Study to Evaluate Arthroplasty Specimens in the Phase 3 Fasinumab Program for Osteoarthritis of the Knee and Hip
Phase: PHASE2
Conditions: Osteoarthritis, Knee, Osteoarthritis, Hip
Sponsor: Regeneron Pharmaceuticals

Clinical Study Protocol 
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Regeneron Pharmaceuticals, Inc. 
Page 1 of 23 
CONFIDENTIAL 
IND Number: 103245 
EudraCT: 2018-001618-13 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
STUDY TO EVALUATE ARTHROPLASTY SPECIMENS IN THE 
PHASE 3 FASINUMAB PROGRAM FOR OSTEOARTHRITIS OF THE 
KNEE AND HIP 
Compound: 
Fasinumab 
Clinical Phase: 
2 
Protocol Number: 
R475-OA-1816 
Protocol Version: 
R475-OA-1816 Original 
Date of Issue: 
See appended electronic signature page 
Medical /Study Director: 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
 
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NCT03949673

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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
Study to Evaluate Arthroplasty Specimens in the Phase 3 Fasinumab 
Program for Osteoarthritis of the Knee and Hip 
Site Location(s) 
 
Principal Investigator 
The site locations for this study are a subset of those at which the parent 
studies, R475-PN-1523, R475-OA-1611, and R475-OA-1688, are 
operational. 
To be determined. 
Objective 
The objective of this exploratory study is to evaluate the cellular and 
connective tissue composition of joints from patients with osteoarthritis 
(OA) who have been treated with fasinumab, compared with those treated 
with placebo or non-steroidal anti-inflammatory drugs (NSAIDs). 
Study Design 
This is a non-randomized, exploratory study designed to evaluate changes 
in joint tissue of patients with OA of the knee or hip who are treated with 
fasinumab, compared with those who are treated with placebo or NSAIDs. 
Patients will follow the screening and pre-randomization requirements for 
their parent study.  If a patient decides to undergo a knee or hip joint 
arthroplasty during the parent study, he/she can consent to this study after 
notifying the site of his/her intended surgery. 
If a patient is eligible for and consents to this study, the site will coordinate 
with the patient’s surgeon and/or pathologist to provide information 
regarding the processing, storage and shipping of tissue samples obtained 
from the arthroplasty.   
Study Duration 
Not applicable for the individual patient. 
End of Study Definition 
The end of study is defined as the last arthroplasty surgery for the last patient 
enrolled in this study.   
Population 
 
 
Sample Size: 
This study will enroll approximately 50 patients.   
 
Target Population: 
Eligible patients for this study will be participating in 1 of the parent studies 
and will undergo knee or hip arthroplasty during the parent study. Patients 
enrolled in the parent studies are men and women who are at least 18 years 
of age at the time of parent study entry with a clinical diagnosis at the 
screening visit of OA of the knee or hip, based on the American College of 
Rheumatology criteria, and with radiologic evidence of OA [K-L score ≥2] 
at the index joint. 
Endpoint 
The endpoint for this exploratory study is descriptive histological evaluation 
of the synovium, cartilage, and bone. 
Procedures and Assessments 
Collection of arthroplasty samples:  Tissue samples will be collected at the 
time of the arthroplasty surgery. A centrally located pathologist will 
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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.  
 
 
 
 
 
 
 
Safety Procedures: Safety procedures described in the parent study protocols 
will be followed. 
Statistical Plan 
Statistical hypothesis: No formal hypothesis testing will be performed in this 
exploratory study. 
Justification of samples size: It is estimated that approximately 50 patients 
will be enrolled from the parent studies, R475-PN-1523, R475-OA-1611, 
and R475-OA-1688. The sample size is not based on power calculations; 
however, it is considered adequate to meet the study objectives. 
Consequently, the sample size may exceed 50 patients to meet the study 
objectives.  
Histological analysis: Data from the histological analysis will be 
summarized descriptively by the treatment received in their parent studies. 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse event 
CRF 
Case report form (electronic or paper) 
 
 
 
 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
EDC 
Electronic data capture 
GCP 
Good Clinical Practice 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
JR 
Joint Replacement 
K-L 
Kellgren-Lawrence 
MRI  
Magnetic Resonance Imaging 
NGF 
Nerve growth factor 
NSAID 
Non-steroidal anti-inflammatory drug 
OA 
Osteoarthritis 
Q4W 
Every 4 weeks 
Q8W 
Every 8 weeks 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
RPOA-1 
Rapidly progressive osteoarthritis type 1 (thinning of cartilage) 
RPOA-2 
Rapidly progressive OA type 2 (partial or complete collapse of articular 
bone) 
SAP 
Statistical analysis plan 
SIF 
Subchondral insufficiency fractures 
 
 
 
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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................4 
1. 
INTRODUCTION ........................................................................................................8 
2. 
STUDY OBJECTIVE ...................................................................................................9 
2.1. 
Objective .......................................................................................................................9 
3. 
RATIONALE ...............................................................................................................9 
3.1. 
Rationale for Study Design ...........................................................................................9 
3.2. 
Rationale for Dose Selection ......................................................................................10 
4. 
STUDY VARIABLES................................................................................................10 
4.1. 
Demographic and Baseline Characteristics ................................................................10 
4.2. 
Endpoint ......................................................................................................................10 
5. 
STUDY DESIGN .......................................................................................................10 
5.1. 
Study Description and Duration .................................................................................10 
5.1.1. 
End of Study Definition ..............................................................................................11 
5.2. 
Planned Interim Analysis ............................................................................................11 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............11 
6.1. 
Number of Patients Planned .......................................................................................11 
6.2. 
Study Population .........................................................................................................11 
6.2.1. 
Inclusion Criteria ........................................................................................................11 
6.2.2. 
Exclusion Criteria .......................................................................................................12 
6.3. 
Premature Withdrawal from the Study .......................................................................12 
7. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................12 
7.1. 
Schedule of Events .....................................................................................................12 
7.1.1. 
Footnotes for the Schedule of Events Table ...............................................................12 
7.2. 
Study Procedures ........................................................................................................13 
7.2.1. 
Procedures Performed Only at the Screening Visit ....................................................13 
7.2.2. 
Collection of Arthroplasty Tissue Samples ................................................................13 
7.2.3. 
Histological Evaluation of Tissue Samples ................................................................13 
 
 
 
 
7.2.6. 
Safety Procedures .......................................................................................................13 
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8. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................14 
8.1. 
Obligations of Investigator .........................................................................................14 
8.2. 
Obligations of Sponsor ...............................................................................................14 
8.3. 
Definitions ..................................................................................................................14 
8.4. 
Recording and Reporting Adverse Events ..................................................................14 
9. 
STATISTICAL PLAN................................................................................................14 
9.1. 
Statistical Hypothesis ..................................................................................................14 
9.2. 
Justification of Sample Size........................................................................................14 
9.3. 
Arthroplasty Analysis Set ...........................................................................................14 
9.4. 
Statistical Methods ......................................................................................................15 
9.4.1. 
Patient Disposition ......................................................................................................15 
9.4.2. 
Demography and Baseline Characteristics .................................................................15 
9.4.3. 
Histological Analysis ..................................................................................................15 
9.5. 
Statistical Considerations Surrounding the Premature Termination of a Study .........15 
10. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS .....................................15 
10.1. 
Data Management .......................................................................................................15 
10.2. 
Electronic Systems ......................................................................................................15 
11. 
STUDY MONITORING ............................................................................................16 
11.1. 
Monitoring of Study Sites ...........................................................................................16 
11.2. 
Source Document Requirements ................................................................................16 
11.3. 
Case Report Form Requirements ................................................................................16 
12. 
AUDITS AND INSPECTIONS .................................................................................16 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................17 
13.1. 
Good Clinical Practice Statement ...............................................................................17 
13.2. 
Informed Consent .......................................................................................................17 
13.3. 
Patients Confidentiality and Data Protection ..............................................................18 
13.4. 
Institutional Review Board/Ethics Committee ...........................................................18 
14. 
PROTOCOL AMENDMENTS ..................................................................................18 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................19 
15.1. 
Premature Termination of the Study ...........................................................................19 
15.2. 
Close-out of a Site ......................................................................................................19 
16. 
STUDY DOCUMENTATION ...................................................................................19 
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16.1. 
Certification of Accuracy of Data ...............................................................................19 
16.2. 
Retention of Records ..................................................................................................19 
17. 
DATA QUALITY ASSURANCE ..............................................................................20 
18. 
CONFIDENTIALITY ................................................................................................21 
19. 
FINANCING AND INSURANCE .............................................................................21 
20. 
PUBLICATION POLICY ..........................................................................................21 
21. 
REFERENCES ...........................................................................................................21 
22. 
INVESTIGATOR’S AGREEMENT ..........................................................................22 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................23 
 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................12 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................11 
 
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1. 
INTRODUCTION  
Fasinumab, also known as REGN475, is a fully-human, high-affinity monoclonal antibody 
directed against nerve growth factor (NGF), which is a molecule with an important role in pain 
perception. By selectively blocking NGF, fasinumab has the potential to modulate NGF-associated 
pain without many of the adverse side effects associated with other analgesic medications, such as 
opioids and non-steroidal anti-inflammatory drugs (NSAIDs).  Indeed, in studies to date, 
fasinumab has demonstrated clinically significant improvement in pain and physical function in 
patients with pain due to osteoarthritis (OA) of the knee or hip and in patients with chronic low 
back pain, compared with placebo.  
Completed studies to date also show that patients treated with fasinumab more frequently 
experience arthralgia, joint swelling, and peripheral edema, compared with patients treated with 
placebo.  In the phase 2/3 study of fasinumab in patients with OA of the hip or knee, 
R475-PN-1227, thinning of cartilage (rapidly progressive OA type 1; RPOA-1), partial or 
complete collapse of articular bone (rapidly progressive OA type 2; RPOA-2) and subchondral 
insufficiency fractures (SIF) occurred at a higher frequency in patients treated with fasinumab.  A 
dose relationship between fasinumab and arthropathy was demonstrated, with 75% of the 
arthropathies occurring in the 2 highest dose groups (6 mg and 9 mg every 4 weeks [Q4W]), 
including both RPOA-2 events reported. Approximately, 60% of the arthropathies reported were 
the RPOA-1 subtype. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
Given the mechanism of action of fasinumab, it is possible that analgesia may predispose the 
patient to increased loading of joints with existing structural damage, thereby exacerbating 
destructive changes. However, other mechanisms that might influence the joint’s underlying 
structural integrity could also potentially contribute to this process, for example: (1) perturbation 
of bone healing/turnover, (2) perturbation of cartilage turnover, (3) ischemia and (4) inflammation.   
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Osteoarthritis itself is a destructive process that tends to evolve over many years, although some 
patients exhibit the typical degenerative changes over a short period (Bartlett, 2011).  All the 
tissues of the joint may show evidence of degeneration, most notably cartilage, subchondral bone 
and synovium (Loeser, 2012).  Cartilage may show fissuring or erosion, clustering of 
chondrocytes, accumulation of calcium crystals, and loss of proteoglycan. Subchondral bone may 
show thickening, cyst formation, necrosis and ingrowth of neurovascular structures. Synovium 
may show one or more phenotypes including villous hyperplasia, fibrosis or inflammatory 
infiltrates. A predominance of, or a change from these typical patterns in patients treated with 
fasinumab may provide insight into the mechanism of joint events.  
The purpose of this exploratory study is to evaluate arthroplasty specimens taken from patients 
who undergo joint replacement (JR) while participating in the fasinumab phase 3 program for pain 
due to OA of the knee and hip. The tissue removed during joint arthroplasty includes subchondral 
bone, cartilage, and synovium.  Given that joint related AEs are identified risks in the fasinumab 
program, it is hypothesized that evaluation of tissue from arthroplasty specimens may provide 
insight into the mechanisms of these events.  Patients in this study (R475-OA-1816) will be 
participants in 1 of 3 ongoing phase 3 studies (R475-PN-1523, R475-OA-1611, and R475-OA-
1688) of fasinumab for pain due to OA of the knee and hip. Hereafter, the term ‘parent studies’ 
will be used to refer to the R475-PN-1523, R475-OA-1611, and R475-OA-1688 studies.  
Additional background information on fasinumab and the fasinumab development program, 
including an assessment of the benefit-risk profile, can be found in the Investigator’s Brochure. 
2. 
STUDY OBJECTIVE  
2.1. 
Objective 
The objective of this exploratory study is to evaluate the cellular and connective tissue composition 
of joints from patients with OA who have been treated with fasinumab, compared with those 
treated with placebo or NSAIDs. 
3. 
 RATIONALE  
3.1. 
Rationale for Study Design 
This is a non-randomized, exploratory study within the fasinumab phase 3 program. The parent 
studies for this study will be the ongoing fasinumab phase 3 studies, R475-PN-1523 
(1-year treatment period), R475-OA-1688 (6-month treatment period), and R475-OA-1611 
(1-year treatment period). These parent studies enroll patients with a clinical diagnosis of OA of 
the knee or hip based on the American College of Rheumatology criteria with radiologic evidence 
of OA (Kellgren-Lawrence [K-L] score ≥2) at the index joint at the screening visit.  Studies 
R475-OA-1688 and R475-OA-1611 each have had a placebo arm, 3 fasinumab arms (1 mg Q4W, 
3 mg Q4W, 6 mg Q8W) and an NSAID arm (naproxen 500 mg twice per day in R475-OA-1611; 
celecoxib 200 mg daily or diclofenac 75 mg twice per day in R475-OA-1688).  R475-PN-1523 
has had a placebo arm and multiple fasinumab dosing arms (1 mg Q8W, 1 mg Q4W, 3 mg Q4W, 
6 mg Q8W, 6 mg Q4W, and 9 mg Q4W).   
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Eligible patients for this study will be those participating in 1 of the parent studies and who 
subsequently plan to undergo a knee or hip joint arthroplasty during the parent study.  Patients will 
consent to this study after notifying the site that they are planning a knee or hip joint arthroplasty.  
Patients who were discontinued from 3 mg Q4W or 6 mg Q8W fasinumab and entered the follow-
up period of a parent study are eligible for this study if they undergo joint replacement before the 
end of the follow-up period.  
In the phase 2/3 study of patients with pain due to OA of the knee or hip (R475-PN-1227), 
approximately 5% of patients in each treatment group had joint arthroplasty performed during the 
36-week study. Comparing changes in joint histology in patients who have been exposed to 
fasinumab versus those treated with placebo may reveal changes specific to anti-NGF therapy, 
which could aid in the understanding of the mechanism underlying the arthropathies. It is 
anticipated that a sufficient number of patients will be enrolled from the parent studies to meet the 
study objectives.  
During a joint replacement, the surgeon must remove subchondral bone, cartilage, and synovium. 
Because OA is asymmetric within the joint, in addition to removing the degenerated section of 
joint, the surgeon must often remove a relatively spared region of the joint to create a flat seat for 
the prosthesis. In this study, tissue removed during arthroplasty will be collected and evaluated in 
a designated central reference pathology laboratory to determine if fasinumab treatment affects the 
typical pathologic changes observed in OA. 
3.2. 
Rationale for Dose Selection  
There is no additional specific dosing requirement of study drug to patients for this exploratory 
study. Dosing of study drug to patients will be performed as indicated in the parent study protocol. 
4. 
STUDY VARIABLES  
4.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will be those listed in the parent study protocols. 
4.2. 
Endpoint 
The endpoint for this exploratory study is descriptive histological evaluation of the synovium, 
cartilage, and bone. 
5. 
Study Design  
5.1. 
Study Description and Duration 
This is a non-randomized, exploratory study designed to evaluate changes in joint tissue of patients 
with OA of the knee or hip who are treated with fasinumab, compared with those who are treated 
with placebo or NSAIDs. 
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Patients will follow the screening and pre-randomization requirements for their parent study.  If a 
patient decides to undergo a knee or hip joint arthroplasty during the parent study, he/she can 
consent to this study after notifying the site of his/her intended surgery.  
An overview of the study timeline is shown in Figure 1.  
Figure 1: 
Study Flow Diagram 
Parent Study  
Screening & Pre-Randomization 
Parent Study  
Treatment and Follow-Up Period 
Day of Joint 
Arthroplasty 
Up to 40 days 
Variable time until joint arthroplasty 
 
 
Parent Study 
Randomization 
 
 
Notification to site 
  that JR is planned 
 
 
 
 
 
Screening 
Pre-randomization  
 
 
 
Up to 30 days  
7 to 10 days 
Parent Study 
Baseline/Day 1 
 
 
 
 
JR: joint replacement 
If a patient is eligible for and consents to this study, the site will coordinate with the patient’s 
surgeon and/or pathologist to provide information regarding the processing, storage, and shipping 
of tissue samples obtained from the arthroplasty.   
5.1.1. 
End of Study Definition 
The end of study is defined as the last arthroplasty surgery for the last patient enrolled in this study.   
5.2. 
Planned Interim Analysis  
No interim analysis is planned.  
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
6.1. 
Number of Patients Planned 
This study will enroll approximately 50 patients.  This study will be conducted at a subset of sites 
operationalizing the parent studies. 
6.2. 
Study Population  
Eligible patients for this study will be participating in 1 of the parent studies and will undergo knee 
or hip arthroplasty during the parent study. Patients enrolled in the parent studies are men and 
women who are at least 18 years of age at the time of parent study entry with a clinical diagnosis 
at the screening visit of OA of the knee or hip, based on the American College of Rheumatology 
criteria, and with radiologic evidence of OA [K-L score ≥2] at the index joint). 
6.2.1. 
Inclusion Criteria  
A patient must meet the following criteria to be eligible for inclusion in the study: 
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1. Previously randomized to R475-PN-1523, R475-OA-1611, or R475-OA-1688 and 
received at least 1 dose of study drug 
2. Notified the site that they are planning a knee or hip arthroplasty during the parent study 
between randomization and 24 weeks after the last dose of SC study drug 
3. Patient’s surgeon/pathologist is willing to coordinate with the site regarding preparation, 
storage, and shipping of joint tissue samples collected during arthroplasty surgery 
4. Willing and able to comply with clinic visits and study-related procedures  
5. Provide informed consent signed by study patient or legally acceptable representative 
6.2.2. 
Exclusion Criteria  
There are no exclusion criteria for this study. 
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. 
7. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
7.1. 
Schedule of Events 
Study assessments and procedures are presented by visit in Table 1. 
Table 1: 
Schedule of Events 
 
Visit 1 
Visit 2 
 
Screening 
Day 11 
Study Day 
N/A2 
1 
Study Procedure 
 
 
Inclusion Criteria 
X3 
 
Informed Consent 
X 
 
Harvesting of tissue from arthroplasty 
 
X 
7.1.1. 
Footnotes for the Schedule of Events Table 
1. Day of arthroplasty. 
2. The day of screening follows when a site learns about a plan for arthroplasty, but prior to 
the actual procedure. 
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3. Patients will be eligible if they are participating in a parent study and plan to have an 
arthroplasty during the time between randomization and 24 weeks after the last dose of SC 
study drug 
7.2. 
Study Procedures 
7.2.1. 
Procedures Performed Only at the Screening Visit 
Inclusion criteria assessments will be performed at the screening visit.  Patients will be consented 
for this study after notifying the site of an intended arthroplasty during the parent study. 
7.2.2. 
Collection of Arthroplasty Tissue Samples 
Tissue samples will be collected at the time of the joint arthroplasty surgery.  Detailed procedures 
for collection, freezing, shipping and storage of tissue samples will be provided in a separate 
document.  
7.2.3. 
Histological Evaluation of Tissue Samples 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
7.2.6. 
Safety Procedures  
Safety procedures described in the parent study protocols will be followed. 
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8. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
8.1. 
Obligations of Investigator 
The investigator obligations are described in the parent study protocols. 
8.2. 
Obligations of Sponsor 
The sponsor obligations are described in the parent study protocols. 
8.3. 
Definitions 
Safety definitions, including definitions for AEs, serious adverse events, and adverse events of 
special interest, are defined in the parent study protocols.  
8.4. 
Recording and Reporting Adverse Events  
Safety reporting and monitoring for this study will be performed through the safety reporting and 
monitoring of the parent studies. For instructions, please reference the appropriate section of the 
parent study protocols. This includes the evaluation of severity and causality for all AEs.  
9. 
STATISTICAL PLAN 
This section provides the basis for the statistical analysis plan (SAP) for the study.  The SAP may 
be revised during the study to accommodate amendments to the clinical study protocol and to make 
changes to adapt to unexpected issues in study execution and data that may affect the planned 
analyses.  The final SAP will be issued before the database is locked. 
Analysis variables are listed in Section 4. 
9.1. 
Statistical Hypothesis  
No formal hypothesis testing will be performed in this exploratory study. 
9.2. 
Justification of Sample Size 
Approximately 50 patients will be enrolled from the parent studies, R475-PN-1523, 
R475-OA-1611, and R475-OA-1688. The sample size is not based on power calculations; 
however, it is considered adequate to meet the study objectives.  Consequently, the sample size 
may exceed 50 patients to meet the study objectives. 
9.3. 
Arthroplasty Analysis Set  
The arthroplasty analysis set includes all patients who are enrolled in this study, have histological 
evaluation data and is based on the treatment received in their parent study (as treated).  
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9.4. 
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. 
9.4.1. 
Patient Disposition 
The following will be provided: 
 The total number of patients in the arthroplasty analysis set 
 A listing of patients in the arthroplasty analysis set 
9.4.2. 
Demography and Baseline Characteristics  
Demographic and baseline characteristics will be summarized descriptively by the treatment 
received in their parent studies, and by all patients combined.   
9.4.3. 
Histological Analysis  
Data from the histological analysis will be summarized descriptively by the treatment received in 
their parent studies.  
9.5. 
Statistical Considerations Surrounding the Premature Termination 
of a Study  
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized.  Investigator and sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 15.1. 
10. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
10.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation, cleaning, correcting, releasing) will be maintained and stored at Regeneron. 
A medical coding plan in place for the parent studies will specify the processes and the dictionary 
used for coding.  All data coding (eg, AEs, baseline findings, medication, medical history, surgical 
history) will be done using internationally recognized and accepted dictionaries. 
The CRF (case report form [electronic or paper]) data for this exploratory study will be collected 
with an electronic data capture (EDC) tool, Rave Medidata. 
10.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
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 Rave Medidata EDC system – data capture 
 Statistical Analysis System (SAS) – statistical review and analysis 
11. 
STUDY MONITORING  
11.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, contract research organization monitor) will visit each site 
prior to enrollment of the first patient, and periodically during the study.   
The investigator must allow study-related monitoring. 
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP), and all applicable 
regulatory requirements. 
11.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). 
The investigator must keep all source documents on file with the CRF.  Case report forms and 
source documents must be available at all times for inspection by authorized representatives of the 
sponsor and regulatory authorities. 
11.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on CRF within the EDC 
system by trained site personnel.  All required CRFs must be completed for each patient enrolled 
in the study.  After review of the clinical data for each patient, the investigator must provide an 
electronic signature.  A copy of each patient CRF casebook is to be retained by the investigator as 
part of the study record and must be available at all times for inspection by authorized 
representatives of the sponsor and regulatory authorities. 
Corrections to the CRF will be entered in the CRF by the investigator or an authorized designee.  
All changes, including date and person performing corrections, will be available via the audit trail, 
which is part of the EDC system.  For corrections made via data queries, a reason for any alteration 
must be provided. 
12. 
AUDITS AND INSPECTIONS 
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities.  Should this occur, the investigator is responsible for: 
 Informing the sponsor of a planned inspection by the authorities as soon as 
notification is received, and authorizing the sponsor’s participation in the inspection 
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 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, informed consent forms (ICFs), Institutional Review Board 
(IRB) or Ethics Committee (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. 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS  
13.1. 
Good Clinical Practice Statement  
It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory 
requirements. 
13.2. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC.  A copy of the IRB/EC -approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient prior to his/her participation in the study and after the 
aims, methods, objectives, and potential hazards of the study have been explained to the patient in 
language that he/she can understand.  The ICF should be signed and dated by the patient and by 
the investigator or authorized designee who reviewed the ICF with the patient.   
 Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
 Patients who can understand but who can neither write nor read will have the ICF 
read to them in presence of an impartial witness, who will sign and date the ICF to 
confirm that informed consent was given. 
The original ICF must be retained by the investigator as part of the patient’s study record, and a 
copy of the signed ICF must be given to the patient. 
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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. 
13.3. 
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. 
13.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve: 
 The protocol, ICF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
 Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the 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  
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. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an 
IRB/EC-approved amendment. 
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15. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
15.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study 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. 
15.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
Investigator’s Decision 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at least 
30 days notice.  The final decision should be made through mutual agreement with the sponsor.  
Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing.  
Reasons may include the following, among others:  
 The investigator has received all items and information necessary to perform the study, 
but has not enrolled any patient within a reasonable period of time 
 The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines  
 The total number of patients required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB/EC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection of 
the patients’ interests. 
16. 
STUDY DOCUMENTATION 
16.1. 
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. 
16.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of CRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
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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.  
17. 
DATA QUALITY ASSURANCE 
In accordance with ICH E6, the sponsor is responsible for quality assurance to ensure that the 
study is conducted and the data generated, recorded, and reported in compliance with the protocol, 
GCP, and any applicable regulatory requirement(s).  The planned quality assurance and quality 
control procedures for the study are summarized.  
Data Management 
The sponsor is responsible for the data management of this study including quality checking of the 
data (Section 10.1). 
Study Monitoring 
The investigator must allow study-related monitoring, IRB/EC review, audits, and inspections 
from relevant health regulatory authorities, and provide direct access to source data documents 
(Section 11.1, Section 11.2, and Section 12)   
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements (Section 11.1).   
All subject/patient data collected during the study will be recorded on paper or electronic CRF 
unless the data are transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for affirming that data entries in the CRF are accurate and correct by 
electronically signing a declaration that accompanies each set of patient final CRF (Section 11.3 
and Section 16.1).  
Study Documentation 
The investigator must maintain accurate documentation (source data) that supports the information 
entered in the CRF (Section 11.2).  
The investigator will retain all records and documents, including signed ICFs, pertaining to the 
conduct of this study for at least 15 years after study completion, unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor (Section 16.2).  
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18. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
19. 
FINANCING AND INSURANCE  
Financing and insurance information is provided as a separate agreement. 
20. 
PUBLICATION POLICY  
Publication rights and procedures will be outlined in a separate clinical study agreement. 
21. 
REFERENCES  
Bartlett SJ, Ling SM, Mayo NE, Scott SC, Bingham CO 3rd. Identifying common trajectories of 
joint space narrowing over two years in knee osteoarthritis. Arthritis Care Res (Hoboken). 2011 
Dec;63(12):1722-8 
Loeser RF, Goldring SR, Scanzello CR, Goldring MB. Osteoarthritis: a disease of the joint as an 
organ. Arthritis Rheum. 2012 Jun;64(6):1697-707 
Kjelgaard-Petersen C, Siebuhr AS, Christiansen T, Ladel C, Karsdal M, Bay-Jensen AC. Synovitis 
biomarkers: ex vivo characterization of three biomarkers for identification of inflammatory 
osteoarthritis. Biomarkers. 2015;20(8):547-56 
Siebuhr AS, Petersen KK, Arendt-Nielsen L, Egsgaard LL, Eskehave T, Christiansen C, et al. 
Identification and characterisation of osteoarthritis patients with inflammation derived tissue 
turnover. Osteoarthritis Cartilage. 2014 Jan;22(1):44-50 
 
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22. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: “Study to Evaluate Arthroplasty Specimens in the Phase 3 
Fasinumab Program for Osteoarthritis of the Knee and Hip” and agree to abide by all provisions 
set forth therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, state, 
or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor or a partnership 
in which the sponsor is involved.  I will immediately disclose it in writing to the sponsor if any 
person who is involved in the study is debarred, or if any proceeding for debarment is pending, or, 
to the best of my knowledge, threatened. 
This document contains confidential information of the sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the 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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SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Medical/Study Director, Regulatory Representative, Clinical Study Team Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the conduct of the study. 
Study Title: 
 Study to Evaluate Arthroplasty Specimens in the Phase 3 Fasinumab Program for 
Osteoarthritis of the Knee and Hip  
Protocol Number: 
R475-OA-1816 
 
See appended electronic signature page 
Sponsor’s Responsible Medical/Study Director 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Liaison 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Team Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
 
 
 
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Signature Page for VV-RIM-00043980 v1.0
Signature Page for VV-RIM-00043980 v1.0 Approved
Approval
2018 16:51:39 GMT+0000
Approval
00
Approval
2018 00:42:08 GMT+0000
Approval
8 17:45:21 GMT+0000
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