used in this sensitivity 
analyses.  Missing WOMAC subscale scores up to week 24 will be imputed using the same 
approach as in Section 5.7.1. 
Tipping Point Analysis 
Sensitivity analysis using a tipping point approach with multiple imputation will be performed to 
assess the robustness of the results due to data that may be missing not-at-random (MNAR). 
This approach will introduce a sensitivity parameter, δ.  Estimations will be performed using 
multiple imputation methodology.  Missing data up to week 24 timepoint will be imputed 50 
times to generate 50 complete datasets by using SAS procedure PROC MI for each δ following 
the 2 steps below: 
 Step 1: The monotone missing pattern is induced by Markov Chain Monte Carlo 
(MCMC) method in MI procedure using seed number 4751688. Any score imputed 
outside the range of the WOMAC subscale score of 0-10 will be truncated to the 
nearest permissible value on the WOMAC scale according to the following 
algorithm: 
 If the imputed score > 10, then the final imputed score will be 10. 
 If the imputed score < 0, then the final imputed score will be 0. 
 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 4751688 and adjustment for covariates including treatment groups, 
randomization strata (K-L category [2 to 3, or 4], index joint [knee, hip], and 
geographical region [Other, Europe, North America]), baseline WOMAC subscale 
score and all WOMAC subscale scores at preceding visits.  Scores that are imputed 
outside the range of the WOMAC subscale will be truncated in the same manner as in 
step 1.  As the regression method imputes missing data sequentially by visits, the 
truncation will be implemented after each visit iteration.  
 Step 3: For missing data because of permanent study treatment discontinuation due to 
adverse events, deaths or lack of efficacy, δ will be added to the imputed values (δ = 
0 corresponds to the MAR assumption). Scores that are adjusted to outside the range 
of the WOMAC subscale will be truncated in the same manner as in step 1. 
Each imputed data set will be analyzed using a MMRM model with terms for baseline WOMAC 
subscale score corresponding to the efficacy variable being analyzed, randomization strata (K-L 
category [2 to 3, or 4], index joint [knee, hip], and geographical region [Other, Europe, North 
America]), treatment, visit, and treatment-by-visit interaction.  For each δ the SAS 
MIANALYZE procedure will be used to generate valid statistical inferences by combining 
results from the 50 analyses using Rubin’s formula.  By progressively increasing δ, the 
sensitivity analysis will explore the tipping points, e.g., δ value when the p-value for a treatment 
comparison is above 0.05. Results will be then summarized using summary tables and graphs. 
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Per Protocol Set Analysis 
Sensitivity analyses based on the PPS will be performed using the same approach as specified for 
the primary analysis in the beginning of this section.  Values of the stratifying variables utilized 
for analysis on the PPS will be those captured in the EDC system. 
USM Analysis Set 
WOMAC Pain and Physical function will be summarized descriptively based on the USM 
Analysis set. No sensitivity analysis will be conducted using the USM analysis set.  
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 
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] 
 Region [North America, Europe, Other] 
 Age group [< 65, 65-74, >=75 ] 
 Sex [Male, Female] 
 Weight group [< Median, ≥ Median] 
 BMI group [≤ Median, > Median] 
 Flare status [Flare, non-flare] : Flare patients are defined as patients who experience a 
≥ 1 point increase in WOMAC pain scores from the Screening to the Baseline Visit 
An MMRM model analogous to that used for the primary analysis will be constructed, also 
including terms for subgroup and subgroup-by-treatment, subgroup-by-visit and subgroup-by 
treatment-by visit interactions as fixed effects.  Multiple imputation will not be performed for the 
subgroup analyses.  In addition to the actual change from baseline values, their LS means, 
differences of LS Means between treatment groups and corresponding 95% CIs within each 
subgroup at each visit will be presented.  The p-value corresponding to the overall effect of the 
overall subgroup-by-treatment interaction will be supplied.  Forest plots for the subgroup 
analysis will be provided. 
5.7.3. 
Analysis of Secondary Efficacy Variables 
The following secondary hypotheses specified in the study protocol that will be tested:  
 H2:  There is no treatment difference between fasinumab 1 mg Q4W and placebo in 
the Patient Global Assessment score at week 24 versus there is treatment difference in 
Patient Global Assessment score at week 24 
 H3:  There is no treatment difference between fasinumab 1 mg Q4W and placebo in 
the proportion of patients with ≥30% improvement in the WOMAC pain subscale 
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scores at week 24 versus there is treatment difference in proportion of patients with 
≥30% improvement in WOMAC pain at week 24 
 H4:  There is no treatment difference between fasinumab 1 mg Q4W and NSAIDs in 
the WOMAC pain subscale scores at week 24 versus there is treatment difference in 
WOMAC pain subscale scores at week 24 
 H5:  There is no treatment difference between fasinumab 1 mg Q4W and NSAIDs in 
the WOMAC physical function subscale scores at week 24 versus there is treatment 
difference in WOMAC physical function subscale scores at week 24 
 H6:  There is no treatment difference between fasinumab 1 mg Q4W and NSAIDs in 
the Patient Global Assessment score at week 24 versus there is treatment difference in 
Patient Global Assessment score at week 24 
The hypotheses H4 and H5 can be tested within the same analysis method used to test H1 as 
described in Section 5.7.1. 
To test H2 and H6, a method analogous to that used to test H1 in Section 5.7.1 can be utilized, 
replacing the respective WOMAC subscale score with the PGA score. The multiple imputation 
algorithm will be modified to truncate values outside the range of the PGA score (0-5) in a 
manner similar to the primary analysis.  
To test H3 the Cochran Mantel Haenszel (CMH) approach stratified by the randomization strata 
(K-L category [2 to 3, or 4], index joint [knee, hip], and geographical region[Other, Europe, 
North America]) will be used with missing data considered as non-response.  
5.7.4. 
Adjustment for Multiple Comparison 
To control the overall Type I Error of the clinical trial at 5%, the sequentially rejective multiple 
test procedure (Bretz 2009) will be applied.  Hypothesis H1 will be tested at α0 = 0.05.  As it is a 
hypothesis test concerning the co-primary endpoints, the hypothesis will be rejected if the 
following is met: 
 The hypothesis of no treatment difference between fasinumab 1 mg Q4W and placebo 
in WOMAC pain subscale at week 24 is rejected 0 = 0.05 
AND 
 The hypothesis of no treatment difference between fasinumab 1 mg Q4W and placebo 
in WOMAC physical function subscale at week 24 between fasinumab and placebo is 
rejected 0 = 0.05 
If a hypothesis is rejected, the alpha level for that hypothesis will be reallocated to other 
hypothesis according to the graph. The graph will be updated according to the pre-specified 
algorithm, as described by Bretz 2009. The rest of the hypotheses will be tested at the updated 
alpha level based on the updated graph. The testing will stop when no hypothesis can be rejected 
at any step.  
If the primary analysis of efficacy is successful, secondary endpoints will be tested according to 
hierarchical testing strategy based on the following order:  
H3 →H2 →H4 → H5 →H6  
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5.7.5. 
Analysis of Other Efficacy Variables  
Responder Analysis 
The percentage of patients who are responders based on WOMAC pain and physical function 
subscale scores defined by at least a 30% reduction and at least a 50%, 70%  reduction from 
baseline to each post-baseline week will be summarized and plotted by treatment group. The 
percentage of patients who are responders based on the Osteoarthritis Research Society 
International Standing Committee for Clinical Trials Response Criterial Initiative and THE 
Outcome Measure in Rheumatology (OMERACT -OARSI) responder criteria will be 
summarized and plotted by treatment group. Cochran -Mantel-Haenszel (CMH) test, stratified by 
the randomization strata will be applied for the responder analysis. Missing data is considered as 
non-response in this analysis.  
Cumulative distribution of percent change from baseline to Week 24 in the WOMAC pain and 
physical function 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 distribution curve.  
Walking Index Joint Pain Numeric Rating Score (NRS) 
For the analysis of average weekly walking index joint pain using the NRS pain scale, baseline is 
defined as the average of the non-missing values during 7 days prior to taking study drug. For 
each week, the average of the non-missing values during the 7 days on or prior to that week will 
be used. If all values are missing for the 7 days, the value for that week is set to missing.  
The MMRM model will include the randomization strata (K-L category [2-3 vs. 4], index joint 
[hip or knee] and geographic region), treatment, week (weeks 1, 2, …, 24), treatment-by-week 
interaction as fixed effects, and baseline average NRS value as a covariate. The least-squares 
(LS) means for the mean change from baseline to each week, as well as the LS mean differences 
between fasinumab doses and placebo, with their corresponding standard errors (SEs), p-values 
and associated 95% confidence intervals, will be provided from the MMRM. If the model does 
not converge using unstructured covariance matrix, an autoregressive 1 covariance structure will 
be used.  
Rescue Medications  
The number (and percentage) of patients using rescue medication, during the Pre-Treatment 
Period will be summarized by treatment group and overall based on the SAF.  Similar analysis 
will be performed for the On-Treatment Period based on the SAF. 
For patients taking rescue medication, descriptive statistics of the number of days patients took 
rescue medications will be presented by treatment group during the On-Treatment Period based 
on the SAF. 
For patients taking rescue medication, weekly average usage of rescue medication (measured in 
mg) is calculated as follows: 
= 
𝑇𝑜𝑡𝑎𝑙 𝑎𝑚𝑜𝑢𝑡 𝑜𝑓 𝑟𝑒𝑠𝑐𝑢𝑒 𝑚𝑒𝑑𝑖𝑐𝑎𝑡𝑖𝑜𝑛 𝑢𝑠𝑒𝑑 𝑖𝑛 𝑡ℎ𝑒 𝑠𝑝𝑒𝑐𝑖𝑓𝑖𝑒𝑑 𝑤𝑒𝑒𝑘 (𝑖𝑛 𝑚𝑔)
# 𝑜𝑓 𝑑𝑖𝑎𝑟𝑦 𝑒𝑛𝑡𝑟𝑖𝑒𝑠 𝑖𝑛 𝑡ℎ𝑒 𝑠𝑝𝑒𝑐𝑖𝑓𝑖𝑒𝑑 𝑤𝑒𝑒𝑘
 
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Descriptive statistics of the weekly average usage of rescue medications for OA pain will be 
presented by treatment group based on the SAF. 
Averagev WOMAC pain ann physical function Score across Week 12 to Week 24 
Change in WOMAC pain and physical function subscale scores from baseline to the average 
score across Weeks 12, 16, 20 and 24 will be analyzed using the same multiple imputation 
method used to analyze the primary efficacy endpoints in Section 5.7.1.  However, the analysis 
model for the average of the WOMAC subscale scores across multiple visits will instead be an 
ANCOVA model with terms for baseline WOMAC subscale score, randomization strata (K-L 
category [2 to 3, or 4], index joint [knee, hip], and geographical region [Europe, North America, 
Other]) and treatment. 
5.7.6. 
Analysis of Quality-of-Life and Health Economic Variables 
The following patient reported outcomes will be summarized and analyzed. Analysis results for 
exploratory objectives will be included in the final CSR. 
EuroQol 5 Dimensions 5 Level Questionnaire (EQ-5D-5L) 
The health states defined by the 5-dimensional classification will be converted into the 
corresponding index score.  The EQ-5D-5L index will be set to missing if any of the 5 
dimensions is missing. 
An MMRM model will be fit to the EQ-5D-5L Visual Analog Scale and index scores include the 
randomization strata (K-L category [2-3 vs. 4], index joint [hip or knee] and geographic region), 
treatment, visit, treatment-by-visit interaction as fixed effects, and baseline value as a covariate. 
The least-squares (LS) means for the mean change from baseline to each visit, as well as the LS 
mean differences between fasinumab and placebo and NSAID groups, with their corresponding 
standard errors (SEs), p-values and associated 95% confidence intervals, will be provided from 
the MMRM. 
36-Item Short Form Medical Outcome Study Questionnaire, Version 2 (SF-36) 
The same analysis used for the EQ-5D-5L will be performed for the subscale scores of the SF-36 
using analogous MMRM models.  SF-36 subscale scores will be computed if at least 50% of 
component items are available. The missing items will be imputed by the mean of available 
items. 
Health Care Resource Utilization Questionnaire (HCRU) 
The utilization of each resource captured on the HCRU will be summarized via descriptive 
statistics by treatment group for each visit. 
Work Productivity and Activity Impairment-Osteoarthritis (WPAI-OA) 
The number and percentage of patients who reported they were working/non-working on 
Question 1 of the WPAI-OA will be presented by treatment group for each visit.  Furthermore, 
for patients who answered ‘YES’ to Question 1 at that visit, the absenteeism, presenteeism, work 
productivity loss and activity impairment scores will also be constructed.  The same analysis 
used for the EQ-5D-5L will be presented for all four scores of the WPAI-OA using analogous 
MMRM models. 
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Treatment Satisfaction Questionnaire for Medicine (TSQM) 
The same analysis used for the EQ-5D-5L will be performed for the effectiveness, side effects, 
convenience and global satisfaction domain scores of the TSQM using analogous MMRM 
models.  The missing items will be imputed by the mean of available items. 
5.8. 
Analysis of Safety Data 
The analysis of safety and tolerance will be performed on the SAF, as defined in Section 3.4. 
The safety analysis will be based on the reported AEs and other safety information (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.  
The summary of safety results will be presented for each treatment group and by visit where 
applicable. 
Day 1 is the first day of investigational product, Day –1 is the day before; there is no Day 0. 
The time interval to detect any AEs, including AESIs (except JR identified at the 72-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 44/Early Termination).  Any study drug-related SAEs 
occurring between the end of Follow-Up clinic visit and the End of Study 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. 
Adverse Events  
The verbatim text, the preferred term (PT), and the primary system organ class (SOC) will be 
displayed in subject listings. Summaries that include frequencies and proportions of patients 
reporting AEs will include the PTs and the SOCs. 
For details on handling missing data and partial dates, see Section 6.3. 
Summaries of AE incidence 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 
 Total number of serious AESIs 
 Patients with any TEAEs 
 Patients with any serious TEAEs 
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 Patients with any AESI’s 
 Patients with any serious AESIs 
 Patients with any TEAEs leading to permanent study treatment discontinuation 
 Patients with any TEAEs leading to withdrawal from study 
 Patients with any TEAEs leading to death 
 TEAEs by SOC and PT 
 All TEAEs 
 TEAEs by severity: mild, moderate or severe 
 TEAEs resulting in permanent study treatment discontinuation 
 Study drug-related TEAEs by SOC and PT 
 All TEAEs 
 TEAEs by severity: mild, moderate or severe 
 TEAEs resulting in permanent study treatment discontinuation 
 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 
 All serious TEAEs 
 Post-treatment Serious AEs by SOC and PT 
 All serious AEs on study by SOC and PT 
 Non - Serious TEAEs by SOC and PT 
 All non-serious TEAEs 
 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 
 Deaths 
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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 descending frequency of the ‘Fasinumab 1 mg SC Q4W’ 
treatment group. Within each primary SOC, PTs will be sorted by decreasing frequency of 
investigational product. 
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 treatment (not applicable to 
post-treatment AEs) 
 TEAEs leading to withdrawal from study 
 Patients with Serious TEAEs 
 AESIs by AESI type 
 Deaths 
 All Joint Replacements 
 Pre-treatment AEs 
 Post-treatment AEs 
5.8.2. 
Analysis of Adverse Events of Special Interest 
Adverse events of special interest (AESI) include adjudicated arthropathies, AEs confirmed as 
SNS dysfunction and 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 
5.8.3. 
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. 
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Listings will be provided with flags indicating the out of laboratory range values.  
A treatment-emergent Potential Clinically Significant abnormal value (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.  Definitions of PCSV is 
listed in Section 10.3.  Treatment-Emergent Potentially clinically significant values (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. 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 other AA subtype except RPOA-1) 
 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 Period.  Lab data 
collected during the Pre-Treatment and Post-Treatment Periods will be displayed in listings. 
5.8.4. 
Analysis of Vital Signs 
Vital signs (blood pressure, temperature and respiration rate) will be summarized by baseline and 
change from baseline to each scheduled assessment time with descriptive statistics. 
A treatment-emergent Potential Clinically Significant abnormal value (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 Potentially clinically significant values (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. 
5.8.5. 
Analysis of 12-Lead ECG 
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 by treatment group. 
A treatment-emergent Potential Clinically Significant abnormal value (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 Potentially clinically significant values (PCSVs) will 
be summarized by treatment group. 
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ECG status (i.e. normal, abnormal) 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. 
5.8.6. 
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. 
5.8.7. 
Analysis of Other Safety Variables 
Other safety data includes the survey of Autonomic Symptoms, cases of AA and joint 
replacements. 
Adjudicated Arthropathry 
Adjudicated arthropathy events based on imaging data overall and by subtype will be 
summarized by treatment group based on the SAF.  Time to first AA event will be summarized 
by Kaplan-Meier method. 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.  
Time to first DA event will be summarized by Kaplan-Meier method. Cox regression model 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. 
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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 
Plots of the Kaplan Meier curves by treatment group (as randomized) of time to JR will be 
presented based on the SAF, regardless of what period in the study the JR occurred. Patients 
without an event will be censored at the last contact. 
Data from Urgent Safety Measure Patients 
Limited safety summaries will be presented based on the USM Analysis set including TEAEs 
and summaries of AAs, DAs and all joint replacements.  
5.9. 
Analysis of Pharmacokinetic Data 
Summaries of fasinumab concentrations in serum will be presented by nominal time point. 
Individual patient concentration data will be plotted by actual time. Plots of mean and median 
serum concentrations of fasinumab will be presented by nominal time. 
Correlation analyses of fasinumab concentrations in serum vs efficacy and safety endpoints may 
be performed, as appropriate. 
5.10. 
Analysis of Immunogenicity Data 
5.10.1. 
Analysis of ADA Data 
The immunogenicity variables described in Section 4.7 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: 
 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. 
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 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 
 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 subjects/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. 
Analysis of Neutralizing Antibody (NAb) Data 
The absolute occurrence (n) and percent of patients (%) with NAb status in the NAb analysis set 
will be provided by treatment groups. 
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5.10.3. 
Association of Immunogenicity with Exposure, Safety and Efficacy 
5.10.3.1. 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 periodInjection site reaction 
(serious or severe and lasting 24 hours or longer) 
 Hypersensitivity (SMQ: Hypersensitivity [Narrow]) 
 Anaphylaxis (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 safety and efficacy analyses mentioned above 
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. 
 NAb positive patients, that is ADA positive patients who were positive in the NAb 
assay at any time point analyzed. 
 Maximum post-baseline titer in treatment-emergent or treatment-boosted ADA 
positive patients: 
 Low (titer <1,000) 
 Moderate (1,000 ≤ titer ≤ 10,000) 
 High (titer >10,000) 
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis. 
6.1. 
Definition of Baseline for Efficacy/Safety Variables 
Unless otherwise specified, the baseline value is defined as the last available valid measurement 
prior to randomization.  
6.2. 
Data Handling Convention for Efficacy Variables  
6.2.1. 
Data Handling Convention for Efficacy Variables due to COVID-19 Pandemic  
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 (Bellamy 2002). Sensitivity analysis may be performed excluding data collected via 
telephone. 
6.3. 
Data Handling Convention for Repeat Measurements 
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 assessments 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: 
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. 
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Patient reported outcomes data 
Should there 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 JPQ.  
6.4. 
Data Handling Convention for Missing Data 
Rules for handling missing data for primary and secondary efficacy variables are described in 
Section 4.5.1 and Section 4.5.2. 
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 dates 
Imputation of AE and Concomitant Missing and Partial start dates:  
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 present, missing AE/concomitant medication end day will imputed to 
the last day of the month.  
There will be no attempt to impute completely missing AE or concomitant medication end dates. 
Events with an end date missing will be assumed to be ongoing at the time of data cut off.  
Handling of 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. 
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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 questionnaires 
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. 
SF-36  
The Half-Scale rule will be used to impute missing item responses in the SF-36 subscale scores 
i.e. a score will be computed if the respondent answers at least 50% of items in that scale. The 
missing items in the scale will be imputed by the mean of available items rounded to the nearest 
whole number.  
The bodily pain subscale consists of Q7 and Q8 of the instrument. Since Q7 is based on 6pt 
Likert score and Q8 is based on a 5pt Likert scale and because mean imputation will be 
meaningless, the bodily pain subscale score will not be imputed if any of the questions making 
up the scale is missing.  
EQ-5D-5L  
Index will be set to missing if any of the 5 dimensions is missing.  
Laboratory Safety Variables below LLOQ or above ULOQ 
For central laboratory data below the lower limit of quantification (LLOQ), 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. 
Handling of Potentially Clinically Significant Abnormalities 
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; e.g., 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. 
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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 case report form (CRF) assessment recorded by the investigator.  For 
assessments without a nominal visit number such as Unscheduled, EOT, EOS assessments, and 
eCOA 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 Appendix 10.2 Schedule of Events.  
The following visit windows will be used to map the unscheduled visits, early study termination visits 
and eCOA assessments, based on the study day: 
Table 1: 
Analysis Windows 
Visit Number 
Visit Name 
Targeted Study Daysa 
Analysis Window in 
Study Days 
1 
Screen 
Day -30 to Day -11 
[-30, -11] 
2 
Pre-randomization 
Day -10 to -7 
[-10, -1] 
3 
Baseline 
1 
1 
Phone 1 
Week 2 
15 
[2, 22] 
4 
Week 4 
29 
[23, 43]  
5 
Week 8 
57 
[44, 71] 
6 
Week 12 
85 
[72, 99] 
7 
Week 16 
113 
[100, 127] 
8 
Week 20 
141 
[128, 155] 
9 
Week 24 
169 
[156, 196] 
10 
Week 28 
197 
[197, 267] 
11 
Week 44 
309 
[268, 407] 
Phone 2 
Week 72 
505 
≥ 408 
a Study days are calculated from the first dose of study drug (Day 1). 
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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. 
Unscheduled Assessments 
The determination of baselines and values at the end of treatment 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 adverse events) will be included in listings, 
but not summaries except for the endpoint determination.  If more than one laboratory value is 
available for a given visit, the first observation will be used in summaries and all observations 
will be presented in listings. 
6.7. 
Pooling of Centers for Statistical Analyses 
Study centers will be pooled according to their geographic region the statistical analysis.  The 
geographic regions are:  
 Europe: Estonia, Germany, Poland, Romania, United Kingdom 
 North America: United States, Canada 
 Other: South Africa, Australia, New Zealand 
6.8. 
Statistical Technical Issues 
Not applicable. 
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7. 
INTERIM ANALYSIS 
 A First-Step Analysis of the data will be conducted when 44 week data are available 
for all randomized patients. No alpha adjustment is necessary, as the week 24 efficacy 
analysis will be the final primary analysis for efficacy.  The results of this analysis 
will be used in the filing for the BLA submission.  
 120-Day Safety Update:  The analysis for the 120-Day Safety Update will include 
additional safety data collected upto to the data cutoff date. 
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8. 
SOFTWARE 
All analyses will be done using SAS Version 9.4. 
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9. 
REFERENCES 
1. ICH. (1996, July 30). ICH Harmonized tripartite guideline: Structure and content of 
clinical study reports (E3). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
2. ICH. (1997, July 17). ICH Harmonized tripartite guideline: General considerations for 
clinical trials (E8). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
3. 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. 
4. Bretz, F., W. Maurer, W. Brannath, and M. Posch.  A graphical approach to sequentially 
rejective multiple test procedures. Stat Med. 2009. 28:586-604. 
5. Bellamy, N., J. Campbell, H. Hill, P. Band. A comparative study of telephone versus 
onsite completion of the WOMAC 3.0 Osteoarthritis Index. J Rheumatol 2002. 29:783–6. 
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10. 
APPENDIX 
10.1. 
Summary of Statistical Analyses 
Efficacy Analysis: 
Endpoint 
Analysis 
Populations 
Primary 
Analysis 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Primary Endpoint 
Co-primary: 
- Change from 
baseline in the 
WOMAC pain 
subscale 
scores  
- Change from 
baseline in the 
WOMAC 
physical 
function 
subscale score  
FAS, PPS 
Change from 
baseline at Week 
24 in the 
WOMAC pain 
subscale scores 
& 
Change from 
baseline at Week 
24 in the 
WOMAC 
physical 
function 
subscale scores 
MMRM with 
multiple 
imputation 
Sensitivity 
Analyses:  
- Treatment 
Policy 
Estimand 
- Tipping 
Point 
Analysis 
- Analysis 
using the 
PPS  
Subgroups: 
K-L 
Category, 
Index 
Joint, 
Region, 
Age 
Group, 
Sex, 
Weight, 
BMI 
Group. 
For Non-flare 
patients - 
Change from 
baseline at Week 
24 in the WOMAC 
pain subscale 
scores 
& 
Change from 
baseline at Week 
24 in the WOMAC 
physical function 
subscale scores 
Secondary/exploratory Endpoints 
- Change from 
baseline in the 
WOMAC pain 
subscale 
scores  
- Change from 
baseline in the 
WOMAC 
physical 
function 
subscale score 
FAS 
 
MMRM with 
multiple 
imputation 
 
 
Change from 
baseline at all 
intermediate visits 
in WOMAC pain 
and physical 
function scores 
- Change from 
baseline in 
WOMAC pain 
subscale 
scores 
averaged 
across 
multiple 
timepoints  
FAS 
Change from 
baseline in 
WOMAC pain 
subscale scores 
averaged across 
Weeks 12, 16, 
20 and 24 
ANCOVA 
with 
multiple 
imputation 
 
 
 
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Endpoint 
Analysis 
Populations 
Primary 
Analysis 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
- Change from 
baseline in 
WOMAC 
physical 
function 
subscale 
scores 
averaged 
across 
multiple 
timepoints 
FAS 
Change from 
baseline in 
WOMAC 
physical 
function 
subscale scores 
averaged across 
Weeks 12, 16, 
20 and 24  
ANCOVA 
with 
multiple 
imputation 
 
 
 
Change from 
baseline in PGA 
scores  
FAS 
Change from 
baseline at Week 
24 in the PGA 
scores 
MMRM with 
multiple 
imputation 
 
Subgroups: 
K-L 
Category, 
Index 
Joint, 
Region, 
Age 
Group, 
Sex, 
Weight, 
BMI 
Group. 
Change from 
baseline at all 
intermediate visits 
in PGA scores 
 
Cumulative 
distribution 
frequency plot 
Proportion of 
patients with ≥ 
30% 
improvement in 
WOMAC pain 
subscale  
FAS 
Proportion of 
patients with ≥ 
30% 
improvement in 
WOMAC pain 
subscale at 
Week 24 
CMH Test 
Sensitivity 
Analyses:  
- Analysis 
treating 
patients who 
discontinue 
treatment 
prior to 
Week 24 as 
non-
responders 
Subgroups: 
K-L 
Category, 
Index 
Joint, 
Region, 
Age 
Group, 
Sex, 
Weight, 
BMI 
Group. 
Proportion of 
patients with ≥ 50 
and 70% 
improvement in 
WOMAC pain 
subscale at Week 
24 
Safety Analyses: 
Endpoint 
Analysis 
Populations 
Primary 
Analysis 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Treatment 
Emergent Adverse 
Events 
SAF  
Percent of 
patients by 
system organ 
class and 
preferred term 
Descriptive 
Statistics 
No 
No 
Percent of 
patients by 
system organ 
class, preferred 
term and 
severity 
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Endpoint 
Analysis 
Populations 
Primary 
Analysis 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Treatment 
Emergent Serious 
Adverse Events 
SAF  
Percent of 
patients by 
system organ 
class and 
preferred term 
Descriptive 
Statistics 
No 
No 
NA 
Treatment-related 
Treatment 
Emergent Adverse 
Events 
SAF  
Percent of 
patients by 
system organ 
class and 
preferred term 
Descriptive 
Statistics 
No 
No 
Percent of 
patients by 
system organ 
class, preferred 
term and 
severity 
Treatment 
Emergent Adverse 
Events of Special 
Interest 
SAF  
Percent of 
patients by 
system organ 
class and 
preferred term 
Descriptive 
Statistics 
No 
No 
No 
Treatment 
Emergent Adverse 
Events Leading to 
Discontinuation 
from Study Drug 
SAF  
Percent of 
patients by 
system organ 
class and 
preferred term 
Descriptive 
Statistics 
No 
No 
NA 
Treatment 
Emergent Non-
Serious Adverse 
Events 
SAF  
Percent of 
patients by 
system organ 
class and 
preferred term 
Descriptive 
Statistics 
No 
No 
NA 
Clinical 
Laboratory 
Measurements 
SAF  
Actual and 
Change from 
baseline values 
Descriptive 
Statistics 
PCVS 
Analysis 
No 
Shift Table 
Analysis 
Vital Sign 
Measurements 
SAF  
Actual and 
Change from 
baseline values 
Descriptive 
Statistics 
PCVS 
Analysis 
No 
Incidence of 
Orthostatic 
Hypotension 
12-Lead ECGs 
SAF  
Actual and 
Change from 
baseline values 
Descriptive 
Statistics 
PCVS 
Analysis 
No 
Shift Table 
Analysis 
Physical & 
Neurological 
Exams 
SAF  
Number of 
patients with 
new-onset 
abnormal 
examinations 
findings 
Descriptive 
Statistics 
NA 
No 
NA 
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Statistical Analysis Plan 
Date: 08Apr2020 
 
CONFIDENTIAL 
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Endpoint 
Analysis 
Populations 
Primary 
Analysis 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Survey of 
Autonomic 
Symptoms 
SAF  
Number of 
patients 
reporting the 
presence of each 
symptom/health 
problem 
Descriptive 
Statistics 
Number of 
Symptoms 
Reported 
Total 
Symptom 
Impact 
Score 
No 
NA 
Adjudicated 
Arthropathy 
SAF  
Number of 
patients 
requiring 
adjudication 
Number of 
patients with 
adjudicated 
arthropathy 
Number of 
patients with 
destructive 
arthropathy  
Descriptive 
Statistics 
Time to AA 
Time to DA 
Break-
down by 
subtypes of 
AA 
No 
NA 
Joint 
Replacements 
SAF  
Number of 
patients with 
joint 
replacements 
Descriptive 
Statistics 
Time to JR 
No 
NA 
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Protocol: R475-OA-1688 
Statistical Analysis Plan 
Date: 08Apr2020 
 
CONFIDENTIAL 
Page 54 of 68 
10.2. 
Schedule of Time and Events 
Table 2: 
Schedule of Events 
 
Screening/ 
Pre-
randomization  
Treatment Period 
Follow-up Period1 
EOS 
Study Week (wk) 
Visit (V)/Phone 
 
Screen 
V 1 
Pre- 
rand 
V 2 
 
Baseline 
V 3 
 
Wk 2 
Phone 1 
 
Wk 4 
V 4 
 
Wk 8 
V 5 
 
Wk 12 
V 6 
 
Wk 16 
V 7 
 
Wk 20 
V 8 
EOT 
Wk 24 
V 9 
ET1/ 
JR 
Pre-
Op 
Visit 
 
Wk 28 
V 10 
 
Wk 44 
V 11 
ET1/ 
JR 
Pre-
Op 
Visit 
 
Wk 72 
Phone 2 
Study Day 
Up to 
30 
Days 
7 to 10 
Days 
1 
15 
29 
57 
85 
113 
141 
169 
197 
309 
505 
Window (days) 
 
 
 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Screening/Baseline: 
Inclusion/ 
Exclusion2 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Main study 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genomics Sub-
study Informed 
Consent3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI for index 
joint, contralateral 
joint & any hip or 
knee with K-L ≥3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Instructions for use 
of diary 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Training on pain 
reporting/patient 
education 
brochures4 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan 
Date: 08Apr2020 
 
CONFIDENTIAL 
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Screening/ 
Pre-
randomization  
Treatment Period 
Follow-up Period1 
EOS 
Study Week (wk) 
Visit (V)/Phone 
 
Screen 
V 1 
Pre- 
rand 
V 2 
 
Baseline 
V 3 
 
Wk 2 
Phone 1 
 
Wk 4 
V 4 
 
Wk 8 
V 5 
 
Wk 12 
V 6 
 
Wk 16 
V 7 
 
Wk 20 
V 8 
EOT 
Wk 24 
V 9 
ET1/ 
JR 
Pre-
Op 
Visit 
 
Wk 28 
V 10 
 
Wk 44 
V 11 
ET1/ 
JR 
Pre-
Op 
Visit 
 
Wk 72 
Phone 2 
Study Day 
Up to 
30 
Days 
7 to 10 
Days 
1 
15 
29 
57 
85 
113 
141 
169 
197 
309 
505 
Window (days) 
 
 
 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Treatment: 
SC study drug 
injection5 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Dispense oral 
study drug 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Oral study drug 
accountability  
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Dispense to home 
acetaminophen/ 
paracetamol 
 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Acetaminophen/ 
paracetamol 
accountability 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Record rescue 
medication use in 
patient diary6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Concomitant 
therapies 
(medications and 
procedures) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Efficacy: 
WOMAC7 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PGA 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
NRS8 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
WPAI-OA 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
SF-36 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
 
EQ-5D-5L  
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
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Statistical Analysis Plan 
Date: 08Apr2020 
 
CONFIDENTIAL 
Page 56 of 68 
 
Screening/ 
Pre-
randomization  
Treatment Period 
Follow-up Period1 
EOS 
Study Week (wk) 
Visit (V)/Phone 
 
Screen 
V 1 
Pre- 
rand 
V 2 
 
Baseline 
V 3 
 
Wk 2 
Phone 1 
 
Wk 4 
V 4 
 
Wk 8 
V 5 
 
Wk 12 
V 6 
 
Wk 16 
V 7 
 
Wk 20 
V 8 
EOT 
Wk 24 
V 9 
ET1/ 
JR 
Pre-
Op 
Visit 
 
Wk 28 
V 10 
 
Wk 44 
V 11 
ET1/ 
JR 
Pre-
Op 
Visit 
 
Wk 72 
Phone 2 
Study Day 
Up to 
30 
Days 
7 to 10 
Days 
1 
15 
29 
57 
85 
113 
141 
169 
197 
309 
505 
Window (days) 
 
 
 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Central vs. 
peripheral pain 
Questionnaire 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HCRU 
X 
 
 
 
 
 
X 
 
 
X 
X 
 
 
 
 
TSQM 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
 
 
 
 
Safety: 
Weight 
X 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
 
Vital Signs9 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical 
Examination 
X 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
 
Orthostatic blood 
pressure and heart 
rate assessment9,10 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Joint pain 
questionnaire 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Survey of 
Autonomic 
Symptoms 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Neurologic 
examination 
X 
Full 
 
X 
Brief 
 
X 
Brief 
X 
Brief 
X 
Brief 
X 
Brief 
X 
Brief 
X 
Full 
X 
Full 
X 
Brief 
X 
Full 
X 
Full 
 
Adverse events 
----------------------------------------------------------------------------------------------------------------------------------------------------------------------> 
 
Injection site 
evaluation 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Bilateral X-rays 
(knee, hip, 
shoulder) 
X11 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
X 
 
Event-triggered 
imaging12 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
                                        VV-RIM-00105092-1.0 Approved - 16 Apr 2020 GMT-5:00


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Protocol: R475-OA-1688 
Statistical Analysis Plan 
Date: 08Apr2020 
 
CONFIDENTIAL 
Page 57 of 68 
 
Screening/ 
Pre-
randomization  
Treatment Period 
Follow-up Period1 
EOS 
Study Week (wk) 
Visit (V)/Phone 
 
Screen 
V 1 
Pre- 
rand 
V 2 
 
Baseline 
V 3 
 
Wk 2 
Phone 1 
 
Wk 4 
V 4 
 
Wk 8 
V 5 
 
Wk 12 
V 6 
 
Wk 16 
V 7 
 
Wk 20 
V 8 
EOT 
Wk 24 
V 9 
ET1/ 
JR 
Pre-
Op 
Visit 
 
Wk 28 
V 10 
 
Wk 44 
V 11 
ET1/ 
JR 
Pre-
Op 
Visit 
 
Wk 72 
Phone 2 
Study Day 
Up to 
30 
Days 
7 to 10 
Days 
1 
15 
29 
57 
85 
113 
141 
169 
197 
309 
505 
Window (days) 
 
 
 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Pre-op 
questionnaire (JR 
follow-up)13 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Electrocardiogram  
X 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
EOS phone 
contact14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
MRI of affected 
joint(s) for AA 
patients only15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Laboratory Testing: 
Hematology16 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
X 
X 
 
Blood Chemistry16 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
X 
X 
 
ESR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hb1AC16 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH and 
estradiol16,17 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
(WOCBP)18 
X 
Serum 
 
X 
Urine 
 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
 
Urinalysis and 
urine electrolytes16 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
X 
X 
 
Urine drug test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK ADA and Research Samples: 
ADA sample19 
 
 
X 
 
 
 
 
X 
 
X 
X 
 
X 
X 
 
PK sample19 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
 
hs-CRP sample19,20 
 
 
X 
 
X 
 
 
X 
 
X 
X 
 
X 
X 
 
Research 
serum/plasma 
sample19, 20 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
 
                                        VV-RIM-00105092-1.0 Approved - 16 Apr 2020 GMT-5:00


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Protocol: R475-OA-1688 
Statistical Analysis Plan 
Date: 08Apr2020 
 
CONFIDENTIAL 
Page 58 of 68 
 
Screening/ 
Pre-
randomization  
Treatment Period 
Follow-up Period1 
EOS 
Study Week (wk) 
Visit (V)/Phone 
 
Screen 
V 1 
Pre- 
rand 
V 2 
 
Baseline 
V 3 
 
Wk 2 
Phone 1 
 
Wk 4 
V 4 
 
Wk 8 
V 5 
 
Wk 12 
V 6 
 
Wk 16 
V 7 
 
Wk 20 
V 8 
EOT 
Wk 24 
V 9 
ET1/ 
JR 
Pre-
Op 
Visit 
 
Wk 28 
V 10 
 
Wk 44 
V 11 
ET1/ 
JR 
Pre-
Op 
Visit 
 
Wk 72 
Phone 2 
Study Day 
Up to 
30 
Days 
7 to 10 
Days 
1 
15 
29 
57 
85 
113 
141 
169 
197 
309 
505 
Window (days) 
 
 
 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Genomic sub-study 
sample (optional)3 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
AA: Adjudicated arthropathy 
NRS: Numeric Rating Scale (for walking index joint pain) 
ADA: Anti-drug antibody 
PGA: Patient Global Assessment 
EOS: End of study 
PK: Pharmacokinetic 
EOT: End of treatment 
Pre-Op: Pre-Operative  
EQ-5D-5L: EuroQoL 5 Dimensions 5 Level Questionnaire 
Pre-rand: Pre-randomization 
ESR: Erythrocyte sedimentation rate 
SC: Subcutaneous 
ET: Early termination 
SF-36: 36-item Short Form Medical Outcomes Study Questionnaire Version 2 
FSH: Follicle stimulating hormone 
TSQM: Treatment Satisfaction Questionnaire for Medication 
HbA1c: Hemoglobin A1c 
Visit: V 
HCRU: Healthcare Resource Utilization 
Week: Wk 
Hs-CRP: High-sensitivity C-reactive Protein 
WOCBP: Women of child-bearing potential 
JR: Joint replacement 
WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index 
K-L: Kellgren-Lawrence 
WPAI-OA: Work Productivity and Activity Impairment-Osteoarthritis 
MRI: Magnetic resonance imaging 
 
Footnotes for Table 2 - the Schedule of Events 
1. Patients who discontinue study medication before week 24 will be encouraged to follow the visit schedule through the 
remainder of the study. If a patient chooses to end study participation, he or she will be asked to return to the clinic 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 
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Protocol: R475-OA-1688 
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CONFIDENTIAL 
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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. Subcutaneous study drug administration will be the last procedure at each dosing visit, and will be done after all laboratory, 
PK, ADA and research samples have been collected and all study assessments 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 24. 
7. Patients will complete the WOMAC pain subscale for both hips and knees at the screening visit. Then, the WOMAC Full 
Survey will be completed only for the index joint at subsequent visits. 
8. Walking index joint pain NRS score will be recorded by the patient each day using their diary, starting during the 
pre-randomization period through week 24. Walking index joint pain NRS score will be recorded by the patient at the site at 
the week 24 visit. 
9. If the pulse is less than 45 bpm, an ECG with rhythm strip will be obtained to confirm the heart rate and rhythm. 
10. Blood pressure measurements to assess orthostatic hypotension may be discontinued following regulatory approval if the 
safety database does not reveal an imbalance for the fasinumab treated patients. 
11. 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. 
12. Imaging (X-ray and possibly 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. 
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CONFIDENTIAL 
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13. In the event that a patient must undergo joint arthroplasty during the study, the patient will complete the pre-operative JR study 
visit and the procedures outlined in the schedule of events for joint arthroplasty follow-up. The pre-operative questionnaire 
would be the Knee Society for knee replacements and the Harris Hip Score questionnaire for hip replacements. The pre-
operative visit should be completed before joint arthroplasty if at all possible. Pre-operative imaging will be performed and 
submitted to the adjudication committee. 
14. The purpose of this phone contact is to ask the patient if they have had or are scheduled (or on a waiting list) to have a JR. Pre-
operative images will be submitted to the central reader for adjudication, if available 
15. If the affected joint has undergone JR an X-ray may be substituted for an MRI 
16. Samples will be analyzed by the central laboratory and results evaluated by the investigator 
17. Only to be performed if postmenopausal status has to be assessed for female patients who are ≤59 years of age. 
18. 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 participation. 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. 
19. Collection of samples for PK, ADA, high sensitivity C-reactive protein (hs-CRP) and research are mandatory at the time points 
specified above. In addition, PK, ADA, hs-CRP 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 SC study drug 
administration on SC study drug dosing days 
20. Research samples should be collected after the patients have been fasting overnight or for 8 hours (in the event of an afternoon 
visit). 
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Protocol: R475-OA-1688 
Statistical Analysis Plan 
Date: 08Apr2020 
 
CONFIDENTIAL 
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Table 3: 
Follow-up Period for Patients Undergoing Joint Replacement Surgery on Study 
Follow-up Study Day (Visit Window)1 
Post-Operative  
Long-Term 
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 3 - 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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Statistical Analysis Plan 
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CONFIDENTIAL 
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10.3. 
Criteria for Potentially Clinically Significant Values (PCSV) 
Parameter 
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  
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 
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. 
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CONFIDENTIAL 
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Parameter 
PCSV 
Comments 
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. 
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 
PCSV 
Comments 
Chloride 
Hypochloraemia 
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 
Hypokalaemia 
Hyperkalaemia 
 
<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 
HbA1c 
Albumin 
≤25 g/L and >25 g/L at baseline 
Albumin 
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 
 
                                        VV-RIM-00105092-1.0 Approved - 16 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R475-OA-1688 
Statistical Analysis Plan 
Date: 08Apr2020 
 
CONFIDENTIAL 
Page 65 of 68 
Parameter 
PCSV 
Comments 
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. 
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. 
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 
                                        VV-RIM-00105092-1.0 Approved - 16 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R475-OA-1688 
Statistical Analysis Plan 
Date: 08Apr2020 
 
CONFIDENTIAL 
Page 66 of 68 
Parameter 
PCSV 
Comments 
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. 
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 parameters 
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-00105092-1.0 Approved - 16 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R475-OA-1688 
Statistical Analysis Plan 
Date: 08Apr2020 
 
CONFIDENTIAL 
Page 67 of 68 
Parameter 
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. 
10.4. 
Protocol Deviations Excluding Patients from the PPS 
PDID 
Description of Protocol Deviation 
1.05, 1.06, 1.08 
Inclusion Criteria 4, 5, and 7 not met but subject randomized 
2.11 
Exclusion Criteria 10 met but subject randomized 
3.02 
Baseline visit not performed 
3.16 
Screening visit was not performed 
5.14 
WOMAC patient assessment was not administered at Week 24 Primary Endpoint Analysis 
8.04 
Rescue medication administered during a protocol-prohibited period prior to scheduled visit during treatment period 
8.05 
Use of opioid medications anytime during treatment period 
8.06 
Use of non-protocol specified NSAIDs any time during the treatment 
F.02 
Confirmed treatment unblinding (in error) 
 
                                        VV-RIM-00105092-1.0 Approved - 16 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R475-OA-1688 
Statistical Analysis Plan 
Date: 08Apr2020 
 
CONFIDENTIAL 
Page 68 of 68 
10.5. 
OMERACT – OARSI RESPONDER CRITERIA  
 
Note that the criteria in the diagram above are based on standardized scores 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-00105092-1.0 Approved - 16 Apr 2020 GMT-5:00


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                                        VV-RIM-00105092-1.0 Approved - 16 Apr 2020 GMT-5:00