Clinical trial NCT02683239
Conditions: Osteoarthritis of the Knee or Hip
Sponsor: Regeneron Pharmaceuticals
Start date: 2016-02-17; Completion date: 2021-06-15
Enrollment: 5331 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study is to describe the safety and tolerability of fasinumab, including adverse events of special interest (AESIs), in patients with pain due to radiographically-confirmed OA of the knee or hip.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Fasinumab intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive sub-cutaneous (SC) injections of fasinumab intervention 2: Participants will receive sub-cutaneous (SC) injections of matching placebo

Protocol documents:
Prot_000.pdf: 
IND: Number:  103245 
EudraCT:  2015-003783-36 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A PHASE 3 RANDOMIZED, DOUBLE-BLIND, MULTI-DOSE, 
PLACEBO-CONTROLLED STUDY TO EVALUATE THE LONG-TERM SAFETY AND 
THE EFFICACY OF FASINUMAB IN PATIENTS WITH PAIN DUE TO 
OSTEOARTHRITIS OF THE KNEE OR HIP 
Compound 
Fasinumab 
Study Name 
FACT LTS & OA 
Clinical Phase: 
3 
Protocol Number: 
R475-PN-1523 
Protocol Version: 
R475-PN-1523 Amendment 9 
Amendment 9 Date of Issue 
See appended electronic signature page 
Amendment 8 Date of Issue 
11 Jul 2018 
Amendment 7 Date of Issue 
24 May 2018 
Amendment 6 Date of Issue: 
02 Oct 2017 
Amendment 5 Global Date of Issue: 
16 Mar 2017 
Amendment 4 EU Date of Issue 
12 Jan 2017 
Amendment 4 Date of Issue: 
25 Aug 2016 
Amendment 3 Date of Issue 
20 June 2016 
Amendment 2 Date of Issue: 
25 January 2016 
Amendment 1 Date of Issue:  
11 December 2015 
Original Date of Issue: 
21 October 2015 
Scientific/Medical Monitor: 
 
 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
 
VV-RIM-00071798-1.0 Approved - 22 Apr 2019 GMT-5:00
NCT02683239


Clinical Study Protocol 
R475-PN-1523 Amendment 9 
Regeneron Pharmaceuticals, Inc 
Page 2 of 110 
CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 9 
The purpose of this non-substantial amendment is to update the text regarding the interim 
analysis so that the protocol and the statistical analysis plan are aligned. Additional minor edits 
have been made as outlined in the table below.  
Change and Rationale 
Sections Changed 
The text describing the interim analysis has been edited 
so that the text in the protocol and the statistical 
analysis plan are aligned. 
Section 3.2 Planned Interim Analysis 
Section 9.5.6 Interim Analysis 
The additional (blinded) medical monitor has been 
listed on the title page. 
Title page 
The formatting error in the footnotes to Table 1 has 
been corrected (ie, a missing footnote number has been 
added and subsequent footnotes have been re-
numbered). 
Table 1 Schedule of Events – Screening through Week 
16 Visit, Footnote 8 (missing number added), Footnote 
9, Footnote 10, Footnote 11, Footnote 12, Footnote 13, 
Footnote 14 (renumbered). 
Text has been added to align with current best practices 
(ie, updated protocol template text). 
Section 13.5 Clinical Study Data Transparency 
Additional minor edits have been made for clarity. 
Clinical Study Protocol Synopsis: Treatment 
Section 1.3.2  Rationale for Dose Selection 
Section 5.1 Investigational and Reference Treatments 
Section 5.5 Method of Treatment Assignment 
Amendment 8 
The primary purpose of this amendment is to gain greater safety exposure to the fasinumab 1 mg 
dose in the main safety study. Patients will be enrolled into the main study and randomized to 
fasinumab 1 mg every 8 weeks (Q8W), 1 mg every 4 weeks (Q4W) or placebo. This will 
increase the size of the fasinumab safety database for potentially clinically relevant doses and, 
thus, will contribute to the overall fasinumab safety assessment.  Minor edits and corrections 
have also been made. The following table outlines the changes made to the protocol and the 
affected sections: 
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Clinical Study Protocol 
R475-PN-1523 Amendment 9 
Regeneron Pharmaceuticals, Inc 
Page 3 of 110 
CONFIDENTIAL 
Change and Rationale 
Sections Changed 
Text has been updated to state that patients will be 
enrolled into the main study and randomized in a 3:3:1 
ratio to fasinumab 1 mg Q8W, 1 mg Q4W or placebo. 
Clinical 
Study 
Protocol 
Synopsis: 
Treatments, 
Statistical Plan 
Section 1.3.2 Rationale for Dose Selection 
Section 3.1 Study Description and Duration 
Section 5.1 Investigational and Reference Treatments 
Section 5.5 Method of Treatment Assignment 
The primary objective and primary endpoint have been 
updated to summarize all safety data rather than 
referring to a particular AE, SAE or AESI as a primary 
or secondary endpoint. The secondary objective and 
secondary 
endpoints 
have 
been 
removed. 
The 
exploratory endpoint ‘Incidence of and time to cases 
meeting pre-specified criteria for needing joint 
replacement’ has been removed. 
Clinical 
Study 
Protocol 
Synopsis: 
Objectives, 
Endpoints 
Section 2.1 Primary Objective 
Section 8.2 Primary Endpoint 
Section 8.3 Exploratory Endpoints 
Minor edits, additions or deletions have been made to 
the text for clarity, to make minor corrections and to 
ensure consistency across the fasinumab program. 
Clinical Study Protocol Synopsis: Treatments, PK and 
ADA Variables 
List of Abbreviations and Definitions of Terms 
Section 1.1 Background 
Section 4.2.2 Additional inclusion criteria for Sub-
Study Patients Only (mis-numbering has been 
corrected) 
Section 5.5 Method of Treatment Assignment 
Table 1 Schedule of Events – Screening through Week 
16 Visit (abbreviations) 
Table 2 Schedule of Events – Week 20 Visit through 
Week 52 Visit (abbreviations) 
Table 3 Schedule of Additional Events – Only for 
Patients Participating in the Efficacy Sub-Study 
(Screening through Week 16 Visit) (abbreviations) 
Section 6.3.1.4 
Western 
Ontario 
and 
McMaster 
Universities Osteoarthritis Index 
Section 6.3.3 
Western 
Ontario 
and 
McMaster 
Universities Osteoarthritis Index 
Section 7.4.3 Other Events that Require Accelerated 
Reporting 
Section 7.6.1.1 Adjudicated Arthropathy 
Section 7.6.1.3 Peripheral Sensory Adverse Events 
Section 8.5 Pharmacokinetic Variables 
Section 8.6 Anti-Drug Antibody Variables 
Section 9.2 Determination of Sample Size 
Section 9.5.3 Safety Analysis 
Section 10.2 Electronic Systems 
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Clinical Study Protocol 
R475-PN-1523 Amendment 9 
Regeneron Pharmaceuticals, Inc 
Page 4 of 110 
CONFIDENTIAL 
Amendment 7 
The primary purpose of this amendment is 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 this 
ongoing study 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 6 
The purpose of this amendment is to incorporate health authority feedback, ensure consistency 
across the program, improve clarity, remove redundant text and correct typos.   
Amendment 5 global 
The primary purpose of this amendment is to improve detections of risks and benefits as follows: 
 Remove from the global version of the protocol the eligibility for treatment from 
patients who were treated under earlier versions of the protocol with the 6 mg every 
4 weeks (Q4W) or 9 mg Q4W dosing regimen. This change was incorporated 
previously into a local version of the protocol, R475-PN-1523.04EU 
 Update the doses, dosing schedule, and the rationale for dose selection for the main 
study (1 mg Q4W, 3 mg Q4W, and 6 mg Q8W) and sub-study (1 mg Q8W, 1 mg 
Q4W, 3 mg Q4W, and 6 mg Q8W)  
 Add an end of study phone contact at 52 weeks following the last dose of study drug 
to determine whether a joint replacement (JR) was performed or is scheduled (or the 
patient is on a waiting list) 
 Update the number of patients enrolled and the randomization allocation  
 Update the language that refers to stopping guidelines for a dose arm, the study or the 
program 
 Clarify the safety objectives and update the associated endpoints and statistical 
methods 
 Simplify the efficacy sub-study objective and update the associated endpoints and 
statistical methods 
 Change the magnetic resonance imaging (MRI) requirement at screening to also 
include the index and contralateral joint 
 Add an end of study definition 
 Add text to describe the interim analysis 
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Clinical Study Protocol 
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Page 5 of 110 
CONFIDENTIAL 
 Update the exclusion criterion regarding contraception to align with Regeneron 
protocol template language 
 Add additional inclusion and exclusion criteria for the efficacy sub-study 
 Reduce the time that patients in the efficacy sub-study are required to discontinue use 
of paracetamol/acetaminophen from 48 hours to 24 hours prior to the start of the 
study visits. 
 Add additional reasons for permanent discontinuation of study drug 
 Change the permitted aspirin dose for cardiac prophylaxis from up to 100 mg to up to 
150 mg per local guidelines 
 Add that an MRI may be requested by the imaging vendor after review of a patient’s 
x-rays 
 Add a PK sample collection at week 32, week 60 (12 weeks following the last dose of 
study drug) and the early termination visit during the follow-up period 
 Add an ADA sample collection at week 32 and the early termination visit during the 
follow-up period 
 Add blood pressure measurement for the assessment of orthostatic hypotension at the 
pre-randomization visit for patients in the efficacy sub-study, and follow-up visit 1 
and follow-up visit 2 for patients who undergo joint replacement surgery, and add 
orthostatic blood pressure to the list of vital signs summarized for descriptive 
statistics 
 Add urinary drug test to the screening and week 16 visit for patients in the efficacy 
sub-study 
 Reduce the number of electrocardiograms (ECG) performed from week 20 to 
week 52 (Treatment period 2) 
 Add joint replacement surgery to the list of AESIs 
 Update the PK and ADA variables, update the definition of the PK and ADA analysis 
sets, and update the analysis of PK data 
In addition, the study name, FACT LTS&OA, has been added to the protocol title page, and 
minor edits have been made to improve clarity and remove redundancy.  
Amendment 4 EU:  12 Jan 2017 
The purpose of this amendment is to: 
 Remove eligibility for treatment from patients who were treated under earlier 
versions of the protocol with the 6 mg every 4 weeks (Q4W) or 9 mg Q4W dosing 
regimen.  
 Update the Rationale for Dose Selection  
 Make minor edits and clarifications 
                                        VV-RIM-00071798-1.0 Approved - 22 Apr 2019 GMT-5:00


Clinical Study Protocol 
R475-PN-1523 Amendment 9 
Regeneron Pharmaceuticals, Inc 
Page 6 of 110 
CONFIDENTIAL 
Amendment 4:  25 Aug 2016 
The purpose of this amendment is to update the laboratory and urine collection timepoints in the 
protocol and to add the collection of serum creatinine, urine creatinine, urine phosphorous, and 
urinalyses.  These tests have been added to better monitor patient safety during the trial. 
Amendment 3:  20 June 2016 
Purpose: 
The purpose of this amendment is to update the protocol and to provide clarifications.  The 
changes to the protocol in this amendment are listed below: 
 Update the dose selection for the study to 6 mg Q8 weeks. 
 Update the randomization ratio for the study to 2:1 for the main portion of the study 
and 1:1 for efficacy sub-study. 
 Replace the terminology “Onset of Efficacy Sub-Study” with “Efficacy Sub-study.” 
 A risk-benefit assessment has been incorporated, and includes a placebo arm 
justification in the rationale for study design. 
 Inclusion criterion 7 was updated to include that unwillingness to take opioids must 
be due to a medically acceptable reason. 
 Added the following inclusion criteria specific for the efficacy sub-study 
 Willing to discontinue glucosamine sulfate and chondroitin sulfate treatments 
during the initial 16 weeks of treatment. 
 Stable treatment with glucosamine sulfate and chondroitin sulfate treatments must 
be stopped during the pre-randomization period. 
 Update the permitted therapy section to include physical therapies provided that 
patients were on a stable regimen prior to entering into the trial and provided that they 
anticipate they will maintain this regimen during the trial, if possible. 
 Updated the prohibited therapy to include glucosamine and chondroitin sulfate during 
treatment period 1 and to include all IL-1 inhibitors including diacerein during 
treatment periods 1 and 2 
 Added chemistry and hematology safety labs at week 16 and week 32 at the request 
of the Voluntary Harmonization Procedure (VHP) process. 
 Added Phosphorous to the serum chemistry panel. 
 Bilateral radiographs of the knee, hip, and shoulder were added to the week 4 and 
week 20 visits following total joint replacement (JR).  
 Added a section defining a suspected unexpected serious adverse reaction (SUSAR) 
and SUSAR reporting. 
 Additional text was added to indicate that all substantial protocol amendments will be 
approved by the competent authorities before changes are implemented according to 
national regulations. 
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Clinical Study Protocol 
R475-PN-1523 Amendment 9 
Regeneron Pharmaceuticals, Inc 
Page 7 of 110 
CONFIDENTIAL 
 Corrected text for response rate endpoints in Section 2.4 and 8.4 to indicate that the 
endpoints are percentages of responders.  
 Updated multiple testing procedure in Section 9.1, sample size determination in 
Section 9.2 and efficacy analysis in Section 9.5.2 corresponding to the dose change. 
Amendment 2:  25 January 2016 
Purpose: 
The purpose of this amendment is to update the protocol and to provide clarifications.  The 
changes to the protocol in this amendment are listed below: 
 Clarify that study medication will be withheld if a patient is determined to have 
orthostatic hypotension and added directions related to the assessment of sympathetic 
nervous system dysfunction 
 Add that new signs and symptoms indicative of carpal tunnel syndrome will be a 
reason for permanent discontinuation of study drug. 
 Add 
that 
continued 
noncompliance 
with 
protocol-defined 
maximum 
acetaminophen/paracetamol use (>2500 mg in Europe or >2600 mg in non-European 
countries) after appropriate counseling will be a reason for permanent discontinuation 
of study drug. 
 Revise the notification requirement for emergency unblinding from “The investigator 
should notify Regeneron and/or designee before unblinding the patient, whenever 
possible” to "The investigator should promptly document and explain to the sponsor 
any premature unblinding."   
 Clarify that the maximum dose of paracetamol/acetaminophen to be used as rescue 
medication was decreased from 3 g to 2500 mg in Europe or 2600 mg in non-
European countries 
 Include a multiplicity adjustment for analysis of the endpoints to be studied in the 
sub-study. 
 Add that corresponding baseline scores for the primary analysis variables for 
sub-study patients will be analyzed. 
 Update Exclusion Criterion #20 to clarify that a transient ischemic attack (TIA) or 
cerebrovascular accident are exclusionary if they have occurred within 12 months of 
screening or myocardial infarctions or acute coronary syndromes are exclusionary if 
they have occurred within 6 months of screening. 
 Remove Exclusion Criterion #26 as it was redundant; alcoholism is exclusionary in a 
subsequent criterion. 
 Add the word “average” to Inclusion Criterion #5 to clarify the criterion to read 
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  
 Add that Hyaluronic Acid Intra-articular Injections are prohibited during period 1 of 
the study. 
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Clinical Study Protocol 
R475-PN-1523 Amendment 9 
Regeneron Pharmaceuticals, Inc 
Page 8 of 110 
CONFIDENTIAL 
 Remove “Clinic Visit 4-weeks post last dose” column from Table 4 as it was a 
duplicate of the  “End of Treatment Visit” column  in Table 2  
Amendment 1:  11 December 2015 
Purpose:   
The purpose of this amendment is to incorporate changes requested by the Food and Drug 
Administration (FDA) as follows: 
 Edit to clearly indicate that participation in the onset of pain relief sub-study is in 
addition to participation in the main study 
 Update imaging language to state that radiographs and/or MRI will or must (rather 
than may or should) be performed on any joint following report of a clinically 
significant worsening or exacerbation of pain in that joint 
 Add a definition of destructive arthropathy and delete the sentence stating that no 
significant treatment emergent adverse events (TEAEs) related to autonomic 
dysfunction have been reported 
 Add follow-up clinic visits 4 and 12 weeks after the last dose of study drug and a 
phone call 8 weeks after the last dose of study drug 
 Update study stopping rules to state that the Independent Data Monitoring Committee 
(IDMC) may recommend temporarily halting the study for additional review and 
communication to regulatory authorities if the IDMC has significant concerns 
regarding a meaningful imbalance in adverse events (AEs) including joint-related 
AEs, sympathetic nervous system dysfunction, or neurosensory disturbances 
 Revise eligibility criteria to clarify that the same diagnostic criteria for osteoarthritis 
(OA) of the knee or hip will apply to all patients and not just to sub-study patients 
 Add willingness to consider JR surgery if necessary as a new inclusion criterion 
 Remove redundancy and consolidate exclusion criteria 
 Add signs or symptoms of carpal tunnel syndrome within 6 months of screening as an 
exclusion criterion 
 Add history or presence of reflex sympathetic dystrophy at the screening visit to 
exclusion criteria 
 Add history or diagnosis of chronic autonomic failure syndrome including pure 
autonomic failure, multiple system atrophy (Shy-Drager Syndrome) as a new 
exclusion criterion 
 Add confirmed elevated screening alanine aminotransaminase (ALT) or aspartate 
aminotransaminase (AST) ≥2.5 times the ULN as a new exclusion criterion 
 Add an upper rate of >100 bpm to, and delete the pre-randomization period as a time 
point from the exclusion criterion for resting heart rate since most patients will not 
have an in-office visit (only sub-study patients have a pre-randomization visit) 
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Clinical Study Protocol 
R475-PN-1523 Amendment 9 
Regeneron Pharmaceuticals, Inc 
Page 9 of 110 
CONFIDENTIAL 
 Add evaluation of the injection site as a safety assessment at baseline and weeks 4, 8, 
12, 16, 20, 24, and at clinic visits between week 28 and the end of treatment 
 Label the Schedule of Events from week 20 through week 52 as Table 2, and indicate 
that it applies for all patients 
 Add assessment of orthostatic blood pressure for sub-study patients at weeks 1, 2, 4, 
8, and 12 and delete at pre-randomization visit 
 Add collection of medical history related to the JR surgery at the post-operative visit 
(follow-up visit 1) and the long-term visit (follow-up visit 2) 
 Add rapidly progressive osteoarthritis type 1 or type 2, significant bone collapse and 
significant bone loss to exclusion criteria 
 Add known history of ocular herpes simplex virus, herpes simplex virus pneumonia, 
or herpes simplex virus encephalitis as a new exclusion criterion 
 Add clinically significant sensory and motor neurologic events grade ≥2 according to 
CTCAE as a reason for permanent discontinuation of study drug and add that study 
sites should use CTCAE v.4 criteria throughout the study for consistency 
 Include carpal tunnel syndrome and state that neurological assessments will include 
nerve conduction studies and other tests as deemed clinically necessary in the 
judgement of the neurologist 
 Add multiplicity adjustment strategy to Section 9.1 and clarify primary efficacy 
analysis method in Section 9.3.1 for the sub-study 
The following changes were also made:  
 Correct the EudraCT number 
 Clarify that standard-of-care therapy permitted beginning at week 16 for inadequate 
pain relief for OA pain is limited to non- non-steroidal anti-inflammatory drugs 
(NSAIDs) 
 Correct that patient participation in the study will be a minimum duration of 37 weeks 
and that maximum study duration is 77 weeks 
 Decrease the maximum daily dose of paracetamol/acetaminophen permitted as rescue 
medication for OA pain from 4 g to 3 g 
 Clarify that treatment with study drug would be stopped after all remaining patients 
randomized to fasinumab or placebo have completed the week 12 study visit  
 Add the requirement for an MRI of the affected joint if screening radiographs are 
inconclusive for potential joint related findings, and before the pre-randomization 
visit for any knee or hip joint with a baseline K-L score ≥3 
 Add that previous surgical modification of the index joint cannot have occurred 
within the past year 
 Change the time period for the exclusion criteria from “baseline visits” to 
“randomization” to be consistent with other exclusion criteria 
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Clinical Study Protocol 
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Page 10 of 110 
CONFIDENTIAL 
 Delete the pre-randomization period from the exclusion criterion for history or 
presence 
of 
orthostatic 
hypotension 
(only 
sub-study 
patients 
have 
a 
pre-randomization visit) 
 Correct the additional exclusion criterion to state that ≥4 consecutive missed diary 
entries during the pre-randomization (not the randomization) period would make 
sub-study patients ineligible to participate in the study 
 Update wording of exclusion criterion relating to alcohol, substance, or prescription 
pain medication abuse to keep consistent across the program 
 Delete exclusion criterion for resting heart rate from section of additional exclusion 
criteria for sub-study patients only as it applies to all patients 
 Clarify that use of other investigational agents, cyclosporine, azathioprine, tumor 
necrosis factor antagonists, corticosteroids (other than topical and inhaled 
formulations), tocilizumab, and abatacept are prohibited during treatment period 2 as 
well as during treatment period 1 
 Change the caption of Table 1 to indicate that the Schedule of Events from screening 
through week 16 applies for all patients 
 Delete assessment of vital signs and associated information at the pre-randomization 
visit for sub-study patients 
 Delete collection of anti-drug antibody (ADA) sample at week 8 
 Add a footnote to state that historical bilateral radiographs may be acceptable as 
outlined in the study imaging acquisition guidelines 
 Clarify that an electrocardiogram (ECG) with rhythm strip will be obtained and sent 
to the central reader only if a patient’s pulse is less than 45 bpm at any visit 
subsequent to randomization 
 Add collection of a research serum/plasma sample at the end of treatment visit 
 Update caption of Schedule of Events table to clarify that it applies only to patients 
who are also participating in the onset of pain relief sub-study 
 Add collection of a PK/drug concentration sample, a research serum/plasma sample, 
and an ADA sample at the end of study visit 
 Update language to reflect added visits at weeks 4 and 12, and phone call at week 8 
during the follow-up period 
 Add a section to indicate that injection site evaluation will be conducted following the 
injection at each dosing visit 
 Remove sitting blood pressure from assessment of vital signs as it is a redundant 
procedure since both supine and standing measurements are part of the assessment of 
orthostatic blood pressure 
 Add that all available medical history/information for patients who undergo JR 
surgery must be collected, including results of histopathologic examination 
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Clinical Study Protocol 
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Page 11 of 110 
CONFIDENTIAL 
 Indicate that patients who agree to participate in the onset of pain relief sub-study will 
be required to sign a separate informed consent form (ICF) 
 Edit section heading to clarify that efficacy procedures for sub-study patients are for 
the onset of pain relief sub-study 
 Indicate that pulse should be measured per the instructions in the study manual.   
 Clarify the definition of orthostatic hypotension and describe the assessment of 
orthostatic blood pressure 
 Clarify that worsening of pain in any joint despite treatment with analgesics, that is 
inconsistent with the normal progression of OA and lasts at least 2 weeks will be 
considered as clinically significant independent of the investigator’s opinion 
 Describe sympathetic nervous system dysfunction and outline assessment and action 
to be taken with regard to study drug 
 Make clarifications and administrative edits 
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CONFIDENTIAL 
CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A 
Phase 
3 
Randomized, 
Double-blind, 
Multi-Dose, 
Placebo-Controlled Study to Evaluate the Long-Term Safety 
and the Efficacy of Fasinumab in Patients with Pain Due to 
Osteoarthritis of the Knee or Hip 
Site Locations 
North 
America, 
Latin 
America, 
Europe, 
and 
Asia/Pacific/South Africa 
Objectives 
Primary Objective: 
To describe the safety and tolerability of fasinumab, including 
adverse events of special interest (AESIs), in patients with 
pain due to radiographically-confirmed OA of the knee of hip  
Additional Objectives for the 
Efficacy Sub-study 
The objective of the sub-study is to evaluate the efficacy of 
fasinumab compared with placebo when administered to 
patients with pain due to radiographically-confirmed OA of 
the knee or hip. 
Study Design 
The study consists of a screening period of up to 30 days 
(Screening 
Period), 
followed 
by 
a 
7 
to 
10 
day 
pre-randomization period (Pre-Randomization Period), a 
16-week 
randomized, 
double-blind, 
placebo-controlled 
treatment 
period 
(Treatment 
Period 
1), 
a 
36-week, 
double-blind, placebo-controlled treatment period (Treatment 
Period 2) in which non-NSAID standard-of-care pain 
medications can also be used in the event of inadequate pain 
relief for OA pain, a 24-week follow-up period, and an end of 
study phone contact at 52 weeks following the last dose of 
study drug to determine whether a joint replacement (JR) has 
been conducted or is scheduled (or the patient is on a waiting 
list).  
A subset of patients will also participate in a 16-week 
sub-study to characterize the efficacy of fasinumab. Efficacy 
assessments will be performed during treatment period 1, 
which will be followed by the 36-week treatment period 2, 
and the 24-week follow-up period. 
Study Duration 
Total duration of participation will be up to 105 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.   
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CONFIDENTIAL 
Population 
 
 
Sample Size: 
Up to 7000 patients are planned to be randomized in this 
study. Enrollment may be less than 7000 depending on 
enrollment across all studies in the fasinumab program. 
Approximately 1000 of these patients will participate in the 
efficacy sub-study. 
 
Target Population: 
Eligible patients for this study will be men and women ≥18 
years of age at the time of study entry with a clinical diagnosis 
of OA of the knee or hip based on the American College of 
Rheumatology criteria with radiologic evidence of OA 
(Kellgren-Lawrence [K-L] score ≥2) at the index joint at the 
screening visit, and WOMAC average pain subscale score of 
≥4 at both the screening and randomization visits.   
Eligibility for this study is also limited to patients who: 
 
have a history of 
inadequate pain 
relief from 
paracetamol/acetaminophen, and 
 
are intolerant or have a history of inadequate pain relief 
from at least 1 oral non-steroidal anti-inflammatory drug 
(NSAID), and 
 
are either intolerant or who have a history of inadequate 
pain relief from opioid therapy, who are unwilling to take 
opioid therapy due to a medically acceptable reason or 
who lack access to opioid therapy 
Treatment 
 
 
Study Drug 
 
Dose/Route/Schedule: 
Randomized patients will receive fixed-dose, subcutaneous 
(SC) injections of fasinumab at 1 mg every 8 weeks (Q8W), 
1 mg every 4 weeks (Q4W), or matching placebo Q4W from 
day 1 up to week 48.  Patients randomized to 1 mg Q8W will 
have alternating placebo injections when study drug is not 
administered. Under amendment 8 and amendment 9, the 
patient allocation into the main safety study will be 3:3:1 to 
1 mg Q8W, 1 mg Q4W or placebo Q4W. 
Anyone previously randomized to 9 mg Q4W or 6 mg Q4W 
(or matching placebo) before amendment 3, or randomized to 
6 mg Q8W or 3 mg Q4W under amendment 3 or subsequent 
amendments, will be discontinued from study drug and 
encouraged to complete all remaining study visits and study 
procedures in the follow up period and the end of study phone 
call. 
There were no patients enrolled into the main safety study 
under amendment 5 or amendment 6. The patient allocation 
for the efficacy sub-study for all patients randomized to 
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amendment 5 global or amendment 6 was 1:1:1:1:1 to 1 mg 
fasinumab Q8W, 1 mg fasinumab Q4W, 3 mg fasinumab 
Q4W, 6 mg fasinumab Q8W or matching placebo Q4W.  
Randomization was stratified by screening K-L score (2-3, 4) 
and by geographic region (North America, Latin America, 
Europe, or Asia/Pacific).  For the sub-study, stratification was 
also by index joint.  After the 16 week sub-study, patients will 
then continue in the main safety study, in which dosing will 
continue through week 48. 
  
Rescue Treatment 
 
Route/Schedule: 
Paracetamol/acetaminophen is the study-provided rescue 
medication for OA pain and may be taken as needed, with a 
maximum daily dose of 2500 mg in Europe and 2600 mg in 
non-European countries throughout the entire treatment 
period. Sub-study patients should discontinue use of 
paracetamol/acetaminophen 24 hours prior to the start of the 
randomization visit (baseline) and subsequent study visits with 
efficacy assessments. 
Beginning at week 16, patients may take non-NSAID 
standard-of-care therapy in the event of inadequate pain relief 
for OA pain. Though use of NSAIDs should generally be 
avoided, limited use is allowed for non-OA related pain or 
fever after week 16. 
Endpoints 
 
 
Primary: 
The primary endpoint is safety monitoring including adverse 
event (AE) incidence, serious adverse event (SAE) incidence, 
AESI incidence, changes in safety laboratory analyses, and 
incidence of anti-fasinumab antibody formation from baseline 
to week 52 (treatment period 1 and 2) and to week 72 (end of 
follow-up period). 
Additional Endpoints for the 
Efficacy Sub-Study 
 
Primary: 
In addition to the main study endpoints, the following 
co-primary endpoints will be evaluated for the efficacy 
sub-study:  
 
Change from baseline to week 16 in the WOMAC pain 
subscale score 
 
Change from baseline to week 16 in the WOMAC 
physical function subscale score 
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Secondary: 
Key secondary efficacy endpoints for the sub-study are: 
 Change from baseline to week 16 in the Patient Global 
Assessment for OA score 
 The percentage of patients who had a response at 
week 16, with response defined as an improvement by 
≥30% in WOMAC pain subscale scores 
PK and ADA variables: 
The 
pharmacokinetic 
(PK) 
variable 
is 
fasinumab 
concentrations in serum at specified sampling time points. 
The anti-drug antibody (ADA) variables include ADA status 
(positive or negative) and titer. 
Procedures and Assessments 
Physical 
examinations, 
medical 
history, 
concomitant 
medication 
assessment, 
vital 
signs, 
electrocardiograms 
(ECGs), 
imaging, 
laboratory 
assessment, 
neurologic 
evaluations, and orthostatic hypotension assessment will be 
performed and the joint pain questionnaire and autonomic 
nervous system survey will be administered to assess safety. 
Adverse events, SAEs, and concomitant medications will be 
assessed at each study visit. Samples to determine serum 
concentrations of functional fasinumab and anti-fasinumab 
antibodies will be collected at predetermined time points. 
Efficacy will be assessed in sub-study patients using the 
WOMAC sub scales, the Patient Global Assessment of OA, 
Numeric Rating Scale (NRS) average walking index joint 
pain, and use of rescue medication. 
Radiographs and/or magnetic resonance imaging (MRI) will 
be performed on any joint following a report of clinically 
significant worsening or exacerbation of pain in that joint. 
Potential events of adjudicated arthropathy (AA) and 
sympathetic nervous system dysfunction will be monitored 
during the course of the study. 
In the event that a patient must undergo JR surgery during the 
treatment or follow-up periods, they will be discontinued from 
study drug and asked to return to the study site for a 
preoperative visit, and for follow-up safety evaluations 4 and 
20 weeks after surgery. 
Approximately 52 weeks after administration of the last study 
drug dose, a phone contact questionnaire will be conducted to 
document patient status with regard to JR surgery (if patient 
underwent, is scheduled for, or is on a wait list for JR 
surgery). Patients who had an AA will have an MRI 
performed of the affected joint(s). 
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Statistical Plan 
This study will contribute to the overall assessment of 
fasinumab safety in patients with pain associated with OA.   
Treatment-emergent 
adverse 
events 
(TEAEs) 
and 
treatment-emergent AESIs will be listed and summarized by 
treatment group.  Differences in event rate for AESIs between 
fasinumab and placebo will be estimated using exact binomial 
confidence intervals.  
The sample size of the efficacy sub-study was selected to have 
a sufficient number of patients to allow treatment comparisons 
of sub-study primary efficacy endpoints.  The effect size for 
WOMAC pain subscale score, WOMAC physical function 
subscale score and Patient Global Assessment were 0.46, 0.46, 
and 0.36, respectively as observed in the phase 2 study 
R475-PN-1227.  Assuming a dropout rate of 15% at week 16, 
200 patients per treatment arm, would provide at least 
96% power to detect an effect size of 0.46 for WOMAC pain 
and physical function subscale scores based on a 2-sided test 
at the 0.0167 significance level.  The sample size will provide 
at least 82% power to detect an effect size of 0.36 in Patient 
Global Assessment score. 
The primary efficacy variables will be analyzed using a 
multiple imputation approach with mixed-effect model for 
repeated measure (MMRM) based on the FAS with 
adjustment for missing data due to treatment discontinuation 
for the reasons of lack of efficacy or AEs assuming the 
WOMAC scores would on average return to baseline values. 
The missing data for patients who discontinued treatment due 
to lack of efficacy or AEs will be imputed with values 
centered at the mean baseline value of the treatment group that 
patients 
were 
randomized 
to. 
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.  Sensitivity analysis using tipping point 
approach with multiple imputation will also be performed to 
assess the robustness of the results due to treatment 
discontinuation.  
For analysis of continuous variables in secondary endpoints, 
the analysis method is the same as for the primary variables.  
For analysis of categorical variables in secondary endpoints (if 
identified later), the Cochran-Mantel-Haenszel approach 
stratified by the randomization strata will be used.  
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................24 
1. 
INTRODUCTION AND RATIONALE .....................................................................26 
1.1. 
Background .................................................................................................................26 
1.2. 
Summary of Risks and Benefits to Patients Participating in this Study .....................29 
1.3. 
Rationale .....................................................................................................................30 
1.3.1. 
Rationale for Study Design .........................................................................................30 
1.3.2. 
Rationale for Dose Selection ......................................................................................31 
2. 
STUDY OBJECTIVES ..............................................................................................33 
2.1. 
Primary Objective .......................................................................................................33 
2.2. 
Exploratory Objectives ...............................................................................................33 
2.3. 
Additional Objectives for the Efficacy Sub-Study .....................................................33 
3. 
STUDY DESIGN .......................................................................................................34 
3.1. 
Study Description and Duration .................................................................................34 
3.1.1. 
Study Stopping Rules .................................................................................................37 
3.1.2. 
End of Study Definition ..............................................................................................37 
3.2. 
Planned Interim Analysis ............................................................................................37 
3.3. 
Study Committees .......................................................................................................37 
3.3.1. 
Independent Data Monitoring Committee ..................................................................37 
3.4. 
Adjudication of Arthropathy .......................................................................................38 
4. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............39 
4.1. 
Number of Patients .....................................................................................................39 
4.2. 
Study Population .........................................................................................................39 
4.2.1. 
Inclusion Criteria ........................................................................................................39 
4.2.2. 
Additional Inclusion Criteria for Sub-Study Patients Only ........................................40 
4.2.3. 
Exclusion Criteria .......................................................................................................40 
4.2.4. 
Additional Exclusion Criteria for Sub-Study Patients Only .......................................43 
4.3. 
Premature Withdrawal from the Study .......................................................................43 
4.4. 
Replacement of Patients .............................................................................................43 
5. 
STUDY TREATMENTS............................................................................................44 
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5.1. 
Investigational and Reference Treatments ..................................................................44 
5.2. 
Rescue Treatments ......................................................................................................45 
5.2.1. 
Paracetamol/Acetaminophen - Weeks 1 through 16 ..................................................45 
5.2.2. 
Paracetamol/Acetaminophen and Non-Steroidal Anti-Inflammatory 
Drugs - Weeks >16 .....................................................................................................45 
5.3. 
Dose Modification and Study Drug Discontinuation Rules .......................................46 
5.3.1. 
Dose Modification ......................................................................................................46 
5.3.2. 
Study Drug Discontinuation .......................................................................................46 
5.3.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................46 
5.3.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................48 
5.4. 
Management of Acute Reactions ................................................................................48 
5.4.1. 
Systemic Injection Reactions ......................................................................................48 
5.5. 
Method of Treatment Assignment ..............................................................................48 
5.5.1. 
Blinding ......................................................................................................................49 
5.5.2. 
Emergency Unblinding ...............................................................................................49 
5.5.3. 
Unblinding for Regulatory Reporting Purposes .........................................................49 
5.6. 
Treatment Logistics and Accountability .....................................................................50 
5.6.1. 
Packaging, Labeling, and Storage ..............................................................................50 
5.6.2. 
Supply and Disposition of Treatments .......................................................................50 
5.6.3. 
Treatment Accountability ...........................................................................................50 
5.6.4. 
Treatment Compliance ................................................................................................50 
5.6.5. 
Patient Drug Accountability .......................................................................................50 
5.7. 
Concomitant Medications ...........................................................................................51 
5.7.1. 
Permitted Therapy ......................................................................................................51 
5.7.2. 
Prohibited Therapy .....................................................................................................51 
6. 
STUDY SCHEDULE OF EVENTS AND VISIT DESCRIPTIONS.........................53 
6.1. 
Schedule of Events .....................................................................................................53 
6.2. 
Study Visit Descriptions .............................................................................................65 
6.2.1. 
Screening Period (Up to 30 days) ...............................................................................65 
6.2.2. 
Rescreening .................................................................................................................65 
6.2.3. 
Pre-Randomization Period (7 to 10 days) ...................................................................65 
6.2.4. 
Baseline/Randomization Visit (Day 1) .......................................................................66 
6.2.5. 
Week 1 through Week 16 ...........................................................................................66 
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6.2.6. 
Week 20 up to Week 52 ..............................................................................................66 
6.2.7. 
Week 52 or End of Treatment Visit ............................................................................67 
6.2.8. 
Week 52 through Week 72 .........................................................................................67 
6.2.9. 
Week 100 ....................................................................................................................67 
6.2.10. 
Early Termination Visit (as Applicable) .....................................................................67 
6.2.11. 
Visits in the Event of Joint Replacement Surgery ......................................................67 
6.2.12. 
Unscheduled Visits .....................................................................................................68 
6.3. 
Study Procedures ........................................................................................................68 
6.3.1. 
Procedures Performed Only at the Screening Visit, Pre-Randomization Visit, 
or Baseline/Randomization Visit ................................................................................68 
6.3.1.1. 
Informed Consent .......................................................................................................68 
6.3.1.2. 
Medical History ..........................................................................................................68 
6.3.1.3. 
Medication History .....................................................................................................68 
6.3.1.4. 
Western Ontario and McMaster Universities Osteoarthritis Index ............................68 
6.3.1.5. 
Assessment of Childbearing Potential ........................................................................68 
6.3.2. 
Efficacy Procedures for the Efficacy Sub-Study Only ...............................................69 
6.3.2.1. 
Walking Index Joint Pain ............................................................................................69 
6.3.2.2. 
Patient Global Assessment of Osteoarthritis ..............................................................69 
6.3.3. 
Western Ontario and McMaster Universities Osteoarthritis Index ............................69 
6.3.4. 
Safety Procedures .......................................................................................................69 
6.3.4.1. 
Physical Examination .................................................................................................69 
6.3.4.2. 
Vital Signs ..................................................................................................................69 
6.3.4.3. 
Electrocardiogram .......................................................................................................70 
6.3.4.4. 
Joint Pain Questionnaire .............................................................................................70 
6.3.4.5. 
Survey of Autonomic Symptoms ................................................................................70 
6.3.4.6. 
Assessment of Orthostatic Hypotension and Heart Rate ............................................70 
6.3.4.7. 
Neurological Evaluation .............................................................................................71 
6.3.4.8. 
Imaging .......................................................................................................................71 
6.3.4.9. 
End of Study Phone Contact .......................................................................................72 
6.3.4.10. 
Procedures to be Performed Only in the Event of a Joint Replacement 
Surgery ........................................................................................................................72 
6.3.4.11. 
Laboratory Testing ......................................................................................................73 
6.3.4.12. 
Injection Site Evaluation .............................................................................................74 
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6.3.5. 
Pharmacokinetic and Antibody Procedures ................................................................74 
6.3.5.1. 
Drug Concentration Measurements and Samples .......................................................74 
6.3.5.2. 
Anti-Drug Antibody Measurements and Samples ......................................................75 
6.3.6. 
Research Samples .......................................................................................................75 
6.3.6.1. 
Use and Storage of Research Samples (Serum and Plasma) ......................................75 
6.3.6.2. 
Optional Genomics Sub-study ....................................................................................75 
7. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................76 
7.1. 
Obligations of Investigator .........................................................................................76 
7.2. 
Obligations of Sponsor ...............................................................................................76 
7.3. 
Definitions ..................................................................................................................76 
7.3.1. 
Adverse Event .............................................................................................................76 
7.3.2. 
Serious Adverse Event ................................................................................................76 
7.3.3. 
Adverse Events of Special Interest .............................................................................77 
7.4. 
Recording and Reporting Adverse Events ..................................................................77 
7.4.1. 
Adverse Events ...........................................................................................................77 
7.4.2. 
Serious Adverse Events ..............................................................................................77 
7.4.3. 
Other Events that Require Accelerated Reporting ......................................................78 
7.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................79 
7.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results .............................79 
7.4.6. 
Follow-up ....................................................................................................................79 
7.5. 
Evaluation of Severity and Causality .........................................................................79 
7.5.1. 
Evaluation of Severity ................................................................................................79 
7.5.2. 
Evaluation of Causality ...............................................................................................80 
7.6. 
Safety Monitoring .......................................................................................................81 
7.6.1. 
Monitoring Adverse Events of Special Interest ..........................................................82 
7.6.1.1. 
Adjudicated Arthropathy ............................................................................................82 
7.6.1.2. 
Sympathetic Nervous System Dysfunction ................................................................83 
7.6.1.3. 
Peripheral Sensory Adverse Events ............................................................................84 
7.6.1.4. 
Joint Replacement Surgery .........................................................................................84 
7.7. 
Investigator Alert Notification ....................................................................................84 
8. 
STUDY VARIABLES................................................................................................85 
8.1. 
Demographic and Baseline Characteristics ................................................................85 
8.2. 
Primary Endpoint ........................................................................................................85 
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8.3. 
Exploratory Endpoints ................................................................................................85 
8.4. 
Additional Endpoints for the Efficacy Sub-Study ......................................................85 
8.5. 
Pharmacokinetic Variables .........................................................................................86 
8.6. 
Anti-Drug Antibody Variables ...................................................................................86 
9. 
STATISTICAL PLAN................................................................................................87 
9.1. 
Statistical Hypothesis for the Sub-Study Population ..................................................87 
9.2. 
Determination of Sample Size ....................................................................................88 
9.3. 
Analysis Sets ...............................................................................................................88 
9.3.1. 
Efficacy Analysis Sets ................................................................................................88 
9.3.2. 
Safety Analysis Set .....................................................................................................89 
9.3.3. 
Per Protocol Set ..........................................................................................................89 
9.3.4. 
Pharmacokinetics Analysis Set ...................................................................................89 
9.3.5. 
Anti-Drug Antibody Analysis Set ..............................................................................89 
9.4. 
Patient Disposition ......................................................................................................89 
9.5. 
Statistical Methods ......................................................................................................89 
9.5.1. 
Demography and Baseline Characteristics .................................................................89 
9.5.2. 
Efficacy Analyses for the Sub-Study Population .......................................................90 
9.5.2.1. 
Primary Efficacy Analysis ..........................................................................................90 
9.5.2.2. 
Secondary Efficacy Analysis ......................................................................................90 
9.5.3. 
Safety Analysis ...........................................................................................................91 
9.5.3.1. 
Adverse Events ...........................................................................................................91 
9.5.3.2. 
Other Safety ................................................................................................................92 
9.5.3.3. 
Treatment Exposure ....................................................................................................92 
9.5.3.4. 
Treatment Compliance ................................................................................................92 
9.5.4. 
Analysis of Pharmacokinetic Data ..............................................................................93 
9.5.5. 
Descriptive Analysis of Anti-Drug Antibody Data ....................................................93 
9.5.6. 
Interim Analysis ..........................................................................................................93 
9.6. 
Additional Statistical Data Handling Conventions .....................................................93 
9.7. 
Statistical Considerations Surrounding the Premature Termination of a Study .........94 
10. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS .....................................95 
10.1. 
Data Management .......................................................................................................95 
10.2. 
Electronic Systems ......................................................................................................95 
11. 
STUDY MONITORING ............................................................................................96 
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11.1. 
Monitoring of Study Sites ...........................................................................................96 
11.2. 
Source Document Requirements ................................................................................96 
11.3. 
Case Report Form Requirements ................................................................................96 
12. 
AUDITS AND INSPECTIONS .................................................................................97 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................98 
13.1. 
Good Clinical Practice Statement ...............................................................................98 
13.2. 
Informed Consent .......................................................................................................98 
13.3. 
Patient Confidentiality and Data Protection ...............................................................98 
13.4. 
Institutional Review Board/Ethics Committee ...........................................................99 
13.5. 
Clinical Study Data Transparency ..............................................................................99 
14. 
PROTOCOL AMENDMENTS ................................................................................100 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ..........................................................................................................................101 
15.1. 
Premature Termination of the Study .........................................................................101 
15.2. 
Close-out of a Site ....................................................................................................101 
16. 
STUDY DOCUMENTATION .................................................................................102 
16.1. 
Certification of Accuracy of Data .............................................................................102 
16.2. 
Retention of Records ................................................................................................102 
17. 
DATA QUALITY ASSURANCE ............................................................................103 
18. 
CONFIDENTIALITY ..............................................................................................104 
19. 
FINANCING AND INSURANCE ...........................................................................105 
20. 
PUBLICATION POLICY ........................................................................................106 
21. 
REFERENCES .........................................................................................................107 
22. 
INVESTIGATOR’S AGREEMENT ........................................................................109 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS ...................................................110 
 
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LIST OF TABLES 
Table 1: 
Schedule of Events - Screening through Week 16 Visit .............................................54 
Table 2: 
Schedule of Events – Week 20 Visit through Week 52 Visit .....................................58 
Table 3: 
Schedule of Additional Events – Only for Patients Participating in the 
Efficacy Sub-Study (Screening through Week 16 Visit) ............................................61 
Table 4: 
Schedule of Events - Follow-up Period (24 Weeks after Last Treatment) and 
End of Study Phone Contact (52 Weeks after Last Treatment) ..................................62 
Table 5: 
Schedule of Events - Follow-up for Patients Who Undergo Joint 
Replacement Surgery ..................................................................................................64 
Table 6: 
Observed Incidence Rate (n/N) and 95% CI (Based on Exact Binomial Test) 
(%) ..............................................................................................................................88 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................36 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AA 
Adjudicated arthropathy 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine Aminotransferase 
ARGUS 
Pharmacovigilance and clinical safety software system 
AST 
Aspartate Aminotransferase 
Cmax 
Maximum observed drug concentration 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
Ctrough 
Concentration measured at the end of a dosing interval at steady state 
(taken directly before next administration) 
DA  
Destructive arthropathy 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EOS 
End of study 
EOT 
End of treatment 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
IVRS 
Interactive voice response system 
JR 
Joint replacement 
K-L 
Kellgren-Lawrence  
LDH 
Lactate dehydrogenase 
LTS 
Long-term safety 
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MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect model repeated measure 
MRI 
Magnetic resonance imaging 
NGF 
Nerve growth factor 
NRS 
Numeric Rating Scale 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
OA 
Osteoarthritis 
OMERACT-OARSI 
Osteoarthritis Research Society International Standing Committee for 
Clinical Trials Response Criteria Initiative and The Outcome 
Measure in Rheumatology 
PCSV 
Potentially clinically significant value 
PK 
Pharmacokinetic 
PPS 
Per protocol set 
PT 
Preferred term 
Q4W 
Every 4 weeks 
Q8W 
Every 8 weeks 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SD 
Standard deviation 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TIA 
Transient ischemic attack 
TrkA 
Tyrosine kinase type 1 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
WOMAC 
Western Ontario and McMaster Universities Osteoarthritis Index 
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1. 
INTRODUCTION AND RATIONALE 
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 which is 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.  
Non-steroidal anti-inflammatory drugs (NSAIDs) are the mainstay of treatment in patients with 
mild-to-moderate OA. Their efficacy is well documented, although modest (Bjordal 2004), but 
their use is not without risk. Many patients with acute and chronic pain do not receive adequate 
pain relief despite the wide variety of analgesic medications that are currently available, either 
because the medications are not effective in all patients, or because their use is limited by 
toxicity or intolerability. The risks associated with long-term NSAID therapy have been well 
characterized and include gastrointestinal bleeding and increased risk of cardiovascular events. 
In some patients (eg, those with hypertension and pre-existing renal or gastrointestinal disease), 
the chronic use of NSAIDs may be contraindicated (see current version of the Investigator’s 
Brochure). Guidelines suggest that opioids may be used in OA only if management with 
NSAIDs is ineffective, intolerable, or otherwise contraindicated.  However, opioid use can be 
associated with both acute and chronic side effects. These include drowsiness, dizziness, 
gastrointestinal tolerability and motor imbalance, all of which can have serious consequences in 
older patients. There is data to support the efficacy of opioids in treating pain over a short 
duration; however, long-term efficacy has not been evaluated. Furthermore, there is no evidence 
to support superiority of opioids over other available pain medications. Additionally, opioids 
must be carefully used in patients vulnerable or potentially vulnerable to abuse or addiction. 
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 and loss of 
productivity. 
As a result, there remains an unmet medical need for alternative treatment options with more 
effective analgesia and/or with an improved side-effect profile. This is an important need 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.   
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 (Smeyne 1994, Crowley 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 
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factor activity is mediated through 2 different membrane-bound receptors, the high-affinity 
tyrosine kinase type 1 (TrkA) and the low-affinity p75 neurotrophin receptors.   
By acting upstream of several relevant molecular pathways, the NGF/TrkA system appears to 
play a major role in the control of pain.  Administration of NGF has been shown to provoke pain 
in both 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 (Indo 1996, Einarsdottir 2004).  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 non-steroidal anti-inflammatory drugs (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 osteoarthritis (OA) of the knee was completed (study 
R475–PN-0901, see current version of the Investigator’s Brochure). Three intravenous (IV) 
doses of fasinumab were evaluated (0.03, 0.1, 0.3 mg/kg every 8 weeks [Q8W]), all of which 
were associated with statistically significant improvement in pain compared with placebo when 
evaluated by walking knee pain, the Western Ontario and McMaster Universities Osteoarthritis 
Index (WOMAC), and the Patient’s Global Impression of Change questionnaire. Additionally, an 
interim analysis of the R475-PN-1227 osteoarthritis study was conducted and 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 each given every 4 weeks [Q4W]) compared to placebo 
(data on file). 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 (Lane 2010, Hefti 2006, Brown 2010, Sanga 2011) and 
in patients with chronic low back pain (Kivitz 2013, Katz 2011).  
In all clinical studies completed to date, fasinumab was generally well tolerated, although 
joint-related events have occurred more frequently in fasinumab-treated patients than in 
placebo-treated patients. Additionally, 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 
fasinumab-treated patients than in placebo-treated patients. These adverse events (AEs) or 
physical examination abnormalities associated with fasinumab were generally mild to moderate 
in intensity and were transient in nature (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 OA. Analyses of 
the tanezumab data by its sponsor, defined by anatomic pathological criteria on specimens 
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obtained on joint replacement (JR), showed that the risk of DA increases with tanezumab dose 
and is further increased with the concomitant use of chronic NSAIDs (>90 days) (Lane 2010). 
Most cases of DA occurred in joints with a documented history of OA.  
Based on the potential risk of DA identified with tanezumab and fulranumab, the US Food and 
Drug Administration (FDA) placed the class of anti-NGF antibodies on clinical hold in 2010. 
Following 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 being implemented for all fasinumab studies, as outlined in Section 7.6.1.1. This 
approach includes sensitive, prospective, and rigorous radiologic screening and monitoring for 
certain changes in joint structure. Patients who develop these changes, termed ‘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, non-clinical studies of the sponsors of other anti-NGF monoclonal antibodies identified 
adverse changes in the sympathetic nervous system of mature animals of several species (rat and 
non-human primate). These effects included a reversible decrease in neuron volume. To date, no 
statistically significant or consistent effects of fasinumab on the sympathetic nervous system 
have been detected in animal studies with up to 6-months of treatment. Based on the potential 
risk of sympathetic nervous system toxicity identified in non-clinical studies of other anti-NGF 
monoclonal antibodies, a risk-mitigation approach is being implemented for all fasinumab 
studies, as outlined in Section 7.6.1.2. 
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).  
Accordingly, 6 mg Q4W and 9 mg Q4W were removed from the present study in an amendment 
issued in June 2016.  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 the present study.  Subsequently, a small Regeneron team reviewed the data 
and agreed with this recommendation.  The DMC noted imbalances in clinically relevant adverse 
events including time to total joint replacement, peripheral edema, arthralgia and a trend towards 
early fractures.  The phase 3 program for OA pain in the hip or knee will continue to evaluate 
fasinumab 1 mg with the highest dose regimen of 1 mg Q4W, which is supported by the 
independent DMC as having a favorable benefit-risk profile.  
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Osteoarthritis is a condition that results in significant morbidity and disability, as well as marked 
loss of productivity for those affected (see current version of the Investigator’s Brochure). For 
those patients affected, fasinumab represents an effective anti-NGF therapy which has the 
potential to help those patients who do not achieve adequate pain relief, are unable to tolerate 
existing therapies, or have absolute or relative contraindications to existing therapies. 
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-1523, patients with pain due to OA will be 
randomized to fasinumab 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 restricted 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. 
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 7.6.1.  
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Finally, the selected dose of fasinumab has been chosen to also contribute to the further 
maintenance of a favorable risk-benefit.   
In summary, the overall benefit risk profile for fasinumab in this study 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 1.3 for additional information on the rationale for including a placebo 
group. 
1.3. 
Rationale 
1.3.1. 
Rationale for Study Design 
The purpose of this randomized, double-blind, placebo-controlled study is to evaluate the 
long-term safety, tolerability, and the efficacy of fasinumab in patients with pain due to 
radiographically confirmed OA of the knee or hip who have a history of inadequate pain relief 
with paracetamol/acetaminophen, and a history of inadequate pain relief or intolerance to oral 
NSAIDs, and opioid therapy. During the initial 16 weeks of the trial, standard-of-care pain 
medications will be prohibited with the exception of paracetamol/acetaminophen, which will be 
provided as a rescue medication. Following the first 16 weeks, patients will be able to utilize 
standard-of-care pain medication including limited use NSAIDs (for non-OA pain or fever), as 
well as paracetamol/acetaminophen (Section 5.2.2), in addition to study drug. Therefore, this 
study will also provide safety data on the concomitant use of fasinumab with other analgesics, 
including limited use NSAIDs.  
A subset of patients will participate in an efficacy sub-study, in addition to participation in the 
main long-term safety study. In the sub-study, efficacy parameters will be assessed over the 
16 weeks following randomization.  
Overall, this study will provide long-term safety data for up to 52 weeks of exposure to 
fasinumab or placebo to allow assessment of risk-benefit of fasinumab in patients with chronic 
pain due to knee or hip OA who have failed or who are intolerant of NSAIDs and opioids, and 
who have inadequate pain relief from acetaminophen. The study is being conducted with 
appropriate eligibility criteria to exclude patients who may be at risk for adjudicated arthropathy 
and sympathetic nervous system effects. In addition, specific questionnaires and physical exams 
are being employed to monitor for events of arthralgia, altered peripheral sensation, adjudicated 
arthropathy, and sympathetic nervous system effects. 
In this study, a placebo arm is important to accurately estimate the risk of AEs, including AEs of 
special interest (AESI) (adjudicated arthropathy, sympathetic nervous system dysfunction, 
peripheral sensory AEs, and JR surgery). Since this study is enrolling patients who have failed or 
are intolerant to NSAIDs or opioids, and who have inadequate pain relief from 
paracetamol/acetaminophen, there are limited other therapeutic options available, supporting 
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equipoise 
with 
randomization 
to 
placebo. 
For 
all 
patients, 
rescue 
medication 
(paracetamol/acetaminophen) will be made available for breakthrough pain.  In addition, 
following the initial 16 weeks of the trial, patients will be allowed to use other pain medications 
for OA pain, with the exception of NSAIDs. Limited NSAID use will be allowed to treat 
non-OA pain or fever after week 16. 
Participation in the study provides additional benefits. All patients included in the study will 
have regular study visits and receive diagnostic procedures 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. Therefore, the use of a placebo arm is justified as 
placebo treated patients will not be placed at significant risk and will have access to rescue 
medication, as appropriate. 
1.3.2. 
Rationale for Dose Selection 
Previous versions of this protocol randomized patients to receive fixed-dose, subcutaneous (SC) 
injections of fasinumab at 6 mg Q8W (amendment 3 onwards in the main study) and 1 mg Q8W, 
1 mg Q4W, 3 mg Q4W, 6 mg Q8W (amendment 5 in the efficacy sub-study), or matching 
placebo.  The purpose of the 1 mg Q8W dose regimen is to aid in the determination of a 
minimally effective dose.  An independent DMC recommended discontinuing 6 mg Q8W and 
3 mg Q4W (expected to have similar exposure to 6 mg Q8W) following a review of unblinded 
data from this ongoing study.  The recommendation 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 patients administered 6 mg Q4W (dose discontinued in 
amendment 3, issued on 20 June 2016) or 6 mg Q8W.  Based on the independent DMC review, 
study of lower dose levels (eg,1 mg Q4W) may continue to be evaluated in this population.  
Under amendment 7, issued on 24 May 2018, all patients previously randomized to 3 mg Q4W 
or 6 mg Q8W under earlier versions of the protocol were discontinued from study drug but 
encouraged to complete all remaining study visits and study procedures in the follow-up period, 
and the end of study phone call.  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 amendment 8, issued on 11 Jul 2018, 
patients will be in a 3:3:1 ratio to fasinumab 1 mg Q8W, 1 mg Q4W or placebo.  This 
randomization ratio was chosen based on the need to enroll more patients on the 1 mg dose 
regimens and the need to include placebo patients for blinding purposes.  
Patients originally randomized to 6 mg Q4W or 9 mg Q4W were transitioned to 6 mg Q8W in 
amendment 3 (issued on 20 June 2016).  These patients and patients on matching placebo were 
subsequently discontinued from study drug in amendment R475-PN-1523.04EU (issued on 
12 January 2017) and amendment 5 global (issued on 16 March 2017), but encouraged to 
otherwise continue all protocol visits and complete all study procedures with the exception of 
receiving study drug.  This decision was based on data from the phase 2/3 study, R475-PN-1227, 
which showed an increase in AA events that occurred more frequently at the highest doses 
evaluated (6 mg and 9 mg Q4W). 
Supportive trials include data from 2 completed fasinumab phase 1 studies in healthy volunteers 
(R475-PN-0817 and TD-11480), as well as data from the completed fasinumab phase 2 
proof-of-concept study in patients with pain due to OA of the knee (R475-PN-0901), results 
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from the phase 2 study in patients with osteoarthritis of the hip or knee (R475-PN-1227), and the 
single-dose, proof-of-concept study in patients with sciatic pain (R475-PN-0908), as well as 
pharmacokinetics (PK).  
Single subcutaneous (SC) doses of fasinumab of up to 30 mg were well tolerated in healthy male 
and female subjects (study TDU-11480). Single IV doses of up to 1 mg/kg were also studied in 
healthy male and female subjects (study R475-PN-0817). In this study, fasinumab was generally 
well tolerated at all but the highest IV dose (1 mg/kg). Neurosensory AEs, which were transient 
and not severe, led to expansion of the 1 mg/kg IV cohort and a decision to not dose-escalate 
beyond this level.  
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 to 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, 6mg, 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 being studied.  Neuromuscular AEs, such as arthralgia and paresthesia, were reported 
more frequently in fasinumab treated patients than in placebo-treated patients, though these 
events were typically mild or moderate in intensity.  The efficacy and safety data from the 1 mg 
and 3 mg Q4W dose regimens in R475-PN-1227 supported the previous dose selection of 1 mg 
and 3 mg Q4W 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. 
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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of the study is to describe the safety and tolerability of fasinumab, 
including adverse events of special interest (AESIs), in patients with pain due to 
radiographically-confirmed OA of the knee or hip. 
2.2. 
Exploratory Objectives 
Other objectives of the study are: 
 To assess the use of paracetamol/acetaminophen for the fasinumab arms compared to 
placebo from baseline to week 16 
 To assess the use of paracetamol/acetaminophen for the fasinumab arms compared to 
placebo from baseline to week 52 
 To assess the use of standard-of-care analgesic medication, including NSAIDs, for 
non-OA pain in patients randomized to fasinumab compared to placebo from week 16 
through the end of treatment 
 To assess time to JR 
2.3. 
Additional Objectives for the Efficacy Sub-Study 
The objective of the stub-study is to evaluate the efficacy of fasinumab compared with placebo 
when administered to patients with pain due to radiographically-confirmed OA of the knee or 
hip. 
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3. 
STUDY DESIGN 
3.1. 
Study Description and Duration 
This study will further characterize the safety profile of fasinumab including the incidence of 
AESIs and provide data on long-term exposure.  A subset of approximately 1000 patients will 
also participate in a sub-study to characterize the efficacy of fasinumab. Participation in the sub-
study will last for the first 16 weeks of this study; patients will then be rolled over into the long-
term safety study. 
The study consists of a screening period of up to 30 days (Screening Period), a 7 to 10 day 
pre-randomization period (Pre-Randomization Period), a 16-week randomized, double-blind, 
placebo-controlled treatment period (Treatment Period 1), a 36-week, double-blind, 
placebo-controlled treatment period (Treatment Period 2) in which non-NSAID standard-of-care 
pain medications can also be used in the event of inadequate pain relief for OA pain, a 24-week 
follow-up period with in-clinic visits (Follow-up Period), and an end of study phone contact at 
52 weeks following the last dose of study drug to evaluate the number of patients who have 
undergone JR surgery, are scheduled for JR surgery, or on a waiting list for JR surgery 
(Figure 1).  
 Screening Period (up to 30 days before the pre-randomization period): After 
informed consent has been signed, eligibility for enrollment will be determined based 
upon parameters assessed during the screening and pre-randomization periods. X-rays 
of the shoulders, hips and knees will be performed during the screening period. 
Magnetic resonance imaging (MRI) of the index and contralateral joint must be 
performed and assessed by the central reader. Any knee or hip joint with a K-L score 
of ≥3 will have an MRI completed during the screening period. Pre-randomization 
visits cannot occur until the MRIs of those joints have been completed and the central 
reader confirms that there are no exclusionary findings. During the screening period, 
all patients may continue to take their current treatment regimen for OA pain. 
 Pre-Randomization Period (7 to 10 days before the randomization/baseline visit 
[day 1]): Patients who meet the initial eligibility criteria, as assessed in the screening 
period, may enter the pre-randomization period. An in-office pre-randomization visit 
will occur for patients enrolled in the sub-study while a phone visit will occur if 
patients are only in the safety portion of the trial without the sub-study.  The 
pre-randomization phone call or visit occurs 7 to 10 days before the randomization 
visit. Patients will stop taking/washout of their standard-of-care pain medications for 
OA during the pre-randomization period.  In the event of inadequate OA pain relief, 
patients may take paracetamol/acetaminophen according to local standard-of-care, 
with a maximum daily dose of 2500 mg in Europe and 2600 mg in countries outside 
of Europe. Sub-study patients should discontinue use of paracetamol/acetaminophen 
24 hours prior to the start of the randomization visit (baseline).  
For any patient who had an MRI of any joint during screening, confirmation that 
there are no exclusionary findings on MRI must be received from the central reader 
before the patient can be randomized.   
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Treatment Period 1 (starts with day 1 and continues through week 16): The 
initial 16-week treatment period (treatment period 1) will begin at the randomization 
visit (baseline/day 1) and continue up to the week 16 visit.  All patients will undergo 
baseline assessments at the day 1 visit and will be randomized to receive one of the 
ongoing study drug dose regimens (1 mg Q4W, 1 mg Q8W, or placebo).  Patients 
randomized to 1 mg Q8W will receive alternating placebo injections at the monthly 
visits where active study medication will not be given to maintain the blind.   
During treatment period 1, patients will be supplied with paracetamol/acetaminophen 
as the study-provided rescue medication.  All patients will record rescue medication 
use in their diaries from the randomization visit through treatment period 1.  All use 
of NSAIDs during treatment period 1, including oral or topical formulations, is 
prohibited (except up to 150 mg/day of aspirin/5-ASA, which is permitted for cardiac 
prophylaxis per local guidelines).  Patients may be withdrawn from the study after 
appropriate counseling if they continue to use NSAIDs during treatment period 1.   
Safety assessments will be performed at each study visit during treatment period 1, as 
outlined in Table 1.  Potential events of adjudicated arthropathy will be monitored via 
clinical signs and symptoms of worsening joint pain during the study (eg, using the 
joint pain questionnaire and imaging).  Potential events of sympathetic nervous 
system dysfunction will be monitored throughout the study through physical 
examination, AE reporting, assessment of orthostatic hypotension and via the Survey 
of Autonomic Symptoms.   
Efficacy assessments will be performed for patients participating in the sub-study as 
outlined 
in 
Table 3. 
Sub-study 
patients 
should 
discontinue 
use 
of 
paracetamol/acetaminophen 24 hours prior to the start of study visits during treatment 
period 1 in order to minimize the confounding effects of the rescue medication on 
efficacy measurements.   
 Treatment Period 2 (starts with study drug administration at week 16 and 
continues through week 52): Treatment period 2 begins at the week 16 visit and 
continues through the week 52 visit.  Patients will continue to receive fasinumab 
1 mg Q8W, 1 mg Q4W or placebo Q4W during this period.  At the week 24 visit, X-
rays of the hips, knees, and shoulders will be obtained.  The last dose of study drug 
will be administered at week 48.  
During treatment period 2, patients may use non-NSAID standard-of-care pain 
treatment as rescue treatment and limited use of oral NSAIDs for non-OA related 
pain or fever.   
Non-steroidal anti-inflammatory drugs will be study-provided as tablets or capsules, 
and may be used for up to 10 days in an 8-week period, 30 days in a 6-month period, 
and 60 days in a 1-year period.  Use of oral NSAIDs in excess of these amounts is 
prohibited.  The daily dose should not exceed the recommended maximum daily dose 
per the product labeling.  Topical NSAIDs are prohibited during treatment period 2.  
Patients may be withdrawn from the study after appropriate counseling if continued 
noncompliance with protocol-defined maximum NSAID use occurs.   
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Patients will continue to be supplied with paracetamol/acetaminophen during 
treatment period 2.   
The use of paracetamol/acetaminophen and/or NSAIDs should be recorded daily by 
the patient in the patient’s diary.  All other pain medications will be obtained and 
used per local standard-of-care; their use will be reported as concomitant medication 
during regular study visits.   
 Follow-up Period (for 24 weeks after the last dose of study drug, up to week 72): 
Patients will be followed for an additional 24 weeks following administration of the 
last dose of study drug.  Patients who were discontinued from 3 mg Q4W or 6 mg 
Q8W fasinumab under amendment 7 were immediately entered into the follow-up 
period.  Patients will have safety assessments performed at clinic visits, which will 
occur at 4 weeks, 12 weeks, and 24 weeks after the last dose of study drug.  
Additionally, a phone contact will be conducted at 8 weeks following the last dose of 
study drug to monitor for AEs and concomitant medications.  
During the follow-up period, patients must still only use the limited use amounts of 
NSAIDs for non-OA pain or fever.  Patients may increase their dose of NSAIDs 
beyond the limit outlined for treatment period 2 starting 16 weeks after their last dose 
of study drug.   
All AEs will continue to be monitored during this period. 
If a patient must undergo JR surgery during the treatment or follow-up periods (up to 
week 24 after the last dose), then the patient will be asked to complete post-surgery 
follow-up assessments, as outlined in Table 5.   
 End of Study Phone Contact (week 100): A phone contact questionnaire will be 
conducted at 52 weeks following the last dose of study drug to document patient 
status with regard to JR surgery (if a patient underwent JR, is scheduled to have JR 
surgery, or is on a waiting 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. 
Figure 1: 
Study Flow Diagram 
 
Screening 
Period 
Pre-Randomization 
Period 
Treatment 
Period 1 
Treatment 
Period 2 
Follow-Up 
Period 
EOS Phone 
Contact 
 
up to 30 days  
 
7 to 10 days  
 
Day 1  
through  
Week 16 
Week 16  
through   
Week 52 
For 24 weeks after 
the last dose of 
study drug  
(up to Week 72) 
At 52 weeks 
after the last 
dose of study 
drug  
(Week 100) 
 
 
 
 
 
 
 
 
           Baseline 
            (Day 1) 
                   EOT 
 
 
EOT: End of treatment; EOS: End of study  
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3.1.1. 
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 the sponsor to temporarily halt, alter or terminate: 
 individual dose arms 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. 
3.1.2. 
End of Study Definition 
The end of the study for this study is defined as the last telephone contact for the last patient.   
3.2. 
Planned Interim Analysis 
The week 72 primary safety analysis will be conducted when 72-week data, including 24-week 
follow-up data, are available for all randomized patients. Additional interim analysis of safety 
data may be performed for regulatory authority or internal decision-making purposes. 
The primary efficacy analysis for the sub-study may be conducted when 16-week data are 
available for all randomized patients in the sub-study.  No alpha adjustment is necessary, as the 
week 16 efficacy analysis will be the final primary analysis for efficacy.  Patient-level results 
will not be disclosed to any site-facing personnel or to any personnel directly involved with the 
conduct of the study. 
3.3. 
Study Committees 
3.3.1. 
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. 
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3.4. 
Adjudication of Arthropathy 
All potential events of arthropathy will be adjudicated by an independent, blinded adjudication 
committee composed of radiologists. Further details will be defined in the Arthropathy 
Adjudication Charter.  
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4. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
4.1. 
Number of Patients 
Up to 7000 patients are planned to participate in this study (enrollment may be less than 7000 
depending on enrollment across all studies in the fasinumab program).  A subset of 
approximately 1000 patients will participate in the efficacy sub-study. 
4.2. 
Study Population 
Eligible patients for this study will be men and women ≥18 years of age with a history of pain 
due to OA of the knee or hip and inadequate pain relief or intolerance to current analgesic 
therapy. 
4.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Male or female ≥18 years of age at the screening visit 
2. Provide signed informed consent 
3. Body mass index ≤39 
4. 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 
 The index joint is defined as the joint with OA under evaluation for this study 
 A joint previously treated with joint replacement surgery cannot be the index joint 
 A joint previously surgically modified within the past year cannot be the index joint 
 If a patient has a K-L score of ≥2 at more than 1 knee or hip joint, the index joint is 
the joint with the greatest WOMAC pain subscore at the screening visit.  If 2 or more 
knee or hip joints have a K-L score of ≥2 and the same WOMAC pain subscore, the 
index joint is the joint with the greater K-L score.  If 2 or more joints have a 
K-L score of ≥2, the same WOMAC pain subscores, and the same K-L scores, then 
the investigator may choose 1 of these joints as the index joint 
5. Moderate-to-severe pain in the index joint defined as a WOMAC average pain subscale 
score of ≥4 at both the screening and randomization visits 
6. Willing to discontinue current pain medications and to adhere to study requirements for 
rescue treatments (paracetamol/acetaminophen to be taken as needed with a maximum 
daily dose of 2500 mg in Europe and 2600 mg in countries outside of Europe and limited 
use of oral NSAIDs [see Section 5.2.2] during treatment period 2) 
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7. A history of 12 weeks of analgesic use for OA of the knee or hip as defined by:  
 Inadequate pain relief from paracetamol/acetaminophen, and 
 Intolerance or inadequate pain relief from at least 1 oral NSAID, and 
 Intolerance to or inadequate pain relief from opioid therapy, unwillingness to take 
opioid therapy for a medically acceptable reason, or lack of access to opioid therapy  
8. History of regular use of analgesic medications for OA pain (defined as an average of 
4 days per week over the 4 weeks prior to the screening visit), including NSAIDs, 
selective cyclooxygenase 2 inhibitors, opioids, paracetamol/acetaminophen, or 
combinations thereof 
9. Willing to maintain current activity and exercise levels throughout the study 
10. Willing and able to comply with clinic visits and study-related procedures, and willing to 
provide follow-up information related to any joint replacement surgery that occurs within 
the period of time covered by their intended participation in the study 
11. Able to understand and complete study-related questionnaires 
12. Willing to consider total JR surgery, if necessary  
4.2.2. 
Additional Inclusion Criteria for Sub-Study Patients Only 
1. Willing to discontinue glucosamine sulfate and chondroitin sulfate treatments during the 
initial 16 weeks of treatment 
2. Stable treatment with glucosamine sulfate and chondroitin sulfate treatments must be 
stopped during the pre-randomization period. 
3. Provide 
consent 
to 
allow 
all 
radiographs/other 
imaging 
and 
medical/surgical/hospitalization records for care received elsewhere during the study 
period to be shared with investigator 
4.2.3. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. History or presence at the screening visit of non-OA inflammatory joint disease 
(eg, rheumatoid arthritis, lupus erythematosus, psoriatic arthritis, pseudogout, gout, 
spondyloarthropathy, polymyalgia rheumatica, joint infections within the past 5 years), 
Paget’s disease of the spine, pelvis or femur, neuropathic disorders, multiple sclerosis, 
fibromyalgia, tumors or infections of the spinal cord, or renal osteodystrophy  
2. History or presence on imaging of arthropathy (osteonecrosis, subchondral insufficiency 
fracture, rapidly progressive osteoarthritis type 1 or type 2), stress fracture, recent stress 
fracture, neuropathic joint arthropathy, hip dislocation (prosthetic hip dislocation is 
eligible), knee dislocation (patella dislocation is eligible), congenital hip dysplasia with 
degenerative joint disease, extensive subchondral cysts, evidence of bone fragmentation 
or collapse, or primary metastatic tumor with the exception of chondromas or pathologic 
fractures during the screening period 
3. Signs or symptoms of carpal tunnel syndrome within 6 months of screening 
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4. Patient is not a candidate for MRI 
5. Is scheduled for a joint replacement surgery to be performed during the study period 
6. Systemic (ie, 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) 
7. History or presence at the screening visit of autonomic neuropathy, diabetic neuropathy, 
or other peripheral neuropathy, including reflex sympathetic dystrophy  
8. History or diagnosis of chronic autonomic failure syndrome including pure autonomic 
failure, multiple system atrophy (Shy-Drager syndrome) 
9. Poorly controlled diabetes (defined as any single value of hemoglobin A1c [HbA1c] 
>9.0%) at the screening visit 
10. Known history of human immunodeficiency virus infection 
11. Known history of ocular herpes simplex virus, herpes simplex virus pneumonia, or herpes 
simplex virus encephalitis 
12. History of sickle cell disease, including S-C disease and S-β thalassemia 
13. Confirmed elevated screening alanine aminotransaminase (ALT) or aspartate 
aminotransaminase (AST) ≥2.5 times the ULN 
14. Resting heart rate of <50 beats per minute (bpm) or >100 bpm (by vital sign assessment 
or as captured during ECG assessment) at the screening or randomization visits 
15. History or presence of 2nd or 3rd degree heart block, 1st degree heart block with abnormal 
QRS, or bifascicular block by ECG assessment at the screening visit  
16. History or presence of orthostatic hypotension, as defined in Section 6.3.4.6, at the 
screening or randomization visits  
17. History of poorly controlled hypertension 
 Systolic blood pressure ≥180 mm Hg or diastolic blood pressure ≥110 mm Hg at the 
screening visit 
 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 [TIA], peripheral arterial disease and 
moderate to advanced retinopathy [hemorrhages or exudates, papilledema]) 
18. Congestive heart failure with NY Heart Classification of stage III or IV 
19. Transient ischemic attack (TIA) or cerebrovascular accident within the past 12 months 
prior to the screening visit, or myocardial infarction, or acute coronary syndromes within 
the past 6 months prior to the screening visit 
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20. 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 
21. New major illness diagnosed within 2 months prior to the screening visit 
22. 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. 
23. Known history of infection with hepatitis C virus.  Patients with a history of hepatitis C 
are eligible if there is documentation of a negative hepatitis C virus RNA test. 
24. 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 
25. Known allergy or sensitivity to doxycycline or related compounds, or monoclonal 
antibodies 
26. History of (within 5 years prior to the screening visit) current alcoholism, alcohol abuse, 
substance abuse, or abuse of prescription pain medication 
27. History of cannabis use for the treatment of pain within the past 6 months prior to the 
screening visit 
28. Ongoing participation in a clinical research study evaluating another investigational drug 
or having received another investigational product with 30 days or 5 half-lives of the 
screening visit, whichever is longer  
29. 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 
30. Member of the clinical site study team and/or his/her immediate family 
31. Pregnant or breast-feeding women 
32. Women of childbearing potential who have a positive pregnancy test result or do not have 
their pregnancy test result at baseline 
33. 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; intrauterine hormone-releasing system; bilateral 
tubal ligation; vasectomized partner; and or sexual abstinence†, ‡. 
* Postmenopausal women must be amenorrheic for at least 12 months in order not to be 
considered of childbearing potential.  Pregnancy testing and contraception are not 
required for women with documented hysterectomy or tubal ligation. 
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† 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, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are 
not acceptable methods of contraception. Female condom and male condom should not 
be used together.  
Note: HIV and/or hepatitis testing will be performed on a country-by-country basis, according to 
local guidelines if required by regulatory authorities or ethics boards. 
4.2.4. 
Additional Exclusion Criteria for Sub-Study Patients Only 
1. Four or more consecutive missed diary entries during the pre-randomization period 
2. Trauma to the index joint within 3 months prior to the screening visit 
3. 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 
4. Presence of orthostatic hypotension at the pre-randomization visit 
5. 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.  
6. History of hospital admission for depression or suicide attempt within 5 years or active, 
severe major depression at screening  
4.3. 
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 sponsor have the right to withdraw a patient from the study in the event of 
an intercurrent illness, AE, treatment failure, protocol violation, cure, and for administrative, or 
other reasons. Patients may also be withdrawn from the study, after appropriate counseling, for 
continued noncompliance with protocol-defined maximum NSAID use.  
An excessive rate of withdrawals would render the study uninterpretable; therefore, unnecessary 
withdrawal of patients should be avoided. 
Patients who withdraw prematurely from the study will be asked to complete study assessments 
per Section 6.2.10. 
4.4. 
Replacement of Patients 
Patients prematurely discontinued from the study will not be replaced. 
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5. 
STUDY TREATMENTS 
5.1. 
Investigational and Reference Treatments 
Under amendment 8 and amendment 9, patients will be enrolled into the main safety study and 
randomized to 1 of the following treatment arms: 
 Fasinumab 1 mg SC Q8W (patients will receive placebo injections at the study visits 
where fasinumab is not administered) 
 Fasinumab 1 mg SC Q4W 
 Placebo SC Q4W 
Prior to amendment 7 (urgent safety measure), patients were randomized to 6 mg Q8W or 
placebo in the main study (after amendment 3), and to the following treatment arms in the 
efficacy sub-study (amendment 5): 
 Fasinumab 1 mg SC Q8W (included in the efficacy sub-study only; patients will 
receive placebo injections at the study visits where fasinumab is not administered) 
 Fasinumab 1 mg SC Q4W  
 Fasinumab 3 mg SC Q4W 
 Fasinumab 6 mg SC Q8W (patients will receive placebo injections at the study visits 
where fasinumab is not administered) 
 Placebo SC Q4W 
Enrollment into the efficacy sub-study was completed prior to amendment 7. 
All patients previously enrolled into the main study had completed treatment prior to amendment 
7.  Under amendment 7, patients randomized to 3 mg Q4W or 6 mg Q8W in the efficacy 
sub-study were discontinued from study drug for the remainder of the study.  All patients who 
were discontinued from study drug immediately entered the follow-up period. 
Patients originally randomized to earlier versions of the protocol (prior to amendment 3) with 
9 mg Q4W, 6 mg Q4W, or placebo Q4W were discontinued from study drug for the remainder 
of the study under an amendment 4EU (issued on 12 January 2017) and amendment 5 global 
(issued on 16 March 2017).  
All patients will receive SC injections Q4W from day 1 up to week 48.  All SC injections will be 
in the abdomen, thigh, or upper arm.  Study drug (fasinumab or placebo) will be administered at 
the study site after all study visit procedures have been completed.  Patients will be observed in 
the clinic for approximately 1 hour after study drug is administered. 
Instructions for study drug administration are provided in the pharmacy manual. 
Doses of study drug must be given within ±7 days from the scheduled dose date.  If the window 
is missed, the dose should not be administered.  The next dose should be administered at the next 
scheduled dosing date. 
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5.2. 
Rescue Treatments 
Rescue treatments will be provided to all patients according to Section 6.1.   
5.2.1. 
Paracetamol/Acetaminophen - Weeks 1 through 16 
Study-provided paracetamol/acetaminophen is the only allowable rescue treatment for OA pain 
during 
treatment 
period 1. 
In 
the 
event 
of 
inadequate 
relief 
for 
OA 
pain, 
paracetamol/acetaminophen may be taken as needed according to local standard-of-care, with a 
maximum daily dose of 2500 mg in Europe and countries with 500 mg tablets/capsules or 
2600 mg in countries outside of Europe with 325 mg tablets/capsules.  Sub-study patients should 
discontinue use of paracetamol/acetaminophen 24 hours prior to the start of the randomization 
visit (baseline) and prior to the start of scheduled study visits during treatment period 1 in order 
to minimize the confounding effects of the rescue medication on efficacy measurements. 
The amount of paracetamol/acetaminophen used in the preceding 24 hours will be reported by 
patients from the randomization visit (day 1) using the patient diary. All patients will record 
rescue medication use starting at the randomization visit. Paracetamol/acetaminophen 
accountability will be conducted at each site visit starting at the week 4 visit. 
Paracetamol/acetaminophen will be sourced by the sites and reimbursed by the sponsor unless 
country-specific regulations and customs require a different approach.  
Patients should be cautioned to avoid consumption of alcoholic beverages while taking 
paracetamol/acetaminophen and to take no more than the maximum daily allowable dose. For 
additional information regarding rescue medication, please refer to the study pharmacy manual. 
5.2.2. 
Paracetamol/Acetaminophen and Non-Steroidal Anti-Inflammatory 
Drugs - Weeks >16 
Study-provided paracetamol/acetaminophen is the only study-provided rescue treatment for OA 
pain during treatment period 2, with a maximum daily dose of 2500 mg in Europe and other 
countries where 500 mg strength tablets/capsules are available and 2600 mg in any countries 
outside of Europe where 325 mg strength tablets/capsules are available.  
Beginning at week 16, patients may take non-NSAID standard-of-care therapy in addition to 
study drug, in the event of inadequate pain relief for OA pain.  Patients may also use limited-use 
NSAIDs for non-OA related pain or fever after week 16.   
Non-steroidal anti-inflammatory drugs will be provided as tablets or capsules.  The daily dose of 
NSAIDs should not exceed the recommended maximum daily dose per the product labeling, and 
their use will be limited to: 
 10 days in an 8-week period 
 30 days in a 6-month period 
 60 days in a 1-year period 
The amount of paracetamol/acetaminophen and NSAIDs used in the prior 24 hours will be 
reported by patients in their diary.  Non-steroidal anti-inflammatory drug accountability will be 
conducted at the end of treatment visit.  Non-steroidal anti-inflammatory drugs will be sourced 
by the sites and reimbursed by the sponsor unless country-specific regulations and customs 
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require a different approach.  Use of all other NSAIDs, including other oral or topical 
formulations, is prohibited.  After appropriate counseling, patients may be withdrawn from 
dosing for continued noncompliance with protocol-defined maximum NSAID use.  During the 
follow-up period, patients may increase their dose of NSAIDs 16 weeks after their last dose of 
study drug.  Additionally, patients who discontinue study medication during the treatment period 
should follow the protocol-specified NSAID requirements; however, the NSAID dose can be 
increased to standard of care doses 16 weeks after their last dose of study medication. 
5.3. 
Dose Modification and Study Drug Discontinuation Rules 
5.3.1. 
Dose Modification 
Dose modification for an individual patient is not allowed.  
5.3.2. 
Study Drug Discontinuation 
Study drug may be permanently or temporarily discontinued due to medical need, as determined 
by the investigator, medical monitor, or the sponsor and according to the study stopping rules 
(Section 3.1.1). 
Patients who permanently discontinue from study drug will be asked to remain in the study and 
to return to the clinic for all remaining study visits, per the visit schedule.  Once patients 
discontinue from study drug, they can restart standard-of-care medications for the treatment of 
their OA pain with the exception of NSAIDs.  Non-steroidal anti-inflammatory drugs can be 
restarted for OA pain 16 weeks after the last dose of study drug.   
Patients who opt to withdraw from the study will be asked to complete the early termination visit 
per Section 6.2.10. 
Patients who discontinue from study drug early due to a clinically relevant joint event (see 
Section 7.6.1.1) 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, 
they 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 6.3.4.10) 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. 
5.3.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
Study drug dosing will be permanently stopped in the event of: 
 A patient being randomized under amendment 3 or a subsequent amendment and 
treated with the 3 mg Q4W or 6 mg Q8W dosing regimen 
 A patient being randomized under an earlier version of the protocol before 
amendment 3 and treated with the 6 mg Q4W, 9 mg Q4W, or placebo Q4W dosing 
regimen 
 A subject developing clinically significant sensory and motor neurologic events 
confirmed by a neurologist’s examination and graded by the neurologist as at least 
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moderate peripheral neuropathy limiting activities of daily living, ie, grade ≥2 
according to v.4 (CTCAE); 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 noncompliance with protocol-defined maximum NSAID use (see 
Section 4.3) after appropriate counseling 
 Continued 
noncompliance 
with 
protocol-defined 
maximum 
acetaminophen/paracetamol use (with a maximum daily dose of 2500 mg in Europe 
and other countries where 500 mg strength tablets/capsules are available and 2600 mg 
in any countries outside of Europe where 325 mg strength tablets/capsules are 
available) after appropriate counseling 
 JR Surgery 
 AESI: 
 Adjudicated arthropathy, as described in Section 7.6.1.1  
 Sympathetic nervous system dysfunction , as described in Section 7.6.1.2  
 Hepatotoxicity  
 Study drug should be discontinued if: 
a) Total bilirubin (TBL) >2x ULN or international normalized ratio (INR) 
>1.5 and 
b) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
>3x ULN and 
c) No other cause for a and b is readily apparent 
Other causes of ALT, AST, and TBL elevations can include alcoholic hepatitis, 
autoimmune hepatitis, non-alcoholic hepatitis, heritable diseases (Gilbert's 
Syndrome), heart failure, and viral hepatitis.   
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 assessed as related to study medication  
 Any other medical need, as determined by the investigator 
 Sponsor decision 
 Patient decision 
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5.3.2.2. 
Reasons for Temporary Discontinuation of Study Drug 
Study drug may be temporarily discontinued due to medical need, as determined by the 
investigator. Study drug will be temporarily withheld while awaiting imaging adjudication for 
worsening joint pain or when routine imaging suggests adjudicated arthropathy and prompts the 
need for additional imaging (Section 7.6.1.1), 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 
(Section 7.6.1.2). Study drug should not be re-started until the next study visit unless 
imaging/evaluation results are available within the current visit window. 
5.4. 
Management of Acute Reactions 
5.4.1. 
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 7.4.1) and graded using the grading scales as instructed in 
Section 7.5.1. 
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.  
5.5. 
Method of Treatment Assignment 
Under amendment 8 and amendment 9, patients will be randomized into the main safety study in 
a 3:3:1 ratio to receive fixed-dose, SC injections of fasinumab at 1 mg Q8W, 1 mg Q4W, or 
placebo.  Patients randomized to 1 mg Q8W will receive alternating placebo injections at the 
monthly visits where active study drug will not be given to maintain the blind.  Randomization 
will be performed according to a predetermined central randomization scheme generated by a 
Regeneron Statistician and provided to the study site personnel by the interactive voice response 
system (IVRS).  Randomization in the study is stratified by baseline K-L score (2-3, 4) and 
geographic region (such as North America, Latin America, Europe, or Asia/Pacific/South 
Africa).  
There were no patients enrolled into the main safety study under amendment 5 or amendment 6.  
The patient allocation for the efficacy sub-study for all patients randomized to amendment 5 
global or amendment 6 was 1:1:1:1:1 to 1 mg of fasinumab Q8W, 1 mg of fasinumab Q4W, 
3 mg of fasinumab Q4W, 6 mg of fasinumab Q8W, or matching placebo Q4W.  Randomization 
was performed according to a predetermined central randomization scheme generated by a 
Regeneron Statistician and provided to the study site personnel by the IVRS.  Randomization in 
the study was stratified by baseline K-L score (2-3, 4) and geographic region (such as North 
America, Latin America, Europe, or Asia/Pacific/South Africa).  For the sub-study, stratification 
was also by index joint (knee, hip). 
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5.5.1. 
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 medication 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 (ADA) 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.   
5.5.2. 
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 before unblinding the 
patient, whenever possible 
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. 
5.5.3. 
Unblinding for Regulatory Reporting Purposes 
Treatment assignments for certain patients may be unblinded to Pharmacovigilance and Risk 
Management personnel for the purpose of regulatory reporting of suspected unexpected serious 
adverse reactions (SUSARs). 
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5.6. 
Treatment Logistics and Accountability 
5.6.1. 
Packaging, Labeling, and Storage 
A medication numbering system will be used in labeling blinded investigational study drug.  
Lists linking medication numbers with product lot numbers will be maintained by the groups (or 
companies) responsible for study drug packaging.  In order to maintain the blind, these lists will 
not be accessible to individuals involved in study conduct. 
Study drug (fasinumab and its placebo) will be refrigerated at the site at a temperature of 2°C to 
8°C; refrigerator temperature will be logged daily.  Storage instructions for study drug will be 
provided in the pharmacy manual.   
5.6.2. 
Supply and Disposition of Treatments 
Study drug (fasinumab and its placebo) will be shipped at a temperature of 2°C to 8°C to the 
investigator or designee at regular intervals or as needed during the study.  At specified time 
points during the study (ie, interim site monitoring visits), at the site close-out visit, and 
following drug reconciliation and documentation by the site monitor, all used and unused study 
drug will be destroyed or returned to the sponsor or designee.   
5.6.3. 
Treatment Accountability 
All drug accountability records for blinded fasinumab and its placebo, and study-provided rescue 
medications must be kept current. 
The investigator must be able to account for all used and unused study drug and rescue 
treatments.  These records should contain the dates, quantity, and study drug: 
 dispensed to each patient, 
 returned from each patient (if applicable), and 
 disposed of at the site or returned to the sponsor or designee. 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
5.6.4. 
Treatment Compliance 
All drug compliance records must be kept current and must be made available for inspection by 
the sponsor and regulatory agency inspectors.   
5.6.5. 
Patient Drug Accountability 
Patients will be asked to bring in their study-provided supplies of paracetamol/acetaminophen to 
each study visit (starting at the week 4 visit through the week 52 visit), and remaining 
medication will be counted to calculate medication use and compliance.   
Patients will be asked to bring in their study-provided supplies of NSAIDs to each visit starting 
at the week 20 visit until their end of treatment visit/early termination visit.  Patients will also be 
instructed to report the daily use of these medications using their diary.   
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5.7. 
Concomitant Medications 
Any treatment administered from screening until the end of the follow-up period or early 
termination is considered concomitant medication.  This includes medications that were started 
prior to the study and are ongoing during the study.  Prior to randomization, all 
paracetamol/acetaminophen will be recorded as a concomitant medication.  Starting from the 
randomization visit, paracetamol/acetaminophen will be recorded as rescue medication in the 
patient diary.   
5.7.1. 
Permitted Therapy 
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 nonpain 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 (up to 150 mg per local guidelines) aspirin/5-ASA for cardiac prophylaxis is also 
permitted.  Paracetamol/acetaminophen taken acutely for treatment of non-OA pain is also 
permitted.  Paracetamol/acetaminophen taken for non-OA pain relief should be reported as 
concomitant medication.  Other permitted medications are glucosamine, chondroitin sulfate and 
rescue treatments (discussed in Section 5.2).  Topical steroids and topical non-NSAID analgesics 
are also permitted.  During treatment period 2 and for 16 weeks after the last dose of study drug, 
NSAIDs for non-OA related pain or fever may be used for up to 10 days in an 8-week period, 
30 days in a 6-month period, and 60 days in a 1-year period.  The daily dose of NSAIDs should 
not exceed the recommended maximum daily dose per the product labeling.  Muscle relaxants 
such as Skelaxin® (metaxalone) are permitted.  Prohibited muscle relaxants are listed in 
Section 5.7.2.   
Physical therapies (such as transcutaneous electrical nerve stimulation and acupuncture) are 
permitted during the trial provided that patients were on a stable regimen prior to entering into 
the trial and provided that they anticipate that they will maintain this regimen during the trial. 
5.7.2. 
Prohibited Therapy 
Patients will be required to discontinue all non-study pain medication (oral or topical; except up 
to 150 mg/day of aspirin/5-ASA, which is permitted for cardiac prophylaxis, per local 
guidelines) and opioid analgesic medications, starting at the pre-randomization phone call/visit.   
Opioid analgesic medications (including tramadol) are prohibited through week 16. 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) during treatment 
period 1. Patients may take non-NSAID standard-of-care therapy (see Section 5.2.2) in addition 
to study drug, in the event of inadequate pain relief for OA pain, starting after the week 16 visit 
(see Section 5.2.2). Though use of oral NSAIDs should generally be avoided, a limited use is 
allowed for non-OA related pain or fever after week 16. A list of medications containing 
NSAIDs will be provided in the study reference manual. The dose of oral NSAIDs may be 
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increased and topical NSAIDs may be used during the follow-up period, but no earlier than 
16 weeks after the last dose of study drug.  
Other excluded drugs during treatment period 1 are: 
 Medical marijuana 
 Hyaluronic Acid Intra-articular Injections 
 Cyclobenzaprine, carisoprodol, orphenadrine, tizanidine 
For sub-study only during treatment period 1: 
 Glucosamine sulfate 
 Chondroitin sulfate 
Other excluded drugs during both treatment periods 1 and 2 are: 
 Any other investigational agent 
 Corticosteroids (topical and inhaled formulations are permitted) 
 Cyclosporine 
 Azathioprine 
 Tumor necrosis factor antagonists 
 IL-1 inhibitors, including diacerein 
 IL-6 or IL-6 receptor antagonists 
 Abatacept 
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6. 
STUDY SCHEDULE OF EVENTS AND VISIT DESCRIPTIONS 
6.1. 
Schedule of Events 
Study assessments and procedures are presented for all patients for screening through week 16 in 
Table 1 and for week 20 through week 52 in Table 2.  Study assessments and procedures only for 
patients participating in the efficacy sub-study are shown in Table 3.  Study assessments and 
procedures are presented in Table 4 for the Follow-up Period (52 weeks after the last treatment) 
and Table 5 shows follow-up assessments for patients who undergo JR surgery during the study.  
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Table 1: 
Schedule of Events - Screening through Week 16 Visit 
Study Week 
Screening 
Period 
Pre-
Randomization 
Period 
Treatment Period 
Pre-
Randomization 
Phone Call 
 
(Baseline) 
4 
8 
12 
16 
Study Day (visit window) 
Up to 
30 days  
7 to 10 days 
1 
29 (±7) 
57 (±7) 
85 (±7) 
113 (±7) 
Screening/Baseline: 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion1 
X 
X 
X 
 
 
 
 
Genomics sub-study informed 
consent2 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Medication history 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
 
 
Bilateral radiograph (knee, hip, 
shoulder)3  
X14 
 
 
 
 
 
 
WOMAC Pain Subscale 
X4 
 
X 
 
 
 
 
MRI3 
X 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
Treatment: 
 
 
 
 
 
 
 
Discontinue non-study pain meds 
 
X 
 
 
 
 
 
SC Study Drug Injection5 
 
 
X 
X 
X 
X 
X 
Dispense paracetamol/acetaminophen 
 
 
X 
X 
X 
X 
X 
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Study Week 
Screening 
Period 
Pre-
Randomization 
Period 
Treatment Period 
Pre-
Randomization 
Phone Call 
 
(Baseline) 
4 
8 
12 
16 
Study Day (visit window) 
Up to 
30 days  
7 to 10 days 
1 
29 (±7) 
57 (±7) 
85 (±7) 
113 (±7) 
Paracetamol/acetaminophen 
accountability 
 
 
 
X 
X 
X 
X 
Dispense NSAID medication 
 
 
 
 
 
 
X 
Recording of rescue treatment use in 
diary6 
 
 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Safety: 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
X 
Vital Signs7 
X 
 
X 
X 
X 
X 
X 
Physical Examination 
X 
 
 
 
 
 
X 
Injection site evaluation 
 
 
X 
X 
X 
X 
X 
Orthostatic blood pressure7 
X 
 
X 
X 
X 
X 
X 
Joint Pain Questionnaire 
X 
 
X 
X 
X 
X 
X 
Survey of autonomic symptoms 
X 
 
X 
X 
X 
X 
X 
Neurologic examination 
Full 
 
Brief 
Brief 
Brief 
Brief 
Full 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Event-triggered imaging8 
 
 
 
X 
X 
X 
X 
Pre-op questionnaire (JR)9 
 
 
 
 
 
 
 
Laboratory Testing:  
 
 
 
 
 
 
 
Hematology 
X 
 
 
 
 
 
X 
Blood Chemistry 
X 
 
 
X 
X 
 
X 
Erythrocyte sedimentation rate 
X 
 
 
 
 
 
 
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Study Week 
Screening 
Period 
Pre-
Randomization 
Period 
Treatment Period 
Pre-
Randomization 
Phone Call 
 
(Baseline) 
4 
8 
12 
16 
Study Day (visit window) 
Up to 
30 days  
7 to 10 days 
1 
29 (±7) 
57 (±7) 
85 (±7) 
113 (±7) 
HbA1c 
X 
 
 
 
 
 
 
FSH and estradiol10 
X 
 
 
 
 
 
 
Pregnancy test (WOCBP) 
Serum11 
 
Urine12 
Urine12 
Urine12 
Urine12 
Urine12 
Urinalysis and Urine Creatinine and 
Phosphorous 
X 
 
 
X 
X 
 
X 
PK/Drug Concentration and ADA Samples: 
PK/Drug concentration sample13 
 
 
 
 
 
 
X 
ADA sample13 
 
 
X 
 
 
 
X 
Genomics sub-study sample2 
 
 
X 
 
 
 
 
Research serum/plasma sample13 
 
 
X 
X 
X 
 
X 
ADA: Anti-drug antibody; FSH: Follicle stimulating hormone; JR: Joint replacement; MRI: Magnetic resonance imaging; NSAID: Non-steroidal anti-
inflammatory drug; PK: Pharmacokinetic; WOCBP: Women of child-bearing potential; WOMAC: Western Ontario and McMaster Universities Osteoarthritis 
Index 
1. 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 
2. 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.   
3. After the patient has otherwise met study eligibility criteria assessed during the screening period, an MRI must be performed before the pre-randomization 
phone call for the index and contralateral joint as well as any knee or hip joint that has a baseline K-L score ≥3. Confirmation from the central reader that 
there are no exclusionary findings on the MRI must be received before the patient can be randomized. 
4. At the screening visit, the WOMAC pain sub-scale will be evaluated for both knees and both hip joints.   
5. Study drug administration will be the last procedure at each dosing visit, and will be done after all laboratory samples have been collected and all study 
assessments and procedures are performed.  Patients should be observed in the clinic for approximately 1 hour after administration of study drug for 
evidence of a hypersensitivity reaction.   
6. Patients will be provided with a diary for recording their daily use of paracetamol/acetaminophen beginning on day 1 through the week 52 visit and their 
NSAID use from week 16 through week 52. 
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7. If the pulse is less than 45 bpm at any visit after the randomization visit, an ECG with rhythm strip will be obtained and sent to the central reader to confirm 
the heart rate and rhythm.   
8. Imaging (X-ray and/or MRI) will be considered for worsening joint pain despite treatment with analgesics, which in the opinion of the investigator, is 
inconsistent with the normal progression of OA and lasts for at least 2 weeks (or less, at the discretion of the investigator). Additionally, pre-operative 
imaging for any JR should be submitted for adjudication, if possible. 
9. In the event that a patient must undergo JR surgery during the treatment or follow-up periods, he or she will be discontinued from study drug and asked to 
return for a pre-operative visit, and for follow-up safety evaluations 4 weeks and 20 weeks after surgery (Table 5). The pre-operative visit should be 
completed before JR surgery if at all possible.  Joint replacement questionnaires are Knee Society Score questionnaire for knee replacements or Harris Hip 
Score questionnaire for hip replacements.  
10. To be performed only if postmenopausal status has to be assessed for female patients ≤59 years of age.   
11. In the event of a positive serum pregnancy test result, 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 5.3.2).   
12. In the event of a positive urine pregnancy test result, the patient should have a serum pregnancy test with a negative result in order to continue study 
participation.  If the serum pregnancy test is positive, the patient should be withdrawn from study drug and should be asked to return to the clinic for all 
remaining study visits per the visit schedule (see Section 5.3.2).   
13. PK, ADA, and research samples may also be drawn at any scheduled visit or unscheduled visit if a patient experiences a treatment-related safety TEAE.  
14. Historical radiographs may be acceptable as outlined in the study imaging acquisition guidelines. 
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Table 2: 
Schedule of Events – Week 20 Visit through Week 52 Visit 
Study Week 
Week 20 
Clinic Visit 
Week 24 
Clinic Visit 
Week 28 
Clinic Visit 
Week 32 
Clinic Visit 
Clinic 
Visits 
Between 
Week 36 
and End of 
Treatment 
Week 52 or End 
of Treatment 
Visit1 
Early 
Termination/JR 
Pre-operative Visit 
Visit Window 
Q4W 
(±7 days) 
(±7 days) 
(±7 days) 
(±7 days) 
(±7 days) 
(±7 days) 
 
Treatment: 
 
 
 
 
 
SC Study Drug Injection2 
X 
X 
X 
X 
X9 
 
 
Dispense 
paracetamol/acetaminophen 
and NSAID medication 
X 
X 
X 
X 
X 
 
 
Paracetamol/acetaminophen 
/NSAID accountability 
X 
X 
X 
X 
X 
X 
X 
Recording of rescue 
treatment use in diary 3 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Safety: 
 
 
 
 
 
Weight 
 
 
 
 
 
X 
X 
Vital Signs4 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram 
 
 
X 
 
 
X 
X 
Injection site evaluation 
X 
X 
X 
X 
X 
 
 
Orthostatic blood pressure 
X 
X 
X 
X 
X 
X 
X 
Joint Pain Questionnaire 
X 
X 
X 
X 
X 
X 
X 
Survey of autonomic 
symptoms 
X 
X 
X 
X 
X 
X 
X 
Neurologic examination 
Full 
Full 
Full 
Full 
Full 
Full 
Full 
Bilateral radiograph (knee, 
hip, shoulder) 10 
 
X 
 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
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Study Week 
Week 20 
Clinic Visit 
Week 24 
Clinic Visit 
Week 28 
Clinic Visit 
Week 32 
Clinic Visit 
Clinic 
Visits 
Between 
Week 36 
and End of 
Treatment 
Week 52 or End 
of Treatment 
Visit1 
Early 
Termination/JR 
Pre-operative Visit 
Visit Window 
Q4W 
(±7 days) 
(±7 days) 
(±7 days) 
(±7 days) 
(±7 days) 
(±7 days) 
 
Event-triggered imaging5 
X 
X 
X 
X 
X 
X 
 
X 
Pre-op questionnaire (JR)6 
 
 
 
 
 
 
X5 
Laboratory Testing: 
 
 
 
 
 
Hematology 
 
 
 
X 
 
X 
X 
Blood Chemistry 
 
 
 
X 
 
X 
X 
Pregnancy test (WOCBP)  
Urine7 
Urine7 
Urine7 
Urine7 
Urine7 
Urine7 
Urine7 
Urinalysis and Urine 
Creatinine and Phosphorus 
 
 
 
X 
 
X 
X 
PK/Drug Concentration and ADA Samples:  
PK/Drug conc. sample8 
 
 
 
X 
 
X 
X 
ADA sample8 
 
 
 
X 
 
X 
X 
Research serum/plasma 
sample8 
 
 
 
X 
X 
ADA: Anti-drug antibody; FSH: Follicle stimulating hormone; JR: Joint replacement; MRI: Magnetic resonance imaging; NSAID: Non-steroidal anti-
inflammatory drug; PK: Pharmacokinetic; WOCBP: Women of child-bearing potential; WOMAC: Western Ontario and McMaster Universities Osteoarthritis 
Index 
1. If treatment is stopped for patients (for example, due to conditions in Section 3.1 or Section 5.3.2.1 being met or for other reasons per the patient or 
investigator), patients should complete the end of treatment/week 52 assessments at their next scheduled visit.  All subsequent visits should be conducted 
according to the schedule of events and all procedures should be completed, except for study medication administration.  Imaging does not need to be 
repeated at a routine visit if all radiographs were conducted within 30 days and submitted for central reading. 
2. Study drug administration will be the last procedure at each dosing visit, and will be done after all laboratory samples have been collected and all study 
assessments and procedures are performed.   
3. Patients will record their daily use of paracetamol/acetaminophen and NSAIDs from the week 16 visit through week 52. 
4. If the pulse is less than 45 bpm at any visit after the randomization visit, an ECG with rhythm strip will be obtained and sent to the central reader to confirm 
the heart rate and rhythm.   
5. Imaging (X-ray and/or MRI) will be considered for worsening joint pain despite treatment with analgesics, which in the opinion of the investigator, is 
inconsistent with the normal progression of OA and lasts for at least 2 weeks (or less, at the discretion of the investigator).  Additionally, pre-operative 
imaging for any joint replacement should be submitted for adjudication, if possible. 
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6. In the event that a patient must undergo JR surgery during the treatment or follow-up periods, he or she will be discontinued from study drug and asked to 
return for a pre-operative visit, and for follow-up safety evaluations 4 weeks and 20 weeks after surgery (Table 5). The pre-operative visit should be 
completed before JR surgery if at all possible. JR questionnaires are Knee Society Score questionnaire for knee replacements or Harris Hip Score 
questionnaire for hip replacements.  
7. In the event of a positive urine pregnancy test result, the patient should have a serum pregnancy test with a negative result in order to continue study 
participation.  If the serum pregnancy test is positive, the patient should be withdrawn from study drug and should be asked to return to the clinic for all 
remaining study visits per the visit schedule (see Section 5.3.2).   
8. PK, ADA, and research samples may also be drawn at any scheduled visit or unscheduled visit if a patient experiences a treatment-related safety TEAE. 
9. SC injections will be given Q4W. For patients randomized to 1 mg Q8W, matching placebo will be administered at alternating visits.  
10. An MRI may be requested by the imaging vendor after review of the x-rays. 
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Table 3: 
Schedule of Additional Events – Only for Patients Participating in the Efficacy Sub-Study (Screening through 
Week 16 Visit) 
 
Screening 
Period 
Pre-
Randomization 
Period 
Treatment 
Early 
Termination/ 
JR 
Pre-Operative 
Visit 
Pre-
Randomization 
Visit 
 
Study Week 
 
(Baseline) 
1 
2 
4 
8 
12 
16 
Up To 
Week 16 
Study Day (visit window) 
Up to 30 
days  
7 to 10 days 
 
1 
8 (±1) 15 (±3) 29 (±7) 57 (±7) 85 (±7) 
113 
(±7) 
 
Screening: 
 
 
 
 
 
 
 
 
 
 
Informed consent for sub-
study 
X 
 
 
 
 
 
 
 
 
 
Efficacy Assessments: 
 
 
 
 
 
 
 
 
 
NRS-average daily walking 
index joint pain1 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Global Assessment of 
OA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
WOMAC Pain Subscale – 
index joint only 
X2 
 
X 
 
 
 
 
 
 
 
WOMAC Full Survey3 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Assessments: 
 
 
 
 
 
 
 
 
 
Orthostatic blood pressure 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinary drug test 
X 
 
 
 
 
 
 
 
X 
 
PK/Drug Concentration: 
 
 
 
 
 
 
 
 
 
 
PK/Drug concentration 
sample 
 
 
X 
 
 
X 
X 
 
X 
X 
JR: Joint replacement; NRS: Numerical Rating Scale; OA: Osteoarthritis; PK: Pharmacokinetic; WOMAC: Western Ontario and McMaster Universities 
Osteoarthritis Index 
1. Walking index joint pain NRS score will be recorded by the site at the pre-randomization visit, and by the patient each day using their diary, starting during 
the pre-randomization period through week 16.   
2. At the screening visit, the WOMAC pain sub-scale will be evaluated for both knees and both hip joints.  
3. WOMAC full survey for index joint only. 
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Table 4: 
Schedule of Events - Follow-up Period (24 Weeks after Last Treatment) and End of Study Phone Contact 
(52 Weeks after Last Treatment) 
 
Phone call 
8 weeks post 
last dose 
Clinic Visit 
12 weeks post 
last dose 
End of Follow 
up Clinic Visit 
24 weeks post 
last dose 
End of Study 
Phone call 
52 weeks post 
last dose 
Early 
Termination/JR 
Pre-Operative 
Visit 
Study Week 
Up to week 56 
(±7 days) 
Up to week 60 
(±7 days) 
Up to week 72 
(±7 days) 
Week 100 
(±7 days) 
During the 
Follow-up Period 
Treatment: 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
 
X 
Safety: 
 
 
 
 
 
Adverse Events 
X 
X 
X 
 
X 
Weight 
 
X 
X 
 
X 
Vital signs1 
 
X 
X 
 
X 
Physical examination 
 
X 
X 
 
X 
Electrocardiogram 
 
X 
X 
 
X 
Orthostatic blood pressure 
 
X 
X 
 
X 
Joint pain questionnaire 
 
X 
X 
 
X 
Survey of autonomic symptoms 
 
X 
X 
 
X 
Neurologic examination 
 
Full 
Full 
 
Full 
Bilateral radiograph 
(knee, hip, shoulder)4 
 
X 
X 
 
X 
Event-triggered imaging2 
 
X 
X 
 
X 
Pre-op questionnaire3 
 
 
 
 
X 
End of study phone contact5 
 
 
 
X 
 
MRI of affected joint(s) for AA patients only6 
 
 
 
X 
 
Laboratory assessments 
 
 
 
 
 
Hematology 
 
 
X 
 
X 
Blood Chemistry 
 
 
X 
 
X 
Pregnancy test (WOCBP) 
 
 
Urine8 
 
Urine8 
Urinalysis and Urine Creatinine and 
Phosphorous 
 
 
X 
 
X 
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Phone call 
8 weeks post 
last dose 
Clinic Visit 
12 weeks post 
last dose 
End of Follow 
up Clinic Visit 
24 weeks post 
last dose 
End of Study 
Phone call 
52 weeks post 
last dose 
Early 
Termination/JR 
Pre-Operative 
Visit 
Study Week 
Up to week 56 
(±7 days) 
Up to week 60 
(±7 days) 
Up to week 72 
(±7 days) 
Week 100 
(±7 days) 
During the 
Follow-up Period 
PK/Drug Concentration and ADA Samples: 
 
 
 
 
PK/Drug concentration sample7 
 
X 
X 
 
X 
ADA sample7 
 
 
X 
 
X 
Research serum/plasma sample7 
 
 
X 
 
X 
ADA: Anti-drug antibody; JR: Joint replacement; PK: Pharmacokinetic; WOCBP: Women of child-bearing potential. 
1. If the pulse is less than 45 bpm, an ECG with rhythm strip will be obtained and sent to the central reader to confirm the heart rate and rhythm.   
2. Imaging (X-ray and/or MRI) will be considered for worsening joint pain despite treatment with analgesics, which, in the opinion of the investigator is 
inconsistent with the normal progression of OA and lasts at least 2 weeks (or less, at the discretion of the investigator). Additionally, pre-operative imaging 
for any JR should be submitted for adjudication, of possible. 
3. In the event that a patient must undergo JR surgery during the treatment or follow-up periods, he or she will be discontinued from study drug and asked to 
return for a pre-operative visit, and for follow-up safety evaluations 4 weeks and 20 weeks after surgery (Table 5). The pre-operative visit should be 
completed before JR surgery, if at all possible.  Pre-operative images should be submitted to the central reader for adjudication, if available.  Joint 
replacement questionnaires are Knee Society Score questionnaire for knee replacements or Harris Hip Score questionnaire for hip replacements.  
4. An MRI may be requested by the imaging vendor after review of the x-rays. 
5. 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. 
6. If the affected joint has undergone JR an X-ray may be substituted for an MRI. 
7.   PK, ADA, and research samples may also be drawn at any scheduled visit or unscheduled visit if a patient experiences a treatment-related safety TEAE. 
8. In the event of a positive urine pregnancy test result, the patient should have a serum pregnancy test. 
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Table 5: 
Schedule of Events - Follow-up for Patients Who Undergo Joint Replacement Surgery 
Follow-up Study Day (Visit Window) 
Follow-up Period1 
Post-Operative 
Long-Term 
Follow-up Visit 1 
4 weeks after the date of the 
joint replacement surgery 
Follow-up Visit 2 
20 weeks after the date of the 
joint replacement surgery 
F/U Day 29 (±5) 
F/U Day 140 (±7) 
Treatment: 
 
 
Concomitant medications 
X 
X 
Safety: 
 
 
Adverse events 
X 
X 
Vital signs 
X 
X 
Orthostatic blood pressure4 
X 
X 
Physical examination with joint exam 
X1 
X 
Medical history related to the joint 
replacement 
X 
X 
Joint pain questionnaire  
X 
X 
Post-operative assessment questionnaire2 
X 
X 
Bilateral radiograph (knee, hip, shoulder)5 
X6 
X 
Event-triggered imaging3 
X 
X 
F/U: Follow-up 
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. Knee Society Score questionnaire for knee replacements or Harris Hip Score questionnaire for hip replacements.   
3. Imaging (x-ray and/or MRI) will be performed on any joint following a report of clinically significant worsening or exacerbation of pain in that joint. 
4. If it is not possible to obtain orthostatic blood pressure following JR then blood pressure and pulse should be recorded. 
5. 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. 
6. Imaging will be done at week 4 if not done pre-operatively. 
 
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6.2. 
Study Visit Descriptions 
6.2.1. 
Screening Period (Up to 30 days) 
Informed consent must be obtained prior to any screening procedures.  After informed consent 
has been obtained, patients may be screened for eligibility.  The screening window is 30 days 
from the time the informed consent has been signed.  If the patient has not met screening 
eligibility criteria by the end of the 30-day screening window, the patient will be identified as a 
screen failure.  Patients who screen fail may rescreen per Section 6.2.2.  Laboratory assessments 
used to determine eligibility may be repeated during the screening period.  The procedures 
outlined in the schedule of events should be completed during the screening period (Table 1).   
When applicable, all pain assessments at the screening visits and subsequent visits should be 
completed prior to the physical examination.  The patient reported outcomes assessments should 
be completed prior to all other efficacy assessments.   
After the patient has otherwise met study eligibility criteria assessed during the screening period, 
an MRI will be performed prior to the pre-randomization phone call/visit for the index and 
contralateral joint and well as any knee or hip joint with a K-L score ≥3. Confirmation from the 
central reader that there are no exclusionary findings on MRI must be received before a patient 
can be randomized.  
6.2.2. 
Rescreening 
Patients who do not meet eligibility criteria may rescreen once and only after approval of the 
sponsor or designee. Rescreening may occur if it is believed by the investigator that the reason 
for screen failure was due to a condition that would resolve or could be treated, or a laboratory 
value that minimally exceeded the cut-off value and is not clinically relevant. Patients cannot 
rescreen if they have screen failed due to not meeting the WOMAC criteria or have orthostatic 
hypotension. 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 screen failed under amendment 3, 4 or 5 may rescreen 
under amendment 6 if they have not previously rescreened. 
Only the assessments that did not meet eligibility criteria during the first screening are required 
to be repeated during the rescreen, if done within the screening period or pre-randomization 
period.  Patients who are rescreened after the screening and pre-randomization windows end, 
must re-consent for study participation and repeat all screening procedures with the exception of 
imaging assessments.  Any imaging assessments need to be repeated only if they were taken 
more than 60 days from when previous screening X-rays and MRI assessments were completed.   
6.2.3. 
Pre-Randomization Period (7 to 10 days) 
Following the screening period, patients will complete a 7 to 10 day pre-randomization period.  
Patients who are not participating in the sub-study will complete the pre-randomization visit as a 
telephone contact.  Sub-study patients will return to the clinic for a pre-randomization visit 7 to 
10 days before the randomization visit.  During the pre-randomization period, all patients will be 
instructed to stop using their standard-of-care pain medications and to use only 
paracetamol/acetaminophen as rescue treatment.  In addition, sub-study patients should 
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discontinue use of paracetamol/acetaminophen 24 hours prior to the start of the randomization 
visit (baseline). 
6.2.4. 
Baseline/Randomization Visit (Day 1) 
If a patient has met all screening eligibility criteria, study sites will complete the procedures as 
detailed in the schedule of events for the baseline visit.  The patient-reported outcomes 
assessments at this and subsequent visits should be completed prior to all other assessments.  
During treatment period 1 (screening to week 16), patients will be observed in the clinic for 
approximately 1 hour for evidence of a hypersensitivity reaction following study drug 
administration.  Paracetamol/acetaminophen will be provided to patients to be used as rescue 
treatment, taken as needed, according to local standards-of-care, to a maximum total dose of 
2500 mg in Europe and 2600 mg in countries outside of Europe per day, starting on day 1.  All 
use of NSAIDs, including oral or topical formulations, is prohibited.  Patients will record their 
daily use of rescue treatment using a diary starting from the randomization visit through the end 
of treatment.  All laboratory samples at this and subsequent visits must be collected and all study 
procedures must be performed before study drug is administered.  At dosing study visits, urine 
pregnancy testing will be done and read before the study drug is administered.  In the event of a 
positive urine pregnancy test result, the patient should have a serum pregnancy test with a 
negative result in order to continue study participation.  If the serum pregnancy test is positive, 
the patient should be withdrawn from study drug and should be asked to return to the clinic for 
all remaining study visits per the visit schedule (see Section 5.3.2).   
The date of the first dose of study drug is designated on day 1.  All subsequent visits should be 
scheduled based on this date.   
6.2.5. 
Week 1 through Week 16 
Complete visits and assessments are outlined in the schedule of events (Table 1 and Table 3).  
For sub-study patients, the patient-reported outcomes should be completed prior to all other 
assessments.  At dosing visits, all study procedures should be completed before administration of 
study drug.  Patients who discontinue study drug should complete the end of treatment visit per 
the schedule of events and return for the remaining study visits, if possible.  If patients are not 
able to continue study participation, they should return for an early termination visit, per the 
schedule of events.  The amount of paracetamol/acetaminophen used in the preceding 24 hours 
will be reported by patients from the randomization visit (day 1) using the patient diary.   
If patients proceed into treatment period 2, all patients, including sub-study patients, will 
continue to follow the same schedule of events.   
6.2.6. 
Week 20 up to Week 52 
Complete visits and assessments are outlined in the schedule of events (Table 2).  Patients who 
discontinue study drug should complete the end of treatment visit per the schedule of events and 
return for the remaining study visits, if possible. If patients are not able to continue study 
participation, they should return for an early termination visit, per the schedule of events.   
During this period, non-NSAID standard-of-care pain medications can be taken in the event of 
inadequate pain relief for OA pain, and limited use NSAIDs can be used for non-OA related pain 
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or fever, as defined in Section 5.2.2.  All patients will report their use of rescue treatment and 
limited use NSAIDs in their diaries from week 16 through week 52.   
6.2.7. 
Week 52 or End of Treatment Visit 
Assessments for the end of treatment visit at week 52 are outlined in the schedule of events 
(Table 2).  
If treatment is stopped for patients (for example, due to conditions in Section 3.1 or 
Section 5.3.2.1 being met or for other reasons per the patient or investigator), patients should 
complete the end of treatment/week 52 assessments at their next scheduled visit. Patients who 
discontinue study drug should be encouraged to continue participation in the study. All 
subsequent visits should be conducted according to the schedule of events and all procedures 
should be completed, except for study medication administration. Imaging does not need to be 
repeated at a routine visit if all radiographs were conducted within 30 days and submitted for 
central reading. 
Although patients are encouraged to continue all scheduled clinic visits, if they refuse to do so 
but are willing to provide safety follow-up over the phone, pertinent safety data should be 
collected. 
6.2.8. 
Week 52 through Week 72 
Patients will be followed and will complete study visits and phone contacts through the end of 
the follow-up period 24 weeks after receiving the last dose of study drug.   
6.2.9. 
Week 100 
Patients will complete an end of study phone contact questionnaire at week 100 to record 
whether the patient has had a JR at any time following the last in-clinic visit of the follow-up 
period or is scheduled (or on a waiting list) to have 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. 
6.2.10. 
Early Termination Visit (as Applicable) 
Patients who do not want to remain in the study following discontinuation of study drug will be 
asked to return to the clinic as soon as possible for the early termination assessments, per the 
schedule of events.  If a patient declines to return to the site for an early termination visit, he or 
she should be contacted by telephone to collect safety information.   
6.2.11. 
Visits in the Event of Joint Replacement Surgery 
In the event that a patient must undergo JR surgery during the treatment or follow-up periods, he 
or she will be discontinued from study drug and asked to return for a pre-operative visit, and for 
follow-up safety evaluations 4 weeks and 20 weeks after surgery. The pre-operative visit should 
be completed before JR surgery and pre-operative X-rays ± MRIs should be submitted to the 
central imaging vendor for adjudication, if at all possible.  
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6.2.12. 
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. 
6.3. 
Study Procedures 
6.3.1. 
Procedures Performed Only at the Screening Visit, Pre-Randomization Visit, or 
Baseline/Randomization Visit 
6.3.1.1. 
Informed Consent 
All patients must sign and date an Institutional Review Board (IRB)-approved or Ethics 
Committee (EC)-approved informed consent form (ICF) before any study procedures are 
performed, per Section 13.2.  Patients who agree to participate in the efficacy sub-study will be 
required to sign a separate ICF.   
6.3.1.2. 
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.   
6.3.1.3. 
Medication History 
The investigator or designee will query patients on the medication(s) they have taken for their 
OA (medication history), including information on their ability to tolerate the medication, and 
will record the information on an electronic case report form (e-CRF) for this purpose. 
6.3.1.4. 
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 scale. This index can be used to monitor the course of a disease or to 
determine effectiveness of medications. Patients will complete the WOMAC Pain Subscale at the 
time points indicated in Section 6.1. If possible, the assessment should be administered and the 
results entered by the same person at the screening and baseline visits.  
A copy of the assessment is provided in the study reference manual. 
6.3.1.5. 
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 
 They have had a tubal ligation, a bilateral oophorectomy, bilateral salpingectomy, or 
hysterectomy 
In women >59 years of age, postmenopausal status is defined as at least 12 continuous months of 
spontaneous amenorrhea.  In women ≤59 years of age, postmenopausal status is defined as at 
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least 12 continuous months of spontaneous amenorrhea, with serum follicle-stimulating hormone 
(FSH) levels >40 IU/L (>40 mIU/mL) and serum estradiol levels <5 ng/dL (<184 pmol/L).   
6.3.2. 
Efficacy Procedures for the Efficacy Sub-Study Only 
6.3.2.1. 
Walking Index Joint Pain 
The patient’s walking index joint pain Numerical Rating Scale (NRS) score, indicating the 
average daily index joint pain over the past 24 hours or weekly index joint pain, will be recorded 
by the site at the pre-randomization visit, and by the patient each day thereafter through week 16 
in the patient diary.  
A copy of the assessment is provided in the study reference manual. 
6.3.2.2. 
Patient Global Assessment of Osteoarthritis 
The Patient Global Assessment of OA is a patient-rated assessment of patient current disease 
state on a 5-point Likert scale (1 = very well; 2 = well; 3 = fair; 4 = poor; and 5 = very poor).  
Sub-study patients will complete the assessment scale at the time points indicated in Section 6.1.   
A copy of the assessment is provided in the study reference manual.   
6.3.3. 
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 scale.  This index can be used to monitor the course of a disease or to 
determine effectiveness of medications.  Sub-study patients will complete the assessment scale at 
the time points indicated in Section 6.1.  If possible, the assessment should be administered and 
the results entered by the same person throughout the study.   
A copy of the assessment is provided in the study reference manual.   
6.3.4. 
Safety Procedures 
6.3.4.1. 
Physical Examination 
Patients will have a thorough and complete physical examination including an examination of 
the knees, hips, and shoulders at the time points indicated in Section 6.1.  Care should be taken to 
examine and assess any abnormalities that may be present, as indicated by the patient’s medical 
history.   
Measurements of patient height and weight should be recorded at the time points indicated in 
Section 6.1.   
6.3.4.2. 
Vital Signs 
Vital signs including temperature, and respiration will be collected at time points indicated in 
Section 6.1.  At visits at which study drug is administered, vital signs should be measured before 
SC injection.  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.   
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6.3.4.3. 
Electrocardiogram 
A standard 12-lead ECG will be performed at the time points indicated in Section 6.1 with the 
patient in the supine position for approximately 5 minutes and prior to blood samples being 
drawn.  Heart rate will be recorded from the ventricular rate and the PR, QRS, and QT, 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.   
6.3.4.4. 
Joint Pain Questionnaire 
A joint pain questionnaire will be completed by the patient at the time points indicated in 
Section 6.1.  For each knee, hip, and shoulder joint, the patient will be prompted to indicate if 
they have experienced pain.   
A copy of the assessment is provided in the study reference manual.   
6.3.4.5. 
Survey of Autonomic Symptoms 
Signs and symptoms of autonomic dysfunction will be assessed by the investigator at time points 
indicated in Section 6.1.  If possible, the assessment should be completed by the same person 
throughout the study.   
A copy of the survey is provided in the study reference manual.   
6.3.4.6. 
Assessment of Orthostatic Hypotension and Heart Rate 
A blood pressure for the assessment of orthostatic hypotension will be conducted at the time 
points indicated in Section 6.1. The assessments should be conducted as per the instructions in 
the study manual. A patient will be determined to have orthostatic hypotension if any of the 
following criteria are met: 
 If the supine blood pressure is <160 mmHg systolic, a decrease in either the 1 or 
3 minute standing systolic blood pressure of ≥20 mmHg or a decrease in the standing 
diastolic blood pressure of ≥10 mmHg from the supine systolic or diastolic blood 
pressure 
OR 
 If the supine blood pressure is ≥160 mmHg systolic, a decrease in either the 1 or 
3 minute standing systolic blood pressure of ≥30 mmHg or a decrease in the standing 
diastolic blood pressure of ≥15 mmHg from the supine systolic or diastolic blood 
pressure 
OR 
 An increase in either the 1 or 3 minute standing heart rate of ≥30 bpm from the supine 
heart rate 
OR 
 The patient is unable to stand for either one of the standing blood pressure 
measurements due to dizziness or lightheadedness 
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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.   
6.3.4.7. 
Neurological Evaluation 
A full or a brief neurological examination will be performed at the time points indicated in 
Section 6.1.  Neurological findings at baseline that are not exclusionary should be recorded in the 
medical history.  Findings at subsequent visits will be assessed by the investigator to determine if 
these should be recorded as an AE.   
The neurological examination will cover the following domains:  motor, sensory, cranial nerves, 
reflexes, and coordination/balance and assessment for presence/absence of signs of carpal tunnel 
syndrome and may be conducted by any clinician at the site qualified to do so.  Whenever 
possible, the same clinician who conducts the baseline neurological examination should continue 
to conduct the examinations on a given patient.  The investigator may refer patients with 
persistent or worsening neurologic symptoms for a neurologic consultation, if clinically 
indicated.  Additional neurologic assessments will include nerve conduction studies and other 
tests as deemed clinically necessary in the judgement of the neurologist.   
Complete guidance on how to conduct the full and the brief neurologic examination is provided 
in the study reference manual.   
6.3.4.8. 
Imaging 
Radiographs of the large joints (knees, hips, and shoulders) will be taken using a standard 
approach at the time points indicated in Section 6.1. An MRI of the index, contralateral, and of 
any hip or knee joint with a K-L score of ≥3 will be completed at screening. In addition, 
radiographs and/or an MRI must be performed of any joint following a report of clinically 
significant worsening or exacerbation of pain in that joint. 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 adjudicated arthropathy such as RPOA type 1 or 2, subchondral 
insufficiency fracture, or osteonecrosis.   
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MRI 
During screening, MRIs of the index, contralateral and of joints with a K-L score ≥3 will be sent 
to a central reader to confirm that there is no evidence of adjudicated arthropathy or other 
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 affected joint has undergone JR an X-ray may be substituted for an MRI. 
Refer to the supplemental imaging manuals for data collection and management procedures. 
6.3.4.9. 
End of Study Phone Contact  
An end of study phone contact will be conducted at 52 weeks following the last dose of study 
drug. Patients will be asked whether they underwent JR surgery following the last in-clinic visit 
of the follow-up period or whether they are scheduled (or on a waiting list) for JR surgery. 
Patients 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. 
6.3.4.10. 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, he 
or she will be discontinued from study drug and asked to return for a pre-operative visit, and for 
follow-up safety evaluations 4 weeks and 20 weeks after surgery (see Table 5).  
In the event that the pre-operative visit is not performed, standard-of-care pre-operative images 
of the joint with the JR must be obtained and submitted to the central imaging vendor. 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 post 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.   
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6.3.4.11. Laboratory Testing 
The central laboratory will analyze all screening and on-study laboratory samples for blood 
chemistry, hematology, HbA1c, urine analysis, urine drug tests (sub-study patients only) and 
serum pregnancy tests.  Urine pregnancy testing will be done at the site using kits provided by 
the central laboratory.   
Regeneron or its designee will be responsible for fasinumab PK, anti-fasinumab antibody, 
biomarker development, and pharmacogenetic sample assessments; the central laboratory will 
ship the samples to Regeneron or a specialty laboratory depending on the assessment.   
All samples will be collected before study drug administration.  Missed tests should be reported 
in the source documents and in the eCRF, as appropriate.  Central laboratory kits will be 
provided for sample collection and shipment.  Detailed instructions for blood sample collection 
are in the laboratory manual provided to study sites.  Samples for laboratory testing will be 
collected at time points according to Section 6.1.   
Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin 
Carbon dioxide 
Aspartate aminotransferase (AST) 
Uric acid 
Calcium 
Alanine aminotransferase (ALT) 
Creatine phosphokinase 
(CPK) 
Creatinine 
Glucose 
Alkaline phosphatase 
Phosphorous 
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 Chemistries 
Creatinine 
Phosphorous 
 
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Other Laboratory Tests 
Serum and urine samples for pregnancy testing will be collected from women of childbearing 
potential (as defined in Section 6.3.1.5) at time points according to Section 6.1.  At dosing study 
visits, urine pregnancy testing will be done before the study drug is administered.  In the event of 
a positive urine pregnancy test result, the patient should have a serum pregnancy test with a 
negative result in order to continue study participation.  If the serum pregnancy test is positive, 
the patient should be withdrawn from study drug and should be asked to return to the clinic for 
all remaining study visits per the visit schedule (see Section 5.3.2).   
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 6.1 and Section 6.3.1.5.   
Samples will be collected for HbA1c and erythrocyte sedimentation rate testing at time points 
according to Section 6.1.   
Blood samples for research (Section 6.3.6) will also be collected.   
Urine samples for the urine drug test will be collected (from sub-study patients only) at time 
points according to Section 6.1. 
Abnormal Laboratory Values and Laboratory Adverse Events 
 All laboratory values must be reviewed by the investigator or authorized designee. 
 Significantly abnormal tests must be repeated to confirm the nature and degree of the 
abnormality.  When necessary, appropriate ancillary investigations should be 
initiated.  If the abnormality fails to resolve or cannot be explained by events or 
conditions unrelated to the study medication or its administration, the medical 
monitor must be consulted. 
 The clinical significance of an abnormal test value, within the context of the disease 
under study, must be determined by the investigator. 
Criteria for reporting laboratory values as an AE are provided in Section 7.4.5. 
6.3.4.12. Injection Site Evaluation 
An injection site evaluation for local reactions should be conducted following the injection at 
each dosing visit, according to Section 6.1.  
6.3.5. 
Pharmacokinetic and Antibody Procedures 
6.3.5.1. 
Drug Concentration Measurements and Samples 
Samples for drug concentration will be collected before administration of study drug at time 
points listed in Section 6.1. Detailed instructions for blood sample collection are included in the 
laboratory manual provided to study sites. 
Any unused samples collected for drug concentration measurements may be used for exploratory 
biomarker research or to investigate unexpected AEs. 
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6.3.5.2. 
Anti-Drug Antibody Measurements and Samples 
Samples for ADA assessment will be collected before administration of study drug at time points 
listed in Section 6.1. Detailed instructions for blood sample collection are included in the 
laboratory manual provided to study sites. 
Any unused samples collected for ADA assessment may be used for exploratory biomarker 
research or to investigate unexpected AEs. 
6.3.6. 
Research Samples 
Serum and plasma samples will be collected at time points according to Section 6.1.  Detailed 
instructions for blood sample collection are in the laboratory manual provided to study sites.   
6.3.6.1. 
Use and Storage of Research Samples (Serum and Plasma) 
Research serum and plasma samples will be collected and stored, and may be used to measure 
biomarkers related to collagen and bone turnover, OA, pain and NGF, and may include 
C-telopeptide of type I collagen (CTX-I; a marker for breakdown of type I collagen found in 
bone), C-telopeptide of type II collagen (CTX-II), high-sensitivity C-reactive protein and matrix 
metalloproteinase-generated fragment of C-reactive protein.  Samples may be used to study other 
markers of collagen and bone turnover, OA, pain and NGF.  If necessary, the samples may also 
be used to identify markers associated with toxicity.  All samples will be single coded to 
maintain patient confidentiality.  The samples may be stored for up to 15 years. 
6.3.6.2. 
Optional Genomics Sub-study 
Patients who agree to participate in the genomics sub-study will be required to sign a separate 
genomics sub-study ICF prior to collection of the DNA sample.  Blood for DNA extraction 
should be collected at the baseline visit, but may be collected at any study visit.  Patients who 
choose not to enroll in the genomics sub-study are still eligible to enroll in the primary study.   
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 may be stored and used for 
up to 15 years after the final date of the clinical study report.   
DNA analyses may be performed to better understand genetic associations with collagen and 
bone turnover, OA, pain, and response to fasinumab.  If indicated, genetic analyses may also be 
performed to identify markers associated with AEs.  Analyses may include sequence 
determination and/or single nucleotide polymorphism (SNP) studies of candidate genes.  
Genome-wide studies, including (but not limited to) SNP analyses and/or genomic sequencing 
may also be performed.   
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7. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
7.1. 
Obligations of Investigator 
The investigator must promptly report to the IRB/EC all unanticipated problems involving risks 
to patients.  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 causality. 
7.2. 
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, IECs/IRBs as appropriate, and to the 
investigators (in a blinded manner).  
Any AE not listed as an expected event in the Reference Safety Information section of the 
Investigator’s Brochure or in this protocol will be considered as unexpected. Any worsening of 
or new onset of symptoms related to OA that occur during the screening period prior to study 
drug administration will be considered expected. 
In addition, the sponsor will report all other SAEs 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 IECs/IRB as appropriate. 
7.3. 
Definitions 
7.3.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug which may or 
may not have a causal relationship with the study drug.  Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease which is 
temporally associated with the use of a study drug, whether or not considered related to the study 
drug. 
An AE also includes any worsening (ie, any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug. 
7.3.2. 
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. 
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 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 1 of the other serious outcomes listed above (eg, 
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).   
7.3.3. 
Adverse Events of Special Interest 
An AESI (serious or non-serious) is one of scientific and medical concern specific to the 
sponsor’s product or program, for which ongoing monitoring and rapid communication by the 
investigator to the sponsor can be appropriate.  Such an event might warrant further investigation 
in order to characterize and understand it.  Depending on the nature of the event, rapid 
communication by the trial sponsor to other parties (eg, regulators) might also be warranted.   
Adverse events of special interest are described in Section 7.4.3.   
7.4. 
Recording and Reporting Adverse Events 
7.4.1. 
Adverse Events 
The investigator (or designee) will record all AEs that occur from the time the informed consent 
is signed until the end of the follow-up period (week 72).  Refer to the study reference manual 
for the procedures to be followed. 
Information on follow-up for AEs is provided in Section 7.4.6.  Laboratory, vital signs, or ECG 
abnormalities are to be recorded as AEs as outlined in Section 7.4.5. 
7.4.2. 
Serious Adverse Events 
All SAEs, regardless of assessment of causal relationship to study drug must be reported to the 
sponsor (or designee) within 24 hours.  Refer to the study reference manual for the procedure to 
be followed. 
Information not available at the time of the initial report must be documented in a follow-up 
report.  Substantiating data such as relevant hospital or medical records and diagnostic test 
reports may also be requested. 
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In the event the investigator is informed of an SAE after the patient completes the follow up 
period, the following will apply: 
 
SAE with an onset within 30 days of the end of follow-up period (week 72)/early 
termination visit - the SAE will be reported to the sponsor.  The investigator should 
make every effort to obtain follow-up information on the outcome until the event is 
considered chronic and/or stable. 
 SAE with an onset day greater than 30 days from the end of follow-up period (week 
72)/early termination visit - 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 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. 
7.4.3. 
Other Events that Require Accelerated Reporting 
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), by telephone within 24 hours of 
identification, any pregnancy occurring in a female patient during the study or within 
20 weeks of the last dose of study drug.  Any complication of pregnancy affecting a 
female study patient and/or fetus and/or newborn 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 7.4.2. Monitoring of AESIs is described in Section 7.6. Events considered to be 
AESIs are: 
 Adjudicated arthropathy (as confirmed by adjudication) 
 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 
 JR surgery (refer to Section 7.6.1.4 for when to report as an AESI) 
 Patients should be counselled that if they require JR surgery during the trial, they 
should contact the site immediately and have pre-operative X-rays and MRI 
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completed of the joint that will be replaced.  The pre-operative images must be 
submitted to the central imaging vendor for adjudication 
7.4.4. 
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.   
7.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results 
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE include: 
 the test result is associated with accompanying symptoms, and/or 
 the test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
 the test result leads to a change in dosing (outside of protocol-stipulated dose 
adjustments), discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy 
Contact the medical monitor in the event the investigator feels that an abnormal test finding 
should be reported as an AE, although it does not meet any of the above criteria. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an 
AE.  Any abnormal test result that is determined to be an error does not require reporting as an 
AE. 
Evaluation of severity of laboratory abnormalities will be assessed according to the scale 
outlined in Section 7.5.1. 
7.4.6. 
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. 
7.5. 
Evaluation of Severity and Causality 
7.5.1. 
Evaluation of Severity 
Adverse events will be graded according to the following scale: 
 Mild:  Does not interfere in a significant manner with the subject’s normal 
functioning level.  It may be an annoyance.  Prescription drugs are not ordinarily 
needed for relief of symptoms, but may be given because of personality of the 
subject. 
 Moderate:  Produces some impairment of functioning but is not hazardous to health.  
It is uncomfortable or an embarrassment.  Treatment for symptom may be needed. 
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 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 
subject hospitalized. 
7.5.2. 
Evaluation of Causality 
Relationship of AEs 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 adverse event 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 
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Relationship of AEs to Study Conduct: 
The relationship of AEs to study conduct will be assessed by the blinded investigator, and will be 
a clinical decision based on all available information.  The following question will be addressed: 
Is there a reasonable possibility that the adverse event 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 
7.6. 
Safety Monitoring 
The investigator will monitor the safety of study patients 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.  The study monitor 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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7.6.1. 
Monitoring Adverse Events of Special Interest 
7.6.1.1. 
Adjudicated Arthropathy 
Adjudicated arthropathy is an umbrella term that encompasses the following conditions:   
 Rapidly progressive OA type 1 and 2 
 Subschondral insufficiency fractures 
 Primary osteonecrosis 
In addition, adjudicated arthropathies will be evaluated to determine if they meet the criteria for 
destructive arthropathy. 
Potential events of adjudicated arthropathy will be monitored via clinical signs and symptoms of 
worsening joint pain (joint pain questionnaire), AE monitoring, and routine imaging.  
Clinically significant worsening of joint pain during the course of this study is defined as 
worsening of pain in any joint despite treatment with analgesics (see Section 5.2), which is 
inconsistent with the normal progression of OA and that lasts at least 2 weeks (or less at the 
discretion of the investigator).   
If a patient reports an increase in joint pain, as described above, then study drug administration 
will be withheld.  Imaging of the affected joint will be performed, as well as any additional 
imaging deemed appropriate to understand the cause of the worsening pain (Section 6.3.4.8).  
The decision to perform imaging after patient reports of worsening joint pain will be documented 
in the respective CRF page.  Images, along with any other radiographic evaluation, will be 
submitted to the Adjudication Committee for review (Section 3.4). The investigator may 
consider aspiration of synovial fluid for further analysis such as cell count and crystal analysis. 
If routine imaging suggests one of the forms of adjudicated arthropathy, then study drug 
administration will be withheld. Any additional imaging deemed appropriate will be obtained. 
Images, along with any other radiographic evaluation, will be submitted to the Adjudication 
Committee for review (Section 3.4).  
If the adjudication does not confirm the case as adjudicated arthropathy according to the 
adjudication criteria, study drug may be restarted.  
Patients with findings that suggest adjudicated arthropathy will have their dosing terminated and 
will be referred for orthopedic consultation, and once confirmed by the adjudication committee, 
the case must be reported as an AESI (Section 7.3.3 and Section 7.4.3).   
Patients should be encouraged to return to the clinic for remaining study visits. Prior to the 
scheduled JR, the patient should complete the pre-operative study visit and week 4 and week 20 
post-operative study visits (Section 6.2.11 and Section 6.3.4.10). Pre-operative images, along 
with any other radiographic evaluation will be submitted to the Adjudication Committee for 
review (Section 3.4).  
Details of data collection for adjudication of events will be provided in the adjudication charter.   
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7.6.1.2. 
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 6.3.4.5). New onset or worsening of signs and symptoms of 
autonomic dysfunction will be evaluated by the investigator.  Sympathetic nervous system 
dysfunction will only be diagnosed after consultation with an appropriate specialist, such as a 
neurologist and/or cardiologist. 
In cases where new or worsening symptoms consistent with sympathetic nervous system 
dysfunction are moderate to severe or are clinically significant and do not resolve or return to 
baseline in 2 weeks (or less at the discretion of the investigator), study drug will be withheld and 
the patient will be referred to a specialist. If the evaluation by the appropriate specialist does not 
suggest sympathetic nervous system dysfunction, study drug may be restarted. If the specialist’s 
evaluation does reveal sympathetic nervous system dysfunction then study drug will be 
permanently discontinued and the case reported as an AESI (Section 7.4.3). 
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 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 can 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 7.4.3). 
 If the patient has asymptomatic orthostatic hypotension, study drug will be withheld, 
and the patient should return to the study site for an unscheduled visit in 1 to 10 days 
for an unscheduled assessment of orthostatic hypotension.  
 If the unscheduled assessment does not reveal orthostatic hypotension then study 
drug may be continued. If the unscheduled assessment demonstrates orthostatic 
hypotension then study drug will continue to be withheld until the patient has 
been evaluated by a specialist (neurologist or a cardiologist) for evidence of 
sympathetic nervous system dysfunction.  
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 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 can 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 7.4.3).  
7.6.1.3. 
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 7.4.3). 
7.6.1.4. 
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 6.3.4.9. 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. 
7.7. 
Investigator Alert Notification 
Regeneron or its 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, and has a reasonable suspected causal relationship to the 
medicinal/investigational product). 
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8. 
STUDY VARIABLES 
8.1. 
Demographic and Baseline Characteristics 
Standard demography will include patient variables (eg, age, race, weight, height, etc.), baseline 
characteristics (eg, K-L categories, geographical regions), medical and surgical history, 
medication history, WOMAC pain score (knee and hip), and bilateral radiograph (knee, hip, and 
shoulder) for each patient.  
8.2. 
Primary Endpoint 
The primary endpoint in the study is safety monitoring including AE incidence, SAE incidence, 
AESI incidence, changes in safety laboratory analyses, and incidence of anti-fasinumab antibody 
formation from baseline to week 52 (treatment period 1 and 2) and to week 72 (end of follow-up 
period). 
8.3. 
Exploratory Endpoints 
Other endpoints in the study are:  
 The proportion of patients taking rescue medication, number of days on rescue 
medication, and weekly average usage of rescue medication 
 The percent of patients using standard-of-care analgesic medication  
 Time to JR decision 
 Survey of Autonomic Symptom scores 
8.4. 
Additional Endpoints for the Efficacy Sub-Study 
In addition to the main long-term safety study endpoints, the following endpoints will be 
evaluated for the efficacy sub-study. 
Co-Primary efficacy endpoints for the sub-study are: 
 Change from baseline to week 16 in the WOMAC pain subscale score 
 Change from baseline to week 16 in the WOMAC physical function subscale score 
Key secondary efficacy endpoints for the sub-study are: 
 Change from baseline to week 16 in the Patient Global Assessment for OA score 
 The percentage of patients who had a response at week 16, with response defined as 
an improvement by ≥30% in WOMAC pain subscale scores 
Additional secondary efficacy endpoints may be evaluated and will be detailed in the statistical 
analysis plan (SAP). 
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8.5. 
Pharmacokinetic Variables 
Pre-dose samples will be collected from patients in the sub-study. The PK variable is fasinumab 
concentrations in serum at specified sampling time points.    
8.6. 
Anti-Drug Antibody Variables 
Samples for ADA evaluation will be collected at baseline and at subsequent study visits. 
Anti-drug antibody variables include ADA status (positive or negative) and titer as follows: 
 Treatment emergent - defined as any post-dose positive ADA response when baseline 
results are negative  
 Treatment boosted - defined as any post-dose positive ADA response that is at least 
9-fold over the baseline level when baseline is positive in the ADA assay  
 Titer Values 
 Titer category ▪ low (titer <1,000); moderate (1,000≤ titer ≤10,000); high (titer 
>10,000) 
 Neutralizing ADA activity for samples positive in the ADA assay 
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9. 
STATISTICAL PLAN 
This section provides the basis for the SAP for the study.  The SAP may be revised during the 
study to accommodate amendments to the clinical study protocol and to make changes to adapt 
to unexpected issues in study execution and data that may affect the planned analyses.  The final 
SAP will be issued before the database is locked. 
Analysis variables are listed in Section 8. 
9.1. 
Statistical Hypothesis for the Sub-Study Population 
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.  Hence, there are 6 hypotheses to be tested between the primary and 
key secondary efficacy endpoints.  A hierarchical testing procedure will be used to control the 
overall type I error rate at 0.05 for the 2 co-primary endpoints and the secondary endpoints 
across the 2 dose regimens.  The hierarchical testing order will be detailed in the SAP.  The 
hypotheses to be tested are: 
 H11:  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 
 H12:  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 
 H13:  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 
 H21:  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 
 H22:  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 
 H23:  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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9.2. 
Determination of Sample Size 
The sample size for this long-term safety study was selected according to regulatory 
requirements for sufficient patients with adequate treatment exposure.  With approximately 
1750 patients expected to be treated with placebo, a total of up to 7000 patients was planned to 
be randomized.  This study will provide an adequate assessment of safety in patients with pain 
associated with OA.  For example, based on Exact Binomial Testing, with approximately 
5250 patients with pain associated with OA exposed to fasinumab, if the observed incidence rate 
is 1.0%, one can be 97.5% confident that the true incidence rate is not greater than 1.3% 
(Table 6).  
Table 6: 
Observed Incidence Rate (n/N) and 95% CI (Based on Exact Binomial Test) 
(%) 
 
2-sided 95% CI 
Observed Incidence Rate 
All fasinumab combined 
(N=5250) 
0.5% 
(0.32%, 0.72%) 
1% 
(0.74%, 1.30%) 
2% 
(1.64%, 2.42%) 
3% 
(2.56%, 3.51%) 
4% 
(3.49%, 4.57%) 
5% 
(4.42%, 5.61%) 
The sample size of the efficacy sub-study has been selected to have a sufficient number of 
patients to allow treatment comparisons of primary efficacy endpoints.  The effect size for 
WOMAC pain subscale score, WOMAC physical function subscale score and Patient Global 
Assessment were 0.46, 0.46, and 0.36, respectively, as observed in the phase 2 study 
R475-PN-1227.  Assuming a dropout rate of 15% at week 16, with 200 patients per treatment 
arm, there will be at least 96% power to detect an effect size of 0.46 for WOMAC pain and 
physical function subscale scores based on a 2-sided test at the 0.0167 significance level.  This 
sample size will provide at least 82% power to detect an effect size of 0.36 for Patient Global 
Assessment score. 
9.3. 
Analysis Sets 
9.3.1. 
Efficacy Analysis Sets 
The full analysis set for the efficacy sub-study includes all randomized patients in the sub-study.  
Efficacy analyses will be based on the treatment allocated (as randomized).  The full analysis set 
for the LTS study includes all randomized patients in the overall study. Patient disposition and 
baseline characteristics will be summarized based on the full analysis set of the LTS study. 
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9.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) for the entire study includes all randomized patients who received 
any study drug; it is based on the treatment received (as treated). Treatment 
compliance/administration and all clinical safety variables will be analyzed using the SAF for the 
entire study. The SAF for the sub-study includes all randomized patients in the sub-study who 
received any study drug; it is based on the treatment received (as treated). Selected safety 
analysis will be performed for the sub-study. Details will be provided in the SAP. 
9.3.3. 
Per Protocol Set 
The per protocol set (PPS) will include all randomized patients in the sub-study who do not have 
major protocol deviations through week 16.  The PPS will be used to perform sensitivity 
analyses for the primary and selected secondary efficacy endpoints. 
9.3.4. 
Pharmacokinetics Analysis Set 
The PK analysis set includes all treated patients who received any study drug and who had at 
least 1 non-missing drug concentration following the first dose of study drug. 
9.3.5. 
Anti-Drug Antibody Analysis Set 
The ADA analysis set includes all treated patients who received any treatment and who had at 
least 1 post-dose ADA result.  
9.4. 
Patient Disposition 
The following will be provided: 
 The total number of screened patients:  met the inclusion criteria regarding the target 
indication and signed the ICF 
 The total number of randomized patients:  received a randomization number 
 The total number of patients in each analysis set  
 The total number of patients who discontinued the study, and the reasons for 
discontinuation 
 A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized 
 A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation 
9.5. 
Statistical Methods 
9.5.1. 
Demography and Baseline Characteristics 
Baseline demographic, disease characteristics, and exposure to study drug will be summarized 
descriptively by treatment group using descriptive statistics.  Continuous variables will be 
summarized with mean, median, standard deviation (SD), minimum, and maximum.  Categorical 
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variables will be summarized with frequency and percentage.  Details of the statistical methods 
will be provided in the SAP.   
9.5.2. 
Efficacy Analyses for the Sub-Study Population 
9.5.2.1. 
Primary Efficacy Analysis 
The primary efficacy variables will be analyzed using a multiple imputation approach with 
mixed-effect model for repeated measure (MMRM) based on the FAS with adjustment for 
missing data due to treatment discontinuation for the reasons of lack of efficacy or AEs assuming 
the WOMAC scores would on average return to baseline values.  The missing data for patients 
who discontinued treatment due to lack of efficacy or AEs will be imputed with values centered 
at the mean baseline value of the treatment group that patients were randomized to.  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 primary efficacy 
variable (eg, WOMAC pain subscale score at baseline for the analysis of change from baseline in 
WOMAC pain subscale score), treatment, randomization strata, visit, and treatment-by-visit 
interaction.  The MMRM will be performed using the MIXED procedure in the 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 means estimates for the mean change from baseline 
to week 16, as well as the difference of the estimates between fasinumab and placebo, with the 
corresponding standard error, p-value and associated 95% confidence interval will be provided.  
Hypothesis testing will be performed as specified in Section 9.1 to control for multiplicity.  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 
Additional sensitivity analysis using tipping point approach with multiple imputation will be 
performed to assess the robustness of the results due to data that may be missing not-at-random 
(MNAR).  Multiple imputation will be based on monotone missing data structure of the change 
from baseline score using regression option in PROC MI.  Monotone missing data structure will 
be achieved using MCMC option of PROC MI.  After each imputation, a fasinumab patient's 
imputed data will subtract k (e.g., 20%, 40%, 100%, …) times the treatment effect at each 
corresponding time point.  By progressively increasing coefficient k, the sensitivity analysis will 
explore the tipping point, ie, the upper bound on the critical value of coefficient k at which 
conclusion from the primary analysis will be overturned (p>0.05).  Additional sensitivity 
analyses will be performed the same way for the primary and selected secondary endpoints using 
the PPS. 
9.5.2.2. 
Secondary Efficacy Analysis 
For analysis of continuous variables in secondary endpoints, the analysis method is the same as 
for the primary variables. For analysis of categorical variables in secondary endpoints (if 
identified later), the Cochran-Mantel-Haenszel approach stratified by the randomization strata 
will be used with missing data considered as non-response.  
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9.5.3. 
Safety Analysis 
The incidence rate is defined as the number of events divided by the duration of the overall 
observation period. The incidence rate will be summarized by treatment group along with 2-
sided 95% confidence interval. The incidence rate differences and ratios between each fasinumab 
dose group and placebo will be computed and presented along with 2-sided 95% confidence 
intervals. 
Change from baseline in joint space width of the index knee or hip will be summarized by 
treatment group. Time to event endpoints, such as time to JR decision, will be analyzed using the 
Kaplan-Meier approach. 
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 
 The on-treatment period is defined as the day of the first dose of study drug to 
4 weeks after the day of the last dose of SC study drug. 
 The follow-up period is defined as from the end of the on-treatment period up to 
24 weeks post the last dose of study drug (week 72). 
9.5.3.1. 
Adverse Events 
Definitions 
Treatment-emergent adverse events are defined as those that are not present at baseline or that 
represent the exacerbation of a preexisting condition during the on-treatment period.   
Analysis 
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®).  Coding will be to lowest level terms.  The 
verbatim text, the preferred term (PT), and the primary system organ class (SOC) will be listed. 
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 7.5.1), 
presented by SOC and PT 
 TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
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. 
Treatment-emergent AESIs will be listed and summarized by treatment group. Differences in 
event rate for AESIs between fasinumab and placebo will be estimated using exact binomial 
confidence intervals. Imaging data related to AA including change from baseline in joint space 
width will be summarized. 
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9.5.3.2. 
Other Safety 
Vital Signs 
Vital signs (temperature, pulse, blood pressure including orthostatic blood pressure, and 
respiration rate) will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each 
scheduled assessment time with descriptive statistics. 
Potentially clinically significant values (PCSVs) will be summarized by treatment group.  
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. 
9.5.3.3. 
Treatment Exposure 
Days of treatment exposure during the study will be presented by treatment and calculated as:  
 (Date of last study drug administration – date of first study drug administration) + 28  
The length of the observation period (days) will be presented by treatment group and calculated 
as: 
 (Date of last study visit – date of first study drug administration) +1.   
The number and percentage of patients randomized and exposed to double-blinded study drug 
will be presented by specific time periods for each treatment group.  
The time periods of interest may consist of exposure intervals 0 - <12, 12 - <24, 24 - <52, and 
≥52 weeks.  In addition, duration of exposure during the study will be summarized for each 
treatment group using number of patients, mean, SD, median, minimum and maximum. 
A summary of the number of doses by treatment group will be provided. 
9.5.3.4. 
Treatment Compliance 
Treatment compliance with protocol-defined investigational product will be calculated as 
follows: 
 Treatment compliance = (Number of actual injections of study drug during exposure 
period)/(Number of planned injections of study drug during exposure period on or 
before the time that the patient discontinues from the study) x 100% 
Treatment compliance will be presented by specific ranges for each treatment group.  The ranges 
of interest may consist of 10 disjoint intervals with width of 10% such as 0% - <10%, 
10% - <20%, 20% - <30%, etc., up to 90% - 100%.   
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9.5.4. 
Analysis of Pharmacokinetic Data 
Summaries of functional fasinumab concentrations will be presented by nominal time point and 
dose.  Plots of individual functional fasinumab concentrations will be presented by actual day 
(linear and log scales).  Plots of mean or median functional fasinumab concentrations will be 
presented by nominal day (linear and log scales). 
9.5.5. 
Descriptive Analysis of Anti-Drug Antibody Data 
Listings of ADA positivity and titers presented by patient, time point, and dose group will be 
provided.  Prevalence of treatment-emergent and treatment-boosted ADA response will be 
assessed as absolute occurrence (N) and percent of patients (%), grouped by study cohorts. 
The influence of ADAs on drug concentrations will be evaluated.  Assessment of impact of 
ADAs on safety and efficacy may be provided. 
9.5.6. 
Interim Analysis 
The week 72 primary safety analysis will be conducted when 72-week data, including 24-week 
follow-up data, are available for all randomized patients. Additional interim analysis of safety 
data may be performed for regulatory authority or internal decision-making purposes. 
The primary efficacy analysis for the sub-study may be conducted when 16-week data are 
available for all randomized patients in the sub-study.  No alpha adjustment is necessary, as the 
week 16 efficacy analysis will be the final primary analysis for efficacy.  Patient-level results 
will not be disclosed to any site-facing personnel or to any personnel directly involved with the 
conduct of the study. 
Detailed interim analysis timing and analyses will be pre-specified in the SAP. 
9.6. 
Additional Statistical Data Handling Conventions 
The following analysis and data conventions will be followed: 
General rules for handling missing data: 
 If the start date of an AE or concomitant medication is incomplete or missing, it will 
be assumed to have occurred on or after the intake of study medication, except if an 
incomplete date (eg, month and year) clearly indicates that the event started prior to 
treatment.  If the partial date indicates the same month or year of the intake of study 
medication date, then the start date by the study medication intake date will be 
imputed, otherwise, the missing day or month by the first day or the first month will 
be imputed.  
 No imputations will be made for missing laboratory data, ECG data, vital signs data, 
or physical examination data.   
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 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. 
9.7. 
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 15.1. 
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10. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
10.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study 
(including data validation, cleaning, correcting, releasing) will be maintained and stored at 
Regeneron. 
A medical coding plan will specify the processes and the dictionary used for coding.  All data 
coding (eg, AEs, baseline findings, medication, medical history/surgical history will be done 
using internationally recognized and accepted dictionaries. 
The CRF data for this study will be collected with an electronic data capture (EDC) tool.   
10.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
 IVRS – randomization 
 Rave Medidata - EDC system 
 Electronic diary may be used for patients in the sub-study to collect rescue 
medication usage and NRS scores 
 Statistical Analysis System (SAS) – statistical review and analysis 
 A pharmacovigilance and clinical safety software system (ARGUS – 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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11. 
STUDY MONITORING 
11.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, contract research organization [CRO] monitor) will visit 
each site prior to enrollment of the first patient, and periodically during the study.  In accordance 
with ICH guidelines, the monitor will compare the CRF entries with the appropriate source 
documents.  Additional review may include, but is not limited to, patient ICFs, documentation of 
patient recruitment and follow-up, AEs, SAEs, and concomitant therapy; as well as records of 
study drug dispensing, compliance, and accountability.  A copy of the drug dispensing log must 
be provided to the sponsor upon request. 
11.2. 
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. 
11.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic CRFs by 
trained site personnel.  A CRF must be completed for each and every 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 CRF page 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 system.  For corrections made via data queries, a reason for any 
alteration must be provided. 
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12. 
AUDITS AND INSPECTIONS 
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities.  Should this occur, the investigator is responsible for: 
 Informing the sponsor of a planned inspection by the authorities as soon as 
notification is received, and authorizing the sponsor’s participation in the inspection 
 Providing access to all necessary facilities, study data, and documents for the 
inspection or audit 
 Communicating any information arising from inspection by the regulatory authorities 
to the sponsor immediately 
 Taking all appropriate measures requested by the sponsor to resolve the problems 
found during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, 
CRFs, medical records, correspondence, ICFs, IRB/EC files, documentation of certification and 
quality control of supporting laboratories, and records relevant to the study maintained in any 
supporting pharmacy facilities.  Conditions of study material storage are also subject to 
inspection.  In addition, representatives of the sponsor may observe the conduct of any aspect of 
the clinical study or its supporting activities both within and outside of the investigator's 
institution. 
In all instances, the confidentiality of the data must be respected. 
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13. 
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1. 
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. 
13.2. 
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/EC.  A copy of the IRB/EC-approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient prior to his/her participation in the study and after the 
aims, methods, objectives, and potential hazards of the study have been explained to the patient 
in language that he/she can understand.  The ICF should be signed and dated by the patient and 
by the investigator or authorized designee who reviewed the ICF with the patient.   
 Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
 Patients who can understand but who can neither write nor read will have the ICF 
read to them in presence of an impartial witness, who will sign and date the ICF to 
confirm that informed consent was given. 
The original ICF must be retained by the investigator as part of the patient's study record, and a 
copy of the signed ICF must be given to the patient. 
If new safety information results in significant changes in the risk/benefit assessment, the ICF 
must be reviewed and updated appropriately.  All study patients must be informed of the new 
information and provide their written consent if they wish to continue in the study.  The original 
signed revised ICF must be maintained in the patient’s study record and a copy must be given to 
the patient. 
The principles of informed consent are described in ICH Guidelines for Good Clinical Practice. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC.  A copy of the IRB/EC-approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
13.3. 
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 initials and a patient 
identification number, only, on CRFs or other documents submitted to the sponsor.  Documents 
that will not be submitted to the sponsor (eg, signed ICF) must be kept in strict confidence. 
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The patient's and investigator's personal data, which may be included in the sponsor database, 
will be treated in compliance with all applicable laws and regulations.  The sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third 
party. 
13.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/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/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/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/EC approval letter with a current list of the IRB/EC members and their 
functions must be received by the sponsor prior to shipment of drug supplies to the investigator.  
The approval letter should include the study number and title, the documents reviewed, and the 
date of the review. 
Records of the IRB/EC review and approval of all study documents (including approval of 
ongoing studies) must be kept on file by the investigator. 
13.5. 
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. 
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14. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design or operation of the protocol or ICF 
without an IRB/EC-approved amendment. All substantial protocol amendments will be approved 
by the competent authorities before changes are implemented according to national regulations. 
Some exceptions may apply in the event of urgent safety actions, in accordance with local 
regulatory procedures. 
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15. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
15.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study or dosing in the study prematurely. Reasons may 
include safety or futility, among others. Should the sponsor decide to terminate the study, the 
investigator(s) will be notified in writing. 
15.2. 
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/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. 
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16. 
STUDY DOCUMENTATION 
16.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the CRFs must be signed 
by the investigator.  This certification form accompanies each set of CRFs.  The signed form will 
be provided to the sponsor with the final set of CRFs for each patient. 
16.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of CRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer if a longer period is required by relevant 
regulatory authorities.  The investigator must consult with the sponsor before discarding or 
destroying any essential study documents following study completion or discontinuation.  
Records must be destroyed in a manner that ensures confidentiality. 
If the investigator's personal situation is such that archiving can no longer be ensured, the 
investigator must inform the sponsor and the relevant records will be transferred to a mutually 
agreed-upon destination. 
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17. 
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 10.1). 
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 11.1, Section 11.2, Section 12). 
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 11.1). 
All patient data collected during the study will be recorded on paper or eCRF unless the data are 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for affirming that data entries in the CRF are accurate and correct by electronically 
signing a declaration that accompanies each set of patient final CRF (Section 11.3, Section 16.1).  
Study Documentation 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF (Section 11.2).  
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 16.2). 
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18. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
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19. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
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20. 
PUBLICATION POLICY 
The publication policy is provided as a separate agreement. 
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21. 
REFERENCES 
Aloe L, Tuveri MA, Carcassi U, Levi-Montalcini R. Nerve growth factor in the synovial fluid of 
patients with chronic arthritis. Arthritis Rheum 1992;35:351-355.  
Bjordal JM, Ljunggren AE, Klovning A, and Slørdal L. Non-steroidal anti-inflammatory drugs, 
including cyclo-oxygenase-2 inhibitors, in osteoarthritic knee pain: meta-analysis of randomized 
placebo controlled trials. BMJ 2004;329(7478): 1317. 
Brown MT, Murphy FT, Radin DM, Davignon I, Smith MD, West CR. Tanezumab reduces 
osteoarthritic knee pain: Results of a randomized, double-blind, placebo-controlled phase 3 trial. 
Ann Rheum Dis 2010;69 (Suppl 3):106.   
Chao M, Rajagopal R, and Lee FS. Neurotrophin signaling in health and disease. ClinSci (Lond) 
2006;110:167.   
Crowley C, Spencer SD, Nishimura MC, Chen KS, Pitts-Meek S, Armanini MP, et al. Mice 
lacking nerve growth factor display perinatal loss of sensory and sympathetic neurons yet 
develop basal forebrain cholinergic neurons. Cell 1994;76:1001-11.   
Einarsdottir E, Carlsson A, Minde J, Toolanen G, Svensson O, Solders G et al. A mutation in the 
nerve growth factor beta gene (NGFB) causes loss of pain perception. Human Molecular 
Genetics 2004;13:799–805.   
Halliday DA, Zettler C, Rush RA, Scicchitano R, McNeil JD. Elevated nerve growth factor 
levels in the synovial fluid of patients with inflammatory joint disease. Neurochem Res 
1998;23:919-22. 
Harris WH. Traumatic arthritis of the hip after dislocation and acetabular fractures: treatment by 
mold arthroplasty. An end-result study using a new method of result evaluation.  J Bone Joint 
Surg Am. 1969 Jun;51(4):737-55. 
Hefti F, Mokhtarani M Gray, M Zhao, C and Chan C.  RN624 (Anti-NGF) reduces pain and 
improves function in subjects with moderate to severe pain form osteoarthritis of the knee.  The 
Journal of Pain 2006: 7:S46.   
Indo Y, Tsuruta M, Hayashida Y, Karim MA, Ohta K, Kawano T et al. Mutations in the 
TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. 
Nature Genetics 1996;13:485-88.   
Insall JN, Dorr LD, Scott RD, Scott WN. Rationale of the Knee Society clinical rating system. 
ClinOrthopRelat Res. 1989 Nov;(248):13-14. 
Katz N, Borenstein DG, Birbara C et al. Efficacy and safety of tanezumab in the treatment of 
chronic low back pain. Pain 2011; 152;2248–58.   
Kivitz A, Gimbel J, Bramson C et al. Efficacy and safety of tanezumab versus naproxen in the 
treatment of chronic low back pain. Pain 2013;154;1009–21. 
Lane NE, Schnitzer TJ, Birbara CA, Mokhtarani M, Shelton DL, Smith MD et al. Tanezumab for 
the treatment of pain from osteoarthritis of the knee.  N Engl J Med 2010;363:1521-31.   
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Lewin GR, Rueff A, Mendell LM. Peripheral and central mechanism of NGF-induced 
hyperalgesia, Eur. J. Neurosci 1994; 6: 1903-12.   
Lowe EM, Anand P, Terenghui RE, Chestnuts-William DV, Osborne JL.  Increased nerve 
growth factor levels in the urinary bladder of women with idiopathic sensory urgency and 
interstitial cystitis. Br. J. Urol. 1997; 79:572–577. 
McArthur JC, Yiannoutsos C, Simpson DM, Adornato BT, Singer EJ, Hollander H, et al. A 
phase II trial of nerve growth factor for sensory neuropathy associated with HIV infection. AIDS 
Clinical Trials Group Team 291. Neurology 2000; 54:1080-8. 
Miller LJ, Fischer K, Goralnick S, Litt M, Burleson J, Arbertsen P et al. Nerve growth factor and 
chronic prostatitis/-chronic pelvic pain syndrome. Urology 2002;59:603–608. 
Pezet S and McMahon SB. Neurotrophins: Mediators and Modulators of Pain. Ann Rev 
Neurosci 2006;29:507-18. 
Ramer MS, Bisby MA. Adrenergic innervation of rat sensory ganglia following proximal or 
distal painful sciatic neuropathy: Distinct mechanisms revealed by anti-NGF treatment.  Eur J 
Neurosci 1999;11:837-846. 
Sanga, P., Katz, N., et al. (2011).  "Efficacy, Safety and Tolerability of Fulranumab, an anti-NGF 
Antibody, in Treatment of Patients with Moderate to Severe Osteoarthritis Pain."  Poster 
presented at the American Pain Society Annual Meeting. 
Sarchielli P, Arberti A, Floridi A, Gallai V. Levels of nerve growth factor in cerebrospinal fluid 
of chronic daily headache patients. Neurology 2001;57:132-134. 
Smeyne RJ, Klein R, Schnapp A, Long LK, Bryant S, Lewin A et al. Severe sensory and 
sympathetic neuropathies in mice carrying a disrupted Trk/NGF receptor gene. Nature 1994; 
368:166-9. 
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22. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: A Phase 3, Randomized, Double-Blind, Multi-Dose, 
Placebo-Controlled Study to Evaluate the Long-Term Safety and the Efficacy of Fasinumab in 
Patients with Pain Due to Osteoarthritis of the Knee or Hip and agree to abide by all provisions 
set forth therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, 
state, or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor or a 
partnership in which the sponsor is involved.  I will immediately disclose it in writing to the 
sponsor if any person who is involved in the study is debarred, or if any proceeding for 
debarment is pending, or, to the best of my knowledge, threatened. 
This document contains confidential information of the sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the EC.  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 protocol accurately describes the conduct of the study. 
Study Title: 
A Phase 3 Randomized, Double-Blind, Multi-Dose, Placebo-Controlled 
Study to Evaluate the Long-term Safety and the Efficacy of Fasinumab in 
Patients with Pain Due to Osteoarthritis of the Knee or Hip 
Protocol Number: 
R475-PN-1523 
Protocol Version: 
R475-PN-1523 Amendment 9 
 
 
 
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: 
See appended electronic signature page 
                                        VV-RIM-00071798-1.0 Approved - 22 Apr 2019 GMT-5:00


Signature Page for VV-RIM-00071798 v1.0
Signature Page for VV-RIM-00071798 v1.0 Approved
ESig Approval
19 14:38:27 GMT+0000
ESig Approval
000
ESig Approval
-2019 20:02:11 GMT+0000
ESig Approval
-2019 20:30:55 GMT+0000
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SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
CONFIDENTIAL 
Page 1 of 71
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-Controlled Study to Evaluate the Long-Term 
Safety and the Efficacy of Fasinumab in patients with 
pain due to Osteoarthritis of the Knee or Hip 
Compound: 
REGN475 
Protocol Number: 
R475-PN-1523 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician (SB): 
Clinical Trial Manager (CTM): 
 
Medical Director (MD): 
 
Version/Date: 
4.0 / 01April2019 
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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 Pharmacokinetics 
 
 
See appended electronic signature page 
Study Bioanalytical Sciences 
 
 
See appended electronic signature page 
Study Medical Director 
 
 
See appended electronic signature page 
Project Biostatistician
 
 
See appended electronic signature page 
Head of BDM or designee 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .....................................................7 
1. 
OVERVIEW .................................................................................................................9 
1.1. 
Background/Rationale ..................................................................................................9 
1.2. 
Study Objectives .........................................................................................................11 
1.2.1. 
Primary Objectives .....................................................................................................11 
1.2.2. 
Exploratory Objectives ...............................................................................................11 
1.2.3. 
Additional Objectives for the Efficacy sub-study .......................................................11 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol ................................11 
1.2.5. 
Revision History for SAP Amendments .....................................................................12 
2. 
INVESTIGATION PLAN ..........................................................................................13 
2.1. 
Study Design and Randomization ...............................................................................13 
2.2. 
Sample Size and Power Considerations .....................................................................14 
2.3. 
Study Plan ...................................................................................................................15 
3. 
ANALYSIS POPULATIONS .....................................................................................17 
3.1. 
Full Analysis Set (FAS) ..............................................................................................17 
3.2. 
The Safety Analysis Set (SAF) ...................................................................................17 
3.3. 
Per Protocol Set ..........................................................................................................18 
3.4. 
The Pharmacokinetic Analysis Set .............................................................................18 
3.5. 
The Anti-drug antibody Analysis Set..........................................................................18 
4. 
ANALYSIS VARIABLES .........................................................................................19 
4.1. 
Demographic and Baseline Characteristics ................................................................19 
4.2. 
Medical History ..........................................................................................................19 
4.3. 
Prior/Concomitant Medications and Procedures, Prohibited Medication ..................20 
4.4. 
Efficacy Variables for the Efficacy sub-study ............................................................21 
4.4.1. 
Primary Efficacy Variable(s) ......................................................................................21 
4.4.2. 
Key Secondary Efficacy Variable(s) ...........................................................................21 
4.4.3. 
Additional Secondary Efficacy Variable(s) ................................................................22 
4.5. 
Safety Variables ..........................................................................................................22 
4.5.1. 
Primary Safety Variables ............................................................................................22 
4.5.2. 
Exploratory Safety Variables ......................................................................................23 
4.5.3. 
Adverse Events of Special Interest .............................................................................23 
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4.5.4. 
Laboratory Safety Variables .......................................................................................24 
4.5.5. 
Biomarker variables ....................................................................................................24 
4.5.6. 
Vital Signs ..................................................................................................................24 
4.5.7. 
Orthostatic Hypotension .............................................................................................24 
4.5.8. 
12-Lead Electrocardiography ......................................................................................25 
4.5.9. 
Physical and Neurological Examination Variables .....................................................25 
4.5.10. 
Other Safety Variables ................................................................................................26 
4.6. 
Pharmacokinetic Variables .........................................................................................26 
4.7. 
Anti-Drug Antibody Variables ...................................................................................26 
5. 
STATISTICAL METHODS .......................................................................................28 
5.1. 
Statistical Methods for Long-Term Safety Study .......................................................28 
5.1.1. 
Demographics and Baseline Characteristics ...............................................................28 
5.1.2. 
Medical History ..........................................................................................................28 
5.1.3. 
Prior / Concomitant Medications ................................................................................28 
5.1.4. 
Prohibited Medications ...............................................................................................29 
5.1.5. 
Patient Disposition ......................................................................................................29 
5.1.5.1. 
Screening Disposition .................................................................................................29 
5.1.5.2. 
LTS study Disposition ................................................................................................30 
5.1.5.3. 
Analysis Set ................................................................................................................30 
5.1.6. 
Extent of Study Treatment Exposure and Compliance ...............................................30 
5.1.6.1. 
Measurement of Treatment Compliance .....................................................................31 
5.1.6.2. 
Exposure to Investigational Product ...........................................................................31 
5.1.6.3. 
Length of Study Observation ......................................................................................31 
5.1.6.4. 
Protocol Deviations ....................................................................................................32 
5.1.7. 
Analysis of Safety Data...............................................................................................32 
5.1.7.1. 
Primary Safety Endpoints ...........................................................................................32 
5.1.8. 
Exploratory Safety Endpoints .....................................................................................33 
5.1.8.1. 
Adverse Events ...........................................................................................................34 
5.1.8.2. 
Adverse Events of Special Interest .............................................................................36 
5.1.8.3. 
Clinical Laboratory Measurements .............................................................................36 
5.1.8.4. 
Analysis of Vital Signs ...............................................................................................37 
5.1.8.5. 
Analysis of 12-Lead ECG ...........................................................................................37 
5.1.8.6. 
Physical Exams ...........................................................................................................37 
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5.1.8.7. 
Joint Pain Questionnaire .............................................................................................37 
5.1.8.8. 
Arthropathy Adjudications .........................................................................................37 
5.1.8.9. 
Neurological Exam .....................................................................................................37 
5.1.8.10. 
Analysis of Pharmacokinetics and Drug Concentration Data .....................................37 
5.1.9. 
Analysis of Anti-Drug Antibody Data ........................................................................38 
5.2. 
Statistical Methods for Efficacy Sub-Study ................................................................38 
5.2.1. 
Demographics and Baseline Characteristics ...............................................................38 
5.2.2. 
Medical History ..........................................................................................................38 
5.2.3. 
Prior / Concomitant Medications ................................................................................38 
5.2.4. 
Prohibited Medications ...............................................................................................39 
5.2.5. 
Patient Disposition ......................................................................................................39 
5.2.5.1. 
Analysis Set ................................................................................................................39 
5.2.6. 
Extent of Study Treatment Exposure and Compliance ...............................................40 
5.2.6.1. 
Measurement of Treatment Compliance .....................................................................40 
5.2.6.2. 
Exposure to Investigational Product ...........................................................................40 
5.2.6.3. 
Length of sub study Observation ................................................................................40 
5.2.6.4. 
Protocol Deviations ....................................................................................................41 
5.2.7. 
Analysis of Efficacy Data ...........................................................................................41 
5.2.7.1. 
Analysis of Primary Efficacy Variable(s) ...................................................................41 
5.2.7.2. 
Analysis of Key Secondary Efficacy Variable(s) ........................................................44 
5.2.7.3. 
Analysis of Additional Secondary Efficacy Variable(s) .............................................44 
6. 
DATA CONVENTIONS ............................................................................................46 
6.1. 
Definition of Baseline for Variables ...........................................................................46 
6.2. 
Data Handling Conventions for Efficacy Data ...........................................................46 
6.3. 
General Data Handling Conventions ..........................................................................46 
6.4. 
Visit Windows ............................................................................................................48 
6.5. 
Unscheduled Assessments ..........................................................................................49 
7. 
TIMING OF STATISTICAL ANALYSES ................................................................50 
8. 
INTERIM ANALYSES ..............................................................................................51 
9. 
SOFTWARE ...............................................................................................................52 
10. 
REFERENCES ...........................................................................................................53 
11. 
APPENDIX .................................................................................................................54 
11.1. 
Schedule of Events and Visits ....................................................................................54 
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11.2. 
Reference for Criteria for Treatment-Emergent Potentially Clinically 
Significant Values (PCSV) .........................................................................................63 
11.3. 
OMERACT-OARSI set of responder criteria .............................................................71 
 
LIST OF TABLES 
Table 1: 
Observed Incidence Rate (n/N) and 95% CI (Based on Exact Binomial Test) 
(%) ..............................................................................................................................15 
Table 2: 
Criteria for Treatment-Emergent Potentially Clinically Significant Values 
(PCSV) ........................................................................................................................63 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................16 
 
 
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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 
ARGUS 
Pharmacovigilance and clinical safety software system 
AST 
Aspartate Aminotransferase 
Cmax 
Maximum observed drug concentration 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
Ctrough 
Concentration measured at the end of a dosing interval at steady state 
(taken directly before next administration) 
DA  
Destructive arthropathy 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EOS 
End of study 
EOT 
End of treatment 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
hs-CRP 
High-sensitivity C-reactive protein 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
IVRS 
Interactive voice response system 
JR 
Joint replacement 
K-L 
Kellgren-Lawrence  
LDH 
Lactate dehydrogenase 
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LTS 
Long-term safety 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect model repeated measure 
MRI 
Magnetic resonance imaging 
NGF 
Nerve growth factor 
NRS 
Numeric Rating Scale 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
OA 
Osteoarthritis 
OMERACT-OARSI 
Osteoarthritis Research Society International Standing Committee for 
Clinical Trials Response Criteria Initiative and The Outcome Measure 
in Rheumatology 
PCSV 
Potentially clinically significant value 
PK 
Pharmacokinetic 
PPS 
Per protocol set 
PT 
Preferred term 
Q4W 
Every 4 weeks 
Q8W 
Every 8 weeks 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SD 
Standard deviation 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TIA 
Transient ischemic attack 
TrkA 
Tyrosine kinase type 1 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
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 definitions and 
statistical methods to be used in the analysis of data for study R475-PN-1523. 
This plan may be revised during the study to accommodate protocol amendments and/or to make 
changes to adapt to unexpected issues in study execution and/or data that affect planned analyses.  
These revisions will be based on blinded review of the study and data, and a final plan will be 
issued prior to the first step database lock and before unblinding of the study. 
1.1. 
Background/Rationale 
This is a Phase 3, randomized, double-blind, placebo-controlled study designed to evaluate the 
long-term safety, tolerability, and the efficacy of fasinumab in patients with pain due to 
radiographically confirmed OA of the knee or hip who have a history of inadequate pain relief 
with paracetamol/acetaminophen, and a history of inadequate pain relief or intolerance to oral 
NSAIDs, and opioid therapy.  During the initial 16 weeks of the trial, standard-of-care pain 
medications will be prohibited with the exception of paracetamol/acetaminophen, which will be 
provided as a rescue medication, and low-dose aspirin for cardiac prophylaxis.  Following the 
first 16 weeks, patients will be able to utilize standard-of-care pain medication including limited 
use NSAIDs (for non-OA pain or fever), as well as paracetamol/acetaminophen, in addition to 
study drug.  Therefore, this study will also provide safety data on the concomitant use of 
fasinumab with other analgesics, including limited use NSAIDs. 
A subset of patients will participate in an efficacy sub-study, in addition to participation in the 
main long-term safety study.  In the sub-study, efficacy parameters will be assessed over the 
16 weeks following randomization to a treatment group.  Details on dosing regimen and 
allocation ratios across amendments for both the main study and efficacy sub-study are provided 
in Section 2.1. 
There have been several modifications to the dosing regimens for the study.  Patients initially 
randomized to the 6 mg or 9 mg Q4W dosing regimen or matching placebo under the original 
protocol and amendments 1 and 2 were discontinued from study medication on 
30December 2016 per US FDA request. The patients were encouraged to otherwise continue all 
protocol visits and complete all study procedures with the exception of receiving study 
medication.  Under amendments 3 and 4, main study patients were randomized to 6 mg Q8W or 
matching placebo.  Under amendment 5 global (Issued 16March 2017) or later amendments, 
main study patients were randomized to 6 mg fasinumab Q8W, 3 mg fasinumab Q4W, 1 mg 
Fasinumab Q4W, or matching placebo.  Efficacy sub-study patients were randomized to 6 mg 
fasinumab Q8W, 3 mg fasinumab Q4W, 1 mg fasinumab Q4W, 1 mg fasinumab Q8W, or 
matching placebo Q4W. Patients randomized to efficacy sub-study will continue in the main 
study on randomized treatment after participation in the efficacy sub-study. Prior to amendment 5 
global all subjects participated only in the main study. Enrollment for the main study under 
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amendment 5 or later was paused on 3January 2017 not due to any safety concern, but to hold 
enrollment of 6 mg Q8W vs placebo until further discussion with health authorities on safety 
database requirement.  The efficacy sub-study has completed enrollment as of 7 February 2018.  
The Data Monitoring Committee recommended that the 3mg Q4W and 6mg Q8W doses be 
discontinued due to safety concerns.  A decision was made by the Sponsor to conduct an 
unplanned interim safety analysis of the data to corroborate these findings. Based on the IDMC 
recommendation and the totality of evidence to date with regards to safety, only the 1mg Q4W, 
1mg Q8W doses and placebo arms would be carried forward in the study.  The 3 mg Q4W and 
6Mg Q8W doses were discontinued from further dosing; however, subjects have been 
encouraged to remain in the study and will be followed for all study visits until completion of the 
end of study visit in order to continue to monitor for safety and to allow complete data collection.  
The Abridged Unblinded DMC Interim Report was made available to members of the study team 
including the study biostatistician and study medical director.  This abridged DMC report 
included the following subject level listings: 
 Listing of Serious of Adverse Events from the Case Report Form (amendment 3) 
 Listing of Serious of Adverse Events from the Case Report Form (amendment 5 
sub-study) 
 Listing of Deaths (amendment 3)  
 Listing of Adjudication Results for Subjects with Arthropathies (amendment 3) 
 Listing of Adjudication Results for Subjects with Arthropathies (amendment 5 
Sub-study), Listing of Subjects with Total Joint Replacement (amendment 3)  
 Listing of Subjects with Total Joint Replacement (amendment 5 Sub-study)  
Restricted to subjects randomized to Placebo SC Q4W or Q8W (amendments 3 or earlier), 6 mg 
SC Q4W or Q8W (amendments 3 or earlier), Placebo SC Q4W (amendment 5 sub-study), 3 mg 
SC Q4W (amendment 5 sub-study), 6 mg SC Q8W (amendment 5 sub-study).  This report did 
not contain any information on the 1mg Q4W and 1mg Q8W doses or their placebo arms that are 
being carried forward; hence there is no risk of unblinding of the blinded study team members to 
doses being continued.  Continued monitoring of all subjects not being dosed also remains 
blinded to the clinical team as to treatment received. 
Given the discontinuation of the 3 mg and 6 mg doses, greater exposure to the fasinumab 1 mg 
dose was required to increase the size of the fasinumab safety database for potentially clinically 
relevant doses.  Therefore, under amendment 8, patients will be randomized in a 3:3:1 ratio to 
fasinumab 1 mg Q8W, 1 mg Q4W or placebo.  This randomization ratio was chosen based on the 
need to enroll more patients on the 1 mg dose regimens and the need to include placebo patients 
for blinding purposes. 
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Supportive trials include data from 2 completed fasinumab phase 1 studies in healthy volunteers 
(R475-PN-0817 and TD-11480), as well as data from the completed fasinumab phase 2 
proof-of-concept study in patients with pain due to OA of the knee (R475-PN-0901), and results 
from the phase 2 study in patients with osteoarthritis of the hip or knee (R475-PN-1227).  
1.2. 
Study Objectives 
1.2.1. 
Primary Objectives 
The primary objective of the study is to describe the safety and tolerability of fasinumab, 
including Adverse events of special interest (AESIs), in patients with pain due to 
radiographically-confirmed OA of the knee or hip. 
1.2.2. 
Exploratory Objectives 
Other objectives of the study are: 
 To assess the use of paracetamol/acetaminophen for the fasinumab arms compared to 
placebo from baseline to week 16 
 To assess the use of paracetamol/acetaminophen for the fasinumab arms compared to 
placebo from baseline to week 52 
 To assess the use of standard-of-care analgesic medication, including NSAIDs, for 
non-OA pain in patients randomized to fasinumab compared to placebo from week 16 
through the end of treatment 
 To assess time to JR 
1.2.3. 
 Additional Objectives for the Efficacy sub-study 
The objective of the stub-study is to evaluate the efficacy of fasinumab compared with placebo 
when administered to patients with pain due to radiographically-confirmed OA of the knee or 
hip. 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol 
The following exploratory endpoint is in the protocol but will not be included in the analysis plan 
since there is no definitive literature or guideline on the criteria for needing joint replacement: 
 Incidence of and time to cases meeting pre-specified criteria for needing joint 
replacement.  
The following exploratory endpoints are not listed in the protocol but are included in the analysis 
plan: 
 Time to Adjudicated Arthropathy (AA), time to Destructive Arthropathy (DA)  
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The following lab safety endpoint is not listed in the protocol but is included in the analysis plan: 
 High-sensitivity C-reactive protein (hs-CRP) 
1.2.5. 
Revision History for SAP Amendments 
The language of Section 7“Timing of Statistical Analysis” was updated to clarify that the week 
72 analysis is not the final analyses. Section 8 “Interim Analyses” was updated to clarify when 
interim analyses may be performed.  
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
This is a Phase 3, randomized, double-blind, multi-dose, placebo-controlled study to evaluate the 
long-term safety and efficacy of fasinumab in patients with pain due to osteoarthritis of the knee 
or hip.  Patients are randomized into either the main study or the efficacy sub-study.  After the 
16-week sub-study, efficacy sub-study patients continue on the randomized treatment as part of 
the Long-Term Safety (LTS) study in which dosing will continue through week 48.  The LTS 
study is made up of both main study patients and efficacy sub-study patients. 
There have been several modifications to the randomization scheme for both the main study and 
the efficacy sub-study as follows:  
 Original Protocol, Amendment 1 & 2 
Under the original protocol and amendments 1 and 2, main study patients were 
randomized to 6 mg or 9 mg Q4W or matching placebo in a 2:2:1 ratio.  Efficacy 
sub-study patients were to be randomized to 6 mg or 9 mg Q4W or matching placebo 
in a 1:1:1 ratio.  Patients randomized to these earlier versions of the protocol with the 
6 mg or 9 mg Q4W dosing regimen or matching placebo were discontinued from 
study medication but encouraged to otherwise continue all protocol visits and 
complete all study procedures with the exception of receiving study medication.  
Efficacy sub-study enrollment did not start under the original protocol and 
amendment 1 and 2. 
 Amendment 3 & 4 
Under amendment 3 and 4, main study patients were randomized to 6 mg Q8W or 
matching placebo in a 2:1 ratio.  Efficacy sub-study patients were to be randomized to 
6 mg Q8W or matching placebo in a 1:1 ratio.  However, there were patients enrolled 
into the efficacy sub-study under amendment 3 and 4. 
 Amendment 5 and 6 
Under amendment 5 global or later, main study patients were to be randomized to 
6mg fasinumab Q8W, 3 mg fasinumab Q4W, 1 mg Fasinumab Q4W, or matching 
placebo Q4W in a 1:2:2:1 ratio.  However, there were no patients enrolled into the 
main safety study under amendment 5 or amendment 6.  Efficacy sub-study patients 
were randomized to 6 mg fasinumab Q8W, 3 mg fasinumab Q4W, 1 mg fasinumab 
Q4W, 1 mg fasinumab Q8W, or matching placebo Q4W in a 1:1:1:1:1 ratio.  Efficacy 
sub-study has completed enrollment as of 7 February 2018. 
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Due to the recommendation of the Independent Data Monitoring Committee, the 3mg Q4W and 
6mg Q8W doses have been discontinued as described above.  This SAP will apply to the 
amended protocol reflecting the most recent change in doses recommended by the IDMC, now 
including only the 1 mg Q4W and 1mg Q8W doses and placebo arms. 
 Amendment 7 (urgent safety measure) 
Issued on 24 May 2018, all patients previously randomized to 3 mg Q4W or 6 mg 
Q8W under earlier versions of the protocol will be were 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.  Anyone previously 
randomized to 9 mg Q4W or 6 mg Q4W (or matching placebo) before amendment 3, 
or randomized to 6 mg Q8W or 3 mg Q4W under amendment 3 or subsequent 
amendments, was discontinued from study drug and encouraged to complete all 
remaining study visits and study procedures in the follow up period and the end of 
study phone call. 
 Amendment 8 
Under amendment 8, patients will be enrolled into the main safety study.  They will 
be randomized in a 3:3:1 ratio of fasinumab 1 mg Q8W, 1 mg Q4W or placebo.  
Patients randomized to 1 mg Q8W will receive alternating placebo injections at the 
monthly visits where active study medication drug will not be given to maintain the 
blind. 
Stratification for the main study and the efficacy sub-study are as follows: 
Main study stratification 
 Randomization is stratified by screening K-L score (2-3, 4) and by geographic region 
(North America, Latin America, Europe, or Asia/Pacific/South Africa). 
Efficacy sub-study stratification 
 Randomization is stratified by screening K-L score (2-3, 4), geographic region 
(North America, Latin America, Europe, or Asia/Pacific), and by index joint. 
2.2. 
Sample Size and Power Considerations 
Long Term Safety study 
The sample size for this long-term safety study was selected according to regulatory requirements 
for sufficient patients with adequate treatment exposure.  With approximately 1750 patients 
expected to be treated with placebo, a total of up to 7000 patients was planned to be randomized.  
This study will provide an adequate assessment of safety in patients with pain associated with 
OA.  For example, based on Exact Binomial Testing, with approximately 5250 patients with pain 
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associated with OA exposed to fasinumab, if the observed incidence rate of is 1.0%, one can be 
97.5% confident that the true incidence rate is not greater than 1.3% (Table 1). 
Departures from planned sample sizes will be described in the CSR. 
Table 1: 
Observed Incidence Rate (n/N) and 95% CI (Based on Exact Binomial Test) 
(%) 
 
2-sided 95% CI 
Observed Incidence Rate 
All fasinumab combined 
(N=5250) 
0.5% 
(0.32%, 0.72%) 
1% 
(0.74%, 1.30%) 
2% 
(1.64%, 2.42%) 
3% 
(2.56%, 3.51%) 
4% 
(3.49%, 4.57%) 
5% 
(4.42%, 5.61%) 
Efficacy Sub-study 
The sample size of the efficacy sub-study was selected to have a sufficient number of patients to 
allow treatment comparisons of primary efficacy endpoints.  The effect size for WOMAC pain 
subscale score, WOMAC physical function subscale score and Patient Global Assessment were 
0.46, 0.46, and 0.36, respectively, as observed in the phase 2 study R475-PN-1227.  To maintain 
the overall significance level of 0.05, the sequential multiple test procedure as described in 
Section 5.6.1 is applied to the hypothesis tests for the primary and secondary endpoints.  
Assuming a dropout rate of 15% at week 16, with 200 patients per treatment arm, there will be at 
least 96% power to detect an effect size of 0.46 for WOMAC pain and physical function subscale 
scores based on a 2-sided test at the 0.0167 significance level.  This sample size will provide at 
least 82% power to detect an effect size of 0.36 for Patient Global Assessment score. 
2.3. 
Study Plan 
Study Visits 
The study consists of a screening period of up to 30 days (Screening Period), followed by a 7 to 
10 day pre-randomization period (Pre-Randomization Period), a 16-week randomized, 
double-blind, placebo-controlled treatment period (Treatment Period 1), a 36-week, 
double-blind, placebo-controlled treatment period (Treatment Period 2) in which non-NSAID 
standard-of-care pain medications can also be used in the event of inadequate pain relief for OA 
pain, a 24-week follow-up period, and an end of study phone contact at 52 weeks following the 
last dose of study drug to determine whether a joint replacement (JR) has been conducted or is 
scheduled (or the patient is on a waiting list). 
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A subset of patients will also be participating in a 16-week efficacy sub-study to characterize the 
efficacy of fasinumab.  Efficacy assessments will be performed during treatment period 1, which 
will be followed by the 36-week treatment period 2, and a 24-week follow-up period.  See 
Figure 1 for the Study Flow Diagram. 
Figure 1: 
Study Flow Diagram 
 
The Schedule of Events table is presented in Appendix 11.1. 
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3. 
ANALYSIS POPULATIONS  
In accordance with guidance from the International Council for Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (1998), the following populations will be used for all 
statistical analyses: 
3.1. 
Full Analysis Set (FAS) 
Efficacy sub-study 
The full analysis set for the efficacy sub-study (FAS-substudy) includes all randomized patients 
in the efficacy sub-study.  Efficacy analyses are based on the treatment allocated (as randomized). 
LTS study 
The full analysis set for the LTS study (FAS-LTS) includes all randomized patients in the overall 
study (randomized within either the efficacy sub-study or the main study). This analysis set will 
be used to summarize baseline characteristics and patient disposition; it is based on the treatment 
allocated (as randomized). 
3.2. 
The Safety Analysis Set (SAF) 
Efficacy sub-study 
The safety analysis set for the efficacy sub-study (SAF-substudy) includes all randomized 
patients in the efficacy sub-study who received any study drug during the efficacy sub-study; it is 
based on the treatment received (as treated).  Patients who receive at least one dose of fasinumab 
will be classified to the respective active treatment arm for the purpose of the analysis.  
Treatment compliance/administration and all clinical safety variables will be analyzed using the 
SAF-sub-study for the efficacy sub-study. 
LTS study 
The safety analysis set for the LTS study (SAF-LTS) includes all randomized patients in the 
overall study (randomized within either the efficacy sub-study or the main study) who received 
any study drug during the LTS study; it is based on the treatment-as-received (as treated).  
Patients who receive at least one dose of active fasinumab will be classified to the respective 
active treatment arm for the purpose of the analysis.  Treatment compliance/administration and 
all clinical safety variables will be analyzed using the SAF for the entire study. 
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3.3. 
Per Protocol Set 
Efficacy sub-study 
PPS will include all FAS-sub-study patients who do not have major protocol deviations through 
week 16.  The PPS will be used to perform sensitivity analyses for the primary and key secondary 
endpoints.  Patients with the following major protocol deviations will be excluded from the PPS: 
 Intolerance or Inadequate pain relief with analgesics assessment was not performed 
 Analgesic medications administered during the week 16 treatment period prohibited 
by protocol 
 Confirmed treatment unblinding that occurred in error.  
 Study drug administered without a randomization record per IVR. 
 Randomization without documented study eligibility 
3.4. 
The Pharmacokinetic Analysis Set  
The PK analysis set includes all treated patients who received any study drug and who had at 
least 1 non-missing drug concentration following the first dose of study drug. 
3.5. 
The Anti-drug antibody Analysis Set 
The ADA analysis set includes all treated patients who received any treatment and who had at 
least 1 non-missing post-dose ADA result. 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (e.g., age, sex, race, ethnicity, weight, 
height, etc.), disease characteristics including index joint, Kellgren-Lawrence score, WOMAC 
pain subscale score at screening, medical history, and medication history for each patient. 
The following demographic and baseline characteristic variables will be summarized by 
treatment group: 
 Age at screening (years) 
 Age category (<65, >=65 years) 
 Sex (Male, Female) 
 Race (American Indian/Alaskan Native, Asian, Black/African American, 
Native Hawaiian/Other Pacific Islander, White, and Other) 
 Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported) 
 Baseline Weight(kg) 
 Baseline Height(cm) 
 Baseline Body mass index (BMI) calculated from weight and height 
 Index Joint (Knee or Hip) 
 K-L score for the Index Joint 
 WOMAC pain score of the index joint at screening  
 Duration of OA at baseline 
 History of analgesic intolerance and inadequate pain relief  
Additional baseline characteristics will be summarized if needed.  
4.2. 
Medical History  
Medical history will be coded to a Preferred Term (PT) and associated primary System Organ 
Class (SOC) according to the latest available version of Medical Dictionary for Regulatory 
Activities (MedDRA®). 
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4.3. 
Prior/Concomitant Medications and Procedures, Prohibited 
Medication 
Medications/Procedures will be recorded from the day of informed consent until the End of 
Follow-up Clinic Visit.  Medications will be coded to the Anatomical Therapeutic Chemical 
(ATC) level 2 (therapeutic main group) and ATC level 4 (chemical/therapeutic subgroup), 
according to the latest available version of WHO Drug Dictionary (WHODD).  Patients will be 
counted once in all ATC categories linked to the medication. 
Medication/Procedure Classifications 
Prior medications/procedures are defined as medications/procedures starting prior to the first 
dose of study drug. 
Concomitant medications/procedures are defined as medications/procedures starting prior to or 
during each respective on-treatment period (as defined in Section 5.8) and ending during or after 
the respective on-treatment period. 
Post treatment medications/procedures are medications/procedures starting after the on-treatment 
period (as defined in Section 5.8). 
Prohibited Medication 
Patients were required to discontinue all non-study pain medication (oral or topical; except up to 
150 mg/day of aspirin/5-ASA, which is permitted for cardiac prophylaxis, per local guidelines) 
and opioid analgesic medications, starting at the pre-randomization phone call/visit. 
Analgesic medications (including tramadol) were prohibited through week 16. Patients were 
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) during treatment 
period 1. Patients could have taken non-NSAID standard-of-care therapy in addition to study 
drug, in the event of inadequate pain relief for OA pain, starting after the week 16 visit. Though 
use of oral NSAIDs should generally be avoided, a limited use is allowed after week 16 for 
non-OA related pain or fever after week 16. A list of medications containing NSAIDs will be 
provided in the study reference manual. The dose of oral NSAIDs may be increased and topical 
NSAIDs may be used during the follow-up period, but no earlier than 16 weeks after the last dose 
of study drug. 
Other excluded drugs during treatment period 1 are: 
 Medical marijuana 
 Hyaluronic Acid Intra-articular Injections 
 Cyclobenzaprine, carisoprodol, orphenadrine, tizanidine 
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For efficacy sub-study only during treatment period 1: 
 Glucosamine sulfate 
 Chondroitin sulfate 
Other excluded drugs during both treatment periods 1 and 2 are: 
 Any other investigational agent 
 Corticosteroids (topical and inhaled formulations are permitted) 
 Cyclosporine 
 Azathioprine 
 Tumor necrosis factor antagonists 
 IL-1 inhibitors, including diacerein 
 IL-6 or IL-6 receptor antagonists 
 Abatacept 
4.4. 
Efficacy Variables for the Efficacy sub-study 
4.4.1. 
Primary Efficacy Variable(s) 
The co-primary efficacy endpoints assessed for the efficacy sub-study only are: 
 Change from baseline to week 16 in the WOMAC pain subscale score 
 Change from baseline to week 16 in the WOMAC physical function subscale score 
4.4.2. 
Key Secondary Efficacy Variable(s) 
The key secondary efficacy endpoints assessed for the efficacy sub-study only are: 
 Change from baseline to week 16 in the Patient Global Assessment for OA score  
 Percentage of patients who had a response at week 16, with response defined as an 
improvement by ≥30% in WOMAC pain subscale score 
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4.4.3. 
Additional Secondary Efficacy Variable(s) 
The additional secondary efficacy endpoints to be assessed in the efficacy sub-study only are: 
 Change from baseline to week 16 in the average weekly walking index joint pain 
using the NRS pain scale 
4.5. 
Safety Variables 
Patient safety will be assessed through the collection of reported adverse events (AEs), clinical 
laboratory data, vital signs, ECG, Survey of Autonomic Symptoms Questionnaire, neurological 
exams and physical exams.  Unless otherwise noted, the baseline value is defined as the last 
available value before the first dose of study drug. 
Adverse events (AE) and Serious Adverse Events (SAE) will be collected from the time of 
informed consent signature and then at each visit until the End of Follow-up Clinic Visit.  All 
AEs are to be coded to a “Preferred Term (PT)” and associated primary “System Organ Class 
SOC” according to the MedDRA® (the latest current available version). 
An Adverse Event is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
A Serious Adverse Event is an adverse event (AE) that is classified as serious according to the 
criteria specified in the protocol. 
Laboratory results, vital signs, or ECG abnormalities are to be recorded as AEs if they are 
medically relevant: symptomatic, requiring corrective therapy, leading to treatment 
discontinuation and/or fulfilling a seriousness criterion. 
4.5.1. 
Primary Safety Variables 
The primary safety endpoint in the study is safety monitoring including AE incidence, SAE, 
incidence, AESI incidence, changes in safety lab analyses, and incidence of anti-fasinumab 
antibody formation from baseline to week 52 (treatment period 1 and 2) and to week 72 (end of 
follow-up period). 
More specifically, this includes: 
 Incidence of adjudicated arthropathy events 
 Incidence of destructive arthropathy events 
 Incidence of JR (All JRs and AESI JRs) events – including endpoint for all JRs by the 
telephone survey approximately 52 weeks after the last dose of study drug 
 Incidence of peripheral neurosensory AESI events 
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 Incidence of sympathetic nervous system dysfunction AESI events 
 AE incidence, SAE incidence, changes from baseline in safety laboratory analyses, 
and incidence of anti-fasinumab antibody formation 
 Change from baseline in minimum joint space width of the index joint (knee, hip) 
 Incidence of confirmed orthostatic hypotension from baseline 
The raw incidence rate is defined as the number of events divided by the duration of the 
observation period and presented as number of events per 100 patient-years. 
4.5.2. 
Exploratory Safety Variables 
Exploratory safety endpoints include: 
 The proportion of patients taking rescue medication, number of days on rescue 
medication, and weekly average usage of rescue medication from baseline to week 16 
and from baseline to week 52 
 The percent of patients using standard-of-care analgesic medication from week 16 to 
week 52 
 Time to joint replacement (JR) decision 
 Survey of Autonomic Symptom scores from baseline to week 52 and from baseline to 
week 72 
 Time to AA, time to DA 
4.5.3. 
Adverse Events of Special Interest 
An AESI (serious or non-serious) is one of scientific and medical concern specific to the 
sponsor’s product or program, for which ongoing monitoring and rapid communication by the 
investigator to the sponsor can be appropriate. 
AESI are selected using e-CRF specific tick box on the AE page. 
Events considered to be AESIs for the study are: 
 Adjudicated arthropathy (as confirmed by adjudication) 
 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 
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 JR surgery (AESI defined in Protocol Section 7.6.1.4 as elective JR surgery not due to 
new or worsening disease) 
4.5.4. 
Laboratory Safety Variables 
The clinical laboratory tests include blood chemistry, hematology, urinalysis, urine chemistries, 
hs-CRP, and others.  Samples for laboratory testing will be collected at the time points specified 
in the Schedule of Events (Appendix 11.1).  Clinical laboratory values will be in standard 
international (SI) units, including associated normal ranges provided by the central laboratory, 
and grouped by function in summary tables.  Clinical laboratory values in conventional (US) 
units will also be available in the database, with associated normal ranges. 
Both actual test values and “change from baseline” values (defined as the post-baseline value 
minus the baseline value) will be used in central lab result summaries.  Potentially clinically 
significant values (PCSV) ranges will be applied to central lab test values as applicable (see 
Appendix 11.2 for PCSV definitions).  
4.5.5. 
Biomarker variables 
Biomarker analysis will be performed in a separate biomarker SAP. 
4.5.6. 
Vital Signs 
The following vital signs parameters will be collected at according to the Schedule of Events in 
Appendix 11.1: 
 Body temperature (oC) 
 Sitting/supine/standing/orthostatic systolic and diastolic blood pressures (mmHg) and 
pulse (bpm) 
 Respiratory rate (bpm) 
Both actual values and “change from baseline” values (defined as the post-baseline value minus 
the baseline value) will be used in the result summaries.  Potentially clinically significant values 
(PCSV) ranges will be applied to the vital sign parameter values as applicable (see 
Appendix 11.2 for PCSV definitions). 
4.5.7. 
Orthostatic Hypotension  
A patient will be determined to have orthostatic hypotension if any of the following criteria are 
met: 
 If the supine blood pressure is <160 mmHg systolic, a decrease in either the 1 or 
3 minute standing systolic blood pressure of ≥20 mmHg or a decrease in the standing 
diastolic blood pressure of ≥10 mmHg from the supine systolic or diastolic blood 
pressure 
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OR 
 If the supine blood pressure is ≥160 mmHg systolic, a decrease in either the 1 or 
3-minute standing systolic blood pressure of ≥30 mmHg or a decrease in the standing 
diastolic blood pressure of ≥15 mmHg from the supine systolic or diastolic blood 
pressure 
OR 
 An increase in either the 1 or 3-minute standing heart rate of ≥30 bpm from the supine 
heart rate 
OR 
 The patient is unable to stand for either one of the standing blood pressure 
measurements due to dizziness or lightheadedness 
Confirmed orthostatic hypotension is defined as initial assessment meeting the above orthostatic 
hypotension criteria confirmed by subsequent repeated assessments per protocol or if initial 
assessment met the above orthostatic hypotension criteria yet repeated assessments were not 
performed. 
4.5.8. 
12-Lead Electrocardiography 
A standard 12-lead ECG will be performed according to the Schedule of Events in 
Appendix 11.1 with the patient in the supine position for approximately 5 minutes and prior to 
blood samples being drawn.  Heart rate will be recorded from the ventricular rate and the PR, 
QRS, and QT, QTc intervals, and ECG status (normal, abnormal not clinical significant or 
abnormal clinical significant) will also be recorded.  
QTcF and QTcB are defined as follows:  
QTcF (ms) =QT/RR1/3 and QTcB (ms) =QT/RR1/2, 
where QT is the uncorrected QT interval measured in ms, and RR is 60/HR with HR being the 
heart rate in beats per minute.  
Potentially clinically significant values (PCSV) ranges will be applied to the ECG parameter 
values as applicable (see Appendix 11.2 for PCSV definitions). 
4.5.9. 
Physical and Neurological Examination Variables 
Patients will have a physical examination including an examination of the knees, hips, and 
shoulders performed according to the Schedule of Events in Appendix 11.1.  The result for each 
body system is an outcome of normal or abnormal.  Neurological evaluations of specific domains 
as listed in the protocol will be described as normal or abnormal. 
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4.5.10. 
Other Safety Variables 
 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 
 Joint replacement: 
 number and percentage of patients with joint replacement (all JRs) 
 time to joint replacement decision (all JRs) 
4.6. 
Pharmacokinetic Variables 
The Pharmacokinetic (PK) variable will be fasinumab concentrations in serum at specified 
sampling time points. 
4.7. 
Anti-Drug Antibody Variables 
Samples for Anti-Drug Antibody (ADA) evaluation will be collected at baseline and at 
subsequent study visits. 
Anti-drug antibody variables will include ADA status (positive or negative) and titer as follows: 
 Total subjects negative in the ADA assay at all time points analyzed 
 Pre-existing immunoreactivity - a positive ADA response at baseline with all 
post-dose ADA results negative, or a positive ADA response at baseline with all 
post-dose ADA responses less than 9-fold over baseline titer levels. 
 Treatment emergent - defined as any post-dose positive ADA response when baseline 
results are negative 
 Persistent - A positive result in the ADA assay detected in at least 2 consecutive 
post baseline samples separated by at least a 16-week post baseline period [based 
on nominal sampling time], with no ADA-negative results in-between, regardless 
of any missing samples 
 Indeterminate - A positive result in the ADA assay at the last collection time point 
analyzed only, regardless of any missing samples 
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 Transient - Not persistent or indeterminate regardless of any missing samples 
 Treatment boosted - defined as any post-dose positive ADA response that is at least 
9-fold over the baseline level when baseline is positive in the ADA assay 
 Titer Values 
 Titer category: low (titer <1,000); moderate (1,000≤ titer ≤10,000); high 
(titer >10,000) 
 Neutralizing ADA activity for samples positive in the ADA assay 
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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 (SD), minimum, maximum, 
and the first and third quartiles (Q1 and Q3). 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
5.1. 
Statistical Methods for Long-Term Safety Study 
5.1.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be descriptively summarized by treatment group, 
combined fasinumab, and overall based on the FAS-LTS.  Parameters to be summarized include 
those described in Section 4.1. 
5.1.2. 
Medical History 
Medical history will be descriptively summarized by treatment group, combined fasinumab and 
overall for the FAS-LTS. Summaries will show patient counts (percentages) by primary SOC and 
PT.  The tables will be sorted by decreasing frequency of primary SOC in the overall group.  
Within each primary SOC, PTs will be sorted by decreasing frequency in the overall group. 
5.1.3. 
Prior / Concomitant Medications 
Prior Medications 
All prior medications, dictionary coded by WHO, will be descriptively summarized by treatment 
group, and combined fasinumab based on the FAS-LTS.  Summaries will present patient counts 
(and percentages) for all prior medications, by decreasing frequency of the overall group 
incidence 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. 
Concomitant Medications 
All concomitant medications, dictionary coded by WHO, will be descriptively summarized by 
treatment group, and combined fasinumab based on the SAF-LTS.  Summaries will present 
patient counts (and percentages) for the concomitant medication groups described in Section 4.3 
for all concomitant medications, by decreasing frequency of the combined fasinumab group 
incidence 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, hence 
may be counted several times for the same medication. 
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The following will be summarized: 
 Prior Medications 
 Concomitant medications 
 Post-treatment medications 
 On-study (Concomitant + Post-Treatment) Medications 
When medication start/end date is missing, the rules for determining whether a medication is 
prior, concomitant, or post-treatment, are specified in Section 6.3. 
5.1.4. 
Prohibited Medications 
Number and percentage of patients with prohibited medications will be descriptively summarized 
by treatment group, and combined fasinumab based on the SAF-LTS.  The tables will be sorted 
by decreasing frequency of ATC Level 2, ATC Level 4, and preferred term in the combined 
fasinumab group. 
The number of patients with NSAID use during treatment period 1 will be summarized by 
treatment group, and combined fasinumab.  Additionally, the number of patients with more than 
the limited amount of NSAID use during treatment period 2 will be summarized by treatment 
group, and combined fasinumab for patients in the SAF-LTS. 
Total NSAIDs-use days during each treatment period and follow-up (before AA for patients with 
AA) will be summarized by treatment group, and combined fasinumab for patients in the 
SAF-LTS.  Additionally, days from last study drug dose to first NSAID dose will be summarized 
by treatment group, and combined fasinumab for patients in the SAF-LTS. 
5.1.5. 
Patient Disposition 
The disposition of patients in the study will be summarized by treatment group, combined 
fasinumab and overall for FAS-LTS.  
5.1.5.1. 
Screening Disposition 
Percentages will be calculated using the number of screened patients as the denominator. 
 Screened patients (defined as having signed the ICF).  
 Patients randomized (defined in the protocol as having received a randomization 
number per IVRS). 
 Patients did not meet inclusion/exclusion criteria but randomized (if applicable). 
 Patients treated but not randomized (if applicable).  
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 Screen Fail patients.  Reason for screen failure will be provided. 
5.1.5.2. 
LTS study Disposition 
 Unless otherwise noted, percentages will be calculated using the number of patients in 
FAS-LTS as the denominator.  This will be summarized by treatment group, 
combined fasinumab, and overall for the LTS study.  Kaplan-Meier plot of time to 
treatment discontinuation will be provided. Summaries will provide the frequency 
(and percentage as applicable) of patients that met the criteria for the following 
variables: 
 Patients randomized (defined as having received a randomization number). This row 
will reflect grouping based on randomization assignment.  
 Patients randomized but not treated. This row will reflect grouping based on 
randomization assignment.  
 Patients randomized and treated. 
 Patients who completed the study, patients who withdrew from the study and reason 
for study withdrawal. 
 Patients who completed study treatment, patients who discontinued treatment and 
reason for treatment discontinuation. 
5.1.5.3. 
Analysis Set 
Summary of the number (and percentage) of patients in each analysis set) will be by treatment 
group, combined fasinumab, and overall for the LTS. 
Additionally, the following listings will be provided (if applicable):  
 Listing of Patients Treated but not Randomized. 
 Listing of Patients Randomized but not Treated. 
 Listing of Patients Randomized but not Treated with the Randomized treatment. 
 Listing of Patient Disposition for all Randomized Patients. 
 Listing of Screening Failures and reasons for all screen failed patients. 
5.1.6. 
Extent of Study Treatment Exposure and Compliance  
The analysis population for the entire LTS study is based on the SAF-LTS. 
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5.1.6.1. 
Measurement of Treatment Compliance  
Compliance with protocol-defined investigational product will be calculated by treatment group 
and combined fasinumab as follows:  
 (Number of actual injections of study drug during the LTS study exposure period) / 
(Number of planned injections of study drug during the LTS study exposure period on 
or before the time that the patient discontinues from the treatment phase of the 
study) x 100% 
Treatment compliance will be presented by descriptive statistics as well as the number (%) of 
patients who have: 
 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 SC injections (for the entire LTS study)  
5.1.6.2. 
Exposure to Investigational Product 
The treatment exposure to fasinumab and placebo SC doses will be calculated as:  
 (Date of last study drug dose – date of first study dose) + 28  
The duration of exposure in will be summarized for each treatment group using the number of 
patients (n), mean, standard deviation, median, Q1, Q3, minimum, and maximum. 
The number (%) of patients with exposure duration periods will be presented by specific time 
periods.  The time periods of interest are specified as: ≥ 1 day, ≥ 29 days, ≥ 57 days, ≥ 85 days, 
≥ 113 days, ≥ 141 days, ≥ 169 days, ≥ 197 days, ≥ 225 days, ≥ 253 days, ≥ 281 days, ≥ 309 days, 
≥ 337 days 
5.1.6.3. 
Length of Study Observation 
The length of the observation period (days) will be calculated as: 
 (Date of last study visit [up to End of Follow-up Clinic Visit] – date of first study 
drug dose) +1. 
The length of the total study observation period (days) will be calculated as: 
 (Date of last study visit [up to End of Study Phone call] – date of first study drug 
dose) +1. 
The observation duration will be summarized for each treatment group using the number of 
patients (n), mean, standard deviation, median, Q1, Q3, minimum, and maximum. 
The number (%) of patients with observation periods will be presented by specific time periods.  
The time periods of interest are specified as: ≥ 1 day, ≥ 29 days, ≥ 57 days, ≥ 85 days, 
≥ 113 days, ≥ 141 days, ≥ 169 days, ≥ 197 days, ≥ 225 days, ≥ 253 days, ≥ 281 days, ≥ 309 days, 
≥ 337 days, ≥ 365 days, ≥ 393 days, ≥ 421 days, ≥ 505 days, ≥ 701 days 
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5.1.6.4. 
Protocol Deviations 
All major and minor protocol deviations have been collected and reviewed on an ongoing basis 
throughout the study as described in the Protocol Deviation Definitions Document (PDDD). 
Protocol deviations will be summarized for patients incurring any major deviation by count and 
percentage, and patients incurring each type of major deviation by count and percentage for 
FAS-LTS. 
A patient listing of all major and minor protocol deviations will be provided. 
5.1.7. 
Analysis of Safety Data 
The analysis of safety and tolerability will be performed on the SAF-LTS, as defined in 
Section 3.2. 
The safety analysis will be based on the reported AEs and other safety information (clinical 
laboratory evaluations, vital signs, 12-lead ECG, Physical Examination, etc.). 
Treatment-Emergent Potential Clinically Significant Values (PCSV) in laboratory variables, vital 
signs and ECG are defined in Appendix 11.2. 
Period of observation: The observation period will be divided into three segments: 
pre-treatment, on-treatment and post-treatment.  
 The pre-treatment period is defined as the time between when the patients give 
informed consent and the start of study drug.  
 The LTS on-treatment period is defined as the time from first dose of study drug up to 
28 days after the last dose of study drug.  The LTS post-treatment period is defined as 
the time starting 29 days after last dose of study drug (after the on-treatment period) to 
up to 24 weeks post the last dose of study drug (up to week 72). 
Day 1 is the first day of study drug, Day –1 is the day before Day 1, and there is no Day 0. 
The time interval to detect any on-treatment event or abnormality is between the first dose of 
double-blind study drug injection and the end of treatment plus 28 days.  Data collected outside 
this interval will be excluded from the estimation of descriptive statistics and identification of 
abnormalities for laboratory evaluations, ECGs and vital signs.  All post-baseline data during the 
interval will be using in the PCSV analysis including scheduled and unscheduled assessments. 
5.1.7.1. 
Primary Safety Endpoints 
Incidence rate ratio estimates and 2-sided 95% confidence interval will be computed using 
Generalized Estimating Equations with a log-linked Poisson model via the PROC GENMOD 
procedure if there are events in the placebo group.  The model will specify the use of a Poisson 
probability distribution with an offset= log (patient-observation period days) and model terms for 
treatment-as-received and each randomization strata.  The 95% confidence interval for the 
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estimates of the difference in incidence rates will be computed using the same model.  If there is 
no event in the placebo group, incidence rate ratio will not be calculated and confidence intervals 
for the incidence rate difference will be computed using Wald method.  The incidence rate 
estimates for each arm, the estimates of the incidence rate ratio and incidence rate difference 
between fasinumab and placebo will be provided with the corresponding 95% confidence 
interval. 
AE and SAE incidence will be summarized by treatment group based on the SAF-LTS by 
treatment group and combined fasinumab group. 
Continuous variables will be summarized by baseline and change from baseline to each 
scheduled assessment time with descriptive statistics based on the SAF-LTS by treatment group 
and combined fasinumab group. 
5.1.8. 
Exploratory Safety Endpoints 
Other safety endpoints in the study are:  
 The proportion of patients taking rescue medication, number of days on rescue 
medication, and weekly average usage of rescue medication 
 The percent of patients using standard-of-care analgesic medication from week 16 to 
week 52 
 Time to JR decision 
 Survey of Autonomic Symptoms Scores: 
 number of patients reporting health symptoms for each symptom/health problem 
assessed at each scheduled visit  
 number of symptoms reported and total symptom impact score at each scheduled 
visit  
 Time to AA, time to DA 
The exploratory safety variables comparing incidence rate of each fasinumab dose group and 
placebo will be analyzed using the same method as the primary safety endpoints. 
The exploratory safety variables comparing change from baseline scores of each fasinumab dose 
group and placebo will be analyzed using the same method as the primary safety endpoints. 
Time to event endpoints will be analyzed using Kaplan-Meier approach and Cox regression will 
be used for comparing each fasinumab dose group and placebo by obtaining hazard ratios and 
their confidence intervals.  The Cox regression model will include the fixed categorical effects of 
treatment-as-received and randomization strata. 
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Additionally, sensitivity analysis of the primary endpoint of incidence of destructive arthropathy 
as well as incidence of DA and JRs will be analyzed excluding patients who used NSAID during 
the trial.  
Rescue Medication 
The percentage of patients who use rescue medication between baseline and week 16 will be 
summarized by the treatment group for FAS-LTS.  
Number of days patients used rescue medication during the treatment period (Day1 to Week 2, 
Week 2 to Week 4, Week 4 to Week 8, Week 8 to Week 12, Week 12 to Week 16...) will be 
summarized descriptively by treatment group. Weekly average amount of rescue medication use 
will be summarized by treatment group. 
5.1.8.1. 
Adverse Events  
The verbatim text, the preferred term, and the primary SOC will be listed in patient listings. 
Summaries that include frequencies and proportions of patients reporting AEs will include the 
preferred terms and the SOCs. 
 Pre-Treatment Adverse Events are defined as AEs that developed or worsened during 
the pre-treatment period. 
 Treatment-Emergent Adverse Events (TEAE) are defined as those that are not present 
at baseline or represent the exacerbation of a pre-existing condition during the 
on-treatment period. 
 Post-Treatment Adverse Events are defined as AEs that developed or worsened more 
than 28 days after the last dose of study drug. 
The focus of adverse event reporting in the clinical study report will be on TEAEs. 
Post-treatment AEs and AEs during the study will be summarized similarly as TEAEs. 
Summaries of TEAEs by treatment group will include: 
 Overview of TEAEs, summarizing number of events, summarizing number and 
percentage of patients within the specified category 
 Total number of TEAEs 
 Total number of Serious TEAEs 
 Patients with any TEAEs 
 Patients with any Serious TEAEs 
 Patients with any TEAEs leading to death 
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 Patients with any TEAEs leading to withdrawal from study 
 Patients with any TEAEs leading to permanent study treatment discontinuation 
 All TEAEs by SOC and PT 
 All TEAEs by SOC, PT, severity 
 Study drug related TEAEs by SOC and PT 
 TEAEs resulting in Permanent Study Drug Discontinuation by SOC and PT 
 AESI by SOC and PT 
 Serious TEAEs by SOC and PT 
 Non-serious TEAEs by SOC and PT  
Listing to include: 
 Listing of AEs leading to death  
 Listing of TEAEs leading to permanent study treatment discontinuation 
 Listing of TEAEs leading to withdrawal from study 
 Listing of Patients with Serious TEAEs  
 Listing of Patients with AESIs 
 Listing of all Joint Replacements 
Counts will be provided according to treatment group and combined fasinumab group for each 
PT within each primary SOC.  Percentages will be calculated based on the SAF-LTS in each 
treatment group. 
Primary SOCs will be sorted by decreasing frequency in the combined fasinumab group.  Within 
each primary SOC, PTs will be sorted by decreasing frequency in the combined fasinumab group. 
For tables presenting severity of events, the worst severity will be chosen for patients with 
multiple instances of the same event. 
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.  TEAEs with preferred terms ≥5% in any treatment group will be summarized in the 
report. 
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5.1.8.2. 
Adverse Events of Special Interest 
AESIs will be listed and summarized by treatment group based on the SAF-LTS. Differences in 
event rate for AESIs between fasinumab and placebo will be estimated using exact binomial 
confidence intervals. 
Radiograph data related to AA including change from baseline in joint space width will be 
summarized by SAF over time.  Within index type, Knee Society Score questionnaire or Harris 
Hip Score questionnaire results will be listed. 
5.1.8.3. 
Clinical Laboratory Measurements  
Laboratory test results will be summarized by baseline and change from baseline to each 
scheduled assessment time with descriptive statistics based on the SAF-LTS by treatment group 
and combined fasinumab group. 
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. 
A Treatment-Emergent Potential Clinically Significant abnormal value (PCSV) is a laboratory 
value that was normal at Screening and Baseline but became abnormal and met PCSV criteria 
after treatment with study drug.  Definition of PCSV is listed in Appendix 11.2.  Treatment 
Emergent Potentially clinically significant values (PCSVs) will be summarized based on the 
SAF-LTS by treatment group and combined fasinumab group. Additional exploratory analyses 
using alternative cut-points may be conducted. 
For hs-CRP, plots of means and medians of the observed values and change from baseline over 
time will presented by treatment group. 
For hs-CRP, subgroup analysis will be performed for the following: 
 Baseline hs-CRP ( [0 – 3], [>3 -10], [>10] ) 
 Adjudicated Arthropathy category 1 (patients without / with AA)  
 Adjudicated Arthropathy category 2 (patients without AA, patients with RPOA-1, and 
patients with non-RPOA-1 AA) 
 Destructive Arthropathy category (patients without AA, patients with non-DA AA, 
patients with DA) 
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5.1.8.4. 
Analysis of Vital Signs 
Vital signs (temperature, pulse, blood pressure, orthostatic blood pressure/heart rate, and 
respiration rate) will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics by treatment group and combined fasinumab for the 
SAF-LTS. 
PCSV summary including orthostatic hypotension will be constructed for on-treatment period, 
post-treatment period and overall during the LTS study. 
5.1.8.5. 
Analysis of 12-Lead ECG 
ECG parameters (Ventricular Rate, PR Interval, QRS Interval, QT Interval, RR Interval, QTcF 
QTcB interval) will be summarized by baseline and change from baseline to each scheduled and 
collected assessment time.  PCSV summary of ECG parameters will be provided for 
on-treatment period (for LTS study), post-treatment period, and overall for the SAF-LTS.  
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. 
5.1.8.6. 
Physical Exams 
The number and percentage of patients with new-onset abnormal physical examinations will be 
summarized by body system by visit based on the SAF-LTS. 
5.1.8.7. 
Joint Pain Questionnaire 
The number and percentage of patients with significantly worse joint pain will be summarized by 
visit and joint based on the SAF-LTS. 
5.1.8.8. 
Arthropathy Adjudications 
The number and percentage of patients with images requiring arthropathy adjudication as well as 
the number and percentage of those patients with confirmed adjudicated arthropathy will be 
summarized by based on the SAF-LTS. Subtypes of AAs and outcomes of AAs will also be 
summarized. Patient listings of cases confirmed by adjudication will be provided. 
5.1.8.9. 
Neurological Exam 
The number and percentage of patients with new-onset abnormal neurological examinations will 
be summarized by Neurological evaluations by visit based on the LTS-SAF. 
5.1.8.10. Analysis of Pharmacokinetics and Drug Concentration Data 
Summaries of concentrations of functional fasinumab will be presented by nominal time point 
and dose. Plots of mean or median concentration of functional fasinumab will be presented by 
nominal day and dose. 
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5.1.9. 
Analysis of Anti-Drug Antibody Data 
The ADA variables described in Section 4.7 will be summarized using descriptive statistics by 
dose/cohort group in the ADA analysis set. Prevalence of treatment-emergent and 
treatment-boosted ADA will be assessed as absolute occurrence (N) and percent of patients (%), 
grouped by study cohorts. For treatment emergent ADA, occurrence (N) and percent of patients 
(%) with persistent, transient and indeterminate ADA will be reported. The influence of 
treatment-emergent or treatment-boosted ADA assay response on individual PK profiles may be 
evaluated.  
Listings of ADA positivity and titers presented by patient, time point, and dose cohort/group will 
also be provided.  
Correlation analysis of safety versus treatment-emergent ADA positivity status may be performed 
on the SAF. Assessment will focus on the following safety events:  
 Hypersensitivity (SMQ: Hypersensitivity [Narrow])  
 Anaphylaxis (SMQ: Anaphylaxis[Narrow])  
Number (%) of patients with the above-mentioned safety events may be summarized by 
treatment-emergent ADA positivity status, during the TEAE period. 
In addition, correlation analysis of key efficacy endpoints versus treatment-emergent ADA status 
in patients who discontinued due to lack of efficacy may be summarized. 
5.2. 
Statistical Methods for Efficacy Sub-Study 
5.2.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be descriptively summarized by treatment group, 
combined fasinumab, and overall based on the FAS-substudy. Parameters to be summarized 
include those described in Section 4.1. 
5.2.2. 
Medical History 
Medical history will be descriptively summarized by treatment group, combined fasinumab, and 
overall based on the FAS-substudy. 
5.2.3. 
Prior / Concomitant Medications 
Prior Medications 
All prior medications, dictionary coded by WHO, will be descriptively summarized by treatment 
group, and combined fasinumab based on the FAS-substudy similar to the summary for 
FAS-LTS.  
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Concomitant Medications 
All concomitant medications, dictionary coded by WHO, will be descriptively summarized by 
treatment group, and combined fasinumab based on the SAF-substudy similar to the summary for 
FAS-LTS. 
5.2.4. 
Prohibited Medications 
Number and percentage of patients with prohibited medications will be descriptively summarized 
by treatment group, and combined fasinumab based on the SAF-substudy. 
The number of patients with NSAID use during treatment period 1 will be summarized by 
treatment group, and combined fasinumab. 
5.2.5. 
Patient Disposition 
The disposition of patients in the sub-study will be summarized by treatment group, combined 
fasinumab, and overall for FAS-Substudy.  
 Unless otherwise noted, percentages will be calculated using the number of patients 
randomized in FAS-substudy as the denominator. This will be summarized by 
treatment group, combined fasinumab, and overall for the efficacy sub-study. 
Kaplan-Meier plot of time to treatment discontinuation will be provided. Summaries 
will provide the frequency (and percentage as applicable) of patients that met the 
criteria for the following variables: 
 Patients randomized (defined as having received a randomization number). This row 
will reflect grouping based on randomization assignment.  
 Patients randomized but not treated. This row will reflect grouping based on 
randomization assignment. 
 Patients randomized and treated. 
 Patients who completed treatment period 1.  Reason for treatment discontinuation 
during the efficacy sub study and efficacy sub-study withdrawal will be provided. 
5.2.5.1. 
Analysis Set 
Summary of the number (and percentage) of patients in each analysis set will be by treatment 
group, combined fasinumab, and overall for the efficacy sub-study. 
Additionally, the following listings will be provided (if applicable):  
 Listing of Patients Treated but not Randomized. 
 Listing of Patients Randomized but not Treated. 
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 Listing of Patients Randomized but not Treated with the Randomized treatment. 
 Listing of Patient Disposition for all Randomized Patients. 
 Listing of Screening Failures and reasons for all screen failed patients. 
5.2.6. 
Extent of Study Treatment Exposure and Compliance  
The analysis population for the efficacy sub-study is based on the SAF-substudy. 
5.2.6.1. 
Measurement of Treatment Compliance  
Compliance with protocol-defined investigational product will be calculated by treatment group 
and combined fasinumab as follows:  
(Number of actual injections of study drug during the efficacy sub-study exposure period) / 
(Number of planned injections of study drug during the efficacy sub-study exposure period on or 
before the time that the patient discontinues from the efficacy sub-study) x 100% 
Treatment compliance will be presented by descriptive statistics as well as the number (%) of 
patients who have: 
 1, 2, 3, and 4 SC injections (for the efficacy sub-study)  
5.2.6.2. 
Exposure to Investigational Product 
The treatment exposure to fasinumab and placebo SC doses will be calculated as:  
 (Date of last efficacy sub-study drug dose – date of first study drug dose) + 28  
The duration of exposure in will be summarized for each treatment group using the number of 
patients (n), mean, standard deviation, median, Q1, Q3, minimum, and maximum. 
The number (%) of patients with exposure duration periods will be presented by specific time 
periods.  The time periods of interest are specified as:  ≥ 1 day, ≥ 29 days, ≥ 57 days, and 
≥ 85 days 
5.2.6.3. 
Length of sub study Observation 
The length of the sub study observation (days) will be calculated as: (Date of last efficacy 
sub-study visit [up to week 16] – date of first study drug dose) +1 
The observation duration will be summarized for each treatment group using the number of patients 
(n), mean, standard deviation, median, Q1, Q3, minimum, and maximum. 
The number (%) of patients with observation periods will be presented by specific time periods.  The 
time periods of interest are specified as: ≥ 1 day, ≥ 29 days, ≥ 57 days, ≥85 days, and ≥ 113 days  
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5.2.6.4. 
Protocol Deviations 
Protocol deviations will be summarized for patients incurring any major deviation by count and 
percentage, and patients incurring each type of major deviation by count and percentage for 
FAS-Substudy. Protocol deviations leading to exclusion from the PPS for the efficacy sub-study 
(see Section 3.3 for definition) will be summarized for any patients incurring any such deviation 
by count and percentage, and patients incurring each type of deviation by count and percentage. 
5.2.7. 
Analysis of Efficacy Data 
5.2.7.1. 
Analysis of Primary Efficacy Variable(s) 
5.2.7.1.1. Primary Efficacy Analysis 
The co-primary efficacy endpoints in the efficacy sub-study are: 
 Change from baseline to week 16 in the WOMAC pain subscale score 
 Change from baseline to week 16 in the WOMAC physical function subscale score 
The primary treatment comparison for the WOMAC pain subscale score as well as the WOMAC 
physical function subscale score is declared superior only if the comparisons are significant for 
both WOMAC pain and physical function subscale scores at any of the allowed doses.  Hence 
there are 6 hypotheses to be tested between the primary and key secondary endpoints.  A 
hierarchical procedure will be used to control the overall Type-1 error rate at 0.05 for the 
2 co-primary endpoints and the secondary endpoints across the 2 dose regimens. Each hypothesis 
will be formally tested only if the preceding one is significant at the 2-sided 0.05 significance 
level.  The hierarchical testing order for the 6 hypothesis is as follows: 
 H11:  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 a 
treatment difference in WOMAC pain and physical function subscale scores at 
week 16 
 H12:  There is no treatment difference between fasinumab 1 mg Q4W and placebo in 
Patient Global Assessment score at week 16 versus there is a treatment difference in 
Patient Global Assessment score at week 16 
 H13:  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 a treatment difference in proportion of patients with 
≥30% improvement in WOMAC pain at week 16 
 H21:  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 a 
treatment difference in WOMAC pain and physical function subscale scores at 
week 16 
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 H22:  There is no treatment difference between fasinumab 1 mg Q8W and placebo in 
Patient Global Assessment score at week 16 versus there is a treatment difference in 
Patient Global Assessment score at week 16 
 H23:  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 a treatment difference in proportion of patients with 
≥30% improvement in WOMAC pain at week 16 
The estimand for the primary efficacy objective is the difference in means between each 
fasinumab dose+protocol-defined rescue medication and placebo+protocol-defined rescue 
medication in the change from baseline to week 16 in the WOMAC pain and physical function 
scores in the FAS-substudy, regardless of whether or not prohibited medication had been taken.  
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.  The missing data for patients 
who discontinued treatment due to lack of efficacy or AEs will be imputed with values centered 
at the mean baseline value of the treatment group that patients were randomized to.  The missing 
data for patients discontinued treatment due to other reasons will be imputed under 
missing-at-random assumption using the regression method with adjustment for covariates 
including treatment group, randomization strata, and baseline score. Intermittently missing data 
will be imputed using Markov Chain Monte Carlo method. 
The primary efficacy variables will be analyzed using a multiple imputation approach with 
mixed-effect model for repeated measure (MMRM) based on the FAS-substudy with adjustment 
for missing data due to treatment discontinuation for the reasons of lack of efficacy or AEs 
assuming the WOMAC scores would on average return to baseline values.  Missing data up to 
week 16 will be imputed 50 times to generate 50 complete data sets by using the SAS procedure 
PROC MI following the 3 steps below: 
 Step 1: 
The monotone missing pattern is induced by Markov Chain Monte Carlo 
(MCMC) method in MI procedure using seed number 
 
 Step 2: 
The missing data at subsequent visits will be imputed using the regression 
method for the monotone pattern with seed number 
and adjustment for 
covariates including treatment groups, randomization strata, relevant baseline and all 
values at preceding visits. 
 Step 3: 
The initially missing and now imputed data for patients discontinued from 
the study treatment due to lack of efficacy or AEs will be adjusted to be centered at 
the mean baseline value for that treatment group, i.e., final imputed score = imputed 
score under MAR - (mean change from baseline score at the post-baseline time point 
for the treatment group based on patients on treatment with non-missing data at that 
time point). 
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Each imputed data set will be analyzed using the MMRM with terms for baseline score 
corresponding to the primary efficacy variable (e.g. WOMAC pain subscale score at baseline for 
the analysis of change from baseline in WOMAC pain subscale score), treatment, randomization 
strata, visit, and treatment by visit interaction. The MMRM will be performed using the MIXED 
procedure in the 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 difference of the estimates between fasinumab and placebo, 
with the corresponding standard error, p-value and associated 95% confidence 
interval will be provided. 
5.2.7.1.2. Sensitivity Analyses 
Sensitivity analyses will be performed to assess the robustness of the results generated for the 
primary efficacy variables. 
Analysis of Treatment Policy Estimand 
Sensitivity analysis of treatment policy estimand for the co-primary endpoints will be performed 
using similar analysis method as the primary efficacy analysis.  The treatment policy estimand is 
the difference in means between each fasinumab dose+protocol-defined rescue medication and 
placebo+protocol-defined rescue medication in the change from baseline to week 16 in the 
WOMAC pain and physical function scores in the FAS-substudy, regardless of study treatment 
discontinuation prior to week 16 and regardless of whether or not prohibited medication had been 
taken.  Hence, data from all patients, including data collected after discontinuing treatment up to 
week 16 will be used in this sensitivity analyses. Missing data for patients discontinued from the 
study up to week 16 will be imputed assuming the WOMAC scores would on average return to 
baseline values using the same approach as in Section 5.2.7.1.1. 
Tipping Point Analysis 
Sensitivity analysis using a tipping point approach with multiple imputation will be performed to 
assess the robustness of the results due to data that may be missing not-at-random (MNAR). 
This approach will introduce a sensitivity parameter, δ, corresponding to a percentage (e.g., 20%, 
40%, …, 100%, 200%, ...) of the treatment effect at each corresponding visit.  Estimations will be 
performed using multiple imputation methodology.  Missing data up to week 16 time-point 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
. 
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 Step 2: The missing data at subsequent visits will be imputed using the regression 
method for the monotone pattern with seed number 
 and adjustment for 
covariates including treatment groups, randomization strata, relevant baseline and 
values from preceding visits. For missing data due to adverse events 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 the MMRM model with treatment, randomization 
strata, and relevant baseline included in the model. 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 0.0167, 0.0333 
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 MMRM approach. 
Subgroup Analysis 
Descriptive analyses will be performed on the primary endpoints and key secondary endpoint of 
PGA to summarize the treatment effects across subpopulations defined by baseline 
randomization strata (index joint and K-L score category), demographics (age group, sex, race) 
and baseline characteristics (weight and BMI categories). Subgroup analysis based on other 
medical conditions may also be performed. Forest plots for the subgroup analysis will be 
provided. 
5.2.7.2. 
Analysis of Key Secondary Efficacy Variable(s) 
Analyses of continuous variables in key secondary endpoints will use the same analysis method 
as the primary efficacy variables. 
Analysis of categorical variables in key secondary endpoints, the Cochran-Mantel-Haenszel 
approach stratified by the randomization strata will be used with missing data considered as 
non-response. 
Control for multiplicity for both the primary and key secondary efficacy analyses are described in 
Section 5.2.7.1. 
5.2.7.3. 
Analysis of Additional Secondary Efficacy Variable(s) 
Analyses of continuous variables in other secondary endpoints will use the same analysis method 
as the primary efficacy variables. 
No control for multiplicity will be made for these analyses.  Tests for comparing each fasinumab 
dose versus placebo will utilize a nominal 2-sided alpha level of 0.05. 
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NRS 
For the analysis of average weekly walking index joint pain using the NRS pain scale, baseline is 
defined as the average of the non-missing values during 7 days prior to taking study drug.  For 
each week, the average of the non-missing values during the 7 days on or prior to that week will 
be used.  If all values are missing for the 7 days, the value for that week is set to missing.  
The MMRM model will be used for the analysis with terms for the randomization strata 
(K-L category [2-3 vs. 4] and index joint [hip or knee], geographic region), treatment, week 
treatment-by-week interaction as fixed effects, and baseline 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, ARH(1) covariance structure 
will be used. 
Responder analyses 
The percentage of patients who are responders based on WOMAC pain and physical function 
subscale scores and Patient Global Assessment scale scores defined by at least a 30% reduction 
and at least a 50% reduction from baseline to each post-baseline week will be summarized and 
plotted by the treatment group. The percentage of patients who are responders based on the 
Osteoarthritis Research Society International Standing Committee for Clinical Trials Response 
Criteria Initiative and The Outcome Measure in Rheumatology (OMERACT-OARSI) responder 
criteria (Appendix 11.3) will be summarized and plotted by the treatment group. 
Cochran-Mantel-Haenszel (CMH) test, stratified by the randomization strata will be applied for 
the responder analysis. Missing data is considered as non-response in this analysis. 
Cumulative distribution of percent change from baseline in WOMAC pain and physical function 
subscale scores and Patient Global Assessment scale scores will be presented by treatment group.  
The cumulative distribution plot displays a continuous plot of the percent change from baseline on 
the X-axis and the percent of patients experiencing that change on the Y-axis.  Different responder 
definitions can be identified along the cumulative distribution curve. 
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis. 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified.  When relevant, the number of patients with missing data 
is presented. 
6.1. 
Definition of Baseline for Variables 
Unless otherwise specified, the baseline assessment for all measurements will be the latest 
available valid measurement prior to randomization.  
6.2. 
Data Handling Conventions for Efficacy Data 
Missing data items for questionnaires 
WOMAC scores will be computed when one pain item, one stiffness item, or at most 3 physical 
function items are missing. The missing items will be imputed by the mean of available items 
within the same subscale. The scores will be set to missing if more items are missing.  
6.3. 
General Data Handling Conventions 
Date of last dose of study treatment 
The date of the last injection is equal to the last date of administration reported on injection 
administration case report form page, or missing if the last administration date is unknown. 
Handling of Adverse Event and Injection Site Reaction Severity 
If the severity of a TEAE is missing, it will be classified as “severe” in the frequency tables by 
severity of TEAEs.  
Handling of Adverse Event Relatedness 
If the assessment of relationship of a TEAE to the study drug or study conduct is missing, it will 
be classified as “related”. 
Handling of Adverse Events or Concomitant Medications with missing or partial start 
date/time 
If the start date of an AE or concomitant medication is incomplete or missing, it will be assumed 
to have occurred on or after the intake of study medication, except if an incomplete date (eg, 
month and year) clearly indicates that the event started prior to treatment. Thus, if the AE does 
not clearly indicate that the AE started prior to treatment or after the TEAE period, the AE will 
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be classified as “treatment-emergent”. This is for classification purposes in the frequency tables 
and will not be used in the listings. 
Handling of Adverse Events or Concomitant Medications with missing or partial end 
date/time 
When only year is present, missing AE/concomitant medication end day and month will be 
imputed to the earlier of (study end date, 31DECYYYY). 
When both month and year are present, missing AE/concomitant medication end date will be 
imputed to the last day of the month. 
There will be no attempt to impute completely missing AE/concomitant medication end dates. 
Events with an end date missing will be assumed to be ongoing at the time of data cut off.  
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. 
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. 
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. 
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For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; eg, for eosinophils the PCSA is >0.5 GIGA/L or >ULN 
if ULN ≥0.5 GIGA/L. When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values. 
6.4. 
Visit Windows 
By-visit analysis (including efficacy, laboratory data, vital signs, ECG, ADA) will be 
summarized by the nominal visit number.  Assessments taken outside of protocol allowable 
windows will be displayed according to the case report form (CRF) assessment recorded by the 
investigator.  For assessments without a nominal visit number such as Unscheduled, EOT, and 
EOS assessments, a visit number will be assigned based on the actual visit date using the study 
day analysis window based on the targeted visit study day in Appendix 11.1 Table 2 Schedule of 
Events.  
The following visit windows will be used to map the unscheduled visits, early end of treatment visits, 
early study termination visits and daily electronic dairy entries, based on the study day: 
 
Visit 
No. 
Visit 
Targeted Study 
Days* 
Analysis Window in 
Study Days 
1 
Screening 
Day -30 to Day -11 
≥ -30 and ≤ -11 
2 
Pre-randomization Phone Call 
Day -10 to -7 
-10 to -1 
3 
Baseline 
1 
≤ 1 
 
Week 1 (efficacy sub-study) 
8 
[2, 11] 
 
Week 2 (efficacy sub-study) 
15 
[12, 22] 
4 
Week 4 
29 
[23,43](efficacy 
substudy);[2,43] 
(LTS) 
5 
Week 8 
57 
[44,71] 
6 
Week 12 
85 
[72,99] 
7 
Week 16 
113 
[100,127] 
8 
Week 20 
141 
[128,155] 
9 
Week 24 
169 
[156,183] 
10 
Week 28 
197 
[184,211] 
11 
Week 32 
225 
[212,239] 
12 
Week 36 
253 
[240,267] 
13 
Week 40 
281 
[268,295] 
14 
Week 44 
309 
[296,323] 
15 
Week 48 
337 
[324,351] 
16 
Week 52  
365 
[352,393] 
17 
Week 60 
421 
[394,463] 
18 
Week 72 
505 
≥464 
 
*Study days are calculated from the first dose of study drug (Day 1). 
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If multiple measurements occur within the same visit window, the following rules will be used to 
determine the analysis value:  
 When multiple valid measurements occur within the same visit window, the one 
closest to the target study day will be used in the analysis.  
 When multiple valid measurements occur within equal distance from the target study 
day, the value after the target study day will be used in the analysis.  
Both scheduled and unscheduled measurements will be considered for determining abnormal/PCSV 
values from laboratory, vital sign or ECG as well as the baseline values. 
6.5. 
Unscheduled Assessments 
The determination of baselines and values at the end of treatment for both efficacy and safety 
variables will be based on available assessments of scheduled and unscheduled visits. For by visit 
summaries, unscheduled visit will be mapped to a visit using the visit windows described in 
Section 6.4 and then included in the by-visit summaries.  
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7. 
TIMING OF STATISTICAL ANALYSES 
The efficacy sub-study and LTS study analyses will be performed based on three different 
database locks: 
 1st Step Analysis: takes place when the last efficacy sub-study patient completes the 
efficacy sub-study visits and includes all patient data collected up to the week 16 visit.  
The primary efficacy analysis for the sub-study will be conducted at this time.  No 
alpha adjustment is needed, as the week 16 efficacy sub-study analysis will be the 
final primary efficacy analysis.  Safety analysis will be performed for internal safety 
monitoring.  Patient level results will not be disclosed to any site-facing personnel or 
to any personnel directly involved with the conduct of the study. 
 Week 72 analysis: takes place when the patient data collected up to the time the last 
LTS patient completes the LTS study visits and assessments at week 72 visit.  The 
week 72 primary safety analysis will be conducted at this time. 
 Final analysis: takes place when patient data collected up to the time the last LTS 
patient completes assessments at week 100.  The only additional analysis to be 
conducted at this time is the analysis of incidence of JRs at the telephone survey 
approximately 52 weeks after the last dose of study drug and updating of outputs with 
any data change from the week 72 database lock. 
Individuals involved in the 1st step analysis of the study will not be involved in the conduct of the 
study after the 1st step database lock until after the week 72 database lock.  The first step analysis 
process, the measures used to protect the blind and the integrity of the study, the communication 
plan, and the confidentiality agreement will be described in a separate document.  The results of 
the first analysis will not be used to change the conduct of the ongoing study in any aspect. 
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8. 
INTERIM ANALYSES 
No interim efficacy analysis is planned.  Additional interim analysis of safety data may be 
performed for regulatory or internal decision-making purposes. 
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9. 
SOFTWARE 
All clinical data analyses will be done using SAS Version 9.4 and above. 
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10. 
REFERENCES 
Bretz, F., W. Maurer, W. Brannath, and M. Posch.  A graphical approach to sequentially rejective 
multiple test procedures. Stat Med. 2009. 28:586-604. 
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11. 
APPENDIX 
11.1. 
Schedule of Events and Visits 
 
 
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11.2. 
Reference for Criteria for Treatment-Emergent Potentially 
Clinically Significant Values (PCSV) 
The PCSV criteria below should be used as a reference; the actual criteria for each study should 
be determined and agreed to by the study team prior to database lock as part of SAP and should 
be based on the study population, indication, and potential effects of study treatment. 
Table 2: 
Criteria for Treatment-Emergent Potentially Clinically Significant Values 
(PCSV) 
Parameter 
Treatment Emergent PCSV 
Comments 
Clinical Chemistry 
ALT* 
>3 and ≤ 5 ULN and baseline ≤ 3 
ULN* 
>5 and ≤ 10 ULN and baseline ≤ 5 
ULN 
>10 and ≤ 20 ULN and baseline ≤ 10 
ULN 
>20 ULN and baseline ≤ 20 ULN 
Enzyme activity must be expressed in 
ULN, not in IU/L.  
FDA DILI Guidance July 2009. 
Each category is calculated 
independently. 
* At least one level is required; 
multiple levels are optional for phase 
2/3 studies.  If it is desirable to get the 
distribution across the different 
PCSV levels, additional shift table on 
≤3, >3 to ≤5, >5 to ≤10, >10 to ≤20, 
and >20 category for baseline vs. post 
baseline may be provided  
                                        VV-RIM-00075335-1.0 Approved - 13 Apr 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R475-PN-1523 
Statistical Analysis Plan 
Date: 25Jul2018 
CONFIDENTIAL 
Page 64 of 71 
Parameter 
Treatment Emergent PCSV 
Comments 
AST* 
>3 and ≤ 5 ULN and baseline ≤ 3 
ULN* 
>5 and ≤ 10 ULN and baseline ≤ 5 
ULN 
>10 and ≤ 20 ULN and baseline ≤ 10 
ULN 
>20 ULN and baseline ≤ 20 ULN 
Enzyme activity must be expressed in 
ULN, not in IU/L.  
FDA DILI Guidance July 2009. 
Each category is calculated 
independently. 
* At least one level is required; 
multiple levels are optional for phase 
2/3 studies.  If it is desirable to get the 
distribution across the different 
PCSV levels, additional shift table on 
≤3, >3 to ≤5, > 5 to ≤10, >10 to ≤20, 
and >20 category for baseline vs. 
post baseline may be provided 
Alkaline 
Phosphatase 
>1.5 ULN and baseline ≤ 1.5 ULN 
Enzyme activity must be expressed in 
ULN, not in IU/L. 
FDA DILI Guidance July 2009. 
Total Bilirubin* >1.5 and ≤ 2 ULN and baseline ≤ 1.5 
ULN* 
>2 ULN and baseline ≤ 2.0 ULN 
Must be expressed in ULN, not in 
µmol/L or mg/L.  Categories are 
cumulative. 
FDA DILI Guidance July 2009. 
* At least one level is required; 
multiple levels are optional for phase 
2/3 studies.  If it is desirable to get the 
distribution of significant level, 
additional shift table on ≤1.5, >1.5 to 
≤2.0 and > 2.0 category for baseline 
vs. post baseline may be provided 
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. 
                                        VV-RIM-00075335-1.0 Approved - 13 Apr 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R475-PN-1523 
Statistical Analysis Plan 
Date: 25Jul2018 
CONFIDENTIAL 
Page 65 of 71 
Parameter 
Treatment Emergent PCSV 
Comments 
ALT/AST and 
Total Bilirubin 
(ALT >3 ULN and TBILI>2 ULN) and 
baseline (ALT <=3 ULN or TBILI <=2 
ULN) 
(AST >3 ULN and TBILI>2 ULN) and 
baseline (AST <=3 ULN or TBILI <=2 
ULN) 
(ALT >3 ULN and TBILI>1.5 ULN) 
and baseline (ALT <=3 ULN or TBILI 
<=1.5 ULN) 
(AST >3 ULN and TBILI>1.5 ULN) 
and baseline (AST <=3 ULN or TBILI 
<=1.5 ULN) 
FDA DILI Guidance July 2009. 
ALT/AST and 
Total Bilirubin 
and ALP 
(ALT >3 ULN and TBILI>2 ULN and 
ALP < 2 ULN) and baseline (ALT <=3 
ULN or TBILI <=2 ULN or ALP >=2 
ULN) 
(AST>3 ULN and TBILI>2 ULN and 
ALP < 2 ULN) and baseline (AST <=3 
ULN or TBILI <=2 ULN or ALP >=2 
ULN) 
FDA DILI Guidance July 2009. 
 
CPK* 
>3 and ≤ 10 ULN and baseline ≤ 
3ULN* 
>10 ULN and baseline ≤ 10ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
* At least one level is required; 
multiple levels are optional for phase 
2/3 studies. If it is desirable to get the 
distribution of significant level, 
additional shift table on ≤3, >3 to 
≤10, and > 10 category for baseline 
vs. post baseline may be provided 
                                        VV-RIM-00075335-1.0 Approved - 13 Apr 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R475-PN-1523 
Statistical Analysis Plan 
Date: 25Jul2018 
CONFIDENTIAL 
Page 66 of 71 
Parameter 
Treatment Emergent PCSV 
Comments 
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 
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. 
                                        VV-RIM-00075335-1.0 Approved - 13 Apr 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R475-PN-1523 
Statistical Analysis Plan 
Date: 25Jul2018 
CONFIDENTIAL 
Page 67 of 71 
Parameter 
Treatment Emergent PCSV 
Comments 
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 
 
Albumin 
≤25 g/L and >25 g/L at baseline 
 
hs-CRP 
2 ULN or > 10 mg/L  
(if ULN not provided) 
FDA Sept. 2005 
Hematology 
WBC 
<3.0 Giga/L and >=3.0 Giga/L at 
baseline (Non-Black);  
<2.0 Giga/L and >=2.0 Giga/L at 
baseline (Black) 
≥16.0 Giga/L and < 16 Giga/L at 
baseline 
Increase in WBC: not relevant. 
 
 
To be interpreted only if no 
differential count available. 
Lymphocytes 
>4.0 Giga/L and <= 4.0 Giga/L at 
baseline 
 
Neutrophils 
<1.5 Giga/L and >=1.5 Giga/L at 
baseline (Non-Black);  
<1.0 Giga/L and >=1.0 Giga/L at 
baseline (Black) 
International Consensus meeting on 
drug-induced blood cytopenias, 1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L <= 0.7 Giga/L at baseline  
Basophils 
>0.1 Giga/L <= 0.1 Giga/L at baseline  
                                        VV-RIM-00075335-1.0 Approved - 13 Apr 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R475-PN-1523 
Statistical Analysis Plan 
Date: 25Jul2018 
CONFIDENTIAL 
Page 68 of 71 
Parameter 
Treatment Emergent PCSV 
Comments 
Eosinophils 
(>0.5 Giga/L and >ULN) and (<=0.5 
Giga/L or <= ULN at baseline) 
Harrison - Principles of internal 
Medicine 17th Ed., 2008. 
Hemoglobin 
≤115 g/L and > 115 g/L at baseline for 
male; 
≤95 g/L and> 95 g/L at baseline for 
Female. 
≥185 g/L and <185 g/L at baseline for 
Male; 
≥165 g/L and < 165 g/L at baseline for 
Female 
Decrease from Baseline ≥20 g/L 
Three criteria are independent. 
 
 
Criteria based upon decrease from 
baseline are more relevant than based 
on absolute value. Other categories 
for decrease from baseline can be 
used (≥30 g/L, ≥40 g/L, ≥50 g/L). 
Hematocrit 
≤0.37 v/v and > 0.37 v/v at baseline for 
Male; ≤0.32 v/v and > 0.32 v/v at 
baseline forFemale 
≥0.55 v/v and < 0.55 v/v at baseline for 
Male; ≥0.5 v/v and < 0.5 v/v at baseline 
for Female 
Two Criteria are independent 
RBC 
Female 
<3 Tera/L and baseline ≥3 Tera/L 
≥6 Tera/L and baseline < 6 Tera/L  
Male 
<4 Tera/L and baseline ≥4 Tera/L 
≥7 Tera/L and baseline < 7 Tera/L 
Unless specifically required for 
particular drug development, the 
analysis is redundant with that of Hb. 
Otherwise, consider FDA criteria. 
Platelets 
<100 Giga/L and >=100 Giga/L at 
baseline 
≥700 Giga/L and < 700 Giga/L at 
baseline 
International Consensus meeting on 
drug-induced blood cytopenias, 1991. 
Two independent criteria 
                                        VV-RIM-00075335-1.0 Approved - 13 Apr 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R475-PN-1523 
Statistical Analysis Plan 
Date: 25Jul2018 
CONFIDENTIAL 
Page 69 of 71 
Parameter 
Treatment Emergent PCSV 
Comments 
Urinalysis 
pH 
≤4.6 and > 4.6 at baseline 
≥8 and < 8 at baseline 
Two independent criteria 
Vital signs 
HR 
≤50 bpm and decrease from baseline 
≥20 bpm 
≥120 bpm and increase from 
baseline≥20 bpm 
To be applied for all positions 
(including missing) except 
STANDING. 
SBP 
≤95 mmHg and decrease from baseline 
≥20mmHg 
≥160 mmHg and increase from baseline 
≥20 mmHg 
To be applied for all positions 
(including missing) except 
STANDING. 
DBP 
≤45 mmHg and decrease from baseline 
≥10 mmHg 
≥110 mmHg and increase from baseline 
≥10 mmHg 
To be applied for all positions 
(including missing) except 
STANDING. 
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. 
                                        VV-RIM-00075335-1.0 Approved - 13 Apr 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R475-PN-1523 
Statistical Analysis Plan 
Date: 25Jul2018 
CONFIDENTIAL 
Page 70 of 71 
Parameter 
Treatment Emergent PCSV 
Comments 
ECG 
Ref.: CPMP 1997 guideline. ICH E14 
2005 
HR 
≤50 bpm and decrease from baseline 
≥20 bpm 
≥120 bpm and increase from baseline 
≥20 bpm 
 
PR 
≥220 ms and increase from baseline 
≥20 ms 
 
QRS 
≥120 ms & < 120 ms at baseline 
 
QTc 
Absolute values (ms) 
>450 ms and baseline <=450 ms 
>480 ms and baseline <=480 ms 
>500 ms and <= 500 ms at baseline 
 
Increase from baseline 
Increase from baseline 30-60 ms 
Increase from baseline >60 ms 
To be applied to any kind of QT 
correction formula.  
 
 
 
QTc>60 ms are the PCSA to be 
identified in individual 
subjects/patients listings. 
 
                                        VV-RIM-00075335-1.0 Approved - 13 Apr 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R475-PN-1523 
Statistical Analysis Plan 
Date: 25Jul2018 
CONFIDENTIAL 
Page 71 of 71 
11.3. 
OMERACT-OARSI set of responder criteria 
 
Note that the criteria in the diagram above are based on standardized score between 0 and 100.  
For this study, WOMAC pain and physical function score are between 0 and 10, so the absolute 
change required for response is the required change in the diagram above divided by 10; PGA is 
1, 2, 3, 4 or 5, so the absolute change required for response is at least 1 point. 
                                        VV-RIM-00075335-1.0 Approved - 13 Apr 2019 GMT-5:00


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                                        VV-RIM-00075335-1.0 Approved - 13 Apr 2019 GMT-5:00