Conditions: Osteoarthritis, Knee Osteoarthritis, Hip
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 3307
Healthy volunteers: no

Brief summary:
The primary objective of the study is to evaluate the efficacy of fasinumab compared with placebo, when administered for up to 16 weeks in patients with pain due to osteoarthritis (OA) of the knee or hip.

The secondary objectives of the study are:

1. To evaluate the efficacy of fasinumab compared with naproxen, when administered for up to 16 weeks in patients with pain due to OA of the knee or hip
2. To evaluate the efficacy of fasinumab compared with placebo, when administered for up to 44 weeks in patients with pain due to OA of the knee or hip
3. To assess the safety and tolerability of fasinumab compared with naproxen, when administered for up to 16 weeks in patients with pain due to OA of the knee or hip
4. To assess the safety and tolerability of fasinumab compared with naproxen, when administered for up to 52 weeks in patients with pain due to OA of the knee or hip
5. To assess the safety and tolerability of fasinumab compared with naproxen, when administered for up to 104 weeks in patients with pain due to OA of the knee or hip
6. To evaluate the pharmacokinetic (PK) profile of fasinumab administered to patients with pain due to OA of the knee or hip for up to 52 weeks
7. To evaluate the PK profile of fasimumab administered to patients with pain due to OA of the knee or hip for up to 104 weeks
8. To evaluate the immunogenicity of fasinumab administered to patients with pain due to OA of the knee or hip for up to 52 weeks
9. To evaluate the immunogenicity of fasinumab administered to patients with pain due to OA of the knee or hip for up to 104 weeks
10. To evaluate the efficacy of fasinumab compared with naproxen, when administered for up to 44 weeks in patients with pain due to OA of the knee or hip

Detailed description:

Arms:
arm 1: Fasinumab Subcutaneous (SC) dosing regimen 1 and naproxen-matching placebo oral arm 2: Fasinumab SC dosing regimen 2 and naproxen-matching placebo oral arm 3: None arm 4: None

Interventions: intervention 1: Fasinumab intervention 2: Naproxen intervention 3: Fasinumab-matching placebo intervention 4: Naproxen-matching placebo
Intervention descriptions: intervention 1: Solution for injection in pre-filled syringe intervention 2: Pharmaceutical form: Capsule intervention 3: Solution for injection in pre-filled syringe intervention 4: Capsule

Protocol document:
Prot_000.pdf: 
IND: Number:  103245 
EudraCT: 2016-005020-29 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A Phase 3 Randomized, Double-Blind, Multi-Dose, Placebo and 
Naproxen-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 OA1 
Clinical Phase: 
3 
Protocol Number: 
R475-OA-1611 
Protocol Version: 
R475-OA-1611 Amendment 9 Global 
Amendment 9 Global Date of Issue 
See appended electronic signature page 
Amendment 8 Global Date of Issue 
01 Jul 2020 
Amendment 7 Global Date of Issue 
23 Apr 2020 
Amendment 6 Global Admin Date of 
Issue: 
18 Jun 2019 
Amendment 6 Global Date of Issue: 
05 Mar 2019 
Amendment 5 Global Date of Issue: 
11 Jul 2018 
Amendment 4 Global Date of Issue: 
24 May 2018 
Amendment 3 Global Date of Issue: 
27 Apr 2018 
Amendment 2VHP Date of Issue: 
20 Oct 2017 
Amendment 1VHP Date of Issue: 
07 Oct 2017 
Amendment 1 Date of Issue: 
26 Sep 2017 
Original Date of Issue: 
27 Mar 2017 
Scientific/Medical Monitor: 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
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NCT03161093


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AMENDMENT HISTORY 
Amendment 9 Global 
Description of 
Change 
Brief Rationale 
Section # and Name 
The purpose of this 
amendment is to 
permanently discontinue 
all patients in the Year 2 
Treatment Period from 
study drug and to complete 
the End of Treatment study 
visit for impacted patients.  
These patients will be 
encouraged to complete all 
remaining study visits and 
procedures in the follow-
up period and the end of 
study phone call. 
On 11August 2020, the independent Data 
Monitoring Committee (DMC) for the 
fasinumab phase 2/3 program recommended 
termination of the program. The 
recommendation was based on a review of 
the totality of evidence, including the 
emerging unblinded data. Based on the 
independent DMC recommendation, the 
sponsor discontinued dosing with 
fasinumab as of 17 August 2020. The only 
patients impacted were the patients 
participating in the optional Year 2 portion 
of the R475-OA-1611 study. These patients 
will be encouraged to enter the safety 
follow-up period for Year 2.  
Protocol Synopsis: Study Design 
Section 1.1 Background 
Section 1.2 Summary of Risks and 
Benefits to Patients Participating in 
this Study 
Section 3.2.1 Rationale for Study 
Design 
Section 3.2.2 Rationale for Dose 
Selection 
Section 5.1 Study Description and 
Duration 
Section 7.3.2.1 Reasons for 
Permanent Discontinuation of Study 
Drug 
 
Amendment 8 Global 
Description of 
Change 
Brief Rationale 
Section # and Name 
Modification to the 
primary and secondary 
efficacy analysis set 
Due to regional irregularities noted in a 
parallel phase 3 study that became fully 
apparent only after unblinding that study, 
and the concern that the same irregularities 
would be present in data from similar sites 
in this study, the primary and secondary 
efficacy analyses will be performed on a 
modified full analysis set that excludes the 
randomization stratum for the region of 
concern. Analyses of the FAS population 
will also be provided.  
Protocol Synopsis: Statistical Plan 
List of Abbreviations and 
Definitions of Terms 
Section 10.2 Justification of FAS 
and mFAS Sample Size 
Section 10.3.2 Modified Full 
Analysis Set 
Section 10.3.3 Per Protocol Set 
Section 10.4.3.1 Primary Efficacy 
Analysis 
Section 10.4.3.2 Secondary Efficacy 
Analysis 
Amendment 7 Global 
Description of 
Change 
Brief Rationale 
Section # and Name 
Added a statement to 
address the impact of the 
COVID-19 pandemic. 
To explain the plan for ensuring continuity 
of clinical study activities and study 
oversight activities during the coronavirus 
Section 1.2 Summary of Risks and 
Benefits to Patients Participating in 
this Study 
Section 8.1 Schedule of Events 
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CONFIDENTIAL 
disease 2019 (COVID-19) public health 
emergency. 
Year 2 to stop enrollment. 
The objective of the Year 2 Extension is to 
collect safety data on patients chronically 
exposed to fasinumab over a 2-year period.  
The on-going COVID-19 pandemic is 
currently limiting patient travel to sites for 
the receipt of study drug.  Therefore, these 
patients will not be chronically exposed to 
fasinumab and, consequently, we are 
stopping enrollment of new patients into 
Year 2.   
Protocol Synopsis: Study Design 
Section 3.2.1 Rationale for Study 
Design 
Section 5.1 Study Description and 
Duration 
Section 6.2.3 Inclusion Criteria for 
Year 2 
Secondary efficacy 
objectives and endpoints at 
week 52 have been 
changed to week 44. 
Due to the COVID-19 pandemic and its 
associated impact on limiting patient travel 
and site operations, it is likely that the 
missing data for the week 52 efficacy 
endpoint will exceed the original 
assumptions as described in Section 
10.2.  Transitioning to week 44 was chosen 
because the number of patients having 
completed the week 44 visit is estimated to 
be the best option to provide the most 
robust/complete data set for secondary 
efficacy analyses.  
Protocol Synopsis: Objectives 
Protocol Synopsis: Endpoints 
Section 2.2 Secondary Objectives 
Section 4.2.2 Secondary Endpoints 
Addition of secondary and 
exploratory endpoints and 
their associated objectives 
and analyses. 
To align with the statistical analysis 
described in detail in the statistical analysis 
plan. 
Protocol Synopsis: Objectives 
Protocol Synopsis: Endpoints 
Protocol Synopsis: Statistical Plan 
Section 2.2 Secondary Objectives 
Section 2.3 Exploratory Objectives 
Section 4.2.2 Secondary Endpoints 
Section 4.2.3 Exploratory 
Endpoints 
Section 5.2 Planned Interim 
Analysis 
Section 10.1 Statistical Hypotheses 
Section 10.3 Analysis Sets 
Section 10.3.1 Full Analysis Set 
Section 10.3.2 Per-Protocol Set 
Section 10.3.3 Safety Analysis Set 
Section 10.3.4 Urgent Safety 
Measure Set 
Section 10.3.5 Pharmacokinetic 
Analysis Set 
Section 10.3.6 Anti-drug Antibody 
Analysis Set 
Section 10.3.7 The Neutralizing 
Antibody Set 
Section 10.4.3.1 Primary Efficacy 
Analysis 
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Section 10.4.3.2 Secondary 
Efficacy Analysis 
Section 10.4.4 Safety Analysis 
Section 10.4.4.1 Adverse Events 
Section 10.4.4.2 Other Safety 
Section 10.4.4.3 Treatment 
Exposure 
Section 10.4.4.4 Treatment 
Compliance 
Section 10.5 Interim Analysis 
Amendment 6 Global Admin 
Change and Rationale  
Sections Changed 
This is a non-substantial amendment to add collection of 
concomitant therapies (medications and procedures) during 
the follow-up period of Year 2 and at the early-termination 
visit for Year 2.  Collection of this information was 
inadvertently omitted from the previous amendment. 
Table 2 Schedule of Events for Year 2 
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Amendment 6 Global 
Changes and Rationale  
Sections Changed 
Main Change: 
The study design has been modified to include a second 
year of treatment with fasinumab or naproxen. The purpose 
of this modification is to obtain longer-term safety data to 
further elucidate the safety profile of fasinumab.   
The initial 52-week treatment period is referred to as Year 1 
and the second 52-week treatment period is referred to as 
Year 2.   
At the end of the 52-week treatment period of Year 1, 
patients who are eligible and willing to participate in Year 2 
will continue in the study for a second 52-week treatment 
period and will then enter the 20-week follow up period. 
Patients who are ineligible for Year 2, or are eligible but 
unwilling to enter Year 2, will enter directly into the 
20-week follow-up period at the completion of Year 1. 
Clinical Study Protocol Synopsis: Objectives, 
Study Design, Study Duration, Treatments, 
Endpoints, Procedures and Assessments, 
Statistical Plan 
Section 2.2 Secondary Objectives 
Section 3.2.1 Rationale for Study Design 
Section 3.2.2 Rationale for Dose Selection 
Section 4.3.1 Safety Endpoints for Year 1 (All 
randomized and Treatment Patients) 
Section 4.3.2 Safety Endpoints for Year 2 (All 
Randomized and Treated Patients Proceeding into 
Year 2) (added) 
Section 5.1 Study Description and Duration 
Figure 1 Study Flow Diagram 
Section 5.1.1 Screening and Pre-Randomization 
Section 5.1.3 Randomization 
Section 5.1.4 Treatment Period for Year 1 
Section 5.1.5 Treatment Period for Year 2 (added) 
Section 5.1.6 Follow-up Period 
Section 5.1.7 End of Study Phone Contact 
Section 5.2 Planned Interim Analysis 
Section 6.2.1 Inclusion Criteria for Year 1 
Section 6.2.2 Exclusion Criteria for Year 1 
Section 6.2.3 Inclusion Criteria for Year 2 (added) 
Section 6.2.4 Exclusion Criteria for Year 2 (added) 
Section 7.1 Investigational and Reference 
Treatments 
Section 7.2 Rescue Treatment(s) 
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 for Year 1 
Table 2 Schedule of Events for Year 2 (added) 
Section 8.1.2 Footnotes for Schedule of Events 
Table 2 (Year 2) (added) 
Section 8.1.4 Early Termination Visit 
Section 8.2.2.1 Western Ontario and McMaster 
Universities Osteoarthritis Index 
Section 8.2.2.4 EuroQoL 5 Dimensions 5 Level 
Questionnaire 
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Changes and Rationale  
Sections Changed 
Section 8.2.2.7 Work Productivity and Activity 
Impairment 
Section 8.2.3.1 Vital Signs 
Section 8.2.3.2 Physical Examination 
Section 8.2.3.3 Electrocardiogram 
Section 8.2.3.4 Assessment of Orthostatic Blood 
Pressure and Heart Rate 
Section 8.2.3.5 Joint Pain Questionnaire 
Section 8.2.3.6 Survey of Autonomic Symptoms 
Section 8.2.3.7 Neurologic Examination 
Section 8.2.3.8 Imaging 
Section 8.2.3.11 Laboratory Testing 
Section 8.2.3.12 Injection Site Evaluations 
Section 8.2.4.1 Drug Concentration Measurements 
and Samples 
Section 8.2.4.2 Anti-Drug Antibody 
Measurements and Samples 
Section 8.2.5.1 Biomarkers 
Section 9.4.1 Adverse Events 
Section 9.4.2 Serious Adverse Events 
Section 10.3.3 Safety Analysis Set 
Section 10.4.3.2 Secondary Efficacy Analysis 
Section 10.4.4 Safety Analysis 
Section 10.4.4.1 Adverse Events 
Section 10.4.4.2 Other Safety 
Section 10.4.4.3 Treatment Exposure 
Section 10.4.4.4 Treatment Compliance 
Section 10.5 Interim Analysis 
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Changes and Rationale  
Sections Changed 
All Other Changes: 
Site locations were added to the Synopsis. 
Clinical Study Protocol Synopsis: Site Locations 
A time frame was defined for the Year 1 safety endpoints. 
Clinical Study Protocol Synopsis: Endpoints 
Section 4.3.1 Safety Endpoints for Year 1 (All 
Randomized and Treated Patients) 
Text was updated to align with current best practices (ie, 
updated protocol template text). 
Section 4.5 Anti-Drug Antibody Variables  
Section 10.4.6 Analysis of Immunogenicity 
Section 14.5 Clinical Study Data Transparency 
(added) 
It has been clarified that patient-reported outcome measures 
should be completed before any clinical assessments. 
Table 1 Schedule of Events for Year 1 
Section 8.1.1 Footnotes for Schedule of Events 
Table 1 (Year 1), footnote #23 
Section 8.2.2 Efficacy Procedures 
Section 8.2.3.5 Joint Pain Questionnaire 
Section 8.2.3.6 Survey of Autonomic Symptoms 
The scale used to assess the WOMAC index has been 
revised to the numerical rating scale (previously incorrectly 
cited as the Likert scale). 
Section 8.2.2.1 Western Ontario and McMaster 
Universities Osteoarthritis Index 
A footnote has been added to the Schedule of Events tables 
to clarify that patients who discontinue study drug early but 
agree to follow/continue to attend regular study visits do 
not complete the assessments associated with EOT/week 52 
at the time they end treatment.  Instead, they complete 
assessments associated with the study visit they are 
attending at the time they end treatment early. 
Table 1 Schedule of Events for Year 1 
Section 8.1.1 Footnotes for Schedule of Events 
Table 1 (Year 1), footnote #24 
Other minor edits have been made to clarify text or correct 
minor errors. 
Clinical Study Protocol Synopsis: Population - 
Sample Size 
List of Abbreviations and Definitions of Terms 
Section 7.3.2 Study Drug Discontinuation 
Table 1 Schedule of Events for Year 1 continued 
(missing study day numbers have been added) 
Section 8.1.1 Footnotes for Schedule of Events 
Table 1 (Year 1), footnotes #1, #17 
Section 8.2.3.11 Laboratory Testing 
Section 10.3.4 Per-Protocol Set 
Section 10.3.5 Pharmacokinetic Analysis Set 
Section 10.3.6 Anti-Drug Antibody Analysis Set 
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Amendment 5 Global 
The purpose of this amendment is to update the exclusion criteria to improve patient safety and to 
include an additional fasinumab dose group of 1 mg every 8 weeks (Q8W).  Additional changes 
were made to ensure consistency across the fasinumab program, improve clarity, and to make 
minor corrections.  The following table outlines the changes made to the protocol and the affected 
sections: 
Changes 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.  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 history of 
naproxen intolerance or existence of a medical 
condition that is high risk for naproxen-associated 
complications, the general statement regarding the use 
of concomitant medications for which naproxen is 
contraindicated has been removed.  Specific 
medications that are not to be taken concomitantly with 
naproxen are listed in the Prohibited Medications 
section.  In addition, patients with conditions requiring 
use of antiplatelet therapy have 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 non-steroidal anti-inflammatory drug (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 #22 and #40 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 
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Changes and Rationale  
Sections Changed 
All other changes: 
A fasinumab 1 mg Q8W dose group has been 
added and the randomization ratio and statistical 
analysis have been updated accordingly. 
Additional changes have been made to the 
statistical analysis methods to be consistent across 
fasinumab program. 
Clinical Study Protocol Synopsis: Study Design, 
Population, Treatments, Statistical Plan. 
Section 3.2.2 Rationale for Dose Selection 
Section 5.1.3 Randomization 
Section 6.1 Number of Patients Planned  
Section 7.1 Investigational and Reference Treatments  
Section 7.5 Method of Treatment Assignment 
Section 10.1 Statistical Hypothesis 
Section 10.2 Justification of Sample Size 
Section 10.3.1 Efficacy Analysis Set 
Section 10.3.3 Safety Analysis Set 
Section 10.4.3.1 Primary Efficacy Analysis 
Clarified that fasinumab and fasinumab-matching 
placebo are referred to as ‘SC study drug’ and that 
naproxen and naproxen-matching placebo are referred 
to as ‘oral study drug’. 
Throughout the document 
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 
osteoarthritis (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 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 antiplatelet 
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; 
Section 7.7.1 Prohibited Medications 
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Changes and Rationale  
Sections Changed 
• 
To include combination therapy of diuretics 
with either an ACE inhibitor or ARB; 
• 
To clarify that cyclobenzaprine, carisoprodol, 
orphenadrine and tizanidine are muscle 
relaxants 
• 
To make minor corrections 
Text has been added or updated to align with current 
Regeneron best practices 
Section 7.4.2 Local Injection Site Reactions (Section 
added) 
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: 
• 
Concomitant medication collection has been 
added to the screening and pre-randomization 
visits 
• 
Added a separate row to the Schedule of 
Events table for high-sensitivity C-reactive 
protein (hs-CRP) 
• 
Event-triggered imaging has been added at the 
week 1 phone visit  
• 
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) 
• 
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 
• 
Corrected a typo in footnote #5 
• 
Clarified that walking index joint pain NRS 
scores are recorded by the patient using their 
diary and not onsite at the pre-randomization 
visit in footnote #8 
Table 1: Schedule of Events 
Section 8.1.1 Footnotes for Schedule of Events Table, 
footnote #4 
Section 8.1.1 Footnotes for Schedule of Events Table, 
footnote #5 
Section 8.1.1 Footnotes for Schedule of Events Table, 
footnote #8 
Section 8.1.1 Footnotes for Schedule of Events Table, 
footnote #18 
Corrected the text describing the Healthcare Resource 
Utilization Questionnaire to state that the sites (not the 
patients) will complete the questionnaire. 
Section 8.2.2.6 Healthcare Resource Utilization 
Questionnaire 
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 
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Changes and Rationale  
Sections Changed 
The section on treatment compliance has been updated 
to include a description of how compliance will be 
calculated for the oral study drug. 
Section 10.4.4.4 Treatment Compliance 
The study Scientific/Medical Monitor has been 
changed from 
 to 
 
Title page 
Minor edits or additions 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. 
List of Abbreviations and Definitions of Terms 
Clinical Study Protocol Synopsis: Study Design, 
Procedures and Assessments, Endpoints 
Section 1.1 Background 
Section 3.2.1 Rationale for Study Design 
Section 3.2.2 Rationale for Dose Selection 
Section 4.3.1 Safety Endpoints 
Section 5.1 Study Design 
Section 5.1.1 Screening and Pre-Randomization 
Section 5.1.2 Rescreening  
Section 5.1.7 End of Study Phone Contact (Week 100) 
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 7.6.1 Packaging, Labeling and Storage 
Section 7.6.2 Supply and Disposition of Treatments 
Section 7.7 Concomitant Medications and Procedures 
Section 8.1.4 Early Termination Visit 
Section 8.2.2.1 Western Ontario and McMaster 
Universities Osteoarthritis Index 
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 8.2.2.7 Work Productivity and Activity 
Impairment 
Section 8.2.2.8 Treatment Satisfaction Questionnaire 
for Medication 
Section 8.2.3.10 Procedures to be Performed Only in 
the Event of a Joint Replacement Surgery 
Section 8.2.3.11 Laboratory Testing 
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Changes and Rationale  
Sections Changed 
Section 8.2.4.1 Drug Concentration Measurements and 
Samples 
Section 8.2.5 Research Samples 
Section 8.2.5.1 Biomarkers 
Section 8.2.5.2 Future Biomedical Research 
Section 9.4.3 Other Events that Required 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 
Amendment 4 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 3 Global (obsolete) 
The primary purpose of this amendment was to update the exclusion criteria to improve patient 
safety. Additional changes were made to ensure consistency across the fasinumab program, 
improve clarity and to make minor corrections. This amendment was not implemented. 
Amendment 2VHP 
The purpose of this amendment was to incorporate health authority feedback, ensure consistency 
across the program, improve clarity, remove redundant text and correct typos.  These changes 
brought Amendment 2VHP in line with Amendment 1. 
Amendment 1VHP 
The purpose of this amendment was to incorporate health authority feedback. 
Amendment 1 
The purpose of this amendment was to incorporate health authority feedback, ensure consistency 
across the program, improve clarity, remove redundant text and correct typos. 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................3 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................21 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................32 
1. 
INTRODUCTION ......................................................................................................35 
1.1. 
Background .................................................................................................................35 
1.2. 
Summary of Risks and Benefits to Patients Participating in this Study .....................38 
2. 
STUDY OBJECTIVES ..............................................................................................39 
2.1. 
Primary Objective .......................................................................................................39 
2.2. 
Secondary Objectives .................................................................................................39 
2.3. 
Exploratory Objectives ...............................................................................................40 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................40 
3.1. 
Hypothesis ..................................................................................................................40 
3.2. 
Rationale .....................................................................................................................41 
3.2.1. 
Rationale for Study Design .........................................................................................41 
3.2.2. 
Rationale for Dose Selection ......................................................................................43 
4. 
STUDY VARIABLES................................................................................................44 
4.1. 
Demographic and Baseline Characteristics ................................................................44 
4.2. 
Primary and Secondary Endpoints..............................................................................44 
4.2.1. 
Primary Endpoint ........................................................................................................44 
4.2.2. 
Secondary Endpoints ..................................................................................................44 
4.2.3. 
Exploratory Endpoints ................................................................................................45 
4.3. 
Safety Endpoints .........................................................................................................46 
4.3.1. 
Safety Endpoints for Year 1 (All Randomized and Treated Patients) ........................46 
4.3.2. 
Safety Endpoints for Year 2 (All Randomized and Treated Patients 
Proceeding into Year 2) ..............................................................................................47 
4.4. 
Pharmacokinetic Variables .........................................................................................47 
4.5. 
Anti-Drug Antibody Variables ...................................................................................47 
5. 
STUDY DESIGN .......................................................................................................47 
5.1. 
Study Description and Duration .................................................................................47 
5.1.1. 
Screening and Pre-Randomization .............................................................................50 
5.1.2. 
Rescreening .................................................................................................................50 
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5.1.3. 
Randomization ............................................................................................................51 
5.1.4. 
Treatment Period for Year 1 .......................................................................................51 
5.1.5. 
Treatment Period for Year 2 .......................................................................................52 
5.1.6. 
Follow-Up Period .......................................................................................................52 
5.1.7. 
End of Study Phone Contact .......................................................................................52 
5.1.8. 
Study Stopping Rules .................................................................................................53 
5.1.9. 
End of Study Definition ..............................................................................................53 
5.2. 
Planned Interim Analysis ............................................................................................53 
5.3. 
Study Committees .......................................................................................................54 
5.3.1. 
Independent Data Monitoring Committee ..................................................................54 
5.3.2. 
Arthropathy Adjudication Committee ........................................................................54 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............54 
6.1. 
Number of Patients Planned .......................................................................................54 
6.2. 
Study Population .........................................................................................................54 
6.2.1. 
Inclusion Criteria for Year 1 .......................................................................................54 
6.2.2. 
Exclusion Criteria for Year 1 ......................................................................................56 
6.2.3. 
Inclusion Criteria for Year 2 .......................................................................................59 
6.2.4. 
Exclusion Criteria for Year 2 ......................................................................................59 
6.3. 
Premature Withdrawal from the Study .......................................................................60 
6.4. 
Replacement of Patients .............................................................................................60 
7. 
STUDY TREATMENTS............................................................................................60 
7.1. 
Investigational and Reference Treatments ..................................................................60 
7.2. 
Rescue Treatment(s) ...................................................................................................62 
7.3. 
Dose Modification and Study Treatment Discontinuation Rules ...............................62 
7.3.1. 
Dose Modification ......................................................................................................62 
7.3.2. 
Study Drug Discontinuation .......................................................................................62 
7.3.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................63 
7.3.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................65 
7.4. 
Management of Acute Reactions ................................................................................65 
7.4.1. 
Systemic Injection Reactions ......................................................................................65 
7.4.2. 
Local Injection Site Reactions ....................................................................................65 
7.5. 
Method of Treatment Assignment ..............................................................................65 
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7.5.1. 
Blinding ......................................................................................................................66 
7.5.2. 
Emergency Unblinding ...............................................................................................66 
7.5.3. 
Unblinding for Regulatory Reporting Purposes .........................................................66 
7.6. 
Treatment Logistics and Accountability .....................................................................66 
7.6.1. 
Packaging, Labeling, and Storage ..............................................................................66 
7.6.2. 
Supply and Disposition of Treatments .......................................................................67 
7.6.3. 
Treatment Accountability ...........................................................................................67 
7.6.4. 
Treatment Compliance ................................................................................................67 
7.7. 
Concomitant Medications and Procedures .................................................................67 
7.7.1. 
Prohibited Medications ...............................................................................................67 
7.7.2. 
Permitted Medications and Procedures ......................................................................68 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................69 
8.1. 
Schedule of Events .....................................................................................................69 
8.1.1. 
Footnotes for the Schedule of Events Table 1 (Year 1) ..............................................77 
8.1.2. 
Footnotes for the Schedule of Events Table 2 (Year 2) ..............................................83 
8.1.3. 
Footnotes for Table 3 - Follow-up Period for Patients Undergoing Joint 
Replacement Surgery ..................................................................................................86 
8.1.4. 
Early Termination Visit ..............................................................................................86 
8.1.5. 
Unscheduled Visits .....................................................................................................86 
8.2. 
Study Procedures ........................................................................................................86 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................86 
8.2.1.1. 
Informed Consent .......................................................................................................86 
8.2.1.2. 
Medical History ..........................................................................................................87 
8.2.1.3. 
Medication History .....................................................................................................87 
8.2.1.4. 
Demographics .............................................................................................................87 
8.2.1.5. 
Determination of Osteoarthritis ..................................................................................87 
8.2.1.6. 
Assessment of Childbearing Potential ........................................................................88 
8.2.1.7. 
Assessment of Peripheral or Central Pain ..................................................................88 
8.2.1.8. 
Instructions for Use of Diary ......................................................................................88 
8.2.1.9. 
Patient Education Brochures.......................................................................................88 
8.2.2. 
Efficacy Procedures ....................................................................................................88 
8.2.2.1. 
Western Ontario and McMaster Universities Osteoarthritis Index ............................88 
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8.2.2.2. 
Patient Global Assessment of Osteoarthritis ..............................................................89 
8.2.2.3. 
Walking Index Joint Pain Numeric Rating Score .......................................................89 
8.2.2.4. 
EuroQoL 5 Dimensions 5 Level Questionnaire..........................................................89 
8.2.2.5. 
36-Item Short Form Medical Outcomes Study Questionnaire Version 2 ...................89 
8.2.2.6. 
Healthcare Resource Utilization Questionnaire ..........................................................89 
8.2.2.7. 
Work Productivity and Activity Impairment ..............................................................90 
8.2.2.8. 
Treatment Satisfaction Questionnaire for Medication ................................................90 
8.2.3. 
Safety Procedures .......................................................................................................90 
8.2.3.1. 
Vital Signs ..................................................................................................................90 
8.2.3.2. 
Physical Examination .................................................................................................90 
8.2.3.3. 
Electrocardiogram .......................................................................................................90 
8.2.3.4. 
Assessment of Orthostatic Blood Pressure and Heart Rate ........................................90 
8.2.3.5. 
Joint Pain Questionnaire .............................................................................................91 
8.2.3.6. 
Survey of Autonomic Symptoms ................................................................................91 
8.2.3.7. 
Neurologic Examination .............................................................................................91 
8.2.3.8. 
Imaging .......................................................................................................................92 
8.2.3.9. 
End of Study Phone Contact .......................................................................................93 
8.2.3.10. 
Procedures to be Performed Only in the Event of a Joint Replacement 
Surgery ........................................................................................................................93 
8.2.3.11. 
Laboratory Testing ......................................................................................................93 
8.2.3.12. 
Injection Site Evaluations ...........................................................................................95 
8.2.4. 
Pharmacokinetic and Anti-Drug Antibody Procedures ..............................................95 
8.2.4.1. 
Drug Concentration Measurements and Samples .......................................................95 
8.2.4.2. 
Anti-Drug Antibody Measurements and Samples ......................................................95 
8.2.5. 
Research Samples .......................................................................................................95 
8.2.5.1. 
Biomarkers ..................................................................................................................95 
8.2.5.2. 
Future Biomedical Research .......................................................................................96 
8.2.5.3. 
Genomics Sub-study - Optional..................................................................................96 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................96 
9.1. 
Obligations of Investigator .........................................................................................96 
9.2. 
Obligations of Sponsor ...............................................................................................96 
9.3. 
Definitions ..................................................................................................................97 
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9.3.1. 
Adverse Event .............................................................................................................97 
9.3.2. 
Serious Adverse Event ................................................................................................97 
9.3.3. 
Adverse Events of Special Interest .............................................................................98 
9.4. 
Recording and Reporting Adverse Events ..................................................................98 
9.4.1. 
Adverse Events ...........................................................................................................98 
9.4.2. 
Serious Adverse Events ..............................................................................................98 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor ...................................99 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................99 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results .............................99 
9.4.6. 
Follow-up ..................................................................................................................100 
9.5. 
Evaluation of Severity and Causality .......................................................................100 
9.5.1. 
Evaluation of Severity ..............................................................................................100 
9.5.2. 
Evaluation of Causality .............................................................................................101 
9.5.2.1. 
Relationship of Adverse Events to Study Drug ........................................................101 
9.5.2.2. 
Relationship of Adverse Events to Study Conduct ...................................................101 
9.6. 
Safety Monitoring .....................................................................................................102 
9.6.1. 
Monitoring Adverse Events of Special Interest ........................................................103 
9.6.1.1. 
Adjudicated Arthropathy ..........................................................................................103 
9.6.1.2. 
Sympathetic Nervous System Dysfunction ..............................................................104 
9.6.1.3. 
Peripheral Sensory Adverse Events ..........................................................................105 
9.6.1.4. 
Joint Replacement Surgery .......................................................................................105 
9.7. 
Investigator Alert Notification ..................................................................................105 
10. 
STATISTICAL PLAN..............................................................................................105 
10.1. 
Statistical Hypothesis ................................................................................................106 
10.2. 
Justification of FAS and mFAS Sample Sizes .........................................................108 
10.3. 
Analysis Sets .............................................................................................................110 
10.3.1. 
Full Analysis Set .......................................................................................................110 
10.3.2. 
Modified Full Analysis Set .......................................................................................110 
10.3.3. 
Per-Protocol Set (PPS) ..............................................................................................110 
10.3.4. 
Safety Analysis Set ...................................................................................................111 
10.3.5. 
Urgent Safety Measure Set .......................................................................................111 
10.3.6. 
Pharmacokinetic Analysis Set ..................................................................................111 
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10.3.7. 
Anti-Drug Antibody Analysis Set ............................................................................111 
10.3.8. 
The Neutralizing Antibody Set .................................................................................111 
10.4. 
Statistical Methods ....................................................................................................111 
10.4.1. 
Patient Disposition ....................................................................................................111 
10.4.2. 
Demography and Baseline Characteristics ...............................................................112 
10.4.3. 
Efficacy Analyses .....................................................................................................112 
10.4.3.1. 
Primary Efficacy Analysis ........................................................................................112 
10.4.3.2. 
Secondary Efficacy Analysis ....................................................................................113 
10.4.4. 
Safety Analysis .........................................................................................................113 
10.4.4.1. 
Adverse Events .........................................................................................................114 
10.4.4.2. 
Other Safety ..............................................................................................................115 
10.4.4.3. 
Treatment Exposure ..................................................................................................115 
10.4.4.4. 
Treatment Compliance ..............................................................................................115 
10.4.5. 
Analysis of Drug Concentration Data .......................................................................116 
10.4.6. 
Analysis of Immunogenicity .....................................................................................116 
10.5. 
Interim Analysis ........................................................................................................117 
10.6. 
Additional Statistical Data Handling Conventions ...................................................117 
10.7. 
Statistical Considerations Surrounding the Premature Termination of a Study .......118 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS ...................................118 
11.1. 
Data Management .....................................................................................................118 
11.2. 
Electronic Systems ....................................................................................................118 
12. 
STUDY MONITORING ..........................................................................................119 
12.1. 
Monitoring of Study Sites .........................................................................................119 
12.2. 
Source Document Requirements ..............................................................................119 
12.3. 
Case Report Form Requirements ..............................................................................119 
13. 
AUDITS AND INSPECTIONS ...............................................................................119 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................120 
14.1. 
Good Clinical Practice Statement .............................................................................120 
14.2. 
Informed Consent .....................................................................................................120 
14.3. 
Patient Confidentiality and Data Protection .............................................................121 
14.4. 
Institutional Review Board/Ethics Committee .........................................................121 
14.5. 
Clinical Study Data Transparency ............................................................................121 
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15. 
PROTOCOL AMENDMENTS ................................................................................121 
16. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ..........................................................................................................................122 
16.1. 
Premature Termination of the Study .........................................................................122 
16.2. 
Close-out of a Site ....................................................................................................122 
17. 
STUDY DOCUMENTATION .................................................................................122 
17.1. 
Certification of Accuracy of Data .............................................................................122 
17.2. 
Retention of Records ................................................................................................122 
18. 
DATA QUALITY ASSURANCE ............................................................................123 
19. 
CONFIDENTIALITY ..............................................................................................123 
20. 
FINANCING AND INSURANCE ...........................................................................124 
21. 
PUBLICATION POLICY ........................................................................................124 
22. 
REFERENCES .........................................................................................................125 
23. 
INVESTIGATOR’S AGREEMENT ........................................................................129 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS ...................................................130 
 
LIST OF TABLES 
Table 1: 
Schedule of Events for Year 1 ....................................................................................70 
Table 2: 
Schedule of Events for Year 2 ....................................................................................79 
Table 3: 
Follow-up Period for Patients Undergoing Joint Replacement Surgery on 
Study ...........................................................................................................................85 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................49 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Phase 3 Randomized, Double-Blind, Multi-Dose, Placebo and 
Naproxen-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) 
Multiple sites in Bulgaria, Denmark, Germany, Hungary, Lithuania, Poland, 
Romania, Russia, South Africa, Spain, Ukraine, UK, and USA. 
 
Principal Investigator 
To be determined 
Objectives 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of fasinumab 
compared with placebo, when administered for up to 16 weeks in patients 
with pain due to osteoarthritis (OA) of the knee or hip. 
Secondary Objectives 
The secondary objectives of the study are: 
1. To evaluate the efficacy of fasinumab compared with naproxen, 
when administered for up to 16 weeks in patients with pain due to 
OA of the knee or hip 
2. To evaluate the efficacy of fasinumab compared with placebo, 
when administered for up to 44 weeks in patients with pain due to 
OA of the knee or hip  
3. To assess the safety and tolerability of fasinumab compared with 
naproxen, when administered for up to 16 weeks in patients with 
pain due to OA of the knee or hip  
4. To assess the safety and tolerability of fasinumab compared with 
naproxen, when administered for up to 52 weeks in patients with 
pain due to OA of the knee or hip  
5. To assess the safety and tolerability of fasinumab compared with 
naproxen, when administered for up to 104 weeks in patients with 
pain due to OA of the knee or hip 
6. To evaluate the pharmacokinetic (PK) profile of fasinumab 
administered to patients with pain due to OA of the knee or hip for 
up to 52 weeks 
7. To evaluate the PK profile of fasinumab administered to patients 
with pain due to OA of the knee or hip for up to 104 weeks 
8. To evaluate the immunogenicity of fasinumab administered to 
patients with pain due to OA of the knee or hip for up to 52 weeks 
9. To evaluate the immunogenicity of fasinumab administered to 
patients with pain due to OA of the knee or hip for up to 104 
weeks  
10. To evaluate the efficacy of fasinumab compared with naproxen, 
when administered for up to 44 weeks in patients with pain due to 
OA of the knee or hip 
 
 
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Exploratory Objectives 
To evaluate additional patient reported outcome measures in patients with 
pain due to OA of the knee or hip treated for up to 44 weeks with fasinumab, 
compared with placebo or naproxen. 
To evaluate the WOMAC pain and physical function subscale scores as well 
as additional patient reported outcome (PRO) measures in patients with pain 
due to OA of the knee or hip treated for an additional 52 weeks with 
fasinumab, compared with naproxen pro re nata (prn).   
To evaluate the use of rescue medication in patients with pain due to OA of 
the knee or hip treated for up to 44 weeks with fasinumab, compared with 
placebo or naproxen. 
To evaluate the use of rescue medication in patients with pain due to OA of 
the knee of hip treated for an additional 52 weeks with fasinumab, compared 
with naproxen prn. 
Study Design 
This study is a randomized, double-blind, placebo- and naproxen-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).  
All randomized patients in this study will participate in Year 1, which is 
intended to provide efficacy and safety data for OA patients exposed for up 
to 52 weeks to fasinumab, a non-steroidal anti-inflammatory drug (NSAID) 
comparator (naproxen), or placebo.  At the end of the 52-week treatment 
period of Year 1, patients who are eligible and willing to participate in Year 
2 will continue in the study for a second 52-week treatment period and will 
then enter the 20-week follow-up period.  Note: As of 26 March 2020, all 
enrollment into Year 2 has been terminated due to the COVID-19 pandemic.  
Any patients currently enrolled in Year 2 are to remain in the study.  Patients 
who are ineligible for Year 2, or are eligible but unwilling to enter Year 2, 
will enter directly into the 20-week follow-up period at the completion of 
Year 1.  
Year 2 is intended to provide safety data for OA patients exposed to 
fasinumab or naproxen for up to 104 weeks (52 weeks in Year 1 and a further 
52 weeks in Year 2).  Note that no patients will receive placebo only in Year 
2 (see Treatment Period for Year 2 below).  Efficacy will be assessed during 
Year 2 to monitor the risk-benefit profile of fasinumab but, as Year 2 is not 
powered for a formal efficacy analysis, efficacy results will be summarized 
descriptively. 
The overall study period for patients in Year 1 who do not participate in 
Year 2 will be up to approximately 105 weeks including screening and 
pre-randomization.  For these patients, 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 52-week treatment period, a 20-week 
follow-up period, and an end of study phone contact at 52 weeks following 
the last subcutaneous (SC) dose of study drug.  Eligible patients who choose 
to participate in Year 2 will receive treatment for a total of 104 weeks and 
will then enter a 20-week follow-up period, followed by the final phone call 
approximately 52 weeks after the last dose of SC study drug. 
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Note: As of 17August 2020, all patients on treatment have been permanently 
discontinued from study drug and will complete the End of Treatment visit. 
This impacts only patients in the Year 2 treatment period as treatment in 
Year 1 has ended. All patients will be encouraged to complete all remaining 
study visits and procedures in the follow-up period and the end of study 
phone call. 
Screening and Pre-Randomization 
At the screening visit, patients will consent to all study assessments planned 
for Year 1 and will be informed that they could potentially continue in the 
study for the second year if eligible.  Eligibility and consent for Year 2 will 
be conducted at the end of Year 1.  Approximately 4 weeks 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 
Kellgren-Lawrence (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 7 to 10 day pre-randomization 
period, during which 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 
At the baseline visit of Year 1, patients will be randomized 3:3:3:1 to the 
following treatment groups as follows: 
• 
Fasinumab 1 mg SC once every 4 weeks (Q4W) and 
naproxen-matching placebo oral, twice daily 
• 
Fasinumab 1 mg SC once every 8 weeks (Q8W) and 
naproxen-matching placebo oral, twice daily 
• 
Fasinumab-matching placebo SC Q4W and naproxen 500 mg oral, 
twice daily 
• 
Fasinumab-matching placebo, SC, Q4W and naproxen-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. 
Treatment Period for Year 1 (Baseline to Week 52) 
During the treatment period of Year 1 (day 1 through week 52), 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 8 (±1 day). 
Safety and efficacy assessments will be performed and potential events of 
adjudicated arthropathy (AA) and sympathetic nervous system dysfunction 
will be monitored. 
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At the end of the treatment period, patients who are eligible and willing to 
participate in Year 2 will continue in the study for a second 52-week 
treatment period.  Patients who are ineligible for Year 2, or are eligible but 
unwilling to enter Year 2, will enter directly into the 20-week follow-up 
period. 
Treatment Period for Year 2 (Week 52E to Week 104E) 
Study weeks during Year 2 will be denoted with an E to represent study 
weeks during the extension (eg, week 52E) and to differentiate them from 
study weeks with the same numbers in the follow-up period for patients who 
only participate in Year 1.   
Eligible patients who choose to participate in Year 2 will not be 
re-randomized at week 52.  Patients will receive treatment based on the 
treatment they received in Year 1, as shown below.   
Year 1 
Year 2 
Fasinumab 1 mg SC Q4W and 
naproxen-matching placebo oral, 
twice daily 
Fasinumab 1 mg SC Q4W and 
naproxen-matching placebo oral, 
prn* 
Fasinumab 
1 mg 
SC 
Q8W 
(patients will receive placebo 
injections at the study visits where 
study drug is not administered) and 
naproxen-matching placebo oral, 
twice daily 
Fasinumab 
1 mg 
SC 
Q8W 
(patients will receive placebo 
injections at the study visits where 
study drug is not administered) and 
naproxen-matching placebo oral, 
prn* 
Fasinumab-matching placebo SC 
Q4W and naproxen 500 mg oral, 
twice daily 
Fasinumab-matching placebo SC 
Q4W and naproxen 500 mg oral, 
prn* 
Fasinumab-matching placebo SC 
Q4W 
and 
naproxen-matching 
placebo oral, twice daily 
Fasinumab-matching placebo SC 
Q4W and naproxen 500 mg oral, 
prn* 
*The maximum naproxen dose (or naproxen placebo dose) allowed will be no more 
than the amount allowed during Year 1 (ie, 500 mg twice daily or 1 capsule of 
placebo twice daily). 
Naproxen (and naproxen-matching placebo) will be administered as needed 
(ie, prn) in Year 2 instead of twice daily as in Year 1, due to the known 
safety profile associated with chronic NSAID use.  
A fasinumab-matching placebo/naproxen-matching placebo group will not 
be included in Year 2 so as not to have patients who are experiencing 
moderate-to-severe pain due to their OA go for an entire 2-year period with 
only rescue medication of acetaminophen/paracetamol available to them for 
pain control.  Patients who were randomized to fasinumab-matching 
placebo/naproxen-matching placebo in Year 1 will be switched to 
fasinumab-matching placebo/naproxen 500 mg prn for the second year of 
treatment to ensure they have access to some form of pain medication in 
addition to acetaminophen/paracetamol. 
During the treatment period of Year 2 (week 52E through week 104E), 
rescue medication (acetaminophen/paracetamol) will continue to be 
permitted for all patients and use will be recorded in a diary. 
Safety and efficacy assessments will continue through Year 2. 
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Follow-up 
At the end of the treatment period (week 52 for patients participating in Year 
1 only, or week 104E for patients participating in Year 1 and Year 2), 
follow-up of patients will continue for an additional 20 weeks.  Safety and 
efficacy assessments will be performed similarly to those of the treatment 
period. 
If a patient must undergo joint replacement surgery during the study, he or 
she will be asked to complete pre-operative imaging and to undergo 
post-surgery follow-up. 
A phone contact questionnaire will be conducted approximately 52 weeks 
after administration of the last SC dose of study drug to document patient 
status with regard to joint replacement surgery (if patient underwent, is 
scheduled for, or is on a wait list for joint replacement surgery). Patients 
who had an AA will have an MRI performed of the affected joint(s). 
Study Duration 
The duration of the study for patients who participate in Year 1 only is up 
to approximately 105 weeks, including the screening and pre-randomization 
periods.  The duration of the study for patients who participate in Year 1 and 
Year 2 is up to approximately 157 weeks, including 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: 
Enrollment of approximately 2845 patients is planned for this study, which 
includes a total of 285 patients who 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 due to the urgent safety measure, and a total 
of approximately 2560 patients who will be randomized to fasinumab 1 mg 
SC Q4W, 1 mg SC Q8W, naproxen, and placebo.  
Approximately 840 patients will be randomized to the fasinumab 1 mg 
SC Q4W group, 840 patients to the naproxen-only group, and 280 patients 
to the placebo group. An estimated 600 patients will be randomized to the 
fasinumab 1 mg Q8W group. 
 
Target Population: 
Men and women who are at least 18 years of age at the time of study entry 
with a clinical diagnosis at the screening visit of OA of the knee or hip, 
based on the American College of Rheumatology criteria, and with 
radiologic evidence of OA (K-L score ≥2) at the index joint. 
Treatments 
 
 
SC Study Drug 
 
Dose/Route/Schedule: 
Fasinumab 
1 mg SC Q4W, 1 mg SC Q8W (patients will receive placebo injections at 
study visits where study drug is not administered) (Year 1 and Year 2) 
 
Oral Study Drug 
 
Dose/Route/Schedule: 
Naproxen  
500 mg oral twice daily (Year 1) or 500 mg oral prn (Year 2) (the 
maximum naproxen dose allowed will be no more than the amount 
allowed during Year 1 [ie, 500 mg twice daily]). 
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SC Study Drug Placebo 
 
Route/Schedule: 
Fasinumab placebo  
SC Q4W (Year 1 and Year 2) 
Oral Study Drug Placebo 
Route/Schedule: 
Naproxen placebo 
Oral, twice daily (Year 1) or oral prn (Year 2) 
 
At the baseline visit of Year 1, patients will be randomized 3:3:3:1 to 
receive 1 of the following treatment regimens under amendment 5 global: 
• 
Fasinumab 1 mg SC Q4W and naproxen-matching placebo oral, 
twice daily  
• 
Fasinumab 1 mg SC Q8W (patients will receive placebo injections 
at the study visits where study drug is not administered) and 
naproxen-matching placebo oral, twice daily 
• 
Fasinumab-matching placebo SC Q4W and naproxen 500 mg oral, 
twice daily 
• 
Fasinumab-matching placebo SC Q4W and naproxen-matching 
placebo oral, twice daily 
Prior to amendment 5 global, patients were randomized 3:3:3:3:1 to 
receive one of the following treatment regimens: 
• 
Fasinumab 1 mg SC Q4W and naproxen-matching placebo oral, 
twice daily 
• 
Fasinumab 3 mg SC Q4W and naproxen-matching placebo oral, 
twice daily 
• 
Fasinumab 6 mg SC Q8W (patients received placebo injections at 
the study visits where study drug was not administered) and 
naproxen-matching placebo oral, twice daily 
• 
Fasinumab-matching placebo SC Q4W and naproxen 500 mg oral, 
twice daily 
• 
Fasinumab-matching placebo SC Q4W and naproxen-matching 
placebo oral, twice daily 
 
Rescue Treatment: 
During 
the 
Year 
1 
and 
Year 
2 
treatment 
periods, 
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. 
Endpoints 
 
 
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 16 in patients treated with fasinumab compared with that 
of patients treated with placebo. 
2. Change in the WOMAC physical function subscale scores from 
baseline to week 16 in patients treated with fasinumab compared 
with that of patients treated with placebo. 
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Secondary: 
The key secondary endpoints of the study are: 
1. Change in the Patient Global Assessment (PGA) scores from 
baseline to week 16 in patients treated with fasinumab compared 
with that of patients treated with placebo 
2. Percentage of patients treated with fasinumab, compared with that 
of patients treated with placebo, who had a response at week 16, 
with response defined as an improvement by ≥30% in the 
WOMAC pain subscale scores 
3. Change in WOMAC pain subscale scores from baseline to week 16 
in patients treated with fasinumab, compared with that of patients 
treated with naproxen 
4. Change in WOMAC physical function subscale scores from 
baseline to week 16 in patients treated with fasinumab, compared 
with that of patients treated with naproxen 
5. Change in WOMAC pain subscale scores from baseline to week 44 
in patients treated with fasinumab, compared with that of patients 
treated with placebo 
6. Change in WOMAC physical function subscale scores from 
baseline to week 44 in patients treated with fasinumab, compared 
with that of patients treated with placebo 
7. Change in the PGA scores from baseline to week 44 in patients 
treated with fasinumab compared with that of patients treated with 
placebo 
8. Change in the PGA scores from baseline to week 16 in patients 
treated with fasinumab compared with that of patients treated with 
naproxen  
9. Change in WOMAC pain subscale scores from baseline to week 44 
in patients treated with fasinumab, compared with that of patients 
treated with naproxen 
10. Change in WOMAC physical function subscale scores from 
baseline to week 44 in patients treated with fasinumab, compared 
with that of patients treated with naproxen 
11. Percentage of patients treated with fasinumab, compared with that 
of patients treated with naproxen, who had a response at week 16, 
with response defined as an improvement by ≥30% in the 
WOMAC pain subscale scores 
12. Change in WOMAC pain subscale scores from baseline to the 
average score across weeks 4, 8, 12 and 16, in patients treated with 
fasinumab compared with that of patients treated with placebo 
13. Change in WOMAC physical function subscale scores from 
baseline to the average score across weeks 4, 8, 12 and 16, in 
patients treated with fasinumab compared with that of patients 
treated with placebo 
14. Change in WOMAC pain subscale scores from baseline to the 
average score across weeks 36, 40 and 44 in patients treated with 
fasinumab compared with that of patients treated with placebo  
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15. Change in WOMAC physical function subscale scores from 
baseline to the average score across weeks 36, 40 and 44 in patients 
treated with fasinumab compared with that of patients treated with 
placebo 
Safety: 
Safety endpoints for Year 1 (all randomized and treated patients) 
Safety endpoints for Year 1 (through week 52) will include: 
• 
Incidence of adjudicated arthropathy (AA) (as confirmed by 
independent adjudication) 
• 
Incidence of destructive arthropathy (DA) (as confirmed by 
independent adjudication) 
• 
Incidence of treatment-emergent adverse events (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 joint replacements (JRs) 
The incidence of JRs at the telephone survey 52 weeks after the last dose of 
study drug (week 100) will also be evaluated. 
Safety endpoints for Year 2 (all randomized and treated patients 
proceeding into Year 2) 
The safety endpoints listed above for Year 1 will be evaluated for Year 2 
from the first dose of study drug given in Year 2 through week 104E (end 
of treatment), as well as for the periods of Year 1 and Year 2 from day 1 
through week 104E.   
The incidence of JRs at the telephone survey approximately 52 weeks after 
the last dose of study drug (week 152E) will also be evaluated. 
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 in Year 1 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 questionnaire, and the Treatment 
Satisfaction Questionnaire for Medication.  The WOMAC total and stiffness 
scores will also be evaluated.  Efficacy in Year 2 will be assessed by the 
change from baseline in the WOMAC pain and physical function subscale 
scores, the EuroQoL 5 Dimensions 5 Level Questionnaire and the Work 
Productivity and Activity Impairment-Osteoarthritis questionnaire. 
Safety assessments will be performed at each study visit 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 
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undergo joint replacement 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. 
After the end-of-study visit and 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 29 hypotheses for the primary and key secondary endpoints.  The 
primary endpoint comparison of study drug with placebo 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 graphical testing procedure will be applied to 
control for multiplicity and to maintain study-wise Type I error rate at a two-
sided 0.05 level for the hypotheses (H1,i, i=1,…,16 for fasinumab 1 mg 
Q4W, and H2,i, i=1,…,13 for fasinumab 1 mg Q8W) for the primary and key 
secondary endpoints. If a hypothesis is rejected, the alpha level for that 
hypothesis will be reallocated to other hypotheses according to the 
pre-specified procedure. 
Justification of FAS and mFAS Sample Size 
The planned sample size was expected to provide adequate power for the 
comparisons between fasinumab doses and naproxen at week 16 for the 
WOMAC pain and physical function scores and the PGA score and provide 
long term data for safety assessment. 
The sample size for the full analysis set (FAS) population was based on 
results of the WOMAC pain and physical function subscale scores and the 
PGA from the R475-PN-1227 study.  The calculation of sample size 
assumed a 2-sided alpha level of 0.025 and a 15% dropout rate up to week 
16 and a 30% dropout rate up to week 52.  Enrollment of 840 patients in the 
fasinumab 1 mg Q4W group and 280 patients in the placebo group would 
have provided at least 99% power to detect an effect size of 0.46 in the 
WOMAC pain and physical function subscale scores at week 16 and week 
52.  This sample size would have provided 99% power to detect an effect 
size of 0.36 in PGA for an absolute treatment difference of 0.4 with a 
standard deviation (SD) of 1.1 at week 16, and 98% power at week 52 for 
the FAS.  
For the fasinumab 1 mg Q8W group, the 600 patients in the FAS population 
were to be compared to approximately 200 patients in the placebo group 
who were enrolled under amendment 5 global. For such comparisons, a 
2-sided alpha level of 0.025 and a 15% dropout rate up to week 16, and a 
30% dropout rate up to week 52, were assumed. Additionally, the effect size 
for such comparisons was assumed to be 80% of the effect size for the 
comparison between fasinumab 1 mg Q4W group and the placebo group. 
Under these assumptions, enrollment of 600 patients in the fasinumab 1 mg 
Q8W group and 200 patients from the placebo group would have provided 
97% power to detect an effect size of 0.368 (=0.46*80%) in the WOMAC 
pain and physical function subscale scores at week 16 and 93% power at 
week 52.  This sample size would have provided 84% power to detect an 
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effect size of 0.288 (=0.36*80%) in PGA at week 16, and 75% power at 
week 52 for the FAS. 
The sample size calculation was also based on previously reported results of 
the WOMAC pain subscale and physical function subscale and the PGA for 
naproxen.  Assuming a 2-sided alpha level of 0.025 and a 15% dropout rate 
up to week 16 and a 30% dropout rate up to week 52, an enrollment of 840 
patients in the fasinumab 1 mg Q4W group and the naproxen group would 
have provided at least 97% power to detect an effect size of 0.22 in the 
WOMAC pain subscale at week 16 and 93% power at week 52 for the FAS.  
This sample size would have provided 98% 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) at week 16 and 96% power at week 52 
for the FAS.  This sample size would have provided 87% power to detect an 
effect size of 0.18 in PGA at week 16 between fasinumab 1 mg Q4W and 
naproxen for the FAS.  
Due to regional irregularities noted in a parallel phase 3 study that became 
fully apparent only after unblinding that study, and the concern that the same 
irregularities would be present in data from similar sites in this study, the 
population for the primary and secondary efficacy analyses was changed in 
Protocol Amendment 8 to be based on a modified full analysis set (mFAS) 
that excludes the randomization stratum for that region.  Based on the 
assumptions above, it is estimated that this mFAS will provide: 
• 
99.9% power to detect a significant difference between the 
1 mg Q4W group and the placebo group in the WOMAC pain 
and physical function subscales at an alpha level of 0.05 
• 
42% and 46% power to detect a significant difference between 
the 1 mg Q8W group and the placebo group in WOMAC pain 
and physical function subscales, respectively, at an alpha level 
of 0.01 
• 
99.9% power to detect a significant difference between the 
1 mg Q4W group and the naproxen group in the WOMAC 
pain and physical function subscales at an alpha level of 0.04 
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 a mixed-effect model for repeated measure (MMRM) based 
on the mFAS with adjustment for missing data due to lack of efficacy, death 
or AEs 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, death 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 treatment 
discontinuation. 
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For analysis of continuous secondary endpoints at fixed timepoints (ie, week 
16 and week 44), the analysis method will be the same as that used for the 
primary efficacy endpoints. For the analysis of secondary endpoints 
involving the averaging over several visits, analysis will be performed using 
a multiple imputation approach with an ANCOVA model based on the 
mFAS with adjustment for missing data performed in the same manner as 
was done for the primary endpoint.  For analysis of secondary endpoints that 
are categorical variables, eg, proportions of patients with ≥30% 
improvement in the WOMAC pain subscale scores at week 16, the Cochran 
Mantel Haenszel approach will be used based on the mFAS, stratifying by 
the randomization strata. 
For Year 2 analysis, the efficacy and patient-reported outcome (PRO) 
endpoints collected will be summarized descriptively.  
The summary of safety results will be presented for Year 1, Year 2, and the 
combined treatment period of Year 1 and Year 2.  
Safety data including TEAEs and treatment emergent adverse events of 
special 
interest, 
vital 
signs, 
physical 
exams, 
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 
ADL 
Activities of daily living 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ARB 
Angiotensin receptor blocker 
bpm 
Beats per minute  
BUN 
Blood urea nitrogen 
Cmax 
Maximal concentration 
COVID-19 
Coronavirus Disease 2019 
CPK 
Creatine phosphokinase 
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 
EDC 
Electronic data capture 
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 
GI 
Gastrointestinal 
HbA1c 
Hemoglobin A1c 
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HCRU 
Healthcare Resource Utilization 
hs-CRP 
High-sensitivity C-reactive protein 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IVRS 
Interactive voice response system  
IWRS 
Interactive web response system 
JR 
Joint replacement 
K-L 
Kellgren-Lawrence 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
mFAS 
Modified Full Analysis Set 
MMRM 
Mixed-effect Model for Repeated Measures 
MRI  
Magnetic Resonance Imaging 
NAb 
Neutralizing antibody 
NGF 
Nerve growth factor 
NRS 
Numeric Rating Scale 
NSAID 
Non-steroidal anti-inflammatory drug 
OA 
Osteoarthritis 
OMERACT-
OARSI 
Osteoarthritis Research Society International Standing Committee for Clinical 
Trials Response Criteria Initiative and The Outcome Measure in Rheumatology 
PCSV 
Potentially clinically significant value 
PGA 
Patient Global Assessment 
PK 
Pharmacokinetic 
PPS 
Per protocol set  
prn 
Pro re nata 
PRO 
Patient-reported outcome 
PT 
Preferred term 
QRS 
Complex of Q, R, and S waves on an electrocardiogram 
Q4W 
Every 4 weeks 
Q8W 
Every 8 weeks 
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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 Survey 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TBL 
Total bilirubin  
TEAE 
Treatment-emergent adverse event 
TJR 
Total joint replacement 
TrkA 
Tyrosine kinase type 1  
TSQM 
Treatment Satisfaction Questionnaire for Medication 
ULN 
Upper limit of normal 
USMS 
Urgent Safety Measure Set 
WBC 
White blood cell 
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  
1.1. 
Background 
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.  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, 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 version of the Fasinumab Investigator’s 
Brochure).  Three intravenous (IV) doses of fasinumab were evaluated (0.03, 0.1, 0.3 mg/kg every 
8 weeks [Q8W]).  All three doses, compared with placebo, were associated with statistically 
significant improvement in pain as evaluated by walking knee pain, the Western Ontario and 
McMaster 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 version 
of the Investigator’s Brochure).  Results from recent clinical studies with other anti-NGF 
antibodies, tanezumab (Pfizer) and fulranumab (Janssen), also support the role of NGF in pain 
modulation in patients with pain due to OA of the knee and hip (Brown 2012) (Hefti 2006) 
(Lane 2010) and in patients with chronic low back pain (Katz 2011) (Kivitz 2013). 
In all clinical studies completed to date, fasinumab was generally well tolerated.  Arthralgia, joint 
swelling, peripheral edema, hypoesthesia, and myalgia were more frequently reported in 
fasinumab-treated patients than in placebo-treated patients.  In neurological evaluations, 
abnormalities in vibration sense were more frequent in the fasinumab patients than in the placebo 
patients.  These adverse events (AEs) or physical examination abnormalities associated with 
fasinumab were generally mild to moderate in intensity and were transient (see current version of 
the Investigator’s Brochure). 
Data from studies of tanezumab and fulranumab 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 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 and monitoring 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 ongoing 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 continued to 
evaluate fasinumab 1 mg with the highest dose regimen of 1 mg Q4W. In August 2020, the 
independent DMC recommended termination of the fasinumab program.  The recommendation 
was based on a review of the totality of evidence, including the emerging unblinded data. Based 
on the independent DMC recommendation, the sponsor has discontinued dosing with fasinumab.  
At the time of this recommendation and amendment, the only patients to be impacted are the 
patients participating in the optional Year 2 portion of the R475-OA-1611 study.  These patients 
will be encouraged to enter the Year 2 safety follow-up period. 
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Fasinumab is currently being evaluated in a phase 3 trial (R475-PN-1523) designed to assess the 
long-term safety and efficacy of multiple doses of fasinumab in patients with OA.  The phase 3 
study described here, R475-OA-1611, is designed to compare the efficacy and safety of fasinumab 
with those of placebo and of naproxen, a standard-of-care NSAID for moderate-to-severe pain due 
to OA.  
Additional background information on fasinumab and the development program may be found in 
the current version of the Investigator’s Brochure. 
1.2. 
Summary of Risks and Benefits to Patients Participating in this 
Study  
As discussed above in Section 1.1, there are potential risks and benefits to patients participating in 
the study. Please refer to the Investigator’s Brochure and informed consent form (ICF) for 
additional detailed information and analysis of the potential risks and benefits associated with 
fasinumab administration.  Pain due to OA is a condition that results in significant morbidity and 
disability as well as marked loss of productivity. There is a significant unmet medical need for 
treatments with this condition. In Study R475-OA-1611, patients with pain due to OA will be 
randomized to fasinumab, naproxen or placebo; each of these treatment groups presents potential 
benefits and risks to patients as described below. 
• Fasinumab 
Fasinumab represents a potentially effective therapy that may be beneficial to patients who do not 
achieve adequate pain relief, are unable to tolerate existing therapies, or have absolute or relative 
contraindications to existing therapies for OA pain of the hip or knee.  Previous fasinumab study 
(R475-PN-1227) results have further confirmed earlier efficacy observations and demonstrate that 
fasinumab provides significant pain relief compared to placebo in OA patients across all doses 
administered.  Some common side effects seen in patients treated with fasinumab are joint-related 
events such as joint pain, joint/limb swelling, joint damage, new or worsening OA and occurrence 
of joint replacement surgery, and upper respiratory tract infection.  The joint damage that has been 
observed usually occurred in a knee or hip and sometimes in multiple joints. The joint damage 
occurred with or without increased joint pain and, at times, was more rapid and more severe than 
what is normally seen with OA.  Some patients treated with fasinumab who develop this joint 
damage have had a higher chance of undergoing joint replacement surgery.  In addition, this higher 
risk of joint replacement surgery has also been noted in fasinumab-treated patients who did not 
develop joint damage.  Further, this joint damage occurred more frequently in patients who 
received NSAIDs along with drugs of the group of anti-NGF and, therefore, concomitant 
administration of fasinumab and NSAIDs, apart from low dose aspirin, is prohibited in this study. 
Other adverse effects that have been seen in patients taking fasinumab include a risk of bone 
fracture and altered peripheral sensation, including hypoesthesia and paraesthesia.  Some patients 
had pain, numbness, or tingling in their wrist/hand and found to have carpal tunnel syndrome, 
which was sometimes treated with a surgical procedure. Finally, events associated with 
sympathetic nervous system dysfunction are being closely monitored due to findings from animal 
studies, although to date, this hasn’t been observed in patients treated with fasinumab. 
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Throughout the entire fasinumab clinical development program, the potential risks noted above 
are being mitigated by implementing close monitoring of patients via extensive clinical and 
radiologic assessments. These mitigation activities are described in detail in Section 9.6.1.  
Based on review of the totality of evidence from ongoing data across the fasinumab program as of 
August 2020, the independent DMC recommended that the fasinumab program be stopped.  The 
Sponsor has discontinued dosing with fasinumab. The only patients impacted were the patients 
participating in the optional Year 2 portion of the R475-OA-1611 study. The Sponsor believes it 
is important to continue off-treatment follow-up for all active patients in the study to complete 
safety follow-up. This safety follow-up is important to understand the benefit/risk for fasinumab. 
• Naproxen 
The benefits and risks of naproxen, an NSAID, at the recommended dosage are well documented. 
NSAIDs are efficacious and are the mainstay of treatment in patients with mild-to-moderate OA. 
The most frequently reported side effects of naproxen include cardiovascular events (eg, edema), 
gastrointestinal symptoms (eg, abdominal pain, nausea, and constipation), dermatological events 
(pruritus, skin eruptions), central nervous system (headache, dizziness, drowsiness) and dyspnea. 
Additional side effects include abnormal renal function, anemia, anaphylactoid reactions, 
gastrointestinal bleeding, hyper- and hypoglycemia, and renal failure.  
The overall benefit risk profile for naproxen is favorable. 
• Placebo 
The main potential risks associated with placebo are the lack of, or inadequate pain relief.  
Measures taken to minimize the risks associated with placebo use are as follows: 
• Availability of rescue medication (acetaminophen/paracetamol). 
• Patients can withdraw from the study at any time if pain persists despite the use of 
acetaminophen/paracetamol at the recommended dosage. 
Please refer to Section 3.2 for additional information on the rationale for including a placebo 
group. 
Patient Considerations in Response to COVID-19 
Measures to account for the COVID-19 pandemic that minimize the risks to the patients in the 
study as well as healthcare providers have been put in place (see Section 8.1 for details). 
2. 
STUDY OBJECTIVES  
2.1. 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of fasinumab compared with placebo, 
when administered for up to 16 weeks in patients with pain due to OA of the knee or hip. 
2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
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1. To evaluate the efficacy of fasinumab compared with naproxen, when administered for up 
to 16 weeks in patients with pain due to OA of the knee or hip 
2. To evaluate the efficacy of fasinumab compared with placebo, when administered for up 
to 44 weeks in patients with pain due to OA of the knee or hip  
3. To assess the safety and tolerability of fasinumab compared with naproxen, when 
administered for up to 16 weeks in patients with pain due to OA of the knee or hip  
4. To assess the safety and tolerability of fasinumab compared with naproxen, when 
administered for up to 52 weeks in patients with pain due to OA of the knee or hip  
5. To assess the safety and tolerability of fasinumab compared with naproxen, when 
administered for up to 104 weeks in patients with pain due to OA of the knee or hip 
6. To evaluate the pharmacokinetic (PK) profile of fasinumab administered to patients with 
pain due to OA of the knee or hip for up to 52 weeks 
7. To evaluate the PK profile of fasinumab administered to patients with pain due to OA of 
the knee or hip for up to 104 weeks 
8. To evaluate the immunogenicity of fasinumab administered to patients with pain due to 
OA of the knee or hip for up to 52 weeks 
9. To evaluate the immunogenicity of fasinumab administered to patients with pain due to 
OA of the knee or hip for up to 104 weeks  
10. To evaluate the efficacy of fasinumab compared with naproxen, when administered for up 
to 44 weeks in patients with pain due to OA of the knee or hip 
2.3. 
Exploratory Objectives 
To evaluate additional patient reported outcome measures in patients with pain due to OA of the 
knee or hip treated for up to 44 weeks with fasinumab, compared with placebo or naproxen.  To 
evaluate the WOMAC pain and physical function subscale scores as well as additional patient 
reported outcome (PRO) measures in patients with pain due to OA of the knee or hip treated for 
an additional 52 weeks with fasinumab, compared with naproxen pro re nata (prn).  To evaluate 
the use of rescue medication in patients with pain due to OA of the knee or hip treated for up to 44 
weeks with fasinumab, compared with placebo or naproxen.  To evaluate the use of rescue 
medication in patients with pain due to OA of the knee of hip treated for an additional 52 weeks 
with fasinumab, compared with naproxen prn. 
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 naproxen-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.   
The target study population was chosen because they currently have unmet medical needs with 
respect to incomplete pain control, despite the availability of NSAIDs.  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. 
Year 1 
All randomized patients in this study will participate in Year 1, which is intended to provide 
efficacy and safety data for OA patients exposed for up to 52 weeks to fasinumab, an NSAID 
comparator (naproxen), or placebo.  At the end of the 52-week treatment period of Year 1, patients 
who are eligible and willing to participate in a second 52-week treatment period will enter Year 2 
(see below).  Patients who are ineligible for Year 2, or are eligible but unwilling to enter Year 2, 
will enter directly into a 20-week follow-up period at the completion of Year 1 and thereby only 
participate in the Year 1 portion of the study. 
At the screening visit, patients will consent to all study assessments planned for Year 1 and will 
be informed that they could potentially continue in the study for the second year if eligible.  
Eligibility and consent for Year 2 will be conducted at the end of Year 1.  Note: As of 26 March 
2020, enrollment into Year 2 has been terminated due to the COVID-19 pandemic and, therefore, 
Year 1 patients reaching week 52 will move directly into the Year 1 follow-up period.   
This study will enroll patients who have failed or are intolerant to opioids and have inadequate 
pain relief from acetaminophen/paracetamol.  As there are currently a limited number of 
therapeutic options available for these patients, enrollment of this study population supports 
equipoise with respect to randomization of patients to fasinumab or to placebo.   
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 (as 
defined in Section 5.1).  The K-L stratification scheme is used here to ensure that there is an equal 
distribution of patients with the most severe OA at baseline across the dosing groups. 
The inclusion of a placebo treatment group in Year 1 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 naproxen is a commonly used and highly effective NSAID (Ong 2007), it has been selected as 
the comparator drug for this study.  
Inclusion of both the placebo group and the active treatment comparator group in Year 1 will be 
important to accurately estimate the risk of AEs, including the AEs of special interest of 
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adjudicated arthropathy, sympathetic nervous system dysfunction, and altered peripheral 
sensation.  Specific questionnaires and physical examinations will be employed to monitor for 
these AEs of special interest.  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.  Patients and 
investigators can choose to end participation at any time.   
Acetaminophen/paracetamol will be made available as rescue treatment for any patient as 
appropriate.  Therefore, the use of a placebo group is justified, as placebo-treated patients will not 
be placed at significant risk.   
Year 2 
Year 2 is intended to provide safety data for OA patients exposed to fasinumab or naproxen for up 
to 104 weeks (52 weeks in Year 1 and a further 52 weeks in Year 2).  Efficacy during Year 2 will 
be assessed via WOMAC to monitor the risk-benefit profile of fasinumab.  However, since Year 
2 of the study is not powered for formal efficacy assessments, efficacy results will be summarized 
descriptively.  Eligible patients must consent to participate in Year 2 at the end of their Year 1 
participation.  As of 26 March 2020, enrollment into Year 2 has been terminated due to the 
COVID-19 pandemic and therefore enrollment for any patients still eligible to enroll into Year 2 
as of this date is no longer an available option.  All patients currently enrolled into Year 2 as of 
this date are to remain in the study. As of 17 August 2020, all patients on treatment have been 
permanently discontinued from study drug and will complete the End of Treatment visit. This 
impacts only patients in the Year 2 treatment period as treatment in Year 1 has ended. All patients 
will be encouraged to complete all remaining study visits and procedures in the follow-up period 
and the end of study phone call. 
Patients who were randomized to fasinumab in Year 1 will continue treatment with the same 
fasinumab dose regimen in Year 2.  Patients who were randomized to a fixed dose of naproxen in 
Year 1 will receive naproxen pro re nata (prn) in Year 2.  To maintain the study blind, patients on 
fasinumab will receive naproxen-matching placebo prn and patients on naproxen will receive 
fasinumab-matching placebo Q4W. 
A fasinumab-matching placebo/naproxen-matching placebo group will not be included in Year 2 
so as not to have patients who are experiencing moderate-to-severe pain due to their OA go for an 
entire 2-year period with only rescue medication of acetaminophen/paracetamol available to them 
for pain control.  Patients who were randomized to fasinumab-matching placebo/naproxen-
matching placebo in Year 1 will be switched to naproxen prn (and fasinumab-matching placebo 
Q4W) for the second year of treatment to ensure they have access to some form of pain medication 
in addition to acetaminophen/paracetamol. 
As in Year 1, all patients in Year 2 will have regular study visits and receive diagnostic procedures 
(ie, X-rays, MRI) to evaluate their ongoing OA.  Adverse event monitoring will be ongoing 
throughout the trial.  Patients and investigators can choose to end participation at any time.   
Acetaminophen/paracetamol will be made available as rescue treatment during Year 2 for any 
patient as appropriate.   
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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 Q8W (with 
alternating placebo injections at the monthly visits where fasinumab will not be given, to maintain 
the blind), naproxen active comparator, or matching placebo. Based on April 2018 
recommendations from the independent DMC for this study 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 4 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. Based on the independent DMC review, study of lower dose levels (eg,1 mg Q4W) may 
continue to be evaluated in the OA population.  Given the discontinuation of the 3 mg and 6 mg 
doses, greater exposure to the fasinumab 1 mg dose is required to increase the size of the fasinumab 
safety database for potentially clinically relevant doses. Under this amendment, exposure to the 
fasinumab 1 mg dose will be increased by continuing to enroll patients into the 1 mg Q4W group 
as planned, and adding a 1 mg Q8W group to increase exposure to the 1 mg dose and to replicate 
the efficacy profile of this dose regimen, which was first evaluated in R475-PN-1523.  
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, the R475-PN-0908 
single-dose, proof-of concept study in patients with sciatic pain.  
Single subcutaneous (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 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 increased risk of AA with both the 9 mg and 6 mg Q4W doses, the latter doses are no longer 
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being studied for the treatment of pain due to OA.  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 and 6 mg Q8W for 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.  The addition of the 1 mg Q8W dose regimen will aid in the determination of 
a minimally efficacious dose. Note, with this amendment all dose regimens of study drug have 
been discontinued.  
All randomized patients in Year 1 will receive orally administered naproxen (500 mg twice daily) 
or matching placebo.  The 500 mg twice daily naproxen dose is a standard, approved dose for pain 
associated with OA.   
All patients who choose to enter Year 2 will take 500 mg naproxen as needed (ie, prn), which is 
considered standard-of-care for pain associated with OA, or naproxen-matching placebo prn.  The 
prn dosing schedule was chosen considering the known safety profile associated with chronic 
NSAID use.  In general, the lowest effective dose should be used for the shortest duration taking 
into consideration the patient’s medical history, concomitant medications, comorbidities, and age.  
The maximum dose allowed will be no more than the amount allowed during Year 1 (ie, 500 mg 
twice daily). 
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 16 in patients treated 
with fasinumab compared with that of patients treated with placebo. 
2. Change in the WOMAC physical function subscale scores from baseline to week 16 in 
patients treated with fasinumab compared with that of patients treated with placebo. 
4.2.2. 
Secondary Endpoints 
The key secondary endpoints of the study are: 
1. Change in the Patient Global Assessment (PGA) scores from baseline to week 16 in 
patients treated with fasinumab compared with that of patients treated with placebo 
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2. Percentage of patients treated with fasinumab, compared with that of patients treated with 
placebo, who had a response at week 16, with response defined as an improvement by 
≥30% in the WOMAC pain subscale scores 
3. Change in WOMAC pain subscale scores from baseline to week 16 in patients treated with 
fasinumab, compared with that of patients treated with naproxen 
4. Change in WOMAC physical function subscale scores from baseline to week 16 in patients 
treated with fasinumab, compared with that of patients treated with naproxen 
5. Change in WOMAC pain subscale scores from baseline to week 44 in patients treated with 
fasinumab, compared with that of patients treated with placebo 
6. Change in WOMAC physical function subscale scores from baseline to week 44 in patients 
treated with fasinumab, compared with that of patients treated with placebo 
7. Change in the PGA scores from baseline to week 44 in patients treated with fasinumab 
compared with that of patients treated with placebo 
8. Change in the PGA scores from baseline to week 16 in patients treated with fasinumab 
compared with that of patients treated with naproxen 
9. Change in WOMAC pain subscale scores from baseline to week 44 in patients treated with 
fasinumab, compared with that of patients treated with naproxen 
10. Change in WOMAC physical function subscale scores from baseline to week 44 in patients 
treated with fasinumab, compared with that of patients treated with naproxen 
11. Percentage of patients treated with fasinumab, compared with that of patients treated with 
naproxen, who had a response at week 16, with response defined as an improvement by 
≥30% in the WOMAC pain subscale scores 
12. Change in WOMAC pain subscale scores from baseline to the average score across weeks 
4, 8, 12 and 16, in patients treated with fasinumab compared with that of patients treated 
with placebo 
13. Change in WOMAC physical function subscale scores from baseline to the average score 
across weeks 4, 8, 12 and 16, in patients treated with fasinumab compared with that of 
patients treated with placebo 
14. Change in WOMAC pain subscale scores from baseline to the average score across weeks 
36, 40 and 44 in patients treated with fasinumab compared with that of patients treated with 
placebo  
15. Change in WOMAC physical function subscale scores from baseline to the average score 
across weeks 36, 40 and 44 in patients treated with fasinumab compared with that of 
patients treated with placebo 
4.2.3. 
Exploratory Endpoints  
The exploratory endpoints in the study are: 
1. Change from baseline to weeks 16 and 44 in patient-reported outcome measures in patients 
with pain due to OA of the knee or hip treated with fasinumab compared to placebo 
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2. Change from baseline to weeks 16 and 44 in patient-reported outcome measures in patients 
with pain due to OA of the knee or hip treated with fasinumab compared to naproxen 
3. The proportion of patients taking rescue medication, number of days on rescue medication, 
and weekly average use of rescue medication from baseline to weeks 16 and 44 in patients 
with pain due to OA of the knee or hip treated with fasinumab compared to placebo 
4. The proportion of patients taking rescue medication, number of days on rescue medication, 
and weekly average use of rescue medication from baseline to weeks 16 and 44 in patients 
with pain due to OA of the knee or hip treated with fasinumab compared to naproxen 
5. Percentage of patients treated with fasinumab, compared with that of patients treated with 
placebo, who had improvements of ≥50% and ≥70% in the WOMAC pain subscale scores 
at weeks 16 and 44 
6. Percentage of patients treated with fasinumab, compared with that of patients treated with 
placebo, who had improvements of ≥30%, ≥50% and ≥70% in the WOMAC pain subscale 
scores at weeks 16 and 44 
7. Percentage of patients treated with fasinumab, compared with that of patients treated with 
placebo who met the OMERACT-OARSI criterion at weeks 16 and 44 
8. Descriptive analyses of the change from baseline at all visits from weeks 52E and 104E of 
the WOMAC pain and physical function subscale scores in patients with pain due to OA 
of the knee or hip treated with fasinumab compared to naproxen prn 
9. Descriptive analyses of the change from baseline at all visits from weeks 52E and 104E in 
patient-reported outcome measures in patients with pain due to OA of the knee or hip 
treated with fasinumab compared to naproxen prn 
10. The proportion of patients taking rescue medication, number of days on rescue medication, 
and weekly average use of rescue medication from weeks 52E to 104E in patients with pain 
due to OA of the knee or hip treated with fasinumab compared to placebo 
11. The proportion of patients taking rescue medication, number of days on rescue medication, 
and weekly average use of rescue medication from weeks 52E to 104E in patients with pain 
due to OA of the knee or hip treated with fasinumab compared to naproxen 
4.3. 
Safety Endpoints 
4.3.1. 
Safety Endpoints for Year 1 (All Randomized and Treated Patients) 
Safety endpoints for Year 1 (through week 52) will include: 
• 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)  
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• Incidence of peripheral sensory AEs that require a neurology or other specialty 
consultation  
• Incidence of all-cause JRs 
The incidence of JRs at the telephone survey 52 weeks after the last dose of study drug (week 100) 
will also be evaluated. 
4.3.2. 
Safety Endpoints for Year 2 (All Randomized and Treated Patients Proceeding 
into Year 2) 
The safety endpoints listed above in Section 4.3.1 will be evaluated for Year 2 from the first dose 
of study drug given in Year 2 through week 104E (end of treatment), as well as for the periods of 
Year 1 and 2 from day 1 through week 104E.   
The incidence of JRs at the telephone survey 52 weeks after the last dose of study drug 
(week 152E) will also be evaluated. 
4.4. 
Pharmacokinetic Variables 
The PK variables will consist of fasinumab concentrations in samples collected at time points 
specified in Table 1 and Table 2. 
4.5. 
Anti-Drug Antibody Variables 
Anti-drug antibody (ADA) variables include ADA status (positive or negative), titer, neutralizing 
antibody (NAb) status, and time point/visit.  Samples in this study will be collected at the clinical 
visits specified in Table 1 and Table 2.  
5. 
STUDY DESIGN  
5.1. 
Study Description and Duration 
This study is a randomized, double-blind, placebo- and naproxen-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 from opioids (or are unwilling to take opioids or have lack of access to 
opioids).   
The overall study period for patients in Year 1 who do not participate in Year 2 will be up to 
approximately 105 weeks including screening and pre-randomization.  For these patients, 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 52-week treatment period, a 20-week follow-up period, and a 
final phone call approximately 52 weeks after the last dose of SC study drug (Figure 1).  At the 
end of the Year 1 treatment period, eligible patients can choose to consent to Year 2 and undergo 
a second year of treatment instead of entering the 20-week follow-up period.  Note: As of 26 March 
2020, all enrollment into Year 2 has been terminated due to the COVID-19 pandemic. Any patients 
currently enrolled in Year 2 are to remain in the study. Patients who participate in Year 2 will 
receive treatment for a total of 104 weeks and will then enter a 20-week follow-up period followed 
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by the final phone call approximately 52 weeks after the last dose of SC study drug (Figure 1). 
Note: As of 17 August 2020, all patients on treatment have been permanently discontinued from 
study drug and will complete the End of Treatment visit. This impacts only patients in the Year 2 
treatment period as treatment in Year 1 has ended. All patients will be encouraged to complete all 
remaining study visits and procedures in the follow-up period and the end of study phone call. 
Study weeks during Year 2 will be denoted with an E to represent study weeks during the extension 
(eg, week 52E) and to differentiate them from study weeks with the same numbers in the follow-up 
period for patients who only participate in Year 1.   
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Figure 1: 
Study Flow Diagram 
 
Screening & Pre-randomization Year 1 Treatment (52 weeks) 
Follow-Up 
EOS-Phone 
Contact 
Up to 40 days 
Day 1 to Week 52 
Week 52 to 72 
Week 100 
 
Randomization 
    End of 
  Treatment 
 
End of 
Follow-up 
 
 
 
 
 
Screening 
Pre-
randomization 
 
 
 
 
Up to 30 days 
7 to 10 days 
  Baseline  
     Day 1 
Week 16 
Week 52 
Week 72  
Week 100 
 
 
 
 
 
 
 
 
 
 
 
 
 
Transition to Year 2 
 
 
Year 2 Treatment (52 weeks) 
Follow-Up 
EOS-Phone 
Contact 
 
Week 52E to 104E 
Week 104E to 124E 
Week 152E 
 
    End of 
  Treatment 
End of 
Follow-up 
 
 
 
 
 
 
 
    Week 52E 
Week 104E 
Week 124E  
 Week 152E 
 
 
 
 
Abbreviation: EOS- End of study 
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5.1.1. 
Screening and Pre-Randomization 
At the screening visit, patients will consent to all study assessments planned for Year 1 and will 
be informed that they could potentially continue in the study for a second year if they meet 
eligibility requirements for Year 2.  Eligibility and consent for Year 2 will be conducted at the end 
of Year 1. 
Prior to randomization, patients will undergo screening procedures, including X-ray of the 
shoulders, hips, and knees.  Magnetic resonance imaging of the index and contralateral joints must 
be performed at screening and the results assessed by the central imaging vendor.  In addition, an 
MRI will be performed on any knee or hip joint with a K-L score of ≥3.  Randomization visits 
cannot occur until there is confirmation from the central imaging vendor that there are no 
exclusionary findings on the X-rays and any required MRIs.  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 the randomization visit.  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. 
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 8.2.3.4) 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 IVRS 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 
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screen failed due to not meeting the WOMAC criteria or have orthostatic hypotension (defined in 
Section 8.2.3.4) during the screening or pre-randomization visit. 
5.1.3. 
Randomization 
Enrollment of approximately 2845 patients is planned for this study, which includes a total of 
285 patients who 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 due to the urgent safety measure, 
and a total of approximately 2560 patients who will be randomized to fasinumab 1 mg SC Q4W, 
1 mg SC Q8W, naproxen, and placebo.  
At the baseline visit of Year 1, patients will be randomized 3:3:3:1 to the following treatment 
groups as follows: 
• Fasinumab 1 mg SC Q4W  
• Fasinumab 1 mg SC Q8W  
• Naproxen 500 mg oral, twice daily  
• Placebo  
Prior to amendment 5 global, it is estimated that approximately 560 patients were randomized as 
follows: 240 patients to the fasinumab 1 mg SC Q4W group, 240 patients to the naproxen-only 
group and 80 patients to the placebo group. Under amendment 5 global, a further 2000 patients 
were planned to be randomized as follows: 600 patients to the fasinumab 1 mg SC Q4W group, 
600 patients to the naproxen-only group, 200 patients to the placebo group, and 600 patients to the 
newly added fasinumab 1 mg SC Q8W group.  Thus, overall, this study will enroll approximately 
2560 patients as follows: 840 patients to the fasinumab 1 mg SC Q4W group, 600 patients to the 
1 mg SC Q8W group, 840 patients to the naproxen group, and 280 patients to the placebo group. 
Prior to amendment 5 global, approximately 285 patients were enrolled in the fasinumab 3 mg SC 
Q4W and fasinumab 6 mg SC Q8W groups. However, dosing in these patients was discontinued, 
as recommended by the independent DMC in April 2018.   
Patients will receive treatment as described in Section 7.1. 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.   
Eligible patients who choose to participate in Year 2 will not be re-randomized at week 52.  See 
Section 7.1 for treatment assignments in Year 2. 
5.1.4. 
Treatment Period for Year 1 
During the treatment period (day 1 through week 52), 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 8 
(±1 day). 
Patients 
will 
record 
their 
use 
of 
acetaminophen/paracetamol in a diary. Patients should discontinue use of acetaminophen/ 
paracetamol at least 24 hours prior to the start of each study visit in order to minimize the 
confounding effects of the rescue medication on efficacy measurements.  
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Efficacy will be assessed by the change from baseline in the WOMAC pain and physical function 
subscale scores, the PGA, the 36-item Short Form Survey (SF-36), the EuroQoL 5 Dimensions 
5 Level Questionnaire (EQ-5D-5L), the Numeric Rating Scale (NRS) of the average walking index 
joint pain, the Work Productivity and Activity Impairment-Osteoarthritis (WPAI-OA), 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. 
At the end of the treatment period, patients will either enter the 20-week follow-up period or will 
be offered by their investigator to enter Year 2, if eligible. 
5.1.5. 
Treatment Period for Year 2 
During the treatment period of Year 2 (week 52E through week 104E), patients will be permitted 
to use only acetaminophen/paracetamol as rescue medication.  Patients will record their use of 
acetaminophen/paracetamol 
in 
a 
diary. 
 
Patients 
should 
discontinue 
use 
of 
acetaminophen/ paracetamol at least 24 hours prior to the start of each study visit in order to 
minimize the confounding effects of the rescue medication on efficacy measurements.  
Efficacy will be assessed by the change from baseline in the WOMAC pain and physical function 
subscale scores, the EQ-5D-5L and the WPAI-OA.  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 2. 
5.1.6. 
Follow-Up Period 
At the end of the treatment period (week 52 for patients participating in Year 1 only, or week 104E 
for patients participating in Year 1 and Year 2), follow-up of patients will continue for an 
additional 20 weeks.  Safety and efficacy assessments will be performed according to the schedule 
outlined in Table 1 (for patients participating in Year 1 only) or Table 2 (for patients participating 
in Year 1 and Year 2). 
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 3. 
5.1.7. 
End of Study Phone Contact 
The end of study phone contact will be at week 100 for patients participating in Year 1 only or 
week 152E for patients participating in Year 1 and Year 2. 
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. 
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5.1.8. 
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.  
5.1.9. 
End of Study Definition 
The end of study is defined as the last phone contact of the last patient in this study. 
5.2. 
Planned Interim Analysis  
No interim analysis of efficacy data from Year 1 will be conducted prior to collection of all data 
necessary for the primary and secondary analysis.   
A first-step analysis of all available efficacy and safety data for Year 1 and select analysis of 
available Year 2 safety data will be performed when all data for Year 1 Treatment Period (baseline 
through week 52) have been collected and validated for all randomized patients (see Section 10.5 
for statistical details of this analysis).   
Another analysis will be performed for regulatory purposes on the remaining Year 1 WOMAC 
and PRO assessments and safety data (collected during the Year 1 follow-up period) and any Year 
2 efficacy and safety data available at the time of the data cut-off for the second analysis. 
Additional analyses of other efficacy and safety data may be performed for regulatory purposes as 
needed. 
Individuals unblinded to patient-level data for the first-step or any of the subsequent analyses will 
no longer be involved in the day-to-day conduct of the ongoing study.  Patient-level results will 
not be released to any site-facing personnel or anyone who is directly involved in the conduct of 
the study. 
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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 comprise independent statistical and medical experts. Further details will be defined 
in the DMC charter. Additional safety monitoring will occur on an ongoing basis by the Regeneron 
Safety Team. 
5.3.2. 
Arthropathy Adjudication Committee 
An independent, expert, blinded adjudication committee, composed of radiologists, 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 
Enrollment of approximately 2845 patients is planned for this study (see Section 5.1.3).  
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 for Year 1 
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 
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) 
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• 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 analgesics use for pain due to OA of the knee or hip, as 
defined by: 
a. Inadequate pain relief from acetaminophen/paracetamol AND 
b. Intolerance to or inadequate pain relief from 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 
initial 16 weeks of treatment 
11. Stable treatment with glucosamine sulfate and chondroitin sulfate treatments must be 
stopped during the pre-randomization period 
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 
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6.2.2. 
Exclusion Criteria for Year 1 
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 visit 
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 naproxen intolerance, or existence of a medical condition that is high risk for 
naproxen-associated complications (eg, high risk of gastrointestinal bleed, previous ulcer, 
condition requiring 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 
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 
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16. Confirmed 
elevated 
screening 
alanine 
aminotransferase 
(ALT) 
or 
aspartate 
aminotransferase (AST) ≥2.5 times the upper limit of normal (ULN) 
17. Resting heart rate of <50 beats per minute (bpm) or >100 bpm (by vital sign assessment or 
as captured during electrocardiogram [ECG] assessment) at the screening or randomization 
visits 
18. History or presence of 2nd or 3rd degree heart block, 1st degree heart block with abnormal 
QRS complex, or bifascicular block by ECG assessment at the screening visit  
19. History or presence of orthostatic hypotension, as defined in Section 8.2.3.4, at the 
screening, pre-randomization, or randomization visits  
20. History of poorly controlled hypertension, as defined by: 
a. Systolic blood pressure ≥180 mm Hg or diastolic blood pressure ≥110 mm Hg at 
the screening visit 
b. Systolic blood pressure of 160 mm Hg to 179 mm Hg or diastolic blood pressure 
of 100 mm Hg to 109 mm Hg at the screening visit, AND a history of end-organ 
damage (including history of left ventricular hypertrophy, heart failure, angina, 
myocardial infraction, stroke, transient ischemic attack, peripheral arterial disease 
and moderate to advanced retinopathy [hemorrhages or exudates, papilledema]) 
21. Congestive heart failure with 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 
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) 
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30. Use of a monoamine reuptake inhibitor, tricyclic antidepressants, selective serotonin 
reuptake inhibitors and serotonin norepinephrine reuptake inhibitors for treatment of pain 
within 4 weeks prior to the screening visit 
31. Has 
positive 
urine 
drug 
test 
results 
during 
screening 
(eg, 
amphetamines/methamphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, 
and opiates), unless in the opinion of the investigator, the positive test results may be due 
to the patient’s current permitted medications. 
32. History of (within 5 years prior to the screening visit) or current alcoholism, alcohol abuse, 
substance abuse, or abuse of prescription pain medication 
33. History of cannabis use for the treatment of pain within the past 6 months prior to the 
screening visit 
34. Ongoing participation in a clinical research study evaluating another investigational drug 
or having received another investigational product within 30 days or 5 half-lives of the 
screening visit, whichever is longer  
35. Exposure to an anti-NGF antibody prior to the screening visit or known sensitivity or 
intolerance to anti-NGF antibodies or participation in a clinical trial evaluating anti-NGF 
antibodies 
36. Member of the clinical site study team and/or his/her immediate family 
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 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 (IUD); intrauterine hormone-releasing system (IUS); 
bilateral tubal ligation; vasectomized partner; and or sexual abstinence†‡.  
* Postmenopausal women must be amenorrheic for at least 12 months (without an 
alternative medical cause) in order not to be considered of childbearing potential.  
Pregnancy testing and contraception are not required for women with documented 
complete hysterectomy or tubal ligation. 
† Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatments.  The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject. 
‡ Periodic abstinence (calendar, symptothermal, and post-ovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method 
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(LAM) 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. 
6.2.3. 
Inclusion Criteria for Year 2 
Note: Any Year 1 patient attending their week 52 visit on or after 26 March 2020 will no longer 
have the option to enroll into Year 2.  
1. Completed the treatment period of Year 1 
2. Did not permanently discontinue study drug during Year 1 
3. Received no less than 10 of the 13 planned doses of SC study drug during the treatment 
period of Year 1 
4. Provide informed consent for Year 2 
5. Willing to continue to maintain current activity and exercise levels throughout Year 2 
6. 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  
6.2.4. 
Exclusion Criteria for Year 2 
Women of childbearing potential who are unwilling to continue to practice highly effective 
contraception 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 (IUD); intrauterine 
hormone-releasing system (IUS); bilateral tubal ligation; vasectomized partner; and or sexual 
abstinence†‡.  
† 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, and post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not 
acceptable methods of contraception.  Female condom and male condom should not be 
used together. 
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 8.1.4. 
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 7.3.2. 
6.4. 
Replacement of Patients 
Patients prematurely withdrawn from the study or study drug will not be replaced. 
7. 
STUDY TREATMENTS 
7.1. 
Investigational and Reference Treatments 
Study drug in this study includes fasinumab, naproxen, and their matching placebo.  Fasinumab 
and its matching placebo are SC study drug. Naproxen 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  
Naproxen 500 mg capsules and naproxen-matching placebo capsules will be provided by the 
sponsor.  
Year 1 
At the baseline visit of Year 1, patients will be randomized 3:3:3:1 to receive 1 of the following 
treatment regimens: 
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• Fasinumab 1 mg SC Q4W and naproxen-matching placebo oral, twice daily 
• Fasinumab 1 mg SC Q8W (patients will receive placebo injections at the study visits 
where study drug is not administered) and naproxen-matching placebo oral, twice daily 
• Fasinumab-matching placebo SC Q4W and naproxen 500 mg oral, twice daily 
• Fasinumab-matching placebo SC Q4W and naproxen-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 Q4W or 6 mg Q8W fasinumab were discontinued from study drug for the 
remainder of the study and moved directly into the follow-up period. 
Naproxen 500 mg or naproxen-matching placebo will be administered orally, twice daily.  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 naproxen or naproxen-matching placebo will 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. 
Year 2 
During Year 2, patients will receive one of the following treatment regimens based on the treatment 
they received during Year 1: 
Year 1 
Year 2 
Fasinumab 
1 mg 
SC 
Q4W 
and 
naproxen-matching placebo oral, twice daily 
Fasinumab 
1 mg 
SC 
Q4W 
and 
naproxen-matching placebo oral, prn* 
Fasinumab 1 mg SC Q8W (patients will 
receive placebo injections at the study visits 
where study drug is not administered) and 
naproxen-matching placebo oral, twice daily 
Fasinumab 1 mg SC Q8W (patients will 
receive placebo injections at the study visits 
where study drug is not administered) and 
naproxen-matching placebo oral, prn* 
Fasinumab-matching placebo SC Q4W and 
naproxen 500 mg oral, twice daily 
Fasinumab-matching placebo SC Q4W and 
naproxen 500 mg oral, prn*  
Fasinumab-matching placebo SC Q4W and 
naproxen-matching placebo oral, twice daily 
Fasinumab-matching placebo SC Q4W and 
naproxen 500 mg oral, prn*  
*The maximum naproxen dose (or naproxen placebo dose) allowed will be no more than the amount allowed during 
Year 1 (ie, 500 mg twice daily or 1 capsule of placebo twice daily). 
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Administration of SC study drug will be performed as stated above for Year 1.  
Naproxen 500 mg or naproxen-matching placebo will be administered prn.  A proton pump 
inhibitor or other gastric protective medication may be prescribed if deemed medically necessary 
by the investigator or sub-investigator. 
7.2. 
Rescue Treatment(s) 
During the Year 1 and Year 2 treatment periods, 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 (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 Year 1 and Year 2 treatment periods in order to minimize the confounding effects of 
rescue medication on efficacy assessments. Use of acetaminophen/paracetamol as study-provided 
rescue medication during the Year 1 and Year 2 treatment periods will be reported daily by patients 
using e-diaries. During the Year 1 and Year 2 treatment periods, 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 end of the treatment period.   
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. 
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 or the Sponsor and according to the study stopping rules (Section 5.1.8).  
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Patients who permanently discontinue from study drug will be encouraged to remain in the study 
and to complete all study procedures and assessments including completion of the diary, the only 
exception being not receiving study drug (oral and SC).  Patients must continue to adhere to the 
prohibited medication list as per Section 7.7.1.  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 early termination study assessments, per Table 1. 
Patients who discontinue from study drug prior to study completion due to an AA (see 
Section 9.6.1.1) should return to the clinic for all remaining study visits per the visit schedule.  
In the event that a patient must undergo JR surgery during the treatment or follow-up periods, 
he/she will be discontinued from study drug and asked to return to the study site for a pre-operative 
visit and for follow-up safety evaluations (as described in Section 8.2.3.10) 4 and 20 weeks after 
surgery.  Pre-operative 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 
As of 17 August 2020, all patients in the Year 2 Treatment Period 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. 
Prior to 17 August 2020, study drug dosing was to 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: 
− 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 
− They have a known GFR <30 mL/minute/1.73m2 or, 
− 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 Q4W 
or 6 mg 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 
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least moderate peripheral neuropathy limiting activities of daily living (ADL), 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 
• 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: 
− Total bilirubin (TBL) >2x ULN or international normalized ratio (INR) >1.5, and 
− ALT or AST >3x ULN, and 
− 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  
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7.3.2.2. 
Reasons for Temporary Discontinuation of Study Drug 
Study drug may be temporarily discontinued due to medical need, as determined by the 
investigator.  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 naproxen 
or naproxen-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. 
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 study drug SC should be treated using clinical 
judgment to determine the appropriate response according to typical clinical practice.  
7.4.2. 
Local Injection Site Reactions 
Local injection site reactions must be reported as AEs and graded according to Section 9.5.1. 
7.5. 
Method of Treatment Assignment  
At the baseline visit of Year 1, patients will be randomized in a 3:3:3:1 ratio to receive fasinumab 
(1 mg SC Q4W, 1 mg SC Q8W), naproxen, or placebo according to a central randomization 
scheme provided by an interactive voice response system (IVRS) / interactive web response system 
(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 5 global, patients were randomized 3:3:3:3:1 to receive fasinumab 
(1 mg Q4W, 3 mg Q4W, 6 mg Q8W), naproxen, or placebo. 
Patients participating in Year 2 will receive treatment as described in Section 7.1.  No 
re-randomization will occur at the time of entry into Year 2.    
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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 database is locked for this study. 
7.5.2. 
Emergency Unblinding 
Unblinding of treatment assignment for a patient may be necessary due to a medical emergency 
or any other significant medical event (eg, pregnancy). 
If unblinding is required: 
• Only the investigator will make the decision to unblind the treatment assignment  
• Only the affected patient 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 serious adverse 
reactions (SUSARs). 
7.6. 
Treatment Logistics and Accountability 
7.6.1. 
Packaging, Labeling, and Storage  
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 
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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 2°C to 8°C while oral study 
drug will be stored at 20°C to 25°C; storage instructions will be provided in the pharmacy manual. 
7.6.2. 
Supply and Disposition of Treatments  
Subcutaneous and oral study drugs 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, study drug will be destroyed or returned to the sponsor or designee. Refer to 
the pharmacy manual for instructions. 
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 study drug compliance records must be kept current and made available for inspection by the 
sponsor and regulatory agency inspectors. 
7.7. 
Concomitant Medications and Procedures 
Any treatment administered and/or procedures performed from screening to the end of the 
follow-up period will be considered concomitant medication and/or procedures, respectively.  This 
includes medications and/or procedures that were started before the study and are ongoing during 
the study. 
7.7.1. 
Prohibited Medications  
Patients will be required to discontinue all non-study pain medication (oral or topical; except up 
to 150 mg/day of aspirin/5-aminosalicylic 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 Year 1 and Year 2 treatment periods. 
Opioid analgesic medications (including tramadol) are prohibited during the Year 1 and Year 2 
treatment periods.  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 
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containing NSAIDs will be provided in the study reference manual and a reference card given to 
the patients. 
Other excluded medications during the Year 1 and Year 2 treatment periods include: 
• Any other investigational agent 
• 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 
• IL-6 or IL-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 also permitted. 
Acetaminophen/paracetamol taken acutely for treatment of non-OA pain is also permitted; 
however, the total daily dosage limits cannot be exceeded, regardless of the reason for 
acetaminophen/paracetamol use.  During the pre-randomization and the Year 1 and Year 2 
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 
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follow-up periods, acetaminophen/paracetamol taken for any reason will be reported as 
concomitant medication.  Topical steroids are also permitted.   
Muscle relaxants, such as Skelaxin® (metaxalone) and others, are permitted.  Prohibited muscle 
relaxants are listed in Section 7.7.1. 
Physical therapies (such as transcutaneous electrical nerve stimulation and acupuncture) are 
permitted during the trial, provided that patients have been on a stable regimen for at least 4 weeks 
prior to entering into the trial and that they expect to maintain this regimen during the trial. 
Joint replacement is a permitted procedure during the study. 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
8.1. 
Schedule of Events 
Study assessments and procedures are presented by study period and visit in Table 1, Table 2 and 
Table 3. 
In light of the public health emergency related to COVID-19, the continuity of clinical study 
conduct 
and 
oversight 
may 
require 
implementation 
of 
temporary 
or 
alternative 
mechanisms.  Examples of such mechanisms may include, but are not limited to, any of the 
following:  phone contact, virtual visits, telemedicine visits, online meetings, non-invasive remote 
monitoring devices, use of local clinic or laboratory locations, and home visits by skilled 
staff.  Additionally, no waivers to deviate from protocol enrollment criteria due to COVID-19 will 
be granted. All temporary mechanisms utilized, and deviations from planned study procedures are 
to be documented as being related to COVID-19 and will remain in effect only for the duration of 
the public health emergency. 
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Table 1: 
Schedule of Events for Year 1 
(To be followed by all Year 1 and Year 2 study participants through week 52.  Patients participating in Year 1 only will follow this table 
for weeks 52 through 100.  Patients who participate in Year 2 will follow Table 2 starting at week 52E after completing the week 52 
visit in Table 1). 
Study Week 
Screen 
Pre-
Random  
Year 1 Treatment (52 weeks) 
 
 
Baseline Week 1 
Week 2 
Week 4 
Week 8 Week 12 Week 16 Week 20 
Week 
24 
Week 28 Week 32 Week 36 
Study Day  
Up to 30 
days 
7 to 10 
days  
1  
8  
15  
29  
57  
85  
113  
141  
169  
197 
225 
253 
Visit Window (days) 
 
 
 
±1 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Visit Number 
Visit 1 
Visit 2 
Visit 3 
Phone 1 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 Visit 11 
Visit 12 Visit 13 
Screening/Baseline: 
Inclusion/Exclusion2 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genomics sub-study 
informed consent3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary instructions 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Training on pain 
reporting/patient education 
brochures4 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
SC study drug injection5 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense 
acetaminophen/paracetamol 
 
X 
X 
 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Acetaminophen/paracetamol 
accountability 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense oral study drug 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Oral study drug 
accountability  
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
                                        VV-RIM-00122598-1.0 Approved - 26 Aug 2020 GMT-5:00


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 Page 71 of 130 
CONFIDENTIAL 
Study Week 
Screen 
Pre-
Random  
Year 1 Treatment (52 weeks) 
 
 
Baseline Week 1 
Week 2 
Week 4 
Week 8 Week 12 Week 16 Week 20 
Week 
24 
Week 28 Week 32 Week 36 
Study Day  
Up to 30 
days 
7 to 10 
days  
1  
8  
15  
29  
57  
85  
113  
141  
169  
197 
225 
253 
Visit Window (days) 
 
 
 
±1 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Visit Number 
Visit 1 
Visit 2 
Visit 3 
Phone 1 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 Visit 11 
Visit 12 Visit 13 
Recording of rescue 
medication use in diary6 
 
X 
X 
X 
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 
Patient-Completed Assessments/Efficacy23: 
 
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 
X 
X 
X 
SF-36  
 
 
X 
 
 
X 
X 
 
X 
 
X 
 
 
 
EQ-5D-5L 
 
 
X 
 
 
X 
X 
 
X 
 
X 
 
 
 
HCRU 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
WPAI-OA 
 
 
X 
 
 
X 
X 
 
X 
 
 
 
 
 
TSQM 
X 
 
 
 
 
X 
X 
 
X 
 
  
 
  
 
Peripheral or central pain 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Safety: 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Vital signs9 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
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 questionnaire23 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Survey of autonomic 
symptoms23 
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- 
BRIEF 
X-
BRIEF 
X-
BRIEF 
X- 
BRIEF 
X-
BRIEF 
Adverse events 
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------→ 
Injection site evaluation 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                        VV-RIM-00122598-1.0 Approved - 26 Aug 2020 GMT-5:00


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 Page 72 of 130 
CONFIDENTIAL 
Study Week 
Screen 
Pre-
Random  
Year 1 Treatment (52 weeks) 
 
 
Baseline Week 1 
Week 2 
Week 4 
Week 8 Week 12 Week 16 Week 20 
Week 
24 
Week 28 Week 32 Week 36 
Study Day  
Up to 30 
days 
7 to 10 
days  
1  
8  
15  
29  
57  
85  
113  
141  
169  
197 
225 
253 
Visit Window (days) 
 
 
 
±1 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Visit Number 
Visit 1 
Visit 2 
Visit 3 
Phone 1 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 Visit 11 
Visit 12 Visit 13 
Bilateral x-rays (knee, hip, 
shoulder) 
X11 
 
 
 
 
 
 
 
X 
 
 
 
  
  
MRI12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Event-triggered imaging13 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pre-op questionnaire (JR 
follow-up)14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Testing:  
Hematology15 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
Blood chemistry15 
X 
 
 
 
 
 
X 
  
X 
 
X 
 
 
 
ESR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c15 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH and estradiol15, 16 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (for 
WOCBP)17 
X- 
Serum 
 
X-  
Urine 
 
 
X-  
Urine 
X-  
Urine 
X-  
Urine 
X-  
Urine 
X-  
Urine 
X-  
Urine 
X-  
Urine 
X-  
Urine 
X-  
Urine 
Urinalysis and urine 
electrolytes15 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
Urine drug test15 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK, Antibody, and Research Sampling: 
PK sample18 
 
 
X 
 
 
X 
X 
 
X 
 
 
 
X 
 
ADA sample18 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
hs-CRP sample18,19 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
Research serum/plasma 
sample18, 19 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
Genomic sub-study sample 
(optional)20 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
                                        VV-RIM-00122598-1.0 Approved - 26 Aug 2020 GMT-5:00


Clinical Study Protocol 
 
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 Page 73 of 130 
CONFIDENTIAL 
ADA: Anti-drug antibody 
NRS: Numeric Rating Scale 
EQ-5D-5L: EuroQoL 5 Dimensions 5 Level Questionnaire 
PGA: Patient Global Assessment 
ESR: Erythrocyte sedimentation rate 
PK: Pharmacokinetic 
FSH: Follicle stimulating hormone 
SC: Subcutaneous 
HbA1c: Glycated hemoglobin 
SF-36: 36-item Short Form Survey 
HCRU: Healthcare Resource Utilization 
TSQM: Treatment Satisfaction Questionnaire for Medication 
Hs-CRP: High-sensitivity C-reactive protein 
WOCBP: Women of child-bearing potential 
JR: Joint replacement 
WOMAC: Western Ontario and McMaster Osteoarthritis Index 
MRI: Magnetic resonance imaging 
WPAI-OA: Work Productivity and Activity Impairment Osteoarthritis 
                                        VV-RIM-00122598-1.0 Approved - 26 Aug 2020 GMT-5:00


Clinical Study Protocol 
 
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 Page 74 of 130 
CONFIDENTIAL 
Table 1: 
Schedule of Events Year 1 (continued)  
(To be followed by all Year 1 and Year 2 study participants through week 52.  Patients participating in Year 1 only will follow this table 
for weeks 52 through 100.  Patients who participate in Year 2 will follow Table 2 starting at week 52E after completing the week 52 
visit in Table 1). 
Study Week 
Year 1 Treatment (52 weeks) 
Follow-up 
End of Study 
Phone Call 
Week 40 
Week 44 
Week 48 
EOT24/  
Week 52 
Early 
Termination 
/JR Pre-
operative1 
Week 56 
Week 72 
Early 
Termination 
/JR Pre-
operative1  
Week 100 
Study Day 
281 
309 
337 
365 
393 
505 
701 
Visit window (days) 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Visit Number 
Visit 14 
Visit 15 
Visit 16 
Visit 17 
Visit 18 
Visit 19 
Phone 2 
Screening/Baseline: 
 
Inclusion/Exclusion2 
 
 
 
 
 
 
 
 
 
Informed consent 
 
 
 
 
 
 
 
 
 
Genomics sub-study 
informed consent3 
 
 
 
 
 
 
 
 
 
Medical history 
 
 
 
 
 
 
 
 
 
Medication history 
 
 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
 
 
Height 
 
 
 
 
 
 
 
 
 
Diary instructions 
 
 
 
 
 
 
 
 
 
Training on pain 
reporting/patient education 
brochures4 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
 
 
Treatment: 
 
SC study drug injection5 
X 
X 
X 
 
 
 
 
 
 
Dispense 
acetaminophen/paracetamol 
X 
X 
X 
 
 
 
 
 
 
Acetaminophen/paracetamol 
accountability 
X 
X 
X 
X 
X 
 
 
 
 
Dispense oral study drug 
X 
X 
X 
 
 
 
 
 
 
Oral study drug 
accountability  
X 
X 
X 
X 
X 
 
 
 
 
Recording of rescue 
medication use in diary6 
X 
X 
X 
X 
X 
 
 
 
 
                                        VV-RIM-00122598-1.0 Approved - 26 Aug 2020 GMT-5:00


Clinical Study Protocol 
 
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 Page 75 of 130 
CONFIDENTIAL 
Study Week 
Year 1 Treatment (52 weeks) 
Follow-up 
End of Study 
Phone Call 
Week 40 
Week 44 
Week 48 
EOT24/  
Week 52 
Early 
Termination 
/JR Pre-
operative1 
Week 56 
Week 72 
Early 
Termination 
/JR Pre-
operative1  
Week 100 
Study Day 
281 
309 
337 
365 
393 
505 
701 
Visit window (days) 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Visit Number 
Visit 14 
Visit 15 
Visit 16 
Visit 17 
Visit 18 
Visit 19 
Phone 2 
Concomitant therapies 
(medications and 
procedures) 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient-Completed Assessments/Efficacy: 23  
 
WOMAC7 
X 
X 
X 
X 
X 
X 
X 
X 
 
PGA 
X 
X 
X 
X 
X 
X 
X 
X 
 
NRS8 
X 
X 
X 
X 
X 
 
 
 
 
SF-36 
X 
 
 
X 
X 
 
X 
X 
 
EQ-5D-5L 
X 
 
 
X 
X 
 
X 
X 
 
HCRU 
 
 
 
X 
X 
 
 
 
 
WPAI-OA 
X 
 
 
X 
X 
 
 
 
 
TSQM 
X 
 
 
X 
X 
 
 
 
 
Safety:   
 
Weight 
 
 
 
X 
X 
 
X 
X 
 
Vital signs9 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical examination 
 
 
 
X 
X 
 
X 
X 
 
Orthostatic blood pressure 
and heart rate assessment9,10 
X 
X 
X 
X 
X 
X 
X 
X 
 
Joint pain questionnaire23 
X 
X 
X 
X 
X 
X 
X 
X 
 
Survey of autonomic 
symptoms23 
X 
X 
X 
X 
X 
X 
X 
X 
 
Neurologic examination 
X-BRIEF 
X-BRIEF 
X-BRIEF 
X-FULL 
X-FULL 
X-BRIEF 
X-FULL 
X-FULL 
 
Adverse events 
--------------------------------------------------------------------------------------------------------------------------------------------→ 
 
Injection site evaluation 
X 
X 
X 
 
 
 
 
 
 
Electrocardiogram 
 
 
 
X 
X 
 
 
 
 
Bilateral x-rays (knee, hip, 
shoulder) 
 
 
 
X 
X 
 
X 
X 
 
Event-triggered imaging13 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pre-op questionnaire (JR 
follow-up)14 
 
 
 
 
X 
 
 
X 
 
                                        VV-RIM-00122598-1.0 Approved - 26 Aug 2020 GMT-5:00


Clinical Study Protocol 
 
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 Page 76 of 130 
CONFIDENTIAL 
Study Week 
Year 1 Treatment (52 weeks) 
Follow-up 
End of Study 
Phone Call 
Week 40 
Week 44 
Week 48 
EOT24/  
Week 52 
Early 
Termination 
/JR Pre-
operative1 
Week 56 
Week 72 
Early 
Termination 
/JR Pre-
operative1  
Week 100 
Study Day 
281 
309 
337 
365 
393 
505 
701 
Visit window (days) 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Visit Number 
Visit 14 
Visit 15 
Visit 16 
Visit 17 
Visit 18 
Visit 19 
Phone 2 
End of study phone contact21 
 
 
 
 
 
 
 
 
X 
MRI of affected joint(s) for 
AA patients only22 
 
 
 
 
 
 
 
 
X 
Laboratory Testing:  
 
 
 
 
 
Hematology15 
 
 
 
X 
X 
 
X 
X 
 
Blood chemistry15 
 
 
 
X 
X 
 
X 
X 
 
Pregnancy test (for 
WOCBP)17  
X-  
Urine 
X- 
Urine 
X- 
Urine 
X – 
Urine 
X-  
Urine 
X-  
Urine 
X-  
Urine 
X-  
Urine 
 
Urinalysis and urine 
electrolytes15 
 
 
 
X 
X 
 
X 
X 
 
PK, Antibody, and Research Sampling:  
 
 
 
 
 
 
PK sample18 
 
 
 
X 
X 
X 
X 
X 
 
ADA sample18 
 
 
 
X 
X 
 
X 
X 
 
Hs-CRP samples18,19 
 
 
 
X 
X 
 
X 
X 
 
Research serum/plasma 
sample18, 19 
 
 
 
X 
X 
 
X 
X 
 
Genomic sub-study sample 
(optional)20 
 
 
 
 
 
 
 
 
 
ADA: Anti-drug antibody 
NRS: Numeric Rating Scale 
EOT: End of Treatment 
PGA: Patient Global Assessment 
EQ-5D-5L: EuroQoL 5 Dimensions 5 Level Questionnaire 
PK: Pharmacokinetic 
ESR: Erythrocyte sedimentation rate 
SC: Subcutaneous 
FSH: Follicle stimulating hormone 
SF-36: 36-item Short Form Survey 
HbA1c: Glycated hemoglobin 
TSQM: Treatment Satisfaction Questionnaire for Medication 
HCRU: Healthcare Resource Utilization 
WOCBP: Women of child-bearing potential 
hs-CRP: High-sensitivity C-reactive protein 
WOMAC: Western Ontario and McMaster Osteoarthritis Index 
JR: Joint replacement 
WPAI-OA: Work Productivity and Activity Impairment-Osteoarthritis 
MRI: Magnetic resonance imaging 
 
                                        VV-RIM-00122598-1.0 Approved - 26 Aug 2020 GMT-5:00


Clinical Study Protocol 
 
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 Page 77 of 130 
CONFIDENTIAL 
8.1.1. 
Footnotes for the Schedule of Events Table 1 (Year 1) 
1. Patients who discontinue study drug before week 52 will be encouraged to follow the visit schedule 
through the remainder of the study.  If a patient chooses to end study participation, he/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 
administered after all laboratory, PK, ADA and research samples have been collected and all study 
related activities have been performed. Patients will be observed in the clinic for approximately 1 
hour after SC study drug is administered. 
6. Use of study-provided rescue medication will be recorded daily in patient diaries.  
Acetaminophen/paracetamol use will be reported from pre-randomization visit to week 52. 
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 the 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 52. Walking index joint pain NRS score 
will be recorded by the patient at the site at the week 52 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. An MRI will be performed on the index and contralateral joints at screening for all patients.  In 
addition, an MRI will be performed on any knee or hip with a K-L of ≥3.  
                                        VV-RIM-00122598-1.0 Approved - 26 Aug 2020 GMT-5:00


Clinical Study Protocol 
 
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 Page 78 of 130 
CONFIDENTIAL 
13. Imaging (X-ray and possible 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. 
14. In the event that a patient must undergo JR surgery during the study, the patient must complete the 
pre-operative study visit (early termination assessments, as applicable) and the procedures outlined 
in the schedule of events for JR follow-up (Table 3).  This will include a Knee Society Score 
questionnaire for knee replacements or Harris Hip Score questionnaire for hip replacements.  The 
pre-operative visit must be completed before the JR surgery. Pre-operative images will be 
submitted to the adjudication committee for review. 
15. Samples will be analyzed by the central laboratory and results evaluated by the investigator. 
16. Assessment of follicle-stimulating hormone (FSH) and estradiol levels are only to be performed if 
assessment of postmenopausal status is required (ie, for female patients ≤59 years of age). 
17. In the event of a positive urine pregnancy test result, the patient should have a serum pregnancy 
test with a negative result in order to continue study drug.  If the serum pregnancy test is positive, 
the patient should be withdrawn from study drug and should be asked to return to the clinic for all 
remaining study visits per the visit schedule (see Section 8.2.3.11). 
18. 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.  
19. Research samples should be collected after an overnight (minimum 8 hours) fast. 
20. Only for patients who provide written informed consent for the optional genomics sub-study.  The 
sample should be collected at the baseline visit but may be collected at any subsequent visit during 
the study.  
21. 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 should be submitted to the central reader for 
adjudication, if available. 
22. If the affected joint has undergone JR an X-ray may be substituted from an MRI. 
23. Patient-reported outcome measures should be completed first at a study visit, prior to any clinical 
assessments and procedures (eg, blood draws, ECGs, study drug administration). 
24. Patients who end treatment early but agree to follow/continue to attend regular study visits do not 
complete the assessments associated with EOT/week 52 at the time they end treatment.  Instead, 
they complete assessments associated with the study visit they are attending at the time they end 
treatment early.
                                        VV-RIM-00122598-1.0 Approved - 26 Aug 2020 GMT-5:00


Clinical Study Protocol 
 
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 Page 79 of 130 
CONFIDENTIAL 
Table 2: 
Schedule of Events for Year 2 
(Only to be followed by patients who participate in Year 2 after they have completed through week 52 [ie, the week 52 visit] in Year 1). 
Study Week 
Year 2 Treatment (52 weeks) 
Week 
52E17 
Week 
56E 
Week 
60E 
Week 
64E 
Week 
68E 
Week 
72E 
Week 
76E 
Week 
80E 
Week 
84E 
Week 
88E 
Week 
92E 
Week 
96E 
Week 
100E 
EOT15 
Week 
104E 
Study Day  
365E 
393E 
421E 
449E 
477E 
505E 
533E 
561E 
589E 
617E 
645E 
673E 
701E 
729E 
Visit Window (days) 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Visit Number 
Visit  
17E 
Visit  
18E 
Visit  
19E 
Visit  
20E 
Visit  
21E 
Visit  
22E 
Visit  
23E 
Visit  
24E 
Visit   
25E 
Visit   
26E 
Visit  
27E 
Visit   
28E 
Visit 
29E 
Visit 
30E 
Screening/Baseline: 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
SC study drug injection2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense 
acetaminophen/paracetamol 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Acetaminophen/paracetamol 
accountability 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense oral study drug 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Oral study drug 
accountability  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Recording of rescue 
medication use in diary3 
 
X 
X 
X 
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 
Patient-Completed Assessments/Efficacy4 
WOMAC5 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
EQ-5D-5L 
 
 
 
X 
 
 
X 
  
 
X 
 
 
 
X 
WPAI-OA 
 
 
 
X 
 
 
X 
  
 
X 
 
 
 
X 
Safety: 
 
Weight 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Vital signs6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
                                        VV-RIM-00122598-1.0 Approved - 26 Aug 2020 GMT-5:00


Clinical Study Protocol 
 
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Regeneron Pharmaceuticals, Inc. 
 
 Page 80 of 130 
CONFIDENTIAL 
Study Week 
Year 2 Treatment (52 weeks) 
Week 
52E17 
Week 
56E 
Week 
60E 
Week 
64E 
Week 
68E 
Week 
72E 
Week 
76E 
Week 
80E 
Week 
84E 
Week 
88E 
Week 
92E 
Week 
96E 
Week 
100E 
EOT15 
Week 
104E 
Study Day  
365E 
393E 
421E 
449E 
477E 
505E 
533E 
561E 
589E 
617E 
645E 
673E 
701E 
729E 
Visit Window (days) 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Visit Number 
Visit  
17E 
Visit  
18E 
Visit  
19E 
Visit  
20E 
Visit  
21E 
Visit  
22E 
Visit  
23E 
Visit  
24E 
Visit   
25E 
Visit   
26E 
Visit  
27E 
Visit   
28E 
Visit 
29E 
Visit 
30E 
Orthostatic blood pressure 
and heart rate assessment6,7 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Joint pain questionnaire4 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Survey of autonomic 
symptoms4 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neurologic examination 
 
X-
BRIEF 
X-
BRIEF 
X-
BRIEF 
X-
BRIEF 
X-
BRIEF 
X-
BRIEF 
X- 
BRIEF 
X- 
BRIEF 
X- 
BRIEF 
X- 
BRIEF 
X- 
BRIEF 
X- 
BRIEF 
X- 
FULL 
Adverse events 
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------→ 
Injection site evaluation 
X 
X 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Electrocardiogram 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Bilateral x-rays (knee, hip, 
shoulder) 
 
 
 
 
 
 
X 
 
 
 
 
 
  
X  
Event-triggered imaging8 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pre-op questionnaire (JR 
follow-up)9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Testing:  
Hematology10 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Blood chemistry10 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Pregnancy test (for 
WOCBP)11 
 
X-  
Urine 
X-  
Urine 
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 
electrolytes10 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
PK, Antibody, and Research Sampling: 
PK sample12 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
ADA sample12 
  
 
 
  
 
 
X 
 
 
  
 
 
  
X 
hs-CRP sample12,13 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Research serum/plasma 
sample12, 13 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
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Table 2: 
Schedule of Events for Year 2 (continued) 
Study Week 
Year 2 Treatment 
(52 weeks) 
Follow-up 
End of Study Phone Call 
Early Termination/ 
JR Preoperative E1 
 
Week 108E 
Week 124E 
Early Termination/ 
JR Preoperative E1 
 
Week 152E 
Study Day  
757E 
869E 
1065E 
Visit Window (days) 
±7 
±7 
±7 
Visit Number 
Visit 31E 
Visit 32E 
Phone 2E 
Screening/Baseline: 
Inclusion/Exclusion 
 
 
 
 
 
Informed consent 
 
 
 
 
 
Treatment 
SC study drug injection2 
 
 
 
 
 
Dispense acetaminophen/paracetamol 
 
 
 
 
 
Acetaminophen/paracetamol accountability 
X 
 
 
 
 
Dispense oral study drug 
 
 
 
 
 
Oral study drug accountability  
X 
 
 
 
 
Recording of rescue medication use in diary3 
X 
 
 
 
 
Concomitant therapies (medications and procedures) 
X 
X 
X 
X 
 
Patient-Completed Assessments/Efficacy4 
WOMAC5 
X 
X 
X 
X 
 
EQ-5D-5L 
X 
 
 
 
 
WPAI-OA 
X 
 
 
 
 
Safety: 
 
Weight 
X 
 
X 
X 
 
Vital signs6 
X 
X 
X 
X 
 
Physical examination 
X 
 
X 
X 
 
Orthostatic blood pressure and heart rate 
assessment6,7 
X 
X 
X 
X 
 
Joint pain questionnaire4 
X 
X 
X 
X 
 
Survey of autonomic symptoms4 
X 
X 
X 
X 
 
Neurologic examination 
X-FULL 
X-BRIEF 
X-FULL 
X-FULL 
 
Adverse events 
----------------------------------------------------------------------------------------------------------→ 
 
Injection site evaluation 
 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
Bilateral x-rays (knee, hip, shoulder) 
X 
 
X 
X 
 
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Study Week 
Year 2 Treatment 
(52 weeks) 
Follow-up 
End of Study Phone Call 
Early Termination/ 
JR Preoperative E1 
 
Week 108E 
Week 124E 
Early Termination/ 
JR Preoperative E1 
 
Week 152E 
Study Day  
757E 
869E 
1065E 
Visit Window (days) 
±7 
±7 
±7 
Visit Number 
Visit 31E 
Visit 32E 
Phone 2E 
Event-triggered imaging8 
X 
X 
X 
X 
 
Pre-op questionnaire (JR follow-up)9 
X 
 
 
X 
 
End of study phone contact14 
 
 
 
 
X 
MRI of affected joint(s) for AA patients only16 
 
 
 
 
X 
Laboratory Testing:  
Hematology10 
X 
 
X 
X 
 
Blood chemistry10 
X 
 
X 
X 
 
Pregnancy test (for WOCBP)11 
X-Urine 
X-Urine 
X-Urine 
X-Urine 
 
Urinalysis and urine electrolytes10 
X 
 
X 
X 
 
PK, Antibody, and Research Sampling: 
PK sample12 
X 
X 
 
X 
 
ADA sample12 
X 
 
X 
X 
 
hs-CRP sample12,13 
X 
 
X 
X 
 
Research serum/plasma sample12,13 
X 
 
X 
X 
 
ADA: Anti-drug antibody 
MRI: Magnetic resonance imaging 
EOT: End of Treatment 
PK: Pharmacokinetic 
EQ-5D-5L: EuroQoL 5 Dimensions 5 Level Questionnaire 
SC: Subcutaneous 
hs-CRP: High-sensitivity C-reactive protein 
WOCBP: Women of child-bearing potential 
JR: Joint replacement 
WPAI-OA: Work Productivity and Activity Impairment-Osteoarthritis 
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8.1.2. 
Footnotes for the Schedule of Events Table 2 (Year 2) 
1. Patients who discontinue study drug before week 104 will be encouraged to follow the visit 
schedule through the remainder of the study.  If a patient chooses to end study participation, he/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. Subcutaneous study drug administration will be the last procedure at each dosing visit and will be 
administered after all laboratory, PK, ADA, and research samples have been collected and all study-
related activities have been performed.  Patients will be observed in the clinic for approximately 1 
hour after SC study drug is administered. 
3. Use of study-provided rescue medication will be recorded daily in patient diaries.  
Acetaminophen/paracetamol use will be reported from pre-randomization visit to week 104. 
4. Patient-reported outcome measures should be completed prior to any clinical assessments (eg, 
blood draws, ECGs, study drug administration). 
5. The WOMAC Full Survey will be completed for the index joint. 
6. If the pulse is less than 45 bpm, an ECG with rhythm strip will be obtained to confirm the heart 
rate and rhythm. 
7. 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. 
8. Imaging (X-ray and possible 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. 
9. In the event that a patient must undergo JR surgery during the study, the patient must complete the 
pre-operative study visit (early termination assessments, as applicable) and the procedures outlined 
in the schedule of events for JR follow-up (Table 3).  This will include a Knee Society Score 
questionnaire for knee replacements or Harris Hip Score questionnaire for hip replacements.  The 
pre-operative visit must be completed before the JR surgery.  Pre-operative images will be 
submitted to the adjudication committee for review. 
10. Samples will be analyzed by the central laboratory and results evaluated by the investigator. 
11. In the event of a positive urine pregnancy test result, the patient should have a serum pregnancy 
test with a negative result in order to continue study drug.  If the serum pregnancy test is positive, 
the patient should be withdrawn from study drug and should be asked to return to the clinic for all 
remaining study visits per the visit schedule (see Section 8.2.3.11). 
12. 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 
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safety TEAE.  Samples should be collected prior to SC study drug administration on SC study drug 
dosing days.  
13. Research samples should be collected after an overnight (minimum 8 hours) fast. 
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 should be submitted to the central reader for 
adjudication, if available. 
15. Patients who end treatment early but agree to follow/continue to attend regular study visits do not 
complete the assessments associated with EOT/week 104E at the time they end treatment.  Instead, 
they complete assessments associated with the study visit they are attending at the time they end 
treatment early. 
16. If the affected joint has undergone JR, an X-ray may be substituted for an MRI. 
17. The week 52E Year 2 visit should occur on the same day as the week 52 Year 1 visit, but could 
occur at any time during the visit window. 
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Table 3: 
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 exam 
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 
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8.1.3. 
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. 
8.1.4. 
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 or Table 2, as applicable).  
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. 
8.1.5. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule.  Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for any 
other reason, as warranted. 
8.2. 
Study Procedures 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed at the screening visit for the sole purpose of 
determining study eligibility or characterizing the baseline population:  
8.2.1.1. 
Informed Consent 
All patients must sign and date the Institutional Review Board (IRB)/ Ethics Committee 
(EC)-approved written ICF before any study procedures are performed, per Section 14.2. 
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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 naproxen. 
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: 
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. 
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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) (Section 8.2.3.11). 
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 Section 8.1. 
A copy of the survey is provided in the study reference manual.  
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 reasons. Retraining should occur as needed throughout the conduct of the 
study. 
8.2.1.9. 
Patient Education Brochures 
At the screening and pre-randomization visits, study staff will review the “Participating in a 
Research Study: What You Need to Know” brochure and the “Reporting Your Pain” brochure 
with patients to ensure they understand what a clinical study is and how to report their pain 
accurately. At subsequent visits, patients will be asked to review the ‘Reporting Your Pain’ 
brochure themselves.  At any time during the conduct of the study, patients may require retraining 
by study staff. 
8.2.2. 
Efficacy Procedures  
All the measures in this section are patient-reported outcome measures and should be completed 
before any clinical assessments. 
8.2.2.1. 
Western Ontario and McMaster Universities Osteoarthritis Index 
The WOMAC index is used to assess patients with OA of the hip or knee using 24 parameters, and 
reported using a numerical rating scale.  This index can be used to monitor the course of a disease 
or to determine effectiveness of study drugs.  Patients will complete the WOMAC Full Survey at 
the time points indicated in Table 1 and Table 2.  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. 
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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 52.  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. 
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 and Table 2. 
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. 
Healthcare Resource Utilization Questionnaire 
The Healthcare Resource Utilization 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 physician office visits.  Sites will complete the 
questionnaire at time points indicated in Table 1.  The overall healthcare resource use will be 
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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.  
8.2.2.7. 
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 and Table 2. 
A copy of the assessment is provided in the study reference manual. 
8.2.2.8. 
Treatment Satisfaction Questionnaire for Medication 
The Treatment Satisfaction Questionnaire for Medication (TSQM) 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. 
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 and Table 2.  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 and Table 2.  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 and Table 2. 
8.2.3.3. 
Electrocardiogram 
A standard 12-lead ECG will be performed at the time points indicated in Table 1 and Table 2, 
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. 
8.2.3.4. 
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 and Table 2.  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: 
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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. 
8.2.3.5. 
Joint Pain Questionnaire 
A joint pain questionnaire will be completed by the patient at the time points indicated in Table 1 
and Table 2.  For each knee, hip, and shoulder joint, the patient will be prompted to indicate if he 
or she has experienced pain.  A patient report of having experienced pain will serve as a tool to 
prompt further evaluations as deemed necessary by the investigator. 
Joint Pain Questionnaire is a patient-reported outcome measure and should be completed along 
with other patient-reported outcome measures but before any clinical assessments. 
A copy of the assessment is provided in the study reference manual. 
8.2.3.6. 
Survey of Autonomic Symptoms 
Signs and symptoms of autonomic dysfunction will be assessed by the investigator at time points 
indicated in Table 1 and Table 2.  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. 
Survey of Autonomic Symptoms is a patient-reported outcome measure and should be completed 
along with other patient-reported outcome measures but before any clinical assessments. 
A copy of the survey is provided in the study reference manual. 
8.2.3.7. 
Neurologic Examination 
A full or a brief neurological examination will be performed at the time points indicated in Table 1 
and Table 2.  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. 
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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. 
8.2.3.8. 
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 and Table 2.  An MRI of the index and contralateral joints 
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 an MRI must 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 
During screening, MRIs of the index and contralateral joints as well as joints with a K-L score ≥3 
will be sent to a central reader to confirm that there is no evidence of an exclusionary features.  
Confirmation that there are no exclusionary findings on MRI must be received before a patient can 
be randomized.  An MRI of any joint will be considered if radiographs taken after randomization 
suggest the presence of an abnormal process inconsistent with normal progression of OA, as 
determined by the investigator or central reader. 
At the end of study phone contact, patients who had an AA will have an MRI performed of the 
affected joint(s). If the affect joint has undergone JR an X-ray may be substituted for an MRI. 
Refer to the supplemental imaging manuals for data collection and management procedures. 
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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 (Table 3). 
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 the results of histopathologic examination. 
Full details of these assessments are provided in the study reference manual. 
Knee Society Score 
The Knee Society Score is an investigator-completed questionnaire that is used to objectively 
measure a patient’s ability to function before and after total knee arthroplasty (Insall 1989).  If 
possible, the assessment should be completed by the same person throughout the study. 
Harris Hip Score 
The Harris Hip Score is an investigator-completed questionnaire that is used to objectively 
measure a patient’s ability to function before and after total hip arthroplasty (Harris 1969).  If 
possible, the assessment should be completed by the same person throughout the study. 
8.2.3.11. 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 development, and pharmacogenetic sample assessments; the central laboratory will ship 
the samples to Regeneron or a specialty laboratory depending on the assessment. 
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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 time points according to Table 1 and Table 2. 
Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin 
Potassium 
Creatinine 
Phosphorus 
Chloride 
Blood urea nitrogen (BUN) 
Uric acid 
Carbon dioxide 
Aspartate aminotransferase (AST) 
Creatine phosphokinase (CPK) 
Calcium 
Alanine aminotransferase (ALT) 
 
Glucose 
Alkaline phosphatase (ALP) 
 
Albumin 
Lactate dehydrogenase (LDH) 
 
Hematology 
Hemoglobin 
Differential: 
Hematocrit 
Neutrophils 
Red blood cells (RBCs) 
Lymphocytes 
White blood cells (WBCs) 
Monocytes 
Red cell indices 
Basophils 
Platelet count 
Eosinophils 
Urinalysis 
Color 
Glucose 
RBC 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBC 
Yeast 
Urine Electrolytes 
Creatinine 
 
 
Phosphorus 
 
 
Other Laboratory Tests 
Serum and urine samples for pregnancy testing will be collected from women of childbearing 
potential (as defined in Section 8.2.1.6) at time points according to Table 1 and Table 2.  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 drug.  If the serum pregnancy 
test is positive, the patient should be withdrawn from study drug and should be asked to return to 
the clinic for all remaining study visits per the visit schedule (see Table 1 and Table 2). 
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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 an 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 drug or its administration, the medical monitor must be consulted. 
• The clinical significance of an abnormal test value, within the context of the disease 
under study, must be determined by the investigator. 
Criteria for reporting laboratory values as an AE are provided in Section 9.4.5.  Evaluation of 
severity of laboratory abnormalities will be assessed according to the scale outlined in 
Section 9.5.1. 
8.2.3.12. Injection Site Evaluations 
An injection site evaluation should be conducted following the injection at each doing visit, 
according to Table 1 and Table 2. 
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 and Table 2.  
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 and Table 2.  
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 and Table 2.  
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 
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markers of collagen and bone turnover, OA and pain. If necessary, samples may also be used to 
identify markers associated with AEs. 
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. 
8.2.5.3. 
Genomics Sub-study - Optional 
Patients who agree to participate in the genomics sub-study will be required to sign a separate 
genomics sub-study ICF before collection of the samples.  Patients are not required to participate 
in the genomics sub-study in order to enroll in the primary study.  Samples for DNA extraction 
should be collected on day 1/baseline (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 
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 (suspected unexpected serious 
adverse reaction [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 unexpected.  Any worsening of or new onset of symptoms related to OA, which occurs 
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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 it is considered related to the 
study drug. 
An AE also includes any worsening (ie, any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug. 
9.3.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death – includes all deaths, even those that appear to be completely unrelated 
to study drug (eg, a car accident in which a patient is a passenger). 
• Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event.  This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
• Requires in-patient hospitalization or prolongation of existing hospitalization.  
In-patient hospitalization is defined as admission to a hospital or an emergency room 
for longer than 24 hours.  Prolongation of existing hospitalization is defined as a 
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. 
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9.3.3. 
Adverse Events of Special Interest 
An adverse event of special interest (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 patient completes the follow-up period, ie, week 72/early termination for those 
patients not proceeding into Year 2, or week 124E/early termination for those patients proceeding 
into Year 2.  Refer to the study reference manual for the procedures to be followed. 
Information on follow-up for AEs is provided in Section 9.4.6.  Laboratory, vital signs, or ECG 
abnormalities are to be recorded as AEs as outlined in Section 9.4.5. 
9.4.2. 
Serious Adverse Events 
All SAEs, regardless of assessment of causal relationship to study drug, must be reported to the 
sponsor (or designee) within 24 hours.  Refer to the study reference manual for the procedure to 
be followed. 
Information not available at the time of the initial report must be documented in a follow-up report.  
Substantiating data such as relevant hospital or medical records and diagnostic test reports may 
also be requested. 
In the event the investigator is informed of an SAE after the patient completes the follow-up period, 
ie, week 72/early termination for those patients not proceeding into Year 2, or week 124E/early 
termination for those patients proceeding into Year 2, the following will apply: 
• SAE with an onset within 30 days of the end of the follow-up period - the SAE will be 
reported to the sponsor.  The investigator should make every effort to obtain follow-up 
information on the outcome until the event is considered chronic and/or stable. 
• SAE with an onset day greater than 30 days from the end of follow-up period - only 
SAEs deemed by the investigator to be drug-related SAEs will be reported to the 
sponsor.  The investigator should make every effort to obtain follow-up information on 
the outcome of a drug-related SAE until the event is considered chronic and/or stable. 
• SAE reported by the patient at the end of the study phone call and deemed by the 
investigator to be drug related will be reported to the sponsor.  The investigator should 
make every effort to obtain follow-up information on the outcome of a drug-related 
SAE until the event is considered chronic and/or stable. 
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9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of learning 
of the event: 
Symptomatic Overdose of Study Drug: 
Accidental or intentional overdose of at least 2 times 
the intended dose of study drug within the intended therapeutic window, if 
associated with an AE  
Pregnancy: 
Although pregnancy is not considered an AE, it is the responsibility of the 
investigator to report to the sponsor (or designee), within 24 hours of identification, 
any pregnancy occurring in a female study subject during the study or within 20 
weeks of the last dose of study drug.  Any complication of pregnancy affecting a 
female study subject 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.  Monitoring of AESIs is described in Section 9.6.1.  
Events considered AESIs are: 
• Adjudicated arthropathy (as confirmed by adjudication)  
• Joint replacement surgery (refer to Section 9.6.1.4 for when to report as an AESI) 
• Sympathetic nervous system dysfunction (as diagnosed after consultation with an 
appropriate specialist, such as a neurologist and/or cardiologist) 
• Peripheral sensory AEs that require a neurology or other specialty consultation 
Refer to the study manual for the procedures to be followed. 
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 
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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: 
• Mild:  Does not interfere in a significant manner with the patient normal functioning 
level.  It may be an annoyance.  Prescription drugs are not ordinarily needed for relief 
of symptoms, but may be given because of personality of the patient. 
• Moderate:  Produces some impairment of functioning but is not hazardous to health.  
It is uncomfortable or an embarrassment.  Treatment for symptom may be needed. 
• Severe:  Produces significant impairment of functioning or incapacitation and is a 
definite hazard to the subject’s health.  Treatment for symptom may be given and/or 
patient hospitalized. 
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
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 ER visit or hospitalization; necrosis or exfoliative dermatitis. 
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9.5.2. 
Evaluation of Causality  
9.5.2.1. 
Relationship of Adverse Events to Study Drug 
The relationship of AEs to study drug will be assessed by the blinded investigator, and will be a 
clinical decision based on all available information.  The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by the study drug? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by the study 
drug. 
Related: 
There is a reasonable possibility that the event may have been caused by the study 
drug. 
The investigator should justify the causality assessment of each SAE. 
A list of factors to consider when assessing the relationship of AEs to study drug is provided below.  
Please note that this list is not exhaustive. 
Is there a reasonable possibility that the event may have been caused by the study drug? 
No: 
• due to external causes such as environmental factors or other treatment(s) being 
administered 
• due to the patient’s disease state or clinical condition 
• do not follow a reasonable temporal sequence following the time of administration of 
the dose of study drug 
• do not reappear or worsen when dosing with study drug is resumed  
Yes: 
• could not be explained by environmental factors or other treatment(s) being 
administered 
• 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 
9.5.2.2. 
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: 
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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 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 conduct? 
No: 
• due to external causes such as environmental factors or other treatment(s) being 
administered 
• due to the patient’s disease state or clinical condition 
• do not follow a reasonable temporal sequence following the course of the study. 
• do not reappear or worsen when dosing with study participation is resumed 
Yes: 
• could not be explained by environmental factors or other treatment(s) being 
administered 
• could not be explained by the patient’s disease state or clinical condition 
• follow a reasonable temporal sequence following the course of the study. 
• resolve or improve after discontinuation from study participation. 
• reappear or worsen when study participation is resumed 
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. 
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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 characterized as a 
worsening of pain in any joint that occurs in spite of treatment with analgesics, is in the opinion of 
the investigator inconsistent with the normal 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 8.2.3.8).  A decision to 
perform imaging after patient reporting of worsening 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 terminated for patients with findings that suggest AA, and the patients 
will be referred for orthopedic consultation.  If presence of AA is confirmed by the adjudication 
committee, the case must be reported as an AESI (Section 9.3.3 and Section 9.4.3).  
Any patient whose study drug is discontinued due to an AA should be encouraged to return to the 
clinic for all remaining study visits.  Prior to the scheduled JR, the patient should complete the 
pre-operative study visit (Section 8.2.3.10) and, after the JR, should complete the week 4 and 
week 20 post-operative study visits (Table 3).  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. 
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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 8.2.3.6).  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 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 electronic CRF (eCRF.).  The following procedures should be followed: 
• If the patient is symptomatic and a clinical explanation for orthostatic hypotension is 
identified (such as a new medication or dehydration due to exercise or illness or 
excessive heat exposure), study drug will be withheld, and the patient should return to 
the study site for an unscheduled visit in 1 to 10 days for an unscheduled assessment 
of orthostatic hypotension. 
− If the orthostatic hypotension has resolved, study drug may be restarted. 
− If the orthostatic hypotension has not resolved, then study drug will be withheld, 
and the patient will be referred to a specialist (neurologist or a cardiologist) for 
evaluation of sympathetic nervous system dysfunction. 
− If the specialist’s evaluation does not reveal new onset 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. 
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− 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). 
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 
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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 1. 
10.1. 
Statistical Hypothesis 
There are 29 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 graphical testing 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 two sets of hypotheses (H1,i, 
i=1,…,16 for fasinumab 1 mg Q4W, and H2,i, i=1,…,13 for fasinumab 1 mg Q8W) for the primary 
and key secondary endpoints.  If a hypothesis is rejected, the alpha level for that hypothesis will 
be reallocated to other hypothesis according to a 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.  
• H1,1: There is no treatment difference between fasinumab 1 mg Q4W and placebo in 
WOMAC pain or physical function subscale scores at week 16 versus there is treatment 
difference in WOMAC pain and physical function subscale scores at week 16 
• H1,2: There is no treatment difference between fasinumab 1 mg Q4W and placebo in 
Patient Global Assessment score at week 16 versus there is treatment difference in 
Patient Global Assessment score at week 16 
• H1,3: 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 16 versus there is treatment difference in proportion of patients with 
≥30% improvement in WOMAC pain at week 16 
• H1,4: There is no treatment difference between fasinumab 1 mg Q4W and naproxen in 
the WOMAC pain subscale scores at week 16 versus there is treatment difference in 
WOMAC pain subscale scores at week 16 
• H1,5: There is no treatment difference between fasinumab 1 mg Q4W and naproxen in 
the WOMAC physical function subscale scores at week 16 versus there is treatment 
difference in WOMAC physical function subscale scores at week 16 
• H1,6: There is no treatment difference between fasinumab 1 mg Q4W and placebo in 
WOMAC pain subscale scores at week 44 versus there is treatment difference in 
WOMAC pain subscale scores at week 44 
• H1,7: There is no treatment difference between fasinumab 1 mg Q4W and placebo in 
WOMAC physical function subscale scores at week 44 versus there is treatment 
difference in WOMAC physical function subscale scores at week 44 
• H1,8: There is no treatment difference between fasinumab 1 mg Q4W and placebo in 
Patient Global Assessment score at week 44 versus there is treatment difference in 
Patient Global Assessment score at week 44 
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• H1,9: There is no treatment difference between fasinumab 1 mg Q4W and naproxen in 
Patient Global Assessment score at week 16 versus there is treatment difference in 
Patient Global Assessment score at week 16 
• H1,10: There is no treatment difference between fasinumab 1 mg Q4W and placebo in 
the WOMAC pain subscale scores averaged across weeks 4, 8, 12 and 16 versus there 
is treatment difference in the WOMAC pain subscale scores averaged across weeks 4, 
8, 12 and 16 
• H1,11: There is no treatment difference between fasinumab 1 mg Q4W and placebo in 
the WOMAC physical function subscale scores averaged across weeks 4, 8, 12 and 
16 versus there is treatment difference in the WOMAC physical function subscale 
scores averaged across weeks 4, 8, 12 and 16  
• H1,12: There is no treatment difference between fasinumab 1 mg Q4W and placebo in 
the WOMAC pain subscale scores averaged across weeks 36, 40 and 44, versus there 
is treatment difference in the WOMAC pain subscale scores averaged across weeks 36, 
40 and 44 
• H1,13: There is no treatment difference between fasinumab 1 mg Q4W and placebo in 
the WOMAC physical function subscale scores averaged across weeks 36, 40 and 44, 
versus there is treatment difference in the WOMAC physical function subscale scores 
averaged across weeks 36, 40 and 44,  
• H1,14: There is no treatment difference between fasinumab 1 mg Q4W and naproxen in 
WOMAC pain subscale scores at week 44 versus there is treatment difference in 
WOMAC pain subscale scores at week 44  
• H1,15: There is no treatment difference between fasinumab 1 mg Q4W and naproxen in 
WOMAC physical function subscale scores at week 44 versus there is treatment 
difference in WOMAC physical function subscale scores at week 44 
• H1,16: There is no treatment difference between fasinumab 1 mg Q4W and naproxen in 
the proportion of patients with ≥30% improvement in the WOMAC pain subscale 
scores at week 16 versus there is treatment difference in proportion of patients with 
≥30% improvement in WOMAC pain at week 16 
• H2,1: There is no treatment difference between fasinumab 1 mg Q8W and placebo in 
WOMAC pain or physical function subscale scores at week 16 versus there is treatment 
difference in WOMAC pain and physical function subscale scores at week 16 
• H2,2: There is no treatment difference between fasinumab 1 mg Q8W and placebo in 
Patient Global Assessment score at week 16 versus there is treatment difference in 
Patient Global Assessment score at week 16 
• H2,3: There is no treatment difference between fasinumab 1 mg Q8W and placebo in 
the proportion of patients with ≥30% improvement in the WOMAC pain subscale 
scores at week 16 versus there is treatment difference in proportion of patients with 
≥30% improvement in WOMAC pain at week 16 
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• H2,4: There is no treatment difference between fasinumab 1 mg Q8W and naproxen in 
the WOMAC pain subscale scores at week 16 versus there is treatment difference in 
WOMAC pain subscale scores at week 16 
• H2,5: There is no treatment difference between fasinumab 1 mg Q8W and naproxen in 
the WOMAC physical function subscale scores at week 16 versus there is treatment 
difference in WOMAC physical function subscale scores at week 16 
• H2,6: There is no treatment difference between fasinumab 1 mg Q8W and placebo in 
WOMAC pain subscale scores at week 44 versus there is treatment difference in 
WOMAC pain subscale scores at week 44 
• H2,7: There is no treatment difference between fasinumab 1 mg Q8W and placebo in 
WOMAC physical function subscale scores at week 44 versus there is treatment 
difference in WOMAC physical function subscale scores at week 44 
• H2,8: There is no treatment difference between fasinumab 1 mg Q8W and placebo in 
Patient Global Assessment score at week 44 versus there is treatment difference in 
Patient Global Assessment score at week 44 
• H2,9: There is no treatment difference between fasinumab 1 mg Q8W and naproxen in 
Patient Global Assessment score at week 16 versus there is treatment difference in 
Patient Global Assessment score at week 16 
• H2,10: There is no treatment difference between fasinumab 1 mg Q8W and placebo in 
the WOMAC pain subscale scores averaged across weeks 4, 8, 12 and 16 versus there 
is treatment difference in the WOMAC pain subscale scores averaged across weeks 4, 
8, 12 and 16 
• H2,11: There is no treatment difference between fasinumab 1 mg Q8W and placebo in 
the WOMAC physical function subscale scores averaged across weeks 4, 8, 12 and 
16 versus there is treatment difference in the WOMAC physical function subscale 
scores averaged across weeks 4, 8, 12 and 16  
• H2,12: There is no treatment difference between fasinumab 1 mg Q8W and placebo in 
the WOMAC pain subscale scores averaged across weeks 36, 40 and 44 versus there is 
treatment difference in the WOMAC pain subscale scores averaged across weeks 36, 
40 and 44  
• H2,13: There is no treatment difference between fasinumab 1 mg Q8W and placebo in 
the WOMAC physical function subscale scores averaged across weeks 36, 40 and 44 
versus there is treatment difference in the WOMAC physical function subscale scores 
averaged across weeks 36, 40 and 44 
10.2. 
Justification of FAS and mFAS Sample Sizes 
In this study, approximately 2560 patients were to be randomized to fasinumab 1 mg SC Q4W 
(840), fasinumab 1 mg SC Q8W (600), naproxen (840), or placebo (280) (see Section 5.1.3).  This 
sample size was expected to provide adequate power for the comparisons between fasinumab and 
naproxen at week 16 for the WOMAC pain and physical function scores and the PGA score and 
provide long term data for safety assessment. 
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The sample size for the full analysis set (FAS) population was based on results of the WOMAC 
pain and physical function subscale scores and the PGA from the R475-PN-1227 study.  The 
calculation of sample size assumed a 2-sided alpha level of 0.025 and a 15% dropout rate up to 
week 16 and a 30% dropout rate up to week 52.  Enrollment of 840 patients in the fasinumab 1 mg 
Q4W group and 280 patients in the placebo group would have provided at least 99% power to 
detect an effect size of 0.46 in the WOMAC pain and physical function subscale scores (ie, an 
absolute treatment difference of 1.1 between fasinumab and placebo and a standard deviation [SD] 
of 2.4 at week 16 and 52 for the FAS).  This sample size would have provided 99% power to detect 
an effect size of 0.36 in PGA for an absolute treatment difference of 0.4 with an SD of 1.1 at week 
16, and 98% power at week 52 for the FAS.  
For the fasinumab 1 mg Q8W group, the 600 patients in the FAS population were to be compared 
to approximately 200 patients in the placebo group who were enrolled after amendment 5 global 
was implemented.  For such comparisons, 2-sided alpha level of 0.025 and a 15% dropout rate up 
to week 16 and a 30% dropout rate up to week 52 were assumed. Additionally, the effect size for 
such comparisons was assumed to be 80% of the effect size for the comparison between fasinumab 
1 mg Q4W group and the placebo group. Under these assumptions, enrollment of 600 patients in 
the fasinumab 1 mg Q8W group and 200 patients from the placebo group would have provided 
97% power to detect an effect size of 0.368 (=0.46*80%) in the WOMAC pain and physical 
function subscale scores at week 16 and 93% power at week 52.  This sample size would have 
provided 84% power to detect an effect size of 0.288 (=0.36*80%) in PGA at week 16, and 75% 
power at week 52 for the FAS. 
The sample size calculation was also based on previously reported results of the WOMAC pain 
subscale and physical function subscale and the PGA for naproxen (Ekman 2014) 
(Schnitzer 2015).  Assuming a 2-sided alpha level of 0.025 and a 15% dropout rate up to week 16 
and a 30% dropout rate up to week 52, an enrollment of 840 patients in the fasinumab 1 mg Q4W 
group and the naproxen group would have provided at least 97% power to detect an effect size of 
0.22 in the WOMAC pain subscale (ie, an absolute treatment difference of 0.51 with an SD of 2.3) 
at week 16, and 92% power at week 52 for FAS.  This sample size would have provided 98% 
power to detect an effect size of 0.24 in WOMAC physical function subscale (ie, absolute 
treatment difference of 0.50 with an SD of 2.1) at week 16, and 96% power at week 52 for FAS.  
This sample size would have provided 87% power to detect an effect size of 0.18 in PGA at week 
16 between fasinumab 1 mg Q4W and naproxen for the FAS.  
Due to regional irregularities noted in a parallel phase 3 study that became fully apparent only after 
unblinding that study, and the concern that the same irregularities would be present in data from 
similar sites in this study, the population for the primary and secondary efficacy analyses was 
changed in Protocol Amendment 8 to be based on a modified full analysis set (mFAS) that excludes 
the randomization stratum for that region.  Based on the assumptions above, it is estimated that 
this mFAS will provide: 
• 99.9% power to detect a significant difference between the 1 mg Q4W group and the 
placebo group in the WOMAC pain and physical function subscales at an alpha level 
of 0.05 
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• 42% and 46% power to detect a significant difference between the 1 mg Q8W group 
and the placebo group in WOMAC pain and physical function subscales, respectively, 
at an alpha level of 0.01 
• 99.9% power to detect a significant difference between the 1 mg Q4W group and the 
naproxen group in the WOMAC pain and physical function subscales at an alpha level 
of 0.04 
10.3. 
Analysis Sets  
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: 
10.3.1. 
Full Analysis Set  
The FAS includes all randomized patients excluding patients affected by the urgent safety measure 
in May 2018 (ie, patients randomized to the 3 mg Q4W or 6 mg Q8W doses) and is based on the 
treatment allocated (as randomized).  Efficacy and patient reported outcome endpoints for Year 1 
will be analyzed using the FAS including patients randomized to fasinumab 1 mg Q4W, fasinumab 
1 mg Q8W, naproxen and placebo.  For the analyses of fasinumab 1 mg Q8W group comparing to 
the control groups, only patients concurrently randomized (ie, after Protocol R475-OA-1611 
Amendment 5 Global was implemented) will be included.  
10.3.2. 
Modified Full Analysis Set  
Due to regional irregularities noted in a parallel phase 3 study that became fully apparent only after 
unblinding that study, and the concern that the same irregularities would be present in data from 
similar sites from the same region in this study, the primary and secondary efficacy analyses will 
be performed on an mFAS.  This mFAS is comprised of the FAS excluding patients from the 
region of concern (Rest of the World stratum).  Efficacy and patient-reported outcome endpoints 
will be analyzed using the mFAS including patients randomized to fasinumab 1 mg Q4W, 
fasinumab 1 mg Q8W, naproxen, and placebo.  For the analysis of fasinumab 1 mg Q8W group 
comparing to the control groups, only the subset of patients concurrently randomized (ie, after 
Protocol R475-OA-1611 Amendment 5 Global was implemented) will be included.   
10.3.3. 
Per-Protocol Set (PPS) 
The per protocol set (PPS) includes all randomized patients from the mFAS who received all 
protocol-required doses during the 16-week treatment period for the week 16 analysis and who do 
not have to be excluded due to relevant protocol violations.  The PPS will be used to perform 
sensitivity analyses for the primary and selected secondary endpoints.  A list of protocol violations 
which lead to exclusion from the PPS and corresponding protocol deviation identification number 
(PDID) will be included in the SAP.  For the analysis of fasinumab 1 mg Q8W group comparing 
to the control groups, only patients concurrently randomized (ie, after Protocol R475-OA-1611 
Amendment 5 Global was implemented) will be included.   
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A PPS using the entire FAS is defined analogously to the above and will be used for performing 
sensitivity analysis on the entire FAS. 
10.3.4. 
Safety Analysis Set 
The Year 1 safety analysis set (SAF - Year 1) 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 for Year 1 will be analyzed using the 
SAF - Year 1 including patients randomized to fasinumab 1 mg Q4W, fasinumab 1 mg Q8W, 
naproxen, and placebo.  
The Year 2 safety analysis set (SAF - Year 2) includes all patients who received at least 1 dose of 
the Year 2 study drug; it is based on the treatment received during Year 2 (as treated).  Treatment 
compliance/administration and all clinical safety variables for Year 2 will be analyzed using this 
SAF – Year 2. 
10.3.5. 
Urgent Safety Measure Set 
The urgent safety measure set (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.  
10.3.6. 
Pharmacokinetic Analysis Set 
The PK analysis set includes all treated patients who had at least 1 non-missing drug concentration 
result following the first dose of study drug.  Patients will be analyzed according to the treatment 
actually received (as treated). 
10.3.7. 
Anti-Drug Antibody Analysis Set 
The ADA analysis set includes all treated 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 (as treated).  
10.3.8. 
The Neutralizing Antibody Set 
The NAb analysis set includes all patients who received any study drug and who are negative in 
the fasinumab ADA assay or with at least 1 non-missing result in the fasinumab NAb assay 
following the 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 (as 
treated). 
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 
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• 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. 
10.4.3. 
Efficacy Analyses 
10.4.3.1. Primary Efficacy Analysis 
The primary efficacy variables will be analyzed using multiple imputation approach with a 
mixed-effect model for repeated measure (MMRM) based on the mFAS with adjustment for 
missing data due to lack of efficacy, death or AEs assuming the WOMAC scores would on average 
return to baseline values. A monotone missing data structure will be achieved using the MCMC 
option of PROC MI. Data collected after discontinuing treatment up to week 16 will not be used 
in the primary efficacy analysis, but used in a treatment policy sensitivity analysis.  Multiple 
imputation for the remaining data will be based on the monotone missing data structure of the 
change from baseline scores using the regression imputation option in PROC MI.  The missing 
data for patients who discontinued treatment due to other reasons will be imputed under missing-
at-random assumption.  The imputed data for patients discontinued from the study treatment due 
to lack of efficacy, death or AEs will be centered at the mean baseline value.   
Missing data will be imputed 50 times to generate 50 complete data sets. Each imputed data set 
will be analyzed using the MMRM with terms for baseline score corresponding to the efficacy 
variable being analyzed, randomization strata (K-L category [2 to 3, or 4], index joint [knee, hip], 
and geographical region [North America, Europe]), treatment, 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 16, as well as the 
differences of the estimates between fasinumab and placebo, and between fasinumab and 
naproxen, with their corresponding standard errors, p values and associated 95% confidence 
intervals, will be provided.  
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Sensitivity analysis of the treatment policy estimand for the co-primary endpoints will be 
performed using similar analysis method as the primary efficacy analysis including data collected 
after discontinuing treatment up to week 16.  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). After each imputation, a fasinumab patient's imputed 
data will subtract  from the imputed score at each corresponding time point.  By progressively 
increasing , the sensitivity analysis will explore the tipping point, ie, the δ value when the p-value 
for a treatment comparison is above 0.05.  Additional analyses will be performed for the primary 
and secondary endpoints using the FAS.  Additional sensitivity analysis will be performed for the 
primary and select secondary endpoints using the PPS.  
10.4.3.2. Secondary Efficacy Analysis 
For analysis of continuous secondary endpoints at fixed timepoints (ie, week 16 and week 44), the 
analysis method will be the same as that used for the primary variables. For the analysis of 
secondary endpoints involving the averaging over several visits (see endpoints 12 to 15 in 
Section 4.2.2), analysis will be performed using a multiple imputation approach with an ANCOVA 
model based on the mFAS with adjustment for missing data performed in the same manner as was 
done for the primary endpoint.  For analysis of categorical variables in secondary endpoints, eg, 
proportions of patients with ≥30% improvement in the WOMAC pain subscale scores at week 16, 
the Cochran Mantel Haenszel approach will be used based on the mFAS, stratifiying by the 
randomization strata (K-L category [2 to 3, or 4], index joint [knee, hip], and geographical region 
[North America, Europe]).  Missing data will be considered as non-response. 
For Year 2 analysis, the efficacy and PRO endpoints collected will be summarized descriptively.  
10.4.4. 
Safety Analysis 
The summary of safety results will be presented for Year 1, Year 2, and the combined Year 1 and 
Year 2 treatment periods.  
Safety data including TEAEs and treatment emergent AESIs, vital signs, physical exams, 
laboratory tests, ECGs, and ADA formation will be listed and summarized by treatment group. 
Thresholds for potentially clinically significant values (PCSVs) in laboratory parameters and vital 
signs will be defined by the sponsor and be in effect at the time of final SAP approval. 
The time interval to detect any AEs, including AESIs (except JRs identified at the End of Study 
Phone Calls) is between the first dose of Year 1 study drug injection and the end of Follow-up 
Period, (either the week 72/Early Termination for those patients not proceeding into Year 2, the 
week 124E/Early Termination E for those patients proceeding into Year 2, or the Post-Op Joint 
Replacement Follow-up Visit 2), as well as study drug-related SAEs occurring between the end of 
Follow-up Period and the End of Study. 
For safety variables, the following observation periods are defined: 
• The Pretreatment Period is defined as the time from signing the ICF to before the first 
dose of study drug in Year 1. 
• The Year 1 On-Treatment Period is defined as the day from first dose of Year 1 study 
drug through the day of last Year 1 dose + 4 weeks for those patients not proceeding 
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into Year 2, or up to the first dose of Year 2 study drug for those patients proceeding 
into Year 2.  Summaries for the Year 1 On-Treatment Period will be based on the SAF 
– Year 1.   
• The Year 1 Post-Treatment Period is defined from the end of the Year 1 On-Treatment 
Period to the Week 72/Early Termination Visit for those patients not proceeding into 
Year 2.  Summaries for the Year 1 Post-Treatment Period will be based on the SAF – 
Year 1. 
• The Year 2 On-Treatment Period is defined as the day from first dose of Year 2 study 
drug through the day of last Year 2 study drug dose + 4 weeks for those patients 
proceeding into Year 2.  Summaries for the Year 2 Post-Treatment Period will be based 
on the SAF – Year 2. 
• The Combined On-Treatment Period is defined as day from first dose of Year 1 study 
drug through the day of last SC dose + 4 weeks. Summaries for the Combined On-
Treatment Period will be based on the SAF – Year 1. 
• The Year 2 Post-Treatment Period is defined from the end of the Year 2 On-Treatment 
Period to the Week 124E/Early Termination E Visit for those patients proceeding into 
Year 2.  Summaries for the Year 2 Post-Treatment Period will be based on the SAF – 
Year 2. 
All safety analyses will be performed on Year 1 and Year 2 using the following common rules: 
• The Year 1 baseline value is defined as the last available value before randomization. 
• The Year 2 baseline value is defined as the last available value after the last dose of 
Year 1 treatment but before the first dose of Year 2 treatment. 
10.4.4.1. Adverse Events 
Definitions 
The Year 1 and Year 2 TEAEs are defined as those that are not present at baseline or represent the 
exacerbation of a pre-existing condition during the respective on-treatment periods. 
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 adverse event 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. 
For the Year 1, Year 2, and Combined On-Treatment Periods, 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 
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• 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 similarly to TEAEs. 
In addition, AESIs will be reported according to the adjudicated diagnosis.  Imaging data related 
to AA including change from baseline in joint space width will be summarized. 
10.4.4.2. Other Safety 
Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiration rate) will be summarized by 
baseline and change from baseline to each scheduled assessment time with descriptive statistics 
for the Year 1, Year 2, the Combined On-Treatment Periods and the Post-treatment periods. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics for the Year 1, Year 2, the Combined On-Treatment 
Periods and the Post-treatment periods. 
Potentially clinically significant value 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 SC study drug exposure for 
the Year 1 and Year 2 On-Treatment Periods will be presented by treatment group and calculated 
as: 
= (Date of last SC injection of study drug in the respective on-treatment period – date of 
the first SC injection of study drug) + 28 
The number and percentage of patients exposed to SC study drug will be presented by specific 
time intervals for each treatment group for the Year 1 and Year 2 On-Treatment Periods 
respectively.  The time intervals of interest will be specified in the SAP. 
10.4.4.4. Treatment Compliance 
Overall treatment compliance to SC study drug injection is defined as the actual number of SC 
injections compared to the expected number of SC injections during the on-treatment period up to 
treatment discontinuation, for the Year 1 and Year 2 On-Treatment Periods respectively.  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 
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The total number of actual doses of fasinumab will be summarized for the Year 1 and Year 2 
On-Treatment Periods respectively. 
Overall treatment compliance to oral 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 for Year 
1 up to treatment discontinuation for Year 1.  It is calculated according to the following formula: 
∑
(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  𝑥100 
Since the oral study drug for Year 2 is naproxen prn, treatment compliance for oral study drug in 
Year 2 is not applicable and will not be summarized. 
10.4.5. 
Analysis of Drug Concentration Data 
Summaries of serum concentrations of functional fasinumab will be presented by nominal time 
point and dose. Plots of individual concentration over time will be presented by actual day (linear 
and log scales). Plots of mean or median concentrations of functional fasinumab will be presented 
by nominal day (linear and log scales). 
No formal statistical analysis will be performed. 
10.4.6. 
Analysis of Immunogenicity 
Immunogenicity will be characterized by the ADA response observed: 
• Pre-existing immunoreactivity, defined as a positive ADA assay response at baseline, 
with all post-dose ADA results negative, or a positive assay response at baseline, with 
all post-dose ADA assay responses less than 9-fold over baseline titer levels 
• Treatment-emergent ADA response, defined as any post-dose positive ADA assay 
response when the baseline results are negative 
• Treatment-boosted ADA response, defined as any post-dose positive ADA assay 
response that is 9-fold over baseline titer levels when baseline is positive in the ADA 
assay 
• Maximum ADA Titer values 
− Low (titer <1,000) 
− Moderate (1,000≤titer ≤10,000) 
− High (titer >10,000) 
• NAb status - samples testing positive in the ADA assay will also be tested in the NAb 
assay and reported as positive or negative.  
Listings of ADA positivity, ADA titers, and NAb positivity presented by patient, time point, and 
dose group will be provided.  Incidence of treatment-emergent ADA will be assessed as absolute 
occurrence (N) and percent of patients (%), grouped by study cohorts and ADA titer level for each 
of the main 52-week treatment and long-term safety extension studies respectively. 
The influence of ADAs on drug concentrations will be evaluated.  Assessment of impact of ADAs 
on safety and efficacy may be provided. 
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10.5. 
Interim Analysis 
The first-step analysis will consist of the primary and secondary efficacy analyses and will be 
conducted as soon as all patients have been randomized and all data for Year 1 (baseline through 
week 52) have been collected and validated.  This will consist of the analyses of the primary and 
secondary efficacy endpoints at week 16 and/or week 44.  Safety analysis will also be performed 
on the safety data for Year 1 and select safety data for Year 2. 
No alpha adjustment is necessary, as the efficacy analyses for Year 1 will be the final primary and 
secondary efficacy analysis for efficacy and the efficacy analyses for Year 2 will only be 
descriptive and exploratory.  The results of the analysis for Year 1 will not be used to change the 
conduct of the ongoing Year 2 period in any aspect.  
Another analysis will be performed for regulatory purposes on the remaining Year 1 WOMAC 
and PRO assessments and safety data (collected during the Year 1 follow-up period) and any Year 
2 efficacy and safety data available at the time of the data cut-off for interim analysis.   
Additional analyses of other efficacy and safety data may be performed for regulatory purposes as 
needed. 
As the primary and secondary efficacy analyses will have been completed in the first-step analysis, 
no adjustments due to multiplicity will be necessary for any subsequent analysis of the data. 
Individuals unblinded to patient-level data for the first-step or any of the subsequent analyses will 
no longer be involved in the day-to-day conduct of the ongoing study.  Patient-level results will 
not be released to any site-facing personnel or anyone who is directly involved in the conduct of 
the study.   
10.6. 
Additional Statistical Data Handling Conventions 
The following analysis and data conventions will be followed: 
General rules for handling missing data:  
• Rules for handling missing data for efficacy assessments due to missing individual item 
data will follow each questionnaire’s instrument manual. 
• If the start date of an AE or concomitant medication is incomplete or missing, it will 
be assumed to have occurred on or after the intake of study 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. 
 
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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. 
10.7. 
Statistical Considerations Surrounding the Premature Termination 
of a Study 
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized.  Investigator and sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 16.1. 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
11.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation, cleaning, correcting, releasing) will be maintained and stored at Regeneron. 
A medical coding plan will specify the processes and the dictionary used for coding.  All data 
coding (eg, AEs, baseline findings, medication, medical history, surgical history) will be done 
using internationally recognized and accepted dictionaries. 
The eCRF data for this study will be collected with an electronic data capture (EDC) tool, Rave 
Medidata. 
11.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
• IVRS / IWRS system – randomization and study drug supply 
• Rave Medidata EDC system – clinical data capture 
• SAS 
• A pharmacovigilance and clinical safety software system – collection and reporting of 
SAEs and AESIs 
• Electronic Clinical Outcome Assessment systems – collect patient-reported outcome 
or patient clinical assessment results 
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12. 
STUDY MONITORING  
12.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, CRO monitor) will visit each site prior to enrollment of 
the first patient, and periodically during the study. 
The investigator must allow study-related monitoring. 
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version as well as 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).  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 eCRF 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 
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• Communicating any information arising from inspection by the regulatory authorities 
to the sponsor immediately 
• Taking all appropriate measures requested by the sponsor to resolve the problems found 
during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, CRFs, 
medical records, correspondence, ICFs, IRB or EC files, documentation of certification and quality 
control of supporting laboratories, and records relevant to the study maintained in any supporting 
pharmacy facilities.  Conditions of study material storage are also subject to inspection.  In 
addition, representatives of the sponsor may observe the conduct of any aspect of the clinical study 
or its supporting activities both within and outside of the investigator's institution. 
In all instances, the confidentiality of the data must be respected. 
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 
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information and provide their written consent if they wish to continue in the study.  The original 
signed revised ICF must be maintained in the patient’s study record and a copy must be given to 
the patient. 
14.3. 
Patient Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained.  Patients should be identified by their patient identification number, 
only, on CRFs or other documents submitted to the sponsor.  Documents that will not be submitted 
to the sponsor (eg, signed ICF) must be kept in strict confidence. 
The patient's 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 patients, in 
which case the IRB or EC should be informed as soon as possible  
• Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
In addition, the IRB or EC should be informed of any event likely to affect the safety of patients 
or the continued conduct of the clinical study. 
A copy of the IRB- or EC-approval letter with a current list of the IRB or EC members and their 
functions must be received by the sponsor prior to shipment of drug supplies to the investigator.  
The approval letter should include the study number and title, the documents reviewed, and the 
date of the review. 
Records of the IRB or EC review and approval of all study documents (including approval of 
ongoing studies) must be kept on file by the investigator. 
14.5. 
Clinical Study Data Transparency 
Final study results will be published on a public clinical trial website according to applicable local 
guidelines and regulations.  Treatment codes will be disseminated to each investigation site 
thereafter. 
15. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an IRB- or 
EC-approved amendment Where required per local legislation, regulatory authority approval will 
also be sought. 
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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 or dosing in 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. 
Investigator’s Decision 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at least 
30 days’ notice.  The final decision should be made through mutual agreement with the sponsor.  
Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing.  
Reasons may include the following, among others:  
• The investigator has received all items and information necessary to perform the study, 
but has not enrolled any patient within a reasonable period of time 
• The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines  
• The total number of patients required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB or EC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection of 
the patients’ interests. 
17. 
STUDY DOCUMENTATION 
17.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the eCRF must be signed 
by the investigator.  This signed declaration accompanies each set of patient final eCRF that will 
be provided to the sponsor. 
17.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of CRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
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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, 
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, Section 13). 
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements (Section 12.1). 
All patient data collected during the study will be recorded on paper or electronic CRF unless the 
data are transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator 
is responsible for affirming that data entries in the CRF are accurate and correct by electronically 
signing a declaration that accompanies each set of patient final CRF (Section 12.3, Section 17.1).  
Study Documentation 
The investigator must maintain accurate documentation (source data) that supports the information 
entered in the CRF (Section 12.2).  
The investigator will retain all records and documents, including signed ICFs, pertaining to the 
conduct of this study for at least 15 years after study completion, unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor (Section 17.2).  
19. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
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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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22. 
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Altman, R., G. Alarcon, D. Appelrouth, D. Bloch, D. Borenstein, K. Brandt, C. Brown, T.D. 
Cooke, W. Daniel, D. Feldman, and et al. The American College of Rheumatology criteria for the 
classification and reporting of osteoarthritis of the hip. Arthritis Rheum. 1991. 34:505-514. 
Altman, R., E. Asch, D. Bloch, G. Bole, D. Borenstein, K. Brandt, W. Christy, T.D. Cooke, 
R. Greenwald, M. Hochberg, and et al. Development of criteria for the classification and reporting 
of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria 
Committee of the American Rheumatism Association. Arthritis Rheum. 1986. 29:1039-1049.  
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23. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol, entitled “A Phase 3 Randomized, Double-Blind, Multi-Dose, 
Placebo and Naproxen-Controlled Study to Evaluate the Efficacy and Safety of Fasinumab in 
Patients with Pain Due to Osteoarthritis of the Knee or Hip,” dated as noted in the appended 
signature page, and agree to abide by all provisions set forth therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, state, 
or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor or a partnership 
in which the sponsor is involved.  I will immediately disclose it in writing to the sponsor if any 
person who is involved in the study is debarred, or if any proceeding for debarment is pending, or, 
to the best of my knowledge, threatened. 
This document contains confidential information of the sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the Institutional Review Board or Ethics 
Committee.  I agree to ensure that this information will not be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of the sponsor. 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
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SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(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 Naproxen-
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-1611  
Protocol Version: 
R475-OA-1611 Amendment 9 Global 
 
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 
                                        VV-RIM-00122598-1.0 Approved - 26 Aug 2020 GMT-5:00


Signature Page for VV-RIM-00122598 v1.0
Signature Page for VV-RIM-00122598 v1.0 Approved
ESig Approval
-2020 17:34:47 GMT+0000
ESig Approval
-2020 17:41:18 GMT+0000
ESig Approval
000
ESig Approval
20 18:16:31 GMT+0000
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SAP_001.pdf: 
Global Clinical Development 
Biostatistics and Data Management 
CONFIDENTIAL 
Page 1 of 93 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 
STATISTICAL ANALYSIS PLAN 
VERSION: FINAL 
Clinical Study Protocol Title: A Phase 3 Randomized, Double-Blind, Multi-Dose, Placebo and 
Naproxen-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-1611 
Clinical Phase:  
Phase 3 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician:  
 
Clinical Trial Manager: 
 
Study Medical Director: 
 
Version/Date:  
2.0 /30JUN2020 
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Statistical Analysis Plan 
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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 Clinical Pharmacologist 
 
 
 
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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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. 
Modifications from the Statistical Section in the Final Protocol ................................10 
1.2.4. 
Revision History for SAP Amendments .....................................................................10 
2. 
INVESTIGATION PLAN ..........................................................................................12 
2.1. 
Study Design and Randomization ..............................................................................12 
2.2. 
Sample Size and Power Considerations .....................................................................13 
2.3. 
Study Plan ...................................................................................................................15 
3. 
ANALYSIS POPULATIONS ....................................................................................16 
3.1. 
The Full Analysis Set (FAS) .......................................................................................16 
3.2. 
The Modified Full Analysis Set (mFAS) ....................................................................16 
3.3. 
The Per Protocol Set (PPS) .........................................................................................16 
3.4. 
The Safety Analysis Sets (SAF) .................................................................................16 
3.5. 
The Urgent Safety Measure Set (USMS) ...................................................................17 
3.6. 
The Pharmacokinetic (PK) Analysis Set ....................................................................17 
3.7. 
The Anti-Drug Antibody Analysis (ADA) Set ...........................................................18 
3.8. 
The Neutralizing Antibody (NAb) Set .......................................................................18 
4. 
ANALYSIS VARIABLES .........................................................................................19 
4.1. 
Demographic and Baseline Characteristics ................................................................19 
4.2. 
Medical History ..........................................................................................................19 
4.3. 
Prior and Concomitant Medication and Procedures ...................................................19 
4.4. 
Prohibited Medication During Study ..........................................................................20 
4.5. 
Efficacy Variable ........................................................................................................21 
4.5.1. 
Primary Efficacy Variables .........................................................................................21 
4.5.2. 
Secondary Efficacy Variables .....................................................................................21 
4.5.3. 
Exploratory Variables .................................................................................................23 
4.6. 
Safety Variables ..........................................................................................................24 
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4.6.1. 
Adverse Events and Serious Adverse Events .............................................................24 
4.6.2. 
Adverse Events of Special Interest .............................................................................24 
4.6.3. 
Laboratory Safety Variables .......................................................................................25 
4.6.4. 
Vital Signs ..................................................................................................................25 
4.6.5. 
Orthostatic Hypotension .............................................................................................25 
4.6.6. 
12-Lead Electrocardiography (ECG) ..........................................................................26 
4.6.7. 
Physical and Neurological Examination Variables ....................................................26 
4.6.8. 
Other Safety Variables ................................................................................................26 
4.7. 
Pharmacokinetic Variables .........................................................................................27 
4.8. 
Immunogenicity Variables ..........................................................................................27 
4.9. 
Quality-of-Life Variables ...........................................................................................27 
4.10. 
Health Economic Variables ........................................................................................28 
5. 
STATISTICAL METHODS .......................................................................................29 
5.1. 
Demographics and Baseline Characteristics ...............................................................29 
5.2. 
Medical History ..........................................................................................................29 
5.3. 
Prior/Concomitant Medications ..................................................................................30 
5.4. 
Prohibited Medications ...............................................................................................30 
5.5. 
Subject Disposition .....................................................................................................31 
5.5.1. 
Screening Disposition .................................................................................................31 
5.5.2. 
Year 1 Treatment and Study Disposition ....................................................................32 
5.5.3. 
Year 2 Disposition ......................................................................................................32 
5.6. 
Extent of Study Treatment Exposure and Compliance ...............................................33 
5.6.1. 
Measurement of Compliance ......................................................................................33 
5.6.2. 
Exposure to Investigational Products .........................................................................33 
5.6.3. 
Length of Study Observation ......................................................................................34 
5.7. 
Analyses of Efficacy Variables ..................................................................................34 
5.7.1. 
Analysis of Primary Efficacy Variables .....................................................................35 
5.7.2. 
Subgroup Analysis ......................................................................................................38 
5.7.3. 
Analysis of Secondary Efficacy Variables .................................................................38 
5.7.4. 
Adjustment for Multiple Comparisons .......................................................................42 
5.7.5. 
Analysis of Other Efficacy Variables .........................................................................43 
5.7.6. 
Analysis of Quality-of-Life and Health Economic Variables ....................................44 
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5.7.7. 
FAS Analysis ..............................................................................................................45 
5.8. 
Analysis of Safety Data ..............................................................................................45 
5.8.1. 
Adverse Events ...........................................................................................................46 
5.8.2. 
Analysis of Adverse Events of Special Interest ..........................................................48 
5.8.3. 
Clinical Laboratory Measurements.............................................................................48 
5.8.4. 
Analysis of Vital Signs ...............................................................................................49 
5.8.5. 
Analysis of 12-Lead ECG ...........................................................................................49 
5.8.6. 
Physical and Neurological Examinations ...................................................................50 
5.8.7. 
Analysis of Other Safety Variables ............................................................................50 
5.9. 
Analysis of Pharmacokinetic Data ..............................................................................51 
5.10. 
Analysis of Immunogenicity Data ..............................................................................51 
5.10.1. 
Analysis of ADA Data ................................................................................................51 
5.10.2. 
Analysis of Neutralizing Antibody (NAb) Data .........................................................52 
5.10.3. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................53 
5.10.3.1. 
Immunogenicity and Exposure ...................................................................................53 
5.10.3.2. 
Immunogenicity and Safety and Efficacy ...................................................................53 
6. 
DATA CONVENTIONS ............................................................................................54 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................54 
6.2. 
Data Handling Convention for Efficacy Variables .....................................................54 
6.2.1. 
Handling of Missing Efficacy Data due to COVID-19 Public Health 
Measures .....................................................................................................................54 
6.3. 
Data Handling Convention for Repeat Data ...............................................................54 
6.4. 
Data Handling Conventions for Missing Data............................................................55 
6.5. 
Visit Windows ............................................................................................................57 
6.6. 
Unscheduled Assessments ..........................................................................................59 
6.7. 
Pooling of Centers for Statistical Analyses ................................................................59 
6.8. 
Statistical Technical Issues .........................................................................................59 
7. 
INTERIM ANALYSIS ...............................................................................................60 
8. 
SOFTWARE ...............................................................................................................61 
9. 
REFERENCES ...........................................................................................................62 
10. 
APPENDIX.................................................................................................................63 
10.1. 
Summary of Statistical Analyses ................................................................................63 
10.2. 
Schedule of Time and Events .....................................................................................67 
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10.3. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................83 
10.4. 
Protocol Deviations Excluding Patients from the PPS ...............................................91 
10.5. 
OMERACT-OARSI Set of Responder Criteria ..........................................................93 
 
LIST OF TABLES 
Table 1: 
Year 1 Analysis Windows ..........................................................................................57 
Table 2: 
Year 2 Analysis Windows ..........................................................................................58 
Table 3: 
Schedule of Events for Year 1 ....................................................................................67 
Table 4: 
Schedule of Events for Year 2 ....................................................................................76 
Table 5: 
Follow-Up Period for Patients Undergoing Joint Replacement Surgery on 
Study ...........................................................................................................................82 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................12 
Figure 2: 
Hypothesis Testing Procedure ....................................................................................42 
 
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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 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate aminotransferase 
CI 
Confidence Interval 
DA 
Destructive Arthropathy 
DMC 
Data Monitoring Committee 
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 
mFAS 
Modified full analysis set 
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 
OMERACT-
OARSI 
Osteoarthritis Research Society International Standing Committee for 
Clinical Trials Response Criteria Initiative and The Outcome Measure in 
Rheumatology 
PCSV 
Potentially clinically significant value 
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PDID 
Protocol deviation identification number 
PGA-OA 
Patient Global Assessment - Osteoarthritis 
PK 
Pharmacokinetic 
PPS 
Per protocol set 
prn 
Pro re nata 
PRO 
Patient Reported Outcomes 
PT 
Preferred term 
Q4W 
Every 4 (weeks) 
Q8W 
Every 8 (weeks) 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
RPOA 
Rapidly Progressive Ostoearthritis 
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 Universities Osteoarthritis Index 
 
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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-1611 study as stipulated in Protocol 
Amendment 8 Global. 
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 naproxen-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 naproxen, which is a member 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 52 weeks 
(with the option to continue for an additional 52 weeks of treatment) to fasinumab, naproxen, 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 with 
placebo, when administered for up to 16 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: 
1. To evaluate the efficacy of fasinumab compared with naproxen, when administered for 
up to 16 weeks in patients with pain due to OA of the knee or hip 
2. To evaluate the efficacy of fasinumab compared with placebo, when administered for up 
to 44 weeks in patients with pain due to OA of the knee or hip 
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3. To evaluate the safety and tolerability of fasinumab compared with naproxen, when 
administered for up to 16 weeks in patients with pain due to OA of the knee or hip 
4. To evaluate the safety and tolerability of fasinumab compared with naproxen, when 
administered for up to 52 weeks in patients with pain due to OA of the knee or hip 
5. To evaluate the safety and tolerability of fasinumab compared with naproxen, when 
administered for up to 104 weeks in patients with pain due to OA of the knee or hip 
6. To evaluate the pharmacokinetic (PK) profile of fasinumab administered to patients with 
pain due to OA of the knee or hip for up to 52 weeks 
7. To evaluate the PK profile of fasinumab administered to patients with pain due to OA of 
the knee or hip for up to 104 weeks 
8. To evaluate the immunogenicity of fasinumab administered to patients with pain due to 
OA of the knee or hip for up to 52 weeks 
9. To evaluate the immunogenicity of fasinumab administered to patients with pain due to 
OA of the knee or hip for up to 104 weeks 
10. To evaluate the efficacy of fasinumab compared with naproxen, when administered for 
up to 44 weeks in patients with pain due to OA of the knee or hip 
Additionally, the following are exploratory objectives: 
• To evaluate additional patient reported outcome (PRO) measures in patients with pain 
due to OA of the knee or hip treated for up to 44 weeks with fasinumab, compared 
with placebo or naproxen.   
• To evaluate the WOMAC pain and physical function subscale scores as well as 
additional PRO measures in patients with pain due to OA of the knee or hip treated 
for an additional 52 weeks with fasinumab, compared with naproxen pro re nata 
(prn).   
• To evaluate the use of rescue medication in patients with pain due to OA of the knee 
of hip treated for up to 44 weeks with fasinumab, compared with placebo or 
naproxen.   
• To evaluate the use of rescue medication in patients with pain due to OA of the knee 
of hip treated for an additional 52 weeks with fasinumab, compared with naproxen 
prn. 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol 
There are no modifications from what is defined and specified in the statistical section of the 
final protocol. 
1.2.4. 
Revision History for SAP Amendments 
This is the second version of the SAP based on Protocol Amendment 8 Global. The original 
version was approved and dated 23APR2020 based on Protocol Amendment 7 Global.  This 
version includes an additional analysis population in Section 3, the Modified Full Analysis Set 
(mFAS).  Due to regional irregularities noted in a parallel phase 3 study that became fully 
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apparent only after unblinding that study, and the concern that the same irregularities would be 
present in data from similar sites in this study, the primary and secondary efficacy analysis will 
be performed on a modified Full Analysis Set that excludes patients in the randomization stratum 
from the region of concern. Analyses using the FAS will also be provided. 
Wording was added to Section 2.2 to quantify how the power was impacted by changing the 
primary analysis population from the FAS to the mFAS.  
The method used to address imputed values that are implausible (Section 5.7.1) was also 
updated. 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
The study consists of a screening period of up to 30 days, followed by a 7 to 10-day pre-
randomization period.  All randomized patients in this study will participate in Year 1, a 52-week 
randomized, double-blind, placebo- and naproxen-controlled treatment period.  At the end of the 
52-week treatment period, eligible patients have the option to continue for another 52-week 
double-blind naproxen-controlled treatment period called Year 2, followed by a 20-week follow-
up period.  Patients who do not consent, or are ineligible, for Year 2 will continue in a 20-week 
follow-up period.  Patients are contacted by phone approximately 52 weeks after their last 
subcutaneous (SC) dose of study drug (Figure 1). 
Figure 1: 
Study Flow Diagram 
 
 
Prior to Protocol R475-OA-1611 Amendment 4 Global, patients were randomized 3:3:3:3:1 to 
receive one of the following treatment regimens: 
• Fasinumab 1 mg Q4W - Fasinumab 1 mg SC Q4W and naproxen-matching placebo 
oral, twice daily 
• Fasinumab 3 mg Q4W - Fasinumab 3 mg SC Q4W and naproxen-matching placebo 
oral, twice daily 
• Fasinumab 6 mg Q8W - Fasinumab 6 mg SC Q8W (patients received placebo 
injections at the study visits where study drug was not administered) and naproxen-
matching placebo oral, twice daily 
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• Naproxen - Fasinumab-matching placebo SC Q4W and naproxen 500 mg oral, twice 
daily 
• Placebo - Fasinumab-matching placebo SC Q4W and naproxen-matching placebo 
oral, twice daily 
A total of 285 patients were enrolled in the fasinumab 3 mg SC Q4W and fasinumab 6 mg SC 
Q8W groups.  However, dosing in these patients was discontinued, as recommended by the 
independent Data Monitoring Committee (DMC)in April 2018. 
Post Protocol R475-OA-1611 Amendment 5 Global approximately 2,560 patients were planned 
to be randomized 3:3:3:1 to receive: 
• Fasinumab 1 mg Q4W - Fasinumab 1 mg SC Q4W and naproxen-matching placebo 
oral, twice daily 
• Fasinumab 1 mg Q8W - Fasinumab 1 mg SC Q8W (patients received placebo 
injections at the study visits where study drug was not administered) and naproxen-
matching placebo oral, twice daily 
• Naproxen - Fasinumab-matching placebo SC Q4W and naproxen 500 mg oral, twice 
daily 
• Placebo - Fasinumab-matching placebo SC Q4W and naproxen-matching placebo 
oral, twice daily 
Randomization was 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 (Europe, North America, and Rest of 
the World [South Africa]). 
Protocol R475-OA-1611 Amendment 6 provided patients the option to continue in the study and 
receive treatment for an additional year (Year 2).  The treatment arm the patients were assigned 
in Year 2 was determined by the treatment arm they were randomized to in Year 1 according to 
the following rules: 
• Patients randomized to receive Placebo or Naproxen in Year 1 will be assigned to 
receive Naproxen prn during Year 2 
• Patients randomized to received Fasinumab 1 mg Q4W in Year 1 will be assigned to 
remain on this dose for Year 2 
• Patients randomized to received Fasinumab 1 mg Q8W in Year 1 will be assigned to 
remain on this dose for Year 2 
2.2. 
Sample Size and Power Considerations 
In this study, approximately 2560 patients were planned to be randomized to fasinumab 1 mg SC 
Q4W (840), fasinumab 1 mg SC Q8W (600), naproxen (840), or placebo (280) (see Section 5.1.3 
of the protocol). This sample size was expected to provide adequate power for the comparisons 
between fasinumab and naproxen at week 16 for the WOMAC pain and physical function scores 
and the Patient Global Assessment - Osteoarthritis (PGA-OA) score and provide long term data 
for safety assessment. 
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The sample size was based on results of the WOMAC pain and physical function subscale scores 
and the PGA from the R475-PN-1227 study.  The calculation of sample size assumed a 2-sided 
alpha level of 0.025 and a 15% dropout rate up to week 16 and a 30% dropout rate up to week 
52. Enrollment of 840 patients in the fasinumab 1 mg Q4W group and 280 patients in the 
placebo group would have provided at least 99% power to detect an effect size of 0.46 in the 
WOMAC pain and physical function subscale scores (i.e., an absolute treatment difference of 1.1 
between fasinumab and placebo and a standard deviation [SD] of 2.4 at week 16 and 52 for the 
full analysis set [FAS]). This sample size would have provided 99 % power to detect an effect 
size of 0.36 in PGA for an absolute treatment difference of 0.4 with a SD of 1.1 at week 16, and 
98% power at week 52 for the FAS. 
For the fasinumab 1 mg Q8W group, the 600 patients would have been compared to the 
approximately 200 patients in the placebo group who were enrolled after Protocol R475-OA-
1611 Amendment 5 Global was implemented. For such comparisons, 2-sided alpha level of 
0.025 and a 15% dropout rate up to week 16 and a 30% dropout rate up to week 52 were 
assumed. Additionally, the effect size for such comparisons were assumed to be 80% of the 
effect size for the comparison between fasinumab 1 mg Q4W group and the placebo group. 
Under these assumptions, enrollment of 600 patients in the fasinumab 1 mg Q8W group and 200 
patients from the placebo group would have provided 97% power to detect an effect size of 
0.368 (=0.46*80%) in the WOMAC pain and physical function subscale scores at week 16 and 
93% power at week 52. This sample size would have provided 84% power to detect an effect 
size of 0.288 (=0.36*80%) in PGA at week 16, and 75% power at week 52 for the full analysis 
set (FAS). 
The sample size calculation was also based on previously reported results of the WOMAC pain 
subscale and physical function subscale and the PGA for naproxen (Ekman 2014) (Schnitzer 
2015).  Assuming a 2-sided alpha level of 0.025 and a 15% dropout rate up to week 16 and a 
30% dropout rate up to week 52, an enrollment of 840 patients in the fasinumab 1 mg Q4W 
group and the naproxen group would have provided at least 97% power to detect an effect size of 
0.22 in the WOMAC pain subscale (i.e., an absolute treatment difference of 0.51 with a SD of 
2.3) at week 16, and 92% power at week 52 for FAS.  This sample size would have provide 98% 
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) at week 16, and 96% power at week 52 for FAS.  
This sample size would have provided 87% power to detect an effect size of 0.18 in PGA at 
week 16 between fasinumab 1 mg Q4W and naproxen for the FAS. 
While the number of patients randomized was based on the sample size calculations in the 
protocol, the analyses of the primary and secondary efficacy endpoints will be performed at 
levels of significance as specified in Section 5.7.4 of this document which differs than the initial 
assumptions used above. 
Due to regional irregularities noted in a parallel phase 3 study, the population for the primary and 
secondary efficacy analyses was changed in Protocol Amendment 8 Global to be performed on a 
modified Full Analysis Set (mFAS) that excludes patients in the randomization stratum for that 
region.  Based on the number of patients randomized and the testing stragefy specified in 
Section 5.7.4  it is estimated that this mFAS will provide: 
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• 99.9% power to detect a statistically significant difference between the 1 mg Q4W 
group and the placebo group in the WOMAC pain and physical function subscales at 
Week 16 using an alpha level of 0.05. 
• 42% and 46% power to detect a statistically significant difference between the 1 mg 
Q8W group and the placebo group in WOMAC pain and physical function subscales, 
respectively, at Week16 using an alpha level of 0.01. 
• 99.9% power to detect a statistically significant difference between the 1 mg Q4W 
group and the naproxen group in the WOMAC pain and physical function subscales 
at Week 16 using an alpha level of 0.04. 
As the analysis for Year 2 will be descriptive only, a targeted sample size based on power 
considerations was not implemented for Year 2. 
2.3. 
Study Plan 
Study assessments and procedures are presented by study period and visit in Section 10.2 Table 3 
and Table 4.  A schedule for follow-up on JR surgery during the study is presented in Section 
10.2 Table 5. 
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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 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 and patient reported outcome endpoints for Year 1 
will be analyzed using the FAS including patients randomized to fasinumab 1 mg Q4W, 
fasinumab 1 mg Q8W, naproxen and placebo.  For the analyses of fasinumab 1 mg Q8W group 
comparing to the control groups, only patients concurrently randomized (i.e. after Protocol 
R475-OA-1611 Amendment 5 Global was implemented) will be included. 
3.2. 
The Modified Full Analysis Set (mFAS) 
Due to regional irregularities noted in a parallel phase 3 study that became fully apparent only after 
unblinding that study, and the concern that the same irregularities would be present in data from 
similar sites from the same region in this study, the primary and secondary efficacy analyses will 
be performed on a modified Full Analysis Set (mFAS). This mFAS is comprised of the FAS 
excluding patients from the region of concern (Rest of the World stratum).  Efficacy and patient 
reported outcome endpoints will be analyzed using the mFAS including patients randomized to 
fasinumab 1 mg Q4W, fasinumab 1 mg Q8W, naproxen and placebo.  For the analysis of 
fasinumab 1 mg Q8W group comparing to the control groups, only the subset of patients 
concurrently randomized (ie, after Protocol R475-OA-1611 Amendment 5 Global was 
implemented) will be included.   
3.3. 
The Per Protocol Set (PPS) 
The per protocol set (PPS) includes all randomized patients from the mFAS who received all 
protocol required doses during the 16-week treatment period for the week 16 analysis and who 
do not have to be excluded due to relevant protocol violations.  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 protocol 
deviation identification number (PDID).  For the analysis of fasinumab 1 mg Q8W group 
comparing to the control groups, only the subset of patients concurrently randomized (i.e. after 
Protocol R475-OA-1611 Amendment 5 Global was implemented) will be included.   
A PPS using the entire FAS is defined analogously to above and will be used for performing 
sensitivity analysis on the entire FAS. 
3.4. 
The Safety Analysis Sets (SAF) 
The Year 1 safety analysis set (SAF – Year 1) 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 for Year 1 will be analyzed using the 
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SAF – Year 1 including patients randomized to fasinumab 1 mg Q4W, fasinumab 1 mg Q8W, 
naproxen, and placebo.  
The Year 2 safety analysis set (SAF – Year 2) includes all patients who received at least 1 dose 
of the Year 2 study drug; it is based on the treatment received during Year 2 (as treated). 
Treatment compliance/administration, all clinical efficacy and safety variables and all patient 
reported outcomes from Year 2 will be analyzed using the SAF – Year 2. 
The following rules will be used to define the actual treatment a patient received: 
• Patients randomized to either the placebo or naproxen arm who receive at least one 
dose of active fasinumab during Year X will be considered as treated with fasinumab 
1 mg Q8W and classified in the fasinumab 1 mg Q8W treatment arm for the purpose 
of analysis using the SAF – Year X, where X = 1 or 2. 
• Patients randomized to the placebo arm who have not received any active fasinumab 
injections but were ever dispensed active naproxen during Year 1 will be considered 
as treated with naproxen and classified in the naproxen treatment arm for the purpose 
of analysis using the SAF – Year 1. 
• For patients randomized to either the fasinumab 1 mg Q8W or Q4W arms, as treated 
is defined to be as randomized and they will be classified in the treatment arm they 
were randomized to for the purpose of the analysis using the SAF – Year X, where X 
= 1 or 2, with the following exceptions: 
− In Year 1, if a patient receives no doses of active naproxen or fasinumab, then the 
patient will be considered as treated with placebo and classified in the placebo 
treatment arm for the purpose of analysis using the SAF – Year 1. 
− In Year 1, if a patient receives no doses of fasinumab but were ever dispensed any 
active dose of naproxen, then the patient will be considered as treated with 
naproxen and classified in the naproxen treatment arm for the purpose of analysis 
using the SAF – Year 1. 
− In Year 2, if a patient receives no doses of fasinumab, then the patient will be 
considered as treated with naproxen prn and classified in the naproxen prn 
treatment arm for the purpose of analysis using the SAF – Year 2. 
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 set includes all treated patients that had at least 1 non-missing drug 
concentration result following the first dose of study drug. Patients will be analyzed according to 
the treatment actually received (as treated). 
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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 (as treated).  
3.8. 
The Neutralizing Antibody (NAb) Set 
The neutralizing antibody (NAb) analysis set includes all patients who received any study drug 
and who are negative in the fasinumab ADA assay or with at least one non-missing result in the 
fasinumab NAb assay following the 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 (as treated). 
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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 range (< 65, 65-74, ≥ 75 years) 
• Sex (Male, Female) 
• Race (American Indian/Alaskan Native, Asian, Black/African American, Native 
Hawaiian/Other Pacific Islander, White and Other) 
• Ethnicity (Hispanic/Latino: Yes, No, Not Reported, and Unknown) 
• Baseline Weight (kg) 
• Baseline Height (cm) 
• Baseline Body mass index (BMI) calculated from weight and height 
• Geographic Region (Europe, North America and Rest of World) 
• Index Joint (Knee or Hip) per IWRS 
• Kellgren-Lawrence score (2, 3, 4) per IWRS for the 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 Medication and Procedures 
For patients who only participate in Year 1, Medications/Procedures will be recorded from the 
day of informed consent until either the Early Termination/JR Pre-operative Visit or End of 
Follow-up Clinic Visit at Week 72, which ever is applicable for each patient. For patients who 
continue into Year 2, Medications/Procedures will be recorded from the day of informed consent 
for Year 2 until the Early Termination E/JR Pre-operative Visit E or End of Follow-up Clinic 
Visit at Week 124E, which ever is applicable for each patient.  
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 
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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. 
Year 1 Concomitant medications/procedures are defined as medications/procedures starting prior 
to or during the Year 1 On-Treatment Period (as defined in Section 5) and ending during or after 
the Year 1 On-Treatment Period.  Year 2 Concomitant medications/procedures are defined 
analogously. 
For patients who do not continue into the Year 2, Year 1 Post-Treatment medications/procedures 
are medications/procedures starting after the Year 1 On-Treatment Period.     
For patients who do continue into the Year 2, Year 2 Post-Treatment medications/procedures are 
medications/procedures starting after the Year 2 On-Treatment Period.     
4.4. 
 Prohibited Medication During Study  
Patients will be required to discontinue all non-study pain medication (oral or topical; except up 
to 150 mg/day of aspirin/5-aminosalicylic acid [5-ASA], which is permitted for cardiac 
prophylaxis, per local guidelines) and opioid analgesic medications, starting at the pre-
randomization visit and through the Year 1 and Year 2 Treatment Periods. 
Opioid analgesic medications (including tramadol) are prohibited during the Year 1 and Year 2 
Treatment Periods. 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 Year 1 and Year 2 Treatment Periods 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 section 7.7.2 of the protocol for permitted muscle relaxants) 
• Corticosteroids (topical, intranasal, and inhaled formulations are permitted), 
adenocorticotropic hormone 
• Cyclosporine, methotrexate, mycophenolate mofetil, tacrolimus 
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• Azathioprine, sulfasalazine, hydroxycholoroquine 
• IL-6 or IL-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 list of concomitant medications taken during the Year 1 and Year 2 Treatment Periods will 
be reviewed by the study team to determine if any medication falls under one of the above 
categories.  If a concomitant medication is adjudicated to be prohibited, a protocol deviation will 
be recorded. 
 The following variables will be summarized for prohibited medications: 
• Number and percentage of patients using at least one prohibited medication during 
the Year 1 and Year 2 Treatment Periods separately. 
• Number and percentage of patients using at least one prohibited medication during 
the Year 1 and Year 2 Follow-up Periods separately.  
• Number and percentage of patients with at least one prohibited NSAID use during the 
Year 1 and Year 2 Treatment Periods separately.  
• Number and percentage of patients with at least one prohibited NSAID use during the 
Year 1 and Year 2 Follow-up Periods separately. 
• Number of days patients used prohibited medications during the Year 1 and Year 2 
Treatment Periods separately.  
• Number of days patients used prohibited NSAID medications during the Year 1 and 
Year 2 Treatment Periods separately.  
4.5. 
Efficacy Variable 
4.5.1. 
Primary Efficacy Variables 
The co-primary efficacy variables in the study are: 
1. Change in the WOMAC pain subscale scores from baseline to week 16 in patients treated 
with fasinumab compared with that of patients treated with placebo.  
2. Change in the WOMAC physical function subscale scores from baseline to week 16 in 
patients treated with fasinumab compared with that of patients treated with placebo. 
4.5.2. 
Secondary Efficacy Variables 
The key secondary efficacy variables in the study are: 
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1. Change from baseline in the Patient Global Assessment (PGA) scores from baseline to 
week 16 in patients treated with fasinumab compared with that of patients treated with 
placebo 
2. Percentage of patients treated with fasinumab, compared with that of patients treated with 
placebo, who had a response at week 16, with response defined as an improvement by ≥ 
30% in the WOMAC pain subscale scores 
3. Change in WOMAC pain subscale scores from baseline to week 16 in patients treated 
with fasinumab, compared with that of patients treated with naproxen 
4. Change in WOMAC physical function subscale scores from baseline to week 16 in 
patients treated with fasinumab, compared with that of patients treated with naproxen 
5. Change in WOMAC pain subscale scores from baseline to week 44 in patients treated 
with fasinumab, compared with that of patients treated with placebo 
6. Change in WOMAC physical function subscale scores from baseline to week 44 in 
patients treated with fasinumab, compared with that of patients treated with placebo 
7. Change in the PGA scores from baseline to week 44 in patients treated with fasinumab 
compared with that of patients treated with placebo 
8. Change in the PGA scores from baseline to week 16 in patients treated with fasinumab 
compared with that of patients treated with naproxen 
9. Change in WOMAC pain subscale scores from baseline to week 44 in patients treated 
with fasinumab, compared with that of patients treated with naproxen 
10. Change in WOMAC physical function subscale scores from baseline to week 44 in 
patients treated with fasinumab, compared with that of patients treated with naproxen 
11. Percentage of patients treated with fasinumab, compared with that of patients treated with 
naproxen, who had a response at week 16, with response defined as an improvement by ≥ 
30% in the WOMAC pain subscale scores 
12. Change in WOMAC pain subscale scores from baseline to the average score across 
Weeks 4, 8, 12 and 16, in patients treated with fasinumab compared with that of patients 
treated with placebo 
13. Change in WOMAC physical function subscale scores from baseline to the average score 
across Weeks 4, 8, 12 and 16, in patients treated with fasinumab compared with that of 
patients treated with placebo 
14. Change in WOMAC pain subscale scores from baseline to the average score across 
Weeks 36, 40 and 44, in patients treated with fasinumab compared with that of patients 
treated with placebo  
15. Change in WOMAC physical function subscale scores from baseline to the average score 
across Weeks 36, 40 and 44, in patients treated with fasinumab compared with that of 
patients treated with placebo 
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4.5.3. 
Exploratory Variables 
The exploratory endpoints in the study are 
1. Change from baseline to week 16 and 44 in patient-reported outcome measures in 
patients with pain due to OA of the knee or hip treated with fasinumab compared to 
placebo 
2. Change from baseline to week 16 and 44 in patient-reported outcome measures in 
patients with pain due to OA of the knee or hip treated with fasinumab compared to 
naproxen 
3. The proportion of patients taking rescue medication, number of days on rescue 
medication, and weekly average use of rescue medication from baseline to week 16 and 
44 in patients with pain due to OA of the knee or hip treated with fasinumab compared to 
placebo 
4. The proportion of patients taking rescue medication, number of days on rescue 
medication, and weekly average use of rescue medication from baseline to week 16 and 
44 in patients with pain due to OA of the knee or hip treated with fasinumab compared to 
naproxen 
5. Percentage of patients treated with fasinumab, compared with that of patients treated with 
placebo, who had improvements of ≥ 50% and ≥ 70% in the WOMAC pain subscale 
scores at week 16 and 44 
6. Percentage of patients treated with fasinumab, compared with that of patients treated with 
placebo, who had improvements of ≥ 30%, ≥ 50% and ≥ 70% in the WOMAC pain 
subscale scores at week 16 and 44 
7. Percentage of patients treated with fasinumab, compared with that of patients treated with 
placebo who met the OMERACT-OARSI criterion at week 16 and 44 
8. Change from baseline at all visits from week 52E and 104E of the WOMAC pain and 
physical function subscale scores in patients with pain due to OA of the knee or hip 
treated with fasinumab compared to naproxen prn 
9. Change from baseline at all visits from week 52E and 104E in patient-reported outcome 
measures in patients with pain due to OA of the knee or hip treated with fasinumab 
compared to naproxen prn 
10. The proportion of patients taking rescue medication, number of days on rescue 
medication, and weekly average use of rescue medication from week 52E to week 104E 
in patients with pain due to OA of the knee or hip treated with fasinumab compared to 
placebo 
11. The proportion of patients taking rescue medication, number of days on rescue 
medication, and weekly average use of rescue medication from week 52E to week 104E 
in patients with pain due to OA of the knee or hip treated with fasinumab compared to 
naproxen 
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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 then at each visit until the end of the study. 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, Version 20 or 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 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 
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 independent 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 cardiologist) selected using eCRF 
specific tick boxes on the AE page and corresponding Supplemental AE page 
indicating it was confirmed by a specialist. 
• Peripheral sensory AEs that require a neurology or other specialty consultation, 
collected using an eCRF specific tick box on the AE page. 
• Joint replacement surgery (refer to Section 9.6.1.4 in the protocol for when to report 
as an AESI) selected using an eCRF specific tick box on the AE page. 
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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 Time and Events (Section 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 
Section 10.3 for PCSV definitions).  
4.6.4. 
Vital Signs 
The following vital signs parameters will be collected according to the Schedule of Time and 
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 Section 10.3 
for PCSV definitions). 
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, 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 
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OR 
• The patient is unable to stand for either one of the standing blood pressure 
measurements due to dizziness or lightheadedness 
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 Time and Events in 
Section 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 clinically significant or abnormal clinically 
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 Section 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 Time and Events in 
Section 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, sensory, cranial nerves, reflexes and coordination/balance and assessment for 
presence/absence of signs of carpal tunnel syndrome. The results of each specific domains will 
be described as normal or abnormal (clinically significant, or not clinically significant) with the 
exception of the carpal tunnel evaluation which will be described as present/absent. 
4.6.8. 
Other Safety Variables 
Exploratory safety endpoints include: 
• Survey of Autonomic Symptoms questionnaire:  
− Potential events of sympathetic nervous system dysfunction are monitored 
throughout the study via the survey of autonomic symptoms. 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 
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be presented at scheduled timepoints.  Change from baseline in the degree of 
bothersomeness will be described as better, same or worse.  
• Joint Pain Questionnaire:  
− Number of subjects with significantly worse joint pain in any joint at each 
scheduled visit 
− Number of subjects with significantly worse joint pain by joint at each scheduled 
visit 
• Joint space width for the 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 
− Number and percentage of patients with 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 each of the 
collection times specified in Table 3 and Table 4 of the Schedule of Time and Events in 
Section 10.2. 
4.8. 
Immunogenicity Variables 
The immunogenicity variables are ADA status, titer, and NAb status at each time-point/visit. 
Serum samples for ADA will be collected at the clinic visits specified in Section 10.2. Samples 
positive in the fasinumab ADA assay will be further characterized for ADA titers and for the 
presence of NAb against fasinumab. 
4.9. 
Quality-of-Life Variables 
The following patient reported quality-of-life outcome measures will be recorded: 
• Change from baseline by visit in the SF-36 subscale scores including physical 
functioning, role-physical, bodily pain, general health, vitality, social functioning, 
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role-emotional, and 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. 
4.10. 
Health Economic Variables 
The following patient reported health economic outcome measures will be recorded: 
• HealthCare Resource Utilization (HCRU) including total and type of usage and 
hospitalizations. 
• Change from baseline by visit in the WPAI-OA item and subscores 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 variables captured at 
multiple visits will be analyzed by the following observations periods:  
• The Pre-Treatment Period is defined as the time from signing the ICF to before the 
first dose of study drug in Year 1.    
• The Year 1 On-Treatment Period is defined as the day from first dose of Year 1 study 
drug through the day of last Year 1 SC dose + 4 weeks for those patients not 
proceeding into Year 2, or up to the first dose of Year 2 study drug for those patients 
proceeding into Year 2.  Summaries for the Year 1 On-Treatment Period will be 
based on the SAF – Year 1.   
• The Year 1 Post-Treatment Period is defined from the end of the Year 1 On-
Treatment Period to the Week 72/Early Termination Visit for those patients not 
proceeding into Year 2.  Summaries for the Year 1 Post-Treatment Period will be 
based on the SAF – Year 1. 
• The Year 2 On-Treatment Period is defined as the day from first dose of Year 2 study 
drug through the day of last Year 2 SC dose + 4 weeks for those patients proceeding 
into Year 2.  Summaries for the Year 2 On-Treatment Period will be based on the 
SAF – Year 2.    
• The Year 1 and 2 On-Treatment Period is defined as day from first dose of Year 1 
study drug through the day of last SC dose + 4 weeks. Summaries for the Year 1 and 
2 On-Treatment Period will be based on both the SAF – Year 1 and SAF-Year 2. 
• The Year 2 Post-Treatment Period is defined from the end of the Year 2 On-
Treatment Period to the Week 124E/Early Termination E Visit for those patients 
proceeding into Year 2.  Summaries for the Year 2 Post-Treatment Period will be 
based on the SAF – Year 2. 
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 mFAS, FAS, SAF – Year 
1 and SAF – Year 2. 
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 – Year 1.  The tables will be sorted by decreasing frequency of primary SOC in the 
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overall group.  Within each primary SOC, PTs will be sorted by decreasing frequency in the 
overall group.  The same summaries will be also be supplied based on the SAF – Year 2. 
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 – Year 1 and the SAF – Year 2 separately.   
• All concomitant medications taken during the Year 1 On-Treatment Period will be 
summarized by treatment group based on the SAF – Year 1.  Similarly, all concomitant 
medications taken during the Year 2 On-Treatment Period will be summarized by 
treatment group based on the SAF – Year 2.   
• All Post-treatment medications taken during the Year 1 Post-Treatment period will be 
summarized by treatment group based on the subset of patients in the SAF – Year 1 who 
do not continue into Year 2.  For patients who continue into Year 2, all concomitant 
medications taken during the Year 2 Post-Treatment period will be summarized by 
treatment group based on the SAF – Year 2. 
5.4. 
 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.  The following will be provided: 
• All prohibited medications taken during the Pre-Treatment Period will be summarized by 
treatment group and overall, based on the SAF – Year 1 and SAF – Year 2 separately.   
• All prohibited medications taken during the Year 1 Treatment and Follow-up Periods will 
be summarized by treatment group based on the SAF – Year 1.  An analogous analysis 
will be performed for Year 2 Treatment and Follow-up Periods based on the SAF – Year 
2. 
• All prohibited NSAID medications taken during the Year 1 Treatment and Follow-up 
Periods will be summarized by treatment group based on the SAF – Year 1.  An 
analogous analysis will be performed for Year 2 Treatment and Follow-up Periods based 
on the SAF – Year 2.   
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• The total number of days using prohibited NSAIDs during the Year 1 Treatment and 
Follow-up Periods (before AA for patients with AA) will be summarized by treatment 
group based on the SAF – Year 1.  An analogous analysis will be performed for the Year 
2 Treatment and Follow-up Periods based on the SAF – Year 2. 
• The number of days from the last dose of study drug in Year 1 to the first NSAID dose 
will be summarized in the subset of patients in the SAF – Year 1 who do not continue 
into Year 2.  Similarly, the number of days from the last dose of study drug in Year 2 to 
the first NSAID dose will be summarized based on the SAF – Year 2.     
5.5. 
Subject Disposition 
In addition to the summaries in the following subsections, the following will be provided: 
• The total number of screened patients: defined as having signed the ICF  
• The total number of randomized patients (defined in the protocol as having received a 
randomization number). 
• The total number of patients in each analysis set. 
• A listing of patients treated but not randomized, patients randomized but not treated 
and patients randomized but not treated as randomized. 
• A listing of disposition for all patients. 
• A listings of screening failures and reasons for screen failing. 
• A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation. 
• A listing of patients who withdrew from the study, along with reasons for study 
withdrawal. 
5.5.1. 
Screening Disposition 
In the summaries below, percentages will be calculated using the number of screened patients as 
the denominator.  Summaries will present the overall frequencies (and percentages as applicable) 
for the following: 
• Screened patients. 
• Patients randomized. 
• 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. 
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5.5.2. 
Year 1 Treatment and Study Disposition 
In the summaries below, percentages will be calculated using the number of patients in the 
mFAS as the denominator.  Summaries will present the frequencies (and percentages as 
applicable) by treatment group for the following: 
• Patients randomized.  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 the Year 1 Treatment Period. 
• Patients who completed study treatment during the Year 1 Treatment Period. 
• Patients who discontinued treatment during the Year 1 Treatment Period separated 
out by reasons for treatment discontinuation. 
• Patients who enrolled in Year 2 (defined as having passed all the Inclusion/Exclusion 
criterion for Year 2 and signed the ICF form for Year 2). 
• Patients who entered the Year 1 Follow-up Period.  
• Patients who completed the Year 1 Follow-up Period. 
• Patients who withdrew from the study during the Year 1 Treatment Period separated 
out by reasons for study withdrawal. 
The same summary described above will also be provided based on the FAS. 
5.5.3. 
Year 2 Disposition 
In the summaries below, percentages will be calculated using the number of patients in the SAF 
– Year 2 as the denominator. Summaries will present the frequencies (and percentages as 
applicable) by treatment group for the following: 
• Patients enrolled and treated in Year 2. The treatment groups reflected in this row are 
based on the treatment received in Year 2 (see Section 3.4). 
• Patients who completed the Year 2 Treatment Period. 
• Patients who completed study treatment during the Year 2 Treatment Period. 
• Patients who discontinued treatment during the Year 2 Treatment Period separated 
out by reason for treatment discontinuation. 
• Patients who entered the Year 2 Follow-up Period.  
• Patients who completed the Year 2 Follow-up Period.  
• Patients who withdrew from the study during the Year 2 Treatment Period separated 
out by reason for study withdrawal. 
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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 
(see Section 5.8) 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 with descriptive statistics for the Year 1 and Year 2 Treatment Periods separately based 
on the SAF – Year 1 and SAF – Year 2 respectively.   
The total number of SC injections will be summarized by treatment groups with descriptive 
statistics for the Year 1 and Year 2 Treatment Periods based on the SAF – Year 1 and SAF – 
Year 2 respectively.  A summary of the number (and percentage) of patients categorized by the 
number of SC injections received will also be included. 
Oral Study Drug 
Overall treatment compliance to oral 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 for 
Year 1 up to treatment discontinuation of the Year 1 Treatment Period. It is calculated according 
to the following formula based on the Naproxen/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  𝑥100 
Overall treatment compliance to oral study drug during the Year 1 Treatment Period will be 
summarized descriptively by treatment group based on the SAF – Year 1. 
Since the oral study drug for Year 2 is naproxen prn, treatment compliance for oral study drug 
during the Year 2 Treatment Period is not applicable and will not be summarized.  
5.6.2. 
Exposure to Investigational Products 
The duration of SC study drug exposure during the Year 1 and Year 2 Treatment Periods is 
calculated as:  
= (Date of last SC injection of study drug in the respective treatment period – date of 
the first SC injection of study drug) + 28 
The duration of oral study drug exposure during the Year 1 and Year 2 Treatment Periods is 
calculated as: 
= (Date of first of oral study drug in the respective treatment period – date of the 
dose of oral study drug) + 1 
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The durations of SC and oral study drug exposures will be summarized by treatment group using 
descriptive statistics for the Year 1 and Year 2 Treatment Periods separately based on the SAF – 
Year 1 and SAF – Year 2 respectively.  
The number and percentage of patients exposed to SC/oral study drug will be presented by 
specific time interval for each treatment group for the Year 1 and Year 2 Treatment Periods 
separately based on the SAF – Year 1 and SAF – Year 2 respectively.  The time intervalss of 
interest are specified as:  
• For Year 1 Treatment Period: ≥ 1 day, ≥ 29 days, ≥ 57 days, ≥ 85 days, ≥ 113 days, ≥ 
141 days, ≥ 169 days, ≥ 197 days, ≥ 225 days, ≥ 253 days, ≥ 281 days, ≥ 309 days, ≥ 
337 days, ≥ 365 days. 
• For Year 2 Treatment Period: ≥ 365 day, ≥ 393 days, ≥ 421 days, ≥ 449 days, ≥ 477 
days, ≥ 505 days, ≥ 533 days, ≥ 561 days, ≥ 589 days, ≥ 617 days, ≥ 645 days, ≥ 673 
days, ≥ 701 days, ≥ 729 days. 
5.6.3. 
 Length of Study Observation 
The length of study observation is calculated as: 
= (Date of the last study visit [up to the end of the follow-up clinic visit, including 
post-op joint replacement follow-up visit 2] – date of the first study drug 
administration in Year 1) + 1 
The total length of study participation is calculated as: 
= (Date of the last scheduled study contact [up to the end of study phone call] – date 
of the first study drug administration in Year 1) + 1 
The lengths of study observation and participation will be summarized by treatment group using 
descriptive statistics based on the SAF – Year 1 and SAF – Year 2 separately. 
The number and percentage of patients with length of study observation/participation within 
specific time intervals will be presented by treatment group based on the SAF – Year 1 and SAF 
– Year 2 separately. The time intervals of interest are specified as: 
• For Year 1: ≥ 1 day, ≥ 29 days, ≥ 57 days, ≥ 85 days, ≥ 113 days, ≥ 141 days, ≥ 169 
days, ≥ 197 days, ≥ 225 days, ≥ 253 days, ≥ 281 days, ≥ 309 days, ≥ 337 days, ≥ 365 
days ≥ 393 days, ≥ 505 days, ≥ 701 days. 
• For Year 2:  ≥ 365 days ≥ 393 days, ≥ 421 days, ≥ 449 days, ≥ 477 days, ≥ 505 days, 
≥ 533 , ≥ 561 days, ≥ 589 days, ≥ 617 days, ≥ 645 days, ≥ 673 days, ≥ 701 days, ≥ 
729 days, ≥ 757 days, ≥ 869 days, ≥ 1065 days. 
5.7. 
Analyses of Efficacy Variables 
Unless stated otherwise, all efficacy analyses will be based on the mFAS using the Year 1 
baseline value.  Confidence intervals will be constructed with level of confidence equal to 95%.  
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 Variables 
The co-primary efficacy variables are: 
1. Change in the WOMAC pain subscale scores from baseline to week 16 
2. Change in the WOMAC physical function subscale score from baseline to week 16 
The following hypotheses will be tested:  
• H1,1: There is no treatment difference between fasinumab 1 mg Q4W and placebo in 
WOMAC pain or physical function subscale at week 16 versus there is treatment 
difference in WOMAC pain and physical function subscale score at week 16 
• H2,1: There is no treatment difference between fasinumab 1 mg Q8W and placebo in 
WOMAC pain or physical function subscale at week 16 versus there is treatment 
difference in WOMAC pain and physical function subscale score at week 16 
For H1,1, the estimand is the difference in means between the fasinumab 1 mg Q4W dose and 
placebo in the change from baseline to week 16 in the WOMAC pain and physical function 
scores in the mFAS, regardless of whether or not rescue medication or prohibited medication had 
been taken.  Any data collected after discontinuing treatment in Year 1 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 mFAS.  For 
patients who permanently discontinued treatment due to lack of efficacy, death or AEs, their 
missing WOMAC subscale scores after discontinuation will be imputed with values centered at 
the mean baseline WOMAC subscale score of the treatment group that patient was randomized 
to.  For patients who discontinued treatment due to other reasons (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 [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 52 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 4751611.  If a randomly 
imputed score is imputed outside the range of the WOMAC subscale score of 0-10, 
then the algorithm will continue to randomly impute scores until one within the range 
of 0-10 is obtained.  
• 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 4751611 and adjustment for covariates including treatment groups, 
randomization strata (K-L category [2 to 3, or 4], index joint [knee, hip], and 
geographical region [Europe, North America]), baseline WOMAC subscale score and 
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all WOMAC subscale scores at preceding visits.  Scores that are imputed outside the 
range of the WOMAC subscale will be addressed in the same manner as in step 1.   
• 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).   
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 [Europe, North America]), treatment, visit, and treatment-by-visit 
interaction as fixed effects.  The MMRM will be fitted using the MIXED procedure in Statistical 
Analysis System (SAS) with an unstructured covariance matrix to model the within-patient 
errors.  The denominator degrees of freedom will be estimated using Kenward-Roger’s 
approximation.  In the event a model cannot be 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 
16, 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 H1,1 will be rejected when the p-values corresponding to the difference in 
change from baseline to week 16 between fasinumab 1 mg Q4W and placebo is less than the 
available α0 (see Section 5.7.4 ) for both the WOMAC pain subscale score and physical function 
subscale score. 
Since the fasinumab 1 mg Q8W treatment arm was not included in the study prior to protocol 
amendment 5, the estimand and analysis method for testing H2,1 will mimic that used for H1,1 
with the exception that only the subset of patients in the mFAS who were randomized post 
amendment 5 will be utilized in the statistical analysis.  
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 and placebo in the change 
from baseline to week 16 in the WOMAC pain and physical function scores in the mFAS, 
regardless of study treatment discontinuation prior to week 52 and regardless of whether or not 
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rescue medication or prohibited medication had been taken.  Hence, data from all patients, 
including data collected after discontinuing treatment up to week 52 will be used in this 
sensitivity analyses.  Missing WOMAC subscale scores up to week 52 will be imputed with the 
same approach used in the primary analysis. 
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 52 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 4751611.  If a randomly 
imputed score is imputed outside the range of the WOMAC subscale score of 0-10, 
then the algorithm will continue to randomly impute scores until one within the range 
of 0-10 is obtained. 
• 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 4751611 and adjustment for covariates including treatment groups, 
randomization strata strata (K-L category [2 to 3, or 4], index joint [knee, hip], and 
geographical region [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 addressed in the same manner as in step 1.   
• Step 3: For missing data because of permanent study treatment discontinuation due to 
adverse events, death or lack of efficacy, δ will be added to the imputed values (δ = 0 
corresponds to the MAR assumption).  
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 [Europe, North 
America]), treatment, visit, and treatment-by-visit interaction as fixed effects.  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 0.025 or 0.05. Results will be then summarized using summary tables and 
graphs. 
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. 
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USM Analysis  
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 [Europe, North America] 
• Age group [< 65, 65-74, ≥ 75 years]  
• Sex [Male, Female] 
• Weight group [< median baseline weight, ≥ median baseline weight kg] 
• BMI group [≤ median baseline BMI, > median baseline BMI] 
• Flare status [Flare, Non-Flare] where 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 subgroup-by-
treatment interaction will be supplied.  Forest plots for the subgroup analyses will also be 
provided. 
5.7.3. 
Analysis of Secondary Efficacy Variables 
The key secondary variables defined in the study protocol are: 
1. Change in the Patient Global Assessment (PGA) scores from baseline to week 16 
2. Percentage of patients who had a response at week 16, with response defined as an 
improvement by ≥30% in the WOMAC pain subscale scores 
3. Change in WOMAC pain subscale scores from baseline to week 44 
4. Change in WOMAC physical function subscale scores from baseline to week 44 
5. Change in the PGA scores from baseline to week 44  
6. Change in WOMAC pain subscale scores from baseline to the average score across 
Weeks 4, 8, 12 and 16  
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7. Change in WOMAC physical function subscale from baseline to the average score across 
Weeks 4, 8, 12 and 16  
8. Change in WOMAC pain subscale scores from baseline to the average score across 
Weeks 36, 40 and 44  
9. Change in WOMAC physical function subscale scores from baseline to the average score 
across Weeks 36, 40 and 44  
The following are secondary hypotheses specified in the study protocol that will be tested:  
• H1,2: There is no treatment difference between fasinumab 1 mg Q4W and placebo in 
Patient Global Assessment score at week 16 versus there is treatment difference in 
Patient Global Assessment score at week 16  
• H1,3: 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 16 versus there is treatment difference in proportion of patients with 
≥30% improvement in WOMAC pain at week 16  
• H1,4: There is no treatment difference between fasinumab 1 mg Q4W and naproxen in 
WOMAC pain subscale scores at week 16 versus there is a treatment difference in the 
WOMAC pain subscale scores at week 16  
• H1,5: There is no treatment difference between fasinumab 1 mg Q4W and naproxen in 
WOMAC physical function subscale scores at week 16 versus there is a treatment 
difference in the WOMAC physical function subscale scores at week 16  
• H1,6: There is no treatment difference between fasinumab 1 mg Q4W and placebo in 
WOMAC pain subscale scores at week 44 versus there is treatment difference in 
WOMAC pain subscale scores at week 44  
• H1,7: There is no treatment difference between fasinumab 1 mg Q4W and placebo in 
WOMAC physical function subscale scores at week 44 versus there is treatment 
difference in WOMAC physical function subscale scores at week 44 
• H1,8: There is no treatment difference between fasinumab 1 mg Q4W and placebo in 
Patient Global Assessment score at week 44 versus there is treatment difference in 
Patient Global Assessment score at week 44  
• H1,9: There is no treatment difference between fasinumab 1 mg Q4W and naproxen in 
Patient Global Assessment score at week 16 versus there is treatment difference in 
Patient Global Assessment score at week 16  
• H1,10: There is no treatment difference between fasinumab 1 mg Q4W and placebo in 
the WOMAC pain subscale scores averaged across Weeks 4, 8, 12 and 16 versus 
there is treatment difference in the WOMAC pain subscale scores averaged across 
Weeks 4, 8, 12 and 16 
• H1,11: There is no treatment difference between fasinumab 1 mg Q4W and placebo in 
the WOMAC physical function subscale scores averaged across Weeks 4, 8, 12 and 
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16 versus there is treatment difference in the WOMAC physical function subscale 
scores averaged across Weeks 4, 8, 12 and 16  
• H1,12: There is no treatment difference between fasinumab 1 mg Q4W and placebo in 
the WOMAC pain subscale scores averaged across Weeks 36, 40 and 44 versus there 
is treatment difference in the WOMAC pain subscale scores averaged across Weeks 
36, 40 and 44  
• H1,13: There is no treatment difference between fasinumab 1 mg Q4W and placebo in 
the WOMAC physical function subscale scores averaged across Weeks 36, 40 and 44 
versus there is treatment difference in the WOMAC physical function subscale scores 
averaged across Weeks 36, 40 and 44  
• H1,14: There is no treatment difference between fasinumab 1 mg Q4W and naproxen 
in WOMAC pain subscale scores at week 44 versus there is treatment difference in 
WOMAC pain subscale scores at week 44  
• H1,15: There is no treatment difference between fasinumab 1 mg Q4W and naproxen 
in WOMAC physical function subscale scores at week 44 versus there is treatment 
difference in WOMAC physical function subscale scores at week 44 
• H1,16: There is no treatment difference between fasinumab 1 mg Q4W and naproxen 
in the proportion of patients with ≥30% improvement in the WOMAC pain subscale 
scores at week 16 versus there is treatment difference in proportion of patients with 
≥30% improvement in WOMAC pain at week 16 
• H2,2: There is no treatment difference between fasinumab 1 mg Q8W and placebo in 
Patient Global Assessment score at week 16 versus there is treatment difference in 
Patient Global Assessment score at week 16  
• H2,3: There is no treatment difference between fasinumab 1 mg Q8W and placebo in 
the proportion of patients with ≥30% improvement in the WOMAC pain subscale 
scores at week 16 versus there is treatment difference in proportion of patients with 
≥30% improvement in WOMAC pain at week 16  
• H2,4: There is no treatment difference between fasinumab 1 mg Q8W and naproxen in 
WOMAC pain subscale scores at week 16 versus there is a treatment difference in the 
WOMAC pain subscale scores at week 16  
• H2,5: There is no treatment difference between fasinumab 1 mg Q8W and naproxen in 
WOMAC physical function subscale scores at week 16 versus there is a treatment 
difference in the WOMAC physical function subscale scores at week 16  
• H2,6: There is no treatment difference between fasinumab 1 mg Q8W and placebo in 
WOMAC pain subscale scores at week 44 versus there is treatment difference in 
WOMAC pain subscale scores at week 44  
• H2,7: There is no treatment difference between fasinumab 1 mg Q8W and placebo in 
WOMAC physical function subscale scores at week 44 versus there is treatment 
difference in WOMAC physical function subscale scores at week 44  
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• H2,8: There is no treatment difference between fasinumab 1 mg Q8W and placebo in 
Patient Global Assessment score at week 44 versus there is treatment difference in 
Patient Global Assessment score at week 44  
• H2,9: There is no treatment difference between fasinumab 1 mg Q8W and naproxen in 
Patient Global Assessment score at week 16 versus there is treatment difference in 
Patient Global Assessment score at week 16  
• H2,10: There is no treatment difference between fasinumab 1 mg Q8W and placebo in 
the WOMAC pain subscale scores averaged across Weeks 4, 8, 12 and 16 versus 
there is treatment difference in the WOMAC pain subscale scores averaged across 
Weeks 4, 8, 12 and 16 
• H2,11: There is no treatment difference between fasinumab 1 mg Q8W and placebo in 
the WOMAC physical function subscale scores averaged across Weeks 4, 8, 12 and 
16 versus there is treatment difference in the WOMAC physical function subscale 
scores averaged across Weeks 4, 8, 12 and 16  
• H2,12: There is no treatment difference between fasinumab 1 mg Q8W and placebo in 
the WOMAC pain subscale scores averaged across Weeks 36, 40 and 44 versus there 
is treatment difference in the WOMAC pain subscale scores averaged across Weeks 
36, 40 and 44  
• H2,13: There is no treatment difference between fasinumab 1 mg Q8W and placebo in 
the WOMAC physical function subscale scores averaged across Weeks 36, 40 and 44 
versus there is treatment difference in the WOMAC physical function subscale scores 
averaged across Weeks 36, 40 and 44  
The hypotheses H1,4, H1,5, H1,6, H1,7, H1,14 and H1,15 can be tested within the same analysis 
method used to test H1,1 as described in Section 5.7.1.  Similarly, H2,4, H2,5, H2,6 and H2,7 can be 
tested within the same analysis methods used to test H2,1 as described in Section 5.7.1.  
Additionally, the treatment policy analysis, per-protocol analysis and subgroup analyses 
described in Section 5.7.1 for the primary endpoint can also be utilized for the hypotheses 
mentioned in this paragraph. 
To test H1,2, H1,8 and H1,9, a method analogous to that used to test H1,1 in Section 5.7.1 can be 
utilized, replacing the respective WOMAC subscale score with the PGA score.  Likewise, H2,2, 
H2,8 and H2,9 can be tested using a method analogous to that used to test H2,1 in Section 5.7.1, 
replacing the respective WOMAC subscale score with the PGA score and only using the subset 
of patients in the mFAS randomized after protocol amendment 5 for the analyses.  The multiple 
imputation algorithm will be modified to resample values outside the range of the PGA score (0-
5) in a manner similar to the primary analysis. 
To test H1,3 and H1,16, 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 [Europe, 
North America]) will be used with missing data considered as non-response.  The same method 
can be utilized to test H2,3, however, only basing the analysis on the subset of patients in the 
mFAS who were randomized post protocol amendment 5. 
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To test hypothesis H1,10, H1,11, H1,12 and H1,13, the same multiple imputation method used to test 
H1,1 in Section 5.7.1 will be utilized.  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]) and treatment.  Hypothesis 
H2,10, H2,11, H2,12 and H2,13 will be tested via an analogous method using only the subset of 
patients in the mFAS randomized after protocol amendment 5 for the analyses. 
5.7.4. 
Adjustment for Multiple Comparisons 
To control the overall Type I Error of the clinical trial at 5%, the graphical testing procedure 
(Bretz 2009) will be applied.  The order the hypothesis will be tested is provided in the schematic 
representation of the multiple testing procedure below (Figure 2). 
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.  
Figure 2: 
Hypothesis Testing Procedure 
 
 
 
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5.7.5. 
Analysis of Other Efficacy Variables 
As additional sensitivity analyses, the following efficacy endpoints will be analyzed using the 
same method as was used for hypotheses H1,1, and H2,1: 
• Change in WOMAC pain subscale scores from baseline to week 48 
• Change in WOMAC physical function subscale scores from baseline to week 48 
• Change in WOMAC pain subscale scores from baseline to week 52 
• Change in WOMAC physical function subscale scores from baseline to week 52 
The same analysis used for hypotheses H1,3, H1,16, and H2,3 will be used to analyze the following 
additional efficacy endpoints: 
• The number and percentage of patients with an improvement of ≥ 50% from baseline 
in the WOMAC pain subscale scores at weeks 16, 44, 52  
• The number and percentage of patients with an improvement of ≥ 70% from baseline 
in the WOMAC pain subscale scores at week 16, 44, 52 
• The number and percentage of patients with an improvement of ≥ 30% from baseline 
in the WOMAC physical function subscale scores at week 16, 44, 52  
• The number and percentage of patients with an improvement of ≥ 50% from baseline 
in the WOMAC physical function subscale scores at week 16, 44, 52  
• The number and percentage of patients with an improvement of ≥ 70% from baseline 
in the WOMAC physical function subscale scores at week 16, 44, 52  
• The number and percentage of patients meeting the OMERACT-OARSI criterion at 
week 16, 44, 52 
Cumulative distribution of percent change from baseline to Week 16 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.  
Walking Index Joint Pain Questionnaire 
Analysis of the WIJPNRS pain scale will be on the weekly averages. 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 [North America, Europe]), treatment, week (weeks 1, 2, …, 52), 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. 
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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 – Year 1 and SAF – 
Year 2.  Analogous analysis will be performed for both the Year 1 On-Treatment Period and 
Year 2 On-Treatment Period based on the SAF – Year 1 and SAF – Year 2 respectively. 
For patients taking rescue medication, descriptive statistics of the number of days patients took 
rescue medications will be presented by treatment group during both the Year 1 On-Treatment 
Period and Year 2 On-Treatment Period based on the SAF – Year 1 and SAF – Year 2 
respectively.    
For patients taking rescue medication, weekly average usage of rescue medications (measured in 
mg) is calculated as follows: 
= 𝑇𝑜𝑡𝑎𝑙 𝑎𝑚𝑜𝑢𝑡 𝑜𝑓 𝑟𝑒𝑠𝑐𝑢𝑒 𝑚𝑒𝑑𝑖𝑐𝑎𝑡𝑖𝑜𝑛 𝑢𝑠𝑒𝑑 𝑖𝑛 𝑡ℎ𝑒 𝑠𝑝𝑒𝑐𝑖𝑓𝑖𝑒𝑑 𝑤𝑒𝑒𝑘 (𝑖𝑛 𝑚𝑔)
𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑑𝑖𝑎𝑟𝑦 𝑒𝑛𝑡𝑟𝑖𝑒𝑠 𝑖𝑛 𝑡ℎ𝑒 𝑠𝑝𝑒𝑐𝑖𝑓𝑖𝑒𝑑 𝑤𝑒𝑒𝑘
 
Descriptive statistics of the weekly average usage of rescue medications will be presented by 
treatment group for both the Year 1 On-Treatment Period and Year 2 On-Treatment Period based 
on the SAF – Year 1 and SAF- Year 2 respectively.. 
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 
[North America, Europe]), 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 doses and placebo and 
naproxen, 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. 
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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. 
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.   
Data from Year 2 
The following endpoints were collected in Year 2: 
• WOMAC 
• EQ-5D-5L 
• WPAI-OA 
• Rescue Medication Usage 
Summary statistics for the above variables will be presented by treatment group for each visit in 
Year 2 based on the SAF – Year 2.  For numeric endpoints, the raw, change from Year 1 baseline 
value and change from Year 2 baseline values will be summarized.  No models will be fit to the 
data, nor will any statistical analysis be performed comparing treatment arms or statistics derived 
from statistical models. 
5.7.7. 
FAS Analysis 
All analyses of the co-primary, secondary, exploratory and PRO endpoints specified in 
Section 5.7.1, Section 5.7.2, Section 5.7.3, Section 5.7.5 and Section 5.7.6 will also be performed 
using the FAS.  For analyses utilizing the stratification variable geographic region, the strata 
included will be: North America, Europe and Rest of World.   
5.8. 
Analysis of Safety Data 
The analysis of safety and tolerability will be performed on the SAF – Year 1 and SAF – Year 2, 
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. 
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The time interval to detect any AEs, including AESIs (except JRs identified at the End of Study 
Phone Calls), or abnormalities is between the first dose of Year 1 study drug dose up to the end 
of the Follow-Up Period (either the week 72/Early Termination for those patients not proceeding 
into Year 2, the week 124E/Early Termination E for those patients proceeding into Year 2 or the 
Post-Op Joint Replacement Follow-up Visit 2).  Any study drug-related SAEs occurring between 
the end of Follow-Up Period 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. 
All safety analyses will be performed on Year 1 and Year 2 using the following common rules: 
• The Year 1 baseline value will be used for all analyses of the Year 1 On-Treatment, 
Year 1 and 2 On-Treatment and Year 1 Post-Treatment Periods. 
• The Year 2 baseline value will be used for all analyses of the Year 2 On-Treatment 
and Year 2 Post-Treatment Periods.   
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. 
Pre-treatment AEs are defined as AEs that developed or worsened during the Pre-Treatment 
Period. 
Treatment-emergent AEs (TEAEs) are defined as AEs that developed or worsened during the 
On-Treatment Periods. 
Post-treatment AEs are defined as AEs that developed or worsened more than 4 weeks after the 
last dose of SC study drug. 
The focus of adverse event reporting in the clinical study report will be on TEAEs. 
For details on handling missing data and partial dates, see Section 6.4. 
Summaries of all TEAEs in each treatment group will include: 
• Overview of TEAEs, summarizing number of events and number and percentage of 
patients within the specified category: 
− Total number of TEAEs 
− Total number of serious TEAEs 
− Total number of treatment-emergent AESIs 
− Patients with any TEAEs 
− Patients with any serious TEAEs 
− Patients with any treatment-emergent AESIs 
− Patients with any TEAEs leading to permanent discontinuation from study drug  
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− Patients with any TEAEs leading to withdrawal from the 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 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 
• All Serious TEAEs by SOC and PT 
• Post-treatment Serious AEs by SOC and PT 
• All serious AEs by SOC and PT 
• All non-serious TEAEs by SOC and PT 
• Post-treatment non-serious AEs by SOC and PT 
• All non-serious AEs by SOC and PT 
• All AEs by SOC and PT 
− All AEs   
− All AEs by severity: mild, moderate or severe 
• Deaths 
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. 
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The above TEAE analyses will be performed for the Year 1 On-Treatment Period, Year 2 On-
Treatment Period, Year 1 and 2 On-Treatment Period, Year 1 Post-Treatment Period and Year 2 
Post-Treatment Period using the corresponding analyses sets specified in Section 5. 
The following listings will be included: 
• AEs leading to death 
• TEAEs leading to permanent discontinuation from study drug (not applicable to post-
treatment AEs) 
• TEAEs leading to withdrawal from study 
• Patients with Serious TEAEs 
• AESIs 
• Deaths 
• All Cause 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.   
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 
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be summarized by treatment group.  The PCSV laboratory summaries will be constructed for 
both Year 1 and Year 2 On-Treatment Periods.   
For hs-CRP and alkaline phosphatase, subgroup analysis will be performed for the following: 
• Adjudicated Arthropathy category 1 (Presence of AA: patients without / with AA)  
• Adjudicated Arthropathy category 2 (Subtype of AA: patients without AA, patients 
with RPOA-1, and patients with other AA subtype except RPOA-1) 
• Destructive Arthropathy category (Presence of DA: patients without AA, patients 
with non-DA AA, patients with DA) 
For hs-CRP, plots of means and medians of the change from baseline over time will be presented 
by treatment group. 
For alkaline phosphatase, plots of means of the observed change from baseline over time will be 
presented by treatment group, overall and by subgroup. 
Lab data collected during the Pre-Treatment Period 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 PCSV laboratory summaries will be constructed for 
both Year 1 and Year 2 On-Treatment Periods 
The incidence of orthostatic hypotension, separated out by the specific criteria leading to an 
orthostatic hypotension diagnosis, will also be summarized by treatment group. 
The above vital sign summaries will be constructed for the Year 1 and 2, Treatment and Follow-
up Periods.  Vital sign data collected during the Pre-Treatment Period 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. 
The above ECG summaries will be presented for both On-Treatment Periods. 
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 study.  Similarly, summaries will be presented for 
neurological exam findings.  These summaries will be constructed for the Treatment and Follow-
up Periods, for both Year 1 and 2. 
5.8.7. 
Analysis of Other Safety Variables 
Other safety data includes the survey of Autonomic Symptoms, cases of AA and joint 
replacements. 
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. 
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. 
All-cause Joint Replacements 
The number and percentage of patients with all-cause joint replacements will be presented by 
treatment group for the, Treatment and Follow-up Periods both Year 1 and Year 2.   The number 
of replacements in joints that were positively adjudicated will be summarized by treatment 
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group.  Joint replacements will also be summarized by KL score of the affected joint at 
screening.   
The time to JR is calculated as: 
= (Date of JR – Date of first dose of study drug in Year 1) + 1 
Plots of the Kaplan Meier curves by treatment group (as randomized to in Year 1) of time to JR 
will be presented based on the SAF – Year 1.  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 serum concentrations of functional fasinumab will be presented by nominal time 
point and dose. Concentrations below the LLOQ of the bioanalytical assay will be set to zero 
when calculating means. 
Plots of individual concentrations over time will be presented by actual day (linear and log 
scales). Plots of mean and/or median serum concentrations of fasinumab will be presented by 
nominal time (linear and log scales). For linear-scaled plots, concentrations below the LLOQ 
will be set to zero; for log-scaled plots, concentrations below the LLOQ will be imputed as 
LLOQ/2. 
Relationships between concentrations of fasinumab and efficacy endpoints, safety endpoints, 
and/or biomarkers may be evaluated, as appropriate. 
5.10. 
Analysis of Immunogenicity Data 
5.10.1. 
Analysis of ADA Data 
The immunogenicity variables described in Section 4.8 will be summarized using descriptive 
statistics.  Immunogenicity will be characterized by ADA responses and titers observed in 
patients in the ADA analysis set. ADA response categories and titer categories are defined as 
follows: 
ADA response categories 
• ADA Negative, defined as ADA negative response at all time points, regardless of 
any missing samples. 
• Pre-existing immunoreactivity, defined as either an ADA positive response in the 
ADA assay at baseline with all post first dose ADA results negative, OR a positive 
response at baseline with all post first dose ADA responses less than 9-fold over 
baseline titer levels. 
• Treatment-emergent response, defined as a positive response in the ADA assay post 
first dose when baseline results are negative or missing. The treatment-emergent 
responses will be further characterized as Persistent, Indeterminate or Transient: 
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− Persistent Response – Treatment-emergent ADA positive response with two or 
more consecutive ADA positive sampling time points, separated by at least 16-
week period (based on nominal sampling time), with no ADA negative samples in 
between, regardless of any missing samples. 
− Indeterminate Response –Treatment-emergent ADA positive response with only 
the last collected sample positive in the ADA assay, regardless of any missing 
samples. 
− Transient Response –Treatment-emergent ADA positive response that is not 
considered persistent or indeterminate, regardless of any missing samples. 
• Treatment-boosted response, defined as a positive response in the ADA assay post 
first dose that is greater than or equal to 9-fold over baseline titer levels, when 
baseline results are positive 
Titer categories (Maximum titer values) 
• Low (titer <1,000) 
• Moderate (1,000 ≤ titer ≤ 10,000) 
• High (titer >10,000) 
The following analysis will be provided: 
• Number (n) and percent (%) of ADA-negative patients (pre-existing 
immunoreactivity or negative in the fasinumab ADA assay at all time points) by 
treatment groups 
• Number (n) and percent (%) of treatment-emergent ADA positive patients by 
treatment groups and ADA titer categories 
− Number (n) and percent (%) of persistent treatment-emergent ADA positive 
patients 
− Number (n) and percent (%) of indeterminate treatment-emergent ADA positive 
patients 
− Number (n) and percent (%) of transient treatment-emergent ADA positive 
patients 
• Number (n) and percent (%) of treatment-boosted ADA positive patients by treatment 
groups and ADA titer categories 
Listing of all ADA titer levels will be provided for patients with pre-existing, treatment-emergent 
and treatment-boosted ADA response. 
5.10.2. 
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 Exposure 
Potential association between immunogenicity variables and systemic exposure to fasinumab 
will be explored by treatment groups. Plots of fasinumab concentration may be provided for 
analyzing the potential impact of ADA response status, titer and NAb on PK.  
5.10.3.2. Immunogenicity and Safety and Efficacy 
Potential association between immunogenicity variables and safety may be explored with a 
primary focus on the following safety events during the TEAE period: 
• Injection site reaction (serious or severe and lasting 24 hours or longer) 
• Hypersensitivity (SMQ: Hypersensitivity [Narrow]) 
• Anaphylactic Reaction (SMQ: Anaphylactic Reaction [Narrow]) 
Potential association between immunogenicity variables and efficacy and safety endpoints may 
be explored (e.g. scatter plot or spaghetti plot). The above-mentioned safety and efficacy 
analyses  will be conducted using the following categories: 
• ADA positive patients, that is patients with treatment-emergent or treatment-boosted 
response. 
• ADA negative patients, that is patients with pre-existing immunoreactivity or 
negative in the ADA assay at all time points. 
• Patients with persistent treatment-emergent ADA response. 
• 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 
The following baselines will be used for both the efficacy and safety analyses. 
• The Year 1 baseline value is defined as the last available value before randomization. 
• The Year 2 baseline value is defined as the last available value after the last dose of 
Year 1 treatment but before the first dose of Year 2 treatment. 
6.2. 
Data Handling Convention for Efficacy Variables  
6.2.1. 
Handling of Missing Efficacy Data due to COVID-19 Public Health Measures 
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 Data 
Orthostatic Hypotension data 
This applies specifically to the data handling of repeat measurements in the assessment of 
orthostatic hypotension. Per protocol, if the initial vital assessment for orthostatic hypotension is 
consistent with the definition of orthostatic hypotension, the supine, standing blood pressure or 
pulse should be repeated up to 2 more times. The guideline for the repeat assessments are shown 
below: 
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 
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Baseline for the assessment of orthostatic hypotension vital assessments uses the last available 
assessment prior to the start of study drug. Measurements post-baseline will not be averaged. 
Rather frequency counts for patients meeting OH criteria for orthostatic hypotension will reflect 
the scenario as shown on the table.  
Patient reported outcomes data 
Should there be duplicate entries for patient reported outcomes data (not including diary data), 
the average of the entries will be used for questionnaires with numerical values such as the 
WOMAC. The worst category will be used in the analysis for questionnaires with categorical 
responses such as the SOAS and JPQ. 
6.4. 
Data Handling Conventions for Missing Data 
Rules for handling missing data for primary and secondary efficacy variables are described in 
Section 5.7.1 and Section Section 5.7.3. 
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 be 
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 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 on 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, End-of-Treatment (EOT), and 
End-of-Study (EOS)/Early Termination (ET) 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 Section 10.2 Schedule of Time and Events. The following visit windows will be used to map the 
unscheduled visits, EOT and EOS /ET visits  and eCOA assessments based on the study day: 
Table 1: 
Year 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 1 
8 
[2, 11] 
4 
Week 2  
15 
[12, 22] 
5 
Week 4 
29 
[23, 43]  
6 
Week 8 
57 
[44, 71] 
7 
Week 12 
85 
[72, 99] 
8 
Week 16 
113 
[100, 127] 
9 
Week 20 
141 
[128, 155] 
10 
Week 24 
169 
[156, 183] 
11 
Week 28 
197 
[184, 211] 
12 
Week 32 
225 
[212, 239] 
13 
Week 36 
253 
[240, 267] 
14 
Week 40 
281 
[268, 295] 
15 
Week 44 
309 
[296, 323] 
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Visit Number 
Visit Name 
Targeted Study Daysa 
Analysis Window in 
Study Days 
16 
Week 48 
337 
[324, 351] 
17 
Week 52  
365 
[352, 393] 
18 
Week 56 
393 
[394, 463] 
19 
Week 72 
505 
[464, 603] 
Phone 2 
Week 100 
701 
≥ 604 
a Study days are calculated from the first dose of study drug (Day 1). 
Table 2: 
Year 2 Analysis Windows 
Visit Number 
Visit Name 
Targeted Study Daysa 
Analysis Window in 
Study Days 
17E 
Week 52E 
365E 
[352, 379] 
18E 
Week 56E 
393E 
[380, 407] 
19E 
Week 60E 
421E 
[408, 435] 
20E 
Week 64E 
449E 
[436, 463] 
21E 
Week 68E  
477E 
[464, 491] 
22E 
Week 72E 
505E 
[492, 519]  
23E 
Week 76E 
533E 
[520, 547] 
24E 
Week 80E 
561E 
[548, 575] 
25E 
Week 84E 
589E 
[576, 603] 
26E 
Week 88E 
617E 
[604, 631] 
27E 
Week 92E 
645E 
[632, 659] 
28E 
Week 96E 
673E 
[660, 687] 
29E 
Week 100E 
701E 
[688, 715] 
30E 
Week 104E 
729E 
[716, 743] 
31E 
Week 108E 
757E 
[744, 813] 
32E 
Week 124E 
869E 
[814, 967] 
Phone 2E 
Week 152E 
1065E 
≥ 968 
a Study days are calculated from the first dose of study drug (Day 1). 
If multiple measurements occur within the same visit window, the following rules will be used to 
determine the analysis value:  
• When multiple valid measurements occur within the same visit window, the one 
closest to the target study day will be used in the analysis.  
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• 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: Bulgaria, Denmark, France, Germany, Hungary, Italy, Lithuania, Poland, 
Romania, Russia, Spain, Ukraine, United Kingdom 
• North America: United States 
• Rest of World: South Africa 
6.8. 
Statistical Technical Issues 
Not applicable. 
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7. 
INTERIM ANALYSIS 
No interim analysis of efficacy data from Year 1 will be conducted prior to collection of all data 
necessary for the the primary and secondary analysis.   
A first-step analysis of all available efficacy and safety data for Year 1 and select analysis of 
available Year 2 safety data will be performed when all data for Year 1 Treatment Period (baseline 
through week 52) have been collected and validated for all randomized patients.   
Another analysis will be performed for regulatory purposes on the remaining Year 1 WOMAC 
and PRO assessments and safety data (collected during the Year 1 follow-up period) and any Year 
2 efficacy and safety data available at the time of the data cut-off for the second analysis.   
Additional analyses of other efficacy and safety data may be performed for regulatory purposes as 
needed. 
Individuals unblinded to patient-level data for the first-step or any subsequent analyses will no 
longer be involved in the day-to-day conduct of the ongoing study.  Patient-level results will not 
be released to any site-facing personnel or anyone who is directly involved in the conduct of the 
study. 
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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  
mFAS, FAS, 
PPS 
Change from baseline 
at Week 16 in the 
WOMAC pain subscale 
scores 
& 
Change from baseline 
at Week 16 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 16 in the WOMAC 
pain subscale scores 
& 
Change from baseline at 
Week 16 in the WOMAC 
physical function subscale 
scores 
Secondary Endpoints 
Change from baseline in 
WOMAC pain subscale 
scores  
mFAS, FAS, 
PPS 
Change from baseline 
at Week 44 in the 
WOMAC pain subscale 
scores 
MMRM with 
multiple 
imputation 
Sensitivity 
Analyses:  
- Treatment 
Policy Estimand 
- Analysis using 
the PPS 
Subgroups: K-L 
Category, Index 
Joint, Region, 
Age Group, Sex, 
Weight, BMI 
Group. 
Change from baseline at all 
other visits in the WOMAC 
pain subscale scores 
Change from baseline in 
WOMAC physical 
function subscale scores  
mFAS, FAS, 
PPS 
Change from baseline 
at Week 44 in the 
WOMAC physical 
function subscale 
scores 
MMRM with 
multiple 
imputation 
Sensitivity 
Analyses:  
- Treatment 
Policy Estimand 
- Analysis using 
the PPS 
Subgroups: K-L 
Category, Index 
Joint, Region, 
Age Group, Sex, 
Weight, BMI 
Group. 
Change from baseline at all 
other visits in the WOMAC 
physical function subscale 
scores 
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Endpoint 
Analysis 
Populations 
Primary Analysis 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Change from baseline in 
WOMAC pain subscale 
scores averaged across 
multiple timepoints  
mFAS, FAS 
Change from baseline 
in WOMAC pain 
subscale scores 
averaged across Weeks 
4, 8, 12 and 16  
ANCOVA with 
multiple 
imputation 
 
 
Change from baseline in 
WOMAC pain subscale 
scores averaged across 
Weeks 36,40 and 44  
Change from baseline in 
WOMAC physical 
function subscale scores 
averaged across multiple 
timepoints 
mFAS, FAS 
Change  from baseline 
in WOMAC physical 
function subscale 
scores averaged across 
Weeks 4, 8, 12 and 16  
ANCOVA with 
multiple 
imputation 
 
 
Change from baseline in 
WOMAC physical function 
subscale scores averaged 
across Weeks 36,40 and 44  
Change from baseline in 
PGA scores  
mFAS, FAS 
Change from baseline 
at Week 44 in the 
WOMAC physical 
function subscale 
scores 
MMRM with 
multiple 
imputation 
 
 
Change from baseline at all 
other visits in PGA scores 
Proportion of patients 
with ≥ 30% improvement 
in WOMAC pain subscale  
mFAS, FAS 
Proportion of patients 
with ≥ 30% 
improvement in 
WOMAC pain subscale 
at Week 16 
CMH Test 
 
 
NA 
 
 
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Safety Analyses: 
Endpoint 
Analysis 
Populations 
Primary Analysis 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Treatment Emergent 
Adverse Events 
SAF – Year 1 & 
SAF – Year 2 
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 
Serious Adverse Events 
SAF – Year 1 & 
SAF – Year 2 
Percent of patients by 
system organ class and 
preferred term 
Descriptive Statistics 
No 
No 
NA 
Treatment-related 
Treatment Emergent 
Adverse Events 
SAF – Year 1 & 
SAF – Year 2 
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 – Year 1 & 
SAF – Year 2 
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 – Year 1 & 
SAF – Year 2 
Percent of patients by 
system organ class and 
preferred term 
Descriptive Statistics 
No 
No 
No 
Treatment Emergent Non-
Serious Adverse Events 
SAF – Year 1 & 
SAF – Year 2 
Percent of patients by 
system organ class and 
preferred term 
Descriptive Statistics 
No 
No 
No 
Clinical Laboratory 
Measurements 
SAF – Year 1 & 
SAF – Year 2 
Actual and Change from 
baseline values 
Descriptive Statistics 
PCVS Analysis 
No 
No 
Vital Sign Measurements 
SAF – Year 1 & 
SAF – Year 2 
Actual and Change from 
baseline values 
Descriptive Statistics 
PCVS Analysis 
No 
Incidence of Orthostatic 
Hypotension 
12-Lead ECGs 
SAF – Year 1 & 
SAF – Year 2 
Actual and Change from 
baseline values 
Descriptive Statistics 
PCVS Analysis 
No 
Shift Table Analysis 
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Endpoint 
Analysis 
Populations 
Primary Analysis 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Physical & Neurological 
Exams 
SAF – Year 1 & 
SAF – Year 2 
Number of patients with 
new-onset abnormal 
examination findings 
Descriptive Statistics 
NA 
No 
No 
Survey of Autonomic 
Symptoms 
SAF – Year 1 & 
SAF – Year 2 
Number of patients 
reporting the presence 
of each symptom/health 
problem 
Descriptive Statistics 
Number of 
Symptoms 
Reported 
 
Total Symptom 
Impact Score 
No 
No 
Adjudicated Arthropathy 
SAF – Year 1 & 
SAF – Year 2 
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 
No 
Joint Replacements 
SAF – Year 1 & 
SAF – Year 2 
Number of patients with 
joint replacements 
Descriptive Statistics 
Time to JR 
No 
No 
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10.2. 
Schedule of Time and Events 
Table 3: 
Schedule of Events for Year 1 
 
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Footnotes for the Schedule of Events Table 3 (Year 1) 
1. Patients who discontinue study drug before week 52 will be encouraged to follow the visit schedule through the remainder of 
the study. If a patient chooses to end study participation, he/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 administered after all 
laboratory, PK, ADA and research samples have been collected and all study related activities have been performed. Patients 
will be observed in the clinic for approximately 1 hour after SC study drug is administered. 
6. Use of study-provided rescue medication will be recorded daily in patient diaries. Acetaminophen/paracetamol use will be 
reported from pre-randomization visit to week 52. 
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 the 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 52. Walking index joint pain NRS score will be recorded by the patient at the site at the 
week 52 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. 
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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. An MRI will be performed on the index and contralateral joints at screening for all patients. In addition, an MRI will be 
performed on any knee or hip with a K-L of ≥3. 
13. Imaging (X-ray and possible 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. 
14. In the event that a patient must undergo JR surgery during the study, the patient must complete the pre-operative study visit 
(early termination assessments, as applicable) and the procedures outlined in the schedule of events for JR follow-up (Table 5). 
This will include a Knee Society Score questionnaire for knee replacements or Harris Hip Score questionnaire for hip 
replacements. The pre-operative visit must be completed before the JR surgery. Pre-operative images will be submitted to the 
adjudication committee for review. 
15. Samples will be analyzed by the central laboratory and results evaluated by the investigator. 
16. Assessment of follicle-stimulating hormone (FSH) and estradiol levels are only to be performed if assessment of 
postmenopausal status is required (ie, for female patients ≤59 years of age). 
17. In the event of a positive urine pregnancy test result, the patient should have a serum pregnancy test with a negative result in 
order to continue study drug. If the serum pregnancy test is positive, the patient should be withdrawn from study drug and 
should be asked to return to the clinic for all remaining study visits per the visit schedule (see Section 8.2.3.11 in the protocol). 
18. 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. 
19. Research samples should be collected after an overnight (minimum 8 hours) fast. 
20. Only for patients who provide written informed consent for the optional genomics sub-study. The sample should be collected 
at the baseline visit but may be collected at any subsequent visit during the study. 
21. 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 should be submitted to the central reader for adjudication, if available. 
22. If the affected joint has undergone JR an X-ray may be substituted from an MRI. 
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23. Patient-reported outcome measures should be completed first at a study visit, prior to any clinical assessments and procedures 
(eg, blood draws, ECGs, study drug administration). 
24. Patients who end treatment early but agree to follow/continue to attend regular study visits do not complete the assessments 
associated with EOT/week 52 at the time they end treatment. Instead, they complete assessments associated with the study visit 
they are attending at the time they end treatment early. 
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Table 4: 
Schedule of Events for Year 2 
 
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Protocol: R475-OA-1611 
Statistical Analysis Plan 
Date: 30JUN2020 
 
CONFIDENTIAL 
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Footnotes for the Schedule of Events Table 4 (Year 2) 
1. Patients who discontinue study drug before week 104 will be encouraged to follow the visit schedule through the remainder of 
the study. If a patient chooses to end study participation, he/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. Subcutaneous study drug administration will be the last procedure at each dosing visit and will be administered after all 
laboratory, PK, ADA, and research samples have been collected and all study related activities have been performed. Patients 
will be observed in the clinic for approximately 1 hour after SC study drug is administered. 
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Regeneron Pharmaceuticals, Inc. 
Protocol: R475-OA-1611 
Statistical Analysis Plan 
Date: 30JUN2020 
 
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3. Use of study-provided rescue medication will be recorded daily in patient diaries. Acetaminophen/paracetamol use will be 
reported from pre-randomization visit to week 104. 
4. Patient-reported outcome measures should be completed prior to any clinical assessments (eg, blood draws, ECGs, study drug 
administration). 
5. The WOMAC Full Survey will be completed for the index joint. 
6. If the pulse is less than 45 bpm, an ECG with rhythm strip will be obtained to confirm the heart rate and rhythm. 
7. 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. 
8. Imaging (X-ray and possible 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. 
9. In the event that a patient must undergo JR surgery during the study, the patient must complete the pre-operative study visit 
(early termination assessments, as applicable) and the procedures outlined in the schedule of events for JR follow-up (Table 5). 
This will include a Knee Society Score questionnaire for knee replacements or Harris Hip Score questionnaire for hip 
replacements. The pre-operative visit must be completed before the JR surgery. Pre-operative images will be submitted to the 
adjudication committee for review. 
10. Samples will be analyzed by the central laboratory and results evaluated by the investigator. 
11. In the event of a positive urine pregnancy test result, the patient should have a serum pregnancy test with a negative result in 
order to continue study drug. If the serum pregnancy test is positive, the patient should be withdrawn from study drug and 
should be asked to return to the clinic for all remaining study visits per the visit schedule (see Section 8.2.3.11 in the protocol). 
12. 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. 
13. Research samples should be collected after an overnight (minimum 8 hours) fast. 
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 should be submitted to the central reader for adjudication, if available. 
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Protocol: R475-OA-1611 
Statistical Analysis Plan 
Date: 30JUN2020 
 
CONFIDENTIAL 
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15. Patients who end treatment early but agree to follow/continue to attend regular study visits do not complete the assessments 
associated with EOT/week 104E at the time they end treatment. Instead, they complete assessments associated with the study 
visit they are attending at the time they end treatment early. 
16. If the affected joint has undergone JR, an X-ray may be substituted for an MRI. 
17. The week 52E Year 2 visit should occur on the same day as the week 52 Year 1 visit, but could occur at any time during the 
visit window. 
 
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Protocol: R475-OA-1611 
Statistical Analysis Plan 
Date: 30JUN2020 
 
CONFIDENTIAL 
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Table 5: 
Follow-Up Period for Patients Undergoing Joint Replacement Surgery on Study 
 
Footnotes for the Schedule of Events Table 5 (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 followinga report of clinically significant worsening or exacerbation of pain in the 
joint. 
 
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Protocol: R475-OA-1611 
Statistical Analysis Plan 
Date: 30JUN2020 
 
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 
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Protocol: R475-OA-1611 
Statistical Analysis Plan 
Date: 30JUN2020 
 
CONFIDENTIAL 
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Parameter 
PCSV 
Comments 
Conjugated Bilirubin 
(Direct Bilirubin >35% Total Bilirubin and 
Total Bilirubin >1.5 ULN) and (Direct 
Bilirubin <=35% Total Bilirubin or Total 
Bilirubin <=1.5 ULN) at baseline 
Conjugated bilirubin dosed on a case-by-case basis. 
ALT/AST and Total 
Bilirubin 
(ALT >3 ULN and TBILI>2 ULN) and 
baseline (ALT <=3 ULN or TBILI <=2 
ULN) 
(AST >3 ULN and TBILI>2 ULN) and 
baseline (AST <=3 ULN or TBILI <=2 
ULN) 
(ALT >3 ULN and TBILI>1.5 ULN) and 
baseline (ALT <=3 ULN or TBILI <=1.5 
ULN) 
(AST >3 ULN and TBILI>1.5 ULN) and 
baseline (AST <=3 ULN or TBILI <=1.5 
ULN) 
FDA DILI Guidance July 2009. 
ALT/AST and Total 
Bilirubin and ALP 
(ALT >3 ULN and TBILI>2 ULN and 
ALP < 2 ULN) and baseline (ALT <=3 
ULN or TBILI <=2 ULN or ALP >=2 
ULN) 
(AST>3 ULN and TBILI>2 ULN and 
ALP < 2 ULN) and baseline (AST <=3 
ULN or TBILI <=2 ULN or ALP >=2 
ULN) 
FDA DILI Guidance July 2009. 
 
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Protocol: R475-OA-1611 
Statistical Analysis Plan 
Date: 30JUN2020 
 
CONFIDENTIAL 
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Parameter 
PCSV 
Comments 
CPK* 
>3 and ≤ 10 ULN and baseline ≤ 3ULN* 
>10 ULN and baseline ≤ 10ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
* At least one level is required; multiple levels are optional for phase 2/3 studies. 
If it is desirable to get the distribution of significant level, additional shift table on 
≤3, >3 to ≤10, and > 10 category for baseline vs. post baseline may be provided 
Creatinine 
≥150 μmol/L (Adults) and baseline < 150 
μmol/L 
>=30% change from baseline and <100% 
change from baseline 
≥100% change from baseline 
Benichou C., 1994 
3 independent criteria  
Uric Acid 
- 
Hyperuricemia  
- 
Hypouricemia  
 
>408 μmol/L and <=408 μmol/L at 
baseline 
<120 μmol/L and >= 120 μmol/L at 
baseline 
Harrison - Principles of internal Medicine 17th Ed., 2008. 
Two independent criteria 
Blood Urea Nitrogen 
≥17 mmol/L and <17 mmol/L at baseline 
Two independent criteria 
Chloride 
- 
Hypochloremia 
- 
Hyperchloremia 
 
<80 mmol/L and baseline ≥ 80 mmol/L  
>115 mmol/L and baseline ≤ 115 mmol/L  
Two independent criteria  
Sodium 
- 
Hyponatremia 
- 
Hypernatremia 
 
≤129 mmol/L and baseline > 129 mmol/L  
≥160 mmol/L and baseline <160 mmol/L  
Two independent criteria 
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Statistical Analysis Plan 
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CONFIDENTIAL 
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Parameter 
PCSV 
Comments 
Potassium 
- 
Hypokalemia 
- 
Hyperkalemia 
 
<3 mmol/L and baseline ≥ 3 mmol/L  
≥5.5 mmol/L and baseline <5.5 mmol/L  
 
FDA Feb 2005. 
Two independent criteria 
Total Cholesterol 
≥7.74 mmol/L and < 7.74 mmol/L at 
baseline 
Threshold for therapeutic intervention. 
Triglycerides 
≥4.6 mmol/L and < 4.6 mmol/L at baseline 
Threshold for therapeutic intervention. 
Glucose 
- 
Hypoglycaemia 
- 
Hyperglycaemia 
 
(≤3.9 mmol/L and <LLN) and (>3.9 
mmol/L or >=LLN) at baseline 
≥11.1 mmol/L (unfasted); ≥7 mmol/L 
(fasted) and < 11.1 mmol/L (unfasted); <7 
mmol/L (fasted) at baseline 
 
ADA May 2005. 
ADA Jan 2008. 
HbA1c 
>8% and <= 8% at baseline 
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. 
                                        VV-RIM-00116751-1.0 Approved - 01 Jul 2020 GMT-5:00


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Statistical Analysis Plan 
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CONFIDENTIAL 
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Parameter 
PCSV 
Comments 
Lymphocytes 
>4.0 Giga/L and <= 4.0 Giga/L at baseline 
 
Neutrophils 
<1.5 Giga/L and >=1.5 Giga/L at baseline 
(Non-Black);  
<1.0 Giga/L and >=1.0 Giga/L at baseline 
(Black) 
International Consensus meeting on drug-induced blood cytopenias, 1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L <= 0.7 Giga/L at baseline 
 
Basophils 
>0.1 Giga/L <= 0.1 Giga/L at baseline 
 
Eosinophils 
(>0.5 Giga/L and >ULN) and (<=0.5 
Giga/L or <= ULN at baseline) 
Harrison - Principles of internal Medicine 17th Ed., 2008. 
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). 
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Statistical Analysis Plan 
Date: 30JUN2020 
 
CONFIDENTIAL 
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Parameter 
PCSV 
Comments 
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 
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Statistical Analysis Plan 
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CONFIDENTIAL 
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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. 
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Statistical Analysis Plan 
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CONFIDENTIAL 
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Parameter 
PCSV 
Comments 
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 
 
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. 
 
 
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Statistical Analysis Plan 
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10.4. 
Protocol Deviations Excluding Patients from the PPS 
Patients in violation of any of the following Inclusion/Exclusion Criterion will be excluded from the Per-Protocol Set. 
• Inclusion Criterion 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 
• Inclusion Criterion 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 
• Inclusion Criterion 7:   A history of at least 12 weeks of analgesics use for pain due to OA of the knee or hip, as defined by: 
− a) Inadequate pain relief from acetaminophen/paracetamol AND 
− 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  
• Exclusion Criterion 10: History of naproxen intolerance, or existence of a medical condition that is high risk for naproxen-
associated complications (eg, high risk of gastrointestinal bleed, previous ulcer, condition requiring use of anti-coagulants 
or anti-platelet therapy, or acute coronary syndrome) 
Additionally, patient who experience any of the Protocol Deviations listed below will be excluded from the Per-Protocol Set. 
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Protocol: R475-OA-1611 
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CONFIDENTIAL 
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PDID 
Description of Protocol Deviation 
3.01 
Baseline visit not performed 
3.24 
Screening visit was not performed 
5.14 
WOMAC patient assessment was not 
administered at Week 16 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) 
 
 
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Statistical Analysis Plan 
Date: 30JUN2020 
 
CONFIDENTIAL 
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10.5. 
OMERACT-OARSI Set of Responder Criteria 
 
Note that the criteria in the diagram above is based on standardized score between 0 and 100. For this study, WOMAC pain and 
physical function score are between 0 and 10, so the absolute change required for response is the required change in the diagram 
above divided by 10; PGA is 1, 2, 3, 4 or 5, so the absolute change required for response is at least 1 point. 
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                                        VV-RIM-00116751-1.0 Approved - 01 Jul 2020 GMT-5:00