Clinical trial NCT03956550
Conditions: Osteoarthritis of the Knee Pain
Sponsor: Regeneron Pharmaceuticals
Start date: 2019-05-21; Completion date: 2020-10-29
Enrollment: 259 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study is to evaluate the efficacy of REGN5069 compared to placebo in patients with pain due to radiographically-confirmed OA of the knee who have a history of inadequate joint pain relief or intolerance to current analgesic therapy.

The secondary objectives of the study are:

* To characterize the concentrations of functional REGN5069 in serum over time when patients are treated for up to 12 weeks
* To assess the safety and tolerability of REGN5069 compared with placebo when patients are treated for up to 12 weeks
* To measure levels of anti-drug antibodies (ADAs) against REGN5069 following multiple IV administrations

Detailed description:

Arms: arm 1: Randomized in a 1:1:1 ratio arm 2: Randomized in a 1:1:1 ratio arm 3: Randomized in a 1:1:1 ratio
Interventions: intervention 1: REGN5069 intervention 2: Matching Placebo
Intervention descriptions: intervention 1: Intravenous (IV) Dose every 4 weeks (Q4W) intervention 2: Intravenous (IV) Dose every 4 weeks (QW4)

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
 
R5069-OA-1849 Amendment 1 
Regeneron Pharmaceuticals, Inc. 
 
Page 1 of 72 
 
CONFIDENTIAL 
EudraCT: 2018-004730-15 
IND: 141725 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A RANDOMIZED, DOUBLE-BLIND, MULTI-DOSE, 
PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY 
AND SAFETY OF REGN5069 IN PATIENTS WITH PAIN DUE TO 
OSTEOARTHRITIS OF THE KNEE 
 
 
Compound: 
REGN5069 
 
 
Clinical Phase: 
2 
 
 
Protocol Number: 
R5069-OA-1849 
 
 
Protocol Version: 
R5069-OA-1849 Amendment 1 
 
 
Amendment 1 Date of Issue:  
See appended electronic signature page 
Original Date of Issue:  
30 Jan 2019 
 
 
Medical/Study Director: 
 
 Early Clinical 
Development and Experimental Sciences 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
 
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Clinical Study Protocol 
 
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Regeneron Pharmaceuticals, Inc. 
 
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CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 1 
The purpose of this amendment is to add an end-of-study phone call to collect long-term 
information on patient status regarding joint replacement surgery beyond the current planned 
follow-up period, per health authority feedback, and to extend the required duration for serious 
adverse event (SAE) reporting, pregnancy reporting, and the use of contraceptive measures. 
Changes were also made to the statistical analysis plan based on health authority feedback. The 
following table outlines the changes made to the protocol and the rationale.  
Change and Rationale 
Sections Changed 
An end-of-study phone call will be conducted approximately 52 
weeks after the first dose of study drug to collect long-term 
information on patient status regarding joint replacement 
surgery (ie, whether the patient underwent, is scheduled for, or 
is on a waiting list to receive joint replacement surgery, or 
whether joint replacement was recommended but the patient 
elected to defer). This change was made per health authority 
feedback.  
As a result of this change, the study duration, end of study 
definition, and any prior reference to the “end of study” that 
now refers to the “end of the follow-up period” were updated 
for accuracy.  
Clinical Study Protocol Synopsis: Study 
Design; Study Duration; End of Study 
Definition; Procedures and Assessments 
Section 3.2.1 Rationale for Study Design 
Section 5.1 Study Description and Duration 
Figure 1: Study Flow Diagram 
Section 5.1.2 End of Study Definition 
Section 7.3.2 Study Drug Discontinuation 
Section 7.7 Concomitant Medications and 
Procedures 
Section 7.7.1 Prohibited Medications and 
Procedures 
Section 7.7.2 Permitted Mediations and 
Procedures 
Table 1: Schedule of Events 
Section 8.1.1 Footnotes for the Schedule of 
Events Table 1, #10 
Section 8.1.2 Footnotes for Schedule of 
Events for Follow-up of Patients Who 
Undergo Joint Replacement Surgery (Table 2) 
Section 8.2.3.8 End-of-Study Phone Call for 
Joint Replacement Status Questionnaire 
(added section) 
Section 9.4.1 Adverse Events 
Section 9.4.2 Serious Adverse Events 
The required duration for pregnancy reporting and the use of 
contraceptive measures for sexually active men and women of 
childbearing potential was extended from 7 months to at least 9 
months after the last dose of study drug. The duration for SAE 
reporting in the event that the investigator is informed of an 
SAE after a patient terminates early from the study was 
increased from onset of the SAE “within 169 days of last study 
drug administration” to “within 226 days of last study drug 
administration.” These changes were based on recently analyzed 
clinical pharmacology data from the ongoing first-in-human 
study R5069-HV-1810.  
Section 6.2.2 Exclusion Criteria, #28 and #31 
Section 9.4.2 Serious Adverse Events 
Section 9.4.3 Other Events that Require 
Accelerated Reporting to Sponsor 
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CONFIDENTIAL 
Details on the planned analyses of X-ray and magnetic 
resonance imaging data were added, per health authority 
feedback.  
Section 8.2.3.6 Imaging 
Section 10.4.4.2 Other Safety, added 
“Imaging” in this analysis subsection 
The primary efficacy analysis plan was updated to reflect that 
change from baseline to week 12 in the Western Ontario and 
McMaster Osteoarthritis Index pain subscale will be a multiple 
imputation approach with analysis of covariance (ANCOVA) 
based on the full analysis set with adjustment for missing data 
using a pattern mixture approach. Additionally, information was 
provided regarding the plan for handling missing data. These 
changes were made per health authority feedback.  
Clinical Study Protocol Synopsis: Statistical 
Plan, Primary Efficacy Analysis 
Section 10.4.3.1 Primary Efficacy Analysis 
The protocol language was modified to remove flexibility for 
dosing of REGN5069. Previously, the low dose of REGN5069 
was estimated to be 100 mg IV every 4 weeks (Q4W) and the 
high dose of REGN5069 was estimated to be 1000 mg IV Q4W. 
Flexibility was built in such that the high dose may have been 
adjusted downward and such that the low dose may have been 
adjusted downward or upward. The REGN5069 100 mg IV 
Q4W and REGN5069 1000 mg IV Q4W doses are the 2 doses 
that will be administered in this study.  
Clinical Study Protocol Synopsis: Study 
Design 
Section 3.2.2 Rationale for Dose Selection 
Section 5.1 Study Description and Duration 
Section 7.1 Investigational Treatments 
Section 7.5 Method of Treatment Assignment 
Genicular nerve block and any similar procedures are now listed 
as prohibited within 3 months of the screening visit to qualify 
for study participation and are prohibited up to the last study site 
visit in the follow-up period. Use of such procedures may 
interfere with pain perception.  
Section 6.2.2 Exclusion Criteria, #32 (added) 
Section 7.7.1 Prohibited Medications and 
Procedures 
The section entitled “Reasons for Temporary Discontinuation of 
Study Drug” was removed, as any discontinuation from study 
drug dosing will be permanent.  
Section 7.3.2.2 Reasons for Temporary 
Discontinuation of Study Drug (deleted 
section) 
Section 6.3 Premature Withdrawal from the 
Study 
To provide guidance to study sites, language was added to state 
that patients with a history of hypothyroidism must have 
thyroid-stimulating hormone levels measured and must be in an 
euthyroid state to be eligible for study participation.  
Section 6.2.2 Exclusion Criteria, #1 
The specific value for follicle-stimulating hormone levels to fall 
in the postmenopausal range was removed for flexibility.  
Section 6.2.2 Exclusion Criteria, #31 
All drug and alcohol testing will be performed with urine 
samples which are sufficient for this test based on central 
laboratory feedback. Thus, any serum sample collection 
previously specified for drug and alcohol testing was changed to 
urine sample collection and instructions in the event of a 
positive drug and/or alcohol test result were updated.  
Section 8.1 Schedule of Events, Table 1 
Schedule of Events 
Section 8.1.1 Footnotes for the Schedule of 
Events Table 1, #11 
Section 8.2.3.10 Laboratory Testing 
Specific statements regarding where laboratory samples will be 
processed were removed to allow flexibility.  
Section 8.2.3.10 Laboratory Testing 
Updated information regarding the first-in-human study 
R5069-HV-1810 based on the current status of the study. 
Section 1.1 Background 
Section 3.2.1 Rationale for Study Design 
Section 3.2.2 Rationale for Dose Selection 
Removed reference to “study reference manual,” as there is no 
study reference manual.  
Throughout the protocol. 
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CONFIDENTIAL 
Minor edits were made to improve clarity throughout the 
protocol. 
Clinical Study Protocol Synopsis: Statistical 
Plan, Justification of the Sample Size 
List of Abbreviations and Definitions of 
Terms 
Section 6.2.1 Inclusion Criteria, #12 
Section 6.2.2 Exclusion Criteria, #21, 23, 24 
Table 1: Schedule of Events 
Section 8.1.3 Early Termination Visit 
Section 8.2.6.1 Pharmacodynamic and 
Biomarker Research 
 
Section 9.3.2 Serious Adverse Event 
Section 10.2 Justification of Sample Size 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Randomized, Double-Blind, Multi-Dose, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of REGN5069 in Patients with Pain due to 
Osteoarthritis of the Knee 
Site Locations 
 
Principal Investigator(s) 
Multiple sites in the United States (US) and ex-US 
To be determined after 50% patient enrollment is completed  
Objectives 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of REGN5069 
compared to placebo in patients with pain due to radiographically-confirmed 
osteoarthritis (OA) of the knee who have a history of inadequate joint pain 
relief or intolerance to current analgesic therapy.  
Secondary Objectives 
The secondary objectives of the study are: 
 
To characterize the concentrations of functional REGN5069 in 
serum over time when patients are treated for up to 12 weeks 
 
To assess the safety and tolerability of REGN5069 compared 
with placebo when patients are treated for up to 12 weeks 
 
To measure levels of anti-drug antibodies (ADAs) against 
REGN5069 
following 
multiple 
intravenous 
(IV) 
administrations 
Study Design 
This multicenter phase 2 study consists of a screening period of up to 
30 days, followed by a 12-week randomized, double-blind, parallel-arm, 
placebo-controlled treatment period, a 24-week follow-up period, and an 
end-of-study phone call approximately 52 weeks after the first dose of study 
drug. The purpose of the end-of-study phone call is to determine whether a 
patient underwent, is scheduled for, or is on a waiting list to receive joint 
replacement surgery, or whether joint replacement was recommended but the 
patient elected to defer. Up to approximately 240 patients will be 
randomized in a 1:1:1 ratio to receive a low dose of REGN5069 at 100 mg 
IV every 4 weeks (Q4W), and a high dose of REGN5069 at 1000 mg IV 
Q4W, or matching placebo Q4W. The index knee joint is defined as the knee 
joint affected by OA and selected for primary assessment for this study. 
Randomization will be stratified by Kellgren-Lawrence (K-L) category (2-3 
vs 4) of the index knee joint at the screening visit and participation in the 
Moticon sub-study (yes vs no).  
Study Duration 
Each patient will be enrolled in the study for approximately 56 weeks, 
including the screening period and the period up to the end-of-study phone 
call. 
End of Study Definition 
The end of study is defined as the date when the last patient completes the 
last phone call, withdraws from the study, or is lost to follow-up (ie, the 
patient can no longer be contacted by the investigator). 
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Population 
 
 
Sample Size: 
Up to approximately 240 patients are planned for enrollment in this study. 
 
Target Population: 
Men and women who are at least 40 years of age at the time of study entry 
with a clinical diagnosis of OA of the knee based on the American College 
of Rheumatology criteria with radiologic evidence of OA (K-L score ≥2) at 
the index knee joint. 
Treatments 
 
 
Study Drug 
 
Dose/Route/Schedule: 
REGN5069 or matching placebo.  
100 mg IV Q4W or 1000 mg IV Q4W or Placebo IV Q4W 
 
Rescue Treatment 
 
Dose/Route/Schedule: 
Starting at the screening visit until after the week-24 study visit is 
completed, acetaminophen is the only study-permitted rescue medication. 
Acetaminophen tablets of selected brand and strength will be provided to 
patients by the study site for use as rescue medication for breakthrough OA 
pain. In advance of initiating the study, each study site must consult with the 
sponsor and select the brand and the strength of acetaminophen tablets that 
will be dispensed to patients as rescue medication. In the event that pain 
relief for OA pain is inadequate, patients will take acetaminophen, as 
needed, in accordance with the instructions provided with the medication by 
each study site, with a maximum of 3000 mg/day. The use of rescue 
medication is not allowed for 48 hours prior to the start of or during a 
scheduled study visit to minimize the confounding effects of rescue 
medication on efficacy measures. 
Endpoints 
 
 
Primary: 
The primary endpoint of the study is the change from baseline to week 12 in 
the Western Ontario and McMaster Osteoarthritis Index (WOMAC) pain 
subscale score in patients treated with REGN5069 compared to patients 
treated with placebo. 
 
Secondary: 
The secondary efficacy endpoints of the study are: 
 
Change from baseline to week 12 in the WOMAC total score 
(based on the full survey) in patients treated with REGN5069 
compared to patients treated with placebo 
 
Change from baseline to week 12 in the WOMAC physical 
function subscale score in patients treated with REGN5069 
compared to patients treated with placebo 
 
Change from baseline to week 12 in the Patient Global 
Assessment score in patients treated with REGN5069 
compared to patients treated with placebo 
 
Change from baseline to week 12 in WOMAC stiffness 
subscale score in patients treated with REGN5069 compared to 
patients treated with placebo 
 
Percentage of patients treated with REGN5069, compared to 
that of patients treated with placebo, who had a response at 
week 12, with response defined as an improvement by ≥30% in 
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CONFIDENTIAL 
the WOMAC pain subscale scores 
The secondary safety endpoints of the study are: 
 
The incidence of treatment-emergent adverse events in patients 
treated with REGN5069 compared to patients treated with 
placebo throughout the study duration 
 
The incidence of imaging abnormalities consistent with 
accelerated arthropathies as assessed by X-ray and magnetic 
resonance imaging in patients treated with REGN5069 
compared to patients treated with placebo throughout the study 
duration 
 
Presence of anti-REGN5069 antibody development in patients 
treated with REGN5069 compared to patients treated with 
placebo throughout the study duration 
Procedures and Assessments 
Efficacy 
Efficacy will be assessed through administration of the WOMAC full survey 
and subsections of the survey, and through administration of the Patient 
Global Assessment of OA.  
Safety 
Safety procedures include monitoring vital signs, orthostatic vital sign 
change, physical and neurological examinations, electrocardiograms, joint 
imaging, a joint pain questionnaire, drug concentration and ADA sample 
collections, and additional laboratory testing. An end-of-study phone call 
will be conducted approximately 52 weeks after the first dose of study drug 
to collect long-term information on patient status regarding joint replacement 
surgery (ie, whether the patient underwent, is scheduled for, or is on a 
waiting list to receive joint replacement surgery, or whether joint 
replacement was recommended but the patient elected to defer). 
Statistical Plan 
Statistical Hypotheses 
The null hypotheses of no treatment difference between a REGN5069 dose 
and placebo against an alternative hypothesis of some treatment difference in 
change from baseline to week 12 in WOMAC pain subscale, physical 
function subscale, and Patient Global Assessment scores will be tested for 
each dose. Multiplicity adjustment for the 6 null hypotheses will be made 
using sequentially rejective multiple test procedure to control Type I error 
rate at 2-sided 0.05 level in the following order: 
 
H1: No treatment difference between 1000 mg REGN5069 and 
placebo groups in change from baseline to week 12 in 
WOMAC pain subscale score 
 
H2: No treatment difference between 100 mg REGN5069 and 
placebo groups in change from baseline to week 12 in 
WOMAC pain subscale score 
 
H3: No treatment difference between 1000 mg REGN5069 and 
placebo groups in change from baseline to week 12 in 
WOMAC physical function subscale score 
 
H4: No treatment difference between 100 mg REGN5069 and 
placebo groups in change from baseline to week 12 in 
WOMAC physical function subscale score 
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CONFIDENTIAL 
 
H5: No treatment difference between 1000 mg REGN5069 and 
placebo groups in change from baseline to week 12 in Patient 
Global Assessment score 
 
H6: No treatment difference between 100 mg REGN5069 and 
placebo groups in change from baseline to week 12 in Patient 
Global Assessment score 
If at any step a null hypothesis is not rejected, the testing will stop and no 
further hypothesis in the order will be tested. Further details will be provided 
in the Statistical Analysis Plan.  
Justification of the Sample Size 
Up to approximately 240 patients (80 per treatment group) will be 
randomized to 3 treatment groups in a 1:1:1 allocation. Assuming a standard 
deviation of 2.3, 80 patients per treatment group will provide approximately 
80% power to detect a treatment difference of 1.1 between the REGN5069 
dose and matching placebo in change from baseline to week 12 in WOMAC 
pain subscale (using a significance level of 0.05, 2-sided t-test and assuming 
a dropout rate of 15% [6% due to lack of efficacy or adverse events, and 9% 
due to other reasons]). 
Primary Efficacy Analysis 
The primary estimand for the primary objective is the difference in means 
between both REGN5069 dose + protocol-defined rescue medication and 
placebo + protocol-defined rescue medication in the change from baseline to 
week 12 in the WOMAC pain subscale score of patients in the FAS.  All 
collected data will be included in the analysis regardless of whether 
prohibited medication was taken. Missing values will be imputed with the 
multiple imputation approach, where intermediate missing data will be first 
imputed using the Markov Chain Monte Carlo method and then the 
remaining missing data with a monotone missing pattern will be imputed 
with a regression method. The regression model will adjust for treatment, 
randomization strata, and baseline score.  For patients who drop out due to 
lack of efficacy or adverse events, each imputed value will be further 
adjusted by subtracting the mean change from baseline to the respective 
post-baseline time point calculated from patients in the same treatment group 
with observed data at that time point.  For each complete dataset, the primary 
efficacy endpoint of change from baseline to week 12 in WOMAC pain 
subscale score will be analyzed using an analysis of covariance (ANCOVA) 
model which will include treatment, randomization strata, and baseline score 
as covariate.  The least-squares means estimates as well as the difference of 
the estimates between each dose and placebo with standard error, p-values, 
and 95% confidence intervals will be provided by combining results from 
the 
analyses 
of 
the 
multiple 
imputed 
datasets 
using 
Rubin’s 
formulae.  Further details will be provided in the statistical analysis plan. 
Secondary Efficacy Analysis 
The continuous secondary endpoints will be analyzed similarly to the 
primary endpoint. For the analyses of categorical secondary endpoints, the 
Cochran-Mantel-Haenszel test stratified by the K-L category (2-3 vs 4) will 
be used with missing data considered as non-response.  
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CONFIDENTIAL 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Acetaminophen 
The United States Adopted Name for the International Nonproprietary Name 
paracetamol. Acetaminophen is the term used throughout this protocol.  
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
Bpm 
Beats per minute 
CFA 
Complete Freund’s adjuvant 
CGRP 
Calcitonin gene-related peptide 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
Ctrough 
Trough concentration 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
ESR 
Erythrocyte sedimentation rate 
EU 
European Union 
FAS 
Full analysis set 
FIH 
First-in-human 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GDNF 
Glial cell-line-derived neurotrophic factor 
GFRα3 
Glial cell-line-derived neurotrophic factor receptor alpha-3 
HbA1c 
Hemoglobin A1c; Glycated hemoglobin 
HIV 
Human immunodeficiency virus 
hsCRP 
High sensitivity C-reactive protein 
HV 
Healthy volunteer 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
Index knee joint 
The knee joint affected by osteoarthritis and selected for primary assessment 
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CONFIDENTIAL 
INN 
International Nonproprietary Name 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
K-L 
Kellgren-Lawrence 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
NGF 
Neuronal growth factor 
NOAEL 
No-observed-adverse-effect level 
NSAID 
Non-steroidal anti-inflammatory drug 
OA 
Osteoarthritis 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PPS 
Per protocol set 
PT 
Preferred term 
Q4W 
Every 4 weeks 
QRS 
Complex of Q, R, and S waves on an electrocardiogram 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
RET 
Receptor tyrosine kinase 
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 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TrkA 
Tropomyosin receptor kinase A 
TRPV1 
Transient receptor potential caption channel subfamily V member 1 
ULN 
Upper limit of normal 
US 
United States 
vs 
Versus 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
WOMAC 
Western Ontario and McMaster Osteoarthritis Index 
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CONFIDENTIAL 
TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................9 
1. 
INTRODUCTION ......................................................................................................17 
1.1. 
Background .................................................................................................................17 
2. 
STUDY OBJECTIVES ..............................................................................................19 
2.1. 
Primary Objective .......................................................................................................19 
2.2. 
Secondary Objectives .................................................................................................19 
2.3. 
Exploratory Objectives ...............................................................................................19 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................20 
3.1. 
Hypothesis ..................................................................................................................20 
3.2. 
Rationale .....................................................................................................................20 
3.2.1. 
Rationale for Study Design .........................................................................................20 
3.2.2. 
Rationale for Dose Selection ......................................................................................21 
3.3. 
Risk-Benefit ................................................................................................................22 
4. 
STUDY ENDPOINTS AND VARIABLES ...............................................................22 
4.1. 
Primary and Secondary Endpoints..............................................................................22 
4.1.1. 
Primary Endpoint ........................................................................................................22 
4.1.2. 
Secondary Endpoints ..................................................................................................22 
4.1.2.1. 
Secondary Efficacy Endpoints ....................................................................................22 
4.1.2.2. 
Secondary Safety Endpoints .......................................................................................22 
4.1.3. 
Exploratory Endpoints ................................................................................................23 
4.2. 
Demographic and Baseline Characteristics ................................................................23 
4.3. 
Pharmacokinetic Variables .........................................................................................23 
4.4. 
Immunogenicity Variables ..........................................................................................23 
5. 
STUDY DESIGN .......................................................................................................24 
5.1. 
Study Description and Duration .................................................................................24 
5.1.1. 
Study Stopping Rules .................................................................................................24 
5.1.2. 
End of Study Definition ..............................................................................................25 
5.2. 
Planned Interim Analysis ............................................................................................25 
5.3. 
Study Committees .......................................................................................................25 
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5.3.1. 
Independent Data Monitoring Committee ..................................................................25 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............25 
6.1. 
Number of Patients Planned .......................................................................................25 
6.2. 
Study Population .........................................................................................................25 
6.2.1. 
Inclusion Criteria ........................................................................................................25 
6.2.2. 
Exclusion Criteria .......................................................................................................26 
6.3. 
Premature Withdrawal from the Study .......................................................................30 
6.4. 
Replacement of Patients .............................................................................................30 
7. 
STUDY TREATMENTS............................................................................................30 
7.1. 
Investigational Treatments ..........................................................................................30 
7.2. 
Rescue Treatment .......................................................................................................30 
7.3. 
Dose Modification and Study Treatment Discontinuation Rules ...............................31 
7.3.1. 
Dose Modification ......................................................................................................31 
7.3.2. 
Study Drug Discontinuation .......................................................................................31 
7.3.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................31 
7.4. 
Management of Acute Reactions ................................................................................31 
7.4.1. 
Acute Intravenous Infusion Reactions ........................................................................31 
7.4.1.1. 
Interruption of the Intravenous Infusion .....................................................................31 
7.4.1.2. 
Termination of the Intravenous Infusion ....................................................................32 
7.5. 
Method of Treatment Assignment ..............................................................................33 
7.5.1. 
Blinding ......................................................................................................................33 
7.5.2. 
Emergency Unblinding ...............................................................................................33 
7.6. 
Treatment Logistics and Accountability .....................................................................34 
7.6.1. 
Packaging, Labeling, and Storage ..............................................................................34 
7.6.2. 
Supply and Disposition of Treatments .......................................................................34 
7.6.3. 
Treatment Accountability ...........................................................................................34 
7.6.4. 
Treatment Compliance ................................................................................................34 
7.7. 
Concomitant Medications and Procedures .................................................................34 
7.7.1. 
Prohibited Medications and Procedures .....................................................................35 
7.7.2. 
Permitted Medications and Procedures ......................................................................35 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................36 
8.1. 
Schedule of Events .....................................................................................................36 
8.1.1. 
Footnotes for the Schedule of Events Table 1 ............................................................40 
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8.1.2. 
Footnotes for Schedule of Events for Follow-up Period of Patients Who 
Undergo Joint Replacement Surgery (Table 2) ..........................................................42 
8.1.3. 
Early Termination Visit ..............................................................................................42 
8.1.4. 
Unscheduled Visits .....................................................................................................42 
8.2. 
Study Procedures ........................................................................................................43 
8.2.1. 
Procedures Performed at the Screening/Baseline Visit ..............................................43 
8.2.1.1. 
Determination of Osteoarthritis of the Knee ..............................................................43 
8.2.1.2. 
Height .........................................................................................................................43 
8.2.1.3. 
Weight .........................................................................................................................43 
8.2.2. 
Efficacy Procedures ....................................................................................................44 
8.2.2.1. 
Western Ontario and McMaster Osteoarthritis Index .................................................44 
8.2.2.2. 
Patient Global Assessment of Osteoarthritis ..............................................................44 
8.2.3. 
Safety Procedures .......................................................................................................44 
8.2.3.1. 
Vital Signs ..................................................................................................................44 
8.2.3.2. 
Orthostatic Vital Sign Assessment .............................................................................44 
8.2.3.3. 
Physical Examination with Joint Exam ......................................................................45 
8.2.3.4. 
Electrocardiogram .......................................................................................................45 
8.2.3.5. 
Neurological Examination ..........................................................................................45 
8.2.3.6. 
Imaging .......................................................................................................................45 
8.2.3.7. 
Joint Pain Questionnaire .............................................................................................46 
8.2.3.8. 
End-of-Study Phone Call for Joint Replacement Status Questionnaire .....................46 
8.2.3.9. 
Knee Society Score for Joint Replacement Follow-up Only ......................................46 
8.2.3.10. 
Laboratory Testing ......................................................................................................46 
8.2.4. 
Drug Concentration and Measurements .....................................................................48 
8.2.5. 
Anti-Drug Antibody Measurements and Samples ......................................................48 
8.2.6. 
Biomarker, Pharmacodynamic, 
and Other Research .................48 
8.2.6.1. 
Pharmacodynamic and Biomarker Research ..............................................................48 
 
 
 
 
8.2.6.4. 
Collection of Arthroplasty Tissue Samples (Joint Replacement Surgery 
Only) ...........................................................................................................................49 
8.2.6.5. 
Histological Evaluation of Tissue Samples (Joint Replacement Surgery 
Only) ...........................................................................................................................49 
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8.2.6.6. 
Moticon Digital Insole Device Sub-Study for Gait Assessments ...............................49 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................50 
9.1. 
Obligations of Investigator .........................................................................................50 
9.2. 
Obligations of Sponsor ...............................................................................................50 
9.3. 
Definitions ..................................................................................................................50 
9.3.1. 
Adverse Event .............................................................................................................50 
9.3.2. 
Serious Adverse Event ................................................................................................51 
9.3.3. 
Adverse Events of Special Interest .............................................................................51 
9.3.4. 
Infusion Reactions ......................................................................................................51 
9.4. 
Recording and Reporting Adverse Events ..................................................................52 
9.4.1. 
Adverse Events ...........................................................................................................52 
9.4.2. 
Serious Adverse Events ..............................................................................................52 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor ...................................52 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................53 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results .............................53 
9.4.6. 
Follow-up ....................................................................................................................53 
9.5. 
Evaluation of Severity and Causality .........................................................................53 
9.5.1. 
Evaluation of Severity ................................................................................................53 
9.5.2. 
Evaluation of Causality ...............................................................................................54 
9.6. 
Safety Monitoring .......................................................................................................56 
9.7. 
Investigator Alert Notification ....................................................................................56 
10. 
STATISTICAL PLAN................................................................................................56 
10.1. 
Statistical Hypothesis ..................................................................................................56 
10.2. 
Justification of Sample Size........................................................................................57 
10.3. 
Analysis Sets ...............................................................................................................57 
10.3.1. 
Efficacy Analysis Sets ................................................................................................57 
10.3.2. 
Safety Analysis Set .....................................................................................................57 
10.3.3. 
Per Protocol Set ..........................................................................................................57 
10.3.4. 
Pharmacokinetic Analysis Sets ...................................................................................58 
10.3.5. 
Anti-Drug Antibody Analysis Sets .............................................................................58 
10.4. 
Statistical Methods ......................................................................................................58 
10.4.1. 
Patient Disposition ......................................................................................................58 
10.4.2. 
Demography and Baseline Characteristics .................................................................58 
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10.4.3. 
Efficacy Analyses .......................................................................................................58 
10.4.3.1. 
Primary Efficacy Analysis ..........................................................................................58 
10.4.3.2. 
Secondary Efficacy Analysis ......................................................................................59 
10.4.4. 
Safety Analysis ...........................................................................................................59 
10.4.4.1. 
Adverse Events ...........................................................................................................59 
10.4.4.2. 
Other Safety ................................................................................................................60 
10.4.4.3. 
Treatment Exposure ....................................................................................................60 
10.4.4.4. 
Treatment Compliance ................................................................................................61 
10.4.5. 
Pharmacokinetics ........................................................................................................61 
10.4.5.1. 
Analysis of Drug Concentration Data .........................................................................61 
10.4.5.2. 
Pharmacokinetics and Pharmacokinetics/Pharmacodynamics Analyses ....................61 
10.4.6. 
Analysis of Anti-Drug Antibody Data ........................................................................61 
10.5. 
Interim Analysis ..........................................................................................................61 
10.6. 
Additional Statistical Data Handling Conventions .....................................................62 
10.7. 
Statistical Considerations Surrounding the Premature Termination of a Study .........62 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS .....................................62 
11.1. 
Data Management .......................................................................................................62 
11.2. 
Electronic Systems ......................................................................................................63 
12. 
STUDY MONITORING ............................................................................................63 
12.1. 
Monitoring of Study Sites ...........................................................................................63 
12.2. 
Source Document Requirements ................................................................................63 
12.3. 
Case Report Form Requirements ................................................................................63 
13. 
AUDITS AND INSPECTIONS .................................................................................64 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................64 
14.1. 
Good Clinical Practice Statement ...............................................................................64 
14.2. 
Informed Consent .......................................................................................................64 
14.3. 
Patients Confidentiality and Data Protection ..............................................................65 
14.4. 
Institutional Review Board/Ethics Committee ...........................................................65 
14.5. 
Clinical Study Data Transparency ..............................................................................66 
15. 
PROTOCOL AMENDMENTS ..................................................................................66 
16. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................66 
16.1. 
Premature Termination of the Study ...........................................................................66 
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16.2. 
Close-out of a Site ......................................................................................................66 
17. 
STUDY DOCUMENTATION ...................................................................................67 
17.1. 
Certification of Accuracy of Data ...............................................................................67 
17.2. 
Retention of Records ..................................................................................................67 
18. 
DATA QUALITY ASSURANCE ..............................................................................67 
19. 
CONFIDENTIALITY ................................................................................................68 
20. 
FINANCING AND INSURANCE .............................................................................68 
21. 
PUBLICATION POLICY ..........................................................................................68 
22. 
REFERENCES ...........................................................................................................68 
23. 
INVESTIGATOR’S AGREEMENT ..........................................................................71 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................72 
 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................37 
Table 2: 
Schedule of Events for Follow-up Period of Patients Who Undergo Joint 
Replacement Surgery ..................................................................................................42 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................24 
 
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1. 
INTRODUCTION  
1.1. 
Background 
Osteoarthritis (OA) is the most prevalent joint disease and a leading source of chronic pain and 
disability within the United States (US) (Murray, 2013) and other developed nations (Vos, 2012). 
Across the European Union (EU) Member States, OA prevalence has been reported to vary from 
2.8% in Romania to 18.3% in Hungary (Network EMCSaI, 2012). From 2013 to 2015 in the US, 
49.6% of adults age 65 years and older reported having a diagnosis of OA, and the prevalence 
continues to rise (Centers for Disease Control and Prevention). As the world’s population 
continues to age, it is estimated that degenerative joint disease disorders such as OA will impact 
at least 130 million individuals around the globe by the year 2050 (Maiese, 2016).  
Knee OA accounts for over 80% of the disease total burden (Vos, 2012). Knee OA is estimated 
to affect at least 19% of American adults 45 years of age and older (Lawrence, 2008). Across 
Europe, a lifetime risk of knee OA is estimated to be 45% (Kingsbury, 2014). More than half of 
patients with symptomatic knee OA are younger than age 65 years and will live for at least 3 
decades after the initial diagnosis, making the burden of knee OA particularly large (Deshpande, 
2016). 
A wide variety of interventions have been evaluated for the management of pain due to OA, 
including: 1) non-pharmacological modalities (eg, education, exercise, and provision of walking 
aids); 2) pharmacological treatments, including acetaminophen, nonsteroidal anti-inflammatory 
drugs (NSAIDs), opioids, and other centrally-active drugs (such as antidepressants); and 
3) intra-articular injections of glucocorticoid and hyaluronan preparations and surgical 
treatments. Surgical treatments alone include a variety of approaches, such as knee aspiration 
and joint lavage, as well as osteotomy, knee fusion, and total joint replacement (Malfait, 2013) 
(Zhang, 2007). However, with the exception of radical surgical interventions, such as total joint 
replacement, the majority of patients do not receive adequate pain relief either because these 
approaches have suboptimal efficacy and/or because their use is limited by tolerability and 
toxicity. Non-pharmacological approaches are less efficacious than pharmacological treatments 
(Zhang, 2007). Among surgical treatments, reliable standardized effect size has been calculated 
for arthroscopic lavage and debridement, which were found to be no more effective than placebo 
(Zhang, 2007). The limitations of currently available analgesic therapies include a variety of 
adverse effects associated with each available treatment. Use of acetaminophen carries a risk of 
hepatic toxicity and of serious allergic reactions. Use of NSAIDs is associated with 
gastrointestinal bleeding and ulceration, cardiovascular events, and renal toxicity. Opioid agents 
are characterized by central nervous system depression, nausea, vomiting, and potential for 
abuse. Inadequate pain relief has a profound impact on the quality of life for patients with an 
associated great cost to society, including healthcare costs and loss of productivity. With the 
increasing number of OA patients, there is a growing unmet medical need for additional 
treatment options with improved pain relief and fewer associated side-effects. 
Glial cell-line-derived neurotrophic factor (GDNF) receptor alpha-3 (GFRα3) is 1 of at least 4 
members 
of 
the 
GDNF 
receptor 
alpha 
(GFRα) 
family. 
These 
receptors 
are 
glycosylphosphatidylinositol-linked proteins expressed in the central and peripheral nervous 
systems and are involved in the sensitization of pain-sensing neurons known as nociceptors 
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(Naveilhan, 1998) (Worby, 1998) (Baloh, 1998a). Artemin, the only known ligand for GFRα3 
(Baloh, 1998b), is a member of the GDNF family of ligands, which also includes GDNF, 
neurturin, and persephin (Baudet, 2000). These secreted ligands signal through the single-pass 
membrane receptor tyrosine kinase (RET) by clustering it with a GFRα receptor (Durbec, 1996) 
(Jing, 1997) (Treanor, 1996) (Trupp, 1999). Functional specificity of RET signaling is achieved 
by the specific GDNF family member binding to its preferred GFRα receptor.  
In adult humans, GFRα3 receptors are localized to dorsal root, trigeminal and sympathetic 
ganglia, as well as peripheral nerves (Bespalov, 2007). GFRα3 is also expressed in the 
gastrointestinal system, and in mice this expression has been localized to the myenteric plexus of 
both the small and large intestine (unpublished results). Artemin RNA expression is observed in 
epithelial cells and keratinocytes (Mabbott, 2013) (unpublished results). Low levels of artemin 
RNA expression have also been reported in adult normal human tissues such as prostate, 
pituitary, and brain. Increased artemin RNA expression is reported in disease states such as 
chronic pancreatitis (Ceyhan, 2007), burning mouth syndrome (Shinoda, 2015), and atopic 
dermatitis (Murota, 2012). In conditions of tissue insult, such as local inflammation or trauma, it 
is hypothesized that the GFRα3-artemin signaling pathway is activated in small diameter sensory 
neurons (positive for RET, Tropomyosin receptor kinase A [TrkA], transient receptor potential 
caption channel subfamily V member 1 [TRPV1], and calcitonin gene-related peptide [CGRP] 
expression). This activation may in turn upregulate these pathways, leading to hyperalgesia or 
allodynia. In support of a role for GFRα3 signaling during pain states, pre-clinical studies have 
demonstrated that both anti-mouse and anti-human GFRα3 receptor antibodies induced 
significant reductions in tactile allodynia and thermal hyperalgesia in the peri-articular complete 
Freund’s adjuvant (CFA) model of inflammatory joint pain. Both mouse and human anti-GFRα3 
receptor antibodies also reduced the level of tactile allodynia in the destabilization of the medial 
meniscus mouse model of knee OA. The preclinical findings suggest that modulating the GFRα3 
pathway may provide an analgesic effect in patients with chronic pain conditions, such as pain 
due to OA of the knee.  
REGN5069 is a human IgG4 monoclonal antibody that binds GFRα3 with subnanomolar 
affinity. Through its binding to the extracellular domain of GFRα3, REGN5069 interferes with 
the interaction of GFRα3 with RET and prevents GFRα3-mediated RET signaling. REGN5069 
was isolated from Regeneron Pharmaceuticals, Inc.’s (Regeneron’s) VelocImmune® human 
antibody mouse platform (Macdonald, 2014) (Murphy, 2014) and contains a human light chain 
variable domain fused to a human kappa constant domain and a human heavy chain variable 
region fused to a human IgG4 constant domain. The IgG4 constant domain contains a serine to 
proline amino acid substitution (S228P, Eu numbering, designated IgG4P) in the hinge region 
that reconstructs the human IgG1 hinge sequence (CPPC) to promote stabilization of disulfide 
bonds between the 2 heavy chains (Yang, 2014).  
A first-in-human (FIH) randomized, double-blind, placebo-controlled, single ascending dose 
study of safety, tolerability, and pharmacokinetics (PK) of REGN5069 is currently ongoing in 
healthy volunteers. The design includes 7 cohorts: 5 cohorts to receive REGN5069 via 
intravenous (IV) injection of 30 mg, 100 mg, 300 mg, 1000 mg, or 3000 mg, and 2 cohorts to 
receive 300 mg or 600 mg by subcutaneous (SC) injection. To date, at which point dosing has 
been completed in the FIH study, REGN5069 has been well tolerated and no serious or severe 
adverse events (AEs) have been reported.  
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To the best of the sponsor’s knowledge, REGN5069 is the first-in-class antibody intervening in 
the GFRα3 signaling pathway to be developed as a potential analgesic agent. This proof-of-
concept study is designed to evaluate efficacy and safety of 2 IV doses of REGN5069 in male 
and female patients with chronic pain due to knee OA after 12 weeks of treatment. The higher 
dose regimen is selected to maintain REGN5069 serum concentrations in excess of those 
associated with efficacy in a mouse model of thermal hyperalgesia and/or those associated with 
saturation of target-mediated disposition in serum, for the duration of each dosing interval. A 
lower dose regimen, which is expected to provide adequate separation in exposure and effect, 
also will be evaluated. 
Additional background information on REGN5069 and the development program may be found 
in the current version of the Investigator’s Brochure.   
2. 
STUDY OBJECTIVES  
2.1. 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of REGN5069 compared to placebo 
in patients with pain due to radiographically-confirmed OA of the knee who have a history of 
inadequate joint pain relief or intolerance to current analgesic therapy. 
2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
 To characterize the concentrations of functional REGN5069 in serum over time when 
patients are treated for up to 12 weeks 
 To assess the safety and tolerability of REGN5069 compared with placebo when 
patients are treated for up to 12 weeks 
 To measure levels of anti-drug antibodies (ADAs) against REGN5069 following 
multiple IV administrations  
2.3. 
Exploratory Objectives  
The exploratory objectives of the study are: 
 To evaluate the effect of REGN5069 on inflammation in patients compared to that of 
placebo 
 To evaluate the use of a digital, wearable, insole device to assess gait parameters and 
functional mobility in patients with OA of the knee without an analgesic treatment 
and after administration of a potential analgesic treatment  
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3. 
HYPOTHESIS AND RATIONALE  
3.1. 
Hypothesis 
Based on its mechanism of action, REGN5069 is expected to provide clinically meaningful pain 
relief as assessed by the Western Ontario and McMaster Osteoarthritis Index (WOMAC) pain 
subscale score in patients with pain due to radiographically-confirmed OA of the knee.  
3.2. 
Rationale 
3.2.1. 
Rationale for Study Design 
This randomized, double-blind, multi-dose, parallel-arm, placebo-controlled study is designed to 
evaluate the safety and efficacy of REGN5069 in patients with pain due to OA of the knee who 
have a history of inadequate pain relief from acetaminophen* and a history of intolerance or 
inadequate pain relief from oral NSAIDs (eg, prescription NSAIDs or over the counter NSAIDs 
at or near prescription doses), and opioid therapy or unavailability of opioid therapy. This study 
will guide further clinical development of REGN5069.  
No safety concerns related to inhibition of the GFRα3 receptor have been identified either in the 
literature or in preclinical toxicology studies performed by the sponsor. Preliminary safety data 
from the FIH study, including the 3000 mg IV cohort in healthy subjects, indicate that 
REGN5069 is well tolerated and that the safety is adequate for continued development. At the 
same time, the present study is planned to be conducted in patients suffering from chronic pain 
due to knee OA, who are either intolerant to or whose pain is not adequately relieved by the 
currently available analgesic agents, including acetaminophen, NSAIDs, and opioids. In 
addition, all of these agents are associated with risks of significant adverse effects, including 
gastrointestinal bleeding, increased risk of cardiovascular events and kidney damage associated 
with long-standing use of NSAIDs, and nausea, constipation, cognitive deficits, and undesired 
behaviors such as abuse and addiction associated with chronic use of opiates. Therefore, the 
subset of OA patients eligible for this study represents a patient population with an unmet 
medical need in whom the high disease burden of painful knee OA and the available safety and 
tolerability information for REGN5069 indicate that it is appropriate to prospectively study the 
hypothesis that REGN5069 provides substantial benefit (ie, clinically meaningful relief of pain 
from knee OA) and has an acceptable safety profile. Rescue medication (acetaminophen) will be 
allowed for any patient with breakthrough pain.  
The study design is based on similar studies in the therapeutic area of chronic pain relief. The 
WOMAC survey, from which the primary endpoint and many of the secondary efficacy 
endpoints will be assessed, is a validated measurement used to assess pain, stiffness, and daily 
functioning in patients with OA.  
Studies investigating agents that block neuronal growth factor (NGF) in a patient population with 
chronic pain due to OA have identified safety concerns, especially adjudicated arthropathies. The 
mechanism for these effects remain unknown but some have postulated that the arthropathy is 
related, at least in part, to the analgesia. Other serious potential risks include those related to 
sympathetic blockade, including potential effects on blood pressure. Accordingly, rigorous, 
precautionary safety monitoring (Section 8.2.3), including regular X-ray and magnetic resonance 
imaging (MRI), a joint pain questionnaire, and physical examinations with a focus on joints, 
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neurological examinations, monitoring of orthostatic vital signs, and laboratory testing is 
implemented in this study. In addition, a prolonged safety follow-up period of 24 weeks (twice 
the duration of the treatment period) is included in this study. While at present, there is no 
evidence that safety concerns associated with anti-NGF agents are associated with blocking 
GFRα3, this rigorous medical monitoring is implemented to identify and protect patients against 
such potential concerns. Additionally, an end-of-study phone call approximately 52 weeks after 
the first dose of study drug will be conducted to collect long-term information beyond the 
follow-up period regarding whether a patient underwent, is scheduled for, or is on a waiting list 
to receive joint replacement surgery, or whether joint replacement was recommended but the 
patient elected to defer. 
* Note: The International Nonproprietary Name (INN) for acetaminophen is paracetamol. This 
protocol will use the US Adopted Name acetaminophen.  
3.2.2. 
Rationale for Dose Selection 
Two dose regimens are planned for evaluation in this study. The high dose, 1000 mg IV Q4W, 
aims to deliver concentrations of REGN5069 in serum expected to exceed those associated with 
efficacy in a mouse thermal hyperalgesia model and those associated with target saturation in 
serum, for the duration of each dosing interval. The goal for the low dose, 100 mg IV Q4W, is to 
probe the dose-response curve with a dose expected to have adequate separation in exposure 
from the high dose and have efficacy that is less than that associated with the high dose but still 
measurably greater than the control.  
For the high dose regimen, the target serum concentration to be exceeded at the end of each 
dosing interval (trough concentration [Ctrough]) includes 80 mg/L, the mean Ctrough for a dose with 
near maximal efficacy identified in a mouse artemin thermal hyperalgesia model, and the 
concentration of REGN5069 in serum associated with saturation of GFRα3. The latter was 
estimated using the available human PK data from the R5069-HV-1810 FIH study (Clinical 
Pharmacology data memo 19 Mar 2019). Both pharmacokinetic and pharmacodynamic (PK/PD) 
data in mice and serum target saturation data in humans were considered since it is not currently 
known which is better correlated with efficacy in humans. As noted above, the high dose 
regimen is selected to maintain serum concentrations of REGN5069 above these target 
concentrations through the end of each dosing interval and to yield a cumulative area under the 
curve (AUC) for the entire treatment period less than that observed for the no-observed-adverse-
effect level (NOAEL) dose of 50 mg/kg in the 13-week monkey toxicology study. Based on 
population PK simulations in a virtual population of 500 subjects, a 1000 mg IV Q4W dosing 
regimen is predicted to yield a serum Ctrough increasing from ~100 mg/L at the end of the first 
dosing interval to ~200 mg/L at the end of the last dosing interval, and a cumulative AUC 
~8-fold less than that observed for the 13-week monkey NOAEL.  
For the low dose regimen, the target serum concentration to be exceeded at the end of each 
dosing interval is 3 mg/L, the estimated mean Ctrough in serum for the minimally efficacious dose 
in a mouse CFA inflammatory joint pain model. Based on population PK simulations, a 100 mg 
IV Q4W dosing regimen is predicted to yield a Ctrough increasing from ~8 mg/L at the end of the 
first dosing interval to ~11 mg/L at the end of the last dosing interval, with a cumulative AUC 
~93-fold less than that observed for the 13-week monkey NOAEL.  
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3.3. 
Risk-Benefit 
Based on the FIH study, the doses selected for this study (Section 3.2.2), and the extensive 
medical monitoring that will be performed (Section 8.2.3), the sponsor expects minimal risk to 
the study participants. Patients with a diagnosis of OA of the knee who participate in this study 
may benefit from study drug administration by experiencing relief of pain due to OA. 
Considering the unmet medical need for patients with pain due to OA, the sponsor considers the 
benefit-risk to be positive for this study. 
Additional risk-benefit assessment information on REGN5069 may be found in the current 
version of the Investigator’s Brochure.  
4. 
STUDY ENDPOINTS AND VARIABLES 
4.1. 
Primary and Secondary Endpoints 
4.1.1. 
Primary Endpoint 
The primary endpoint of the study is the change from baseline to week 12 in the WOMAC pain 
subscale score in patients treated with REGN5069 compared to patients treated with placebo. 
4.1.2. 
Secondary Endpoints 
4.1.2.1. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints of the study are: 
 Change from baseline to week 12 in the WOMAC total score (based on the full 
survey) in patients treated with REGN5069 compared to patients treated with placebo 
 Change from baseline to week 12 in the WOMAC physical function subscale score in 
patients treated with REGN5069 compared to patients treated with placebo 
 Change from baseline to week 12 in the Patient Global Assessment score in patients 
treated with REGN5069 compared to patients treated with placebo 
 Change from baseline to week 12 in WOMAC stiffness subscale score in patients 
treated with REGN5069 compared to patients treated with placebo 
 Percentage of patients treated with REGN5069, compared to that of patients treated 
with placebo, who had a response at week 12, with response defined as an 
improvement by ≥30% in the WOMAC pain subscale scores 
4.1.2.2. 
Secondary Safety Endpoints 
The secondary safety endpoints of the study are: 
 The incidence of treatment-emergent adverse events (TEAEs) in patients treated with 
REGN5069 compared to patients treated with placebo throughout the study duration 
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 The incidence of imaging abnormalities consistent with accelerated arthropathies as 
assessed by X-ray and MRI in patients treated with REGN5069 compared to patients 
treated with placebo throughout the study duration 
 Presence of anti-REGN5069 antibody development in patients treated with 
REGN5069 compared to patients treated with placebo throughout the study duration 
4.1.3. 
Exploratory Endpoints 
The exploratory endpoints of the study are: 
 Area under the curve for WOMAC pain subscale score (for the 12-week treatment 
period) for patients treated with REGN5069 compared to patients treated with 
placebo 
 Change in high sensitivity C-reactive protein (hsCRP) from baseline to week 12 in 
patients treated with REGN5069 compared to patients treated with placebo 
 Change in alkaline phosphatase from baseline to week 12 in patients treated with 
REGN5069 compared to patients treated with placebo 
 Conditional endpoints: if a mean 10% increase in alkaline phosphatase is observed at 
week 4, CTX-1, P1NP, Osteocalcin, C1M, and C3M will be measured and change 
from baseline to week 12 in patients treated with REGN5069 compared to patients 
treated with placebo will be exploratory endpoints 
 Change in gait and functional mobility parameters recorded by a wearable insole 
device from baseline to week 12 in a subset of patients treated with REGN5069 
compared to patients treated with placebo at participating sites 
4.2. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height, etc.), 
disease characteristics including medical and surgical history, and medication history for each 
patient. 
4.3. 
Pharmacokinetic Variables 
The PK variable is the concentration of functional REGN5069 in serum at each time point that 
sample is collected (Table 1). 
4.4. 
Immunogenicity Variables 
The immunogenicity variables are ADA status and titer for analyzed samples collected at the 
specified study site visits (Table 1).  
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5. 
STUDY DESIGN  
5.1. 
Study Description and Duration 
This multicenter phase 2 study is planned for US and ex-US study site locations. The study 
consists of a screening period of up to 30 days, followed by a 12-week randomized, 
double-blind, placebo-controlled treatment period, a 24-week follow-up period, and an end-of-
study phone call approximately 52 weeks after the first dose of study drug (Figure 1). The 
purpose of the end-of-study phone call is to determine whether a patient underwent, is scheduled 
for, or is on a waiting list to receive joint replacement surgery, or whether joint replacement was 
recommended but the patient elected to defer. Thus, each patient will be enrolled in the study for 
approximately 56 weeks, including the screening period and the period up to the end-of-study 
phone call. Patients will be randomized in a 1:1:1 ratio to receive a low dose of REGN5069 at 
100 mg IV Q4W, a high dose of REGN5069 at 1000 mg IV Q4W, or matching placebo Q4W 
(Section 7). The index knee joint is defined as the knee joint affected by OA and selected for 
primary assessment for this study. Randomization will be stratified by Kellgren-Lawrence (K-L) 
category (2-3 vs 4) of the index knee joint at the screening visit and participation in the Moticon 
sub-study (yes vs no). The use of the stratification factor based on participation in the Moticon 
sub-study ensures balance in the treatment assignments within the Moticon sub-study.  
Efficacy will be measured according to the assessments detailed in Section 8.2.2. Safety will be 
assessed according to the procedures in Section 8.2.3.  
Figure 1: 
Study Flow Diagram 
 
 
Screening 
Period 
 
Treatment Perioda 
 
Follow-Up Period 
 
Phone Call for 
Joint 
Replacement 
Status 
Questionnaire 
 
 
 
 
 
 
 
 
Up to 30 
days 
12 weeks 
24 weeks 
16 weeks 
 
 
Day 1 
(Baseline) 
 
Week 12 
(End of Treatment) 
 
Week 36 
(End of Follow-up) 
Week 52 
(End of Study) 
 
 
 
a - Study drug will be administered every 4 weeks throughout the 12-week treatment period. Thus, study drug will be 
administered at the day 1 (baseline) visit and at the week 4 and week 8 visits. 
5.1.1. 
Study Stopping Rules 
An independent Data Monitoring Committee (IDMC) will monitor unblinded data 
(Section 5.3.1). Based on these reviews in the context of the totality of evidence, if there are 
significant concerns at any time regarding a safety issue, the IDMC may make a 
recommendation to the sponsor to temporarily pause, alter, or terminate the study. Once 
recommendations from the IDMC have been received, further discussions may be conducted, if 
appropriate, and the sponsor will determine if these or other actions should be taken.  
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5.1.2. 
End of Study Definition 
The end of study is defined as the date when the last patient completes the last phone call, 
withdraws from the study, or is lost to follow-up (ie, the patient can no longer be contacted by 
the investigator).  
5.2. 
Planned Interim Analysis  
No interim analysis is planned. Upon completion of 12 weeks of treatment for all patients, a 
12-week analysis will be performed for the primary efficacy endpoint.  
5.3. 
Study Committees  
5.3.1. 
Independent Data Monitoring Committee 
An IDMC will be implemented in the study. The IDMC will meet periodically to review 
unblinded data as the study progresses, and based upon the findings, will make recommendations 
to the sponsor about the conduct of the study. The IDMC will be comprised of independent 
statistical and medical/medical imaging experts. Further details will be defined in the IDMC 
charter.  
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
6.1. 
Number of Patients Planned 
Up to approximately 240 patients are planned for enrollment in this study. 
6.2. 
Study Population 
Men and women who are at least 40 years of age at the time of study entry with a clinical 
diagnosis of OA of the knee based on the American College of Rheumatology criteria with 
radiologic evidence of OA (K-L score ≥2) at the index knee joint. 
6.2.1. 
Inclusion Criteria  
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Male or female, ≥40 years of age at the screening visit 
2. Generally in good health at the screening visit 
3. Body mass index (BMI) ≤39 kg/m2 at the screening visit 
4. Clinical diagnosis of OA of the knee based on the American College of Rheumatology 
criteria (Altman, 1986) with radiologic evidence of OA (K-L score ≥2) at the index joint 
at the screening visit 
 The index joint is defined as the joint with OA under evaluation for this study 
 A joint that has previously undergone joint replacement surgery cannot be the index 
joint 
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 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 joint, the index joint is the joint 
with the greatest WOMAC pain subscore at the screening visit. If both knee 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 both knee 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 pain subscore of ≥4 at 
both the screening and baseline visits 
6. A history of inadequate pain relief from or intolerance to analgesics used for OA as 
defined by:  
 inadequate pain relief from acetaminophen, and 
 intolerance to or inadequate pain relief from at least 1 oral NSAID, and 
 intolerance to or inadequate pain relief from at least 1 opioid, or unwillingness to take 
opioid therapy or lack of access to opioid therapy 
7. History of regular use of analgesic medications for OA pain (defined as use with regular 
frequency with an optimal regimen over a period of at least 4 weeks), including NSAIDs, 
selective cyclooxygenase 2 inhibitors, opioids, acetaminophen, or combinations thereof 
within 2 years prior to screening 
8. No use of opioid medications for at least 4 weeks prior to the screening visit 
9. Willing to discontinue current acetaminophen or NSAID medications (oral or topical; 
except up to 150 mg/day of aspirin, which is permitted for cardiac prophylaxis) starting at 
the screening visit through the end of the study treatment 
10. Willing to maintain current activity and exercise levels throughout the study 
11. Willing to provide follow-up information related to any joint replacement surgery that 
occurs within the period of time covered by the patient’s intended participation in the 
study 
12. Willing to consent to providing joint material and having histological and molecular 
analyses conducted on this material if the patient undergoes a joint replacement surgery 
while participating in the study 
13. Willing and able to comply with clinic visits and study-related procedures 
14. Provide informed consent signed by study patient or legally acceptable representative 
15. Able to understand and complete study-related questionnaires 
6.2.2. 
Exclusion Criteria  
A patient who meets any of the following criteria will be excluded from the study: 
1. Diagnosis of systemic diseases that may affect joints, including but not limited to 
inflammatory joint diseases, pseudogout, endocrinopathies (with exception of 
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hypothyroidism), lupus erythematosus, rheumatoid arthritis, joint infections, neuropathic 
disorders, avascular necrosis, Paget’s disease, renal osteodystrophy, sickle cell disease, 
including S-C disease and S-β thalassemia, or tumors. 
Note: Patients with a history of hypothyroidism must have thyroid-stimulating hormone 
levels measured and must be in an euthyroid state to be eligible for study participation. 
2. History or presence of osteonecrosis, destructive arthropathy, neuropathic joint 
arthropathy, pathologic fractures in any shoulder, hip, or knee joint(s), hip dislocation 
(prosthetic hip dislocation is eligible), or knee dislocation (patella dislocation is eligible) 
at the screening visit. Presence of subchondral insufficiency fracture on screening films 
or MRI as assessed by the central imaging reader. 
3. Trauma to the index joint within 30 days prior to the screening visit, significant enough in 
the opinion of the investigator to interfere with response to investigational agent 
4. Active fibromyalgia, as diagnosed by the investigator and/or documented in the patient’s 
medical history, regional pain caused by lumbar or cervical compression with 
radiculopathy or other moderate-to-severe pain that may confound assessments or 
self-evaluation of the pain associated with OA 
5. Is scheduled for a joint replacement surgery to be performed during the study period 
6. Not suitable for MRI scan in the judgement of the investigator 
7. Received an intra-articular injection of hyaluronic acid in any joint within 90 days prior 
to the screening visit 
8. Systemic (ie, IV, oral, or intramuscular) corticosteroids within 30 days prior to the 
screening visit. Intra-articular corticosteroids in the index joint within 12 weeks prior to 
the screening visit, or to any other joint within 30 days prior to the screening visit 
(topical, intranasal, or inhaled corticosteroids are permitted). 
9. Use of a monoamine reuptake or a monoamine oxidase inhibitor (eg, tricyclic 
antidepressants, selective serotonin reuptake inhibitors, and serotonin norepinephrine 
reuptake inhibitors) for treatment of pain within 4 weeks prior to the screening visit.  
Notes:  
 Use of a monoamine reuptake or monoamine oxidase inhibitor is acceptable if used 
for treatment of anxiety and/or depression at a stable dose during at least 3 months 
prior to screening 
 If in the judgement of an investigator a monoamine reuptake or a monoamine oxidase 
inhibitor is used for treatment of both pain and anxiety/depression at a stable dose 
during at least 3 months prior to screening, use of the monoamine reuptake or 
monoamine oxidase inhibitor is acceptable if the investigator is able to provide 
appropriate documentation (eg, medical records with appropriate diagnoses, clinical 
opinions of the patient’s treating physicians, documentation of the investigator’s 
clinical opinion). 
10.  History or presence at the screening visit of multiple sclerosis, autonomic neuropathy, 
diabetic neuropathy, or other peripheral neuropathy 
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11. 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 
12. History of hospital admission for depression or suicide attempt within 5 years or active, 
severe major depression at screening 
13. Resting heart rate of <45 beats per minute (bpm) (by vital sign assessment or as captured 
during electrocardiogram [ECG] assessment) or history or presence of second- or 
third-degree heart block at the screening visit. Resting heart rate may be rechecked up to 
2 times at the screening visit. 
14. History or presence of orthostatic hypotension at the screening visit. If the initial 
assessment for orthostatic hypotension is positive, orthostatic vital signs can be repeated 
up to 2 more times to confirm orthostatic hypotension prior to making the decision to 
exclude the patient. Refer to Section 8.2.3.2 for more information regarding this 
assessment. 
15. History of poorly controlled hypertension, as defined by: 
 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, peripheral arterial disease, and 
moderate-to-advanced retinopathy [hemorrhages or exudates, papilledema]).  
Note: Blood pressure can be rechecked twice at the screening visit.  
16. History of myocardial infarction, acute coronary syndromes, transient ischemic attack, or 
cerebrovascular accident within 12 months prior to the screening visit 
17. Poorly controlled diabetes (defined as hemoglobin A1c [HbA1c] >9.0%) at the screening 
visit. This parameter may be re-checked once during the screening period.  
18. Known history of human immunodeficiency virus (HIV) infection, except for patients 
who are stable on treatment for at least 1 year prior to the screening visit 
19. 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.  
20. 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. 
21. History or presence of malignancy within approximately 5 years prior to screening or 
continuing active treatment of malignancy regardless of history, except patients who have 
been treated successfully with no recurrence for >1 year of basal or squamous cell 
carcinoma of the skin or in situ cervical cancer 
22. Known allergy or sensitivity to doxycycline or related compounds, or monoclonal 
antibodies 
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23. History of (within approximately 5 years prior to the screening visit) or current 
alcoholism, alcohol abuse, substance abuse, or abuse of prescription pain medication, as 
documented in the medical history or in the judgement of the investigator 
24. History of cannabis use for the treatment of pain or for recreational use within 
approximately the past 6 months prior to the screening visit 
25. Participation in any clinical research study evaluating another investigational drug within 
30 days or at least 5 half-lives, whichever is longer, of the investigational drug, prior to 
the screening visit 
26. History of exposure to an anti-NGF treatment 
27. Members of the clinical site study team and/or his/her immediate family, unless prior 
approval granted by the Sponsor 
28. Sexually active men who are unwilling to use the following forms of medically 
acceptable birth control during the study drug treatment period and for at least 9 months 
after the last dose of study drug: vasectomy with medical assessment of surgical success 
OR consistent use of a condom. Sperm donation is prohibited during the study and for at 
least 9 months after the last dose of study drug.  
29. Women of childbearing potential (WOCBP)* who have a positive pregnancy test result, 
or who do not have their pregnancy test results at baseline. 
30. Pregnant or breastfeeding women. 
31. Women of childbearing potential* who are unwilling to practice highly effective 
contraception from the screening visit until at least 9 months after the last dose of study 
drug. Highly effective contraceptive measures include: 
a. stable use of combined (estrogen and progestogen containing) hormonal 
contraception (oral, intravaginal, transdermal) or progestogen-only hormonal 
contraception (oral, injectable, implantable) associated with inhibition of ovulation 
initiated 2 or more menstrual cycles prior to screening 
b. intrauterine device; intrauterine hormone-releasing system 
c. bilateral tubal ligation 
d. vasectomized partner 
e. and/or sexual abstinence†, ‡ 
* Postmenopausal women must be amenorrheic for at least 12 months and must have 
follicle-stimulating hormone (FSH) in the postmenopausal range in order not to be 
considered of childbearing potential. Pregnancy testing and contraception are not 
required for women with documented hysterectomy or tubal ligation.  
† Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the 
study 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 patient. 
‡ Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method are not 
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acceptable methods of contraception. Female condom and male condom should not 
be used together.  
32. Use of genicular nerve block or any similar procedure(s) within 3 months of the 
screening visit 
6.3. 
Premature Withdrawal from the Study 
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and/or sponsor have the right to withdraw a patient from the study if it is no 
longer in the interest of the patient to continue in the study, or if the patient’s continuation in the 
study places the scientific outcome of the study at risk (eg, if a patient does not or cannot follow 
study procedures). An excessive rate of withdrawals would render the study uninterpretable; 
therefore, unnecessary withdrawal of patients should be avoided. 
Patients who are withdrawn prematurely from the study will be asked to complete study 
assessments, as described in Section 8.1.3.  
Rules for discontinuation of study treatment are discussed in Section 7.3.2.  
6.4. 
Replacement of Patients  
Patients prematurely withdrawn from the study or study drug will not be replaced. 
7. 
STUDY TREATMENTS  
7.1. 
Investigational Treatments 
REGN5069 will be supplied for this study in blinded kits as follows: 
 REGN5069 lyophilized powder, 265 mg in a vial 
 REGN5069 lyophilized powder, placebo in a vial 
Instructions for dose preparation and study drug administration are provided in the pharmacy 
manual. 
Randomized patients will receive a total of 3 fixed-dose IV infusions of either REGN5069 at 
100 mg, REGN5069 at 1000 mg, or placebo (depending on their treatment assignment) Q4W 
during the 12-week treatment period at the visits indicated in the Schedule of Events (Table 1).  
7.2. 
Rescue Treatment 
Starting at the screening visit until after the week-24 study visit is completed, acetaminophen is 
the only study-permitted rescue medication. Acetaminophen tablets of selected brand and 
strength will be provided to patients by the study site for use as rescue medication for 
breakthrough OA pain. In advance of initiating the study, each study site must consult with the 
sponsor and select the brand and the strength of acetaminophen tablets that will be dispensed to 
patients as rescue medication. In the event that pain relief for OA pain is inadequate, patients will 
take acetaminophen, as needed, in accordance with the instructions provided with the medication 
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by each study site, with a maximum of 3000 mg/day. To prevent liver damage, the maximum 
allowed daily dose of 3000 mg of acetaminophen must not be exceeded and excessive alcohol 
consumption must be avoided. The use of rescue medication is not allowed for 48 hours prior to 
the start of or during a scheduled study visit to minimize the confounding effects of rescue 
medication on efficacy measures.  
7.3. 
Dose Modification and Study Treatment Discontinuation Rules 
7.3.1. 
Dose Modification 
Dose modification for an individual patient is not allowed. 
7.3.2. 
Study Drug Discontinuation 
Patients who permanently discontinue from study drug and who do not withdraw from the study 
will be asked to return to the clinic for all remaining study visits and to participate in all study 
phone calls per the visit schedule. 
Patients who permanently discontinue from study drug and who opt to withdraw from the study 
will be asked to complete study assessments, per Section 8.1.3.  
7.3.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
Study drug dosing will be permanently stopped in the event of: 
 Continued noncompliance with the protocol-defined maximum allowed dosage of 
acetaminophen 
 Evidence of pregnancy 
 Serious or severe allergic reactions considered related to study drug 
 If there are specific types of liver dysfunction (eg, Hy’s law is met). Hy's law consists 
of elevation of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
by 3-fold of upper limit of normal (ULN) or more and elevation of serum total 
bilirubin by 2-fold of ULN or more and there are no other reasons to explain observed 
elevations in aminotransferases and bilirubin. 
 Patient withdraws consent  
7.4. 
Management of Acute Reactions 
7.4.1. 
Acute Intravenous Infusion Reactions 
Emergency equipment and medication for the treatment of infusion reactions must be available 
for immediate use. All infusion reactions must be reported as AEs (as defined in Section 9.4.1) 
and graded using the grading scales (as instructed in Section 9.5.1).  
7.4.1.1. 
Interruption of the Intravenous Infusion 
The infusion should be interrupted if any of the following AEs are observed: 
 cough 
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 rigors/chills 
 rash, pruritus (itching) 
 urticaria (hives, welts, wheals) 
 diaphoresis (sweating) 
 hypotension 
 dyspnea (shortness of breath) 
 vomiting 
 flushing 
The reaction(s) should be treated symptomatically, and the infusion may be restarted at 50% of 
the original rate or based on the clinical judgement of the investigator. 
If investigators feel there is a medical need for treatment or discontinuation of the infusion, they 
should use clinical judgment to provide the appropriate response according to typical clinical 
practice. 
7.4.1.2. 
Termination of the Intravenous Infusion 
The infusion should be terminated and NOT restarted if any of the following AEs occur: 
 Anaphylaxis* 
 laryngeal/pharyngeal edema 
 severe bronchospasm 
 chest pain 
 seizure 
 severe hypotension 
 other neurological symptoms (confusion, loss of consciousness, paresthesia, paralysis, 
etc.) 
 any other symptom or sign that, in the opinion of the investigator, warrants 
termination of the IV infusion 
*Consider anaphylaxis if the following is observed (Sampson, 2006): acute onset of an illness 
(minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, generalized 
hives, pruritus or ﬂushing, swollen lips-tongue-uvula) AND AT LEAST 1 OF THE 
FOLLOWING: 
 Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia) 
 Reduced blood pressure or associated symptoms of end-organ dysfunction 
(eg, hypotonia [collapse], syncope, incontinence)  
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7.5. 
Method of Treatment Assignment  
Up to approximately 240 patients will be randomized in a 1:1:1 ratio (approximately 80 patients 
per treatment group) to receive REGN5069 at 100 mg IV Q4W, REGN5069 at 1000 mg IV 
Q4W, or matching placebo Q4W according to a central randomization scheme provided by an 
Interactive Web Response System (IWRS) to the designated study pharmacist (or qualified 
designee). Randomization will be stratified by K-L category (2-3 vs 4) of the index knee joint at 
the screening visit and participation in the Moticon sub-study (yes vs no).  
7.5.1. 
Blinding  
Study patients, the principal/coordinating investigators, and study site personnel will remain 
blinded to all randomization assignments throughout the study. The Regeneron study team and 
contract research organization (CRO) personnel who are in regular contact with the study sites 
will remain blinded to all patient randomization assignments.  
Blinded study drug kits coded with a drug numbering system will be used. 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 and PK results will not be communicated to the sites before the end of the 
study and the final database lock, and the sponsor’s operational team will not have access to 
results associated with patient identification until after the final database lock.  
Selected individuals not involved in the conduct of the study may have access to unblinded data 
(individual treatment assignments) as needed for safety review or other data review. No study 
personnel involved in the day-to-day conduct of the study will have access to any individual 
unblinded data before the database is locked for this study.  
7.5.2. 
Emergency Unblinding 
Unblinding of treatment assignment for a patient may be necessary due to a medical emergency 
or any other significant medical event (eg, pregnancy) and when a treatment decision is 
contingent upon knowing the patient’s treatment assignment. Study drug will be discontinued for 
patients whose treatment has been unblinded.  
If unblinding is required: 
 Only the investigator will make the decision to unblind the treatment assignment. 
 Only the affected patients will be unblinded. 
 The designated study pharmacist(s)/designee at the study site will provide the 
treatment assignment to the investigator. If there is no study pharmacist, the 
investigator for the site will unblind the patient. Unblinding is performed using the 
IWRS, which will notify Regeneron.  
 The investigator will notify Regeneron and/or designee as soon as possible after 
unblinding the patient. 
Treatment assignment is not to be provided to site personnel, other than the unblinded study 
pharmacist (when applicable), at any time during the conduct of the study, except in the case of a 
true emergency and when a treatment decision is contingent on knowing the patient’s treatment 
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assignment. In the event that there is no study pharmacist, the individual at the site fulfilling that 
role will be the only unblinded member of the site personnel. 
7.6. 
Treatment Logistics and Accountability 
7.6.1. 
Packaging, Labeling, and Storage  
A medication numbering system will be used to label blinded investigational study drug. Lists 
linking medication numbers with product lot numbers will be maintained by the groups (or 
companies) responsible for study drug packaging. In order to maintain the blind, these lists will 
not be accessible to individuals involved in study conduct. 
Study drug will be stored at the site at a temperature of 2ºC to 8ºC; storage instructions will be 
provided in the pharmacy manual. 
7.6.2. 
Supply and Disposition of Treatments  
Study drug will be shipped at a temperature of 2ºC to 8ºC to the investigator or designee at 
regular intervals or as needed during the study. At specified time points during the study (eg, 
interim site monitoring visits), at the site close-out visit, and following drug reconciliation and 
documentation by the site monitor, all opened and unopened study drug will be returned to the 
sponsor or designee for destruction. 
7.6.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug. These records 
should contain the dates, quantity, and study medication 
 dispensed to each patient, 
 returned from each patient (if applicable), and 
 returned to the sponsor or designee. 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
7.6.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the 
sponsor and regulatory agency inspectors. 
7.7. 
Concomitant Medications and Procedures  
Any treatment administered and/or procedures performed from screening to the end of the 
follow-up period will be considered concomitant medication and/or procedures, respectively. 
This includes medications and/or procedures that were started before the study and are ongoing 
during the study.  
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7.7.1. 
Prohibited Medications and Procedures 
Patients will be required to discontinue all non-study-permitted pain medication (oral or topical) 
starting at the screening visit until after completion of the week-24 study visit. Concomitant 
medications that contain NSAIDs are prohibited from the screening visit until after completion 
of the week-24 study visit. This applies even if a patient discontinues study drug prematurely but 
remains in the study to participate in the remaining study visits. The only exception is 
aspirin/5-aminosalicylic acid, which is permitted for cardiac prophylaxis (Section 7.7.2). Opioid 
analgesic medications (including tramadol) are prohibited starting at least 4 weeks prior to the 
screening visit until the end of the follow-up period with no exceptions.  
Other excluded medications/procedures starting at the screening period include: 
 Any other investigational agent 
 Medical or regular recreational use of marijuana 
 Chondroitin sulfate 
 Glucosamine  
 Hyaluronic Acid Intra-articular injections 
 Anticoagulants and antiplatelets (eg, warfarin, heparins, factor Xa inhibitors, 
thrombin inhibitors, aspirin >150 mg daily, clopidogrel) 
 Muscle relaxants including cyclobenzaprine, carisoprodol, orphenadrine, tizanidine 
(see Section 7.7.2 for permitted muscle relaxants) 
 Corticosteroids (topical, intranasal, and inhaled formulations are permitted), 
adrenocorticotropic hormone 
 Cyclosporine, methotrexate, mycophenolate mofetil, tacrolimus (topical tarcolimus 
allowed) 
 Azathioprine, sulfasalazine, hydroxychloroquine 
 IL-6 or IL-6 receptor antagonists 
 Abatacept, ustekinumab  
 Tumor necrosis factor antagonists 
 IL-1 inhibitors, including diacerein  
 PDE-4 and Jak-kinase inhibitors 
 Genicular nerve block and any other similar procedures (prohibited from within 
3 months of the screening visit and up to the last study site visit in the follow-up 
period) 
7.7.2. 
Permitted Medications and Procedures 
Patients receiving any chronic medication therapy must be on a stable dose of such medication 
for at least 3 months prior to the screening visit except for the prohibited medications listed in 
Section 7.7.1.  
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Monoamine reuptake inhibitors (including selective serotonin reuptake inhibitors and serotonin 
norepinephrine reuptake inhibitors) and tricyclic antidepressants, are permitted for 
non-pain-related treatment.  
Low-dose aspirin/5-aminosalicylic acid (up to 150 mg/day) for cardiac prophylaxis is also 
permitted, per local guidelines. Acetaminophen taken acutely for treatment of non-OA pain or 
fever is also permitted; however, the total daily dosage limits cannot be exceeded, regardless of 
the reason for acetaminophen use. During the treatment period and through the week-24 study 
visit, acetaminophen use will be captured in the diary; use for relief of pain other than pain due 
to OA will be reported in the diary as “other.” During the screening period and after the week-24 
study visit is completed, acetaminophen taken for any reason will be reported as concomitant 
medication.  
Topical steroids and topical calcineurin inhibitors are permitted. 
Muscle relaxants, such as Skelaxin® (metaxalone) and others, are permitted. Prohibited muscle 
relaxants are listed in Section 7.7.1.  
Physical therapies (such as transcutaneous electrical nerve stimulation and acupuncture) are 
permitted during the study, provided that patients have been on a stable regimen for at least 
4 weeks prior to entering the trial and that they expect to maintain this regimen until the end of 
the follow-up period. 
Use of mobility aids (such as canes, crutches, and joint stabilization appliances) are also 
permitted, provided that patients have been on a stable level of usage for at least 4 weeks prior to 
screening. Patients will be encouraged to maintain their use of such aids at a stable level starting 
from the screening visit until the week-24 visit is completed. Use of mobility aids should be 
recorded in the CRF.  
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
8.1. 
Schedule of Events 
Study assessments and procedures are presented by study period and visit in Table 1. 
 
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Table 1: 
Schedule of Events 
 
Screening 
Period 
Treatment Period 
Follow-up Period 
EOS 
Study 
Procedure/Visit 
Screening 
Visit 1 
Base-
line 
Visit 2 
Visit  
3 
Visit  
4 
Visit  
5 
Visit  
6 
EOT 
Visit 7 
ET/ 
JR 
Pre-
op10 
Visit  
8 
PC 1 
Visit 
9 
PC 
2 
PC 
3 
EOF  
Visit 10 
ET/ 
JR 
Pre-
op10 
PC 
4 
Study Week 
 
 
Wk 1 
Wk 2 
Wk 4 
Wk 8 
Wk 12 
 
Wk 
16 
Wk 
20 
Wk 
24 
Wk 
28 
Wk 
32 
Wk 36 
 
Wk 
52 
Study Day (Visit 
Window, days) 
Up to 30 
days 
1 
8 
(±1) 
15  
(±3) 
29  
(±7) 
57 
(±7) 
85 
(±7) 
 
113 
(±7) 
141 
(±7) 
169 
(±7) 
197 
(±7) 
225 
(±7) 
253 
(±7) 
 
365 
(±7) 
Screening/Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and 
medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Weight 
X 
 
 
 
 
 
X 
X 
 
 
 
 
 
X 
X 
 
Dispense patient 
diary and train1 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Assessments2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WOMAC Pain 
Subscale 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WOMAC Full 
Survey 
 
X 
X  
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
X 
 
Patient Global 
Assessment of OA 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
X 
 
Treatment Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Check diary for 
recording of rescue 
medication use3 
 
 
X 
X 
X 
X 
X 
X 
 X 
 
X 
 
 
 
X 
 
Concomitant 
therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
IV study drug 
administration4 
 
X 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
Orthostatic vital 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
X 
 
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Screening 
Period 
Treatment Period 
Follow-up Period 
EOS 
Study 
Procedure/Visit 
Screening 
Visit 1 
Base-
line 
Visit 2 
Visit  
3 
Visit  
4 
Visit  
5 
Visit  
6 
EOT 
Visit 7 
ET/ 
JR 
Pre-
op10 
Visit  
8 
PC 1 
Visit 
9 
PC 
2 
PC 
3 
EOF  
Visit 10 
ET/ 
JR 
Pre-
op10 
PC 
4 
Study Week 
 
 
Wk 1 
Wk 2 
Wk 4 
Wk 8 
Wk 12 
 
Wk 
16 
Wk 
20 
Wk 
24 
Wk 
28 
Wk 
32 
Wk 36 
 
Wk 
52 
Study Day (Visit 
Window, days) 
Up to 30 
days 
1 
8 
(±1) 
15  
(±3) 
29  
(±7) 
57 
(±7) 
85 
(±7) 
 
113 
(±7) 
141 
(±7) 
169 
(±7) 
197 
(±7) 
225 
(±7) 
253 
(±7) 
 
365 
(±7) 
sign assessment5 
Physical 
examination with 
joint exam 
X  
(full) 
X  
(full) 
X  
(brief) 
  
X  
(brief) 
X  
(brief) 
X  
(full) 
X  
(full) 
X  
(brief) 
 
X  
(brief
) 
 
 
X  
(full) 
X  
(full) 
 
Electrocardiogram 
X 
 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
Neurologic 
examination 
X  
(full) 
X  
(brief) 
X  
(brief) 
  
 
 
X  
(full) 
X  
(full) 
X  
(brief) 
 
X  
(brief
) 
 
 
X  
(full) 
X  
(full) 
 
Radiograph 
collection (bilateral 
knees, hips, and 
shoulders, unless 
otherwise stated)6 
X 
 
 
 
 
 
X 
(index 
knee 
only) 
X7 
 
 
 
 
 
X  
X7 
 
MRI8 
X (index 
knee)9 
 
 
 
 
 
X 
(index 
knee) 
X 
(index 
knee)7 
 
 
 
 
 
X (index 
knee) 
X 
(index 
knee)7 
 
Joint pain 
questionnaire2 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Knee Society Score 
(for JR follow-
up)2,10 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Adverse events 
 
 
JR status 
questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Laboratory Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug and alcohol 
test11 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
 
Hematology12 
X 
X 
 
 
X 
X 
X 
X 
X 
 
X 
 
 
X 
X 
 
Blood chemistry12 
X 
X 
 
 
X 
X 
X 
X 
X 
 
X 
 
 
X 
X 
 
ESR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
Pregnancy test (for 
X 
X 
X  
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
X 
 
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Screening 
Period 
Treatment Period 
Follow-up Period 
EOS 
Study 
Procedure/Visit 
Screening 
Visit 1 
Base-
line 
Visit 2 
Visit  
3 
Visit  
4 
Visit  
5 
Visit  
6 
EOT 
Visit 7 
ET/ 
JR 
Pre-
op10 
Visit  
8 
PC 1 
Visit 
9 
PC 
2 
PC 
3 
EOF  
Visit 10 
ET/ 
JR 
Pre-
op10 
PC 
4 
Study Week 
 
 
Wk 1 
Wk 2 
Wk 4 
Wk 8 
Wk 12 
 
Wk 
16 
Wk 
20 
Wk 
24 
Wk 
28 
Wk 
32 
Wk 36 
 
Wk 
52 
Study Day (Visit 
Window, days) 
Up to 30 
days 
1 
8 
(±1) 
15  
(±3) 
29  
(±7) 
57 
(±7) 
85 
(±7) 
 
113 
(±7) 
141 
(±7) 
169 
(±7) 
197 
(±7) 
225 
(±7) 
253 
(±7) 
 
365 
(±7) 
WOCBP)13 
(serum) 
(urine) 
(urine) 
(urine) 
(urine) 
(urine) 
(urine) 
(seru
m) 
(urine
) 
(urine
) 
(serum) 
(seru
m) 
FSH14 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK, Biomarker, and Research Samples 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK sample  
 
X15 
X 
X  
X15 
X15 
X 
X 
X 
 
X 
 
 
X 
X 
 
ADA samples 
 
X 
(pre-
dose) 
 
 
 
 
X 
X 
 
 
 
 
 
X 
X 
 
hsCRP12 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
 
Research 
serum/plasma 
samples12 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X  
X  
 
DNA16 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RNA (whole 
blood) 
 
X 
 
X 
 
 
X 
X 
 
 
 
 
 
 
 
 
Moticon Insole Sub-study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moticon sub-study 
informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moticon insole 
training17 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moticon insole 
recording18 
 
X 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
ADA: Anti-drug antibody 
HbA1c: Hemoglobin A1c (Glycated hemoglobin) 
Pre-op: Pre-operative 
EOF: End of follow-up 
hsCRP: high sensitivity C-reactive protein 
V: Visit 
EOS: End of study 
IV: Intravenous 
Wk: Week 
EOT: End of treatment 
JR: Joint replacement 
WOCBP: Women of childbearing potential 
ESR: Erythrocyte sedimentation rate 
MRI: Magnetic resonance imaging 
WOMAC: Western Ontario and McMaster Osteoarthritis Index 
ET: Early termination 
PC: Phone call 
 
FSH: Follicle-stimulating hormone 
PK: Pharmacokinetic 
 
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8.1.1. 
Footnotes for the Schedule of Events Table 1 
1. The patient will receive a diary in which he/she will record use of study-permitted rescue 
medication from baseline through the week-24 study visit. The patient will receive 
training on use of the diary (can be conducted at the baseline visit or earlier at the 
discretion of the investigator). The patient will be required to bring the diary to each 
study visit and it will be collected at the week-24 visit, or early if the patient terminates 
the study early.  
2. Questionnaires (including WOMAC, Patient Global Assessment score, joint pain 
questionnaire, and Knee Society Score, if necessary) will be completed by the patient. 
These assessments should be the first procedures performed during study site visits at the 
indicated visits. 
3. At each study visit indicated in the schedule of events table (Table 1), study site 
personnel will check that the patient is recording his/her use of acetaminophen as the 
study-permitted rescue medication in the patient diary. Retraining on patient diary usage 
may be requested at any visit during the study, as needed. The diary will be returned at 
the week-24 visit or at the early termination visit, if applicable.  
4. Study drug administration will be the last procedure at each dosing visit, and will be done 
after all laboratory samples have been collected (except for those specifically stated for 
collection after study drug administration), and after all study assessments and procedures 
are performed. Patients will be observed in the clinic for 1 hour after study drug 
administration.  
5. Refer to Section 8.2.3.1 for more instructions surrounding the vital sign assessment and 
to Section 8.2.3.2 for instructions for rechecking orthostatic vital sign assessments and 
for defining orthostatic hypotension.  
6. In addition to scheduled imaging, radiographs should 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 or lasts at least 2 weeks (or less at the 
discretion of the investigator). Based on the imaging results, a patient may be 
discontinued from study drug. If this occurs, the patient should be asked to remain in the 
study and participate in study visits per the visit schedule.  
7. Early Termination: Imaging assessments (X-rays of bilateral knees, hips, and shoulders 
and MRI of the index knee) need to be repeated only if it has been >30 days since the 
joints were last imaged. If it has been ≤30 days since the joints were last imaged, imaging 
assessment may be completed at the discretion of the investigator.  
8. In addition to scheduled MRIs, an MRI should 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, lasts at least 2 weeks (or less at the discretion of the 
investigator), and if the X-rays are inconclusive. 
9. After the patient has otherwise met study eligibility criteria assessed during the screening 
period, an MRI of the index knee will be performed prior to the baseline visit.  
Confirmation that the images have been accepted and confirmed query-free by the central 
reader must be received by the site before the baseline visit. Confirmation that there are 
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no exclusionary findings on the MRI must be received from the central reader before a 
patient can be randomized. 
10. In the event that a patient must undergo joint replacement surgery during the study up to 
the end of the follow-up period at week 36, the patient will complete the early 
termination/joint replacement pre-operative visit as per Table 1 Schedule of Events and 
the procedures outlined in the schedule of events for joint replacement surgery follow-up 
(Table 2). The early termination/joint replacement pre-operative visit should be 
completed before the joint replacement surgery, if possible. 
11. In the event of a confirmed positive drug screen result for opiates and/or alcohol at 
screening, the patient will be excluded. A confirmed positive drug screen result for 
opiates and/or alcohol prior to the initial dose of study drug and/or during the treatment 
period must be discussed with the sponsor prior to administration of the next dose of 
study drug once the results are available. 
12. Blood samples to be obtained after at least approximately an 8-hour fast. 
13. In the event of a positive urine pregnancy test result, a serum pregnancy test should be 
performed. If the serum pregnancy test is negative, the patient may continue to receive 
study drug per the visit schedule. If the serum pregnancy test is positive, the patient 
should discontinue study drug, but should be asked to return to the clinic for all 
remaining study visits per the visit schedule. 
14. The FSH sample should be collected to confirm the postmenopausal status of a female 
patient.  
15. Two pharmacokinetic samples will be collected: the first sample prior to the dose 
administration and the second sample within 30 minutes after the end of infusion. 
16. Samples for DNA extraction should be collected at the baseline visit (pre-dose), but may 
be collected at any later study visit. 
17. Moticon insole training session will be conducted for patients in the Moticon insole 
device sub-study only, and will be held at participating clinical sites prior to recording 
sessions. 
18. Moticon insole recording sessions will be conducted for patients in the Moticon insole 
device sub-study only and will include a 3-minute walking test. 
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Table 2: 
Schedule of Events for Follow-up Period of Patients Who Undergo Joint 
Replacement Surgery 
 
Post-Operative1 
Long-Term1 
Follow-up Study Day (Visit window, days) 
Follow-up Visit 1 
4 weeks after joint 
replacement surgery 
Follow-up Visit 2 
20 weeks after joint 
replacement surgery 
Follow-up Day 29 (±7) 
Follow-up Day 140 (±7) 
Collection of surgically resected tissue for histological 
and molecular analyses 
X 
Treatment 
 
Concomitant medications and therapy 
X 
X 
Safety 
 
 
Medical history related to the joint replacement 
X 
X 
Adverse events 
 
Vital signs 
X 
X 
Physical examination with joint exam 
X 
X 
Knee Society Score2 
X 
X 
Radiograph of knees, hips, and shoulders (bilateral) 
 
X 
8.1.2. 
Footnotes for Schedule of Events for Follow-up Period of Patients Who Undergo 
Joint Replacement Surgery (Table 2) 
1. Any patient who has joint replacement surgery during the study up to the end of the 
follow-up period at week 36 will be asked to return to the site at 4 and 20 weeks after the 
surgery date for safety evaluations. Relevant information related to the surgery will be 
collected at the week-4 visit, including placement of the prosthesis and healing of the 
surgical wound. The visit at 20 weeks after surgery will include an assessment of OA 
progression (including repeat radiographs of both knees) and the collection of any 
information about joint-related pain or AEs (including joint replacement) that may have 
taken place since the last clinic visit. 
2. Formal post-operative assessment of joint replacements will be done by completing the 
Knee Society Score questionnaire for knee replacements. 
8.1.3. 
Early Termination Visit 
Patients who are withdrawn from the study before the primary endpoint visit (week 12) will be 
asked to return to the clinic for 2 visits: once for an early termination visit consisting of the early 
termination assessments described in Table 1 and again at the primary endpoint visit (week 12), 
for studies with a primary efficacy endpoint. Patients who are withdrawn from the study after the 
primary endpoint visit will be asked to return to the clinic for early termination assessments, 
only. 
8.1.4. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule. Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for 
any other reason, as warranted. 
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8.2. 
Study Procedures 
8.2.1. 
Procedures Performed at the Screening/Baseline Visit 
Inclusion and exclusion criteria will be assessed at the screening visit to determine study 
eligibility, including an assessment of medical and medication history. This will include the 
determination of whether a patient has a diagnosis of knee OA (Section 8.2.1.1). Height and 
weight measurements will be recorded at the screening visit to calculate BMI (see 
Section 8.2.1.2 and Section 8.2.1.3 for details on height and weight measurements, respectively). 
Demographics will be recorded at the screening visit to characterize the baseline population. 
Eligible patients are required to sign the informed consent form (ICF) prior to undergoing any 
study procedures. The inclusion and exclusion criteria will again be assessed at the baseline visit 
to confirm study eligibility.  
Patient diaries will be distributed to eligible and enrolled patients at the baseline visit or prior to 
the baseline visit if patient’s eligibility for the study has been established. Patients will be trained 
on use of the diary to record daily usage of study-permitted rescue medication in the event of 
breakthrough OA pain. Patients will be instructed to bring the diary to each study visit.  
Randomization will occur for eligible and enrolled patients at the baseline visit (day 1).  
8.2.1.1. 
Determination of Osteoarthritis of the Knee 
Diagnosis of OA of the knee will be based on the American College of Rheumatology criteria 
with radiologic evidence of OA (K-L score ≥2). The American College of Rheumatology clinical 
and radiographic criteria for the diagnosis of OA of the knee (Altman, 1986) criteria consist of 
the following combinations: 
 Knee pain 
 Osteophytes on radiograph 
 At least 1 of the following 3 features: 
 Age >50 years 
 Stiffness <30 minutes 
 Crepitus 
Erythrocyte sedimentation rate (ESR) will be measured for use as part of the diagnosis for OA, 
as applicable.  
8.2.1.2. 
Height 
Patients should not be wearing shoes during height assessment. Height will be recorded to the 
nearest 1 cm.  
8.2.1.3. 
Weight 
Body weight will be measured at the screening visit for the BMI calculation and throughout the 
study as a safety procedure at the specified visits (Table 1). Body weight should be measured 
using calibrated scales and will be recorded to the nearest 0.1 kg. Patients should void (empty 
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bladder) prior to weight assessment and should only be wearing undergarments and should not 
be wearing shoes during weight assessments.  
8.2.2. 
Efficacy Procedures  
8.2.2.1. 
Western Ontario and McMaster Osteoarthritis Index 
The WOMAC index is used to assess patients with OA of the knee using 24 parameters and is 
reported using a Numerical Rating Scale score. This index can be used to monitor the course of a 
disease or to determine efficacy of study drugs. Patients will complete the WOMAC full survey 
or the pain subscale (a portion of the full survey) at the time points indicated in Table 1.  
8.2.2.2. 
Patient Global Assessment of Osteoarthritis 
The Patient Global Assessment of OA is a patient-rated assessment of current disease state on a 
5-point Likert scale (1 = very good; 2 = good; 3 = fair; 4 = poor; and 5 = very poor). Patients will 
complete the assessment scale at the time points indicated in Table 1.  
8.2.3. 
Safety Procedures  
8.2.3.1. 
Vital Signs 
Vital signs include blood pressure, pulse, body temperature, and respiratory rate. Vital signs will 
be obtained in accordance with the study site procedures at the specified visits (Table 1). The 
patient should be resting semi-recumbent for approximately 10 minutes prior to having vital 
signs obtained. Semi-recumbent vital signs include blood pressure and pulse. If at any visit after 
the baseline visit the pulse is less than 45 bpm confirmed in up to 2 measurements, an ECG with 
rhythm strip will be obtained to confirm the heart rate and rhythm.  
8.2.3.2. 
Orthostatic Vital Sign Assessment 
Orthostatic blood pressure and heart rate are measured with the patient lying semi-recumbent for 
10 minutes and after standing for 2 minutes. Prior to starting an assessment of orthostatic blood 
pressure and heart rate, patients should ambulate for at least 5 minutes. This assessment will be 
performed at the specified visits (Table 1).  
In case any of the following criteria are met, up to 2 re-checks (within approximately 5 minutes 
of the original measurement) should be performed (patient should remain standing): 
If the semi-recumbent systolic blood pressure is <160 mm Hg, a decrease in the 2-minute 
standing systolic blood pressure of ≥20 mm Hg or a decrease in the standing diastolic blood 
pressure of ≥10 mm Hg from the semi-recumbent systolic or diastolic blood pressure, 
respectively 
OR 
If the semi-recumbent systolic blood pressure is ≥160 mm Hg, a decrease in the 2-minute 
standing systolic blood pressure of ≥30 mm Hg or a decrease in the standing diastolic blood 
pressure of ≥15 mm Hg from the semi-recumbent systolic or diastolic blood pressure, 
respectively 
OR 
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An increase in the 2-minute standing heart rate of ≥30 bpm from the semi-recumbent heart rate. 
An AE of orthostatic vital sign change should be reported if the change is confirmed upon the 
repeat tests. 
If the patient is unable to stand for standing blood pressure measurements due to dizziness or 
lightheadedness, the patient is considered to have orthostatic hypotension, which should be 
reported.  
8.2.3.3. 
Physical Examination with Joint Exam 
A full or brief physical examination will be performed according to the site’s procedures at the 
time points in Table 1. Both the full and brief physical examinations will include joint 
examination. The brief physical examination will include assessment of heart, lungs, abdomen, 
peripheral pulses, and skin.  
8.2.3.4. 
Electrocardiogram 
A standard 12-lead ECG will be performed at the time points indicated in Table 1, with the 
patient in the semi-recumbent position for approximately 10 minutes and prior to blood samples 
being drawn. Heart rate will be recorded from the ventricular rate, and the PR/PQ, QRS, and the 
QT and QTc intervals will be recorded. The ECG strips/reports will be retained with the source. 
The following parameters will be recorded in the case report form (CRF): ventricular heart rate, 
PR/PQ, QRS, QT, and QTc intervals.  
8.2.3.5. 
Neurological Examination 
A full or brief neurological examination will be performed at the time points indicated in 
Table 1. Neurological findings at baseline that are not exclusionary should be recorded in the 
medical history. Findings at subsequent visits will be assessed by the investigator to determine if 
these should be recorded as an AE.  
The full neurological examination will cover the following domains: mental status, motor, 
sensory, cranial nerves, reflexes, and coordination/balance. A brief neurological examination will 
include assessment of orientation, cranial nerves, sensory and motor function, and basic reflexes. 
Any clinician at the site qualified to do so may conduct the neurological examination. Whenever 
possible, the same clinician who conducts the baseline neurological examination should continue 
to conduct the examinations on a given patient.  
8.2.3.6. 
Imaging 
Radiographs of patients’ knees, hips, and shoulders will be taken using a standard approach at 
the time points indicated in Table 1. In addition to scheduled imaging, radiographs should 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). The investigator is to consult the sponsor prior to 
scheduling additional imaging.  
Magnetic resonance imaging of the index knee will be performed at the time points indicated in 
Table 1. In addition to scheduled MRIs, an MRI should be considered for worsening joint pain 
despite treatment with analgesics, which in the opinion of the investigator is inconsistent with the 
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normal progression of OA and lasts at least 2 weeks (or less at the discretion of the investigator), 
and if X-rays are inconclusive. The investigator is to consult the sponsor prior to scheduling 
additional imaging. 
If a patient undergoes a joint replacement surgery, patients will have additional radiographs at 
the time points indicated in Table 2.  
Screening and on-study radiographs of the knees and hips will be evaluated for joint space width 
to identify excessive loss of joint space. In addition, all radiographs and MRI scans will be 
evaluated for the presence of adjudicated arthropathy.  
Detailed procedures will be available in a separate manual provided by the central imaging 
center. Radiographs or MRIs will be sent to a central reader, where the images will be digitized.  
8.2.3.7. 
Joint Pain Questionnaire 
A joint pain questionnaire will be completed by the patient at the time points indicated in 
Table 1. For each knee, hip, and shoulder joint, the patient will be prompted to indicate if he or 
she has experienced pain. A patient report of having experienced pain will serve as a tool to 
prompt further evaluations as deemed necessary by the investigator.  
8.2.3.8. 
End-of-Study Phone Call for Joint Replacement Status Questionnaire 
An end-of-study phone call will be conducted at approximately 52 weeks after the first dose of 
study drug (Table 1). The purpose of the end-of-study phone call is to determine whether a 
patient underwent, is scheduled for, or is on a waiting list to receive joint replacement surgery, or 
whether joint replacement was recommended but the patient elected to defer since his/her last in-
clinic visit. Patients will also be asked to submit pre-operative imaging (X-ray and MRI, if 
available) for adjudication and to provide joint material for histological and molecular analyzes, 
if feasible.  
8.2.3.9. 
Knee Society Score for Joint Replacement Follow-up Only 
The Knee Society Score is an investigator-completed questionnaire that is used to objectively 
measure a patient’s ability to function before (Table 1) and after (Table 2) total knee arthroplasty 
(Insall, 1989). If possible, the assessment should be completed by the same qualified person 
throughout the study. 
8.2.3.10. Laboratory Testing 
Regeneron or its designee will be responsible for PK, ADA, biomarker, 
, and 
pharmacogenetic sample assessments. Other samples may be analyzed by either a central 
laboratory, local laboratories, or at the study sites.  
All samples will be collected before study drug administration (unless otherwise mentioned in 
the Schedule of Events Table [Table 1] and associated footnotes [Section 8.1.1]). Missed tests 
should be reported in the source documents and in the CRF, as appropriate. Central laboratory 
kits will be provided for sample collection and shipment. Detailed instructions for blood sample 
collection are in the laboratory manual provided to study sites. 
Samples for laboratory testing will be collected at visits according to Table 1. Tests will include: 
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Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin 
Potassium 
Creatinine 
Total cholesterol* 
Chloride 
Blood urea nitrogen (BUN) 
Triglycerides 
Carbon dioxide 
Aspartate aminotransferase (AST) 
Uric acid 
Calcium 
Alanine aminotransferase (ALT) 
Creatine phosphokinase (CPK) 
Glucose 
Alkaline phosphatase 
 
Albumin 
Lactate dehydrogenase (LDH) 
 
 
*(low-density lipoprotein [LDL] and high-density lipoprotein [HDL]) 
Hematology 
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
Urinalysis 
Color (optional) 
Glucose 
RBC 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBC 
Yeast 
Other Laboratory Tests 
Drug (including cannabis and opioids) and alcohol test 
Pregnancy test; urine or serum samples, as indicated 
Follicle-stimulating hormone (FSH) (will be tested in women to confirm postmenopausal status) 
Erythrocyte sedimentation rate (ESR) 
Hemoglobin A1c (HbA1c, Glycated hemoglobin) 
High sensitivity C-reactive protein (hsCRP) 
Abnormal Laboratory Values and Laboratory Adverse Events 
All laboratory values must be reviewed by the investigator or authorized designee. 
Significantly abnormal test results that occur after start of treatment must be repeated to confirm 
the nature and degree of the abnormality. When necessary, appropriate ancillary investigations 
should be initiated. If the abnormality fails to resolve or cannot be explained by events or 
conditions unrelated to the study medication or its administration, the Medical/Study Director 
must be consulted.  
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The clinical significance of an abnormal test value, within the context of the disease under study, 
must be determined by the investigator. 
Criteria for reporting laboratory values as an AE are provided in Section 9.4.5. 
8.2.4. 
Drug Concentration and Measurements 
Samples for drug concentration will be collected at visits listed in Table 1. Instructions for blood 
sample collection will be included in the laboratory manual provided to study sites. 
 
 
8.2.5. 
Anti-Drug Antibody Measurements and Samples 
Samples for ADA measurements will be collected at visits listed in Table 1. Instructions for 
blood sample collection will be included in the laboratory manual provided to study sites. 
 
.  
8.2.6. 
Biomarker, Pharmacodynamic, 
 and Other Research  
8.2.6.1. 
Pharmacodynamic and Biomarker Research 
Serum and plasma pharmacodynamic and biomarker samples will be collected at time points 
according to Table 1. HsCRP will be measured to assess non-specific inflammation. If an 
increase in hsCRP is observed, other inflammatory cytokines may be measured (eg, ILb, IL6, 
TNFa, etc.). Alkaline phosphatase will be measured as part of the laboratory testing and, if an 
increase is observed, bone and collagen markers (CTX-1, P1NP, Osteocalcin, C1M, C3M) may 
be assessed.  
Research assessments may be performed to explore how REGN5069 may modify the perception 
of pain in patients with pain due to OA of the knee. Pharmacodynamic and biomarker 
measurements will be performed using the collected samples to determine effects on biomarkers 
of pain sensation or relevant physiological and pathogenic processes regarding pain and/or pain 
due to OA. The biomarkers studied may be relevant to the pathophysiology of indication target 
engagement, mechanism of action of REGN5069, and/or possible toxicities. If necessary, 
samples may also be used to identify markers associated with AEs.  
RNA sequencing (or other methods used to quantitate RNA expression) may be performed on 
arthroplasty tissue samples collected from any patient who may undergo a joint replacement 
surgery (Table 2) to compare the molecular signature of samples from patients treated with 
REGN5069 relative to placebo. RNA in situ hybridization by RNAscope may also be performed 
on the tissue samples to measure and localize genes identified in the molecular signature by 
RNA sequencing and including but not limited to other genes involved in bone metabolism, 
inflammation, pain, and REGN5069 efficacy and/or safety.  
 
 
 
 
 
  
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8.2.6.4. 
Collection of Arthroplasty Tissue Samples (Joint Replacement Surgery Only) 
Tissue samples will be collected at the time of the joint arthroplasty surgery (Table 2). Detailed 
procedures for collection, freezing, shipping, and storage of tissue samples will be provided in a 
separate document.  
8.2.6.5. 
Histological Evaluation of Tissue Samples (Joint Replacement Surgery Only) 
A centrally located pathologist will evaluate any slides prepared locally and will oversee 
processing of tissue shipped in formalin. Hematoxylin and eosin, a basic staining for tissue 
morphology, will be performed on all samples. Additional stains to be considered include 
Safranin O/Toluidine blue (stain proteoglycans), Goldner’s trichrome (stains collagen fibers), 
and Alizarin Red S (stains calcium crystals). Immunohistochemistry will be considered but will 
be limited by the formalin fixation. 
8.2.6.6. 
Moticon Digital Insole Device Sub-Study for Gait Assessments 
Only study sites selected for participation in the Moticon sub-study for gait assessments using 
the digital insole device will perform the Moticon-related procedures at the time points according 
to Table 1. This sub-study will enroll approximately 13 patients per treatment group to obtain 
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data on at least 10 patients per treatment group for a total of approximately 30 patients across the 
entire sub-study. For details on these procedures, participating sites will be provided with a 
Moticon digital insole device manual. 
The principle purpose of this sub-study is to assess functional mobility gait parameters as 
measured by the Moticon insole device in patients with pain due to OA of the knee without an 
analgesic treatment and in the presence of potential analgesic treatment. The study will also 
examine correlations of these gait parameters with the WOMAC pain subscale score.  
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
9.1. 
Obligations of Investigator 
The investigator must promptly report to the Institutional Review Board (IRB)/EC all 
unanticipated problems involving risks to patients, according to local regulations. This may 
include death from any cause and all serious adverse events (SAEs) related to the use of the 
study drug. It is recommended that all SAEs be reported to the IRB/EC, according to local 
regulations. 
9.2. 
Obligations of Sponsor 
During the course of the study, the sponsor will report in an expedited manner all SAEs that are 
both unexpected and at least reasonably related to the study drug (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 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 in an expedited manner all other SAEs to the health 
authorities, according to local regulations. 
At the completion of the study, the sponsor will report all safety observations made during the 
conduct of the study in the clinical study report to health authorities and IECs/IRB, as 
appropriate. 
9.3. 
Definitions 
9.3.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug which may or 
may not have a causal relationship with the study drug. Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease which is 
temporally associated with the use of a study drug, whether or not considered related to the study 
drug. 
An AE also includes any worsening (ie, any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug. 
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9.3.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death – includes all deaths, even those that appear to be completely 
unrelated to study drug (eg, a car accident in which a patient is a passenger). 
 Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event. This does not include an AE that, had it occurred in a 
more severe form, might have caused death. 
 Requires inpatient hospitalization or prolongation of existing hospitalization. 
Inpatient hospitalization is defined as a hospital admission (any duration) or an 
emergency room visit for longer than 24 hours. Prolongation of existing 
hospitalization is defined as a hospital stay that is longer than was originally 
anticipated for the event, or is prolonged due to the development of a new AE, as 
determined by the investigator or treating physician. 
 Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions).  
 Is a congenital anomaly/birth defect 
 Is an important medical event – Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent one of the other serious outcomes listed above 
(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). 
Criteria for reporting SAEs must be followed for these events. See Section 9.4 for more 
information on recording and reporting SAEs. 
9.3.3. 
Adverse Events of Special Interest 
An adverse event of special interest (AESI; serious or non-serious) is one of scientific and 
medical concern specific to the sponsor’s product or program, for which ongoing monitoring and 
rapid communication by the investigator to the sponsor can be appropriate. Such an event might 
warrant further investigation in order to characterize and understand it. Depending on the nature 
of the event, rapid communication by the trial sponsor to other parties (eg, regulators) might also 
be warranted (Section 9.4.3). 
9.3.4. 
Infusion Reactions 
Infusion reactions are defined as any relevant AE that occurs during the infusion or within 
2 hours after the infusion is completed. All infusion reactions must be reported as AEs (defined 
in Section 9.4.1) and graded using the grading scales as instructed in Section 9.5.1. 
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9.4. 
Recording and Reporting Adverse Events  
9.4.1. 
Adverse Events 
The investigator (or designee) will record all AEs that occur from the time the informed consent 
is signed until the end of the follow-up period.  
Information on follow-up for AEs is provided in Section 9.4.6. Laboratory, vital signs, or ECG 
abnormalities are to be recorded as AEs as outlined in Section 9.4.5. 
9.4.2. 
Serious Adverse Events 
All SAEs, regardless of assessment of causal relationship to study drug, must be reported to the 
sponsor (or designee) within 24 hours.  
Information not available at the time of the initial report must be documented in a follow-up 
report. Substantiating data such as relevant hospital or medical records and diagnostic test reports 
may also be requested. 
In the event the investigator is informed of an SAE after the patient completes the study, the 
following will apply: 
 SAE with an onset within 30 days of the end of the follow-up period or within 226 
days of last study drug administration if the patient early terminated from the study - 
the SAE will be reported to the sponsor. The investigator should make every effort to 
obtain follow-up information on the outcome until the event is considered chronic 
and/or stable. 
 SAE with an onset day greater than 30 days from the end of the follow-up 
period/early termination visit - only fatal SAEs and those 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. 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of 
learning of the event: 
Symptomatic Overdose of Study Drug: 
Accidental or intentional overdose of at least 
2 times the intended dose of study drug within the intended therapeutic window, if 
associated with an AE. 
Pregnancy: 
Although pregnancy is not considered an AE, it is the responsibility of the 
investigator to report to the sponsor (or designee), within 24 hours of 
identification, any pregnancy occurring in a female or female partner of a male, 
during the study or within 274 days (9 months) of the last dose of study drug. Any 
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complication of pregnancy affecting a female study patient or female partner of a 
male study patient, and/or fetus and/or newborn that meets the SAE criteria must 
be reported as an SAE. Outcome for all pregnancies should be reported to the 
sponsor.  
Adverse Events of Special Interest: All AESIs, serious and non-serious, must be reported 
within 24 hours of identification using the same reporting process as for SAE 
reporting, per Section 9.4.2. No AESIs have been defined for this study.  
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study 
All AEs that lead to a patient’s withdrawal from the study must be reported to the sponsor’s 
Medical/Study Director within 30 days. 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results 
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE include: 
 the test result is associated with accompanying symptoms, and/or 
 the test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
 the test result leads to a change in dosing (outside of protocol-stipulated dose 
adjustments), discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy 
Contact the Medical/Study Director in the event the investigator feels that an abnormal test 
finding should be reported as an AE, although it does not meet any of the above criteria. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an 
AE. Any abnormal test result that is determined to be an error does not require reporting as an 
AE. 
Evaluation of severity of laboratory abnormalities will be assessed according to the scale 
outlined in Section 9.5.1. 
9.4.6. 
Follow-up 
Adverse event information will be collected until the patient’s last study visit. 
Serious adverse event information will be collected until the event is considered chronic and/or 
stable. 
9.5. 
Evaluation of Severity and Causality 
9.5.1. 
Evaluation of Severity 
The severity of AEs will be graded according to the following scale: 
 Mild: Does not interfere in a significant manner with the patient’s normal functioning 
level. It may be an annoyance. Prescription drugs are not ordinarily needed for relief 
of symptoms, but may be given because of personality of the patient. 
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 Moderate: Produces some impairment of functioning but is not hazardous to health. 
It is uncomfortable or an embarrassment. Treatment for symptom may be needed. 
 Severe: Produces significant impairment of functioning or incapacitation and is a 
definite hazard to the patient’s health. Treatment for symptom may be given and/or 
patient hospitalized. 
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
Infusion Reactions 
The severity of infusion reactions will be graded according to the following scale (semi-colon 
indicates “or” within description of the grade): 
 Mild: Mild transient reaction; infusion interruption not indicated; intervention not 
indicated. 
 Moderate: Therapy or infusion interruption indicated but responds promptly to 
symptomatic treatment (eg, antihistamines, NSAIDs, narcotics, IV fluids); 
prophylactic medications indicated for ≤24 hours.  
 Severe:  Prolonged (eg, not rapidly responsive to symptomatic medication and/or 
brief interruption of infusion); recurrence of symptoms following initial 
improvement; hospitalization indicated for clinical sequelae; life-threatening 
consequences; urgent intervention indicated; death. 
9.5.2. 
Evaluation of Causality 
Relationship of Adverse Events to Study Drug: 
The relationship of AEs to study drug will be assessed by the “blinded” investigator, and will be 
a clinical decision based on all available information. The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by the study drug? 
The possible answers are: 
 Not Related: There is no reasonable possibility that the event may have been caused 
by the study drug 
 Related: There is a reasonable possibility that the event may have been caused by the 
study drug 
The investigator should justify the causality assessment of each SAE. 
A list of factors to consider when assessing the relationship of AEs to study drug is provided 
below. Please note that this list is not exhaustive. 
Is there a reasonable possibility that the event may have been caused by the study drug? 
No: 
 due to external causes such as environmental factors or other treatment(s) being 
administered 
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 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 
 are not a suspected response to the study drug based upon preclinical data or prior 
clinical data 
Yes: 
 could not be explained by environmental factors or other treatment(s) being 
administered 
 could not be explained by the patient’s disease state or clinical condition 
 follow a reasonable temporal sequence following the time of administration of the 
dose of study drug  
 resolve or improve after discontinuation of study drug  
 reappear or worsen when dosing with study drug  
 are known or suspected to be a response to the study drug based upon preclinical data 
or prior clinical data 
Relationship of Adverse Events to Study Conduct: 
The relationship of AEs to study conduct will be assessed by the blinded investigator, and will be 
a clinical decision based on all available information. The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by study conduct? 
The possible answers are: 
 Not Related: There is no reasonable possibility that the event may have been caused 
by study conduct 
 Related: There is a reasonable possibility that the event may have been caused by 
study conduct 
The investigator should justify the causality assessment of each SAE. 
A list of factors to consider when assessing the relationship of AEs to study conduct is provided 
below. Please note that 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 
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Yes: 
 could not be explained by environmental factors or other treatment(s) being 
administered 
 could not be explained by the patient’s disease state or clinical condition 
 follow a reasonable temporal sequence following the course of the study 
 resolve or improve after discontinuation from study participation 
 reappear or worsen when study participation is resumed 
9.6. 
Safety Monitoring 
The investigator will monitor the safety of study patient at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP). Any questions or 
concerns should be discussed with the sponsor in a timely fashion. The sponsor will monitor the 
safety data from across all study sites. The Medical/Study Director will have primary 
responsibility for the emerging safety profile of the compound, but will be supported by other 
departments (eg, Pharmacovigilance and Risk Management; Biostatistics and Data 
Management). Safety monitoring will be performed on an ongoing basis (eg, individual review 
of SAEs) and on a periodic cumulative aggregate basis. 
9.7. 
Investigator Alert Notification 
Regeneron (or designee) will inform all investigators participating in this clinical trial, as well as 
in any other clinical trial using the same investigational drug, of any SAE that meets the relevant 
requirements for expedited reporting (an AE that is serious, unexpected based on the reference 
safety information in the Investigator’s Brochure, and has a reasonable suspected causal 
relationship to the study drug). 
10. 
STATISTICAL PLAN 
This section provides the basis for the statistical analysis plan (SAP) for the study. The SAP may 
be revised during the study to accommodate amendments to the clinical study protocol and to 
make changes to adapt to unexpected issues in study execution and data that may affect the 
planned analyses. The final SAP will be issued before the database is locked. Analyses related to 
the Moticon sub-study will not be in the scope of the final SAP.  
Analysis variables are listed in Section 4.  
10.1. 
Statistical Hypothesis  
The null hypotheses of no treatment difference between a REGN5069 dose and placebo against 
an alternative hypothesis of some treatment difference in change from baseline to week 12 in 
WOMAC pain subscale, physical function subscale, and Patient Global Assessment scores will 
be tested for each dose. Multiplicity adjustment for the 6 null hypotheses will be made using 
sequentially rejective multiple test procedure to control Type I error rate at 2-sided 0.05 level in 
the following order: 
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 H1: No treatment difference between 1000 mg REGN5069 and placebo groups in 
change from baseline to week 12 in WOMAC pain subscale score 
 H2: No treatment difference between 100 mg REGN5069 and placebo groups in 
change from baseline to week 12 in WOMAC pain subscale score 
 H3: No treatment difference between 1000 mg REGN5069 and placebo groups in 
change from baseline to week 12 in WOMAC physical function subscale score 
 H4: No treatment difference between 100 mg REGN5069 and placebo groups in 
change from baseline to week 12 in WOMAC physical function subscale score 
 H5: No treatment difference between 1000 mg REGN5069 and placebo groups in 
change from baseline to week 12 in Patient Global Assessment score 
 H6: No treatment difference between 100 mg REGN5069 and placebo groups in 
change from baseline to week 12 in Patient Global Assessment score 
If at any step a null hypothesis is not rejected, the testing will stop and no further hypothesis in 
the order will be tested. The details will be provided in the SAP.  
10.2. 
Justification of Sample Size 
Up to approximately 240 patients (80 per treatment group) will be randomized to 3 treatment 
groups in a 1:1:1 allocation. Assuming a standard deviation (SD) of 2.3, 80 patients per treatment 
group will provide approximately 80% power to detect a treatment difference of 1.1 between the 
REGN5069 dose and the matching placebo in change from baseline to week 12 in WOMAC pain 
subscale (using a significance level of 0.05, 2-sided t-test and assuming a dropout rate of 15% 
[6% due to lack of efficacy or AEs, and 9% due to other reasons]). 
10.3. 
Analysis Sets  
10.3.1. 
Efficacy Analysis Sets 
The full analysis set (FAS) will include all randomized patients and will be based on the 
treatment allocated (as randomized). Efficacy endpoints will be analyzed using the FAS.  
10.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) will include all randomized patients who received any study drug 
and is based on the treatment received. Treatment compliance/administration and all safety 
variables will be analyzed using the SAF.  
10.3.3. 
Per Protocol Set 
The per protocol set (PPS) will include all randomized patients who complete the 12-week 
treatment period and who do not have major protocol deviations through week 12. The PPS will 
be used for sensitivity analyses for the primary and selected secondary endpoints, as will be 
defined in the SAP.  
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10.3.4. 
Pharmacokinetic Analysis Sets 
The PK analysis set will include all treated patients who received any study drug and who had at 
least 1 non-missing drug concentration measurement following the first dose of study drug.  
10.3.5. 
Anti-Drug Antibody Analysis Sets 
The ADA analysis set will include all treated patients who received any study drug and who had 
at least 1 non-missing ADA result following the first dose of study drug. 
10.4. 
Statistical Methods  
For continuous variables, descriptive statistics will include the following information:  the 
number of patients reflected in the calculation (n), mean, median, standard deviation, minimum, 
and maximum.  
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
10.4.1. 
Patient Disposition 
The following will be provided: 
 The total number of screened patients: met the inclusion criteria regarding the target 
indication and signed the ICF 
 The total number of randomized patients: received a randomization number 
 The total number of patients in each analysis set (eg, FAS, provided in Section 10.3) 
 The total number of patients who discontinued the study, and the reasons for 
discontinuation 
 A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized 
 A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation 
10.4.2. 
Demography and Baseline Characteristics 
Baseline demographic, disease characteristics, and exposure to study drug will be summarized 
descriptively by treatment groups using descriptive statistics. Continuous variables will be 
summarized with mean, median, and SD, minimum, and maximum. Categorical variables will be 
summarized with counts and percentages. 
10.4.3. 
Efficacy Analyses 
10.4.3.1. Primary Efficacy Analysis 
The primary estimand for the primary objective is the difference in means between both 
REGN5069 dose + protocol-defined rescue medication and placebo + protocol-defined rescue 
medication in the change from baseline to week 12 in the WOMAC pain subscale score of 
patients in the FAS. All collected data will be included in the analysis regardless of whether 
prohibited medication was taken. Missing values will be imputed with the multiple imputation 
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approach, where intermediate missing data will be first imputed using the Markov Chain Monte 
Carlo method and then the remaining missing data with a monotone missing pattern will be 
imputed with a regression method. The regression model will adjust for treatment, randomization 
strata, and baseline score.  For patients who drop out due to lack of efficacy or AEs, each 
imputed value will be further adjusted by subtracting the mean change from baseline to the 
respective post-baseline time point calculated from patients in the same treatment group with 
observed data at that time point.  For each complete dataset, the primary efficacy endpoint of 
change from baseline to week 12 in WOMAC pain subscale score will be analyzed using 
analysis of covariance (ANCOVA) model which will include treatment, randomization strata, 
and baseline score as covariate.  The least-squares means estimates, as well as the difference of 
the estimates between each dose and placebo with standard error, p-values, and 95% confidence 
intervals will be provided by combining results from the analyses of the multiple imputed 
datasets using Rubin’s formulae.  Further details will be provided in the SAP.  
10.4.3.2. Secondary Efficacy Analysis 
The continuous secondary endpoints will be analyzed similarly as specified in Section 10.4.3.1.  
For the analyses of categorical secondary endpoints, the Cochran-Mantel-Haenszel test stratified 
by the K-L category (2-3 vs 4) will be used with missing data considered as non-response. The 
continuous secondary endpoints will be analyzed similarly as specified in Section 10.4.3.1.  
10.4.4. 
Safety Analysis 
The safety data including TEAEs and other safety information (clinical laboratory evaluations, 
vital signs and 12-lead ECG) will be summarized by treatment groups.  
Thresholds for potentially clinically significant values (PCSVs) in laboratory parameters and 
vital signs will be defined by the sponsor and be in effect at the time of the final SAP approval.  
10.4.4.1. Adverse Events 
Definitions 
For safety variables, 3 observation periods are defined: 
 The pre-treatment period is defined as the time from signing the ICF to before the 
first dose of study drug. 
 The treatment period is defined as the day from first dose of study drug to the last 
dose of study drug + 4 weeks (week 12) 
 The post-treatment period is defined as the time after the treatment period (after 
week 12). 
Treatment-emergent adverse events are defined as those that are not present at baseline or 
represent the exacerbation of a pre-existing condition during the 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.  
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Summaries of all TEAEs by treatment group will include: 
 The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
 TEAEs by severity (according to the grading scale outlined in Section 9.5.1), 
presented by SOC and PT 
 TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
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. 
10.4.4.2. Other Safety 
Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiration rate) will be summarized by 
baseline and change from baseline to each scheduled assessment time with descriptive statistics. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each 
scheduled assessment time with descriptive statistics. 
Number and percentage of patients with a PCSV at any post-randomization time point will be 
summarized for each clinical laboratory test.  
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
Listings will be provided with flags indicating the out-of-laboratory range values. 
Imaging 
Change from baseline (ie, screening visit) in joint space width of the knees and hips will be 
summarized by treatment group over time. The number and percentages with images requiring 
arthropathy adjudication, as well as the number and percentage of patients with confirmed 
adjudicated arthropathy, will be summarized by treatment group. Patient listings of cases 
confirmed by adjudication will also be provided. 
10.4.4.3. Treatment Exposure 
Because of the half-life of the biologic being studied, the duration of exposure (in days) during 
the study will be presented by treatment group and calculated as: 
 (Date of last administration of study drug - date of the first study drug administration 
after randomization) + 28  
The number and percentage of patients randomized and exposed to double-blinded study drug 
will be presented by specific time period for each treatment group. The time periods will be 
specified in the final SAP.  
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10.4.4.4. Treatment Compliance 
Overall treatment compliance is defined as the actual dose administered compared to the 
prescribed dose of treatment during the treatment phase up to treatment discontinuation. It is 
calculated according to the following formula: 
100 * total dose administered /prescribed dose. 
The total number of doses will be summarized by treatment groups. 
10.4.5. 
Pharmacokinetics 
10.4.5.1. Analysis of Drug Concentration Data 
Summaries of trough concentrations (Ctrough) of functional REGN5069 will be presented by 
nominal time point and dose. Plots of individual Ctrough will be presented by actual day (linear 
and log scales). Plots of mean and median Ctrough will be presented by nominal day (linear and 
log scale).  
10.4.5.2. Pharmacokinetics and Pharmacokinetics/Pharmacodynamics Analyses 
Population PK and exposure-response analyses for biomarkers, efficacy, and safety endpoints 
may be performed, as appropriate, and presented in separate reports. 
10.4.6. 
Analysis of Anti-Drug Antibody Data 
Listings of ADA positivity and titers presented by patient, time point, and treatment 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 treatment group. 
Plots of drug concentrations will be examined and the influence of ADAs on individual PK 
profiles evaluated. Assessment of impact of ADAs on safety may be provided. 
Anti-drug antibody parameters include status (positive or negative) and titer as follows:  
 Treatment emergent - defined as any post-dose ADA positive response when baseline 
results are negative or missing. 
 Treatment boosted - defined as any post-dose ADA response that is at least 9-fold 
over baseline titer levels when baseline results are positive 
 Titer values 
 Titer category for patients, by patient’s maximal titer value: 
o Low (titer <1,000) 
o Moderate (1,000≤ titer ≤10,000) 
o High (titer >10,000) 
10.5. 
Interim Analysis 
No formal interim analysis is planned for the study. The unblinded primary efficacy analysis will 
be conducted when 12-week data are available for all randomized patients. No individual 
treatment assignments will be unblinded to personnel directly involved with the conduct of the 
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study until after the final database lock. The unblinded summarized results based on 12-week 
data will be disclosed.  
10.6. 
Additional Statistical Data Handling Conventions 
General rules for handling missing data:  
 Rules for handling missing data for efficacy assessments will be provided in the final 
SAP 
 If the start date of an AE or concomitant medication is incomplete or missing, it will 
be assumed to have occurred on or after the intake of study drug, except if an 
incomplete date (eg, month and year) clearly indicates that the event started prior to 
treatment. If the partial date indicates the same month or year of the intake of study 
drug date, then the start date by the study drug intake date will be imputed; otherwise, 
the missing day or month by the first day or the first month will be imputed.  
 No imputations for missing laboratory data, ECG data, vital sign data, or physical 
examination data will be made. 
Visit windows: 
 Assessments taken outside of protocol allowable windows will be displayed 
according to the CRF assessment recorded by the investigator. 
Unscheduled assessments: 
 Extra assessments (laboratory data or vital signs associated with non-protocol clinical 
visits or obtained in the course of investigating or managing AEs) will be included in 
listings, but not summaries. If more than 1 laboratory value is available for a given 
visit, the first observation will be used in summaries and all observations will be 
presented in listings. 
10.7. 
Statistical Considerations Surrounding the Premature Termination 
of a Study 
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized. Investigator and sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 16.1. 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
11.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study, 
including data validation will be maintained and stored at Regeneron (Sponsor). 
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. 
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The CRF data for this study will be collected with an electronic data capture (EDC) tool called 
Medidata RAVE.  
11.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
 IWRS system – randomization, study drug supply 
 EDC system – data capture – Medidata Rave 
 Statistical Analysis System (SAS) – statistical review and analysis 
 Pharmacovigilance safety database 
 Patient diary 
 Moticon wearable insole device (for use at selected sites only) 
12. 
STUDY MONITORING  
12.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, CRO monitor) will visit each site prior to enrollment of 
the first patient, and periodically during the study. This study will use the principles of risk-based 
monitoring (ICH). This means that the number of visits for any given site may vary based on site 
risk indicators. The investigator must allow study-related monitoring. 
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH 
GCP, and all applicable regulatory requirements.  
12.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). The site is responsible for ensuring quality within their records and systems and is 
accountable for ensuring that all source data and CRF data are timely, accurate, and complete. 
The investigator must keep all source documents on file with the CRF (throughout this protocol, 
CRF refers to either a paper CRF or an electronic CRF). Case report forms and source 
documents must be available at all times for inspection by authorized representatives of the 
sponsor and regulatory authorities. 
12.3. 
Case Report Form Requirements 
Study data obtained during the course of the clinical study will be recorded on electronic CRFs 
within the EDC system by trained site personnel. All required CRFs must be completed for each 
patient enrolled in the study. The investigator must ensure the accuracy, completeness, and 
timeliness of the data reported to the sponsor in the CRFs. After review of the clinical data for 
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each patient, the investigator must provide an electronic signature. A copy of each patient CRF 
casebook is to be retained by the investigator as part of the study record and must be available at 
all times for inspection by authorized representatives of the sponsor and regulatory authorities. 
Corrections to the CRF will be entered in the CRF by the investigator or an authorized designee. 
All changes, including date and person performing corrections, will be available via the audit 
trail, which is part of the EDC system. For corrections made via data queries, a reason for any 
alteration must be provided. 
13. 
AUDITS AND INSPECTIONS  
This study may be patient 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. 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS 
14.1. 
Good Clinical Practice Statement  
It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable 
regulatory requirements. 
14.2. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP. 
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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.  
14.3. 
Patients Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained. Patients should be identified by 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. 
The patient’s and investigator's personal data, which may be included in the sponsor database, 
will be treated in compliance with all applicable laws and regulations. The sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third 
party. 
14.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve: 
 The protocol, ICF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
 Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patient, in 
which case the IRB/EC should be informed as soon as possible  
 Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
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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. 
14.5. 
Clinical Study Data Transparency 
Final study results will be published on a public clinical trial website according to applicable 
local guidelines and regulations. Treatment codes will be disseminated to each investigation site 
after the study results are posted on a clinical trial registry. 
15. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an 
IRB/EC-approved amendment. Where required per local regulations regulatory authority, 
approval will also be sought. 
16. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
16.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely. Reasons may include efficacy, 
safety, or futility, among others. Should the sponsor decide to terminate the study, the 
investigator(s) will be notified in writing. 
16.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
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 
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 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. 
17. 
STUDY DOCUMENTATION 
17.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the CRF must be signed 
electronically by the investigator. This signed declaration accompanies each set of patient final 
CRF that will be provided to the sponsor. 
17.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of CRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
regulatory authorities. The investigator must obtain written approval from the sponsor before 
discarding or destroying any essential study documents during the retention period following 
study completion or discontinuation. Records must be destroyed in a manner that ensures 
confidentiality. 
If the investigator's personal situation is such that archiving can no longer be ensured, the 
investigator must inform the sponsor (written notification) and the relevant records will be 
transferred to a mutually agreed-upon destination.  
18. 
DATA QUALITY ASSURANCE 
In accordance with ICH E6, the sponsor is responsible for quality assurance to ensure that the 
study is conducted and the data generated, recorded, and reported in compliance with the 
protocol, GCP, and any applicable regulatory requirement(s). The planned quality assurance and 
quality control procedures for the study are summarized.  
Data Management 
The sponsor is responsible for the data management of this study including quality checking of 
the data (Section 11.1). 
Study Monitoring 
The investigator must allow study-related monitoring, IRB/EC review, audits, and inspections 
from relevant health regulatory authorities, and provide direct access to source data documents 
(Section 12.1, Section 12.2, and Section 13). 
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The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH 
GCP, and all applicable regulatory requirements (Section 12.1).  
All patient data collected during the study will be recorded on paper or electronic CRFs unless 
the data are transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for affirming that data entries in the CRF are accurate and correct by 
electronically signing a declaration that accompanies each set of patient final CRF (Section 12.3 
and Section 17.1).  
Study Documentation 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF (Section 12.2).  
The investigator will retain all records and documents, including signed ICFs, pertaining to the 
conduct of this study for at least 15 years after study completion, unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor (Section 17.2).  
19. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
20. 
FINANCING AND INSURANCE  
Financing and insurance information is provided as a separate agreement. 
21. 
PUBLICATION POLICY  
Publication rights and procedures will be outlined in a separate clinical study agreement. 
22. 
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Trupp M, Scott R, Whittemore SR, Ibanez CF. Ret-dependent and -independent mechanisms of 
glial cell line-derived neurotrophic factor signaling in neuronal cells. J Biol Chem 1999; 
274(30):20885-94. 
Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, et al. Years lived with 
disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic 
analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380(9859):2163-96. 
Worby CA, Vega QC, Chao HH, Seasholtz AF, Thompson RC, Dixon JE. Identification and 
characterization of GFRalpha-3, a novel Co-receptor belonging to the glial cell line-derived 
neurotrophic receptor family. J Biol Chem 1998; 273(6):3502-8. 
Yang X, Ambrogelly A. Enlarging the repertoire of therapeutic monoclonal antibodies platforms: 
domesticating half molecule exchange to produce stable IgG4 and IgG1 bispecific antibodies. 
Curr Opin Biotechnol 2014; 30(225-9. 
Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N, et al. OARSI 
recommendations for the management of hip and knee osteoarthritis, part I: critical appraisal of 
existing treatment guidelines and systematic review of current research evidence. Osteoarthritis 
Cartilage 2007; 15(9):981-1000. 
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Clinical Study Protocol 
 
R5069-OA-1849 Amendment 1 
Regeneron Pharmaceuticals, Inc. 
 
Page 71 of 72 
 
CONFIDENTIAL 
23. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: A Randomized, Double-Blind, Multi-Dose, Placebo-
Controlled Study to Evaluate the Efficacy and Safety of REGN5069 in Patients with Pain due to 
Osteoarthritis of the Knee 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 IRB/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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Clinical Study Protocol 
 
R5069-OA-1849 Amendment 1 
Regeneron Pharmaceuticals, Inc. 
 
Page 72 of 72 
 
CONFIDENTIAL 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Medical/Study Director, Regulatory Representative, Clinical Study Leader, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the conduct of the study. 
Study Title: 
 A Randomized, Double-Blind, Multi-Dose, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of REGN5069 in Patients with Pain due to Osteoarthritis of the 
Knee   
 
Protocol Number: 
R5069-OA-1849 
Protocol Version:  
R5069-OA-1849 Amendment 1 
 
See appended electronic signature page 
Sponsor’s Responsible Medical/Study Director 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Liaison 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Leader 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
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Signature Page for VV-RIM-00083543 v1.0
Signature Page for VV-RIM-00083543 v1.0 Approved
ESig Approval
ESig Approval
ESig Approval
ESig Approval
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SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
CONFIDENTIAL 
Page 1 of 68 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 
STATISTICAL ANALYSIS PLAN 
VERSION 2 
 
A RANDOMIZED, DOUBLE-BLIND, MULTI-DOSE, 
PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY 
AND SAFETY OF REGN5069 IN PATIENTS WITH PAIN DUE TO 
OSTEOARTHRITIS OF THE KNEE 
 
Compound: 
REGN5069 
Protocol Number: 
R5069-OA-1849 
Clinical Phase: 
Phase 2 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Biostatistician: 
  
Clinical Trial Manager: 
 
Medical Director: 
 
Version/Date: 
Version 2.0 / 17 Nov 2020  
Original Version 1.0 / 29 May 2020 
 
                                        VV-RIM-00133697-1.0 Approved - 18 Nov 2020 GMT-5:00
NCT03956550 


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R5069-OA-1849 
Statistical Analysis Plan 
Date: 17 November 2020 
 
CONFIDENTIAL 
Page 2 of 68 
The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
 
See appended electronic signature page 
Study Biostatistician   
 
 
 
See appended electronic signature page 
Study Clinical Pharmacologist 
 
 
See appended electronic signature page 
Study Bioanalytical Sciences  
 
 
See appended electronic signature page 
Study Medical Director 
 
 
 
See appended electronic signature page 
Project Biostatistician   
 
 
 
See appended electronic signature page 
Head of BDM or designee 
 
 
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Protocol: R5069-OA-1849 
Statistical Analysis Plan 
Date: 17 November 2020 
 
CONFIDENTIAL 
Page 3 of 68 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................7 
1. 
OVERVIEW .................................................................................................................9 
1.1. 
Background/Rationale ..................................................................................................9 
1.2. 
Study Objectives ...........................................................................................................9 
1.2.1. 
Primary Objectives .......................................................................................................9 
1.2.2. 
Secondary Objectives ...................................................................................................9 
1.2.3. 
Exploratory Objectives ...............................................................................................10 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol ................................10 
1.2.4.1. 
SAP Version 1.0 .........................................................................................................10 
1.2.4.2. 
SAP Version 2.0 .........................................................................................................16 
1.2.5. 
Revision History for SAP Amendments .....................................................................20 
2. 
INVESTIGATION PLAN ..........................................................................................21 
2.1. 
Study Design and Randomization ..............................................................................21 
2.2. 
Sample Size and Power Considerations .....................................................................21 
2.3. 
Study Plan ...................................................................................................................21 
3. 
ANALYSIS POPULATIONS ....................................................................................23 
3.1. 
Full Analysis Set (FAS) ..............................................................................................23 
3.2. 
The Safety Analysis Set (SAF) ...................................................................................23 
3.3. 
The Pharmacokinetic Analysis Set .............................................................................23 
3.4. 
The Immunogenicity Analysis Set..............................................................................23 
4. 
ANALYSIS VARIABLES .........................................................................................24 
4.1. 
Demographic and Baseline Characteristics ................................................................24 
4.2. 
Medical History ..........................................................................................................24 
4.3. 
Prior/Concomitant Medications and Procedures ........................................................24 
4.3.1. 
Rescue Medication and Prohibited Medication and Procedures During the 
Study ...........................................................................................................................25 
4.4. 
Efficacy Variables ......................................................................................................27 
4.4.1. 
Primary Efficacy Variable ..........................................................................................27 
4.4.2. 
Secondary Efficacy Variables .....................................................................................27 
4.4.2.1. 
Supportive variables ...................................................................................................27 
4.4.3. 
Exploratory Efficacy Variables ..................................................................................28 
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Statistical Analysis Plan 
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4.5. 
Safety Variables ..........................................................................................................28 
4.5.1. 
Adverse Events and Serious Adverse Events .............................................................28 
4.5.2. 
Safety Variables (Secondary Study Endpoints) ..........................................................29 
4.5.3. 
Exploratory Safety Variables ......................................................................................29 
4.5.4. 
Adverse Events of Special Interest .............................................................................29 
4.5.5. 
Acute Intravenous Infusion Reactions ........................................................................29 
4.5.6. 
Laboratory Safety Variables .......................................................................................29 
4.5.7. 
Vital Signs ..................................................................................................................29 
4.5.8. 
Orthostatic Hypotension .............................................................................................30 
4.5.9. 
12-Lead Electrocardiography (ECG) ..........................................................................30 
4.5.10. 
Physical Examination (PE) Variables .........................................................................31 
4.5.11. 
Neurological Examination Variables ..........................................................................31 
4.5.12. 
Other Safety Variables ................................................................................................31 
4.6. 
Imaging .......................................................................................................................32 
4.7. 
Pharmacokinetic Variables .........................................................................................32 
4.8. 
Immunogenicity Variables ..........................................................................................32 
4.9. 
Moticon Digital Insole Device Sub-Study for Gait Assessments ...............................33 
5. 
STATISTICAL METHODS .......................................................................................34 
5.1. 
Demographics and Baseline Characteristics ...............................................................34 
5.2. 
Medical History ..........................................................................................................34 
5.3. 
Prior / Concomitant Medications ................................................................................34 
5.4. 
Prohibited Medications ...............................................................................................35 
5.5. 
Patient Disposition ......................................................................................................35 
5.6. 
Extent of Study Treatment Exposure and Compliance ...............................................37 
5.6.1. 
Exposure to Investigational Product ...........................................................................37 
5.6.2. 
Measurement of Compliance ......................................................................................37 
5.6.3. 
Protocol Deviations ....................................................................................................38 
5.7. 
Statistical Methods for Efficacy .................................................................................38 
5.7.1. 
Primary Efficacy Analysis ..........................................................................................38 
5.7.1.1. 
Supportive Analysis ....................................................................................................40 
5.7.1.2. 
Subgroup Analysis ......................................................................................................41 
5.7.2. 
Analysis of Secondary and Exploratory Efficacy Variables ......................................41 
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Statistical Analysis Plan 
Date: 17 November 2020 
 
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5.7.3. 
Adjustment for Multiple Comparison .........................................................................41 
5.8. 
Analysis of Safety Data ..............................................................................................42 
5.8.1. 
Adverse Events ...........................................................................................................42 
5.8.2. 
Clinical Laboratory Measurements.............................................................................43 
5.8.3. 
Analysis of Vital Signs ...............................................................................................44 
5.8.4. 
Analysis of 12-Lead ECG ...........................................................................................44 
5.8.5. 
Physical Exams ...........................................................................................................44 
5.8.6. 
Joint Pain Questionnaire .............................................................................................44 
5.8.7. 
Neurological Exam .....................................................................................................44 
5.8.8. 
Imaging Data ..............................................................................................................45 
5.9. 
Analysis of Pharmacokinetic and Immunogenicity Data ...........................................45 
5.9.1. 
Analysis of Pharmacokinetics and Drug Concentration Data ....................................45 
5.9.2. 
Analysis of ADA Data ................................................................................................45 
5.10. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................46 
5.10.1. 
Immunogenicity and Exposure ...................................................................................46 
5.10.2. 
Immunogenicity and Safety and Efficacy ...................................................................47 
6. 
DATA CONVENTIONS ............................................................................................48 
6.1. 
Definition of Baseline for Variables ...........................................................................48 
6.2. 
Data Handling Conventions for Efficacy Data ...........................................................48 
6.2.1. 
Handling of Missing Efficacy Data due to COVID-19 Public Health 
Measures .....................................................................................................................48 
6.3. 
Data Handling Convention for Missing Data .............................................................48 
6.4. 
Visit Windows ............................................................................................................50 
6.5. 
Unscheduled Assessments ..........................................................................................51 
6.6. 
Pooling of Centers for Statistical Analyses ................................................................51 
6.7. 
Statistical Technical Issues .........................................................................................51 
7. 
INTERIM ANALYSES ..............................................................................................52 
8. 
SOFTWARE ...............................................................................................................53 
9. 
SUMMARY OF MEASURES AND ANALYSES ADDRESSING IMPACT 
OF COVID-19 ............................................................................................................54 
10. 
REFERENCES ...........................................................................................................56 
11. 
APPENDIX.................................................................................................................57 
11.1. 
Schedule of Events and Visits ....................................................................................57 
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Statistical Analysis Plan 
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11.2. 
Reference for Criteria for Treatment-Emergent Potentially Clinically 
Significant Values (PCSV) .........................................................................................62 
11.3. 
Arthropathy Adjudication ...........................................................................................68 
 
LIST OF TABLES 
Table 1: 
SAP Version 1 Modifications from Final Protocol Amendment PA1 .......................11 
Table 2: 
SAP Version 2.0 Modifications from SAP Version 1.0 .............................................16 
Table 3: 
Schedule of Events .....................................................................................................57 
Table 4: 
Schedule of Events for Follow-up Period of Patients Who Undergo Joint 
Replacement Surgery ..................................................................................................61 
Table 5: 
Criteria for Treatment-Emergent Potentially Clinically Significant Values 
(PCSV) ........................................................................................................................62 
Table 6: 
Definitions of Radiologic Findings for Adjudicated Arthropathy and Joint-
Related Diseases .........................................................................................................68 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................22 
 
 
 
 
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Statistical Analysis Plan 
Date: 17 November 2020 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AA 
Accelerated arthropathy 
DA 
Destructive arthropathy 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
CPK 
Creatine phosphokinase 
ECG 
Electrocardiogram 
EDC 
Electronic data collection system  
EOS 
End of study 
EOT 
End of treatment 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
hs-CRP 
High-sensitivity C-reactive protein 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IRT 
Interactive response technology 
IWRS 
Interactive web response system 
K-L 
Kellgren-Lawrence  
MedDRA 
Medical Dictionary for Regulatory Activities 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
OA 
Osteoarthritis 
PCSV 
Potentially clinically significant value 
PK 
Pharmacokinetic 
PT 
Preferred term 
QTcF 
QT interval with Fridericia’s correction 
Q4W 
Every 4 weeks 
RBC 
Red blood cell 
SAE 
Serious adverse event 
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Statistical Analysis Plan 
Date: 17 November 2020 
 
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SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SD 
Standard deviation 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WHODD 
World Health Organization Drug Dictionary 
WOMAC 
Western Ontario and McMaster Universities Osteoarthritis Index 
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Statistical Analysis Plan 
Date: 17 November 2020 
 
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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 R5069-OA-1849. 
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. 
Due to public health measures implemented to address the world-wide COVID-19 pandemic, 
some sites may suspend onsite study visits or patients may opt not to attend. The handling of 
missing data and analyses related to COVID-19 are specified through the SAP and summarized 
in Section 9. There is, however, expected to be no impact on missing data at the Week 12 
WOMAC data due to COVID-19 mitigations of remote data collection. 
1.1. 
Background/Rationale 
This is a multicenter, Phase 2, randomized, double-blind, multi-dose, parallel-arm, placebo-
controlled study designed to evaluate the safety and efficacy of REGN5069 in patients with pain 
due to osteoarthritis (OA) of the knee who have a history of inadequate pain relief from 
acetaminophen and a history of intolerance or inadequate pain relief from oral non-steroidal anti-
inflammatory drugs (NSAIDs) (eg, prescription NSAIDs or over the counter NSAIDs at or near 
prescription doses), and opioid therapy or unavailability of opioid therapy. 
1.2. 
Study Objectives 
1.2.1. 
Primary Objectives 
The primary objective of the study is to evaluate the efficacy of REGN5069 compared to placebo 
in patients with pain due to radiographically-confirmed OA of the knee who have a history of 
inadequate joint pain relief or intolerance to current analgesic therapy. 
1.2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To characterize the concentrations of functional REGN5069 in serum over time when 
patients are treated for up to 12 weeks 
• To assess the safety and tolerability of REGN5069 compared with placebo when 
patients are treated for up to 12 weeks 
• To measure levels of anti-drug antibodies (ADAs) against REGN5069 following 
multiple IV administrations  
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Protocol: R5069-OA-1849 
Statistical Analysis Plan 
Date: 17 November 2020 
 
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1.2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
• To evaluate the effect of REGN5069 on inflammation in patients compared to that of 
placebo 
• To evaluate, for a subset of patients, the use of a digital, wearable, insole device to 
assess gait parameters and functional mobility in patients with OA of the knee 
without an analgesic treatment and after administration of a potential analgesic 
treatment 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol  
1.2.4.1. 
SAP Version 1.0 
SAP V1.0 is based on Protocol R5069-OA-1849 Amendment 1. The following were modified or 
were not specified in the protocol but are clarified/added in the SAP V1.0. 
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Protocol: R5069-OA-1849 
Statistical Analysis Plan 
Date: 17 November 2020 
 
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Table 1: 
SAP Version 1 Modifications from Final Protocol Amendment PA1 
Item 
no. 
Issue Addressed 
Protocol Amendment 1 Text 
SAP V1 Clarification or Addition 
1. 
In order to be in compliance 
with SOP-CTM2620 Protocol 
Deviations Management, the 
terminology for PD 
classification changed, from 
minor and major, to minor and 
important. 
 
 
2. 
The Per Protocol analysis set 
definition is clarified, as not all 
major/important PDs are to 
produce exclusions from PP. 
The per protocol set (PPS) will include 
all randomized patients who complete 
the 12-week treatment period and who 
do not have major protocol deviations 
through week 12. The PPS will be used 
for sensitivity analyses for the primary 
and selected secondary endpoints.  
The per protocol set (PPS) includes all randomized 
patients who complete the 12-week treatment period and 
who do not have relevant protocol deviations (PDs) 
through week 12. The PPS is to be used for sensitivity 
analyses for the primary and selected secondary 
endpoints. The relevant PDs are defined as a subset of the 
important PDs in Appendix 11.4. 
3. 
The statistical model used for 
categorical analyses: 
randomization strata is clarified 
as only the KL-score to be used 
besides baseline endpoint 
score.  
The regression model will adjust for 
treatment, randomization strata, and 
baseline score. 
“… is to be analyzed using a MMRM with terms for 
baseline WOMAC Pain subscale score, randomization 
strata (K-L category [2 to 3, or 4]), treatment, visit, and 
treatment-by-visit interaction as fixed effects.” 
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Protocol: R5069-OA-1849 
Statistical Analysis Plan 
Date: 17 November 2020 
 
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Page 12 of 68 
Item 
no. 
Issue Addressed 
Protocol Amendment 1 Text 
SAP V1 Clarification or Addition 
4. 
The statement on planned 
interim analysis is clarified 
5.2 Planned Interim Analysis  
No interim analysis is planned. Upon 
completion of 12 weeks of treatment for 
all patients, a 12-week analysis will be 
performed for the primary efficacy 
endpoint.  
and: 10.5. Interim Analysis  
No formal interim analysis is planned for 
the study. The unblinded primary 
efficacy analysis will be conducted when 
12-week data are available for all 
randomized patients. No individual 
treatment assignments will be unblinded 
to personnel directly involved with the 
conduct of the study until after the final 
database lock. The unblinded 
summarized results based on 12-week 
data will be disclosed. 
7. Interim Analysis  
No interim analysis for the purpose of early study-
termination is planned for the study. The unblinded 
primary efficacy analysis will be conducted when all 
randomized patients have been followed for 12 weeks 
after the first dose of study medication. The unblinded 
summarized results based on 12-week data is to be 
disclosed to the study team. No individual treatment 
assignments will be unblinded to personnel directly 
involved with the conduct of the study until after the final 
database lock. 
5 
Subgroup analysis by 
geographic region was added 
for demographics and baseline 
characteristics, use of rescue 
and prohibited medication, and 
efficacy. 
 
 
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Statistical Analysis Plan 
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Item 
no. 
Issue Addressed 
Protocol Amendment 1 Text 
SAP V1 Clarification or Addition 
6 
Study Observation periods are 
clarified  
 
10.4.4.1 Adverse Events 
Definitions 
For safety variables, 3 observation 
periods are defined: 
• 
The pre-treatment period is 
defined as the time from signing the 
ICF to before the first dose of study 
drug. 
• 
The treatment period is defined as 
the day from first dose of study drug 
to the last dose of study drug + 4 
weeks (week 12) 
• 
The post-treatment period is 
defined as the time after the 
treatment period (after week 12). 
Study Observation Period – Unless otherwise stated, 
analysis of all safety and non-safety variables captured at 
multiple visits are to be analyzed by the following 
observations periods:  
• 
The Pre-Treatment Period is defined as the time from 
signing the ICF to before the first dose of study drug.  
• 
The Treatment Period is defined as the days from first 
dose of study drug to the day of last dose + 28 days (4 
weeks). Summaries for the Treatment Period are 
based on the SAF. 
• 
The Follow-Up Period is defined from the end of the 
Treatment Period to the Week 36 Visit/Early 
Termination Visit, regardless of the patient having 
completed the treatment period (week 12 visit) or not.  
• 
The Post-Follow-Up Period is defined from the end of 
the Follow-Up Period to the phone call/Early 
Termination Visit. 
7. 
COVID-19 mitigation as per 
regulatory guidance 
These were not described in the protocol. 
Missing data handling and analyses related to COVID-19 
are specified in the SAP.  
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Statistical Analysis Plan 
Date: 17 November 2020 
 
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Item 
no. 
Issue Addressed 
Protocol Amendment 1 Text 
SAP V1 Clarification or Addition 
8. 
Some sensitivity analyses and 
supportive efficacy variables 
are added. 
1. Protocol-defined exploratory 
endpoint:  
Area under the curve for WOMAC pain 
subscale score (for the 12-week 
treatment period) for patients treated 
with REGN5069 compared to patients 
treated with placebo 
 
 
 
 
2. Secondary supportive variables that 
were not described in the protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. The exploratory endpoint area under the curve for 
WOMAC pain subscale score is being replaced with 
the following two supportive primary endpoint 
analyses:  
• 
WOMAC pain subscale scores averaged across 
Weeks 4, 8, and 12.  
• 
WOMAC pain subscale scores averaged across 
Weeks 8 and 12.  
The same method as for the primary endpoint will be used 
for handling missing data 
 
2. Secondary Supportive variables 
Other timepoints of interest are Week 16, 24 and 36. 
• 
Change in WOMAC pain subscale scores from 
baseline to week 16, 24, 36 
• 
Change in WOMAC physical function subscale scores 
from baseline to week 8, 16, 24, 36 
• 
Change in WOMAC stiffness subscale scores from 
baseline to week 8, 16, 24, 36 
• 
Change in WOMAC Total subscale scores from 
baseline to week 8, 16, 24, 36 
• 
Change in the PGA scores from baseline to week 8, 
16, 24, 36 
The following supportive variables are included in order 
to assess duration of treatment effect:  
• 
Change in WOMAC pain subscale scores from week 
12 to week 24 and 36 
• 
Change in WOMAC physical function subscale scores 
week 12 to week 24 and 36 
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Date: 17 November 2020 
 
CONFIDENTIAL 
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Item 
no. 
Issue Addressed 
Protocol Amendment 1 Text 
SAP V1 Clarification or Addition 
 
 
 
 
 
 
 
3. COVID-19 mitigation that was not 
described in the protocol 
 
• 
Change in WOMAC stiffness subscale scores from 
week 12 to week 24 and 36 
• 
Change in WOMAC Total subscale scores from week 
12 to week 24 and 36 
• 
Change in the PGA scores from week 12 to week 24 
and 36 
 
3. COVID-19 mitigation 
A sensitivity analysis will be performed excluding data 
collected via telephone, using the same method as for the 
primary endpoint 12-weeks analysis. 
9. 
Decision on analyzing bone-
specific laboratory results will 
be made independent of the 
condition described in the 
protocol. 
Conditional endpoints: if a mean 10% 
increase in alkaline phosphatase is 
observed at week 4, CTX-1, P1NP, 
Osteocalcin, C1M, and C3M are to be 
measured and change from baseline to 
week 12 are exploratory endpoints 
CTX-1, P1NP, Osteocalcin, C1M, and C3M may be 
measured and change from baseline to week 12 would be 
analyzed as exploratory endpoints. If analyzed, there will 
be a separate analysis plan and report. 
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1.2.4.2. 
SAP Version 2.0  
In this section we summarize the modifications to the original SAP V1.0, as presented in this 
current version of SAP (V2.0).   
After reviewing the interim analysis data from the Phase 2 clinical study (R5069-OA-1849), 
Regeneron has concluded that the week 12 data did not show significance between the placebo 
and each of the REGN5069 treatment arms in the WOMAC pain subscale score as well as other 
efficacy parameters evaluated. Additionally, there were no new safety findings or concerns 
associated with REGN5069. Based on the failure to demonstrate additional benefit in the 
REGN5069 dose groups compared to placebo, Regeneron made the decision to discontinue 
REGN5069 in the OA pain indication. The Phase 2 study (R5069-OA-1849) will be prematurely 
terminated after all patients have completed the  Week 36 visit (visit 10) and will not be required 
to complete the Week 52 phone call, specified in Schedule of Events (Protocol Amendment 1, 
Section 8.1).  
An abbreviated CSR will now be produced for this study, and this SAP amendment describes 
analysis changes stemming from this decision.  
Table 2 presents the details of these changes from SAP Version 1.0.  
Table 2: 
SAP Version 2.0 Modifications from SAP Version 1.0 
Sections 
Changed 
Changes and Rationale 
Section 2.3 Study 
Plan 
Inserted: 
As the Interim Analysis showed no treatment effect, and there were no 
safety signals observed, it was decided to terminate the study at the time 
last patient completes week 36 visit; thus, a limited number of study 
patients will have completed week 52 phone call.  
Rationale: 
The Interim Analysis showed no treatment effect, and there were no safety 
signals observed, thus the PA1 study extension to 52 weeks is no further 
necessary. 
Section 3.2 
Analysis 
Datasets, 
Per Protocol Set 
Deleted Section 3.2 
Rationale:  
As the Interim Analysis showed no treatment effect, the sensitivity 
analyses are no further necessary. Per Protocol Set analysis was intended 
as sensitivity analysis, thus defining this analysis set is no further 
necessary. 
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Sections 
Changed 
Changes and Rationale 
Section 4.4.2.1 
Supportive 
analyses 
Deleted:  
Further supportive analyses will be performed, using estimands at other 
timepoints of interest than Week 12 (Week 16, 24 and 36). 
• Change in WOMAC pain subscale scores from baseline to week 16, 
24, 36 
• Change in WOMAC physical function subscale scores from baseline 
to week 8, 16, 24, 36 
• Change in WOMAC stiffness subscale scores from baseline to week 8, 
16, 24, 36 
• Change in WOMAC Total subscale scores from baseline to week 8, 
16, 24, 36 
• Change in the PGA scores from baseline to week 8, 16, 24, 36 
The following supportive variables are included in order to assess 
duration of treatment effect:  
• Change in WOMAC pain subscale scores from week 12 to week 24 
and 36 
• Change in WOMAC physical function subscale scores week 12 to 
week 24 and 36 
• Change in WOMAC stiffness subscale scores from week 12 to week 
24 and 36 
• Change in WOMAC Total subscale scores from week 12 to week 24 
and 36 
• Change in the PGA scores from week 12 to week 24 and 36 
Rationale:  
As the Interim Analysis showed no treatment effect, these supportive 
analyses are no further necessary. 
Section 4.5.12  
Joint 
Replacement 
Inserted: 
As the study will now end when the last patient completes the week 36 
visit, the week 52 phone call will not be performed for most of the 
patients; all available Joint Replacement information will be summarized 
in a listing. 
Rationale:  
Provided clarification on the collection and reporting of information on 
joint replacement.  
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Sections 
Changed 
Changes and Rationale 
Section 4.5.3 
Exploratory 
Variables 
Deleted: 
Changes in CTX-1, P1NP, Osteocalcin, C1M, and C3M from baseline to 
week 12 may also be measured and analyzed, pending further decisions. 
Rationale:  
As the Interim Analysis showed no treatment effect, and there were no 
safety signals observed, these exploratory analyses are no further necessary. 
Section 5.3 
Rescue 
medication 
Change from: 
Analogous analyses are to be performed for the Follow-up Period. 
Change to: 
Analogous analyses are to be performed for the Follow-up Period, up to 
Week 24 visit. Rescue medication inadvertently collected in the diary past 
Week 24 (e.g. due to missing visits because of COVID-19 pandemic) will 
be censored and not included in the outputs. 
Rationale:  
The protocol-planned rescue medication collection is limited to up to 
Week 24 visit. Due to COVID-19, a few patients missed this visit or 
completed it remotely, and continued to complete the rescue medication 
diary past Week 24. As this information is to be collected as concomitant 
medication past week 24, it will be reported only as such. 
Section 5.7.1.1 
Sensitivity 
analysis  
Deleted Section 5.7.1.1  
Rationale:  
As the Interim Analysis showed no treatment effect, the sensitivity 
analyses (that were not already performed at IA time) are no further 
necessary. 
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Sections 
Changed 
Changes and Rationale 
Section 5.7.1.3 
Subgroup 
analyses 
Change from: 
Age groups [< 65, >= 65-74, ≥ 75 years]  
Forest plots for the subgroup analysis are to be provided. 
Change to: 
Age groups [< 65, >= 65]  
Forest plots for the subgroup analysis are to be provided for all above 
subgroups for the primary endpoint. Summaries and plots by visit are to 
be provided for the primary endpoint and secondary endpoints of physical 
function subscale score and PGA by K-L category and geographic region.  
Rationale:  
The number of patients >=75 is too small for the model to converge. 
Also provided a clarification on how the subgroup analysis will be 
presented. 
Section 5.8.1 
Adverse Events 
Inserted: 
• All TEAEs by SOC, PT, relationship  
• All AEs by SOC, PT 
• All SAEs, by study period 
• All SAEs by severity and study period 
• All SAEs by relationship, treatment and follow-up period 
Follow-up AEs will be summarized similarly as TEAEs, as well as AEs 
occurring during Treatment and Follow-up Periods combined. 
• Listing of TEAEs leading to infusion interruption 
Rationale:  
Provided further clarification on the AE analyses to be performed. 
Section 5.8.1 
Adverse Events 
Deleted: 
• Non-serious TEAEs by SOC and PT  
• All Joint replacements 
Rationale:  
As at the IA there were no safety issues detected, there is no further need 
to summarize non-serious AEs separately. All AEs and Serious AEs 
summaries suffice. Also, joint replacement was performed for a single 
patient, so a summary table is no further necessary, all information 
collected will be presented in the joint replacement listing.  
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Statistical Analysis Plan 
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Sections 
Changed 
Changes and Rationale 
Section 5.8.2 
Clinical 
Laboratory 
Measurements 
Deleted: 
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.  
Inserted: 
For all analytes, plots of change from baseline by visit are to be presented 
by treatment group. 
Rationale:  
As at the IA there were no safety issues detected, the PCSV analysis is 
sufficient, shift tables are no further necessary. Also provided clarification 
on what figures will be presented for laboratory data. 
Appendix 11.2 
Reference for 
Criteria for 
Treatment-
Emergent 
Potentially 
Clinically 
Significant 
Values (PCSV) 
Deleted 
Conjugated Bilirubin  
ALT/AST and Total Bilirubin  
ALT/AST and Total Bilirubin and ALP 
Total Cholesterol 
Triglycerides 
Rationale:  
As at the IA there were no safety issues detected, these PCSVs were not 
of further interest.  
Appendix 11.2 
Reference for 
Criteria for … 
PCSV 
Deleted 
HbA1c 
Rationale:  
This analyte was only to be collected at baseline, so no PCSV analysis is 
to be performed.  
Appendix 11.4  
Per Protocol 
Exclusions 
Deleted Appendix 11.4 
Rationale:  
As the PPS sensitivity analysis is no further being performed, the list of 
protocol deviations leading to PPS exclusion is not further necessary.  
1.2.5. 
Revision History for SAP Amendments 
Original SAP Version 1.0 was finalized on 29 May 2020 and was based on Protocol 
Amendment 1.  
Revised SAP Version 2.0 is revised as summarized in Section 1.2.4.2 above. 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
This is a multicenter, Phase 2, multicenter, randomized, double-blind, multi-dose, parallel-arm, 
placebo-controlled study designed to evaluate the safety and efficacy of REGN5069 in patients 
with pain due to osteoarthritis of the knee. Up to approximately 240 patients are randomized in a 
1:1:1 ratio to receive a low dose of REGN5069 at 100 mg IV Q4W, a high dose of REGN5069 at 
1000 mg IV Q4W, or matching placebo Q4W, for a total of 3 doses Q4W during the 12-week 
treatment period.  
Randomization is stratified by Kellgren-Lawrence (K-L) category (2-3 vs 4) of the index knee 
joint at the screening visit and participation in the Moticon sub-study (yes vs no). The use of the 
stratification factor based on participation in the Moticon sub-study ensures balance in the 
treatment assignments within the Moticon sub-study. The index knee joint is defined as the knee 
joint affected by OA and selected for primary assessment for this study. 
An independent Data Monitoring Committee (IDMC) is monitoring unblinded data. Based on 
these reviews in the context of the totality of evidence, if there are significant concerns at any 
time regarding a safety issue, the IDMC may make a recommendation to the sponsor to 
temporarily pause, alter, or terminate the study. Once recommendations from the IDMC have 
been received, further discussions may be conducted, if appropriate, and the sponsor is to 
determine if these or other actions should be taken. 
2.2. 
Sample Size and Power Considerations 
Up to approximately 240 patients (80 per treatment group) are randomized to 3 treatment groups 
in a 1:1:1 allocation. Assuming a standard deviation (SD) of 2.3, 80 patients per treatment group 
provides approximately 80% power to detect a treatment difference of 1.1 between the 
REGN5069 dose and the matching placebo in change from baseline to week 12 in Western 
Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale score (using a 
significance level of 0.05, 2-sided t-test and assuming a dropout rate of 15% [6% due to lack of 
efficacy or AEs, and 9% due to other reasons]). 
The WOMAC index is comprised of 24 parameters grouped in subscales (pain, physical 
function, stiffness) and is reported using a Numerical Rating Scale score of 1-10. 
2.3. 
Study Plan 
The study was intended to consist of a screening period of up to 30 days, followed by a 12-week 
randomized, double-blind, placebo-controlled treatment period, a 24-week follow-up period, and 
an end-of-study phone call approximately 52 weeks after the first dose of study drug (Figure 1). 
The purpose of the end-of-study phone call was to determine whether a patient underwent, is 
scheduled for, or is on a waiting list to receive joint replacement surgery, or whether joint 
replacement was recommended but the patient elected to defer. Thus, each patient was to be 
enrolled in the study for approximately 56 weeks, including the screening period and the period 
up to the end-of-study phone call. 
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As the Interim Analysis showed no treatment effect, and there were no safety signals observed, it 
was decided to terminate the study at the time last patient completes week 36 visit; thus, a 
limited number of study patients will have completed week 52 phone call. 
Figure 1: 
Study Flow Diagram 
 
 
Screening 
Period 
 
Treatment Perioda 
 
Follow-Up Period 
 
Phone Call for 
Joint 
Replacement 
Status 
Questionnaire 
 
 
 
 
 
 
 
 
Up to 30 
days 
12 weeks 
24 weeks 
16 weeks 
 
 
Day 1 
(Baseline) 
 
Week 12 
(End of Treatment) 
 
Week 36 
(End of Follow-up) 
Week 52 
(End of Study) 
 
 
 
a - Study drug is to be administered every 4 weeks throughout the 12-week treatment period. Thus, study drug is to be 
administered at the day 1 (baseline) visit and at the week 4 and week 8 visits. 
The Schedule of Events table is presented in Appendix 11.1, Table 3 . 
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3. 
ANALYSIS POPULATIONS  
In accordance with guidance from the International Council for Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (1998), the following populations are used for all 
statistical analyses: 
3.1. 
Full Analysis Set (FAS) 
The full analysis set (FAS) includes all randomized patients and is based on the treatment 
allocated (as randomized). Efficacy endpoints are analyzed using the FAS. 
3.2. 
The Safety Analysis Set (SAF) 
The safety analysis set (SAF) includes all randomized patients who received any study drug and 
is based on the treatment received (as treated). Treatment compliance/administration and all 
safety variables are analyzed using the SAF.  
Determination of "as treated" is done as follows: 
• Patients randomized to the placebo arm who receive at least one dose of active 
REGN5069 1000mg will be considered as treated with REGN5069 1000mg.    
• Patients randomized to the placebo arm who receive at least one dose of active 
REGN5069 100mg and no dose of REGN5069 1000mg will be considered as treated 
with REGN5069 100mg.    
• Patients randomized to any of the REGN5069 arms that did not receive any dose of either 
REGN5069 1000mg or 100mg will be considered as treated with placebo and classified 
in the placebo treatment arm for the purpose of analysis using the SAF. 
 
3.3. 
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 measurement following the first dose of study drug. 
Patients are analyzed according to the treatment actually received (as treated). 
3.4. 
The Immunogenicity Analysis Set 
The anti-drug antibody (ADA) analysis set (AAS) includes all treated patients who received any 
study drug and had at least one non-missing ADA result from the REGN5069 ADA assay after 
the first dose of study drug. Patients will be analyzed according to the treatment actually 
received. 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
The following demographic and baseline characteristic variables are to 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 
• K-L screening score of index knee, as per the electronic data collection system (EDC) 
(and by the integrated response system (IRT) if different) 
• Subjects participating in the MOTICON sub-study 
• WOMAC pain subscale at baseline. 
• Geographic region: USA, MGU (Republic of Moldova, Georgia, Ukraine), and 
Poland 
• Duration of OA at baseline 
• Walking aid use at baseline 
• History of analgesic intolerance and inadequate pain relief 
4.2. 
Medical History  
Medical history was recorded at screening and is to be coded to a Preferred Term (PT) and 
associated primary System Organ Class (SOC) according to the Medical Dictionary for 
Regulatory Activities (MedDRA®) Version 23 or later. 
4.3. 
Prior/Concomitant Medications and Procedures 
Prior medication and procedures were collected at the screening visit as medication and 
procedure history. Any treatment administered and/or procedures performed from screening to 
the end of the follow-up period is considered concomitant medication and/or procedures, 
respectively. This includes medications and/or procedures that were started before the study and 
are ongoing during the study. These are to be analyzed as per the study observation periods 
defined in Section 5. 
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Medications are coded to the Anatomical Therapeutic Chemical (ATC) level 2 (therapeutic main 
group) and ATC level 4 (chemical/therapeutic subgroup), according to WHO Drug Dictionary 
(WHODD) Version REGENERONWHOB3Global202003 or higher. Patients are counted once 
in all ATC categories linked to the medication. 
Medication/Procedure Classifications 
Prior medications/procedures are defined as medications administered and/or procedures 
performed starting prior to the patient signing the informed consent form (ICF).  
Pre-treatment concomitant medications/procedures are defined as medications administered 
and/or procedures performed starting as follows: 
On-treatment concomitant medications/procedures are defined as any treatment administered 
and/or procedures performed after the administration of first dose until 28 days after 
administration of last dose.  
Follow-Up concomitant medications/procedures are defined as medications administered and/or 
procedures performed after the on-treatment period, and up to Week 36 Visit.  
• for opioids, the pre-treatment period is defined as starting 4 weeks before ICF 
• for genicular nerve block and any other similar procedures, it is defined starting 3 months 
before ICF 
• for the rest of concomitant medications/procedures, starting on or after the patient signing 
the informed consent form (ICF) 
and until before the first dose of study drug 
4.3.1. 
Rescue Medication and Prohibited Medication and Procedures During the Study 
Rescue Medication 
Starting at the screening visit until after the week-24 study visit is completed, acetaminophen is 
the only study-permitted rescue medication. Acetaminophen tablets of selected brand and 
strength are being provided to patients by the study site for use as rescue medication for 
breakthrough OA pain. In advance of initiating the study, each study site must consult with the 
sponsor and select the brand and the strength of acetaminophen tablets that are to be dispensed to 
patients as rescue medication. In the event that pain relief for OA pain is inadequate, patients are 
to take acetaminophen, as needed, in accordance with the instructions provided with the 
medication by each study site, with a maximum of 3000 mg/day. To prevent liver damage, the 
maximum allowed daily dose of 3000 mg of acetaminophen must not be exceeded and excessive 
alcohol consumption must be avoided. The use of rescue medication is not allowed for 48 hours 
prior to the start of or during a scheduled study visit to minimize the confounding effects of 
rescue medication on efficacy measures.  
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Prohibited Medication and Procedures 
Patients are required to discontinue all non-study-permitted pain medication (oral or topical) 
starting at the screening visit until after completion of the week-24 study visit. Concomitant 
medications that contain NSAIDs are prohibited from the screening visit until after completion 
of the week-24 study visit. This applies even if a patient discontinues study drug prematurely but 
remains in the study to participate in the remaining study visits. The only exception is 
aspirin/5-aminosalicylic acid, which is permitted for cardiac prophylaxis. Opioid analgesic 
medications (including tramadol) are prohibited starting at least 4 weeks prior to the screening 
visit until the end of the follow-up period with no exceptions.  
Other excluded medications/procedures starting at the screening period include: 
• Any other investigational agent 
• Medical or regular recreational use of marijuana 
• Chondroitin sulfate 
• Glucosamine  
• Hyaluronic Acid Intra-articular infusions 
• Anticoagulants and antiplatelets (eg, warfarin, heparins, factor Xa inhibitors, 
thrombin inhibitors, aspirin >150 mg daily, clopidogrel) 
• Muscle relaxants including cyclobenzaprine, carisoprodol, orphenadrine, tizanidine 
(see Section 7.7.2 in the protocol for permitted muscle relaxants) 
• Corticosteroids (topical, intranasal, and inhaled formulations are permitted), 
adrenocorticotropic hormone 
• Cyclosporine, methotrexate, mycophenolate mofetil, tacrolimus (topical tarcolimus 
allowed) 
• Azathioprine, sulfasalazine, hydroxychloroquine 
• IL-6 or IL-6 receptor antagonists 
• Abatacept, ustekinumab  
• Tumor necrosis factor antagonists 
• IL-1 inhibitors, including diacerein  
• PDE-4 and Jak-kinase inhibitors 
• Genicular nerve block and any other similar procedures (prohibited from within 
3 months of the screening visit and up to the last study site visit in the follow-up period) 
The list of concomitant medications taken by study patients is reviewed by the study team to 
determine if any medication falls under one of the above categories. If a concomitant medication 
is adjudicated to be prohibited, a protocol deviation is recorded. 
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The following variables are to be summarized for prohibited medications, overall and by 
geographical region: 
• Use of at least one prohibited medication during Pre-treatment Period, Treatment 
Period, and Follow-up Period.  
• Use of any prohibited medications, as well as selected prohibited medications 
(NSAIDs, opioids and corticosteroids), by visit. 
• Receiving prohibited procedures during Pre-treatment Period, Treatment Period, and 
Follow-up Period.  
4.4. 
Efficacy Variables 
4.4.1. 
Primary Efficacy Variable 
The primary endpoint of the study is the change from baseline to week 12 in the WOMAC pain 
subscale score. 
The WOMAC index is comprised of 24 parameters grouped 3 in subscales (pain, physical 
function, and stiffness) and is reported using a Numerical Rating Scale score of 1-10.    
4.4.2. 
Secondary Efficacy Variables 
The secondary efficacy endpoints of the study are: 
• Change from baseline to week 12 in the WOMAC physical function subscale score  
• Change from baseline to week 12 in the Patient Global Assessment (PGA) score  
• Change from baseline to week 12 in WOMAC stiffness subscale score  
• Change from baseline to week 12 in the WOMAC total score (based on the full survey)  
• Percentage of patients who had a response at week 12, with response defined as an 
improvement by ≥30% in the WOMAC pain subscale scores 
The Patient Global Assessment of OA (PGA) is a patient-rated assessment of current 
disease state on a 5-point Likert scale (1 = very good; 2 = good; 3 = fair; 4 = poor; and 
5 = very poor). 
4.4.2.1. 
Supportive variables 
The following two supportive endpoints are to be analyzed instead of the exploratory area under 
the curve endpoint:   
• WOMAC pain subscale scores averaged across Weeks 4, 8, and 12.  
• WOMAC pain subscale scores averaged across Weeks 8 and 12.  
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4.4.3. 
Exploratory Efficacy Variables 
The exploratory efficacy endpoints of the study are: 
• The exploratory endpoint described in the protocols as “Area under the curve for 
WOMAC pain subscale score (for the 12-week treatment period)” is being replaced 
by supportive endpoints described in section 4.4.2.1. 
• Change in gait and functional mobility parameters recorded by a wearable insole 
device from baseline to week 12 in a subset of patients at participating sites. 
4.5. 
Safety Variables 
Patient safety is assessed through the collection of reported adverse events (AEs), clinical 
laboratory data, vital signs, ECG, 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. 
4.5.1. 
Adverse Events and Serious Adverse Events 
Adverse event information is to be collected until the patient’s last study visit. Serious adverse 
event information is to be collected until the event is considered chronic and/or stable and/or 
resolved.  
Adverse events (AE) and Serious Adverse Events (SAE) are collected from the time of informed 
consent signature and then at each visit until the end of follow-up visit (week 36) for AEs and 
until end of study visit (week 52) for SAEs. 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 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. 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. 
An SAE is an AE that is classified as serious according to the criteria specified in the protocol. 
SAEs with an onset within 30 days of the end of the follow-up period or within 226 days of last 
study drug administration if the patient early terminated from the study is to be reported to the 
sponsor. SAEs with an onset day greater than 30 days from the end of the follow-up period/early 
termination visit: only fatal SAEs and those deemed by the investigator to be drug-related SAEs 
are to be reported to the sponsor. SAEs reported by the patient at the end-of-study phone call and 
deemed by the investigator to be drug-related are to be reported to the sponsor. 
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4.5.2. 
Safety Variables (Secondary Study Endpoints) 
The secondary safety endpoints of the study are: 
• The incidence of treatment-emergent adverse events (TEAEs) throughout the study 
duration 
• The incidence of imaging abnormalities consistent with accelerated arthropathies as 
assessed by X-ray and MRI throughout the study duration 
• Presence of anti-REGN5069 antibody development throughout the study duration 
4.5.3. 
Exploratory Safety Variables 
Exploratory safety endpoints include: 
• Change in high sensitivity C-reactive protein (hsCRP) from baseline to week 12  
• Change in alkaline phosphatase from baseline to week 12  
4.5.4. 
Adverse Events of Special Interest 
No AESIs have been defined for this study. 
4.5.5. 
Acute Intravenous Infusion Reactions 
Infusion reactions are defined as any relevant AE that occurs during the infusion or within 2 hours 
after the infusion is completed. All infusion reactions must be reported as AEs and graded using 
the grading scales as instructed in the protocol. 
4.5.6. 
Laboratory Safety Variables 
The clinical laboratory tests include blood chemistry, hematology, urinalysis, urine chemistries, 
hs-CRP, and others. Samples for laboratory testing are to be collected at the time points specified 
in the Schedule of Events (Table 3). Clinical laboratory values are 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 are also to be 
available in the database, with associated normal ranges. For laboratory measurements 
performed at local laboratories, the corresponding local laboratory normal ranges will be used. 
Both actual test values and “change from baseline” values (defined as the post-baseline value 
minus the baseline value) are used in central lab result summaries. Potentially clinically 
significant values (PCSV) ranges are to be applied to central lab test values as applicable (see 
Appendix 11.2 for PCSV definitions).  
4.5.7. 
Vital Signs 
The following vital signs parameters are to be collected according to the Schedule of Events in 
Table 3: 
• Body temperature (oC) 
• Semi-recumbent/2-minute standing systolic and diastolic blood pressures (mmHg) 
and heart rate (bpm) 
• Respiratory rate (bpm) 
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Both actual values and “change from baseline” values (defined as the post-baseline value minus 
the baseline value) are to be used in the result summaries. Potentially clinically significant values 
(PCSV) ranges are to be applied to the vital sign parameter values as applicable (see 
Appendix 11.2 for PCSV definitions). 
4.5.8. 
Orthostatic Hypotension  
A patient is to be determined to have orthostatic hypotension if any of the following criteria are 
met: 
• If the semi-recumbent systolic blood pressure is <160 mm Hg, a decrease in the 2-
minute standing systolic blood pressure of ≥20 mm Hg or a decrease in the standing 
diastolic blood pressure of ≥10 mm Hg from the semi-recumbent systolic or diastolic 
blood pressure, respectively 
OR 
• If the semi-recumbent systolic blood pressure is ≥160 mm Hg, a decrease in the 2-
minute standing systolic blood pressure of ≥30 mm Hg or a decrease in the standing 
diastolic blood pressure of ≥15 mm Hg from the semi-recumbent systolic or diastolic 
blood pressure, respectively 
OR 
• An increase in the 2-minute standing heart rate of ≥30 bpm from the semi-recumbent 
heart rate. 
OR 
• The patient is unable to stand for standing blood pressure measurements due to 
dizziness or lightheadedness 
In case any of the following criteria are met, up to 2 re-checks (within approximately 5 minutes 
of the original measurement) should be performed (patient should remain standing). An AE of 
orthostatic vital sign change should be reported if the change is confirmed upon the repeat tests. 
4.5.9. 
12-Lead Electrocardiography (ECG) 
A standard 12-lead ECG is to be performed according to the Schedule of Events in Table 3 with 
the patient in the semi-recumbent position for approximately 10 minutes and prior to blood 
samples being drawn. Heart rate is recorded from the ventricular rate and the PR/PQ, QRS, and 
QT, QTcF intervals, and ECG status (normal, abnormal not clinical significant or abnormal 
clinical significant) is also recorded.  
QTcF is defined as follows:  
QTcF (ms) =QT/RR1/3, 
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 are to be applied to the ECG parameter 
values as applicable (see Appendix 11.2 for PCSV definitions). 
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4.5.10. 
Physical Examination (PE) Variables 
No PE variables are defined, as, if clinically significant PE abnormalities are observed, an AE is 
entered. Otherwise no PE examination information is collected. 
4.5.11. 
Neurological Examination Variables 
A full or brief neurological examination is to be performed at the time points indicated in 
Table 3. Neurological evaluations of specific domains as listed in the protocol are to be described 
as normal or abnormal not clinically significant or abnormal clinically significant.  
Neurological findings at baseline that are not exclusionary should be recorded in the medical 
history. Findings at subsequent visits are to be assessed by the investigator to determine if these 
should be recorded as an AE. Clinically significant neurological abnormalities are recorded and 
will be summarized.  
4.5.12. 
Other Safety Variables 
• Joint Pain Questionnaire: A joint pain questionnaire is to be completed by the patient 
at the time points indicated in the Schedule of Events in Table 3. For each knee, hip, 
and shoulder joint, the patient is prompted to indicate if he or she has experienced 
worse pain. Assessments include: 
− Patients with significantly worse joint pain in any joint at each scheduled visit 
− Patients with significantly worse joint pain by joint at each scheduled visit 
• Joint replacement: an end-of-study phone call was to be conducted at approximately 
52 weeks after the first dose of study drug. The purpose of the end-of-study phone 
call was to determine whether a patient underwent, is scheduled for, or is on a waiting 
list to receive joint replacement surgery, or whether joint replacement was 
recommended but the patient elected to defer since his/her last in-clinic visit. Patients 
were to also be asked to submit pre-operative imaging (X-ray and MRI, if available) 
for adjudication and to provide joint material for histological and molecular analyzes, 
if feasible. Assessments included: 
− Patients with joint replacement (all joint replacements) 
− Reason for joint replacement (all joint replacements) 
− Time to joint replacement (all joint replacements) 
• Knee society score for joint replacement: an investigator-completed questionnaire 
that is used to objectively measure a patient’s ability to function before and after total 
knee arthroplasty 
As the study will now end when the last patient completes the week 36 visit, the week 52 phone 
call will not be performed for most of the patients; all available Joint Replacement information 
will be summarized in a listing. 
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4.6. 
Imaging 
Radiographs of patients’ knees, hips, and shoulders are to be taken using a standard approach at 
the time points indicated in Appendix 11.1, Table 3  In addition to scheduled imaging, 
radiographs should be considered for worsening joint pain. The investigator is to consult the 
sponsor prior to scheduling additional imaging. Magnetic resonance imaging of the index knee is 
to be performed at the time points indicated in Appendix 11.1, Table 3. In addition to scheduled 
MRIs, an MRI should be considered for worsening joint pain and if X-rays are inconclusive. The 
investigator is to consult the sponsor prior to scheduling additional imaging. If a patient 
undergoes a joint replacement surgery, patients will have additional radiographs at the time 
points indicated in Table 4.  
As described in the Charter for Arthropathy Adjudication Committee, the screening and on-study 
radiographs of the knees and hips are to be evaluated for joint space width to identify excessive 
loss of joint space. In addition, all radiographs and MRI scans are to be evaluated for the 
presence of adjudicated arthropathy. See Appendix 11.1, Table 3, Arthropathy Adjudication, for 
details on adjudication criteria. 
The imaging data summaries and listings will include: 
• Adjudicated accelerated arthropathy (AA): 
− Patients and events of AA 
− Subtypes of AA 
− Patients and events of destructive arthropathy (DA) 
− Time to AA  
− Time to DA 
• Clinically Significant Imaging Events not Considered Arthropathies  
• Adjudicated Arthropathy Findings at Event-Driven Imaging Timepoint 
• Adjudicated Arthropathy Imaging Events at EOT (Week12) or EOF (Week 36) 
Imaging Timepoint   
• Joint replacements: 
− Patients with joint replacement 
− Time to joint replacement 
4.7. 
Pharmacokinetic Variables 
The Pharmacokinetic (PK) variables are concentrations of functional REGN5069 in serum and 
time. 
4.8. 
Immunogenicity Variables 
The immunogenicity variables are ADA status, titer, and timepoint/visit. Serum samples for 
ADA will be collected at the clinic visits specified in Appendix 11.1. Samples positive in the 
REGN5069 ADA assay will be further characterized for ADA titers. 
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4.9. 
Moticon Digital Insole Device Sub-Study for Gait Assessments 
Only study sites selected for participation in the Moticon sub-study for gait assessments using 
the digital insole device are to perform the Moticon-related procedures at the time points 
according to Table 3. This sub-study is to enroll approximately 13 patients per treatment group to 
obtain data on at least 10 patients per treatment group for a total of approximately 30 patients 
across the entire sub-study.  
The principal purpose of this sub-study is to assess functional mobility gait parameters as 
measured by the Moticon insole device in patients with pain due to OA of the knee without an 
analgesic treatment and in the presence of potential analgesic treatment. The study is to also 
examine correlations of these gait parameters with the WOMAC pain subscale score.  
Moticon sub-study will be analyzed outside of this SAP. This data will be as an Appendix of the 
clinical study report. All listings outputs produced under this SAP, however, will contain a 
MOTICON participation flag. 
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5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics 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 are displayed for each category. 
Unless otherwise specified, table content is to be presented sorted by descending order of 
frequency of system organ class for the REGN5069 1000 mg group. 
Study Observation Period – Unless otherwise stated, analysis of all safety and non-safety 
variables captured at multiple visits are to be analyzed by the following observations periods:  
• The Pre-Treatment Period is defined as the time from signing the ICF to before the 
first dose of study drug.  
• The Treatment Period is defined as the days from first dose of study drug to the day 
of last dose + 28 days (4 weeks). Summaries for the Treatment Period are based on 
the SAF. 
• The Follow-Up Period is defined from the end of the Treatment Period to the Week 
36 Visit/Early Termination Visit, regardless of the patient having completed the 
treatment period (week 12 visit) or not. 
• The Post-Follow-Up Period is defined from the end of the Follow-Up Period to the 
phone call/Early Termination Visit. 
5.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics are to be descriptively summarized by treatment group, 
combined REGN5069, and overall based on the FAS. Parameters to be summarized include 
those described in Section 4.1. 
5.2. 
Medical History 
Medical history is to be descriptively summarized by treatment group, combined REGN5069 and 
overall for the FAS. Summaries are to show patient counts (percentages) by primary SOC and 
PT. The tables are to be sorted by descending order of frequency of system organ class for the 
REGN5069 1000 mg group. Within each primary SOC, PTs are to be sorted by descending order 
of frequency of system organ class for the REGN5069 1000 mg group. 
5.3. 
Prior / Concomitant Medications 
The analysis population is based on the SAF. 
Prior Medications 
All prior medications, dictionary coded by WHO, are to be descriptively summarized by 
treatment group, and combined REGN5069 based on the FAS. Summaries are to present patient 
counts (and percentages) for all prior medications, by descending order of frequency of ATC 
followed by ATC level 2, ATC level 4 and preferred term for the REGN5069 1000 mg group. In 
case of equal frequency across anatomic or therapeutic categories, alphabetical order is to be 
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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, are to be descriptively summarized by 
treatment group, and combined REGN5069 based on the SAF. Summaries are to present patient 
counts (and percentages) for the concomitant medication groups described in Section 4.3 for all 
concomitant medications, by descending order of frequency of ATC level 2, followed by ATC 
level 4 and preferred term. In case of equal frequency across anatomic or therapeutic categories, 
alphabetical order is to be used. Patients are to be counted once in each ATC category (anatomic 
or therapeutic) linked to the medication, hence may be counted several times for the same 
medication. 
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. 
Rescue Medication 
The number (percentage) of patients using rescue medication during the Treatment Period are to 
be summarized by treatment group and overall based on the SAF. Analogous analyses are to be 
performed for the Follow-up Period, up to Week 24 visit. Rescue medication inadvertently 
collected in the diary past Week 24 (e.g. due to missing visits because of COVID-19 pandemic) 
will be censored and not included in the outputs. 
For patients taking rescue medication, usage of rescue medications (measured in mg) is 
summarized by study week. 
Descriptive statistics of the weekly average usage of rescue medications are to be presented by 
treatment group based on the SAF. 
5.4. 
Prohibited Medications 
The analysis population is based on the SAF. 
The number (percentage) of patients with prohibited medications are to be descriptively 
summarized by treatment group, and combined REGN5069 based on the SAF. The tables are to 
be sorted by decreasing frequency of ATC Level 2, ATC Level 4, and preferred term in the 
REGN5069 1000 mg group. 
5.5. 
Patient Disposition 
The analysis population is based on the FAS. 
The end of study is defined as the date when the last patient completes the last phone call, 
withdraws from the study, or is lost to follow up (ie, the patient can no longer be contacted by 
the investigator).  
Dose modification for an individual patient is not allowed. 
Patients who permanently discontinue from study drug and who do not withdraw from the study 
are asked to return to the clinic for all remaining study visits and to participate in all study phone 
calls per the visit schedule.  
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Patients who permanently discontinue from study drug and who opt to withdraw from the study 
are asked to complete study assessments as follows:  
• Patients who are withdrawn from the study before the primary endpoint visit (week 
12) are asked to return to the clinic for 2 visits: once for an early termination visit 
consisting of the early termination assessments described in Table 3 and again at the 
primary endpoint visit (week 12).  
• Patients who are withdrawn from the study after the primary endpoint visit are asked 
to return to the clinic for early termination assessments, only. 
The disposition of patients in the study are to be summarized by treatment group, combined 
REGN5069 and overall for FAS.  
Percentages are to be calculated using the number of screened patients as the denominator for: 
• Screened patients (defined as having signed the ICF).  
• Screen Fail patients. Reason for screen failure is to be provided. 
• Patients treated but not randomized (if applicable) 
• Patients randomized (defined as having received a randomization number per IWRS). 
This row is to reflect grouping based on randomization assignment.  
• Patients did not meet inclusion/exclusion criteria but randomized (if applicable). 
Percentages are to be calculated using the number of randomized patients as the denominator for: 
• Patients randomized but not treated. This row is to reflect grouping based on 
randomization assignment.  
• Patients randomized and treated. 
• Patients treated differently than randomized. This row is to reflect grouping based on 
randomization assignment.  
• Patients who completed study treatment, patients who discontinued treatment  
• Patients who completed study treatment period (defined as completing Week 12 visit), 
patients who discontinued study treatment period and reason for study treatment period 
discontinuation, patients who had infusion interruptions and reason. 
• Patients who completed study follow-up period (defined as completing Week 36 visit). 
• Patients who completed the study (defined as having completed Week 52 phone call), 
patients who withdrew from the study and reason for study withdrawal. 
In addition, a summary of the impact of COVID-19, with all information described in Section 9, 
will be provided. 
Summary of the number (percentage) of patients in each analysis set are to be by treatment 
group, combined REGN5069, and overall. 
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Additionally, the following listings are to be provided (if applicable):  
• Listing of patients treated but not randomized, patients randomized but not treated, 
patients randomized but not treated with the randomized treatment, patient disposition 
for all randomized patients, and patients prematurely discontinued from treatment, 
with reasons. 
• Listing of screening failures and reasons for all screen-failed patients. 
5.6. 
Extent of Study Treatment Exposure and Compliance 
The analysis population is based on the SAF. 
5.6.1. 
Exposure to Investigational Product 
The treatment exposure to REGN5069 and placebo doses is calculated as:  
• (Date of last administration of study drug - date of the first study drug administration 
after randomization) + 28  
The duration of exposure are to be summarized for each treatment group using the number of 
patients (n), mean, standard deviation, median, Q1, Q3, minimum, and maximum. 
The number (percentage) of patients with exposure duration periods are to be presented by 
specific time periods. The time periods of interest are specified as: ≥ 1 day, ≥ 4 weeks, ≥ 8 
weeks. 
The length of the study observation period (days) are to 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 participation period (days) will be calculated as: 
• (Date of last study Visit or last Phone call - date of first study drug dose) +1 
The study observation duration is to be summarized for each treatment group using the number 
of patients (n), mean, standard deviation, median, Q1, Q3, minimum, and maximum. 
The number (percentage) of patients with observation periods is to 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, ≥ 365 days 
5.6.2. 
Measurement of Compliance 
Compliance with protocol-defined investigational product is to be calculated by treatment group 
and combined REGN5069 as follows:  
• (Number of actual infusions of study drug during the exposure period) / (Number of 
planned infusions of study drug during the exposure period on or before the time that 
the patient discontinues from the treatment phase of the study) x 100% 
Treatment compliance is to be presented by descriptive statistics as well as the number 
(percentage) of patients who have 1, 2, 3 infusions. 
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5.6.3. 
Protocol Deviations 
All important and minor protocol deviations have been collected and reviewed on an ongoing 
basis throughout the study as described in the protocol deviation plan. 
Protocol deviations are to be summarized for patients incurring any important deviation by count 
and percentage, and patients incurring each type of important deviation by count and percentage 
for FAS. 
A patient listing of all important and minor protocol deviations is to be provided. 
5.7. 
Statistical Methods for Efficacy 
Unless stated otherwise, all efficacy analyses are to be based on the FAS. Confidence intervals 
are to be constructed with level of confidence equal to 95%. With the exception of analyses 
based on the PPS, models including stratifying variables are to utilize the value of these variables 
as captured in the IWRS system. Analyses based on the PPS are to utilize the value of these 
variables as captured in the EDC system.  
If no more than 10% of patients are available in a stratification cell, that stratification factor will 
not be used. 
5.7.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint is change from baseline to week 12 in the WOMAC pain subscale 
score. 
The null hypotheses of no treatment difference between a REGN5069 dose and placebo against 
an alternative hypothesis of some treatment difference in change from baseline to week 12 in 
WOMAC pain subscale, physical function subscale, and Patient Global Assessment scores are to 
be tested for each dose. Multiplicity adjustment for the 6 null hypotheses are to be made using 
sequentially rejective multiple test procedure to control Type I error rate at 2-sided 0.05 level in 
the following order: 
• H1: No treatment difference between 1000 mg REGN5069 and placebo groups in 
change from baseline to week 12 in WOMAC pain subscale score 
• H2: No treatment difference between 100 mg REGN5069 and placebo groups in 
change from baseline to week 12 in WOMAC pain subscale score 
• H3: No treatment difference between 1000 mg REGN5069 and placebo groups in 
change from baseline to week 12 in WOMAC physical function subscale score 
• H4: No treatment difference between 100 mg REGN5069 and placebo groups in 
change from baseline to week 12 in WOMAC physical function subscale score 
• H5: No treatment difference between 1000 mg REGN5069 and placebo groups in 
change from baseline to week 12 in Patient Global Assessment score 
• H6: No treatment difference between 100 mg REGN5069 and placebo groups in 
change from baseline to week 12 in Patient Global Assessment score 
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If at any step a null hypothesis is not rejected, the testing is to stop and no further hypothesis in 
the order are to be tested. 
The primary estimand for the primary objective is the difference in means between REGN5069 
dose + protocol-defined rescue medication  and placebo + protocol-defined rescue medication in 
the change from baseline to week 12 in the WOMAC pain subscale score of patients in the FAS. 
All collected data are to be included in the analysis regardless of whether prohibited medication 
was taken.  
The above primary and secondary efficacy variables are to be analyzed using a multiple 
imputation approach with a mixed-effect model for repeated measures (MMRM) based on the 
FAS.  
Intermittently missing WOMAC subscale scores prior to treatment discontinuation are first to be 
imputed using the Markov Chain Monte Carlo method, and then the remaining missing data with 
a monotone missing pattern are to be imputed with a regression method. For patients who 
discontinued treatment due to reasons other than lack of efficacy, death or AEs, (reasons 
including discontinuation because of public health measures implemented in response to 
COVID-19, see Section 9 for details on the CRF implemented for collecting this information), 
their missing WOMAC subscale scores after discontinuation will be imputed under the 
missing-at-random assumption using the regression method with adjustment for covariates 
including treatment group, randomization strata (K-L category [2 to 3, or 4]), and baseline 
WOMAC subscale score. For patients who permanently discontinue treatment due to lack of 
efficacy, death or AEs, each imputed value obtained through the above method will be further 
adjusted by subtracting the mean change from baseline to the respective post-baseline time point 
calculated from patients in the same treatment group with observed data at that time point. 
Missing data up to week 12 will be imputed 50 times to generate 50 complete data sets by using 
the SAS procedure PROC MI following the steps below: 
• Step 1: The monotone missing pattern is induced by Markov Chain Monte Carlo 
(MCMC) method in MI procedure using seed number 1849. Any score imputed 
outside the range of the WOMAC subscale score of 0-10 is to be truncated to the 
nearest permissible value on the WOMAC scale according to the following 
algorithm: 
− If the imputed score > 10, then the final imputed score will be 10. 
− If the imputed score < 0, then the final imputed score will be 0.  
• Step 2: The missing data at visits subsequent to treatment discontinuation are to be 
imputed using the regression method for the monotone pattern with seed number 
1849 and adjustment for covariates including treatment groups, randomization strata 
(K-L category of index knee at screening, 2-3 or 4), WOMAC score at baseline and 
all values at preceding visits. Scores that are imputed outside the range of the 
WOMAC subscale will be truncated in the same manner as in step 1.  As the 
regression method imputes missing data sequentially by visits, the truncation will be 
implemented after each visit iteration, during the MI procedure. 
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• Step 3: For patients who permanently discontinued study treatment due to lack of 
efficacy, death or AEs, the initially missing and now imputed WOMAC subscale 
scores at visits subsequent to treatment discontinuation are to be adjusted to be 
centered at the mean baseline value for that treatment group, i.e.: 
imputed score = initial imputed score under MAR – (mean change from baseline subscale 
score at the post-baseline time point for the treatment group based on patients on 
treatment with non-missing data at that time point).  
Scores that are adjusted to outside the range of the WOMAC subscale will be truncated 
following the same algorithm as in step 1.  
Each imputed data set is to be analyzed using a MMRM with terms for baseline WOMAC Pain 
subscale score, randomization strata (K-L category [2 to 3, or 4]), treatment, visit, and treatment-
by-visit interaction as fixed effects. The MMRM is to be fitted using the MIXED procedure in 
Statistical Analysis System (SAS) with an unstructured covariance matrix to model the within-
patient errors. The denominator degrees of freedom is to be estimated using Kenward-Roger’s 
approximation. In the event a model cannot be fit due to the estimation algorithm failing to 
converge, the covariance matrix for within-patient errors is to be modeled by an autoregressive 1 
structure, followed by a compound symmetry structure if convergence is still not achieved for 
the prior.  
The results from the 50 analyses are combined using Rubin’s formulae (PROC MIANALYZE). 
The least squares means estimates for the mean change from baseline to week 12, as well as the 
difference of the estimates between REGN5069 each dose and placebo, with the corresponding 
standard error, p-value and associated 95% confidence interval are to be provided. Similar 
estimates at other visits are also to be presented. 
The hypothesis for H1 is to be rejected when the p-value corresponding to the difference in 
change from baseline to week 12 between 1000 mg REGN5069 and placebo groups is less than 
0.05 in WOMAC pain subscale score. 
5.7.1.1. 
Supportive Analysis  
The following two supportive primary endpoint analyses will be performed:  
• WOMAC pain subscale scores averaged across Weeks 4, 8, and 12.  
• WOMAC pain subscale scores averaged across Weeks 8 and 12.  
The same method as for the primary endpoint will be used for handling missing data 
Similarly, all supportive analyses described in Section 4.4.2.1 will be analyzed in a similar 
manner as the primary endpoint.  
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5.7.1.2. 
Subgroup Analysis 
Descriptive analyses are to be performed on the primary endpoint and secondary endpoints of 
physical function subscale score and PGA to summarize the treatment effects across 
subpopulations defined by: 
• K-L category [2-3, or 4] 
• Geographical region [USA, MGU (Republic of Moldova, Georgia, Ukraine), Poland] 
• Age group [< 65, >= 65]  
• Sex [Male, Female] 
• Weight group [< median baseline weight, ≥ median baseline weight kg] 
• BMI group [≤ median baseline BMI, > median baseline BMI] 
• Duration of OA (DOA) at baseline [≤ median baseline DOA, > median baseline 
DOA] 
Forest plots for the subgroup analysis are to be provided for all above subgroups for the primary 
endpoint. Summaries and plots by visit are to be provided for the primary endpoint and 
secondary endpoints of physical function subscale score and PGA by K-L category and 
geographic region.  
5.7.2. 
Analysis of Secondary and Exploratory Efficacy Variables 
Analyses of continuous variables in secondary (Section 4.4.2) and exploratory (Section 4.4.3) 
endpoints are to use the same analysis method as the primary efficacy variables. 
Analysis of categorical variables in secondary endpoints (Section 4.4.2) is to use the Cochran-
Mantel-Haenszel approach stratified by the K-L category (2-3 vs 4 for index knee at screening) 
with missing data considered as non-response. 
Exploratory endpoints for MOTICON (Section 4.9) will be addressed in a separate SAP. 
Plots of mean values and change from baseline in PGA, WOMAC subscale and total score by 
Visit: Least Squares Mean (+/- SE) will be presented. 
Cumulative distribution of percent change from baseline to Week 12 in the WOMAC pain and 
physical function scores will be presented by treatment group. The cumulative distribution plot 
displays a continuous plot of the percent change from baseline on the X-axis and the percent of 
patients experiencing that change on the Y-axis. 
5.7.3. 
Adjustment for Multiple Comparison 
Control for multiplicity for both the primary and key secondary efficacy analyses is described in 
Section 5.7.1. 
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5.8. 
Analysis of Safety Data 
The analysis of safety and tolerability is to be performed on the SAF, as defined in Section 3.2. 
The safety analysis is to be based on the reported AEs and other safety information (clinical 
laboratory evaluations, vital signs, 12-lead ECG, Physical Examination, etc.) and is to be 
summarized by treatment group. 
Treatment-Emergent Potential Clinically Significant Values (PCSV) in laboratory variables, vital 
signs and ECG are defined in Appendix 11.2. 
The summary of safety results will be presented for each treatment group and by visit where 
applicable. 
Study observation period: The observation period is divided into the four segments defined in 
Section 5. 
5.8.1. 
Adverse Events  
The verbatim text, the preferred term, and the primary SOC are to be listed in patient listings. 
Summaries that include frequencies and proportions of patients reporting AEs are to include the 
preferred terms and the SOCs. 
Pre-treatment AEs are defined as AEs that developed or worsened during the Pre-Treatment 
Period. 
Treatment-emergent AEs (TEAEs) are defined as AEs that developed or worsened during the 
Treatment Periods. 
Follow-Up AEs are defined as AEs that developed or worsened after treatment period end (more 
than 4 weeks after the last dose of study drug) but before Week 36 visit. 
The focus of adverse event reporting in the clinical study report is on TEAEs.  
Summaries of TEAEs by treatment group, summarizing number (percentage) of patients within 
the specified category, during the study and by study period as applicable include: 
• Overview of TEAEs, summarizing number of events,  
− 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 
− 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  
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• All TEAEs by SOC, PT, relationship 
• Study drug related TEAEs by SOC and PT 
• TEAEs resulting in permanent study drug discontinuation by SOC and PT 
• TEAEs leading to study drug infusion interruption by SOC and PT 
• Serious TEAEs by SOC and PT 
• All AEs by SOC and PT 
• All AEs by severity    
• All SAEs, by study period 
• All SAEs by severity and study period 
• All SAEs by relationship, treatment and follow-up period 
Follow-up AEs will be summarized similarly as TEAEs, as well as AEs occurring during 
Treatment and Follow-up Periods combined.  
Listing to include: 
• Listing of AEs leading to death  
• Listing of TEAEs leading to permanent study treatment discontinuation 
• Listing of TEAEs leading to infusion interruption 
• Listing of TEAEs leading to withdrawal from study 
• Listing of patients with Serious TEAEs  
• Listing of all joint replacements 
Counts are to be provided according to treatment group and combined REGN5069 group for 
each PT within each primary SOC. Percentages are to be calculated based on the SAF in each 
treatment group and sorted by descending order of frequency of system organ class for the 
REGN5069 1000 mg group. 
Within each primary SOC, PTs are to be sorted by decreasing frequency in the REGN5069 
1000 mg group. For tables presenting severity of events, the worst severity is to be chosen for 
patients with multiple instances of the same event. 
Counts of each PT in decreasing order of frequency are to also be provided. TEAEs with 
preferred terms ≥5% in any treatment group are to be summarized in the report. 
5.8.2. 
Clinical Laboratory Measurements  
Laboratory test results are to be summarized by baseline and change from baseline to each 
scheduled assessment time with descriptive statistics based on the SAF by treatment group and 
combined REGN5069 group for Treatment Period and Follow-Up Period. 
Listings are to be provided with flags indicating the out of laboratory range values. 
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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) are to be summarized based on the 
SAF by treatment group and combined REGN5069 group, as well as presented in a listing. 
For Alkaline phosphatase, hemoglobin, WBC, ALT, AST, creatinine, potassium, bilirubin, plots 
of means of the observed values by visit are to be presented by treatment group. For all analytes, 
plots of change from baseline by visit are to be presented by treatment group. 
For hs-CRP, plots of medians of the observed values and change from baseline over time are to 
be presented by treatment group. 
If it is decided that CTX-1, P1NP, Osteocalcin, C1M, and C3M are to be measured and analyzed, 
the analyses will be made under a separate SAP. 
5.8.3. 
Analysis of Vital Signs 
Vital signs - temperature, blood pressure, heart rate (semi-recumbent and standing), orthostatic 
blood pressure/heart rate, and respiration rate- are to be summarized by baseline and change 
from baseline to each scheduled assessment time with descriptive statistics by treatment group 
and combined REGN5069 for the SAF, for treatment period and follow-up period. 
PCSV summary including orthostatic hypotension is to be constructed for treatment period, 
period and overall during the study, as well as presented in a listing. 
5.8.4. 
Analysis of 12-Lead ECG 
ECG parameters (Ventricular Rate, PR/PQ, QRS, QT and QTcF intervals) are to be summarized 
by baseline and change from baseline to each scheduled and collected assessment time. PCSV 
summary of ECG parameters is to be provided for treatment period, Follow-up period, and 
overall, for the SAF.  
ECG status (ie, normal, abnormal) is to be reported. Shift tables are to be provided to present the 
post-baseline status according to the baseline status (normal or missing / abnormal) by treatment. 
Listings are to be provided with flags indicating the abnormal values. 
5.8.5. 
Physical Exams 
N/A 
5.8.6. 
Joint Pain Questionnaire 
The number (percentage) of patients with worse joint pain are to be summarized by visit and 
joint (index, non-index) based on the SAF, as well as presented in a listing. 
5.8.7. 
Neurological Exam 
New-onset clinically significant abnormal neurological examinations and the number 
(percentage) of patients with new-onset clinically significant abnormal neurological 
examinations are to be summarized by visit based on the SAF. Listings are to be provided with 
flags indicating the abnormal values. 
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5.8.8. 
Imaging Data 
The number (percentage) of patients with images requiring arthropathy adjudication, as well as 
the number (percentage) of patients with confirmed adjudicated arthropathy (by type of 
arthropathy), as well as joint replacements and other findings are to be summarized by treatment 
group. A KM analysis of time to these events will be provided if data allows. Patient listings of 
cases confirmed by adjudication are to also be provided, as well as of clinically significant 
imaging findings that did not require adjudication. 
5.9. 
Analysis of Pharmacokinetic and Immunogenicity Data 
5.9.1. 
Analysis of Pharmacokinetics and Drug Concentration Data 
The concentrations of functional REGN5069 in serum over time will be summarized by 
descriptive statistics for each treatment group. Plots of individual subject concentrations of 
functional REGN5069 in serum will be presented by actual day (linear and log scales). Plots of 
mean and median concentrations of functional REGN5069 in serum will be presented by 
nominal day (linear and log scale). 
Select PK parameters may also be calculated and summarized descriptively by treatment group. 
No formal statistical hypothesis testing will be performed. 
Population PK and exposure-response analyses for biomarkers, efficacy, and safety endpoints 
may be performed, as appropriate, and presented in separate reports. 
5.9.2. 
Analysis of ADA Data 
The immunogenicity variables described in Section 4.8 will be summarized using descriptive 
statistics. 
Immunogenicity will be characterized by ADA responses and titers observed in patients in the 
ADA analysis set. ADA response categories and titer categories are defined as follows:  
ADA response categories: 
• ADA Negative, defined as ADA negative response in the REGN5069 ADA assay at 
all time points, regardless of any missing samples. 
• Pre-existing immunoreactivity, defined as either an ADA positive response in the 
REGN5069 ADA assay at baseline with all post first dose ADA results negative, OR 
a positive response at baseline with all post first dose ADA responses less than 9-fold 
over baseline titer levels. 
• Treatment-emergent response, defined as an ADA positive response in the REG5069 
ADA assay post first dose when baseline results are negative or missing. The 
treatment-emergent responses will be further characterized as Persistent, 
Indeterminate or Transient.   
− Persistent Response – Treatment-emergent ADA positive response with two or 
more consecutive ADA positive sampling time points, separated by at least 16-
week period (based on nominal sampling time), with no ADA negative samples in 
between, regardless of any missing samples. 
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− Indeterminate Response –Treatment-emergent ADA positive response with only 
the last collected sample positive in the ADA assay, regardless of any missing 
samples. 
− Transient Response –Treatment-emergent ADA positive response that is not 
considered persistent or indeterminate, regardless of any missing samples. 
• Treatment-boosted response, defined as a positive response in the REGN5069 ADA 
assay post first dose that is greater than or equal to 9-fold over baseline titer levels, 
when baseline results are positive 
Titer categories (Maximum titer values): 
− Low (titer <1,000) 
− Moderate (1,000 ≤ titer ≤ 10,000) 
− High (titer >10,000) 
The following analysis will be provided: 
• Number (n) and percent (%) of ADA-negative patients (pre-existing 
immunoreactivity or negative in the REGN5069 ADA assay at all time points) by 
treatment groups  
• Number (n) and percent (%) of treatment-emergent ADA positive patients by 
treatment groups and ADA titer categories and at the 
− Number (n) and percent (%) of persistent treatment-emergent ADA positive 
subjects/patients 
− Number (n) and percent (%) of indeterminate treatment-emergent ADA positive 
subjects/patients 
− Number (n) and percent (%) of transient treatment-emergent ADA positive 
subjects/patients 
• Number (n) and percent (%) of treatment-boosted ADA positive patients by treatment 
groups and ADA titer categories  
Listing of all ADA titer levels will be provided for patients with pre-existing, treatment-emergent 
and treatment-boosted ADA response. 
5.10. 
Association of Immunogenicity with Exposure, Safety and Efficacy  
5.10.1. 
Immunogenicity and Exposure 
Potential association between immunogenicity variables and systemic exposure to REGN5069 
will be explored by treatment groups. Plots of REGN5069 drug concentration time profiles may 
be provided to examine the potential impact of ADA response status, and titer on these profiles.  
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5.10.2. 
Immunogenicity and Safety and Efficacy 
Potential association between immunogenicity variables and safety may be explored with a 
primary focus on the following safety events during the TEAE period:  
• 
Injection site reaction (serious or severe and lasting 24 hours or longer) 
• 
Infusion reactions  
• 
Hypersensitivity (SMQ: Hypersensitivity [Narrow]) 
• 
Anaphylaxis (SMQ: Anaphylaxis [Narrow]) 
Potential association between immunogenicity variables and efficacy endpoints may be explored 
(e.g., scatter plot or spaghetti plot).  
The safety and efficacy analyses mentioned above will be conducted using the following 
categories: 
• ADA positive patients: patients with treatment-emergent or treatment-boosted response. 
• ADA negative patients, that is patients with pre-existing immunoreactivity or negative in 
the ADA assay at all time points. 
• Patients with persistent treatment-emergent ADA response 
• Maximum post-baseline titer in treatment-emergent or treatment-boosted ADA positive 
patients:  
o Low (titer <1,000) 
o Moderate (1,000 ≤ titer ≤ 10,000) 
o High (titer >10,000) 
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6. 
DATA CONVENTIONS 
The following analysis conventions are to 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 is the latest available 
valid measurement prior to randomization.  
6.2. 
Data Handling Conventions for Efficacy Data 
WOMAC scores are computed when one pain item, one stiffness item, or at most 3 physical 
function items are missing. The missing items are to be imputed by the mean of available items 
within the same subscale. The scores are to be set to missing if more items are missing.  
6.2.1. 
Handling of Missing Efficacy Data due to COVID-19 Public Health Measures 
Due to public health measures implemented to address the world-wide COVID-19 pandemic, 
some sites may suspend onsite study visits or patients may opt not to attend. To mitigate data 
loss, patients may be contacted via telephone and the results of their efficacy measures 
transcribed verbally and entered into the eCOA devices. For analysis purposes, this data will be 
treated the same as efficacy data collected in an onsite visit and will be utilized in the efficacy 
analyses.   
A sensitivity analysis will be performed excluding data collected via telephone. 
6.3. 
Data Handling Convention for Missing Data 
Date of last dose of study treatment 
The date of the last infusion is equal to the last date of administration reported on infusion 
administration case report form page or missing if the last administration date is unknown. 
Handling of Adverse Event and Infusion Site Reaction Severity 
If the severity of a TEAE is missing, it is 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 is 
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 is assumed to 
have occurred on or after the intake of study drug, except if an incomplete date (eg, month and 
year) clearly indicates that the event started prior to treatment. Thus, if the AE does not clearly 
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indicate that the AE started prior to treatment or after the TEAE period, the AE is classified as 
“treatment-emergent”. Otherwise, the missing day or month is imputed by the first of the months 
or first month of the year This is for classification purposes in the frequency tables and is not to 
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 is imputed 
to the last day of the month. 
There is no imputing completely missing AE/concomitant medication end dates. Events with an 
end date missing are 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 is to 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 are 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. 
Completely missing medical history dates are not imputed. Missing month is imputed to January 
and missing day is imputed to the first day of the month. 
Handling of missing item data on questionnaires 
See section 6.2 
WOMAC 
See section 6.2. 
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) is 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 are made. 
Handling of Potentially Clinically Significant Values/Abnormalities (PCSA/PCSVs) 
If patients have a missing baseline value, they are 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 is based only 
on the second condition. 
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For a PCSA defined on a threshold and/or a normal range, this PCSA is 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 are not be summarized or considered in the 
computation of PCSA values. 
6.4. 
Visit Windows 
By-visit analysis (including efficacy, laboratory data, vital signs, ECG, ADA) is summarized by 
the nominal visit number. Assessments taken outside of protocol allowable windows are 
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 is assigned based on the actual visit date using the study day analysis window based 
on the targeted visit study day in Table 3 Schedule of Events.  
The following visit windows are to 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 -1 
≥ -30 and ≤ -1 
2 
Baseline** 
1 
1 
3 
Week 1  
8 
[2, 11] 
4 
Week 2  
15 
[12, 22] 
5 
Week 4 
29 
[23, 43] 
6 
Week 8 
57 
[44,71] 
7 
Week 12 
85 
[72,99] 
8 
Week 16 
113 
[100,127] 
9 
Week 20 
141 
[128,155] 
10 
Week 24 
169 
[156,183] 
11 
Week 28 
197 
[184,211] 
12 
Week 32 
225 
[212,239] 
13 
Week 36 
253 
[240,309] 
14 
Week 52  
365 
≥310 
 
*Study days are calculated from the first dose of study drug (Day 1). 
**For the purpose of change-from-baseline calculations, if a patient has missing data on Day 1 
(Baseline Visit), the closest available data from the screening visit window may be used, unless 
otherwise specified.  
If multiple measurements occur within the same visit window, the following rules are to 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 is used in the analysis.  
• When multiple valid measurements occur within equal distance from the target study 
day, the value after the target study day is used in the analysis.  
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Both scheduled and unscheduled measurements are 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 is based on available assessments of scheduled and unscheduled visits. For by visit 
summaries, unscheduled visits are mapped to a visit using the visit windows described in 
Section 6.4 and then included in the by-visit summaries. If the mapped window belongs to a visit 
that does not perform that assessment, the visit will be mapped to the closest visit that does 
perform the assessment, within the same study-period. 
Extra assessments (laboratory data or vital signs associated with non-protocol clinical visits or 
obtained in the course of investigating or managing adverse events) are included in listings, but 
not summaries except for the endpoint determination. If more than one laboratory value is 
available for a given visit, the first observation is used in summaries and all observations are 
presented in listings. 
6.6. 
Pooling of Centers for Statistical Analyses 
Pooling of centers is not planned at this time. 
6.7. 
Statistical Technical Issues 
Not applicable. 
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7. 
INTERIM ANALYSES 
No interim analysis is planned for the study.  
The unblinded primary efficacy analysis will be conducted when all randomized patients have 
been followed for 12 weeks after the first dose of study medication. The unblinded summarized 
results based on 12-week data is to be disclosed to the study team. No individual treatment 
assignments will be unblinded to personnel directly involved with the conduct of the study until 
after the final database lock. 
 
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8. 
SOFTWARE 
All clinical data analyses are to be done using SAS Version 9.4 and above. 
 
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9. 
SUMMARY OF MEASURES AND ANALYSES ADDRESSING 
IMPACT OF COVID-19 
In light of the public health emergency related to COVID-19, in accordance with the regulatory 
guidance and in order to ensure the clinical study patient’s safety and the continuity of clinical 
study conduct and oversight, the following measures are explored and implemented for this study 
conduct and analysis: 
1. Phone contact will be used for the remote collection of safety and questionnaire efficacy 
data (WOMAC, PGA, Joint pain Questionnaire).  
2. Use of local laboratory locations when shipping to the Central Lab is not available 
3. A Regeneron-standard CRF is implemented to collect COVID-19 related information: 
• Subject's Visit Impact due to COVID-19: 
− Entire visit not performed 
− Partial face to face visit 
− Remote Visit (Phone, Tele-medicine/Skype etc.) 
− Hybrid Visit (Partial face to face AND Remote Visit) 
− Home Visit by site staff or home health services 
• Reasons: 
− Subject unable/unwilling to travel due to COVID-19 
− Subject/Guardian under quarantine due to COVID-19 
− Limited site personnel availability due to COVID-19 
− Site closure due to COVID-19  
− Other 
• Discontinuation of treatment or study due to COVID-19 
• Reasons: 
− Subject has COVID-19  
− Subject decided to stop due to COVID-19 
− Subject can no longer travel due to COVID-19 
− Physician decision due to COVID-19 
− Sponsor decision due to COVID-19 
− Other 
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• Discontinuation of study due to COVID-19 
• Reasons: 
− Subject has COVID-19  
− Subject decided to stop due to COVID-19 
− Subject can no longer travel due to COVID-19 
− Physician decision due to COVID-19 
− Sponsor decision due to COVID-19 
− Other 
• Complete the AE form if subject tested positive or has symptoms of COVID-19 
4. An updated version of MedDRA version 23.0 is to be released on 19 April 2020 to 
include new COVID-19 terms. The study team is to implement this re-released version 
23.0 by 4 May 2020, in line with the currently established procedure 
5. A sensitivity analysis will be performed excluding data collected via telephone, using the 
same method as for the primary endpoint 12-weeks analysis. 
Additionally, no waivers to deviate from protocol enrollment criteria due to COVID-19 will be 
granted. All temporary mechanisms utilized, and deviations from planned study procedures are 
to be documented as being related to COVID-19 and will remain in effect only for the duration 
of the public health emergency. 
 
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10. 
REFERENCES 
ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for clinical 
trials (E9). International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. 
Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic 
Version 1 (20/03/2020)  
FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic, 
Guidance for Industry, Investigators, and Institutional Review Boards, March 2020 
 
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11. 
APPENDIX 
11.1. 
Schedule of Events and Visits 
Table 3: 
Schedule of Events 
 
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1. The patient received a diary in which he/she records use of study-permitted rescue medication from 
baseline through the week-24 study visit. The patient received training on use of the diary (can be 
conducted at the baseline visit or earlier at the discretion of the investigator). The patient is required to 
bring the diary to each study visit and it is to be collected at the week-24 visit, or early if the patient 
terminates the study early.  
2. Questionnaires (including WOMAC, Patient Global Assessment score, joint pain questionnaire, and 
Knee Society Score, if necessary) are to be completed by the patient. These assessments should be the 
first procedures performed during study site visits at the indicated visits. 
3. At each study visit indicated in the schedule of events table, study site personnel checks that the patient 
is recording his/her use of acetaminophen as the study-permitted rescue medication in the patient diary. 
Retraining on patient diary usage may be requested at any visit during the study, as needed. The diary 
is to be returned at the week-24 visit or at the early termination visit, if applicable.  
4. Study drug administration is the last procedure at each dosing visit and is to be done after all laboratory 
samples have been collected (except for those specifically stated for collection after study drug 
administration), and after all study assessments and procedures are performed. Patients are to be 
observed in the clinic for 1 hour after study drug administration.  
5. Refer to Section 8.2.3.1 in the protocol for more instructions surrounding the vital sign assessment and 
to Section 8.2.3.2 in the protocol for instructions for rechecking orthostatic vital sign assessments and 
for defining orthostatic hypotension.  
6. In addition to scheduled imaging, radiographs should 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 or lasts at least 2 weeks (or less at the discretion of the investigator). Based on the 
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imaging results, a patient may be discontinued from study drug. If this occurs, the patient should be 
asked to remain in the study and participate in study visits per the visit schedule.  
7. Early Termination: Imaging assessments (X-rays of bilateral knees, hips, and shoulders and MRI of the 
index knee) need to be repeated only if it has been >30 days since the joints were last imaged. If it has 
been ≤30 days since the joints were last imaged, imaging assessment may be completed at the discretion 
of the investigator.  
8. In addition to scheduled MRIs, an MRI should 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, lasts at least 2 weeks (or less at the discretion of the investigator), and if the X-rays are 
inconclusive. 
9. After the patient has otherwise met study eligibility criteria assessed during the screening period, an 
MRI of the index knee is to be performed prior to the baseline visit. Confirmation that the images have 
been accepted and confirmed query-free by the central reader must be received by the site before the 
baseline visit. Confirmation that there are no exclusionary findings on the MRI must be received from 
the central reader before a patient can be randomized. 
10. In the event that a patient must undergo joint replacement surgery during the study up to the end of the 
Follow-Up period at week 36, the patient is to complete the early termination/joint replacement pre-
operative visit as per Schedule of Events and the procedures outlined in the schedule of events for joint 
replacement surgery follow-up. The early termination/joint replacement pre-operative visit should be 
completed before the joint replacement surgery, if possible. 
11. In the event of a confirmed positive drug screen result for opiates and/or alcohol at screening, the patient 
is to be excluded. A confirmed positive drug screen result for opiates and/or alcohol prior to the initial 
dose of study drug and/or during the treatment period must be discussed with the sponsor prior to 
administration of the next dose of study drug once the results are available. 
12. Blood samples to be obtained after at least approximately an 8-hour fast. 
13. In the event of a positive urine pregnancy test result, a serum pregnancy test should be performed. If 
the serum pregnancy test is negative, the patient may continue to receive study drug per the visit 
schedule. If the serum pregnancy test is positive, the patient should discontinue study drug, but should 
be asked to return to the clinic for all remaining study visits per the visit schedule. 
14. The FSH sample should be collected to confirm the postmenopausal status of a female patient.  
15. Two pharmacokinetic samples are to be collected: the first sample prior to the dose administration and 
the second sample within 30 minutes after the end of infusion. 
16. Samples for DNA extraction should be collected at the baseline visit (pre-dose) but may be collected 
at any later study visit. 
17. Moticon insole training session was conducted for patients in the Moticon insole device sub-study only 
and was held at participating clinical sites prior to recording sessions. 
18. Moticon insole recording sessions is conducted for patients in the Moticon insole device sub-study only 
and included a 3-minute walking test. 
                                        VV-RIM-00133697-1.0 Approved - 18 Nov 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R5069-OA-1849 
Statistical Analysis Plan 
Date: 17 November 2020 
 
CONFIDENTIAL 
Page 61 of 68 
Table 4: 
Schedule of Events for Follow-up Period of Patients Who Undergo Joint 
Replacement Surgery 
 
Post-Operative1 
Long-Term1 
Follow-up Study Day (Visit window, days) 
Follow-up Visit 1 
4 weeks after joint 
replacement surgery 
Follow-up Visit 2 
20 weeks after joint 
replacement surgery 
Follow-up Day 29 (±7) 
Follow-up Day 140 (±7) 
Collection of surgically resected tissue for 
histological and molecular analyses 
X 
Treatment 
 
Concomitant medications and therapy 
X 
X 
Safety 
 
 
Medical history related to the joint replacement 
X 
X 
Adverse events 
 
Vital signs 
X 
X 
Physical examination with joint exam 
X 
X 
Knee Society Score2 
X 
X 
Radiograph of knees, hips, and shoulders (bilateral) 
 
X 
1. Any patient who has joint replacement surgery during the study up to the end of the Follow-Up period 
at week 36 is to be asked to return to the site at 4 and 20 weeks after the surgery date for safety 
evaluations. Relevant information related to the surgery is collected at the week-4 visit, including 
placement of the prosthesis and healing of the surgical wound. The visit at 20 weeks after surgery 
includes an assessment of OA progression (including repeat radiographs of both knees) and the 
collection of any information about joint-related pain or AEs (including joint replacement) that may 
have taken place since the last clinic visit. 
2. Formal post-operative assessment of joint replacements is to be done by completing the Knee Society 
Score questionnaire for knee replacements. 
 
                                        VV-RIM-00133697-1.0 Approved - 18 Nov 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R5069-OA-1849 
Statistical Analysis Plan 
Date: 17 November 2020 
 
CONFIDENTIAL 
Page 62 of 68 
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 5: 
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  
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. 
                                        VV-RIM-00133697-1.0 Approved - 18 Nov 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R5069-OA-1849 
Statistical Analysis Plan 
Date: 17 November 2020 
 
CONFIDENTIAL 
Page 63 of 68 
Parameter 
Treatment-Emergent PCSV 
Comments 
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 
CPK* 
>3 and ≤ 10 ULN and baseline ≤ 3ULN* 
>10 ULN and baseline ≤ 10ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
* At least one level is required; 
multiple levels are optional for phase 
2/3 studies. If it is desirable to get the 
distribution of significant level, 
additional shift table on ≤3, >3 to ≤10, 
and > 10 category for baseline vs. post 
baseline may be provided 
Creatinine 
≥150 μmol/L (Adults) and baseline 
< 150 μmol/L 
>=30% change from baseline and <100% 
change from baseline 
≥100% change from baseline 
Benichou C., 1994 
3 independent criteria  
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 μmol/L and <=408 μmol/L at 
baseline 
<120 μmol/L and >= 120 μmol/L at 
baseline 
Harrison - Principles of internal 
Medicine 17th Ed., 2008. 
Two independent criteria 
Blood Urea 
Nitrogen 
≥17 mmol/L and <17 mmol/L at baseline Two independent criteria 
                                        VV-RIM-00133697-1.0 Approved - 18 Nov 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R5069-OA-1849 
Statistical Analysis Plan 
Date: 17 November 2020 
 
CONFIDENTIAL 
Page 64 of 68 
Parameter 
Treatment-Emergent PCSV 
Comments 
Chloride 
Hypochloremia 
Hyperchloremia 
 
<80 mmol/L and baseline ≥ 80 mmol/L  
>115 mmol/L and baseline ≤ 115 
mmol/L  
Two independent criteria  
Sodium 
Hyponatremia 
Hypernatremia 
 
≤129 mmol/L and baseline > 129 
mmol/L  
≥160 mmol/L and baseline <160 mmol/L 
Two independent criteria 
Potassium 
Hypokalemia 
Hyperkalemia 
 
<3 mmol/L and baseline ≥ 3 mmol/L  
≥5.5 mmol/L and baseline <5.5 mmol/L  
FDA Feb 2005. 
Two independent criteria 
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. 
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 
                                        VV-RIM-00133697-1.0 Approved - 18 Nov 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R5069-OA-1849 
Statistical Analysis Plan 
Date: 17 November 2020 
 
CONFIDENTIAL 
Page 65 of 68 
Parameter 
Treatment-Emergent PCSV 
Comments 
Hematology 
WBC 
<3.0 Giga/L and >=3.0 Giga/L at 
baseline (Non-Black);  
<2.0 Giga/L and >=2.0 Giga/L at 
baseline (Black) 
≥16.0 Giga/L and < 16 Giga/L at 
baseline 
Increase in WBC: not relevant. 
 
 
To be interpreted only if no differential 
count available. 
Lymphocytes 
>4.0 Giga/L and <= 4.0 Giga/L at 
baseline 
 
Neutrophils 
<1.5 Giga/L and >=1.5 Giga/L at 
baseline (Non-Black);  
<1.0 Giga/L and >=1.0 Giga/L at 
baseline (Black) 
International Consensus meeting on 
drug-induced blood cytopenias, 1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L <= 0.7 Giga/L at baseline 
 
Basophils 
>0.1 Giga/L <= 0.1 Giga/L at baseline 
 
Eosinophils 
(>0.5 Giga/L and >ULN) and (<=0.5 
Giga/L or <= ULN at baseline) 
Harrison - Principles of internal 
Medicine 17th Ed., 2008. 
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 
                                        VV-RIM-00133697-1.0 Approved - 18 Nov 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R5069-OA-1849 
Statistical Analysis Plan 
Date: 17 November 2020 
 
CONFIDENTIAL 
Page 66 of 68 
Parameter 
Treatment-Emergent PCSV 
Comments 
RBC 
Female 
<3 Tera/L and baseline ≥3 Tera/L 
≥6 Tera/L and baseline < 6 Tera/L  
Male 
<4 Tera/L and baseline ≥4 Tera/L 
≥7 Tera/L and baseline < 7 Tera/L 
Unless specifically required for 
particular drug development, the 
analysis is redundant with that of Hb. 
Otherwise, consider FDA criteria. 
Platelets 
<100 Giga/L and >=100 Giga/L at 
baseline 
≥700 Giga/L and < 700 Giga/L at 
baseline 
International Consensus meeting on 
drug-induced blood cytopenias, 1991. 
Two independent criteria 
Urinalysis 
pH 
≤4.6 and > 4.6 at baseline 
≥8 and < 8 at baseline 
Two independent criteria 
Vital signs 
HR 
≤50 bpm and decrease from baseline ≥20 
bpm 
≥120 bpm and increase from baseline≥20 
bpm 
To be applied for all positions 
(including missing) except 
STANDING. 
SBP 
≤95 mmHg and decrease from baseline 
≥20mmHg 
≥160 mmHg and increase from baseline 
≥20 mmHg 
To be applied for all positions 
(including missing) except 
STANDING. 
DBP 
≤45 mmHg and decrease from baseline 
≥10 mmHg 
≥110 mmHg and increase from baseline 
≥10 mmHg 
To be applied for all positions 
(including missing) except 
STANDING. 
                                        VV-RIM-00133697-1.0 Approved - 18 Nov 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R5069-OA-1849 
Statistical Analysis Plan 
Date: 17 November 2020 
 
CONFIDENTIAL 
Page 67 of 68 
Parameter 
Treatment-Emergent PCSV 
Comments 
Orthostatic 
Hypotension 
Su SBP < 160 mmHg - 
SBP St – Su  - 20 mmHg 
DBP St – Su  - 10 mmHg 
Su SBP  160 mmHg - 
SBP St – Su  - 30 mmHg 
DBP St – Su  - 15 mmHg 
and 
HR change: >=30 bpm from semi-
recumbent to standing 
 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 
ECG 
Ref.: CPMP 1997 guideline. ICH E14 
2005 
HR(ECG 
Ventricular Rate 
(beats/min) in 
the data) 
≤50 bpm and decrease from baseline ≥20 
bpm 
≥120 bpm and increase from baseline 
≥20 bpm 
 
PR/PQ 
≥220 ms and increase from baseline ≥20 
ms 
 
QRS 
≥120 ms & < 120 ms at baseline 
 
QTcF 
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-00133697-1.0 Approved - 18 Nov 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R5069-OA-1849 
Statistical Analysis Plan 
Date: 17 November 2020 
 
CONFIDENTIAL 
Page 68 of 68 
11.3. 
Arthropathy Adjudication 
Table 6: 
Definitions of Radiologic Findings for Adjudicated Arthropathy and Joint-
Related Diseases 
Feature 
Definition 
RPOA Type 1 
Rapid loss of joint space width from baseline without evidence of bone fragmentation or 
destruction. 
• 
Rapid loss of joint space width must be confirmed by the adjudicator to ensure it 
is not impacted by inconsistency in view/projection. If inconsistencies in 
view/projection are present, the adjudicator may request a repeat X-ray or an 
MRI. 
• 
If rapid loss of joint space width from baseline is observed by X-ray, an MRI 
must be obtained and substantial focal or diffuse loss of hyaline/articular cartilage 
from baseline consistent with RPOA 1 must also be observed by MRI. 
• 
If a baseline MRI has not been obtained and the confirmatory MRI suggests that 
view/projection may account for the changes in JSW by X ray, the adjudicator 
may  equest a repeat X-ray. If the confirmatory MRI is not consistent with RPOA 
1 or provides an alternate explanation (eg meniscal extrusion), the adjudicator 
may determine that RPOA 1 is not present. 
• 
If an X-ray has not been obtained and an MRI suggests RPOA Type 1, an X-ray 
will be requested 
Rapid change in joint space width from baseline is defined as: 
• 
Knee joints 
o 
If JSW is ≥ 2mm at baseline, a decrease of ≥ 2mm or 50% from baseline 
JSW at any time point during the study (whichever is greater) o If JSW is 
<2mm at baseline or where accurate JSW measurement is not possible, a 
change in JSW to 0 mm o Due to technical limitations of the JSW 
measurement and precision error, if the JSW is ≤ 0.5 mm at baseline, RPOA 
Type 1 cannot be determined 
• 
Hip joints 
o 
If JSW is >1.5mm at baseline, a decrease of ≥1.5mm from baseline 
o 
If JSW is <1.5mm at baseline or where accurate JSW measurement is not 
possible, a change in JSW to 0 mm 
o 
Due to technical limitations of the JSW measurement and precision error, if 
the JSW is ≤ 0.5 mm at baseline, RPOA Type 1 cannot be determined 
• 
Any joint without previous image for comparison 
o If a prior image of the same joint is not available for comparison, by 
definition, RPOA Type 1 cannot be determined. 
RPOA Type 2 
Abnormal bone fragmentation or destruction over a short period of time, including limited 
collapse of at least one articular surface and which is observed principally by MRI but 
may be detected by X-rays. 
Primary ON 
Focal circumscribed or extended region of mottled radiolucency and sclerosis (infarcted 
bone) which is confirmed by MRI. No evidence of subchondral collapse or bone 
fragmentation preceding or concurrent with the diagnosis of primary ON. 
Subchondral 
Stress or 
Insufficiency 
Fracture (SIF) 
Subchondral radiolucency, which may have a sclerotic linear component and articular 
surface flattening and is confirmed by MRI. Does not include significant collapse or 
fragmentation of an articular surface. 
 
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