Conditions: Chronic Low Back Pain Osteoarthritis
Keywords: Knee Hip
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 63
Healthy volunteers: no

Brief summary:
The primary objective of the study is to evaluate the efficacy of fasinumab in relieving Chronic low back pain (CLBP) as compared to placebo in participants with a clinical diagnosis of moderate-to-severe non-radicular CLBP and Osteoarthritis (OA) of the knee or hip when treated for up to 16 weeks. The secondary objectives of the study are: To evaluate the safety and tolerability of fasinumab compared to placebo when participants with a clinical diagnosis of moderate-to-severe non-radicular CLBP and OA of the knee or hip are treated for up to 16 weeks; To characterize the concentrations of fasinumab in serum over time when participants with a clinical diagnosis of moderate-to-severe non-radicular CLBP and OA of the knee or hip are treated for up to 16 weeks; To evaluate the immunogenicity of fasinumab when treated for up to 16 weeks in participants with a clinical diagnosis of moderate-to-severe non-radicular CLBP and OA of the knee or hip.

Detailed description:

Arms:
arm 1: Subcutaneous (SC) every 4 weeks (Q4W) arm 2: SC every 4 weeks

Interventions: intervention 1: Fasinumab intervention 2: Placebo
Intervention descriptions: intervention 1: Subcutaneous (SC) every 4 weeks (Q4W) intervention 2: Subcutaneous (SC) every 4 weeks (Q4W)

Protocol document:
Prot_002.pdf: 
IND Number: 103245 
EudraCT: 2017-001943-12 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate 
the Efficacy and Safety of Fasinumab in Patients with Moderate-to-Severe 
Chronic Low Back Pain and Osteoarthritis of the Hip or Knee 
Compound: 
REGN475/Fasinumab 
Study Name: 
FACT CLBP 1 
Clinical Phase: 
3 
Protocol Number: 
R475-PN-1612 
Date of Issue: 
See appended electronic signature page 
Scientific/Medical Monitor: 
 
Director, Clinical Sciences 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
  
 
 
 
  
 
 
 
VV-RIM-00014095-1.0 Approved - 25 Jul 2017 GMT-5:00
NCT03285646


Clinical Study Protocol 
R475-PN-1612 
Regeneron Pharmaceuticals, Inc. 
 
CONFIDENTIAL 
TABLE OF CONTENTS 
 
TABLE OF CONTENTS .................................................................................................................2 
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................9 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................15 
1. 
INTRODUCTION ......................................................................................................18 
2. 
STUDY OBJECTIVES ..............................................................................................21 
2.1. 
Primary Objective .......................................................................................................21 
2.2. 
Secondary Objectives .................................................................................................21 
2.3. 
Exploratory Objectives ...............................................................................................21 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................21 
3.1. 
Hypothesis ..................................................................................................................21 
3.2. 
Rationale .....................................................................................................................22 
3.2.1. 
Rationale for Study Design .........................................................................................22 
3.2.2. 
Rationale for Dose Selection ......................................................................................22 
4. 
STUDY VARIABLES................................................................................................24 
4.1. 
Demographic and Baseline Characteristics ................................................................24 
4.2. 
Primary and Secondary Endpoints..............................................................................24 
4.2.1. 
Primary Endpoint ........................................................................................................24 
4.2.2. 
Secondary Endpoints ..................................................................................................24 
4.2.3. 
Exploratory Endpoints ................................................................................................24 
4.3. 
Safety Endpoints .........................................................................................................24 
4.4. 
Pharmacokinetic Variables .........................................................................................25 
4.5. 
Anti-Drug Antibody Variables ...................................................................................25 
5. 
STUDY DESIGN .......................................................................................................25 
5.1. 
Study Description and Duration .................................................................................25 
5.1.1. 
Screening and Pre-randomization ...............................................................................26 
5.1.2. 
Rescreening .................................................................................................................26 
5.1.3. 
Randomization ............................................................................................................27 
5.1.4. 
Treatment Period ........................................................................................................27 
5.1.5. 
Follow-up Period ........................................................................................................28 
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CONFIDENTIAL 
5.1.6. 
End of Study Phone Contact and Additional Imaging ................................................28 
5.1.7. 
Study Stopping Rules .................................................................................................28 
5.1.8. 
End of Study Definition ..............................................................................................28 
5.2. 
Planned Interim Analysis ............................................................................................28 
5.3. 
Study Committees .......................................................................................................29 
5.3.1. 
Independent Data Monitoring Committee ..................................................................29 
5.3.2. 
Arthropathy Adjudication Committee ........................................................................29 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............29 
6.1. 
Number of Patients Planned .......................................................................................29 
6.2. 
Study Population .........................................................................................................29 
6.2.1. 
Inclusion Criteria ........................................................................................................29 
6.2.2. 
Exclusion Criteria .......................................................................................................30 
6.3. 
Premature Withdrawal from the Study .......................................................................34 
6.4. 
Replacement of Patients .............................................................................................34 
7. 
STUDY TREATMENTS............................................................................................34 
7.1. 
Investigational Treatment ...........................................................................................34 
7.2. 
Rescue Treatment .......................................................................................................34 
7.3. 
Dose Modification and Study Treatment Discontinuation Rules ...............................35 
7.3.1. 
Dose Modification ......................................................................................................35 
7.3.2. 
Study Drug Discontinuation .......................................................................................35 
7.3.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................35 
7.3.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................36 
7.4. 
Management of Acute Reactions ................................................................................37 
7.4.1. 
Acute Injection Reactions ...........................................................................................37 
7.4.1.1. 
Systemic Injection Reactions ......................................................................................37 
7.5. 
Method of Treatment Assignment ..............................................................................37 
7.5.1. 
Blinding ......................................................................................................................37 
7.5.2. 
Emergency Unblinding ...............................................................................................37 
7.5.3. 
Unblinding for Regulatory Reporting Purposes .........................................................38 
7.6. 
Treatment Logistics and Accountability .....................................................................38 
7.6.1. 
Packaging, Labeling, and Storage ..............................................................................38 
7.6.2. 
Supply and Disposition of Treatments .......................................................................38 
7.6.3. 
Treatment Accountability ...........................................................................................38 
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CONFIDENTIAL 
7.6.4. 
Treatment Compliance ................................................................................................39 
7.7. 
Concomitant Medications and Procedures .................................................................39 
7.7.1. 
Prohibited Medications ...............................................................................................39 
7.7.2. 
Permitted Medications and Procedures ......................................................................40 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................40 
8.1. 
Schedule of Events .....................................................................................................40 
8.1.1. 
Footnotes for the Schedule of Events Table ...............................................................45 
8.1.2. 
Footnotes for Table 2 - Follow-up Period for Patients Who Undergo Joint 
Replacement Surgery ..................................................................................................47 
8.1.3. 
Early Termination Visit ..............................................................................................48 
8.1.4. 
Unscheduled Visits .....................................................................................................48 
8.2. 
Study Procedures ........................................................................................................48 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................48 
8.2.1.1. 
Main Study Informed Consent ....................................................................................48 
 
 
8.2.1.3. 
Medical History ..........................................................................................................48 
8.2.1.4. 
Medication History .....................................................................................................48 
8.2.1.5. 
Demographics .............................................................................................................48 
8.2.1.6. 
Beck Depression Inventory – II Assessment ..............................................................49 
8.2.1.7. 
Assessment of Childbearing Potential ........................................................................49 
8.2.1.8. 
Determination of Osteoarthritis ..................................................................................49 
8.2.1.9. 
Assessment of Peripheral or Central Pain ..................................................................50 
8.2.1.10. 
eDiary Training ...........................................................................................................50 
8.2.1.11. 
Patient Education Brochures.......................................................................................50 
8.2.2. 
Patient-Completed Assessments and Efficacy Procedures .........................................50 
8.2.2.1. 
Western Ontario and McMaster Osteoarthritis Index .................................................50 
8.2.2.2. 
Low Back Pain Intensity Numerical Rating Scale Score ...........................................51 
8.2.2.3. 
Roland Morris Disability Questionnaire Total Score .................................................51 
8.2.2.4. 
Patient Global Assessment of Low Back Pain Score .................................................51 
8.2.2.5. 
PainDETECT Questionnaire ......................................................................................51 
8.2.2.6. 
Brief Pain Inventory Short Form ................................................................................51 
8.2.2.7. 
Medical Outcomes Study Sleep Scale Revised ..........................................................52 
8.2.2.8. 
Short Form-36 Health Survey .....................................................................................52 
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CONFIDENTIAL 
8.2.2.9. 
Patient Health Questionnaire 8-Item Version .............................................................52 
8.2.2.10. 
EuroQoL 5 Dimensions 5 Level Questionnaire..........................................................52 
8.2.2.11. 
Work Productivity and Activity Impairment - Low Back Pain ..................................53 
8.2.2.12. 
Healthcare Resource Utilization Questionnaire ..........................................................53 
8.2.2.13. 
Treatment Satisfaction Questionnaire for Medication ................................................53 
8.2.3. 
Safety Procedures .......................................................................................................53 
8.2.3.1. 
Weight .........................................................................................................................53 
8.2.3.2. 
Vital Signs ..................................................................................................................53 
8.2.3.3. 
Physical Examination .................................................................................................53 
8.2.3.4. 
Joint Pain Questionnaire .............................................................................................54 
8.2.3.5. 
Survey of Autonomic Symptoms ................................................................................54 
8.2.3.6. 
Neurologic Examination .............................................................................................54 
8.2.3.7. 
Imaging .......................................................................................................................54 
8.2.3.8. 
Assessment of Orthostatic Blood Pressure and Heart Rate ........................................55 
8.2.3.9. 
Electrocardiogram .......................................................................................................56 
8.2.3.10. 
End of Study Phone Contact and Additional Imaging ................................................56 
8.2.3.11. 
Procedures to be Performed Only in the Event of a Joint Replacement 
Surgery ........................................................................................................................56 
8.2.3.12. 
Laboratory Testing ......................................................................................................57 
8.2.3.13. 
Injection Site Evaluations ...........................................................................................58 
8.2.4. 
Pharmacokinetic and Anti-Drug Antibody Procedures ..............................................59 
8.2.4.1. 
Drug Concentration Measurements and Samples .......................................................59 
8.2.4.2. 
Anti-Drug Antibody Measurements and Samples ......................................................59 
8.2.5. 
Research Samples .......................................................................................................59 
8.2.5.1. 
Biomarker Serum and Biomarker Plasma Samples ....................................................59 
 
 
 
 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................60 
9.1. 
Obligations of Investigator .........................................................................................60 
9.2. 
Obligations of Sponsor ...............................................................................................60 
9.3. 
Definitions ..................................................................................................................60 
9.3.1. 
Adverse Event .............................................................................................................60 
9.3.2. 
Serious Adverse Event ................................................................................................61 
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CONFIDENTIAL 
9.3.3. 
Adverse Events of Special Interest .............................................................................61 
9.4. 
Recording and Reporting Adverse Events ..................................................................61 
9.4.1. 
Adverse Events ...........................................................................................................61 
9.4.2. 
Serious Adverse Events ..............................................................................................62 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor ...................................62 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................63 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results .............................63 
9.4.6. 
Follow-up ....................................................................................................................63 
9.5. 
Evaluation of Severity and Causality .........................................................................63 
9.5.1. 
Evaluation of Severity ................................................................................................63 
9.5.2. 
Evaluation of Causality ...............................................................................................64 
9.6. 
Safety Monitoring .......................................................................................................66 
9.6.1. 
Monitoring Adverse Events of Special Interest ..........................................................66 
9.6.1.1. 
Adjudicated Arthropathy ............................................................................................66 
9.6.1.2. 
Sympathetic Nervous System Dysfunction ................................................................67 
9.6.1.3. 
Peripheral Sensory Adverse Events ............................................................................68 
9.6.1.4. 
Joint Replacement Surgery .........................................................................................69 
9.7. 
Investigator Alert Notification ....................................................................................69 
10. 
STATISTICAL PLAN................................................................................................69 
10.1. 
Statistical Hypothesis ..................................................................................................69 
10.2. 
Justification of Sample Size........................................................................................70 
10.3. 
Analysis Sets ...............................................................................................................70 
10.3.1. 
Efficacy Analysis Sets ................................................................................................70 
10.3.2. 
Safety Analysis Set .....................................................................................................70 
10.3.3. 
Per-Protocol Set ..........................................................................................................70 
10.3.4. 
Pharmacokinetic Analysis Set ....................................................................................70 
10.3.5. 
Anti-Drug Anti-Body Analysis set .............................................................................70 
10.4. 
Statistical Methods ......................................................................................................70 
10.4.1. 
Patient Disposition ......................................................................................................71 
10.4.2. 
Demography and Baseline Characteristics .................................................................71 
10.4.3. 
Efficacy Analyses .......................................................................................................71 
10.4.3.1. 
Primary Efficacy Analysis ..........................................................................................71 
10.4.3.2. 
Secondary Efficacy Analysis ......................................................................................72 
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CONFIDENTIAL 
10.4.4. 
Safety Analysis ...........................................................................................................72 
10.4.4.1. 
Adverse Events ...........................................................................................................72 
10.4.4.2. 
Other Safety ................................................................................................................73 
10.4.4.3. 
Treatment Exposure ....................................................................................................73 
10.4.4.4. 
Treatment Compliance ................................................................................................73 
10.4.5. 
Analysis of Drug Concentration Data .........................................................................74 
10.4.6. 
Analysis of Anti-Drug Antibody Data ........................................................................74 
10.5. 
Additional Statistical Data Handling Conventions .....................................................74 
10.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .........75 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS .....................................75 
11.1. 
Data Management .......................................................................................................75 
11.2. 
Electronic Systems ......................................................................................................75 
12. 
STUDY MONITORING ............................................................................................75 
12.1. 
Monitoring of Study Sites ...........................................................................................75 
12.2. 
Source Document Requirements ................................................................................76 
12.3. 
Case Report Form Requirements ................................................................................76 
13. 
AUDITS AND INSPECTIONS .................................................................................76 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................77 
14.1. 
Good Clinical Practice Statement ...............................................................................77 
14.2. 
Informed Consent .......................................................................................................77 
14.3. 
Patients Confidentiality and Data Protection ..............................................................77 
14.4. 
Institutional Review Board/Ethics Committee ...........................................................78 
15. 
PROTOCOL AMENDMENTS ..................................................................................78 
16. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................78 
16.1. 
Premature Termination of the Study ...........................................................................78 
16.2. 
Close-out of a Site ......................................................................................................78 
17. 
STUDY DOCUMENTATION ...................................................................................79 
17.1. 
Certification of Accuracy of Data ...............................................................................79 
17.2. 
Retention of Records ..................................................................................................79 
18. 
DATA QUALITY ASSURANCE ..............................................................................79 
19. 
CONFIDENTIALITY ................................................................................................80 
20. 
FINANCING AND INSURANCE .............................................................................80 
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CONFIDENTIAL 
21. 
PUBLICATION POLICY ..........................................................................................80 
22. 
REFERENCES ...........................................................................................................81 
23. 
INVESTIGATOR’S AGREEMENT ..........................................................................84 
Signature of Sponsor’s Responsible Officers ................................................................................85 
 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................41 
Table 2: 
Follow-up Period for Patients Who Undergo Joint Replacement Surgery .................47 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................26 
 
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CONFIDENTIAL 
CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of Fasinumab in Patients with Moderate-to-
Severe Chronic Low Back Pain and Osteoarthritis of the Hip or Knee 
Site Location(s) 
 
Principal Investigator 
To be determined 
Objectives 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of fasinumab in 
relieving chronic low back pain (CLBP) as compared to placebo in patients 
with a clinical diagnosis of moderate-to-severe non-radicular CLBP and 
osteoarthritis (OA) of the knee or hip when treated for up to 16 weeks.  
Secondary Objectives 
The secondary objectives of the study are: 
 
To evaluate the safety and tolerability of fasinumab compared to 
placebo 
when 
patients 
with 
a 
clinical 
diagnosis 
of 
moderate-to-severe non-radicular CLBP and OA of the knee or hip 
are treated for up to 16 weeks  
 
To characterize the concentrations of fasinumab in serum over time 
when patients with a clinical diagnosis of moderate-to-severe 
non-radicular CLBP and OA of the knee or hip are treated for up to 
16 weeks  
 
To evaluate the immunogenicity of fasinumab when treated for up 
to 16 weeks in patients 
with a clinical diagnosis of 
moderate-to-severe non-radicular CLBP and OA of the knee or hip 
Exploratory Objectives 
The exploratory objectives are: 
 
To evaluate the patient-reported outcomes when patients with a 
clinical diagnosis of moderate-to-severe non-radicular CLBP and 
OA of the knee or hip are treated for up to 16 weeks with fasinumab 
compared to placebo 
 
To evaluate the use of rescue medication in patients with a clinical 
diagnosis of moderate-to-severe non-radicular CLBP and OA of the 
knee or hip when treated for up to 16 weeks with fasinumab 
compared to placebo 
Study Design 
This is a phase 3, randomized, double-blind, placebo-controlled, 
parallel-group study to evaluate the efficacy and safety of fasinumab in 
patients 
with 
moderate-to-severe 
non-radicular 
CLBP 
who 
have 
radiographically confirmed OA of the knee or hip, and who have a history of 
inadequate relief of their CLBP or intolerance to current analgesic therapy 
and inadequate relief of their CLBP from non-pharmacologic therapy. The 
study consists of a screening period of up to 30 days, a 7 (+3 day)-day 
pre-randomization period during which all pain medication except 
study-provided rescue medication will be discontinued, a 16-week treatment 
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CONFIDENTIAL 
period, a 20-week follow-up period, and a final phone contact approximately 
52 weeks after the last dose of study drug is administered. Additionally at 
this time, patients with confirmed adjudicated arthropathy (AA) during the 
study with have imaging of the AA joint(s). 
Screening and Pre-randomization 
Prior to randomization, patients will undergo screening procedures, 
including X-ray of the shoulders, hips, and knees, and magnetic resonance 
imaging (MRI) of the lumbar spine.  An MRI will also be performed on any 
knee joint with a Kellgren-Lawrence (K-L) score of ≥3 and any hip joint 
with a K-L score of ≥2. A lumbar spine anterior-posterior/lateral X-ray must 
be obtained if the MRI of the lumbar spine shows evidence suggestive of a 
destructive or unstable process.  Randomization visits cannot occur until 
there is confirmation from the central reader that there are no exclusionary 
findings on the joint and lumbar spine images (X-rays and MRI, as 
applicable).  During the screening period patients may continue to take their 
current pain medications. 
Patients will then complete a pre-randomization period, during which all 
pain medication, except for the study-provided rescue medication 
(acetaminophen/paracetamol), will be discontinued.  The pre-randomization 
visit will be 7 (+3) days before randomization. Patients will be instructed to 
stop using all prohibited medications at the pre-randomization visit. Patients 
will receive paracetamol/acetaminophen to be used as a study-provided 
rescue 
medication. 
In 
the 
event 
of 
inadequate 
CLBP 
relief, 
paracetamol/acetaminophen may be taken according to the regional 
standard-of-care, with a maximum daily dose of 2500 mg (countries where 
500 mg strength tablets/capsules are available) or 2600 mg (countries where 
325 mg strength tablets/capsules are available).  Paracetamol/acetaminophen 
must not be taken within 24 hours prior to the randomization visit.  Patients 
will be instructed in the use of the electronic diary (eDiary) for recording 
daily use of rescue medication and for recording Low Back Pain Intensity 
(LBPI) Numerical Rating Scale (NRS) score.  
Randomization visits cannot occur until there is confirmation from the 
central imaging vendor that there are no exclusionary findings on the joint 
and lumbar spine images (X-rays and MRI, as applicable). 
Randomization 
Eligible patients will be randomized on day 1 (baseline) to 1 of 2 treatment 
arms in a 1:1 ratio as follows: 
 
Fasinumab 3 mg subcutaneous (SC) every 4 weeks (Q4W) 
 
Fasinumab-matching placebo SC Q4W 
Treatment 
During the treatment period (day 1 through week 16), patients will be 
permitted to use only acetaminophen/paracetamol as rescue medication.  The 
treatment period will include both study visits and a phone contact on day 8 
(±3 days). Patients will record their use of acetaminophen/paracetamol in 
their eDiary. Patients should discontinue use of acetaminophen/paracetamol 
for at least 24 hours prior to the start of study visits in order to minimize the 
confounding effects of the rescue medication on efficacy measurements.  
Efficacy assessments for evaluation of CLBP will include the daily average 
LBPI NRS, Roland Morris Disability Questionnaire (RMDQ), PGA of LBP, 
Brief Pain Inventory-short form (BPI-sf), the Medical Outcomes Study Sleep 
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Scale Revised (MOS Sleep-R), 36-item Short Form Survey (SF-36), the 
EuroQoL 5 Dimensions 5 Level Questionnaire (EQ-5D-5L), Work 
Productivity and Activity Impairment-Low Back Pain (WPAI-LBP), 
Healthcare Resource Utilization (HCRU), and the Treatment Satisfaction 
Questionnaire for Medication (TSQM). Efficacy assessments will be 
performed at the study visits. Western Ontario and McMaster Universities 
Osteoarthritis Index (WOMAC) pain subscale scores will be performed at 
baseline for safety reporting and application of study stopping criteria and at 
the week 16 study visit, as well as at any early termination visit during the 
treatment period, in support of pain relief for OA in patients who have CLBP 
and OA. 
Safety assessments will be performed at each study visit during treatment 
period and upon occurrence of any joint (AEs). Potential events of AA will 
be monitored via clinical signs and symptoms of worsening joint pain during 
the study (eg, using the joint pain questionnaire and imaging) and 
adjudication of pre-operative imaging for patients who undergo joint 
replacement (JR) surgery during the conduct of the study. Potential events of 
sympathetic nervous system (SNS) dysfunction will be monitored 
throughout the study through physical examination, AE reporting, 
assessment of orthostatic hypotension, and the Survey of Autonomic 
Symptoms. 
Follow-up 
After the end of treatment, follow-up of patients will continue for an 
additional 20 weeks after the last treatment period visit. Both safety and 
efficacy assessments will be performed during this period. Potential events 
of AA and SNS dysfunction will be monitored, as previously described for 
the treatment period. 
If a patient must undergo JR surgery during the study, he or she will be 
asked to complete pre-operative imaging and to undergo post-surgery 
follow-up. 
End of Study Phone Contact and Additional Imaging 
Phone contact will be made approximately 52 weeks after administration of 
the last dose of fasinumab or placebo to document patient status with regard 
to JR surgery (if patient underwent, is scheduled for, or is on a wait list for 
JR surgery). Additionally, patients who had an AA confirmed during the 
study will have an MRI performed of the affected joint(s). If the AA joint(s) 
have undergone JR, an X-ray may be substituted for an MRI. 
Study Duration 
The duration of the study is up to 64 weeks excluding the screening and 
pre-randomization periods. Patients who discontinue study drug will be 
requested to return for all scheduled visits and to complete all planned 
assessments, including phone contacts.  
Population 
 
 
Sample Size: 
The study will enroll approximately 1020 patients at about 140 global sites. 
Each arm (fasinumab and placebo) will enroll approximately 510 patients. 
 
Target Population: 
Men and women who are at least 18 years of age at the time of study entry 
with a clinical diagnosis of moderate-to-severe non-radicular CLBP and OA 
of the knee or hip and who have a history of inadequate pain relief or 
intolerance to current analgesic therapy and inadequate pain relief from 
non-pharmacologic therapy. 
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Treatments 
 
 
Study Drug 
 
Dose/Route/Schedule: 
Fasinumab 
3 mg SC Q4W 
 
Placebo 
 
Route/Schedule: 
Fasinumab-matching placebo 
3 mg SC Q4W 
 
Rescue Treatment: 
Starting at pre-randomization to the end of the 16-week treatment period, 
acetaminophen/paracetamol is the only study-provided rescue medication. In 
the event of inadequate pain relief for CLBP, acetaminophen/paracetamol 
may be taken as needed according to the local standard of care. The 
maximum daily dose during the treatment and follow-up periods is currently 
2500 mg (countries where 500 mg strength tablets/capsules are available) or 
2600 mg (countries where 325 mg strength tablets/capsules are available). 
Use of acetaminophen/paracetamol as study-provided rescue medication will 
be reported daily using diaries. Acetaminophen/paracetamol must not be 
taken within 24 hours prior to visits during the treatment period. 
Endpoints 
 
 
Primary: 
The primary endpoint is change in the daily average LBPI NRS score from 
baseline to week 16 in patients treated with fasinumab compared to patients 
treated with placebo. 
 
Secondary: 
The secondary endpoints of the study are: 
 
Change from baseline to week 16 in RMDQ total score in patients 
treated with fasinumab compared to patients treated with placebo 
 
Change from baseline to week 16 in PGA of LBP score in patients 
treated with fasinumab compared to patients treated with placebo 
 
Proportion of patients who are responders as defined by ≥30% 
reduction from baseline to week 16 in daily average LBPI NRS 
score in patients treated with fasinumab compared to patients 
treated with placebo 
 
Change from baseline to week 16 in the BPI-sf pain interference 
score in patients treated with fasinumab compared to patients 
treated with placebo 
Safety: 
The safety endpoints in this study are: 
 
Incidence of AA (as confirmed by an independent adjudication 
committee) 
 
Incidence of destructive arthropathy (DA) (as confirmed by an 
independent adjudication committee) 
 
Incidence of treatment-emergent adverse event (TEAEs) 
 
Incidence of SNS dysfunction (as diagnosed after consultation with 
an appropriate specialist, such as a neurologist and/or cardiologist) 
 
Incidence of peripheral sensory AEs that require a neurology 
consultation 
 
Incidence of all-cause JR surgeries through week 16 and through the 
end of follow-up period (week 36)  
 
Incidence of JRs at telephone survey approximately 52 weeks after 
last dose of study drug 
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Procedures and Assessments 
At the screening visit, patients will provide informed consent, medical 
history, and medication history. Determination of a patient’s diagnosis of 
CLBP and OA of the knee or hip will be assessed according to the inclusion 
and exclusion criteria, along with other requirements for study participation.  
Patients will be assessed for childbearing potential, if appropriate. 
Efficacy assessments for evaluation of CLBP will include the daily average 
LBPI NRS, RMDQ, PGA of LBP, BPI-sf, the MOS SLEEP-R, SF-36, the 
EQ-5D-5L, WPAI-LBP, HCRU, and the TSQM. The WOMAC pain 
subscale scores will be performed at baseline for safety reporting and 
application of study stopping criteria, and at the week 16 study visit and in 
the event of an early termination visit during this time, in support of pain 
relief for OA in patients with CLBP and OA. 
Safety assessments will be performed at each study visit during treatment 
period and upon occurrence of any joint AEs. Potential events of AA will be 
monitored via clinical signs and symptoms of worsening joint pain during 
the study (eg, using the joint pain questionnaire and imaging) and 
adjudication of pre-operative imaging for patients who undergo JR surgery 
during the conduct of the study. Potential events of SNS dysfunction will be 
monitored throughout the study through physical examination, AE reporting, 
assessment of orthostatic hypotension, and the Survey of Autonomic 
Symptoms. 
Statistical Plan 
Statistical Hypothesis 
The primary endpoint in the study is the change from baseline to week 16 in 
the average daily LBPI NRS score. The following hypothesis will be tested: 
H01: There is no treatment difference between fasinumab 3mg Q4W and 
placebo in the change from baseline to week 16 in the average daily LBPI 
NRS score. 
The secondary null hypotheses of interest are: 
H02: There is no treatment difference between fasinumab 3mg Q4W and 
placebo in the change from baseline to week 16 in the RMDQ total score  
H03: There is no treatment difference between fasinumab 3mg Q4W and 
placebo in the change from baseline to week 16 in the PGA LBP score  
H04: There is no treatment difference between fasinumab 3mg Q4W and 
placebo in the change from baseline to week 16 in the BPI-sf.  
Fixed sequence hierarchical testing will be applied to maintain the study 
wise Type-I error rate at the 2 sided 0.05 level for the primary and key 
secondary endpoints. Secondary endpoints will only be tested if the primary 
endpoint is statistically significant in favor of fasinumab. Details will be 
provided a priori in the statistical analysis plan. 
Justification of Sample Size 
Approximately 1020 patients will be randomized in a 1:1 ratio to either 
fasinumab (3mg Q4W) or placebo. Assuming a 2-sided alpha level of 0.05 
and a 20% dropout rate at week 16, an enrolment of 510 patients per arm 
will provide 90% power to detect an effect size of 0.23 in the daily average 
LBPI NRS score (ie, an absolute treatment difference of 0.5 between 
fasinumab 3mg Q4W and placebo with an associated standard deviation 
[SD] of 2.2). This sample size also provides at least 99% power to detect an 
effect size of 0.42 (absolute treatment difference of 2.2 with an associated 
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SD of 5.2) in the RMDQ total score and 0.44 (absolute treatment difference 
of 0.4 with an associated SD of 0.9) in the PGA at week 16. The sample size 
assumptions are based on results of the R475-PN-1524 study data on file at 
Regeneron Pharmaceuticals, Inc. 
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, Q1, Q3, and maximum. For 
categorical or ordinal data, frequencies and percentages will be displayed for 
each category. 
Demographic and baseline characteristics, including medical history and 
exposure to study drug will be summarized descriptively by treatment group, 
and by all patients combined. 
The primary efficacy variables will be analyzed using multiple imputation 
approach with mixed-effect model for repeated measure (MMRM) based on 
the full analysis set (FAS) with adjustment for missing data due to lack of 
efficacy or adverse events assuming the LBPI NRS scores would on average 
return to baseline values. The imputed data for patients discontinued from 
the study due to a lack of efficacy or adverse events will be centered at the 
mean baseline value. 
Sensitivity analysis using pattern mixture model and tipping point approach 
with multiple imputation to impute missing data will be performed to assess 
the robustness of the results due to treatment discontinuation.  Additional 
sensitivity analyses will be performed the same way for the primary and 
selected secondary endpoints using the per-protocol set (PPS). 
For analysis of continuous secondary endpoints, the analysis method will be 
the same as that used for the primary variables. For analysis of categorical 
variables in secondary endpoints, eg, proportions of patients with ≥30% 
reduction from baseline to week 16 in the daily average LBPI NRS score; 
the Cochran Mantel Haenszel approach stratified by the randomization strata 
will be used with missing data considered as non-response. 
Safety data including TEAEs and treatment emergent adverse events of 
special 
interest, 
vital 
signs, 
physical 
exams, 
laboratory 
tests, 
electrocardiograms, and anti-drug antibody formation will be listed and 
summarized by treatment group. 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AA 
Adjudicated arthropathy 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
BDI-II 
Beck Depression Inventory - II 
BPI-sf 
Brief Pain Inventory-short form 
bpm 
Beats per minute 
CLBP 
Chronic low back pain 
Cmax 
Maximal concentration 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
Ctrough 
Trough concentrations 
CTCAE 
Common Terminology Criteria for Adverse Events 
DA 
Destructive arthropathy 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
eDiary 
Electronic diary 
EQ-5D-5L 
EuroQoL 5 Dimensions 5 Level Questionnaire 
ESR 
Erythrocyte sedimentation rate 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
HCRU 
Healthcare Resource Utilization 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
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IV 
Intravenous 
IVRS 
Interactive voice response system 
IWRS 
Interactive web response system 
JR 
Joint replacement 
K-L 
Kellgren-Lawrence 
LBP 
Low back pain 
LBPI 
Low back pain intensity 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect model for repeat measure 
MOS Sleep-R 
Medical Outcomes Study Sleep Scale Revised 
MRI 
Magnetic resonance imaging 
NGF 
Nerve growth factor 
NRS 
Numerical Rating Scale 
NSAID 
Non-steroidal anti-inflammatory drug 
OA 
Osteoarthritis 
PCSV 
Potentially clinically significant value 
PGA 
Patient Global Assessment 
PHQ-8 
Patient Health Questionnaire 8-Item Version 
PK 
Pharmacokinetic 
PPS 
Per-protocol set 
PT 
Preferred term 
Q4W 
Every 4 weeks 
Q8W 
Every 8 weeks 
QRS 
Complex of Q, R, and S waves on an electrocardiogram 
RBC 
Red blood cell 
RMDQ 
Roland Morris Disability Questionnaire 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Software 
SC 
Subcutaneous 
SD 
Standard deviation 
SF-36 
36-item Short Form Survey 
SNS 
Sympathetic nervous system 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
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TBL 
Total bilirubin 
TEAE 
Treatment-emergent adverse event 
TrkA 
Tyrosine kinase type 1 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WOCBP 
Woman/women of childbearing potential 
WOMAC 
Western Ontario and McMaster Universities Osteoarthritis Index 
WPAI-LBP 
Work Productivity and Activity Impairment-Low Back Pain 
 
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1. 
INTRODUCTION 
Low back pain (LBP) remains a major international health problem with lifetime prevalence 
ranging 
widely 
from 
49 
to 
70% 
(van 
Tulder, 
2002) 
up 
to 
80 
to 
85% 
(WHO Scientific Group, 2003). The majority of patients with LBP (90%) experience 
non-specific LBP with the most important symptoms being pain and disability 
(van Tulder, 2002) (Deyo, 2001). Pain in patients with non-specific LBP may arise from multiple 
pathologies including facet osteoarthritis, central and foramen stenosis, disc herniation, and 
muscle spasm. Most patients are believed to recover rapidly from LBP with approximately 90% 
no longer consulting a physician within 3 months (Croft, 1998). This does not necessarily imply 
resolution of symptoms and subsequent episodes of LBP are common. Estimates for recurrence 
range from 24% to 80% at 1 year due to the variation in definitions for recurrence and remission 
(Hoy, 2014). A literature review found that between 42% and 75% of patients still experienced 
pain after 12 months, and that the risk of LBP was about twice as high for those with a history of 
LBP (Hestbaek, 2003). 
Chronic low back pain (CLBP) is characterized as LBP that persists for ≥3 months. Recent 
guidelines from the American College of Physicians recommend that patients with CLBP are 
first 
treated 
with 
non-pharmacologic 
interventions. 
If 
ineffective, 
non-steroidal 
anti-inflammatory drugs (NSAIDs) are recommended as first-line treatments and tramadol 
(opiod) or duloxetine (serotonin-norepinephrine reuptake inhibitor) as second-line treatments 
(Qaseem, 2017). Evidence for non-pharmacologic management is low to moderate quality, at 
best, and dependent on the intervention. The risks associated with long-term use of NSAIDs have 
been well characterized and include gastrointestinal bleeding and increased risk of 
cardiovascular events (Lanas, 2010) (Trelle, 2011). Opioid use is limited by central nervous 
system effects, nausea and vomiting, constipation, and the potential for abuse and dependence. 
Opioid use may be associated with drowsiness, dizziness, motor imbalance, respiratory 
depression, and even death, and must be closely monitored in patients who are vulnerable to 
abuse or addiction. Moreover, there is no evidence to support the superiority of opioids over 
other available pain medications. While treatment with opioids over a short duration is supported 
by research data, long-term efficacy has not been evaluated. Thus, there remains an unmet 
medical need for alternative treatment options that have a more effective analgesic effect, 
particularly as there are a significant number of patients who are intolerant to or do not have 
adequate pain relief from current treatment options. Inadequate pain relief has a profound impact 
on quality of life for millions of people worldwide with an associated substantial cost to society, 
including healthcare costs (Salmon, 2016) and loss of productivity (Dibonaventura, 2011). 
Neurotrophins are a family of peptide growth factors that play a role in the development, 
differentiation, survival, and death of neuronal and non-neuronal cells (Chao, 2006). Nerve 
growth factor (NGF) was the first neurotrophin to be identified, and its role in the development 
and survival of both peripheral and central neurons in the developing nervous system is well 
characterized (Smeyne, 1994) (Crowley, 1994). In the adult, NGF is not required as a survival 
factor but acts as a pain mediator that sensitizes neurons (Pezet, 2006). Nerve growth factor 
activity is mediated through 2 different membrane-bound receptors, the high-affinity tyrosine 
kinase type 1 (TrkA) and the low-affinity p75 neurotrophin receptors.  
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By acting upstream of several relevant molecular pathways, the NGF/TrkA system appears to 
play a major role in controlling pain. Administration of NGF provokes pain in both rodents 
(Lewin, 1994) and humans (McArthur, 2000), while NGF antagonists prevent hyperalgesia and 
allodynia in animal models of neuropathic and chronic inflammatory pain (Ramer, 1999). 
Humans with mutations in TrkA (hereditary sensory and autonomic neuropathy IV) or NGF 
(hereditary sensory and autonomic neuropathy V) have a loss of deep pain perception 
(Indo, 1996) (Einsardottir, 2004). In addition, NGF is elevated in the synovial fluid of patients 
with rheumatoid arthritis and other types of arthritis (Aloe, 1992) (Halliday, 1998). Nerve growth 
factor is also up-regulated in injured and inflamed tissues in conditions such as cystitis, 
prostatitis, and chronic headache (Lowe, 1997) (Miller, 2002) (Sarchielli, 2001). Thus, it was 
postulated that NGF blockage would provide pain relief via a novel mechanism, avoiding the 
limitations of many currently used analgesic medications, such as NSAIDs and opioids. 
Fasinumab is a fully-human, high-affinity, monoclonal antibody directed against NGF. By 
selectively blocking NGF, fasinumab has the potential to effectively modulate NGF-associated 
pain without some of the adverse side effects of other analgesic medications, such as opioids and 
NSAIDs. Following an evaluation of the safety and tolerability of the antibody in a 
single-ascending-dose first-in-human study (study R475-PN-0817), a proof-of-concept study 
evaluating the effect of fasinumab on pain in 217 patients with osteoarthritis (OA) of the knee 
was completed (study R475-PN-0901, see current edition of Fasinumab Investigator’s Brochure). 
Three intravenous (IV) doses of fasinumab were evaluated (0.03, 0.1, 0.3 mg/kg every 8 weeks 
[Q8W]). All 3 doses, compared with placebo, were associated with statistically significant 
improvement in pain as evaluated by walking knee pain, the Western Ontario and McMaster 
Osteoarthritis Index (WOMAC), and the Patient’s Global Impression of Change questionnaire.  
Additionally, the R475-PN-1227 study in patients with OA revealed significant efficacy in the 
WOMAC pain subscale score for each of the doses of fasinumab evaluated (1 mg, 3 mg, 6 mg, 
and 9 mg given every 4 weeks [Q4W]) compared with placebo (see current edition of the 
Investigator’s Brochure). Results from recent clinical studies with other anti-NGF antibodies, 
tanezumab (Pfizer) and fulranumab (Janssen), also support the role of NGF in pain modulation in 
patients with pain due to OA of the knee and hip (Brown, 2012) (Hefti, 2006) (Lane, 2010) and 
in patients with CLBP (Katz, 2011) (Kivitz, 2013). 
In all clinical studies completed to date, fasinumab was generally well tolerated. Arthralgia, joint 
swelling, peripheral edema, hypoesthesia, and myalgia were more frequently reported in 
fasinumab-treated patients than in placebo-treated patients. In neurological evaluations, 
abnormalities in vibration sense were more frequent in the fasinumab patients than in the placebo 
patients. These adverse events (AEs) or physical examination abnormalities associated with 
fasinumab were generally mild to moderate in intensity and were transient (see current version of 
the Investigator’s Brochure). 
Data from studies of tanezumab and fulranumab demonstrated that these molecules were 
associated with an increased risk of destructive arthropathy (DA), a unique clinical form of 
rapidly destructive arthropathy over and above that seen in the normal progression of OA. 
Analyses of the tanezumab data by its sponsor revealed that the risk of DA increases with 
tanezumab dose and is further increased with the concomitant chronic use of NSAIDs (>90 days) 
(Lane, 2010). Most cases of DA occurred in joints with a documented history of OA. 
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Based on the potential risk of DA identified in tanezumab and fulranumab studies, the US Food 
and Drug Administration (FDA) placed this class of anti-NGF antibodies on clinical hold in 
2010. Following a review of anti-NGF antibody clinical data in March 2012, the FDA 
determined that clinical studies of anti-NGF therapies could resume if mitigation strategies are 
implemented to minimize the risk of DA. The risk-mitigation approach being implemented for 
all fasinumab studies is outlined in Section 9.6.1.1. This approach includes sensitive, 
prospective, and rigorous radiologic screening for select changes in joint structure. Patients who 
develop these changes, which are referred to throughout this document as adjudicated 
arthropathy (AA), are required to discontinue study therapy.  
To date, of the completed studies in the fasinumab program, 26 AA events have occurred in 
24 patients. There was an increase in AA events that appeared to be related to a greater 
fasinumab dose. Although these events were milder than the DA events presented at the 2012 
FDA Arthritis Advisory Committee, because efficacy in OA was not greater with the 6 mg or 
9 mg Q4W regimens compared with the 3 mg Q4W regimen, the benefit-risk ratio was deemed 
unfavorable for the fasinumab 6 mg Q4W and 9 mg Q4W dose regimens in patients with OA in 
comparison to the other, lower fasinumab dose regimens studied. Accordingly, those higher dose 
regimens are no longer being studied in the OA program. The current study evaluates a lower 
fasinumab dose that potentially has a more favorable benefit-risk profile in this patient 
population that also has OA of the knee or hip.  
In 2012, studies of other anti-NGF monoclonal antibodies identified adverse changes in the 
sympathetic nervous system (SNS) of mature animals of several species (rat and non-human 
primate). These effects include a reversible decrease in neuron volume. To date, no statistically 
significant or consistent effects of fasinumab on the SNS have been detected in animal studies 
with up to 6 months of treatment. In completed studies, no patients have developed SNS 
dysfunction. Nonetheless, based on the potential risk of SNS toxicity associated with these other 
anti-NGF monoclonal antibodies in animal studies, a risk mitigation approach is being 
implemented for all fasinumab studies, as outlined in Section 9.6.1.2. 
Since the FDA removed the clinical hold, Regeneron Pharmaceuticals, Inc. (Regeneron) has 
conducted or initiated several clinical trials of fasinumab. In completed clinical studies to date, 
fasinumab was associated with a low rate of discontinuation due to AEs. Patients treated with 
fasinumab generally had more frequent events than did placebo-treated patients of arthralgia, 
joint swelling, peripheral edema, altered peripheral sensation (eg, paresthesia, dysesthesia), and 
myalgia. As noted above, there is a dose-related trend for AAs; more severe DAs have 
infrequently been observed.  
Fasinumab is currently being evaluated in 3 phase 3 OA efficacy and safety studies. Study 
R475-PN-1523 is ongoing and is designed to assess the long-term safety and efficacy of multiple 
doses of fasinumab compared to placebo in patients with OA of the hip or knee. The 2 other 
studies will include comparison to standard-of-care NSAIDs for moderate-to-severe pain due to 
OA. Study R475-OA-1611 is designed to compare the efficacy and safety of fasinumab to 
placebo and to naproxen, and study R475-OA-1688 is designed to compare the efficacy and 
safety of fasinumab to placebo, and to a pooled NSAID arm (celecoxib or diclofenac) in patients 
with moderate-to-severe pain due to OA of the hip or knee. 
The phase 3 study described here is designed to evaluate the efficacy and safety of fasinumab 
compared to placebo for moderate-to-severe non-radicular CLBP in patients who also have 
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radiographically confirmed OA of the knee or hip, and who have a history of inadequate pain 
relief or intolerance to current analgesic therapy and inadequate pain relief from 
non-pharmacologic therapy.  
Additional background information on the study drug and development program can be found in 
the Investigator’s Brochure. 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of fasinumab in relieving CLBP as 
compared to placebo in patients with a clinical diagnosis of moderate-to-severe non-radicular 
CLBP and OA of the knee or hip when treated for up to 16 weeks.  
2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
 To evaluate the safety and tolerability of fasinumab compared to placebo when 
patients with a clinical diagnosis of moderate-to-severe non-radicular CLBP and OA 
of the knee or hip are treated for up to 16 weeks  
 To characterize the concentrations of fasinumab in serum over time when patients 
with a clinical diagnosis of moderate-to-severe non-radicular CLBP and OA of the 
knee or hip are treated for up to 16 weeks  
 To evaluate the immunogenicity of fasinumab when treated for up to 16 weeks in 
patients with a clinical diagnosis of moderate-to-severe non-radicular CLBP and OA 
of the knee or hip 
2.3. 
Exploratory Objectives 
The exploratory objectives are: 
 To evaluate the patient-reported outcomes when patients with a clinical diagnosis of 
moderate-to-severe non-radicular CLBP and OA of the knee or hip are treated for up 
to 16 weeks with fasinumab compared to placebo 
 To evaluate the use of rescue medication in patients with a clinical diagnosis of 
moderate-to-severe non-radicular CLBP and OA of the knee or hip when treated for 
up to 16 weeks with fasinumab compared to placebo  
3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypothesis 
Fasinumab is expected to provide effective pain relief based on improvement in the Low Back 
Pain Intensity (LBPI) Numerical Rating Scale (NRS) score and improved functionality based on 
Roland Morris Disability Questionnaire (RMDQ). 
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3.2. 
Rationale 
3.2.1. 
Rationale for Study Design 
The present study is a phase 3, randomized, double-blind, placebo-controlled, parallel-group 
study designed to evaluate the efficacy and safety of fasinumab in patients with 
moderate-to-severe non-radicular CLBP, who also have radiographically confirmed OA of the 
knee or hip, and who have a history of inadequate relief of their CLBP or intolerance to current 
analgesic therapy and inadequate relief of their CLBP from non-pharmacologic therapy. This 
study will evaluate the efficacy and safety of fasinumab compared to placebo using the LBPI 
NRS score as the primary endpoint. 
The target population will consist of patients who have inadequate CLBP relief with 
acetaminophen/paracetamol, or who are unable to tolerate or have inadequate CLBP relief with 
NSAIDs and opioids (or unwilling to take opioids). The patients will also have inadequate CLBP 
relief from non-pharmacologic management. This population was chosen because these patients 
have unmet medical needs with respect to inadequate pain relief despite the availability of the 
aforementioned therapeutic options. Thus, this population is appropriate for prospectively 
studying the hypothesis that fasinumab provides effective relief for CLBP with an acceptable 
safety profile at the dose being administered.  
The study will be conducted with appropriate eligibility criteria to exclude patients who may be 
at increased risk for events of joint damage and SNS dysfunction. Specific questionnaires, 
physical examinations, and imaging will be employed to monitor for any events of arthralgia, 
worsening joint pain, AA, altered peripheral sensation, and SNS effects. Inclusion of the placebo 
treatment group is important to determine accurately the efficacy of fasinumab at the dose being 
evaluated and to estimate the risk of AEs, including the AEs of special interest (AESI) of AA 
and SNS dysfunction. Rescue medication (paracetamol/acetaminophen) will be made available 
to any patient with breakthrough pain. Therefore, the use of a placebo group is justified, as 
placebo-treated patients will not be placed in significant discomfort. A patient or investigator can 
choose to end participation at any time.At randomization, patients will be stratified by baseline 
LBPI NRS score (<7, ≥7), duration of CLBP (<5 years, ≥5 years), maximum Kellgren-Lawrence 
(K-L) score (2-3; 4) for any knee or hip joint at screening, and by geographical region.  
3.2.2. 
Rationale for Dose Selection 
As the target population for this study has concomitant OA of the knee or hip, randomized 
patients will receive a fixed-dose, subcutaneous (SC) injection of fasinumab 3 mg Q4W or 
fasinumab-matching placebo Q4W. This is the proposed maximum dose of fasinumab at this 
dosing frequency for patients who have OA of the knee or hip. 
Clinical trial data, including pharmacokinetic (PK) data, that support selection of this fasinumab 
dose include those from the phase 1 studies in healthy volunteers (R475-PN-0817 and 
TDU-11480), the R475-PN-0901 phase 2 proof-of-concept study in patients with pain due to OA 
of the knee, the R475-PN-1227 phase 2 study in patients with OA of the hip or knee, and the 
R475-PN-0908 single-dose proof-of-concept study in patients with sciatic pain.  
Single SC doses of fasinumab of up to 30 mg were well tolerated in healthy male and female 
subjects in the TDU-11480 study. All single IV doses of fasinumab in the R475-PN-0817 study 
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in healthy male and female subjects were generally well tolerated at all but the highest IV dose 
(1 mg/kg). The occurrence of neurosensory AEs, which were transient and non-severe, led to the 
decision to refrain from escalating above the 1 mg/kg IV dose and instead, to expand enrollment 
of the 1 mg/kg IV cohort.  
In the R475-PN-0901 phase 2, proof-of-concept study of fasinumab in patients with pain due to 
OA of the knee, multiple IV doses of up to 0.3 mg/kg administered Q8W demonstrated efficacy 
with regard to pain relief and were well tolerated in Caucasian subjects. All 3 doses of fasinumab 
(0.03 mg/kg, 0.1 mg/kg, and 0.3 mg/kg IV Q8W) were associated with greater improvement 
compared with placebo in walking index knee pain, standardized total WOMAC score, WOMAC 
subscales (pain, function, and stiffness) and Patient’s Global Impression of Change. However, it 
was noted that pain relief had the slowest onset with the lowest (0.03 mg/kg) dose.  
In the R475-PN-1227 phase 2 study of fasinumab in patients with pain due to OA of the hip or 
knee, all SC doses (1 mg, 3 mg, 6 mg, and 9 mg Q4W) demonstrated greater efficacy relative to 
placebo in pain relief and physical function measures, based upon WOMAC pain and physical 
function scales assessed after 16 weeks of treatment. Considering the relative lack of an observed 
dose-response for efficacy and the increased risk of AA with both the 9 mg and 6 mg Q4W 
doses, the latter doses are no longer being evaluated in studies of fasinumab for the treatment of 
pain due to OA. Neuromuscular AEs, such as arthralgia and paresthesia, were reported more 
frequently in fasinumab-treated patients than in placebo-treated patients, though these events 
were typically mild or moderate in intensity.  
An ongoing phase 2/3 study in patients with non-radicular CLBP (R475-PN-1524) is evaluating 
the efficacy and safety of fasinumab (6 mg Q4W SC, 9 mg Q4W SC and 9 mg Q8W IV) 
compared to placebo. The study enrolled patients with CLBP, some of whom had advanced OA, 
and an event of AA in 1 such patient led the FDA to place the study on partial clinical hold until 
the protocol could be amended to either exclude patients with OA of the knees, hips, or shoulders 
or reduce the doses. As 563 of 800 planned patients had been randomized at the time of the 
partial clinical hold, Regeneron performed an unplanned interim analysis of the data. This 
interim analysis showed evidence of efficacy with improvement in LBPI NRS pain scores in all 
fasinumab groups compared to placebo at the 8- and 12-week time points. The interim safety 
results were generally consistent with what has been previously reported for fasinumab studies. 
The maximum fasinumab doses being evaluated in the OA program are 3 mg Q4W and 6 mg 
Q8W. The PK of fasinumab is described as linear, with concentrations in serum and exposure, as 
measured by similar area under the concentration-time curve (AUC), increasing in a 
dose-proportional manner. Therefore, the 6 mg Q8W dose is expected to achieve similar AUC to 
that of the 3 mg Q4W dose studied in the R475-PN-1227 trial. Maximal concentration (Cmax) and 
trough concentrations (Ctrough) of the 6 mg Q8W dose are expected to be within the range 
observed in the phase 2 study, R475-PN-1227. However, in a patient population with CLBP, a 
more frequent administration of fasinumab, ie, 3 mg Q4W, may be more beneficial in providing 
effective CLBP relief in patients with concomitant OA of the knee or hip. 
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4. 
STUDY VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height, etc.), 
disease characteristics including medical and surgical history, and medication history for each 
patient. 
4.2. 
Primary and Secondary Endpoints 
4.2.1. 
Primary Endpoint 
The primary endpoint is change in the daily average LBPI NRS score from baseline to week 16 
in patients treated with fasinumab compared to patients treated with placebo. 
4.2.2. 
Secondary Endpoints 
The secondary endpoints of the study are: 
 Change from baseline to week 16 in RMDQ total score in patients treated with 
fasinumab compared to patients treated with placebo 
 Change from baseline to week 16 in Patient Global Assessment (PGA) of LBP score 
in patients treated with fasinumab compared to patients treated with placebo 
 Proportion of patients who are responders as defined by ≥30% reduction from 
baseline to week 16 in daily average LBPI NRS score in patients treated with 
fasinumab compared to patients treated with placebo 
 Change from baseline to week 16 in the Brief Pain Inventory Short Form (BPI-sf) 
pain interference score in patients treated with fasinumab compared to patients treated 
with placebo 
4.2.3. 
Exploratory Endpoints 
Exploratory endpoints will be defined in the Statistical Analysis Plan (SAP).  
4.3. 
Safety Endpoints 
The safety endpoints in this study are: 
 Incidence of AA (as confirmed by an independent adjudication committee) 
 Incidence of DA (as confirmed by an independent adjudication committee) 
 Incidence of treatment-emergent adverse event (TEAEs) 
 Incidence of SNS dysfunction (as diagnosed after consultation with an appropriate 
specialist, such as a neurologist and/or cardiologist) 
 Incidence of peripheral sensory AEs that require a neurology consultation 
 Incidence of all-cause joint replacement (JR) surgeries through week 16 and through 
the end of follow-up period (week 36)  
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 Incidence of JRs at telephone survey approximately 52 weeks after last dose of study 
drug 
4.4. 
Pharmacokinetic Variables 
The PK variable is fasinumab concentration measured in samples collected at time points 
specified in Table 1.  
4.5. 
Anti-Drug Antibody Variables 
Anti-drug antibody (ADA) variables include status (positive or negative) and titer as follows:  
 Treatment emergent - defined as any post-dose ADA positive response when baseline 
results are negative 
 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 
 Low (titer <1,000) 
 Moderate (1,000≤ titer ≤10,000) 
 High (titer >10,000) 
 Neutralizing ADA - samples that are confirmed positive in the ADA assay will be 
analyzed for neutralizing ADA activities 
5. 
STUDY DESIGN 
5.1. 
Study Description and Duration 
This is a phase 3, randomized, double-blind, placebo-controlled, parallel-group study to evaluate 
the efficacy and safety of fasinumab in patients with moderate-to-severe non-radicular CLBP 
who have radiographically confirmed OA of the knee or hip, and who have a history of 
inadequate relief of their CLBP or intolerance to current analgesic therapy and inadequate relief 
of their CLBP from non-pharmacologic therapy. The study consists of a screening period of up 
to 30 days, a 7 (+3 day)-day pre-randomization period during which all pain medication except 
study-provided rescue medication will be discontinued, a 16-week treatment period (with the last 
Q4W dose of study drug administered at week 12), a 20-week follow-up period, and a final 
phone contact approximately 52 weeks after the last dose of study drug is administered 
(Figure 1). 
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Figure 1: 
Study Flow Diagram 
Screening and Pre-
randomization 
Treatment 
Follow-up 
EOS Phone 
Contact 
Up to 40 days 
Day 1 to Week 16 
Week 17 to 36 Up to Week 64 
 
Randomization 
 
End of 
Treatment  
End of 
Follow-up 
 
 
 
 
 
Screening 
Pre-
randomization 
 
 
 
 
Up to 30 days 
7 to 10 days Baseline 
Day 1 
 
Week 16 
Week 36 
Week 64 
EOS- End of study 
5.1.1. 
Screening and Pre-randomization 
Prior to randomization, patients will undergo screening procedures, including X-ray of the 
shoulders, hips, and knees, and magnetic resonance imaging (MRI) of the lumbar spine. An MRI 
will also be performed on any knee joint with a K-L score of ≥3 and any hip joint with a K-L 
score of ≥2. A lumbar spine anterior-posterior/lateral X-ray must be obtained if the MRI of the 
lumbar spine shows evidence suggestive of a destructive or unstable process. During the 
screening period, patients may continue to take their current pain medications.  
Patients will then complete a pre-randomization period, during which all pain medication, except 
for the study-provided rescue medication (acetaminophen/paracetamol), will be discontinued. 
The pre-randomization visit will be 7 (+3) days before randomization. Patients will be instructed 
to stop using all prohibited medications at the pre-randomization visit. Patients will receive 
paracetamol/acetaminophen to be used as a study-provided rescue medication. In the event of 
inadequate CLBP relief, paracetamol/acetaminophen may be taken according to the regional 
standard-of-care, with a maximum daily dose of 2500 mg (countries where 500 mg strength 
tablets/capsules are available) or 2600 mg (countries where 325 mg strength tablets/capsules are 
available). Paracetamol/acetaminophen must not be taken within 24 hours prior to the 
randomization visit. Patients will be instructed in the use of the electronic diary (eDiary) for 
recording daily use of rescue medication and for recording LBPI NRS score.  
Randomization visits cannot occur until there is confirmation from the central imaging vendor 
that there are no exclusionary findings on the joint and lumbar spine images (X-rays and MRI, as 
applicable). 
5.1.2. 
Rescreening 
Patients who do not meet eligibility criteria may rescreen once if it is believed that the reason for 
failure was due to a condition that would resolve or could be treated, or a lab value that 
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minimally exceeded the cut-off value, and only after approval of the Sponsor or designated 
Medical Monitor. Patients cannot rescreen if they do not meet the LBPI NRS or PGA criteria, if 
they have orthostatic hypotension at the screening, pre-randomization, or randomization visit or 
have exclusionary findings on screening imaging. 
Only the assessments that did not meet the eligibility criteria during the first screening will 
require a repeat assessment during the rescreen, if done within the screening period or 
pre-randomization period. Patients who are rescreened after the pre-randomization windows 
must re-consent for study participation and repeat all screening procedures, with the exception of 
imaging assessments. Any imaging assessments would need to be repeated only if they were 
taken more than 60 days from completion of the previous screening X-rays and MRI 
assessments. 
5.1.3. 
Randomization 
Eligible patients will be randomized on day 1 (baseline) to 1 of 2 treatment arms in a 1:1 ratio as 
follows: 
 Fasinumab 3 mg SC Q4W 
 Fasinumab-matching placebo SC Q4W 
Patients will receive treatment as described in Section 7.1.  The method of treatment assignment 
is described in Section 7.5. 
5.1.4. 
Treatment Period 
During the treatment period (day 1 through week 16), patients will be permitted to use only 
acetaminophen/paracetamol as rescue medication. The treatment period will include both study 
visits and a phone contact on day 8 (±3 days). Patients will record their use of 
acetaminophen/paracetamol in their eDiary. Patients should discontinue use of acetaminophen/ 
paracetamol for at least 24 hours prior to the start of study visits in order to minimize the 
confounding effects of the rescue medication on efficacy measurements.  
Efficacy assessments for evaluation of CLBP will include the daily average LBPI NRS, RMDQ, 
PGA of LBP, BPI-sf, the Medical Outcomes Study Sleep Scale Revised (MOS Sleep-R), 36-item 
Short Form Survey (SF-36), the EuroQoL 5 Dimensions 5 Level Questionnaire (EQ-5D-5L), 
Work Productivity and Activity Impairment-Low Back Pain (WPAI-LBP), Healthcare Resource 
Utilization (HCRU), and the Treatment Satisfaction Questionnaire for Medication (TSQM). 
Efficacy assessments will be performed at the study visits outlined in Table 1.  The WOMAC 
pain subscale scores will be performed at baseline for safety reporting and application of study 
stopping criteria and as outlined in Table 1 in support of pain relief for OA in patients CLBP and 
with OA. 
Safety assessments will be performed at each study visit during treatment period, as outlined in 
Table 1 and upon occurrence of any joint AEs. Potential events of AA will be monitored via 
clinical signs and symptoms of worsening joint pain during the study (eg, using the joint pain 
questionnaire and imaging) and adjudication of pre-operative imaging for patients who undergo 
JR surgery during the conduct of the study. Potential events of SNS dysfunction will be 
monitored throughout the study through physical examination, AE reporting, assessment of 
orthostatic hypotension, and the Survey of Autonomic Symptoms. 
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5.1.5. 
Follow-up Period 
After the end of treatment, follow-up of patients will continue for an additional 20 weeks after 
the last treatment period visit.  Safety and efficacy assessments will be performed according to 
the schedule outlined in Table 1.  Potential events of AA and SNS dysfunction will be 
monitored, as previously described for the treatment period. 
If a patient must undergo JR surgery during the study, he or she will be asked to complete 
pre-operative imaging and to undergo post-surgery follow-up as outlined in Table 2. 
5.1.6. 
End of Study Phone Contact and Additional Imaging 
Phone contact will be made approximately 52 weeks after administration of the last dose of 
fasinumab or placebo to document patient status with regard to JR surgery (if patient underwent, 
is scheduled for, or is on a wait list for JR surgery). Additionally, patients who had an AA 
confirmed during the study will have an MRI performed of the AA joint(s). If the AA joint(s) 
have undergone JR, an X-ray may be substituted for an MRI.  
5.1.7. 
Study Stopping Rules 
An independent Data Monitoring Committee (DMC) will monitor unblinded data on an ongoing 
basis to assess the risk/benefit profile of fasinumab. The DMC will review the totality of 
evidence including patient safety data and apply the formal program-wide statistical stopping 
criteria as detailed in the DMC charter. Based on these reviews, in the context of the totality of 
evidence, if the DMC has significant concerns at any time regarding a meaningful imbalance 
between treatment groups in joint-related AEs, SNS dysfunction, or neurosensory disturbances, 
the DMC may make a recommendation to temporarily halt, alter, or terminate:  
 individual dose groups within the study or across studies 
 the full study (screening, randomization, dosing of study drug) 
 the fasinumab program 
for additional review and communication to regulatory authorities. Based on the outcome of the 
review and discussions with the appropriate regulatory authorities, the study may be suspended, 
restarted, or terminated. 
Study stopping criteria for clinical studies involving fasinumab are detailed in the DMC charter. 
5.1.8. 
End of Study Definition 
The end of study is defined as the last phone contact of the last patient in this study.  
5.2. 
Planned Interim Analysis 
No interim analysis of efficacy is planned for this study. The primary efficacy analysis may be 
conducted when week 16 data are available for all randomized patients. No alpha adjustment is 
necessary, as the week 16 efficacy analysis will be the final primary analysis for efficacy. The 
results will not be disclosed to any site-facing personnel or to any personnel directly involved 
with the conduct of the study.  
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5.3. 
Study Committees 
5.3.1. 
Independent Data Monitoring Committee 
An independent DMC will meet periodically to review unblinded data as the study progresses, 
and based on the findings, will make recommendations to the sponsor about the conduct of the 
study. The DMC will be comprised of independent statistical and medical experts. Further details 
including the formal program-wide statistical stopping criteria will be defined in the DMC 
charter. Additional safety monitoring will occur on an ongoing basis by the Regeneron Safety 
Team. 
5.3.2. 
Arthropathy Adjudication Committee 
An independent, expert, blinded adjudication committee composed of radiologists will adjudicate 
all potential joint AEs of AA (defined in Section 9.6.1.1), as well as pre-operative images in 
patients undergoing JR. 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
6.1. 
Number of Patients Planned 
The study will enroll approximately 1020 patients at about 140 global sites. Each arm 
(fasinumab and placebo) will enroll approximately 510 patients.  
6.2. 
Study Population 
Eligible patients for this study include male and female patients who are at least 18 years of age 
at the time of study entry with non-radicular CLBP and concomitant OA of the knee or hip, who 
have a history of inadequate relief of their CLBP or intolerance to current analgesic therapies and 
inadequate relief of their CLBP from non-pharmacologic therapy.  
6.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Male and female patients ≥18 years of age at screening visit 
2. Body mass index ≤39 at screening visit 
3. Clinical diagnosis of non-radicular moderate-to-severe CLBP for ≥3 months (prior to 
screening visit) as defined by the following: 
a. Quebec taskforce category 1 (pain without radiation) or 2 (pain with proximal 
radiation above the knee), and 
b. Primary pain between 12th thoracic vertebra and lower gluteal folds, and 
c. At both screening and randomization visit, a LBPI NRS score ≥4 over previous 
24 hours, and 
d. Mean daily LBPI score ≥4 during pre-randomization period, and 
e. PGA of LBP of fair, poor, or very poor at screening visit 
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4. Clinical diagnosis of OA in at least 1 hip or knee joint based on the American College of 
Rheumatology Criteria with radiographic evidence of OA (K-L ≥2) at screening as 
described in Section 8.2.1.8 
5. History of inadequate relief of CLBP from non-pharmacologic therapy (eg, exercise, 
physical therapy, acupuncture, or multidisciplinary rehabilitation) 
6. History of inadequate pain relief or intolerance to analgesics used for CLBP defined by: 
a. Inadequate pain relief from paracetamol/acetaminophen, and 
b. Intolerance or inadequate pain relief from at least 1 oral NSAID, and 
c. Intolerance or inadequate pain relief from at least 1 opioid or tramadol, unwillingness 
to take opioid therapy for a medically acceptable reason, or lack of access to opioid 
therapy 
7. History of regular use of analgesic medications for LBP pain (defined as an average of 4 
days per week over the 4 weeks prior to the screening visit), including NSAIDs, selective 
cyclooxygenase 2 inhibitors, opioids, paracetamol/acetaminophen, or combinations 
thereof 
8. Willing to discontinue current pain medications and to adhere to study requirements for 
rescue treatments (paracetamol/acetaminophen to be taken as needed with a maximum 
daily dose of 2500 mg (countries where 500 mg strength tablets/capsules are available) or 
2600 mg (countries where 325 mg strength tablets/capsules are available) 
9. Willing to maintain current activity and exercise levels throughout the study 
10. Willing to undergo joint replacement (JR) surgery, if necessary 
11. Willing and able to comply with clinic visits and study-related procedures and willing to 
provide follow-up information related to any JR surgery that occurs within the period of 
time covered by their intended participation in the study 
12. Consent to allow all radiographs and medical/surgical/hospitalization records of care 
received elsewhere prior to and during the study period to be shared with the investigator 
13. Provide signed informed consent 
14. Able to understand and complete study-related questionnaires 
6.2.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. Non-compliance with the LBPI NRS data entries during the pre-randomization period, as 
defined by more than 2 missing entries 
2. History of Quebec taskforce category >2 (pain with proximal radiation above the knee) 
lumbosacral radiculopathy within the past 2 years prior to the screening visit 
3. Patient is not a candidate for MRI 
4. Evidence on baseline lumbar spine MRI (or lumbar X-ray, if requested) of severe spinal 
stenosis, disc herniation with substantial nerve compression, recent vertebral fracture, an 
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active destructive process or marked segmental instability (eg, severe scoliosis, bone 
marrow edema, or Modic type 1 change) 
5. History of major trauma or back surgery in the past 6 months prior to the screening visit 
6. History or presence of pyriformis syndrome 
7. Current or pending worker’s compensation, litigation, disability, or any other monetary 
settlement related to LBP 
8. History or presence on imaging of arthropathy (osteonecrosis, subchondral insufficiency 
fracture, rapidly progressive OA type 1 or type 2), recent fracture, recent stress fracture, 
neuropathic joint arthropathy, hip dislocation (prosthetic hip dislocation is eligible), knee 
dislocation (patella dislocation is eligible), congenital hip dysplasia with degenerative 
joint disease, extensive subchondral cysts, evidence of bone fragmentation or collapse, or 
primary metastatic tumor with the exception of chondromas, or pathological fractures 
during the screening period 
9. History or presence at the screening visit of non-OA inflammatory joint disease (eg, 
rheumatoid arthritis, lupus erythematosus, psoriatic arthritis, pseudo-gout, gout, 
spondyloarthropathy, joint infections within the past 5 years, Paget’s disease of the spine, 
pelvis, or femur, neuropathic disorders, multiple sclerosis, fibromyalgia, tumors or 
infections of the spinal cord, or renal osteodystrophy) 
10. History of hospital admission for depression or suicide attempt within 2 years or active, 
severe major depression at screening 
11. Beck Depression Inventory - II (BDI-II) score ≥29 at screening  
12. Use of a monoamine reuptake inhibitor, tricyclic antidepressants, selective serotonin 
reuptake inhibitors and serotonin norepinephrine reuptake inhibitors for treatment of 
CLBP within 4 weeks prior to the screening visit 
13. Use of extended-release or controlled-release opioids (eg, oxycontin), transdermal 
fentanyl or methadone within 3 months prior to the screening visit 
14. Use of opioids with a morphine equivalent dose of ≥30 mg per day for more than 4 days 
per week 
15. Use of systemic (ie, oral or intramuscular) corticosteroids or intra-articular 
corticosteroids in any joint within 30 days prior to the screening visit (topical, intranasal, 
and inhaled corticosteroids are permitted) 
16. Epidural steroid injections within 3 months prior to the screening visit 
17. Botox injections for LBP within 6 months prior to the screening visit 
18. History of cannabis use for the treatment of LBP within the past 6 months prior to the 
screening visit 
19. History of (within 5 years prior to the screening visit) or current alcoholism, alcohol 
abuse, substance abuse, or abuse of prescription pain medication 
20. Is scheduled for JR surgery during the study period  
21. Signs and symptoms of carpal tunnel syndrome within 6 months of screening 
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22. History or presence at the screening visit of autonomic neuropathy, diabetic neuropathy, 
or other peripheral neuropathy, including reflex sympathetic dystrophy  
23. Evidence of autonomic neuropathy 
24. History or diagnosis of chronic autonomic failure syndrome, including pure autonomic 
failure and multiple system atrophy (Shy-Drager syndrome) 
25. Poorly controlled diabetes (defined as any single value of hemoglobin A1c [HbA1c] 
>9.0%) at the screening visit 
26. Confirmed 
elevated 
screening 
alanine 
aminotransferase 
(ALT) 
or 
aspartate 
aminotransferase (AST) ≥2.5x upper limit of normal (ULN) 
27. Resting heart rate of <50 beats per minute (bpm) or >100 bpm (by vital sign assessment 
or as captured during electrocardiogram [ECG] assessment) at the screening or 
randomization visits 
28. History or presence of second or third degree heart block, first degree heart block with 
abnormal complex of Q, R, and S waves on an electrocardiogram (QRS), or bifascicular 
block by ECG at the screening visit 
29. History or presence of orthostatic hypotension, as defined in Section 8.2.3.8, at the 
screening, pre-randomization, or baseline visits 
30. History of poorly controlled hypertension, as defined by: 
a. Systolic blood pressure ≥180 mm Hg or diastolic blood pressure ≥110 mm Hg at the 
screening visit 
b. Systolic blood pressure of 160 mm Hg to 179 mm Hg or diastolic blood pressure of 
100 mm Hg to 109 mm Hg at the screening visit, AND a history of end-organ damage 
(including history of left ventricular hypertrophy, heart failure, angina, myocardial 
infraction, stroke, transient ischemic attack, peripheral arterial disease and moderate 
to advanced retinopathy [hemorrhages or exudates, papilledema]) 
31. Congestive heart failure with New York Heart Classification of stage III or IV 
(Dolgin, 1994) 
32. Transient ischemic attack or cerebrovascular accident within the past 12 months prior to 
the screening visit, or myocardial infarction, or acute coronary syndromes within the past 
6 months prior to the screening visit 
33. Known history of human immunodeficiency virus (HIV) infection 
34. Known history of ocular herpes simplex virus, herpes simplex virus pneumonia, or herpes 
simplex virus encephalitis 
35. 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 
36. Known history of infection with the hepatitis C virus. Patients with a history of 
hepatitis C are eligible if there is documentation of a negative hepatitis C virus RNA test 
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37. History or presence of malignancy within the last 5 years prior to screening, except 
patients who have been treated successfully with no recurrence for >1 year of basal cell 
or squamous cell carcinoma of the skin or in-situ cervical cancer 
38. New major illness diagnosed within 2 months prior to the screening visit 
39. 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 
40. Known allergy or sensitivity to doxycycline or related compounds, excipients, or 
monoclonal antibodies 
41. Ongoing participation in a clinical research study evaluating another investigational drug 
or having received another investigational product within 30 days or 5 half-lives, 
whichever is longer 
42. Exposure to an anti-NGF antibody prior to the screening visit or known sensitivity or 
intolerance to anti-NGF antibodies 
43. Member of the clinical site study team and/or his/her immediate family 
44. Pregnant or breastfeeding women 
45. Women of childbearing potential (WOCBP)* who have a positive pregnancy test result 
or do not have their pregnancy test result at baseline 
46. Women of childbearing potential* who are unwilling to practice highly effective 
contraception prior to the initial dose/start of the first treatment, during the study, and for 
at least 20 weeks after the last dose. 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 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 subject. 
‡Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method are not 
acceptable methods of contraception. Female condom and male condom should not be 
used together.  
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Note: HIV and/or hepatitis testing will be performed on a country-by-country basis, according to 
local guidelines if required by regulatory authorities or ethics boards. 
6.3. 
Premature Withdrawal from the Study 
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion.  
The investigator and/or sponsor have the right to withdraw a patient from the study if it is no 
longer in the interest of the patient to continue in the study, or if the patient’s continuation in the 
study places the scientific outcome of the study at risk (eg, if a patient does not or cannot follow 
study procedures). An excessive rate of withdrawals would render the study uninterpretable; 
therefore, unnecessary withdrawal of patients should be avoided. 
Patients who are withdrawn prematurely from the study will be asked to complete study 
assessments, as described in Section 8.1.3. 
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 7.3.2. 
6.4. 
Replacement of Patients 
Patients prematurely discontinued from the study or study drug will not be replaced. 
7. 
STUDY TREATMENTS 
7.1. 
Investigational Treatment 
Fasinumab drug product is supplied for this study in 1 mL single-use pre-filled syringes that 
deliver 0.5 mL of 6 mg/mL solution to provide a single 3 mg dose of study drug. 
All patients will receive SC injections of fasinumab or fasinumab-matching placebo. Patients 
will be randomized to 2 treatment arms in a 1:1 ratio to receive either fasinumab 3 mg SC Q4W 
or fasinumab-matching placebo SC Q4W. All SC injections will be in the abdomen, thigh, or 
upper arm. Instructions for dose preparation and study drug administration are provided in the 
pharmacy manual.  
Doses of study drug must be given within ±7 days from the scheduled dose date. If the window 
is missed, the dose should not be administered. The next dose should be administered at the next 
scheduled dosing date. 
7.2. 
Rescue Treatment 
Starting 
at 
pre-randomization 
to 
the 
end 
of 
the 
16-week 
treatment 
period, 
acetaminophen/paracetamol is the only study-provided rescue medication. In the event of 
inadequate pain relief for CLBP, acetaminophen/paracetamol may be taken as needed according 
to the local standard of care. The maximum allowed daily dose during the treatment and 
follow-up periods is 2500 mg (countries where 500 mg strength tablets/capsules are available) or 
2600 mg (countries where 325 mg strength tablets/capsules are available). Use of 
acetaminophen/paracetamol as study-provided rescue medication will be reported daily using 
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diaries.  Acetaminophen/paracetamol must not be taken within 24 hours prior to visits during the 
treatment period. 
Acetaminophen/paracetamol will be sourced by the study sites and reimbursed by the sponsor 
unless country-specific regulations and customs require a different approach. 
7.3. 
Dose Modification and Study Treatment Discontinuation Rules 
7.3.1. 
Dose Modification 
Dose modification for an individual patient is not allowed. 
7.3.2. 
Study Drug Discontinuation 
Study drug may be temporarily or permanently discontinued due to medical need, as determined 
by the investigator, medical monitor, or the Sponsor and according to the study stopping rules 
(Section 5.1.7). 
Patients who permanently discontinue from study drug will be encouraged to remain in the study 
and to complete all study assessments. Patients who agree and thus do not withdraw from the 
study will be asked to return to the clinic for all remaining study visits per Table 1. 
Patients who permanently discontinue from study drug and who opt to withdraw from the study 
will be asked to complete an early termination visit (Section 8.1.3). 
Patients who discontinue from study drug prior to study completion due to an AA 
(Section 9.6.1.1) should return to the clinic for all remaining study visits per the visit schedule.  
In the event that a patient must undergo JR surgery during the treatment or follow-up periods, 
he/she will be discontinued from study drug and asked to return to the study site for a 
pre-operative visit and for follow-up safety evaluations (as described in Section 8.2.3.11). 
Pre-operative imaging (X-rays and/or MRI) will be obtained and submitted to the independent 
adjudication committee for review to exclude or confirm the presence of an AA event. 
Instructions for the submission process are provided in the study manual. 
7.3.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
Study drug dosing will be permanently stopped in the event of: 
 Evidence of pregnancy 
 A patient developing clinically significant peripheral sensory or motor neurologic 
events confirmed by a neurologist’s examination and graded by the neurologist as 
moderately severe peripheral neuropathy limiting activities of daily living, grade ≥2 
according to Common Terminology Criteria for Adverse Events (CTCAE) v.4; study 
sites should use CTCAE v.4 criteria throughout the study for consistency 
 A patient developing new or worsening signs and symptoms indicative of carpal 
tunnel syndrome 
 Continued 
noncompliance 
with 
protocol-defined 
maximum 
acetaminophen/ 
paracetamol use (with a maximum daily dose of 2500 mg [countries where 500 mg 
strength tablets/capsules are available] or 2600 mg [countries where 325 mg strength 
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CONFIDENTIAL 
tablets/capsules are available]) during the treatment and follow-up periods, after 
appropriate counseling 
 Continued noncompliance with the protocol, including usage of NSAIDs or other 
medications that are not permitted in the study 
 Joint replacement surgery 
 Adverse event of special interest 
 Adjudicated arthropathy, as described in Section 9.6.1.1 
 Sympathetic nervous system dysfunction, as described in Section 9.6.1.2  
 Hepatotoxicity: Study drug should be discontinued if any of the following is 
observed: 
1. Total bilirubin (TBL) >2x ULN or international normalized ratio >1.5, and 
2. ALT or AST >3x ULN, and 
3. No other cause for 1 and 2 is readily apparent 
Other causes of ALT, AST, and TBL elevations may include alcoholic hepatitis, 
autoimmune hepatitis, non-alcoholic hepatitis, heritable diseases (Gilbert's 
Syndrome), heart failure, and viral hepatitis. 
NOTE: Study drug may be withheld in patients who do not meet criteria for 
permanently discontinuing study drug, until an alternative cause for drug-induced 
liver injury can be determined. The patient may be re-challenged if an alternative 
cause for elevated liver function tests is found and the liver function tests return to 
baseline, but only after discussion with the sponsor. 
 Serious or severe allergic reactions considered related to study drug Any other 
medical need, as determined by the investigator 
 Sponsor decision 
 Patient withdraws consent 
7.3.2.2. 
Reasons for Temporary Discontinuation of Study Drug 
Study drug may be temporarily discontinued due to medical need, as determined by the 
investigator. Study drug will be temporarily withheld while awaiting imaging adjudication for 
worsening joint pain or when routine imaging suggests AA and prompts the need for additional 
imaging (Section 9.6.1.1), or for patients who are determined to have orthostatic hypotension or 
determined to have new or worsening symptoms suggestive of SNS dysfunction while awaiting 
evaluation by a specialist (Section 9.6.1.2). 
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CONFIDENTIAL 
7.4. 
Management of Acute Reactions  
7.4.1. 
Acute Injection Reactions 
7.4.1.1. 
Systemic Injection Reactions 
Emergency equipment and medication for the treatment of systemic reactions must be available 
for immediate use.  
Acute systemic reactions following injection of SC study drug should be treated using clinical 
judgment to determine the appropriate response according to typical clinical practice.  
All systemic injection 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. 
7.5. 
Method of Treatment Assignment 
Approximately 1020 patients will be randomized in a 1:1 ratio to receive either fasinumab 3 mg 
or placebo Q4W according to a central randomization scheme provided by an interactive web 
response system (IWRS). Randomization will be stratified by geographical region, baseline 
LBPI NRS score (<7, ≥7), duration of CLBP (<5 years, ≥5 years), and maximum K-L score (2-3; 
4) of any knee or hip joint at the screening visit. 
7.5.1. 
Blinding  
Study patients, the principal investigators, and study site personnel will remain blinded to all 
randomization assignments throughout the study. The Regeneron study team and contract 
research organization (CRO) personnel who are in regular contact with the study site will remain 
blinded to all patient randomization assignments.  
Blinded study drug kits coded with a drug numbering system will be used. In order to maintain 
the blind, lists linking these codes with product lot numbers will not be accessible to individuals 
involved in study conduct.  
Anti-drug antibody results will not be communicated to the sites before the end of the study, and 
the sponsor operational team will not have access to results associated with patient identification 
until after the final database lock.  
Selected individuals not involved in the conduct of the study may have access to unblinded data 
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 unblinded data before the database is locked for this 
study.  
7.5.2. 
Emergency Unblinding 
Unblinding of treatment assignment for a patient may be necessary due to a medical emergency 
or any other significant medical event (eg, pregnancy). 
If unblinding is required: 
 Only the investigator will make the decision to unblind the treatment assignment. 
 Only the affected patients will be unblinded. 
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CONFIDENTIAL 
 The designated study pharmacist(s)/designee at the study site will provide the 
treatment assignment to the investigator. If there is no study pharmacist, the 
investigator for the site will unblind the patient. 
 The investigator will notify Regeneron and/or designee before unblinding the patient, 
whenever possible. 
Treatment assignment is not to be provided to site personnel, other than the unblinded study 
pharmacist (when applicable), at any time during the conduct of the study, except in the case of a 
true emergency. In the event that there is no study pharmacist, the individual at the site fulfilling 
that role will be the only unblinded member of the site personnel. 
7.5.3. 
Unblinding for Regulatory Reporting Purposes 
Treatment assignments for certain patients may be unblinded to Pharmacovigilance and Risk 
Management personnel for the purpose of regulatory reporting of Suspected Unexpected Serious 
Adverse Reactions (SUSARs). 
7.6. 
Treatment Logistics and Accountability 
7.6.1. 
Packaging, Labeling, and Storage 
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 
 Storage instructions will be 
provided in the pharmacy manual. 
7.6.2. 
Supply and Disposition of Treatments 
Study drug will be shipped 
 to the investigator or designee at 
regular intervals or as needed during the study. At specified time points during the study (eg, 
interim site monitoring visits), at the site close-out visit, and following drug reconciliation and 
documentation by the site monitor, all unopened fasinumab and placebo will be returned to the 
sponsor or designee for destruction; opened fasinumab and placebo can be destroyed at the site. 
7.6.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug. These records 
should contain the dates, quantity, and study drug that is: 
 dispensed to each patient, 
 returned from each patient (if applicable),  
 disposed of at the site, 
 or returned to the sponsor or designee. 
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CONFIDENTIAL 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
7.6.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the 
sponsor and regulatory agency inspectors. 
7.7. 
Concomitant Medications and Procedures 
Any treatment administered and/or procedures performed from screening to the end of the 
follow-up period will be considered concomitant medication and/or procedures, respectively. 
This includes medications and/or procedures that were started before the study and are ongoing 
during the study. 
7.7.1. 
Prohibited Medications 
Patients will be required to discontinue all non-study pain medication (oral or topical; except up 
to 150 mg/day of aspirin/5-ASA, which is permitted for cardiac prophylaxis, per local 
guidelines), starting at the pre-randomization visit and through the treatment period.  
Opioid analgesic medications (including tramadol) and muscle relaxants are prohibited through 
the week 16 study visit. Patients will be directed not to take concomitant medications that 
contain NSAIDs (oral or topical, except up to 150 mg/day of aspirin, which is permitted for 
cardiac prophylaxis) until at least 16 weeks after the last study drug injection. A list of 
medications containing NSAIDs will be provided in the study reference manual. 
Other excluded medications during the treatment and follow-up period include: 
 Any other investigational agent 
 Medical marijuana  
 Cyclobenzaprine, carisoprodol, orphenadrine, tizanidine 
 Corticosteroids (topical, intranasal, and inhaled formulations are permitted), 
adrenocorticotropic hormone 
 Cyclosporine, mycophenolate mofetil, tacrolimus 
 Azathioprine, sulfasalazine, hydroxychloroquine 
 IL-6 or IL-6 receptor antagonists 
 Abatacept, ustekinumab  
 Tumor necrosis factor antagonists 
 IL-1 inhibitors, including diacerein 
 Apremilast, and tofacitinib 
 Tocilizumab 
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CONFIDENTIAL 
7.7.2. 
Permitted Medications and Procedures 
Monoamine reuptake inhibitors are permitted for non-pain-related treatment (eg, tricyclic 
antidepressants, selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake 
inhibitors). Patients receiving these chronic medications must be on therapy for at least 
8 consecutive weeks and on a stable dose for at least 4 weeks prior to the screening visit and 
throughout the planned duration of the patient’s participation in the study. 
Low-dose 
aspirin 
(up 
to 
150 mg/day) 
for 
cardiac 
prophylaxis 
is 
permitted. 
Acetaminophen/paracetamol taken acutely for treatment of pain other than CLBP is permitted, 
however, the total daily dosage limits cannot be exceeded regardless of the reason for 
acetaminophen/paracetamol use. Acetaminophen/paracetamol taken for pain other than CLBP 
relief will be reported in the eDiary as "other" during the treatment period. 
Acetaminophen/paracetamol use during the follow-up period will be reported as concomitant 
medication. Topical steroids are permitted. 
Physical therapies (such as chiropractic therapy, transcutaneous electrical nerve stimulation, and 
acupuncture) are permitted during the trial, provided that patients have been on a stable regimen 
for at least 4 weeks prior to entering into the trial and that they expect to maintain this regimen 
during the trial. 
In the event that a patient must undergo JR surgery during the study, the patient will complete 
the early termination visit and the procedures outlined in the schedule of events for JR follow-up 
(Table 2).  The early termination visit should be completed before JR surgery if possible and 
pre-operative images will be submitted to the adjudication committee for review. 
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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Clinical Study Protocol 
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CONFIDENTIAL 
Table 1: 
Schedule of Events 
 
Screening/ 
Pre-rand 
Treatment Period 
Follow-up Period 
 
Study Week 
Screen 
Pre-
rand 
Base
-line 
Wk 
1 
Wk 
2 
Wk 
4 
Wk 
8 
Wk 
12 
EOT 
Wk 16 
ET1/ 
JR 
Pre-
op 
Wk 
20 
Wk 
24 
Wk 
28 
Wk 
32 
Wk 
36 
ET2/
JR 
Pre-
op 
EOS 
Wk 64 
Study Visit/Phone 
Visit 
1 
Visit 
2 
Visit 
3 
Phone 
1 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
 
Visit 
9 
Phone 
2 
Phone 
3 
Phone 
4 
Visit 
10 
 
Phone 
519 
Study Day 
(visit window) 
Up to 
30 
days 
7 to 
10 
days 
1 
8 
(±1) 
15 
(±3) 
29 
(±7) 
57 
(±7) 
85 
(±7) 
113 
(±7) 
141 
(±7) 
169 
(±7) 
197 
(±7) 
225 
(±7) 
253 
(±7) 
449 
(±7) 
Screening/Baseline: 
Inclusion/Exclusion 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Main study informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lumbar spine MRI5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LBPI NRS/eDiary 
training6 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BDI-II 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient-Completed Assessments/Efficacy: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient education 
brochures7 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
LBPI NRS8, 9 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
RMDQ 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
PGA LBP 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
PHQ-8 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
 
 
 
 
 
WOMAC pain 
subscale score, both 
knees and both hips 
 
 
X 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
Peripheral or central 
pain assessment 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PainDETECT 
Questionnaire 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BPI-sf 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
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Clinical Study Protocol 
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CONFIDENTIAL 
 
Screening/ 
Pre-rand 
Treatment Period 
Follow-up Period 
 
Study Week 
Screen 
Pre-
rand 
Base
-line 
Wk 
1 
Wk 
2 
Wk 
4 
Wk 
8 
Wk 
12 
EOT 
Wk 16 
ET1/ 
JR 
Pre-
op 
Wk 
20 
Wk 
24 
Wk 
28 
Wk 
32 
Wk 
36 
ET2/
JR 
Pre-
op 
EOS 
Wk 64 
Study Visit/Phone 
Visit 
1 
Visit 
2 
Visit 
3 
Phone 
1 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
 
Visit 
9 
Phone 
2 
Phone 
3 
Phone 
4 
Visit 
10 
 
Phone 
519 
Study Day 
(visit window) 
Up to 
30 
days 
7 to 
10 
days 
1 
8 
(±1) 
15 
(±3) 
29 
(±7) 
57 
(±7) 
85 
(±7) 
113 
(±7) 
141 
(±7) 
169 
(±7) 
197 
(±7) 
225 
(±7) 
253 
(±7) 
449 
(±7) 
MOS Sleep-R 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
SF-36 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
EQ-5D-5L 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
WPAI-LBP 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
HCRU 
X 
 
 
 
 
 
X 
 
X 
X 
 
 
 
 
 
 
 
TSQM  
X 
 
 
 
 
 
X 
 
X 
X 
 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SC study drug 
injection10 
 
 
X 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Study drug 
accountability 
 
 
X 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Dispense to home 
paracetamol/ 
acetaminophen 
 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Paracetamol/ 
acetaminophen 
accountability 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
eDiary compliance9 
 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Concomitant 
therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Safety: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
X 
X 
 
Vital signs 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
 
Orthostatic blood 
pressure and heart 
rate assessment11, 12 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
 
Electrocardiogram 
X 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
X 
X 
 
Neurologic 
examination 
X 
Full 
 
X 
Brief 
 
X 
Brief 
X 
Brief 
X 
Brief 
X 
Brief 
X 
Full 
X 
Full 
X 
Brief 
 
 
 
X 
Full 
X 
Full 
 
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Clinical Study Protocol 
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Regeneron Pharmaceuticals, Inc. 
 
CONFIDENTIAL 
 
Screening/ 
Pre-rand 
Treatment Period 
Follow-up Period 
 
Study Week 
Screen 
Pre-
rand 
Base
-line 
Wk 
1 
Wk 
2 
Wk 
4 
Wk 
8 
Wk 
12 
EOT 
Wk 16 
ET1/ 
JR 
Pre-
op 
Wk 
20 
Wk 
24 
Wk 
28 
Wk 
32 
Wk 
36 
ET2/
JR 
Pre-
op 
EOS 
Wk 64 
Study Visit/Phone 
Visit 
1 
Visit 
2 
Visit 
3 
Phone 
1 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
 
Visit 
9 
Phone 
2 
Phone 
3 
Phone 
4 
Visit 
10 
 
Phone 
519 
Study Day 
(visit window) 
Up to 
30 
days 
7 to 
10 
days 
1 
8 
(±1) 
15 
(±3) 
29 
(±7) 
57 
(±7) 
85 
(±7) 
113 
(±7) 
141 
(±7) 
169 
(±7) 
197 
(±7) 
225 
(±7) 
253 
(±7) 
449 
(±7) 
Survey of autonomic 
symptoms 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
 
Joint pain 
questionnaire 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
 
Event-triggered 
imaging13 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
 
Adverse events 
-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------> 
 
SC injection site 
evaluation 
 
 
X 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Bilateral X-rays 
(knee, hip, shoulder) 
X14 
 
 
 
 
 
 
 
X16 
X16 
 
 
 
 
X16 
X16 
 
MRI (any knee with 
K-L ≥3 and any hip 
with K-L ≥2 at 
screening)15 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-op questionnaire 
(JR)17, 18 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
EOS phone contact19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
MRI affected joint(s) 
- AA patients only20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Laboratory Testing: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology21 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
 
Blood chemistry21 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
 
ESR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c21 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis and urine 
electrolytes21 
X 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
X 
X 
 
FSH and 
estradiol21,22 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (for 
WOCBP)23 
X21 
Serum 
 
X 
Urine 
 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
X 
Urine 
 
 
 
 
X 
Urine 
X 
Urine 
 
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Clinical Study Protocol 
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CONFIDENTIAL 
 
Screening/ 
Pre-rand 
Treatment Period 
Follow-up Period 
 
Study Week 
Screen 
Pre-
rand 
Base
-line 
Wk 
1 
Wk 
2 
Wk 
4 
Wk 
8 
Wk 
12 
EOT 
Wk 16 
ET1/ 
JR 
Pre-
op 
Wk 
20 
Wk 
24 
Wk 
28 
Wk 
32 
Wk 
36 
ET2/
JR 
Pre-
op 
EOS 
Wk 64 
Study Visit/Phone 
Visit 
1 
Visit 
2 
Visit 
3 
Phone 
1 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
 
Visit 
9 
Phone 
2 
Phone 
3 
Phone 
4 
Visit 
10 
 
Phone 
519 
Study Day 
(visit window) 
Up to 
30 
days 
7 to 
10 
days 
1 
8 
(±1) 
15 
(±3) 
29 
(±7) 
57 
(±7) 
85 
(±7) 
113 
(±7) 
141 
(±7) 
169 
(±7) 
197 
(±7) 
225 
(±7) 
253 
(±7) 
449 
(±7) 
PK, Antibody, and Research Samples: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK sample24 
 
 
X 
 
X 
X 
X 
 
X 
X 
 
 
 
 
X 
X 
 
ADA samples 24 
 
 
X 
 
 
 
 
 
X 
X 
 
 
 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker serum 
and biomarker 
plasma24,25 
 
 
X 
 
 
X 
 
X 
X 
X 
 
 
 
 
X 
X 
 
AA: Adjudicated arthropathy 
MRI: Magnetic resonance imaging 
ADA: Anti-drug antibody 
NRS: Numerical Rating Scale  
BPI-sf: Brief Pain Inventory-Short Form 
PGA: Patient Global Assessment 
BDI-II: Beck Depression Inventory - II 
PHQ-8: Patient Health Questionnaire 8-Item Version 
EOS: End of study 
PK: Pharmacokinetic 
EOT: End of treatment 
Pre-op: Pre-operative 
ET: Early termination 
Pre-rand: Pre-randomization 
EQ-5D-5L: EuroQoL 5 Dimensions 5 Level Questionnaire 
RMDQ: Roland Morris Disability Questionnaire 
ESR: Erythrocyte sedimentation rate 
SC: Subcutaneous 
FSH: Follicle stimulating hormone 
SF-36: 36-item Short Form Survey 
HbA1c: Glycated hemoglobin 
TSQM: Treatment Satisfaction Questionnaire for Medication 
HCRU: Healthcare Resource Utilization 
Wk: Week 
JR: Joint replacement 
WOCBP: Women of childbearing potential 
LBP: Low Back Pain 
WOMAC: Western Ontario and McMaster Osteoarthritis Index 
LBPI: Low Back Pain Intensity 
WPAI-LBP: Work Productivity and Activity Impairment-Low Back Pain 
MOS Sleep-R: Medical Outcomes Study Sleep Scale Revised 
 
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Clinical Study Protocol 
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CONFIDENTIAL 
8.1.1. 
Footnotes for the Schedule of Events Table 
1. Patients who discontinue study drug before week 16 will be encouraged to follow the 
visit schedule through the remainder of the study. If a patient chooses to end study 
participation at or before week 16, he/she will be asked to return to the clinic as soon as 
possible for an early termination (ET) visit. 
2. Patients who discontinue study participation after week 16 will be asked to return to the 
clinic as soon as possible for an early termination (ET) visit following early termination 
assessments. 
 
 
 
  
4. Patients’ demographic characteristics will be recorded, including age, height, weight, 
gender, race, and ethnicity. 
5. At the request of the central reader, a lumbar spine anterior-posterior/lateral should be 
obtained if the MRI of the lumbar spine shows evidence suggestive of a destructive or 
unstable process. Confirmation from the central reader that there are no exclusionary 
findings on MRI and X-ray (if requested) must be received before a patient can be 
randomized. 
6. Patients will be trained to use the eDiary after initial patient eligibility has been 
confirmed during the screening period. Patients will use the eDiary to report their daily 
NRS LBP score (entered to week 20) and daily use of paracetamol/acetaminophen 
(entered to week 16). Retraining should occur as needed throughout the conduct of the 
study. 
7. At the screening and pre-randomization visits, study staff will review the “Reporting 
Your Pain” brochure with the patient to ensure the patient understands how to report pain 
accurately. At subsequent clinic visits, patients will be asked to review the “Reporting 
Your Pain” brochure themselves. At the screening and baseline visit, study staff will 
review with the patient the “Participating in a Research Study: What You Need to Know” 
brochure. At any time during the conduct of the study, patients may require retraining by 
study staff. 
8. Low back pain intensity NRS score will be recorded by the site at the screening visit and 
at the pre-randomization visit, and by the patient each day (at approximately 6:00 PM) 
using the eDiary, starting during the pre-randomization period and to week 20.  
9. A review of compliance with daily entry of LBPI NRS and rescue medication use will 
occur at specified study visits, as well as re-education of patients, if applicable. Patients 
will record their daily LBPI NRS score in the eDiary up to week 20 and their rescue 
medication usage up to week 16.  
10. Study drug administration will be the last procedure at each dosing visit, and will be done 
after all laboratory samples have been collected and all study assessments and procedures 
are performed, including blood draws for drug concentration and ADA.  
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11. Assessments for orthostatic hypotension may be discontinued following regulatory 
approval if the safety database does not reveal an imbalance for the fasinumab-treated 
patients.  
12. If the pulse is less than 45 bpm at any visit, an ECG with rhythm strip will be obtained 
and sent to the central reader to confirm the heart rate and rhythm. 
13. Imaging (X-ray and/or MRI) will be performed on any joint following a report of 
clinically significant worsening or exacerbation of pain in that joint. This imaging will be 
submitted to the adjudication committee for review.  
14. If screening radiographs are inconclusive for potential joint-related findings, an MRI of 
the affected joint must be performed. Confirmation from the central reader that there are 
no exclusionary findings on X-ray and MRI must be received before a patient can be 
randomized. Imaging may be performed during pre-randomization, if needed. 
15. After the patient has otherwise met study eligibility criteria assessed during the screening 
period, an MRI of any knee with screening K-L ≥3 or hip with screening K-L ≥2 must be 
performed. Confirmation from the central reader that there are no exclusionary findings 
on MRI must be received before a patient can be randomized.  
16. Imaging assessments (X-rays and MRI) need to be repeated only if it has been >30 days 
since the joints were last imaged for the modality. If it has been ≤30 days since imaging 
assessments were completed, imaging assessments may be completed at the discretion of 
the investigator. 
17. In the event that a patient must undergo JR surgery during the study, the patient will 
complete the pre-operative visit (early termination assessments, as applicable) and the 
procedures outlined in the schedule of events for JR follow-up (Table 2). The 
pre-operative visit should be completed before JR surgery if possible. Pre-operative 
images will be submitted to the adjudication committee for review.  
18. Joint replacement questionnaires are Knee Society Score questionnaire for knee 
replacements or Harris Hip Score questionnaire for hip replacements.  
19. The purpose of this phone contact is to ask the patient if he/she has had or is scheduled 
(or on a waiting list) to have JR surgery. Pre-operative images will be submitted to the 
central reader for adjudication, if available. 
20. If the AA joint(s) has undergone JR, an X-ray may be substituted for an MRI. 
21. Samples will be analyzed by the central laboratory and results will be evaluated by the 
investigator. 
22. The follicle-stimulating hormone (FSH) and estradiol laboratory tests are to be performed 
only if postmenopausal status has to be assessed for female patients who are ≤59 years of 
age. 
23. In the event of a positive urine pregnancy test result, the patient must have a serum 
pregnancy test with a negative result in order to continue study participation. If the serum 
pregnancy test is positive, the patient must be withdrawn from study drug and should be 
asked to return to the clinic for all remaining study visits per the visit schedule. 
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24. PK, ADA, and biomarker samples may also be drawn at any non-specified scheduled 
visit or any unscheduled visit if a patient experiences a treatment-related safety TEAE. 
Samples should be collected prior to study drug administration on study drug dosing 
days. 
25. Biomarker samples should be collected after the patients have been fasting overnight or 
for 8 hours (in the event of an afternoon visit). 
Table 2: 
Follow-up Period for Patients Who Undergo Joint Replacement Surgery 
 
Post-Operative  
Long-Term 
Follow-up Study Day (Visit Window)1 
Follow-up Visit 1 
4 weeks after joint replacement 
surgery 
Follow-up Visit 2 
20 weeks after joint 
replacement surgery 
Follow-up Day 29 (±7) 
Follow-up Day 140 (±7) 
Treatment: 
 
Concomitant medications and therapy 
X 
X 
Safety: 
 
Adverse events 
X 
X 
Vital signs 
X 
X 
Orthostatic blood pressure and heart rate2 
X 
X 
Physical examination with joint exam 
X 
X 
Medical history related to the joint replacement 
X 
X 
Joint pain questionnaire 
X 
X 
Post-operative questionnaire3 
X 
X 
Bilateral X-rays (shoulders, hips, knees)4 
 X5 
X 
Event-triggered imaging6 
X 
X 
8.1.2. 
Footnotes for Table 2 - Follow-up Period for Patients Who Undergo Joint 
Replacement Surgery 
1. All available information for patients who undergo JR surgery must be collected, 
including placement of the prosthesis, healing of the surgical wound, and the results of 
the histopathologic examination. 
2. If it is not possible to obtain orthostatic blood pressure following JR, then blood pressure 
and pulse should be recorded. Assessments for orthostatic hypotension may be 
discontinued following regulatory approval if the safety database does not reveal an 
imbalance for the fasinumab-treated patients. 
3. A Knee Society Score questionnaire for knee replacements or Harris Hip Score 
questionnaire for hip replacements. 
4. In the event of more than 1 JR, imaging assessments should be repeated if it has been 
>60 days since the joints were last imaged. If it has been ≤60 days since imaging 
assessments were completed, imaging assessments may be completed at the discretion of 
the investigator. An MRI may be requested by the imaging vendor after review of the X-
rays.  
5. Imaging will be done at week 4 if not done pre-operatively. 
6. Imaging may be performed on any joint following a report of clinically significant 
worsening or exacerbation of pain in that joint. 
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8.1.3. 
Early Termination Visit 
Patients who are withdrawn from study drug early should be encouraged to continue in the study 
and complete all other study assessments without receiving study drug. If a patient decides to 
completely withdraw from the study, every attempt should be made to have the patient complete 
an early termination visit (following the assessments described in Table 1). 
8.1.4. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule. Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for 
any other reason, as warranted. 
8.2. 
Study Procedures 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed to determine study eligibility or characterize the 
baseline population:  
8.2.1.1. 
Main Study Informed Consent 
All patients must sign and date the Institutional Review Board (IRB) or Ethics Committee 
(EC)-approved written informed consent form (ICF) before any study procedures are performed, 
per Section 14.2. 
 
 
 
 
 
8.2.1.3. 
Medical History 
The investigator or designee will take a complete medical history that includes information on 
concurrent medical conditions and the severity for each condition that has not resolved. This 
history will include a patient’s history of surgical procedures. 
8.2.1.4. 
Medication History 
The investigator or designee will query patients on the medication(s) they have taken for their 
LBP (medication history), including information on their ability to tolerate the medication, and 
will record the information on an electronic clinical report form ([e]CRF) for this purpose. 
8.2.1.5. 
Demographics 
Patients’ demographic characteristics will be recorded, including age, height, weight, gender, 
race, and ethnicity. Patient weight will also be recorded at designated visits during the treatment 
period and the follow-up period, as well as at early termination or pre-operative visits in the 
event of a JR surgery (Table 1).  
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8.2.1.6. 
Beck Depression Inventory – II Assessment 
The BDI-II assessment will be performed at screening as part of the determination of eligibility 
for participation in the study. Patients with a score of ≥29, indicative of severe depression, at the 
screening visit will be excluded. The BDI-II is a 21-item patient-completed questionnaire with 
each item scored on a scale of 0 to 3 (Beck, 1996). Total scores range from 0 to 63 with higher 
scores indicating worse depression. Cut-offs for severity of depression have been identified as 
follows: 0-13: minimal depression; 14-19: mild depression; 20-28: moderate depression; and 
29-63 as severe depression. 
8.2.1.7. 
Assessment of Childbearing Potential 
Each female patient will be evaluated for childbearing potential.  
Women will be considered to be of childbearing potential unless they are postmenopausal, or 
have had a tubal ligation, a bilateral oophorectomy, bilateral salpingectomy, or complete 
hysterectomy. 
For women ≥60 years of age, postmenopausal is defined as at least 12 continuous months of 
spontaneous amenorrhea. In women ≤59 years of age, postmenopausal is defined as at least 12 
continuous months of spontaneous amenorrhea, with serum FSH levels >40 IU/L (>40 mIU/mL) 
and serum estradiol levels <5 ng/dL (<184 pmol/L).  
8.2.1.8. 
Determination of Osteoarthritis 
Diagnosis of OA of the knee or hip will be based on the American College of Rheumatology 
criteria with radiologic evidence of OA (K-L score ≥2). 
In addition, diagnosis of OA of the hip and knee will use the following criteria: 
Hip 
The American College of Rheumatology clinical and radiographic criteria for the diagnosis of 
OA of the hip (Altman, 1991) should be used to confirm a diagnosis of OA of the hip, as 
applicable, at screening. The criteria consist of the following combinations: 
 Hip pain, and 
 At least 2 of the following 3 features: 
 Erythrocyte sedimentation rate (ESR) <20 mm/hour 
 Radiographic femoral or acetabular osteophytes  
 Radiographic joint space narrowing (superior, axial, and/or medial) 
Additional information is provided in the study reference manual. 
Knee 
The American College of Rheumatology clinical and radiographic criteria for the diagnosis of 
OA of the knee (Altman, 1986) should be used to confirm a diagnosis of OA of the knee, as 
applicable, at screening.  The criteria consist of the following combinations: 
 Knee pain 
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 Osteophytes on radiograph 
 At least 1 of the following 3 features: 
 Age >50 years 
 Stiffness <30 minutes 
 Crepitus 
Additional information is provided in the study reference manual. 
8.2.1.9. 
Assessment of Peripheral or Central Pain 
Patients will complete a self-reported survey to evaluate the peripheral versus central nature of 
their pain at time points indicated in Table 1. 
A copy of the survey is provided in the study reference manual. 
8.2.1.10. eDiary Training 
At the pre-randomization visit, patients will be instructed on the use of the NRS for scoring their 
LBP. Patients will be trained on the use of the eDiary to report their LBPI NRS score and their 
daily paracetamol/acetaminophen use for CLBP and other non-CLBP related reasons. Retraining 
should occur as needed throughout the conduct of the study. 
8.2.1.11. Patient Education Brochures 
The patient education brochure “Reporting Your Pain” will be used to have an interactive 
discussion with patients at both the screening and pre-randomization visits to ensure patients 
understand how to report their pain accurately (Table 1). At subsequent clinic visits, patients will 
be asked to review the “Reporting Your Pain” brochure themselves. The “Participating in a 
Research Study: What You Need to Know” brochure will also be reviewed with the patient at the 
screening visit to ensure appropriate patient expectations in participating in a clinical trial.  
8.2.2. 
Patient-Completed Assessments and Efficacy Procedures 
8.2.2.1. 
Western Ontario and McMaster Osteoarthritis Index 
The WOMAC index is used to assess patients with OA of the hip or knee using 24 parameters 
reported using a Likert scale. This index can be used to monitor the course of a disease or to 
determine effectiveness of study drugs. For this CLBP study, patients will complete the 
WOMAC Pain Subscale only using the 5 parameters of pain, at the time points indicated in 
Table 1. The WOMAC Pain Subscale scores will be performed at baseline for safety reporting in 
the event an AA is detected and for the application of study stopping criteria and as outlined in 
Table 1 in support of assessing pain relief for OA in patients who have CLBP and OA. If 
possible, the assessment should be administered and entered by the same person throughout the 
study.  
A copy of WOMAC assessments is provided in the study reference manual. 
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8.2.2.2. 
Low Back Pain Intensity Numerical Rating Scale Score 
At the screening visit and the pre-randomization visit, the investigator or designee will record the 
LBPI NRS score indicating pain over the past 24 hours based on the patients’ reports as indicated 
in Table 1. Once initial eligibility is confirmed, from the pre-randomization visit to the week 20 
study visit, LBPI NRS scores will be reported by the patient into the eDiary (Section 8.2.1.10) 
every day at approximately 6 PM.  
A copy of the assessment is provided in the study reference manual.  
8.2.2.3. 
Roland Morris Disability Questionnaire Total Score 
The RMDQ is a self-administered, validated, widely used health status measure for LBP 
(Roland, 1983). It measures pain and function using 24 items describing limitations to everyday 
life that can be caused by LPB. The score of the RMDQ is the total number of items checked (ie, 
from a minimum of 0 to a maximum of 24). Patients will complete the questionnaire at the time 
points indicated in Table 1. 
A copy of the assessment is provided in the study reference manual. 
8.2.2.4. 
Patient Global Assessment of Low Back Pain Score 
The PGA of LBP is a patient-rated assessment of their current disease state on a 5-point Likert 
scale (1 = very good; 2 = good; 3 = fair; 4 = poor; and 5 = very poor). Patients will complete the 
assessment scale at the time points indicated in Table 1. 
A copy of the assessment is provided in the study reference manual. 
8.2.2.5. 
PainDETECT Questionnaire 
Patients will complete the PainDETECT questionnaire to evaluate the neuropathic versus 
nociceptive nature of their pain at the time points indicated in Table 1. The questionnaire is 
self-administered and consists of 7 questions that address the quality of neuropathic pain 
symptoms.  The first 5 questions ask about the gradation of pain on a 6-point Likert scale (0 = 
never; 1 = hardly noticed; 2 = slightly; 3 = moderately; 4 = strongly; 5 = very strongly). Question 
6 asks about the pain course pattern (scored from -1 to 2), and question 7 asks about radiating 
pain, answered ‘yes’ or ‘no’ (scored as 0 or 2, respectively). 
A copy of the assessment is provided in the study reference manual. 
8.2.2.6. 
Brief Pain Inventory Short Form 
The BPI-sf is a self-administered questionnaire (for patients to rate the severity of their pain and 
the degree to which their pain interferes with common dimensions of feeling and function. With 
a recall period of 24 hours, the questionnaire contains the front and back body diagrams, the 
4 pain severity items and 7 pain interference items rated on 0–10 scales, and the question about 
percentage of pain relief by analgesics. The BPI assesses pain at its “worst,” “least,” “average,” 
and “now” (current pain). The BPI pain interference is typically scored as the mean of the 
7 interference items. Patients will complete the questionnaire at the time points indicated in 
Table 1. 
A copy of the assessment is provided in the study reference manual. 
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8.2.2.7. 
Medical Outcomes Study Sleep Scale Revised 
The MOS Sleep-R is a brief, self-administered assessment designed to measure key aspects of 
sleep (Maurish, 2012). With a 4-week recall period, the MOS Sleep-R has 12-items with 
5 response options, and yields scores on 6 sub-scales, each consisting of 1 to 4 items: sleep 
disturbance, sleep quantity, sleep adequacy, somnolence, shortness of breath or headache, and 
snoring; and 2 global indices reflecting a respondent's overall sleep quality across multiple 
domains of sleep outcomes: Sleep Problem Index I and Sleep Problem Index II. Lower scale 
scores indicate worse sleep problems. Patients will complete the questionnaire at time points 
indicated in Table 1. 
A copy of the assessment is provided in the study manual. 
8.2.2.8. 
Short Form-36 Health Survey 
The SF-36 Health Survey version 2 standard is a health status measure with a 4-week recall 
period (Ware, 1992) (Ware, 1993). The SF-36 measures 8 concepts: physical functioning, role 
limitations due to physical health, bodily pain, general health perceptions, vitality, social 
functioning, role limitations due to emotional problems, and general mental health. Two 
summary measures of physical and mental health are constructed from the 8 scales. Patients will 
complete the questionnaire at time points indicated in Table 1. Higher scores on the scales and 
summary measures indicate better health status. 
A copy of the assessment is provided in the study reference manual. 
8.2.2.9. 
Patient Health Questionnaire 8-Item Version 
The Patient Health Questionnaire 8-Item Version (PHQ-8) is a standardized patient-reported 
measure of depression symptoms (Kroenke, 2001). It has 8 questions containing mood, anxiety, 
alcohol, eating, and somatoform modules. With a recall period of 2 weeks, depression severity is 
calculated by assigning scores of 0, 1, 2, and 3, to the response categories of “not at all,” “several 
days,” “more than half the days,” and “nearly every day,” respectively. The PHQ-8 total score 
for the 8 items ranges from 0 to 24, with scores of 5, 10, 15, and 20 representing cut-off points 
for mild, moderate, moderately severe and severe depression, respectively. Patients will 
complete the questionnaire at time points indicated in Table 1. 
A copy of the assessment is provided in the study reference manual. 
8.2.2.10. EuroQoL 5 Dimensions 5 Level Questionnaire 
The EQ-5D-5L is a standardized measure of health status developed by the EuroQoL Group to 
provide a simple, generic measure of health for clinical and economic appraisal. The EQ-5D-5L, 
as a measure of health-related quality of life, defines health in terms of 5 dimensions: mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression.  
Each dimension has 5 ordinal levels of severity: “no problems” (1), “slight problems” (2), 
“moderate problems” (3), “severe problems” (4), and “unable to” (5). Overall health state is 
defined as a 5-digit number. Health states defined by the 5-dimensional classification can be 
converted into corresponding index scores that quantify health status, which ranges from <0 for 
states worse than dead to 1 (full health), anchoring dead at 0. Patients will complete the 
questionnaire at time points indicated in Table 1. 
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A copy of the assessment is provided in the study reference manual.  
8.2.2.11. Work Productivity and Activity Impairment - Low Back Pain 
The WPAI-LBP is a validated measure of impairments in work and daily activities (Reilly, 1993) 
(Zhang, 2010). This assessment will be administered according to time points in Table 1. 
A copy of the assessment is provided in the study reference manual.  
8.2.2.12. Healthcare Resource Utilization Questionnaire 
The HRCU questionnaire is a tool designed to capture, over a preceding 8-week period, 
healthcare utilization events that are not collected as part of the safety assessments in the current 
study. Examples of these types of events include a patient's use of walking aid, emergency room 
visits, and physician office visits. Patients will complete the questionnaire at time points 
indicated in Table 1. Overall healthcare resource use will be computed based on responses to the 
HCRU questionnaire, as well as any hospital visits that are captured in the safety database.  
A copy of the assessment is provided in the study reference manual. 
8.2.2.13. Treatment Satisfaction Questionnaire for Medication  
The TSQM is a standardized instrument to assess patients' satisfaction with medication 
(Atkinson, 2004). The questionnaire provides scores on 4 domains – side effects, effectiveness, 
convenience, and global satisfaction. The TSMQ will be administered according to time points in 
Table 1. 
A copy of the assessment is provided in the study reference manual. 
8.2.3. 
Safety Procedures 
8.2.3.1. 
Weight 
Patient weight will be recorded at screening and at designated visits during the treatment period 
and the follow-up period, as well as at an early termination or pre-operative visit in the event of a 
JR surgery (Table 1). 
8.2.3.2. 
Vital Signs 
Vital signs, including body temperature and respiration, will be collected pre-dose at time points 
according to Table 1. Blood pressure and heart rate will be collected as part of the orthostatic 
hypotension assessments. If at any visit after the randomization visit the pulse is less than 45 
bpm, an ECG with rhythm strip will be obtained to confirm the heart rate and rhythm. 
8.2.3.3. 
Physical Examination 
A thorough and complete physical examination will be performed at time points according to 
Table 1. Care should be taken to examine and assess any abnormalities that may be present, as 
indicated by the patient’s medical history.  
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8.2.3.4. 
Joint Pain Questionnaire 
A joint pain questionnaire will be completed by the patient at the time points indicated in 
Table 1. For each knee, hip, and shoulder joint, the patient will be prompted to indicate if he or 
she has experienced pain. A patient report of having experienced pain will serve as a tool to 
prompt further evaluations as deemed necessary by the investigator. 
A copy of the survey is provided in the study reference manual. 
8.2.3.5. 
Survey of Autonomic Symptoms 
Signs and symptoms of autonomic dysfunction will be assessed by the investigator at time points 
indicated in Table 1. If possible, the assessment should be completed by the same person 
throughout the study. A patient report of having experienced symptoms that may be consistent 
with autonomic dysfunction will serve as a tool to prompt further evaluations as deemed 
necessary by the investigator. 
A copy of the survey is provided in the study reference manual. 
8.2.3.6. 
Neurologic Examination 
A full or a brief neurological examination will be performed at the time points indicated in 
Table 1. Neurological findings at baseline that are not exclusionary should be recorded in the 
medical history. Findings at subsequent visits will be assessed by the investigator to determine if 
these should be recorded as an AE.  
The neurological examination will cover the following domains:  motor, sensory, cranial nerves, 
reflexes, and coordination/balance, and assessment for presence/absence of signs of carpal tunnel 
syndrome. 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. The investigator may refer 
patients with persistent or worsening neurologic symptoms for a neurologic consultation, if 
clinically indicated. Additional neurologic assessments will include nerve conduction studies and 
other tests as deemed clinically necessary in the judgement of the neurologist. 
Complete guidance on how to conduct the full and the brief neurologic examination is provided 
in the study reference manual. 
8.2.3.7. 
Imaging 
Radiographs of the large joints (knees, hips, and shoulders) will be taken using a standard 
approach at the time points indicated in Table 1. Magnetic resonance imaging will be performed 
on any knee with K-L ≥3 and any hip with K-L ≥2 at screening. Radiographs and/or an MRI 
must be performed on any joint following a report of clinically significant worsening or 
exacerbation of pain in that joint. An X˗ray and an MRI should also be performed 
pre-operatively if a patient is to have a JR during the study. Event-based and pre-operative 
images will be submitted for adjudication. Detailed procedures will be available in a separate 
manual provided by the central imaging center. Radiograph or MRI will be sent to a central 
reader, where the images will be digitized. 
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Radiographs 
Weight-bearing (standing) posterior-anterior radiographs of both knees in the semi-flexed 
position, and anterior-posterior radiographs of both hips and both shoulders, will be conducted at 
these visits. Additional instructions for positioning of joints are provided in the study reference 
manual. 
Radiographs of the knees, hips, and shoulders will be sent to a central reader and evaluated to 
confirm no evidence of AA such as rapidly progressive osteoarthritis type 1 or 2, subchondral 
insufficiency fracture, osteonecrosis, or DA. 
MRI 
An MRI of the lumbar spine will be taken using standard acquisition sequences at the time point 
indicated in Table 1 to assess for evidence of the following: disc degeneration or herniation, disc 
signal and height loss, Modic endplate changes, bone marrow edema, central subarticular or 
foraminal stenosis, spondylolisthesis, spondylolysis, and facet joint arthropathy. If the MRI 
suggests an adjudicated or unstable spinal process, flexion/extension radiographs may be 
requested. Confirmation from the central reader that there are no exclusionary findings on MRI, 
and X-ray if applicable, must be received before a patient can be randomized. 
An MRI of any knee with K-L ≥3 and any hip with K-L ≥2 will be obtained at the time point 
indicated in Table 1. Prior to subject randomization, MRIs will be sent to a central reader and 
evaluated to confirm no evidence of adjudicated arthropathy or other exclusionary features. 
Confirmation from the central reader that there are no exclusionary findings on MRI must be 
received before a patient can be randomized. Additionally, an MRI of any joint will be 
considered if radiographs taken after randomization suggest the presence of an abnormal process 
inconsistent with normal progression of OA, as determined by the investigator or central reader. 
At the end of study phone contact, patients who had a confirmed AA during the study will have 
an MRI performed of the AA joint(s). If the AA joint has undergone JR an X-ray may be 
substituted for an MRI. 
Refer to the supplemental imaging manuals for data collection and management procedures. 
8.2.3.8. 
Assessment of Orthostatic Blood Pressure and Heart Rate 
An assessment of orthostatic blood pressure will be conducted at the time points indicated in 
Table 1. The assessments should be conducted as per the instructions in the study manual. A 
patient will be determined to have orthostatic hypotension if any of the following criteria are 
met: 
If the supine systolic blood pressure is <160 mmHg, a decrease in either the 1 or 3 minute 
standing systolic blood pressure of ≥20 mmHg or a decrease in the standing diastolic blood 
pressure of ≥10 mmHg from the supine systolic or diastolic blood pressure, respectively 
OR 
If the supine systolic blood pressure is ≥160 mmHg, a decrease in either the 1 or 3 minute 
standing systolic blood pressure of ≥30 mmHg or a decrease in the standing diastolic blood 
pressure of ≥15 mmHg from the supine systolic or diastolic blood pressure, respectively 
OR 
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An increase in either the 1 or 3 minute standing heart rate of ≥30 bpm from the supine heart rate 
OR 
The patient is unable to stand for either one of the standing blood pressure measurements due to 
dizziness or lightheadedness 
If the initial assessment for orthostatic hypotension is consistent with the above definition, the 
supine and standing blood pressures and/or pulse should be repeated as outlined above, up to 
2 more times. 
8.2.3.9. 
Electrocardiogram 
A standard 12-lead ECG will be performed at the time points indicated in Table 1, with the 
patient in the supine position for approximately 5 minutes and prior to blood samples being 
drawn. Heart rate will be recorded from the ventricular rate, and the PR, QRS, and the QT and 
QTc intervals will be recorded. The ECG data will be read by a central reading center. Detailed 
procedures will be provided in a separate manual provided by the central reading center. 
8.2.3.10. End of Study Phone Contact and Additional Imaging 
An end of study phone contact will be conducted approximately 52 weeks following the last dose 
of study drug. Patients will be asked whether they underwent JR surgery following the last 
in-clinic visit of the follow-up period or whether they are scheduled (or on a waiting list) for JR 
surgery. In addition, any serious adverse events (SAEs) reported by the patient during the post 
follow-up period (from week 36 to the end of study phone contact) and considered related to 
study drug by the investigator should also be collected. Patients who had JR surgery will also be 
asked to submit pre-operative imaging (X-ray and MRI, if available) for adjudication.  
Additionally, patients who had a confirmed AA prior to week 36 will have an MRI performed of 
the affected joint(s). If the affected joint has undergone JR, an X-ray may be substituted for an 
MRI. 
8.2.3.11. Procedures to be Performed Only in the Event of a Joint Replacement Surgery 
In the event that a patient must undergo JR surgery during the treatment or follow-up periods, 
he/she will be discontinued from study drug and asked to return for a pre-operative visit 
(Table 1), and for follow-up safety evaluations at 4 weeks and 20 weeks after surgery (Table 2).  
In the event that the pre-operative visit is not performed, standard-of-care pre-operative images 
of the joint with JR must be obtained and submitted to the central imaging vendor's adjudication 
committee for review. Imaging of all other joints per the pre-operative visit procedures will be 
done post-operatively at the first JR follow-up study visit (4 weeks after surgery) if not done 
before surgery. 
All available medical history/information for patients who undergo JR surgery must be collected, 
including the results of histopathologic examination. 
Full details of these assessments are provided in the study reference manual. 
Knee Society Score 
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The Knee Society Score is an investigator-completed questionnaire that is used to objectively 
measure a patient’s ability to function before and after total knee arthroplasty (Insall, 1989).  If 
possible, the assessment should be completed by the same person throughout the study. 
Harris Hip Score 
The Harris Hip Score is an investigator-completed questionnaire that is used to objectively 
measure a patient’s ability to function before and after total hip arthroplasty (Harris, 1969).  If 
possible, the assessment should be completed by the same person throughout the study. 
8.2.3.12. Laboratory Testing  
The central laboratory will analyze all screening and on-study laboratory samples for blood 
chemistry, hematology, HbA1c, urine analysis, and serum pregnancy tests. Urine pregnancy 
testing will be done at the site using kits provided by the central laboratory.  
Regeneron or its designee will be responsible for fasinumab PK, anti-fasinumab antibody, 
biomarker assessments, and pharmacogenetic sample assessments. The central laboratory will 
ship the samples to Regeneron or a specialty laboratory depending on the assessment.  
All samples will be collected before study drug administration. Missed tests should be reported 
in the source documents and in the eCRF, as appropriate. Central laboratory kits will be provided 
for sample collection and shipment. Detailed instructions for blood sample collection are in the 
laboratory manual provided to study sites. 
Samples for laboratory testing will be collected at visits according to Table 1. Tests will include: 
Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin 
Potassium 
Creatinine 
Phosphorus 
Chloride 
Blood urea nitrogen 
Uric acid 
Carbon dioxide 
Aspartate aminotransferase (AST) 
Creatine phosphokinase 
Calcium 
Alanine aminotransferase (ALT) 
 
Glucose 
Alkaline phosphatase 
 
Albumin 
Lactate dehydrogenase 
 
Hematology 
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
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Urinalysis 
Color 
Glucose 
RBC 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBC 
Yeast 
Urine Electrolytes 
Creatinine 
 
 
Phosphorus 
 
 
Other Laboratory Tests 
Serum and urine samples for pregnancy testing will be collected from WOCBP (as defined in 
Section 8.2.1.7) at time points according to Table 1. At dosing study visits, urine pregnancy 
testing will be done before the study drug is administered. In the event of a positive urine 
pregnancy test result, the patient should have a serum pregnancy test with a negative result in 
order to continue study participation. If the serum pregnancy test is positive, the patient should 
be withdrawn from study drug and should be asked to return to the clinic for all remaining study 
visits per the visit schedule (Table 1).  
To assess postmenopausal status for women ≤59 years of age, serum samples to test for FSH 
levels and estradiol levels will be collected for analysis at the central laboratory according to 
Section 8.2.1.7.  
Samples will be collected for HbA1c and ESR testing at time points according to Table 1. 
Blood samples for study drug PK and ADA assessment (Section 8.2.4) will also be collected. 
Abnormal Laboratory Values and Laboratory Adverse Events 
All laboratory values must be reviewed by the investigator or authorized designee. 
Significantly abnormal 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 monitor must be 
consulted. 
The clinical significance of an abnormal test value, within the context of the disease under study, 
must be determined by the investigator. 
Criteria for reporting laboratory values as an AE are provided in Section 9.4.5. 
8.2.3.13. Injection Site Evaluations 
An injection site evaluation should be conducted following the injection at each dosing visit, 
according to Table 1. 
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8.2.4. 
Pharmacokinetic and Anti-Drug Antibody Procedures 
8.2.4.1. 
Drug Concentration Measurements and Samples 
Samples for drug concentration will be collected at time points listed in Table 1. Detailed 
instructions for blood sample collection are included in the laboratory manual provided to study 
sites. 
Any unused samples may be used for exploratory biomarker research. 
8.2.4.2. 
Anti-Drug Antibody Measurements and Samples 
Samples for ADA assessment will be collected at time points listed in Table 1. Detailed 
instructions for blood sample collection are included in the laboratory manual provided to study 
sites. 
Any unused samples may be used for exploratory biomarker research. 
8.2.5. 
Research Samples 
8.2.5.1. 
Biomarker Serum and Biomarker Plasma Samples 
Serum and plasma samples will be collected at time points according to Table 1. These samples 
should be collected after the patients have been fasting overnight or for 8 hours (in the event of 
an afternoon visit) and prior to the administration of study drug. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
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9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
9.1. 
Obligations of Investigator 
The investigator must promptly report to the IRB or EC all unanticipated problems involving 
risks to patients, according to local regulations. This includes death from any cause and all SAEs 
related to the use of the study drug.  It is recommended that all SAEs be reported to the IRB or 
EC, regardless of assessed causality, 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 (SUSAR), to the health 
authorities, IRBs or ECs as appropriate, and to the investigators (in a blind manner).  
Any AE not listed as an expected event in the Reference Safety Information section of the 
Investigator’s Brochure or in this protocol will be considered unexpected. Any worsening of or 
new onset of symptoms related to CLBP 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 SAEs that are expected and at 
least reasonably related to the study drug to the health authorities, according to local regulations. 
At the completion of the study, the sponsor will report all safety observations made during the 
conduct of the trial in the clinical study report to health authorities and IRBs or ECs as 
appropriate. 
9.3. 
Definitions 
9.3.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug that 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 that is temporally 
associated with the use of a study drug, whether or not considered related to the study drug. 
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An AE also includes any worsening (ie, any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug. 
9.3.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death – includes all deaths, even those that appear to be completely 
unrelated to study drug (eg, a car accident in which a patient is a passenger). 
 Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event. This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
 Requires in-patient hospitalization or prolongation of existing hospitalization. 
In-patient hospitalization is defined as admission to a hospital or an emergency room 
for longer than 24 hours. Prolongation of existing hospitalization is defined as a 
hospital stay that is longer than was originally anticipated for the event, or is 
prolonged due to the development of a new AE as determined by the investigator or 
treating physician. 
 Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions). 
 Is a congenital anomaly/birth defect 
 Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent 1 of the other serious outcomes listed above (eg, 
intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development 
of drug dependency or drug abuse). 
9.3.3. 
Adverse Events of Special Interest 
An AESI (serious or non-serious) is one of scientific and medical concern specific to the 
sponsor’s product or program, for which ongoing monitoring and rapid communication by the 
investigator to the sponsor can be appropriate. Such an event might warrant further investigation 
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). 
9.4. 
Recording and Reporting Adverse Events 
9.4.1. 
Adverse Events 
The investigator (or designee) will record all AEs that occur from the time the informed consent 
is signed until the end of the follow-up period (week 36). Refer to the study reference manual for 
the procedures to be followed.  
Information on follow-up for AEs is provided in Section 9.4.6. Laboratory, vital signs, or ECG 
abnormalities are to be recorded as AEs as outlined in Section 9.4.5. 
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9.4.2. 
Serious Adverse Events 
All SAEs, regardless of assessment of causal relationship to study drug, must be reported to the 
sponsor (or designee) within 24 hours. Refer to the study reference manual for the procedure to 
be followed.  
Information not available at the time of the initial report must be documented in a follow-up 
report. Substantiating data such as relevant hospital or medical records and diagnostic test reports 
may also be requested. 
In the event the investigator is informed of an SAE after the patient completes the follow-up 
period (week 36)/early termination visit, the following will apply: 
 SAE with an onset within 30 days of the end of the follow-up period (week 36)/early 
termination visit - the SAE will be reported to the sponsor. The investigator should 
make every effort to obtain follow-up information on the outcome until the event is 
considered chronic and/or stable.  
 SAE with an onset day greater than 30 days from the end of the follow-up period 
(week 36)/early termination visit - only SAEs deemed by the investigator to be 
drug-related will be reported to the sponsor. The investigator should make every 
effort to obtain follow-up information on the outcome of a drug-related SAE until the 
event is considered chronic and/or stable.  
 SAE reported by the patient at the end of study phone contact 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 20 weeks of the last dose of study drug. Any 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 AESI, serious and non-serious, must be reported within 
24 hours of identification using the same reporting process as for SAE reporting, per 
Section 9.4.2. Adverse events of special interest for this study include the following: 
 Adjudicated arthropathy (as confirmed by adjudication)  
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 Joint replacement surgery (refer to Section 9.6.1.4 for when to report as an 
AESI) 
 Sympathetic nervous system dysfunction (as diagnosed after consultation with 
an appropriate specialist, such as a neurologist and/or cardiologist) 
 Peripheral sensory AEs that require a neurology consultation 
Refer to the study manual for the procedures to be followed. 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study 
All AEs that lead to a patient’s withdrawal from the study must be reported to the sponsor’s 
Medical/Study Director within 30 days. 
Refer to the study reference manual for the procedures to be followed. 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results 
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE include: 
 the test result is associated with accompanying symptoms, and/or 
 the test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
 the test result leads to a change in dosing (outside of protocol-stipulated dose 
adjustments), discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy 
Contact the Medical/Study Director in the event that the investigator feels that an abnormal test 
finding should be reported as an AE, although it does not meet any of the above criteria. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an 
AE. Any abnormal test result that is determined to be an error does not require reporting as an 
AE. 
Evaluation of severity of laboratory abnormalities will be assessed according to the scale 
outlined in Section 9.5.1. 
9.4.6. 
Follow-up 
Adverse event information will be collected until the patient’s last study visit. 
Serious adverse event information will be collected until the event is considered chronic and/or 
stable. 
9.5. 
Evaluation of Severity and Causality 
9.5.1. 
Evaluation of Severity 
The severity of AEs will be graded according to the following scale: 
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 Mild: Does not interfere in a significant manner with the patient normal functioning 
level. It may be an annoyance. Prescription drugs are not ordinarily needed for relief 
of symptoms, but may be given because of personality of the patient. 
 Moderate: Produces some impairment of functioning but is not hazardous to health.  
It is uncomfortable or an embarrassment. Treatment for symptom may be needed. 
 Severe: Produces significant impairment of functioning or incapacitation and is a 
definite hazard to the subject’s health. Treatment for symptom may be given and/or 
patient hospitalized. 
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
Injection Site Reactions 
The severity of injection site reactions will be graded according to the following scale 
(semi-colon indicates “or” within description of grade): 
 Mild: Pain that does not interfere with activity; mild discomfort to touch; <5 cm of 
erythema or induration that does not interfere with activity 
 Moderate: Pain that requires repeated use of non-narcotic pain reliever >24 hours or 
interferes with activity; discomfort with movement; 5.1 cm to 10 cm erythema or 
induration or induration that interferes with activity 
 Severe: Pain that requires any use of narcotic pain reliever or that prevents daily 
activity; significant discomfort at rest; >10 cm erythema or induration; prevents daily 
activity; requires emergency room visit or hospitalization; necrosis or exfoliative 
dermatitis. 
9.5.2. 
Evaluation of Causality 
Relationship of Adverse Events to Study Drug: 
The relationship of AEs to study drug will be assessed by the "blinded" investigator, and will be 
a clinical decision based on all available information. The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by the study drug? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by 
the study drug. 
Related: 
There is a reasonable possibility that the event may have been caused by 
the study drug. 
The investigator should justify the causality assessment of each SAE. 
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A list of factors to consider when assessing the relationship of AEs to study drug is provided 
below: 
Relationship of Adverse Events to Injection Procedure or Study Procedure: 
The relationship of AEs to injection procedure or study procedure 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 injection procedure or 
study procedure? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by the 
injection procedure or study procedure. 
Related: 
There is a reasonable possibility that the event may have been caused by the 
injection procedure or study procedure. 
The sponsor will request information to justify the causality assessment of SAEs, as needed. 
A list of factors to consider when assessing the relationship of AEs to injection procedure or 
study procedure is provided below. 
Factors to Consider in Assessing the Relationship of AEs to Study Drug, Injection Procedure, 
or Study Procedure: 
Is there a reasonable possibility that the event may have been caused by the study drug, injection 
procedure, or study procedure? 
No: 
 due to external causes such as environmental factors or other treatment(s) being 
administered 
 due to the patient’s disease state or clinical condition 
 do not follow a reasonable temporal sequence following the time of administration of 
the dose of study drug or injection procedure, study procedure, or background 
treatment, etc. 
 do not reappear or worsen when dosing with study drug or injection procedure, study 
procedure, or background treatment, etc. is resumed 
 are not a suspected response to the study drug or injection procedure, study 
procedure, or background treatment, etc. 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 
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 follow a reasonable temporal sequence following the time of administration of the 
dose of study drug or injection procedure, study procedure, or background treatment, 
etc. 
 resolve or improve after discontinuation of study drug or injection procedure, study 
procedure, or background treatment, etc. 
 reappear or worsen when dosing with study drug or injection procedure, study 
procedure, or background treatment, etc. is resumed 
 are known or suspected to be a response to the study drug or injection procedure, 
study procedure, or background treatment, etc. based upon preclinical data or prior 
clinical data 
NOTE: This list is not exhaustive. 
9.6. 
Safety Monitoring 
The investigator will monitor the safety of study patient at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP). Any questions or 
concerns should be discussed with the sponsor in a timely fashion. The sponsor will monitor the 
safety data from across all study sites. The medical monitor will have primary responsibility for 
the emerging safety profile of the compound, but will be supported by other departments (eg, 
Pharmacovigilance and Risk Management; Biostatistics and Data Management). Safety 
monitoring will be performed on an ongoing basis (eg, individual review of SAEs) and on a 
periodic cumulative aggregate basis. 
9.6.1. 
Monitoring Adverse Events of Special Interest 
9.6.1.1. 
Adjudicated Arthropathy 
Adjudicated arthropathy is an umbrella term that encompasses the following conditions:  
 Rapidly progressive OA type 1 and 2 
 Subchondral insufficiency fractures 
 Osteonecrosis 
 Destructive arthropathy 
Potential events of AA will be monitored via clinical signs and symptoms of worsening joint 
pain during the course of the study (eg, by applying adverse experiences, the joint pain 
questionnaire and imaging), as well as scheduled imaging and pre-operative imaging, if a patient 
requires a JR during the study.  
Clinically significant worsening of joint pain during the course of this study is defined as a 
worsening of pain in any joint that occurs in spite of treatment with analgesics, is in the opinion 
of the investigator inconsistent with the normal fluctuation of pain or progression of OA, and is 
at least 2 weeks duration (or less than 2 weeks if deemed clinically significant at the discretion of 
the investigator). 
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If a patient reports an increase in pain as described above, study drug administration will be 
withheld while imaging of the affected joint, as well as any additional imaging deemed 
appropriate to understand the cause of the worsening pain, is performed (Section 8.2.3.7). A 
decision to perform imaging after patient reported worsening of joint pain will be documented in 
the respective CRF page. Images, along with any other radiographic evaluation, will be 
submitted to the adjudication committee for review (Section 5.3.2). The investigator may 
consider aspiration of synovial fluid for further analysis such as cell count and crystal analysis. 
If routine imaging suggests the presence of 1 of the types of AA, study drug administration will 
be withheld. Any additional imaging deemed appropriate will be obtained. The images, along 
with results of any other radiographic evaluation, will be submitted to the Adjudication 
Committee for review (Section 5.3.2). 
If the adjudication does not confirm the presence of AA, according to the adjudication criteria, 
study drug may be restarted.  
Study drug dosing will be permanently discontinued for patients with findings that suggest AA; 
the patients will be referred for orthopedic consultation. If presence of AA is confirmed by the 
Adjudication Committee, the case must be reported as an AESI (Section 9.3.3, Section 9.4.3).  
Any patient whose study drug is discontinued due to an AA should be encouraged to return to 
the clinic for all remaining study visits. If JR surgery is warranted, prior to the scheduled JR, the 
patient should complete the pre-operative study visit and, after the JR, should complete the week 
4 and week 20 post-operative study visits (Section 8.2.3.5, Table 1). Pre-operative images, along 
with any other radiographic evaluation will be submitted to the Adjudication Committee for 
review (Section 5.3.2). 
Details of data collection for adjudication of events will be provided in the adjudication charter. 
9.6.1.2. 
Sympathetic Nervous System Dysfunction 
Sympathetic nervous system dysfunction will be monitored throughout the study through 
physical examination, AE reporting, assessment of orthostatic hypotension, and the Survey of 
Autonomic Symptoms (Section 8.2.2.5). New onset or worsening of signs and symptoms of 
autonomic dysfunction will be evaluated by the investigator. Sympathetic nervous system 
dysfunction will only be diagnosed after consultation with an appropriate specialist, such as a 
neurologist and/or cardiologist. 
In cases in which new or worsening symptoms consistent with SNS dysfunction are 
moderate-to-severe or are clinically significant and do not resolve or return to baseline in 2 
weeks (or less at the discretion of the investigator), study drug will be withheld and the patient 
will be referred to a specialist. If the evaluation by the appropriate specialist does not suggest 
SNS dysfunction, study drug may be restarted. If the specialist’s evaluation does reveal SNS 
dysfunction then study drug will be permanently discontinued and the case will be reported as an 
AESI (Section 9.4.3). 
Orthostatic hypotension may be a manifestation of SNS dysfunction. If a patient is determined to 
have orthostatic hypotension, study drug should be withheld and the AE should be entered in the 
CRF. The following procedures should be followed: 
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 If the patient is symptomatic and a clinical explanation for orthostatic hypotension is 
identified (such as a new medication or dehydration due to exercise or illness or 
excessive heat exposure), study drug will be withheld, and the patient should return to 
the study site for an unscheduled visit in 1 to 10 days for an unscheduled assessment 
of orthostatic hypotension.  
 If the orthostatic hypotension has resolved, study drug may be restarted. 
 If the orthostatic hypotension has not resolved, then study drug will be withheld, 
and the patient will be referred to a specialist (neurologist or a cardiologist) for 
evaluation of SNS dysfunction.  
 If the specialist’s evaluation does not reveal new onset SNS dysfunction, 
including symptoms of bradycardia (lightheadedness), orthostatic hypotension 
(lightheadedness on standing), syncope, absence of sweating in conditions 
where sweating would be expected, or if the specialist’s evaluation identifies 
an alternative cause, such as initiation of a new medication known to cause 
orthostasis, then study drug may be given at the next visit. 
 If the specialist’s evaluation does reveal SNS dysfunction, then study drug 
will be permanently discontinued and the case reported as an AESI 
(Section 9.4.3). 
 If the patient has asymptomatic orthostatic hypotension, study drug will be withheld, 
and the patient should return to the study site for an unscheduled visit in 1 to 10 days 
for an unscheduled assessment of orthostatic hypotension. 
 If the unscheduled assessment does not reveal orthostatic hypotension then study 
drug may be continued. 
 If the unscheduled assessment demonstrates orthostatic hypotension then study 
drug will continue to be withheld until the patient has been evaluated by a 
specialist (neurologist or a cardiologist) for evidence of SNS dysfunction. 
 If the specialist’s evaluation does not reveal new SNS dysfunction including 
symptoms 
of 
bradycardia 
(lightheadedness), 
orthostatic 
hypotension 
(lightheadedness on standing), syncope, absence of sweating in conditions 
where sweating would be expected, or if the specialist’s evaluation identifies 
an alternative cause such as initiation of a new medication known to cause 
orthostasis, then study drug may be restarted. 
 If the specialist’s evaluation does reveal SNS dysfunction then study drug will 
be permanently discontinued and the case reported as an AESI (Section 9.4.3). 
9.6.1.3. 
Peripheral Sensory Adverse Events 
Altered peripheral sensation (eg, paraesthesia and hypoaesthesia) is an important identified risk 
with fasinumab (see Investigator’s Brochure) and other anti-NGF compounds. Any peripheral 
sensory AE that, per the investigator’s judgment, requires a neurology consultation must be 
reported as an AESI. If any peripheral sensory event persists for 2 months the patient must be 
referred for a neurology consultation and the event must be reported as an AESI.  
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9.6.1.4. 
Joint Replacement Surgery 
Any elective JR surgery planned before completion of the ICF would be part of the exclusion 
criteria and would not be considered an AE. 
After signing of the ICF, report JR surgery as an AESI if the JR surgery is an elective event that 
is not associated with a new/worsening AE. 
Do not report JR surgery as an AE/AESI if the JR surgery is for the treatment of a new or 
worsening AE. In this case, the new or worsening AE should be the reported AE/AESI term. 
An end of study phone contact will be conducted approximately 52 weeks following the last dose 
of study drug to evaluate the number of patients who have undergone or are scheduled for JR 
surgery as described in Section 8.2.3.10. 
9.7. 
Investigator Alert Notification 
Regeneron (or designee) will inform all investigators participating in this clinical trial, as well as 
in any other clinical trial using the same investigational drug, of any SAE that meets the relevant 
requirements for expedited reporting (an AE that is serious, unexpected based on the 
Investigator’s Brochure or this protocol, and has a reasonable suspected causal relationship to the 
medicinal/study drug). 
10. 
STATISTICAL PLAN 
This section provides the basis for the SAP for the study. The SAP may be revised during the 
study to accommodate amendments to the clinical study protocol and to make changes to adapt 
to unexpected issues in study execution and data that may affect the planned analyses. The final 
SAP will be issued before the database is locked. 
Analysis variables are listed in Section 4. 
10.1. 
Statistical Hypothesis 
The primary endpoint in the study is the change from baseline to week 16 in the average daily 
LBPI NRS score. The following hypothesis will be tested: 
H01: There is no treatment difference between fasinumab 3mg Q4W and placebo in the 
change from baseline to week 16 in the average daily LBPI NRS score. 
The secondary null hypotheses of interest are: 
H02: There is no treatment difference between fasinumab 3mg Q4W and placebo in the 
change from baseline to week 16 in the RMDQ total score  
H03: There is no treatment difference between fasinumab 3mg Q4W and placebo in the 
change from baseline to week 16 in the PGA LBP score  
H04: There is no treatment difference between fasinumab 3mg Q4W and placebo in the 
change from baseline to week 16 in the BPI-sf.  
Fixed sequence hierarchical testing will be applied to maintain the study wise Type-I error rate at 
the 2 sided 0.05 level for the primary and key secondary endpoints. Secondary endpoints will 
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only be tested if the primary endpoint is statistically significant in favor of fasinumab. Details 
will be provided a priori in the SAP.  
10.2. 
Justification of Sample Size 
Approximately 1020 patients will be randomized in a 1:1 ratio to either fasinumab (3mg Q4W) 
or placebo. Assuming a 2-sided alpha level of 0.05 and a 20% dropout rate at week 16, an 
enrolment of 510 patients per arm will provide 90% power to detect an effect size of 0.23 in the 
daily average LBPI NRS score (ie, an absolute treatment difference of 0.5 between fasinumab 
3mg Q4W and placebo with an associated standard deviation [SD] of 2.2). This sample size also 
provides at least 99% power to detect an effect size of 0.42 (absolute treatment difference of 2.2 
with an associated SD of 5.2) in the RMDQ total score and 0.44 (absolute treatment difference of 
0.4 with an associated SD of 0.9) in the PGA at week 16. The sample size assumptions are based 
on results of the R475-PN-1524 study data on file at Regeneron. 
10.3. 
Analysis Sets 
10.3.1. 
Efficacy Analysis Sets 
The full analysis set (FAS) includes all randomized patients, and is based on the treatment 
allocated (as randomized). Efficacy endpoints will be analyzed using the FAS. 
10.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized patients who received any study drug. 
Patients randomized to placebo who receive fasinumab at least once will be classified to the 
fasinumab treatment arm. Treatment compliance/administration and all clinical 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 16-week 
treatment period and who do not have any major protocol deviations through week 16 leading to 
exclusion from the per-protocol set. The PPS will be used to perform sensitivity analysis for the 
primary and selected secondary endpoints.  
10.3.4. 
Pharmacokinetic Analysis Set 
The PK population includes all treated patients who received any study drug and who had a 
non-missing result for drug concentration following the first dose of study drug. 
10.3.5. 
Anti-Drug Anti-Body Analysis set 
The ADA population includes all patients who had received any study drug or placebo (safety 
population) and 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, 
Q1, Q3, and maximum.  
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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 
 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 
Demographic and baseline characteristics, including medical history and exposure to study drug 
will be summarized descriptively by treatment group, and by all patients combined.  
10.4.3. 
Efficacy Analyses 
10.4.3.1. Primary Efficacy Analysis 
The primary efficacy variables will be analyzed using multiple imputation approach with 
mixed-effect model for repeated measure (MMRM) based on the FAS with adjustment for 
missing data due to lack of efficacy or adverse events assuming the LBPI NRS scores would on 
average return to baseline values. The imputed data for patients discontinued from the study due 
to a lack of efficacy or adverse events will be centered at the mean baseline value. 
Missing data will be imputed 50 times to generate 50 complete data sets. Each imputed complete 
data set will be analyzed using the MMRM with terms for baseline score corresponding to the 
efficacy variable being analyzed, randomization strata, treatment, visit, and treatment-by-visit 
interaction. The fitting of MMRM will be performed using the MIXED procedure in Statistical 
Analysis System (SAS) with an unstructured covariance matrix to model the within-patient 
errors. 
Denominator degrees of freedom will be estimated using Kenward-Roger’s approximation.  The 
results from the 50 analyses will be combined using Rubin’s formula (PROC MIANALYZE). 
The least-squares mean estimates for the mean change from baseline to week 16, as well as the 
differences of the estimates between fasinumab and placebo, with corresponding standard errors, 
p values and associated 95% confidence intervals, will be provided. Data from all patients, 
including data collected after discontinuing treatment up to week 16, will be used in the efficacy 
analyses according to the intent to-treat principle. Sensitivity analysis using pattern mixture 
model and tipping point approach with multiple imputation to impute missing data will be 
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performed to assess the robustness of the results due to treatment discontinuation.  Additional 
sensitivity analyses will be performed the same way for the primary and selected secondary 
endpoints using the PPS. 
10.4.3.2. Secondary Efficacy Analysis 
For analysis of continuous secondary endpoints, the analysis method will be the same as that 
used for the primary variables. For analysis of categorical variables in secondary endpoints, 
eg, proportions of patients with ≥30% reduction from baseline to week 16 in the daily average 
LBPI NRS score; the Cochran Mantel Haenszel approach stratified by the randomization strata 
will be used with missing data considered as non-response. 
10.4.4. 
Safety Analysis 
Safety data including TEAEs and treatment emergent AESIs, vital signs, physical exams, 
laboratory tests, ECGs, and ADA formation will be listed and summarized by treatment group. 
Thresholds for potentially clinically significant values (PCSVs) in laboratory parameters and 
vital signs will be defined by the sponsor and be in effect at the time of final SAP approval. 
The time interval to detect any AEs, including AESIs, is between the first dose of double blinded 
study drug injection and the week 36 visit. 
10.4.4.1. Adverse Events 
Definitions 
For safety variables, 3 observation periods are defined: 
 The pretreatment period is defined as the time from signing the ICF to before the first 
dose of study drug. 
 The on-treatment period is defined as the day from first dose of study drug to the day 
of the last dose of study drug (week 12) + 4 weeks.  
 The follow up period is defined as the time from the end of the on-treatment period 
(week 16) to the week 36 visit. 
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 on-treatment period. 
Analysis 
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®). Coding will be to lowest level terms. The 
verbatim text, the preferred term (PT), and the primary system organ class (SOC) will be listed. 
The focus of adverse event reporting in the clinical study report will be on TEAEs. Post 
treatment AEs and all AEs during the study will be summarized similarly as TEAEs. 
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 
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 TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
 Treatment-emergent AESIs (defined with a PT or a pre-specified grouping) 
Deaths and other SAEs will be listed and summarized by treatment group. 
Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized by treatment group. 
In addition, AESIs will be reported according to the adjudicated diagnosis.  Imaging data related 
to AA including change from baseline in joint space width will be summarized. 
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. 
10.4.4.3. Treatment Exposure 
Because of the half-life of the biologic being studied, the duration of fasinumab exposure during 
the study will be presented by treatment group and calculated as: 
(Date of last administration of study drug - date of the first study drug administration after 
randomization) + 28 
The number and percentage of patients randomized and exposed to double-blind study drug will 
be presented by specific time period for each treatment group.  The time periods of interest will 
be specified in the SAP. 
10.4.4.4. Treatment Compliance 
Overall treatment compliance is defined as the actual dose of injection compared to the 
prescribed dose of treatment during the treatment phase up to treatment discontinuation.  It is 
calculated according to the following formula: 
100* Total actual injection dose taken/Total prescribed dose. 
The total number of actual doses of fasinumab will be summarized. 
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10.4.5. 
Analysis of Drug Concentration Data 
Summaries of the mean concentrations of functional fasinumab will be presented by nominal 
time point and dose. Individual patient concentration data will be provided by actual time. Plots 
of individual concentration will be presented by actual day (linear and log scales). Plots of mean 
or median concentration of functional fasinumab will be presented by nominal time (linear and 
log scales). 
No formal statistical analysis will be performed. 
10.4.6. 
Analysis of Anti-Drug Antibody Data 
Listings of ADA positivity and titers presented by patient, time point, and dose group will be 
provided. Prevalence of treatment-emergent and treatment-boosted ADA will be assessed as 
absolute occurrence (N) and percent of patients (%), grouped by study cohorts. 
Plots of drug concentrations will be examined and the influence of ADAs on individual PK 
profiles evaluated. Assessment of impact of ADA on safety and efficacy may be provided. 
10.5. 
Additional Statistical Data Handling Conventions 
The following analysis and data conventions will be followed.  
General rules for handling missing data:  
 Rules for handling missing data for efficacy assessments will be provided in the 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 medication, except if an 
incomplete date (eg, month and year) clearly indicates that the event started prior to 
treatment. If the partial date indicates the same month or year of the intake of study 
medication date, then the start date by the study medication intake date will be 
imputed; otherwise, the missing day or month by the first day or the first month will 
be imputed.  
 No imputations for missing laboratory data, ECG data, vital sign data, or physical 
examination data will be made. 
Visit windows: 
 Assessments taken outside of protocol allowable windows will be displayed 
according to the CRF assessment recorded by the investigator. 
Unscheduled assessments: 
 Extra assessments (laboratory data or vital signs associated with non-protocol 
specified clinical visits or obtained in the course of investigating or managing AEs) 
will be included in listings, but not summaries. If more than 1 laboratory value is 
available for a given visit, the first observation will be used in summaries and all 
observations will be presented in listings. 
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10.6. 
Statistical Considerations Surrounding the Premature Termination 
of a Study 
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized.  Investigator and sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 16.1. 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
11.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study 
(including data validation, cleaning, correcting, releasing) will be maintained and stored at 
Regeneron. 
A medical coding plan will specify the processes and the dictionary used for coding. All data 
coding (eg, AEs, baseline findings, medication, medical history, surgical history) will be done 
using internationally recognized and accepted dictionaries. 
The CRF data for this study will be collected with an electronic data capture (EDC) tool, Rave 
Medidata.  
11.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
 IVRS/IWRS system – randomization, study drug supply 
 Rave Medidata EDC system – clinical data capture 
 Statistical Analysis System – statistical review and analysis 
 Argus – pharmacovigilance and clinical safety software system for the collection and 
reporting of SAEs and AESIs 
 Electronic Clinical Outcome Assessment (eCOA) systems – collect subject reported 
outcome or subject clinical assessment results 
12. 
STUDY MONITORING 
12.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, CRO monitor) will visit each site prior to enrollment of 
the first patient, and periodically during the study. 
The investigator must allow study-related monitoring, IRB or EC review, audits, and inspections 
from relevant health regulatory authorities. 
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, 
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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 investigator must keep all source documents on file with the CRF (throughout this protocol, 
CRF refers to either a paper CRF or an electronic CRF). Case report forms and source 
documents must be available at all times for inspection by authorized representatives of the 
sponsor and regulatory authorities. 
12.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic CRFs within 
the EDC system by trained site personnel. All required CRFs must be completed for each and 
every patient enrolled in the study. After review of the clinical data for each patient, the 
investigator must provide an electronic signature. A copy of each 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. 
The investigator must ensure the accuracy, completeness, and timeliness of the data reported to 
the sponsor in the CRFs.  
Corrections to the CRF will be entered in the CRF by the investigator or an authorized designee.  
All changes, including date and person performing corrections, will be available via the audit 
trail, which is part of the EDC system. For corrections made via data queries, a reason for any 
alteration must be provided. 
13. 
AUDITS AND INSPECTIONS  
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities. Should this occur, the investigator is responsible for: 
 Informing the sponsor of a planned inspection by the authorities as soon as 
notification is received, and authorizing the sponsor’s participation in the inspection 
 Providing access to all necessary facilities, study data, and documents for the 
inspection or audit 
 Communicating any information arising from inspection by the regulatory authorities 
to the sponsor immediately 
 Taking all appropriate measures requested by the sponsor to resolve the problems 
found during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, 
CRFs, medical records, correspondence, ICFs, IRB, or EC files, documentation of certification 
and quality control of supporting laboratories, and records relevant to the study maintained in 
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any supporting pharmacy facilities. Conditions of study material storage are also subject to 
inspection. In addition, representatives of the sponsor may observe the conduct of any aspect of 
the clinical study or its supporting activities both within and outside of the investigator's 
institution. 
In all instances, the confidentiality of the data must be respected. 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS 
14.1. 
Good Clinical Practice Statement 
It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable 
regulatory requirements. 
14.2. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB or EC. A copy of the IRB- or EC-approved ICF and 
documentation of approval must be provided to the sponsor before study drug will be shipped to 
the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient prior to his/her participation in the study and after the 
aims, methods, objectives, and potential hazards of the study have been explained to the patient 
in language that he/she can understand. The ICF should be signed and dated by the patient and 
by the investigator or authorized designee who reviewed the ICF with the patient. 
 Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
 Patients who can understand but who can neither write nor read will have the ICF 
read to them in presence of an impartial witness, who will sign and date the ICF to 
confirm that informed consent was given. 
The original ICF must be retained by the investigator as part of the patient’s study record, and a 
copy of the signed ICF must be given to the patient. 
If new safety information results in significant changes in the risk/benefit assessment, the ICF 
must be reviewed and updated appropriately. All study patients must be informed of the new 
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 
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on CRFs or other documents submitted to the sponsor. Documents that will not be submitted to 
the sponsor (eg, signed ICF) must be kept in strict confidence. 
The patient’s and investigator's personal data, which may be included in the sponsor database, 
will be treated in compliance with all applicable laws and regulations. The sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third 
party. 
14.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB or EC, as described in ICH guidelines for GCP, must review 
and approve: 
 The protocol, ICF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
 Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patient, in 
which case the IRB or EC should be informed as soon as possible 
 Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
In addition, the IRB or EC should be informed of any event likely to affect the safety of patients 
or the continued conduct of the clinical study. 
A copy of the IRB or EC approval letter with a current list of the IRB or EC members and their 
functions must be received by the sponsor prior to shipment of drug supplies to the investigator.  
The approval letter should include the study number and title, the documents reviewed, and the 
date of the review. 
Records of the IRB or EC review and approval of all study documents (including approval of 
ongoing studies) must be kept on file by the investigator. 
15. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an IRB- or 
EC-approved amendment. 
16. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
16.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely. Reasons may include efficacy, 
safety, or futility, among others. Should the sponsor decide to terminate the study, the 
investigator(s) will be notified in writing. 
16.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
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Investigator’s Decision 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at 
least 30 days’ notice. The final decision should be made through mutual agreement with the 
sponsor. Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing.  
Reasons may include the following, among others:  
 The investigator has received all items and information necessary to perform the 
study, but has not enrolled any patient within a reasonable period of time 
 The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable 
ICH guidelines  
 The total number of patients required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB or EC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection 
of the patients’ interests. 
17. 
STUDY DOCUMENTATION 
17.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the eCRF must be signed 
electronically by the investigator. This signed declaration accompanies each set of patient final 
eCRF that will be provided to the sponsor. 
17.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of CRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
regulatory authorities. The investigator must consult with the sponsor before discarding or 
destroying any essential study documents following study completion or discontinuation.  
Records must be destroyed in a manner that ensures confidentiality. 
If the investigator's personal situation is such that archiving can no longer be ensured, the 
investigator must inform the sponsor and the relevant records will be transferred to a mutually 
agreed-upon destination. 
18. 
DATA QUALITY ASSURANCE 
In accordance with ICH E6, the sponsor is responsible for quality assurance to ensure that the 
study is conducted and the data generated, recorded, and reported in compliance with the 
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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).  
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH 
GCP, and all applicable regulatory requirements (Section 12.1).  
All patient data collected during the study will be recorded on paper or eCRF unless the data are 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for affirming that data entries in the CRF are accurate and correct by electronically 
signing a declaration that accompanies each set of patient final CRF (Section 12.3, Section 17.1).  
Study Documentation 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF (Section 12.2).  
The investigator will retain all records and documents, including signed ICFs, pertaining to the 
conduct of this study for at least 15 years after study completion, unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor (Section 17.2).  
19. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
20. 
FINANCING AND INSURANCE  
Financing and insurance information is provided as a separate agreement. 
21. 
PUBLICATION POLICY 
The publication policy is provided as a separate agreement. 
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22. 
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CONFIDENTIAL 
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improves function in subjects with moderate to severe pain form osteoarthritis of the knee. The 
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review of studies of general patient populations. Eur Spine J 2003; 12: 149-165. 
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J, Murray C, Burstein R, Buchbinder R. The global burden of low back pain: estimates from the 
Global Burden of Disease 2010 study. Ann Rheum Dis 2014. 73: 968-974. 
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TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. 
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Insall JN, Dorr LD, Scott RD, and Scott WN. Rationale of the Knee Society clinical rating 
system. Clin Orthop Relat Res. 1989.13-14. 
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Kivitz A, Gimbel J, Bramson C et al. Efficacy and safety of tanezumab versus naproxen in the 
treatment of chronic low back pain. Pain. 2013. 154;1009–21. 
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Rheumatology (Oxford) 2010;49 Suppl 2: ii3-10. 
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the treatment of pain from osteoarthritis of the knee. N Engl J Med 2010. 363:1521-31. 
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Chronic Low Back Pain: A Clinical Practice Guideline From the American College of 
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CONFIDENTIAL 
23. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: A Phase 3, Randomized, Double-Blind, Placebo-Controlled 
Study to Evaluate the Efficacy and Safety of Fasinumab in Patients with Moderate-to-Severe 
Chronic Low Back Pain and Osteoarthritis of the Hip or 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 Institutional Review Board or 
Ethics Committee. I agree to ensure that this information will not be used for any purpose other 
than the evaluation or conduct of the clinical investigation without the prior written consent of 
the sponsor. 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
 
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CONFIDENTIAL 
Signature of Sponsor’s Responsible Officers 
(Scientific/Medical Monitor, Regulatory Representative, Clinical Study Team Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the conduct of the study. 
Study Title: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of Fasinumab in Patients with 
Moderate-to-Severe Chronic Low Back Pain and Osteoarthritis of the Hip 
or Knee 
Protocol Number: 
R475-PN-1612 
 
See appended electronic signature page 
Sponsor’s Responsible Scientific/Medical Monitor 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Representative 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Team Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
Page 85 of 85
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Signature Page for VV-RIM-00014095 v1.0
Signature Page for VV-RIM-00014095 v1.0 Approved
Approval
24-Jul-2017 19:23:15 GMT+0000
Approval
24-Jul-2017 19:44:53 GMT+0000
Approval
24-Jul-2017 20:42:45 GMT+0000
Approval
25-Jul-2017 13:37:51 GMT+0000
                                        VV-RIM-00014095-1.0 Approved - 25 Jul 2017 GMT-5:00

SAP_003.pdf: 
STATISTICAL ANALYSIS PLAN 
VERSION: FINAL 
Clinical Study Protocol Title: 
A Phase 3, Randomized, Double-Blind, 
Placebo-Controlled Study to Evaluate the Efficacy 
and Safety of Fasinumab in Patients with 
Moderate-to-Severe Chronic Low Back Pain and 
Osteoarthritis of the Hip or Knee 
Compound: 
REGN475 
Protocol Number: 
R475-PN-1612 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician (SB): 
 
Clinical Trial Manager (CTM): 
 
Medical Director (MD): 
 
Version/Date: 
1.0 / 29Nov2018 
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The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
 
See appended electronic signature page 
Study Biostatistician  
(
 
 
See appended electronic signature page 
Study Pharmacokinetics 
(
 
 
See appended electronic signature page 
Study Bioanalytical Sciences 
 
 
See appended electronic signature page 
Study Medical Director 
(
 
 
See appended electronic signature page 
Project Biostatistician 
 
 
See appended electronic signature page 
Head of BDM or designee 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................6 
1. 
OVERVIEW .................................................................................................................9 
1.1. 
Background/Rationale ..................................................................................................9 
1.2. 
Study Objectives .........................................................................................................10 
1.2.1. 
Primary Objectives .....................................................................................................10 
1.2.2. 
Secondary Objectives .................................................................................................10 
1.2.3. 
Exploratory Objectives ...............................................................................................10 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol ................................10 
1.2.5. 
Revision History for SAP Amendments .....................................................................10 
2. 
INVESTIGATION PLAN ..........................................................................................11 
2.1. 
Study Design and Randomization ..............................................................................11 
2.2. 
Sample Size and Power Considerations .....................................................................11 
2.3. 
Study Plan ...................................................................................................................11 
3. 
ANALYSIS POPULATIONS ....................................................................................13 
3.1. 
Full Analysis Set (FAS) ..............................................................................................13 
3.2. 
The Safety Analysis Set (SAF) ...................................................................................13 
3.3. 
The Pharmacokinetic (PK) Analysis Set ....................................................................13 
3.4. 
The Anti-Drug Antibody (ADA) Analysis Set ...........................................................13 
4. 
ANALYSIS VARIABLES .........................................................................................14 
4.1. 
Demographic and Baseline Characteristics ................................................................14 
4.2. 
Medical History ..........................................................................................................14 
4.3. 
Prior, Concomitant, and Prohibited Medications and Procedures ..............................15 
4.4. 
Efficacy Variables ......................................................................................................16 
4.4.1. 
Primary Efficacy Variable(s) ......................................................................................16 
4.4.2. 
Secondary Efficacy Variable(s) ..................................................................................16 
4.4.3. 
Exploratory Efficacy Variable(s) ................................................................................16 
4.5. 
Safety Variables ..........................................................................................................17 
4.5.1. 
Safety Variables ..........................................................................................................17 
4.5.2. 
Adverse Events of Special Interest .............................................................................18 
4.5.3. 
Laboratory Safety Variables .......................................................................................18 
4.5.4. 
Biomarker variables ....................................................................................................18 
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4.5.5. 
Vital Signs ..................................................................................................................18 
4.5.6. 
Orthostatic Hypotension .............................................................................................19 
4.5.7. 
12-Lead Electrocardiography .....................................................................................19 
4.5.8. 
Physical and Neurological Examination Variables ....................................................19 
4.5.9. 
Other Safety Variables ................................................................................................20 
4.6. 
Pharmacokinetic Variables .........................................................................................20 
4.7. 
Anti-Drug Antibody Variables ...................................................................................20 
5. 
STATISTICAL METHODS .......................................................................................21 
5.1. 
Demographics and Baseline Characteristics ...............................................................21 
5.2. 
Medical History ..........................................................................................................21 
5.3. 
Prior and Concomitant Medications ...........................................................................21 
5.4. 
Prohibited Medications ...............................................................................................22 
5.5. 
Patient Disposition ......................................................................................................22 
5.5.1. 
Screening Disposition .................................................................................................22 
5.5.2. 
Treatment and Study Disposition ...............................................................................22 
5.5.3. 
Analysis Set ................................................................................................................23 
5.6. 
Extent of Study Treatment Exposure and Compliance ...............................................23 
5.6.1. 
Measurement of Treatment Compliance ....................................................................23 
5.6.2. 
Exposure to Investigational Product ...........................................................................23 
5.6.3. 
Length of Study Observation ......................................................................................24 
5.7. 
Protocol Deviations ....................................................................................................24 
5.8. 
Analysis of Efficacy Data ...........................................................................................24 
5.8.1. 
Analysis of Primary Efficacy Variable(s) ...................................................................24 
5.8.2. 
Analysis of Additional Efficacy Variable(s) ..............................................................24 
5.9. 
Analysis of Safety Data ..............................................................................................25 
5.9.1. 
Safety Endpoints .........................................................................................................25 
5.9.2. 
Adverse Events ...........................................................................................................25 
5.9.3. 
Adverse Events of Special Interest .............................................................................27 
5.9.4. 
Clinical Laboratory Measurements.............................................................................27 
5.9.5. 
Analysis of Vital Signs ...............................................................................................27 
5.9.6. 
Analysis of 12-Lead ECG ...........................................................................................27 
5.9.7. 
Physical Exams ...........................................................................................................28 
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5.9.8. 
Joint Pain Questionnaire .............................................................................................28 
5.9.9. 
Arthropathy Adjudications .........................................................................................28 
5.9.10. 
Neurological Exam .....................................................................................................28 
5.9.11. 
Analysis of Pharmacokinetics and Drug Concentration Data ....................................28 
5.9.12. 
Analysis of Anti-Drug Antibody Data ........................................................................28 
6. 
DATA CONVENTIONS ............................................................................................30 
6.1. 
Definition of Baseline for Variables ...........................................................................30 
6.2. 
Data Handling Conventions for Patient reported Outcomes data ...............................30 
6.3. 
General Data Handling Conventions ..........................................................................33 
6.4. 
Visit Windows ............................................................................................................35 
6.5. 
Unscheduled Assessments ..........................................................................................36 
7. 
TIMING OF STATISTICAL ANALYSES ................................................................37 
8. 
INTERIM ANALYSES ..............................................................................................38 
9. 
SOFTWARE ...............................................................................................................39 
10. 
REFERENCES ...........................................................................................................40 
11. 
APPENDIX.................................................................................................................41 
11.1. 
Schedule of Events and Visits ....................................................................................41 
11.2. 
Reference for Criteria for Treatment-Emergent Potentially Clinically 
Significant Values (PCSV) .........................................................................................50 
11.3. 
Prohibited Non-Steroidal Anti-Inflammatory Drug (NSAID) Medication List .........57 
 
LIST OF TABLES 
Table 1: 
Visit Windows ............................................................................................................35 
Table 2: 
Schedule of Events .....................................................................................................42 
Table 3: 
Follow up Period for Patients Who Undergo Joint Replacement Surgery .................48 
Table 4: 
Criteria for Treatment-Emergent Potentially Clinically Significant Values 
(PCSV) ........................................................................................................................50 
Table 5 
List of Prohibited Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) .....................57 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................12 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AA 
Adjudicated arthropathy 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine Aminotransferase 
ARGUS 
Pharmacovigilance and clinical safety software system 
AST 
Aspartate Aminotransferase 
AUC 
Area under the concentration-time curve 
BPI-sf 
Brief Pain Inventory-short form 
Cmax 
Maximum observed drug concentration 
CLBP 
Chronic low back pain 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
Ctrough 
Concentration measured at the end of a dosing interval at steady state 
(taken directly before next administration) 
DA  
Destructive arthropathy 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EOS 
End of study 
EOT 
End of treatment 
EQ-5D-5L 
EuroQoL 5 Dimensions 5 Level Questionnaire 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HCRU 
Healthcare Resource Utilization 
hs-CRP 
High-sensitivity C-reactive protein 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
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IRB 
Institutional Review Board 
IVRS 
Interactive voice response system 
JR 
Joint replacement 
K-L 
Kellgren-Lawrence  
LBP 
Low back pain 
LBPI 
Low back pain intensity 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect model repeated measure 
MOS Sleep-R 
Medical Outcomes Study Sleep Scale Revised 
MRI 
Magnetic resonance imaging 
NGF 
Nerve growth factor 
NRS 
Numeric Rating Scale 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
OA 
Osteoarthritis 
PCSV 
Potentially clinically significant value 
PGA 
Patient Global Assessment 
PK 
Pharmacokinetic 
PPS 
Per protocol set 
PT 
Preferred term 
Q4W 
Every 4 weeks 
Q8W 
Every 8 weeks 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
RMDQ 
Roland Morris Disability Questionnaire 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SD 
Standard deviation 
SF-36 
36-item Short Form Survey 
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SNS 
Sympathetic nervous system 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TIA 
Transient ischemic attack 
TrkA 
Tyrosine kinase type 1 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
WOMAC 
Western Ontario and McMaster Universities Osteoarthritis Index 
WPAI-LBP 
Work Productivity and Activity Impairment-Low Back Pain 
 
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1. 
OVERVIEW 
The purpose of the Statistical Analysis Plan (SAP) is to ensure the credibility of the study results 
by pre-specifying the statistical approaches for the analysis of study data prior to database lock.  
The SAP is intended to be a comprehensive and detailed description of the definitions and 
statistical methods to be used in the analysis of data for study R475-PN-1612. 
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 database lock and before unblinding of the study. 
1.1. 
Background/Rationale 
This is a phase 3, randomized, double-blind, placebo-controlled, parallel-group study to evaluate 
the efficacy and safety of fasinumab in patients with moderate-to-severe non-radicular Chronic 
Low-Back Pain (CLBP).  
The target population for the study are patients who have inadequate CLBP relief with 
acetaminophen/paracetamol, and who are unable tolerate or have inadequate CLBP relief with 
NSAIDs and opioids (or unwilling to take opioids) and who have inadequate CLBP relief from 
non-pharmacologic management. The target population for this study will also have concomitant 
radiographically confirmed OA of the knee or hip.  
An unplanned interim analysis in the R475-PN-1524 study in patients with non-radicular CLBP 
showed evidence of efficacy with improvement in LBPI NRS pain scores in all fasinumab 
groups (6mg SC Q4W, 9 mg SC Q4W and 9 mg IV Q8W) compared to placebo at the 8 and 
12-week timepoints. 
At the time the protocol for this study was written, the maximum fasinumab dosages being 
evaluated in the OA program were 3mg SC Q4W and 6mg SC Q8W. The PK of fasinumab is 
described as linear, with concentrations in serum and exposure, as measured by similar area 
under the concentration-time curve (AUC), increasing in a dose-proportional manner. Therefore, 
the 6mg Q8W dose was expected to achieve similar AUC to that of the 3mg Q4W dose.  
Therefore, in this target population of patients with CLBP with concomitant OA of the knee or 
hip, the 3mg SC Q4W dose or matching placebo was chosen as the dose regimen under study 
since 3mg was considered the maximum dose expected to be tolerable in CLBP patients who 
also had OA.  
On May 3, 2018, following the independent and multidisciplinary fasinumab Data Monitoring 
Committee (DMC) review, the DMC recommended based on the risk benefit assessment of the 
entirety of the available data that higher dose regimens (3mg Q4W and 6mg Q8W) of fasinumab 
be discontinued across the OA program. As a result of this decision, dosing in this 
R475-PN-1612 evaluating the 3mg SC Q4W dose in patients with moderate-to-severe 
non-radicular CLBP who have radiographically confirmed OA of the knee or hip was 
discontinued for all patients who were still on study drug and the study was closed to enrollment. 
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 At the time of the study drug discontinuation, 63 patients had been randomized into the study. 
Patients will be encouraged to remain in the study and be followed for the off-treatment period 
study visits until completion of the study to continue to monitor safety for patients that were 
randomized.  
1.2. 
Study Objectives 
1.2.1. 
Primary Objectives 
The primary objective of the study is to evaluate the efficacy of fasinumab in relieving chronic 
low back pain (CLBP) as compared to placebo in patients with a clinical diagnosis of 
moderate-to-severe non-radicular CLBP and osteoarthritis (OA) of the knee or hip when treated 
for up to 16 weeks. 
1.2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
 To evaluate the safety and tolerability of fasinumab compared to placebo when 
patients with a clinical diagnosis of moderate-to-severe non-radicular CLBP and OA 
of the knee or hip are treated for up to 16 weeks 
 To characterize the concentrations of fasinumab in serum over time when patients 
with a clinical diagnosis of moderate-to-severe non-radicular CLBP and OA of the 
knee or hip are treated for up to 16 weeks 
 To evaluate the immunogenicity of fasinumab when treated for up to 16 weeks in 
patients with a clinical diagnosis of moderate-to-severe non-radicular CLBP and OA 
of the knee or hip 
1.2.3. 
Exploratory Objectives 
The exploratory objectives are: 
 To evaluate the patient-reported outcomes when patients with a clinical diagnosis of 
moderate-to-severe non-radicular CLBP and OA of the knee or hip are treated for up 
to 16 weeks with fasinumab compared to placebo 
 To evaluate the use of rescue medication in patients with a clinical diagnosis of 
moderate-to-severe non-radicular CLBP and OA of the knee or hip when treated for 
up to 16 weeks with fasinumab compared to placebo 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol 
The following lab safety endpoint is not listed in the statistical section of the protocol but is 
included in the analysis plan: 
 High-sensitivity C-reactive protein (hs-CRP) 
1.2.5. 
Revision History for SAP Amendments 
None 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
The study consists of a screening period of up to 30 days, a 7 (+3 day)-day pre-randomization 
period during which all pain medication except study-provided rescue medication will be 
discontinued, a 16-week treatment period, a 20-week follow-up period, and a final phone contact 
approximately 52 weeks after the last dose of study drug is administered.  
Approximately 1020 patients were to be randomized in a 1:1 ratio to one of the following 
treatment groups: 
 Fasinumab 3 mg subcutaneous (SC) every 4 weeks (Q4W) 
 Fasinumab-matching placebo SC Q4W 
Randomization is stratified by geographical region (Europe, North America, Other), baseline 
LBPI NRS score (<7, ≥7), duration of CLBP (<5 years, ≥5 years), and maximum K-L score 
(2-3, 4) of any knee or hip joint at the screening visit. 
Due to the recommendation of the DMC, dosing has been discontinued in this study. At the time 
of study drug discontinuation for all patients, sixty-three patients had been randomized.  
This statistical analysis plan reflects this change in dosing as a result of the IDMC 
recommendation.  
2.2. 
Sample Size and Power Considerations 
Approximately 1020 patients were to be randomized in a 1:1 ratio to either fasinumab (3mg 
Q4W) or placebo. Assuming a 2-sided alpha level of 0.05 and a 20% dropout rate at week 16, an 
enrolment of 510 patients per arm will provide 90% power to detect an effect size of 0.23 in the 
daily average LBPI NRS score (i.e., an absolute treatment difference of 0.5 between fasinumab 
3mg Q4W and placebo with an associated standard deviation [SD] of 2.2). This sample size also 
provides at least 99% power to detect an effect size of 0.42 (absolute treatment difference of 2.2 
with an associated SD of 5.2) in the RMDQ total score and 0.44 (absolute treatment difference of 
0.4 with an associated SD of 0.9) in the PGA at week 16. The sample size assumptions are based 
on results of the R475-PN-1524 study data on file at Regeneron. 
2.3. 
Study Plan 
Study Visits 
The study consists of a screening period of up to 30 days (Screening Period), followed by a 7 to 
10 day pre-randomization period (Pre-Randomization Period), a 16-week randomized, 
double-blind, placebo-controlled treatment period (Treatment Period), a 20-week follow-up 
period, and an end of study phone contact at 52 weeks following the last dose of study drug to 
determine whether a joint replacement (JR) has been conducted or is scheduled (or the patient is 
on a waiting list). See Figure 1 for the Study Flow Diagram. 
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Figure 1: 
Study Flow Diagram 
 
The Schedule of Events table is presented in Appendix 11.1. 
Prior to randomization, patients will undergo screening procedures. During the screening period, 
patients may continue to take their current pain medications.  
Patients will then complete a pre-randomization period, during which all pain medication, except 
study-provided rescue medication (acetaminophen/paracetamol) will be discontinued. 
Paracetamol/acetaminophen must not be taken within 24 hours prior to the randomization visit.  
Following randomization (day 1), patients will enter into the treatment phase of the study during 
which study drug will be administered at scheduled visits and patients are permitted to use only 
acetaminophen/paracetamol as rescue medication.  Use of acetaminophen/paracetamol is 
prohibited within 24 hours prior to the start of the study visits to minimize the confounding 
effects of the rescue medication on efficacy measurements. During the treatment period, efficacy 
and safety assessments will be performed at each study visit as outline in the schedule of events.  
At the end of the 16-week treatment period, follow-up of patients will continue for an additional 
20-weeks after the last treatment visit. Safety and efficacy assessments will be performed as 
outlined in the schedule of events.  
Phone contact will be made approximately 52 weeks after administration of the last dose of study 
drug to document patient status with regards to JR surgery (if a patient underwent, is schedule 
for, or is on a waitlist for JR surgery).  
The end of study is defined as the last phone contact for the last patient in the study.  
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3. 
ANALYSIS POPULATIONS  
In accordance with guidance from the International Council for Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (1998), the following populations will be used for all 
statistical analyses. 
3.1. 
Full Analysis Set (FAS) 
The full analysis set (FAS) includes all randomized patients and is based on the treatment 
allocated (as randomized). Efficacy endpoints will be analyzed using the FAS. 
3.2. 
The Safety Analysis Set (SAF) 
The safety analysis set (SAF) includes all randomized patients who received any study drug. 
Patients randomized to placebo who receive fasinumab at least once will be classified to the 
fasinumab treatment arm. Treatment compliance/administration and all clinical safety variables 
will be analyzed using the SAF. 
3.3. 
The Pharmacokinetic (PK) Analysis Set 
The PK population includes all treated patients who received any study drug and who had a 
non-missing result for drug concentration following the first dose of study drug. 
3.4. 
The Anti-Drug Antibody (ADA) Analysis Set 
The ADA population includes all patients who had received any study drug or placebo (safety 
population) and had at least 1 non-missing ADA result following the first dose of study drug. 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (e.g. age, sex, race, ethnicity, weight, 
height, etc.), disease characteristics including Maximum Kellgren-Lawrence score for any knee 
or hip joint at screening, baseline LBPI NRS Score, Duration of CLBP, geographical region, 
medical history, and medication history for each patient. 
The following demographic and baseline characteristic variables will be summarized by 
treatment group: 
 Age at screening (years) 
 Age category (<65, >=65 years) 
 Sex (Male, Female) 
 Race (American Indian/Alaskan Native, Asian, Black/African American, Native 
Hawaiian/Other Pacific Islander, White, and Other) 
 Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported) 
 Baseline Weight (kg) 
 Baseline Height (cm) 
 Baseline Body mass index (BMI) calculated from weight and height 
 Geographical region (Europe, North America, Other)  
 Baseline LBPI NRS score  
 Baseline LBPI NRS score strata (<7, ≥7) 
 Maximum K-L score for any knee or hip joint at screening per IVRS/IWRS (2-3, 4) 
 Maximum K-L score for any knee or hip joint at screening  
 Duration of CLBP at baseline strata (<5 years, ≥5 years) 
 Duration of CLBP (years) 
 History of analgesic intolerance and inadequate pain relief  
Additional baseline characteristics will be summarized as needed.  
4.2. 
Medical History 
Medical history will be coded to a Preferred Term (PT) and associated primary System Organ 
Class (SOC) according to the latest available version of Medical Dictionary for Regulatory 
Activities (MedDRA®). 
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4.3. 
Prior, Concomitant, and Prohibited Medications and Procedures 
Medications and Procedures will be recorded from the day of informed consent until the End of 
Follow-up Clinic Visit.  Medications will be coded to the Anatomical Therapeutic Chemical 
(ATC) level 2 (therapeutic main group) and ATC level 4 (chemical/therapeutic subgroup), 
according to the latest available version of WHO Drug Dictionary (WHODD).  Patients will be 
counted once in all ATC categories linked to the medication. 
Medication and Procedure Classifications 
Prior medications and procedures are defined as medications or procedures starting prior to the 
first dose of study drug. 
Concomitant medications or procedures are defined as medications or procedures starting prior 
to or during the on-treatment period (as defined in Section 5.9) AND ending during or after the 
on-treatment period. 
Post treatment medications or procedures are medications or procedures starting after the 
on-treatment period (as defined in Section 5.9). 
Prohibited Medication 
Patients will be required to discontinue all non-study pain medication (oral or topical; except up 
to 150 mg/day of aspirin/5-ASA, which is permitted for cardiac prophylaxis, per local 
guidelines), starting at the pre-randomization visit and through the treatment period. 
Opioid analgesic medications (including tramadol) and muscle relaxants are prohibited through 
the week 16 study visit. Patients will be directed not to take concomitant medications that 
contain NSAIDs (oral or topical, except up to 150 mg/day of aspirin, which is permitted for 
cardiac prophylaxis) until at least 16 weeks after the last study drug injection. A list of the 
prohibited medications containing NSAIDs is provided in Appendix 11.3. 
Other excluded medications during the treatment and follow-up period include: 
 Any other investigational agent 
 Medical marijuana 
 Cyclobenzaprine, carisoprodol, orphenadrine, tizanidine 
 Corticosteroids (topical, intranasal, and inhaled formulations are permitted), 
 adrenocorticotropic hormone 
 Cyclosporine, mycophenolate mofetil, tacrolimus 
 Azathioprine, sulfasalazine, hydroxychloroquine 
 IL-6 or IL-6 receptor antagonists 
 Abatacept, ustekinumab 
 Tumor necrosis factor antagonists 
 IL-1 inhibitors, including diacerein 
 Apremilast, and tofacitinib 
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 Tocilizumab 
4.4. 
Efficacy Variables 
4.4.1. 
Primary Efficacy Variable(s) 
The primary efficacy endpoint assessed for the study is: 
 Change from baseline to week 16 in the average daily LBPI NRS Score 
4.4.2. 
Secondary Efficacy Variable(s) 
The secondary efficacy endpoints assessed for the study are: 
 Change from baseline to week 16 in the RMDQ total score 
 Change from baseline to week 16 in the PGA LBP score  
 Proportion of patients who are responders as defined by a ≥30% reduction from 
baseline to week 16 in the daily average LBPI NRS score  
 Change from baseline to week 16 in the Brief Pain Inventory Short Form (BPI-sf) 
pain interference score  
4.4.3. 
Exploratory Efficacy Variable(s) 
The exploratory efficacy endpoints to be assessed in the efficacy are: 
 Change from baseline to week 16 in MOS Sleep-R Subscale Scores 
 Change from baseline to week 16 in the 36-item Short Form Survey (SF-36) Subscale 
Scores 
 Change from baseline to week 16 in the EuroQoL 5 Dimensions 5 Level 
Questionnaire (EQ-5D-5L) Scores 
 Percentage of patients who used rescue medication 
 Change from baseline to week 16 in Work Productivity and Activity Impairment-Low 
Back Pain (WPAI-LBP) questionnaire 
 percent of work time missed due to CLBP 
 percent of impairment while working due to CLBP 
 percent of overall work impairment due to CLBP 
 percent activity impairment due to CLBP  
 Change from baseline to week 16 in the WOMAC pain subscale score 
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4.5. 
Safety Variables 
Patient safety will be assessed through the collection of reported adverse events (AEs), clinical 
laboratory data, vital signs, ECG, Survey of Autonomic Symptoms Questionnaire, neurological 
exams and physical exams.  Unless otherwise noted, the baseline value is defined as the last 
available value before the first dose of study drug. 
Adverse events (AE) and Serious Adverse Events (SAE) will be collected from the time of 
informed consent signature and then at each visit until the End of Follow-up Clinic Visit.  All 
AEs are to be coded to a “Preferred Term (PT)” and associated primary “System Organ Class 
SOC” according to the MedDRA® (the latest current available version). 
An Adverse Event is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. 
A Serious Adverse Event is an adverse event (AE) that is classified as serious according to the 
criteria specified in the protocol. 
Laboratory results, vital signs, or ECG abnormalities are to be recorded as AEs if they are 
medically relevant: symptomatic, requiring corrective therapy, leading to treatment 
discontinuation and/or fulfilling a seriousness criterion. 
4.5.1. 
Safety Variables 
The safety endpoints in the study are: 
 Incidence of Adjudicated Arthropathy (AA) (as confirmed by an independent 
adjudication committee) 
 Incidence of Destructive Arthropathy (DA) (as confirmed by an independent 
adjudication committee) 
 Incidence of treatment-emergent adverse event (TEAEs) 
 Incidence of SNS dysfunction (as diagnosed after consultation with an appropriate 
 specialist, such as a neurologist and/or cardiologist) 
 Incidence of peripheral sensory AEs that require a neurology consultation 
 Incidence of all-cause joint replacement (JR) surgeries through week 16 and through 
 the end of follow-up period (week 36) 
 Incidence of JRs at telephone survey approximately 52 weeks after last dose of study 
drug 
The raw incidence rate is defined as the number of events divided by the duration of the 
observation period and presented as number of events per 100 patient-years. 
Additional safety endpoints that may be evaluated include: 
 Survey of Autonomic Symptom scores from baseline to week 16 and from baseline to 
week 36 
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4.5.2. 
Adverse Events of Special Interest 
An AESI (serious or non-serious) is one of scientific and medical concern specific to the 
sponsor’s product or program, for which ongoing monitoring and rapid communication by the 
investigator to the sponsor can be appropriate. 
AESI are selected using e-CRF specific tick box on the AE page. 
Events considered to be AESIs for the study are: 
 Adjudicated arthropathy (as confirmed by adjudication) 
 Sympathetic nervous system dysfunction (as diagnosed after consultation with an 
appropriate specialist, such as a neurologist and/or cardiologist) 
 Peripheral sensory AEs that require a neurology or other specialty consultation 
 JR surgery (AESI defined in Protocol Section 9.6.1.4 as elective JR surgery not due 
to new or worsening disease) 
4.5.3. 
Laboratory Safety Variables 
The clinical laboratory tests include blood chemistry, hematology, urinalysis, urine chemistries, 
hs-CRP, and others.  Samples for laboratory testing will be collected at the time points specified 
in the Schedule of Events (Appendix 11.1).  Clinical laboratory values will be in standard 
international (SI) units, including associated normal ranges provided by the central laboratory, 
and grouped by function in summary tables.  Clinical laboratory values in conventional (US) 
units will also be available in the database, with associated normal ranges. 
Both actual test values and “change from baseline” values (defined as the post-baseline value 
minus the baseline value) will be used in central lab result summaries.  Potentially clinically 
significant values (PCSV) ranges will be applied to central lab test values as applicable (see 
Appendix 11.2 for PCSV definitions).  
4.5.4. 
Biomarker variables 
Biomarker analysis will be performed in a separate biomarker SAP. 
4.5.5. 
Vital Signs 
Vital Sign parameters include: 
 Body temperature (oC) 
  Supine/standing/orthostatic systolic and diastolic blood pressures (mmHg) and pulse 
(bpm) 
 Respiratory rate (bpm) 
Both actual values and “change from baseline” values (defined as the post-baseline value minus 
the baseline value) will be used in the result summaries.  Potentially clinically significant values 
(PCSV) ranges will be applied to the vital sign parameter values as applicable (see 
Appendix 11.2 for PCSV definitions). 
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4.5.6. 
Orthostatic Hypotension 
A patient will be determined to have orthostatic hypotension if any of the following criteria are 
met: 
 If the supine blood pressure is <160 mmHg systolic, a decrease in either the 1 or 
3-minute standing systolic blood pressure of ≥20 mmHg or a decrease in the standing 
diastolic blood pressure of ≥10 mmHg from the supine systolic or diastolic blood 
pressure 
OR 
 If the supine blood pressure is ≥160 mmHg systolic, a decrease in either the 1 or 
3-minute standing systolic blood pressure of ≥30 mmHg or a decrease in the standing 
diastolic blood pressure of ≥15 mmHg from the supine systolic or diastolic blood 
pressure 
OR 
 An increase in either the 1 or 3-minute standing heart rate of ≥30 bpm from the 
supine heart rate 
OR 
 The patient is unable to stand for either one of the standing blood pressure 
measurements due to dizziness or lightheadedness 
Confirmed orthostatic hypotension is defined as initial assessment meeting the above orthostatic 
hypotension criteria confirmed by subsequent repeated assessments per protocol or if initial 
assessment met the above orthostatic hypotension criteria yet repeated assessments were not 
performed. 
4.5.7. 
12-Lead Electrocardiography 
Standard12-lead ECG parameters include P-R interval, QT interval, QTc interval including 
QTcF and QTcB, QRS interval, ventricular rate and heart rate.  
QTcF and QTcB corrections are defined as follows: 
QTcF and QTcB are defined as follows:  
QTcF (ms) =QT/RR1/3 and QTcB (ms) =QT/RR1/2, 
where QT is the uncorrected QT interval measured in ms, and RR is 60/HR with HR being the 
heart rate in beats per minute.  
Potentially clinically significant values (PCSV) ranges will be applied to the ECG parameter 
values as applicable (see Appendix 11.2 for PCSV definitions). 
4.5.8. 
Physical and Neurological Examination Variables 
Physical examination assessments will be described as normal or abnormal for each body system 
examined.  Neurological evaluations of specific domains as listed in the protocol will be 
described as normal or abnormal. 
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4.5.9. 
Other Safety Variables 
 Joint Pain Questionnaire:  
 Number of subjects with significantly worse joint pain in any joint at each 
scheduled visit 
 Number of subjects with significantly worse joint pain by joint at each scheduled 
visit 
 Joint space width for specified joints at each scheduled visit. 
 Joint replacement:  
 number and percentage of patients with joint replacement (all JRs) 
4.6. 
Pharmacokinetic Variables 
The Pharmacokinetic (PK) variable will be fasinumab concentrations in serum at specified 
sampling time points. 
4.7. 
Anti-Drug Antibody Variables 
Samples for Anti-Drug Antibody (ADA) evaluation will be collected at baseline and at 
subsequent study visits. 
Anti-drug antibody variables will include ADA status (positive or negative) and titer as follows: 
 Total subjects negative in the ADA assay at all time points analyzed 
 Pre-existing immunoreactivity - a positive ADA response at baseline with all 
post-dose ADA results negative, or a positive ADA response at baseline with all 
post-dose ADA responses less than 9-fold over baseline titer levels. 
 Treatment emergent - defined as any post-dose positive ADA response when baseline 
results are negative 
 Persistent - A positive result in the ADA assay detected in at least 2 consecutive 
post baseline samples separated by at least a 16-week post baseline period [based 
on nominal sampling time], with no ADA-negative results in-between, regardless 
of any missing samples 
 Indeterminate - A positive result in the ADA assay at the last collection time point 
analyzed only, regardless of any missing samples 
 Transient - Not persistent or indeterminate regardless of any missing samples 
 Treatment boosted - defined as any post-dose positive ADA response that is at least 
9-fold over the baseline level when baseline is positive in the ADA assay 
 Titer Values 
 Titer category: low (titer <1,000); moderate (1,000≤ titer ≤10,000); high 
(titer >10,000) 
 Neutralizing ADA activity for samples positive in the ADA assay 
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5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, median, standard deviation (SD), minimum, maximum, 
and the first and third quartiles (Q1 and Q3). 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
5.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be descriptively summarized by treatment group 
and overall based on the FAS.  Parameters to be summarized include those described in 
Section 4.1. 
5.2. 
Medical History 
Medical history will be descriptively summarized by treatment group and overall for the FAS. 
Summaries will show patient counts (percentages) by primary SOC and PT.  The tables will be 
sorted by decreasing frequency of primary SOC in the fasinumab group.  Within each primary 
SOC, PTs will be sorted by decreasing frequency in the fasinumab group. 
5.3. 
Prior and Concomitant Medications 
Prior Medications 
All prior medications, dictionary coded by WHO, will be descriptively summarized by treatment 
group based on the FAS.  Summaries will present patient counts (and percentages) for all prior 
medications, by decreasing frequency of the fasinumab group incidence of ATC followed by 
ATC level 2, ATC level 4 and preferred term.  In case of equal frequency across anatomic or 
therapeutic categories, alphabetical order will be used. Patients will be counted once in each 
ATC category (anatomic or therapeutic) linked to the medication but may be counted several 
times for the same medication. 
Concomitant Medications 
All concomitant medications, dictionary coded by WHO, will be descriptively summarized by 
treatment group based on the SAF.  Summaries will present patient counts (and percentages) for 
the concomitant medication groups described in Section 4.3 for all concomitant medications, by 
decreasing frequency of the fasinumab group incidence of ATC followed by ATC level 2, ATC 
level 4 and preferred term.  In case of equal frequency across anatomic or therapeutic categories, 
alphabetical order will be used. Patients will be counted once in each ATC category (anatomic or 
therapeutic) linked to the medication, hence may be counted several times for the same 
medication. 
The following will be summarized: 
 Prior Medications 
 Concomitant medications 
 Post-treatment medications 
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 On-study (Concomitant + Post-Treatment) Medications 
When medication start/end date is missing, the rules for determining whether a medication is 
prior, concomitant, or post-treatment, are specified in Section 6.3. 
5.4. 
Prohibited Medications 
Number and percentage of patients with prohibited medications will be descriptively 
summarized by treatment group based on the SAF.  The tables will be sorted by decreasing 
frequency of ATC Level 2, ATC Level 4, and preferred term in the fasinumab group. 
The number of patients with NSAID use during the treatment period will be summarized by 
treatment group based on the SAF. 
Total NSAIDs-use days during the treatment period and within 16 weeks after last study drug 
administration (before AA for patients with AA) will be summarized by treatment group for 
patients in the SAF. 
5.5. 
Patient Disposition 
The disposition of patients in the study will be summarized by treatment group and overall for 
FAS.  
5.5.1. 
Screening Disposition 
Percentages will be calculated using the number of screened patients as the denominator. 
 Screened patients (defined as having signed the ICF).  
 Patients randomized (defined in the protocol as having received a randomization 
number per IVRS). 
 Patients did not meet inclusion/exclusion criteria but randomized (if applicable). 
 Patients treated but not randomized (if applicable).  
 Screen Fail patients.  Reason for screen failure will be provided. 
Additionally, the following listings will be provided (if applicable):  
 Listing of Patients Treated but not Randomized. 
 Listing of Screening Failures and reasons for all screen failed patients. 
5.5.2. 
Treatment and Study Disposition 
Unless otherwise noted, percentages will be calculated using the number of patients in FAS as 
the denominator.  This will be summarized by treatment group and overall for the study.  
Summaries will provide the frequency (and percentage as applicable) of patients that met the 
criteria for the following variables: 
 Patients randomized (defined as having received a randomization number). This row 
will reflect grouping based on randomization assignment.  
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 Patients randomized but not treated. This row will reflect grouping based on 
randomization assignment.  
 Patients randomized and treated. 
 Patients who completed study treatment, patients who discontinued treatment and 
reason for treatment discontinuation. 
 Patients who completed the study, patients who withdrew from the study and reason 
for study withdrawal. 
Additionally, the following listings will be provided (if applicable):  
 Listing of Patients Randomized but not Treated. 
 Listing of Patients Randomized but not Treated with the Randomized treatment. 
 Listing of Patient Disposition for all Randomized Patients. 
5.5.3. 
Analysis Set 
Summary of the number (and percentage) of patients in each analysis set will be presented by 
treatment group and overall. 
5.6. 
Extent of Study Treatment Exposure and Compliance  
The analysis population is based on the SAF. 
5.6.1. 
Measurement of Treatment Compliance  
Compliance with protocol-defined investigational product will be calculated by treatment group 
as follows:  
 
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑎𝑐𝑡𝑢𝑎𝑙 𝑖𝑛𝑗𝑒𝑐𝑡𝑖𝑜𝑛𝑠 𝑜𝑓 𝑠𝑡𝑢𝑑𝑦 𝑑𝑟𝑢𝑔 𝑟𝑒𝑐𝑒𝑖𝑣𝑒𝑑 𝑑𝑢𝑟𝑖𝑛𝑔 𝑡ℎ𝑒 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑒𝑥𝑝𝑠𝑜𝑢𝑟𝑒 𝑝𝑒𝑟𝑖𝑜𝑑
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑝𝑙𝑎𝑛𝑛𝑒𝑑 𝑖𝑛𝑗𝑒𝑐𝑡𝑖𝑜𝑛𝑠 𝑜𝑓 𝑠𝑡𝑢𝑑𝑦 𝑑𝑟𝑢𝑔 𝑑𝑢𝑟𝑖𝑛𝑔 𝑡ℎ𝑒 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑒𝑥𝑝𝑜𝑠𝑢𝑟𝑒 𝑝𝑒𝑟𝑖𝑜𝑑 𝑜𝑛 𝑜𝑟 
 𝑏𝑒𝑓𝑜𝑟𝑒𝑡ℎ𝑒 𝑡𝑖𝑚𝑒 𝑡ℎ𝑎𝑡 𝑡ℎ𝑒 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 𝑑𝑖𝑠𝑐𝑜𝑛𝑡𝑖𝑛𝑢𝑒𝑑 𝑓𝑟𝑜𝑚 𝑡ℎ𝑒 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑝ℎ𝑎𝑠𝑒 𝑜𝑓 𝑡ℎ𝑒 𝑠𝑡𝑢𝑑𝑦
 𝑥 100: 
Treatment compliance will be presented by the descriptive statistics and the number (%) of 
patients who have 1, 2, 3, and 4 SC injections will be displayed. 
5.6.2. 
Exposure to Investigational Product 
The duration of treatment exposure to fasinumab and placebo SC doses will be calculated as:  
 (Date of last dose of study drug– date of first dose of study drug) + 28  
The duration of exposure will be summarized for each treatment group using the number of 
patients (n), mean, standard deviation, median, Q1, Q3, minimum, and maximum. 
The number (%) of patients with exposure duration periods will be presented by specific time 
periods.  The time periods of interest are specified as: ≥ 1 day, ≥ 29 days, ≥ 57 days, ≥ 85 days, 
and ≥ 113 days. 
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5.6.3. 
Length of Study Observation 
The length of the observation period (days) will be calculated as: 
 (Date of last study visit [up to End of Follow-up Clinic Visit] – date of first study 
drug dose) +1. 
The observation duration will be summarized for each treatment group using the number of 
patients (n), mean, standard deviation, median, Q1, Q3, minimum, and maximum. 
The number (%) of patients with observation periods will be presented by specific time periods.  
The time periods of interest are specified as: ≥ 1 day, ≥ 29 days, ≥ 57 days, ≥ 85 days, 
≥ 113 days, ≥ 141 days, ≥ 169 days, ≥ 197 days, ≥ 225 days, ≥ 253 days, and ≥ 449 days 
5.7. 
Protocol Deviations 
All major and minor protocol deviations are collected and reviewed on an ongoing basis 
throughout the study as described in the Protocol Deviation Definitions Document (PDDD). 
Protocol deviations will be summarized for patients incurring any major deviation by count and 
percentage, and patients incurring each type of major deviation by count and percentage for FAS. 
A patient listing of all major and minor protocol deviations will be provided. 
5.8. 
Analysis of Efficacy Data 
As a result of the DMC recommendation resulting in treatment discontinuation for all patients, 
no hypothesis testing will be conducted. The analysis of efficacy data will be descriptive based 
on the FAS by treatment group. 
5.8.1. 
Analysis of Primary Efficacy Variable(s) 
5.8.1.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint in the study is: 
 Change from baseline to week 16 in the average daily LBPI NRS Score 
Primary efficacy data will be summarized by baseline and change from baseline to each 
scheduled assessment time with descriptive statistics based on the FAS by treatment group. 
No sensitivity analyses will be performed for the primary efficacy variable.  
5.8.2. 
Analysis of Additional Efficacy Variable(s) 
Analyses of continuous efficacy endpoints will use the same analysis method as the primary 
efficacy variable. 
For analysis of categorical efficacy endpoints, e.g., proportions of patients with ≥30% reduction 
from baseline to week 16 in the daily average LBPI NRS score, the Cochran Mantel Hanszel 
approach stratified by the randomization strata will be used with missing data considered as 
non-response. 
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Rescue Medication 
The percentage of patients who use rescue medication between baseline and week 16 will be 
summarized by the treatment group using the FAS.  
Number of days patients used rescue medication during the treatment period (Day1 to Week 2, 
Week 2 to Week 4, Week 4 to Week 8, Week 8 to Week 12, Week 12 to Week 16) will be 
summarized descriptively by treatment group. Weekly average amount of rescue medication use 
will be summarized by treatment group. 
5.9. 
Analysis of Safety Data 
The analysis of safety and tolerability will be performed on the SAF, as defined in Section 3.2. 
The safety analysis will be based on the reported AEs and other safety information (clinical 
laboratory evaluations, vital signs, 12-lead ECG, Physical Examination, etc.). 
Treatment-Emergent Potential Clinically Significant Values (PCSV) in laboratory variables, vital 
signs and ECG are defined in Appendix 11.2. 
Period of observation: The observation period will be divided into three segments: 
pre-treatment, on-treatment and post-treatment. 
 The pre-treatment period is defined as the time between when the patients give 
informed consent and the start of study drug. 
 The on-treatment period is defined as the time from first dose of study drug up to 
28 days after the last dose of study drug. 
 The post-treatment period is defined as the time starting 29 days after last dose of 
study drug (after the on-treatment period) to up to 24 weeks post the last dose of 
study drug (up to week 36). 
Day 1 is the first day of study drug, Day –1 is the day before Day 1, and there is no Day 0. 
The time interval to detect any on-treatment event or abnormality is between the first dose of 
double-blind study drug injection and the end of treatment plus 28 days.  Data collected outside 
this interval will be excluded from the on-treatment estimation of descriptive statistics and 
identification of abnormalities for laboratory evaluations, ECGs and vital signs.  All 
post-baseline data during the interval will be used in the PCSV analysis including scheduled and 
unscheduled assessments. 
5.9.1. 
Safety Endpoints 
Raw incidence rates will be summarized by treatment group based on the SAF.  
5.9.2. 
Adverse Events 
The verbatim text, the preferred term, and the primary SOC will be listed in patient listings. 
Summaries that include frequencies and proportions of patients reporting AEs will include the 
preferred terms and the SOCs. 
 Pre-Treatment Adverse Events are defined as AEs that developed or worsened during 
the pre-treatment period. 
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 Treatment-Emergent Adverse Events (TEAE) are defined as those that are not present 
at baseline or represent the exacerbation of a pre-existing condition during the 
on-treatment period. 
 Post-Treatment Adverse Events are defined as AEs that developed or worsened more 
than 28 days after the last dose of study drug. 
The focus of adverse event reporting in the clinical study report will be on TEAEs. 
Post-treatment AEs and AEs during the study will be summarized similarly as TEAEs. 
Summaries of TEAEs by treatment group will include: 
 Overview of TEAEs, summarizing number of events, summarizing number and 
percentage of patients within the specified category 
 Total number of TEAEs 
 Total number of Serious TEAEs 
 Patients with any TEAEs 
 Patients with any Serious TEAEs 
 Patients with any TEAEs leading to death 
 Patients with any TEAEs leading to withdrawal from study 
 Patients with any TEAEs leading to permanent study treatment discontinuation 
 All TEAEs by SOC and PT 
 All TEAEs by SOC, PT, severity 
 Study drug related TEAEs by SOC and PT 
 TEAEs resulting in Permanent Study Drug Discontinuation by SOC and PT 
 AESI by SOC and PT 
 Serious TEAEs by SOC and PT 
Listing to include: 
 Listing of AEs leading to death  
 Listing of TEAEs leading to permanent study treatment discontinuation 
 Listing of TEAEs leading to withdrawal from study 
 Listing of Patients with Serious TEAEs  
 Listing of Patients with AESIs 
 Listing of all Joint Replacements 
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Counts will be provided according to treatment group for each PT within each primary SOC.  
Percentages will be calculated based on the SAF in each treatment group. 
Primary SOCs will be sorted by decreasing frequency in the fasinumab group.  Within each 
primary SOC, PTs will be sorted by decreasing frequency in the fasinumab group. For tables 
presenting severity of events, the worst severity will be chosen for patients with multiple 
instances of the same event. 
TEAEs with preferred terms ≥5% in any treatment group will be summarized in the report. 
5.9.3. 
Adverse Events of Special Interest 
AESIs will be listed and summarized by treatment group based on the SAF.  
Radiograph data related to AA including change from baseline in joint space width will be 
summarized by SAF over time.  
Knee Society Score questionnaire or Harris Hip Score questionnaire results will be listed if 
applicable. 
5.9.4. 
Clinical Laboratory Measurements 
Laboratory test results will be summarized by baseline and change from baseline to each 
scheduled assessment time with descriptive statistics based on the SAF by treatment group. 
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
Listings will be provided with flags indicating the out of laboratory range values. 
A Treatment-Emergent Potential Clinically Significant abnormal value (PCSV) is a laboratory 
value that was normal at Screening and Baseline but became abnormal and met PCSV criteria 
after treatment with study drug.  Definition of PCSV is listed in Appendix 11.2.  Treatment 
Emergent Potentially clinically significant values (PCSVs) will be summarized based on the SAF 
by treatment group. Additional exploratory analyses using alternative cut-points may be 
conducted. 
For hs-CRP, plots of means and medians of the observed values and change from baseline over 
time will presented by treatment group. 
5.9.5. 
Analysis of Vital Signs 
Vital signs (temperature, pulse, blood pressure, orthostatic blood pressure/heart rate, and 
respiration rate) will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics by treatment group and combined fasinumab for the 
SAF. 
PCSV summary including orthostatic hypotension will be summarized. 
5.9.6. 
Analysis of 12-Lead ECG 
ECG parameters (Ventricular Rate, PR Interval, QRS Interval, QT Interval, RR Interval, QTcF 
QTcB interval) will be summarized by baseline and change from baseline to each scheduled 
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assessment time.  PCSV summary of ECG parameters will be provided for on-treatment period, 
follow-up period, and overall for the SAF.  
ECG status (i.e. normal, abnormal) will be reported. Shift tables will be provided to present the 
post-baseline status according to the baseline status (normal or missing / abnormal) by treatment. 
5.9.7. 
Physical Exams 
The number and percentage of patients with new-onset abnormal physical examinations will be 
summarized by body system by visit based on the SAF. 
5.9.8. 
Joint Pain Questionnaire 
The number and percentage of patients with significantly worse joint pain will be summarized by 
visit and joint based on the SAF. 
5.9.9. 
Arthropathy Adjudications 
The number and percentage of patients with images requiring arthropathy adjudication as well as 
the number and percentage of those patients with confirmed adjudicated arthropathy will be 
summarized based on the SAF. Subtypes of AAs and outcomes of AAs will also be summarized. 
Patient listings of cases confirmed by adjudication will be provided. 
5.9.10. 
Neurological Exam 
The number and percentage of patients with new-onset abnormal neurological examinations will 
be summarized by Neurological evaluations by visit based on the SAF. 
5.9.11. 
Analysis of Pharmacokinetics and Drug Concentration Data 
Summaries of concentrations of functional fasinumab will be presented by nominal time point 
and dose. Plots of mean or median concentration of functional fasinumab will be presented by 
nominal day and dose. 
5.9.12. 
Analysis of Anti-Drug Antibody Data 
The ADA variables described in Section 4.7 will be summarized using descriptive statistics by 
dose/cohort group in the ADA analysis set. Prevalence of treatment-emergent and 
treatment-boosted ADA will be assessed as absolute occurrence (N) and percent of patients (%), 
grouped by study cohorts. For treatment emergent ADA, occurrence (N) and percent of patients 
(%) with persistent, transient and indeterminate ADA will be reported. The influence of 
treatment-emergent or treatment-boosted ADA assay response on individual PK profiles may be 
evaluated.  
Listings of ADA positivity and titers presented by patient, time point, and dose cohort/group will 
also be provided.  
Correlation analysis of safety versus treatment-emergent ADA positivity status may be 
performed on the SAF. Assessment will focus on the following safety events:  
 Hypersensitivity (SMQ: Hypersensitivity [Narrow])  
 Anaphylaxis (SMQ: Anaphylaxis[Narrow])  
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Number (%) of patients with the above-mentioned safety events may be summarized by 
treatment-emergent ADA positivity status, during the TEAE period.  
In addition, correlation analysis of key efficacy endpoints versus treatment-emergent ADA status 
in patients who discontinued due to lack of efficacy may be summarized. 
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis. 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified.  When relevant, the number of patients with missing data 
is presented. 
6.1. 
Definition of Baseline for Variables 
Unless otherwise specified, the baseline assessment for all efficacy measurements/ patient 
reported outcomes will be the latest available valid measurement prior to or on the day of 
randomization. Baseline for safety assessments such as labs, ECGs, vital signs etc. will be the 
latest assessment prior to the start of treatment. 
6.2. 
Data Handling Conventions for Patient reported Outcomes data 
LBPI NRS 
Baseline Average daily LBPI NRS score is defined as the average of the non-missing daily LBPI 
NRS scores for 7 days prior to randomization (from Day -6 to Day 1). Average daily LBPI NRS 
scores is calculated using the non-missing entries of the days as defined in the visit window 
mapping for electronic diaries in Section 6.4.  
RMDQ 
The total score of the RMDQ is the total number of items checked by the patient (range of 0 to 
24, with lower scores indicative of better function). The score can therefore vary from 0 to a 
maximum value of 24.  
PGA LBP 
The PGA LBP is a patient assessed 5-point Likert scale of LBP (1=very well; 2=well; 3=fair; 
4=poor; and 5=very poor).  
BPI-sf 
The BPI-sf pain interference domain is a measure of how much pain has interfered with seven 
daily activities (items 9A-9G) including general activity, walking, normal work, mood, 
enjoyment of life, relations with others and sleep.  The BPI-sf pain interference score is 
measured as the mean of the seven interference items. 
WPAI-LBP 
WPAI outcomes are expressed as impairment percentages, with higher numbers indicating 
greater impairment and less productivity, i.e., worse outcomes as follows: 
Questions: 
1 = Currently employed? 
2= hours missed due to LBP 
3= hours missed due to other reasons 
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4= hours actually worked 
5= degree LBP affected productivity while working  
6= degree LBP affected regular activities  
Scoring for the WPAI is as follows: 
Percent work time missed due to LBP = 𝑄2 
𝑄2 + 𝑄4
⁄
 
Percent impairment while working due to problem = 𝑄5
10
⁄
 
Percent overall work impairment due to problem = 𝑄2
(𝑄2 + 𝑄4)
⁄
+ [(1 −
𝑄2
𝑄2+𝑄4)  𝑥 (
𝑄5
10)] 
Percent activity impairment due to problem = 𝑄6 
10
⁄
 
 
Multiply scores by 100 to express as a percentage 
SF -36 
The half-scale rule will be used to impute missing item responses in the SF-36 subscale scores 
i.e. a score will be computed if the responded answers at least 50% of items in that scale. The 
missing items in the scale will be imputed by the mean of the available items rounded to the 
nearest whole number.  
The bodily pain subscale consists of Q7 and Q8 of the instrument. Since Q7 is based on 6pt 
Likert score and Q8 is based on a 5pt Likert scale and because mean imputation will be 
meaningless, the bodily pain subscale will not be imputed if any of the questions making up the 
scale is missing.  
EQ-5D-5L 
Index will be set to missing if any of the 5 dimensions is missing.  
MOS-Sleep 
MOS-Sleep subscale scores will be computed if at least 50% of items are available. The missing 
items will be imputed by the mean of available items.  
Western Ontario and McMaster osteoarthritis index (WOMAC)  
WOMAC scores will be computed when one pain item, one stiffness item, or at most 3 physical 
function items are missing. The missing items will be imputed by the mean of available items 
within the same subscale. The scores will be set to missing if more items are missing.  
HealthCare Resource Use (HCRU) Questionnaire  
HCRU include the following categories 
1. Use of walking aid over the past 8 weeks 
2. Healthcare office visits over the past 8 weeks 
a. Any use 
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b. # of use  
c. Any use related to OA 
d. Any use related to CLBP 
e. # of use related to OA 
f. # of use related to CLBP 
3. Emergency department (ED) visit over the past two months 
a. Any ED visits  
b. # of ED visits 
c. Any ED visit related to OA 
d. Any ED visit related to CLBP 
e. # of ED visits related to OA 
f. # of ED visits related to CLBP 
4. Hospitalization visit 
a. Any hospitalization 
b. # of hospitalization 
c. Length of hospitalization 
d. # of hospitalization related to OA 
e. # of hospitalization related to CLBP 
Treatment Satisfaction Questionnaire for Medication (TSQM) 
TSQM Scale scores computed by adding the items loading on each factor.  The lowest possible 
score is subtracted from this composite score and divided by the greatest possible score minus 
the lowest possible score. This provided a transformed score between 0 and 1 that should be 
multiplied by 100.  (see below) [Note that only one item may be missing from each scale before 
the subscale should be considered invalid for that respondent] 
 EFFECTIVENESS 
([(Item 1 + Item 2 + Item 3) – 3] divided by 18) * 100 
If one item is missing 
([(Sum(Item 1? + Item 2? + Item 3?)) – 2] divided by 12) * 100 
 SIDE-EFFECTS 
If Question 4 is answered ‘No’ then score = 100 
Else… 
([Sum(Item 5 to Item 8) – 4] divided by 16) * 100 
If one item is missing 
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([(Sum(Item5? to Item8?)) – 3] divided by 12) * 100 
 CONVENIENCE 
([Sum(Item 9 to Item 11) – 3] divided by 18) * 100 
If one item is missing 
([(Sum(Item9? to Item11?)) – 2] divided by 12) * 100 
 GLOBAL SATISFACTION 
([Sum(Item 12 to Item 14) – 3] divided by 14) * 100 
If either Item 12 or 13 is missing 
([(Sum(Item12? to Item14?)) – 2] divided by 10) * 100 
If Item 14 is missing 
([(Sum(Item12 and Item13)) – 2] divided by 8) * 100 
Beck Depression Inventory – II (BDI-II) 
The BDI-II total score is a sum of each of the 21 items rated on a 4-point scale ranging from 0 to 
3 based on the severity of each item. The maximum total score is 63. Total Score of 0-13 is 
considered minimal range; 14-19 is mild; 20-28 is moderate, and 29-63 is severe depression.  
Assessment of Peripheral vs. Central Pain 
The instrument assesses widespread pain as well as symptom severity. Widespread pain is a sum 
of the areas in which pain is indicated with a score ranging from 1- 19. Symptom severity is a 
measured on a scale of 1-12 by assigning points to responses according to the following rule: 
No problem – 0 points; Slight or Mild Problem – 1 point; Moderate problem- 2; Severe 
problem -3;  
And assigning a point of 1 to responses of ‘Yes’ for questions with a ‘Yes’/’No’ answer.  
6.3. 
General Data Handling Conventions 
Date of first/ last dose of study treatment 
The date of first injection is the first non-missing start date of dosing recorded in the eCRF.  
The date of the last injection is equal to the last date of administration reported on injection 
administration case report form page or missing if the last administration date is unknown. 
Handling of Adverse Event and Injection Site Reaction Severity and relatedness 
If the severity of a TEAE is missing, it will be classified as “severe” in the frequency tables by 
severity of TEAEs.  
If the assessment of relationship of a TEAE to the study drug or study conduct is missing, it will 
be classified as “related” to the investigation product. 
Handling of Missing/Incomplete AE/Concomitant Medication dates 
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If the start date of an AE or concomitant medication is incomplete or missing, it will be assumed 
to have occurred on or after the intake of study medication, except if an incomplete date (e.g., 
month and year) clearly indicates that the event started prior to treatment. Thus, if the AE does 
not clearly indicate that the AE started prior to treatment or after the TEAE period, the AE will 
be classified as “treatment-emergent”. This is for classification purposes in the frequency tables 
and will not be used in the listings. 
When only year is present, missing AE/concomitant medication end day and month will be 
imputed to the earlier of (study end date, 31DECYYYY). 
When both month and year are present, missing AE/concomitant medication end date will be 
imputed to the last day of the month. 
There will be no attempt to impute completely missing AE/concomitant medication end dates. 
Events with an end date missing will be assumed to be ongoing at the time of data cut off.  
Handling of Adverse Events classification with missing or partial date/time of first study drug 
administration 
When the date and time of first study drug dose is missing, the date of randomization will be 
used as the start date for classification of AEs. 
When the time of the first study treatment dose is missing, all AEs that occurred on the date of 
the first study drug dose will be considered as TEAEs. 
Missing/Incomplete Medical history dates  
Medical history start dates are used to determine the duration of OA at baseline per eCRF data. 
Completing missing medical history dates will not imputed. Missing month will be imputed to 
January and missing day will be imputed to the first day of the month. 
Laboratory Safety Variables below LLOQ or above ULOQ 
For central laboratory data below the lower limit of quantification (LLOQ), half of the lower 
limit value (i.e., LLOQ/2) will be used for quantitative analyses.  
Missing laboratory, ECG, vital sign, physical exam, neurological exam 
No imputations for missing laboratory data, ECG data, vital sign data, physical examination, or 
neurological examination data will be made. 
Handling of Potentially Clinically Significant Abnormalities (PCSA) 
If a patient has a missing baseline value they will be grouped in the category “normal/missing at 
baseline”. 
For PCSAs with 2 conditions, one based on a change from baseline value and the other on a 
threshold value or a normal range, with the first condition being missing, the PCSA will be based 
only on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; e.g., for eosinophils the PCSA is >0.5 GIGA/L or 
>ULN if ULN ≥0.5 GIGA/L. When ULN is missing, the value 0.5 should be used. 
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Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values. 
6.4. 
Visit Windows 
By-visit analysis (including efficacy, laboratory data, vital signs, ECG, ADA) will be 
summarized by the nominal visit number.  Assessments taken outside of protocol allowable 
windows will be displayed according to the case report form (CRF) assessment recorded by the 
investigator.  For assessments without a nominal visit number such as Unscheduled, ‘EOT Week 
16’, and ‘EOS Week 64’ assessments, a visit number will be assigned based on the actual visit 
date using the study day analysis window based on the targeted visit study day in Appendix 11.1 
Table 2 Schedule of Events. 
The following visit windows will be used to map the unscheduled visits, early end of treatment visits, 
early study termination visits and daily electronic dairy entries, based on the study day: 
Table 1: 
Visit Windows 
Visit 
No. 
Visit 
Targeted Study Days* 
Analysis Window in 
Study Days 
1 
Screening 
Day -30 to Day -11 
≥ -30 and ≤ -11 
2 
Pre-randomization Phone Call 
Day -10 to -7 
-10 to -1 
3 
Baseline# 
1 
1 
4 
Week 1 
8 
[2, 11] 
5 
Week 2 
15 
[12,20] 
6 
Week 4 
29 
[21,43] 
7 
Week 8 
57 
[44,71] 
8 
Week 12 
85 
[72,99] 
9 
Week 16 
113 
[100,127] 
10 
Week 20 
141 
[128,155] 
11 
Week 24 
169 
[156,183] 
12 
Week 28 
197 
[184,211] 
13 
Week 32 
225 
[212,239] 
14 
Week 36 
253 
[240,267] 
15 
Week 64 
449 
[436,456+] 
*Study days are calculated from the first dose of study drug (Day 1). 
# Baseline for the LBPI electronic diary entry will be mapped from day -7 to day 1.  
If multiple measurements occur within the same visit window, the following rules will be used to 
determine the analysis value:  
 When multiple valid measurements occur within the same visit window, the one 
closest to the target study day will be used in the analysis. 
 When multiple valid measurements occur within equal distance from the target study 
day, the value after the target study day will be used in the analysis.  
Both scheduled and unscheduled measurements will be considered for determining abnormal/PCSV 
values from laboratory, vital sign or ECG as well as the baseline values. 
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6.5. 
Unscheduled Assessments 
The determination of baselines and values at the end of treatment for both efficacy and safety 
variables will be based on available assessments of scheduled and unscheduled visits. For by 
visit summaries, unscheduled visit will be mapped to a visit using the visit windows described in 
Section 6.4 and then included in the by-visit summaries.  
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7. 
TIMING OF STATISTICAL ANALYSES 
The analyses will be performed based on two different database locks: 
 Week 36 Analysis: takes place when the last patient completes the last safety 
follow-up visit and includes all patient data collected up through the week 36 visit.  
The efficacy and safety analyses will be conducted at this time. 
 Week 64 analysis: takes place when the patient data collected up to the time the last 
patient completes assessments at week 64 phone call.  The only additional analysis to 
be conducted at this time is the analysis of incidence of JRs at the telephone survey 
approximately 52 weeks after the last dose of study drug and updating of outputs with 
any data change from the Week 36 Analysis. 
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8. 
INTERIM ANALYSES 
No interim efficacy analysis is planned. 
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9. 
SOFTWARE 
All clinical data analyses will be done using SAS Version 9.4 and above. 
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10. 
REFERENCES 
ICH. (1996, July 30). ICH Harmonized tripartite guideline: Structure and content of clinical 
study reports (E3). International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. 
ICH. (1997, July 17). ICH Harmonized tripartite guideline: General considerations for clinical 
trials (E8). International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. 
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. 
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11. 
APPENDIX 
11.1. 
Schedule of Events and Visits 
Study assessments and procedures are presented by study period and visit in Table 2. 
 
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Table 2: 
Schedule of Events 
 
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Footnotes for the Schedule of Events Table: 
1. Patients who discontinue study drug before week 16 will be encouraged to follow the 
visit schedule through the remainder of the study. If a patient chooses to end study 
participation at or before week 16, he/she will be asked to return to the clinic as soon as 
possible for an early termination (ET) visit. 
2. Patients who discontinue study participation after week 16 will be asked to return to the 
clinic as soon as possible for an early termination (ET) visit following early termination 
assessments. 
 
 
 
  
4. Patients’ demographic characteristics will be recorded, including age, height, weight, 
gender, race, and ethnicity. 
5. At the request of the central reader, a lumbar spine anterior-posterior/lateral should be 
obtained if the MRI of the lumbar spine shows evidence suggestive of a destructive or 
unstable process. Confirmation from the central reader that there are no exclusionary 
findings on MRI and X-ray (if requested) must be received before a patient can be 
randomized. 
6. Patients will be trained to use the eDiary after initial patient eligibility has been 
confirmed during the screening period. Patients will use the eDiary to report their daily 
NRS LBP score (entered to week 20) and daily use of paracetamol/acetaminophen 
(entered to week 16). Retraining should occur as needed throughout the conduct of the 
study. 
7. At the screening and pre-randomization visits, study staff will review the “Reporting 
Your Pain” brochure with the patient to ensure the patient understands how to report pain 
accurately. At subsequent clinic visits, patients will be asked to review the “Reporting 
Your Pain” brochure themselves. At the screening and baseline visit, study staff will 
review with the patient the “Participating in a Research Study: What You Need to Know” 
brochure. At any time during the conduct of the study, patients may require retraining by 
study staff. 
8. Low back pain intensity NRS score will be recorded by the site at the screening visit and 
at the pre-randomization visit, and by the patient each day (at approximately 6:00 PM) 
using the eDiary, starting during the pre-randomization period and to week 20.  
9. A review of compliance with daily entry of LBPI NRS and rescue medication use will 
occur at specified study visits, as well as re-education of patients, if applicable. Patients 
will record their daily LBPI NRS score in the eDiary up to week 20 and their rescue 
medication usage up to week 16.  
10. Study drug administration will be the last procedure at each dosing visit, and will be done 
after all laboratory samples have been collected and all study assessments and procedures 
are performed, including blood draws for drug concentration and ADA.  
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11. Assessments for orthostatic hypotension may be discontinued following regulatory 
approval if the safety database does not reveal an imbalance for the fasinumab-treated 
patients.  
12. If the pulse is less than 45 bpm at any visit, an ECG with rhythm strip will be obtained 
and sent to the central reader to confirm the heart rate and rhythm. 
13. Imaging (X-ray and/or MRI) will be performed on any joint following a report of 
clinically significant worsening or exacerbation of pain in that joint. This imaging will be 
submitted to the adjudication committee for review.  
14. If screening radiographs are inconclusive for potential joint-related findings, an MRI of 
the affected joint must be performed. Confirmation from the central reader that there are 
no exclusionary findings on X-ray and MRI must be received before a patient can be 
randomized. Imaging may be performed during pre-randomization, if needed. 
15. After the patient has otherwise met study eligibility criteria assessed during the screening 
period, an MRI of any knee with screening K-L ≥3 or hip with screening K-L ≥2 must be 
performed. Confirmation from the central reader that there are no exclusionary findings 
on MRI must be received before a patient can be randomized.  
16. Imaging assessments (X-rays and MRI) need to be repeated only if it has been >30 days 
since the joints were last imaged for the modality. If it has been ≤30 days since imaging 
assessments were completed, imaging assessments may be completed at the discretion of 
the investigator. 
17. In the event that a patient must undergo JR surgery during the study, the patient will 
complete the pre-operative visit (early termination assessments, as applicable) and the 
procedures outlined in the schedule of events for JR follow-up (Table 3). The 
pre-operative visit should be completed before JR surgery if possible. Pre-operative 
images will be submitted to the adjudication committee for review.  
18. Joint replacement questionnaires are Knee Society Score questionnaire for knee 
replacements or Harris Hip Score questionnaire for hip replacements.  
19. The purpose of this phone contact is to ask the patient if he/she has had or is scheduled 
(or on a waiting list) to have JR surgery. Pre-operative images will be submitted to the 
central reader for adjudication, if available. 
20. If the AA joint(s) has undergone JR, an X-ray may be substituted for an MRI. 
21. Samples will be analyzed by the central laboratory and results will be evaluated by the 
investigator. 
22. The follicle-stimulating hormone (FSH) and estradiol laboratory tests are to be performed 
only if postmenopausal status has to be assessed for female patients who are ≤59 years of 
age. 
23. In the event of a positive urine pregnancy test result, the patient must have a serum 
pregnancy test with a negative result in order to continue study participation. If the serum 
pregnancy test is positive, the patient must be withdrawn from study drug and should be 
asked to return to the clinic for all remaining study visits per the visit schedule. 
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24. PK, ADA, and biomarker samples may also be drawn at any non-specified scheduled 
visit or any unscheduled visit if a patient experiences a treatment-related safety TEAE. 
Samples should be collected prior to study drug administration on study drug dosing 
days. 
25. Biomarker samples should be collected after the patients have been fasting overnight or 
for 8 hours (in the event of an afternoon visit). 
Table 3: 
Follow up Period for Patients Who Undergo Joint Replacement Surgery 
 
Post-Operative  
Long-Term 
Follow-up Study Day (Visit Window)1 
Follow-up Visit 1 
4 weeks after joint replacement 
surgery 
Follow-up Visit 2 
20 weeks after joint 
replacement surgery 
Follow-up Day 29 (±7) 
Follow-up Day 140 (±7) 
Treatment: 
 
Concomitant medications and therapy 
X 
X 
Safety: 
 
Adverse events 
X 
X 
Vital signs 
X 
X 
Orthostatic blood pressure and heart rate2 
X 
X 
Physical examination with joint exam 
X 
X 
Medical history related to the joint 
replacement 
X 
X 
Joint pain questionnaire 
X 
X 
Post-operative questionnaire3 
X 
X 
Bilateral X-rays (shoulders, hips, knees)4 
 X5 
X 
Event-triggered imaging6 
X 
X 
Footnotes for Table of Follow-up Period for Patients Who Undergo Joint Replacement 
Surgery 
1. All available information for patients who undergo JR surgery must be collected, 
including placement of the prosthesis, healing of the surgical wound, and the results of 
the histopathologic examination. 
2. If it is not possible to obtain orthostatic blood pressure following JR, then blood pressure 
and pulse should be recorded. Assessments for orthostatic hypotension may be 
discontinued following regulatory approval if the safety database does not reveal an 
imbalance for the fasinumab-treated patients. 
3. A Knee Society Score questionnaire for knee replacements or Harris Hip Score 
questionnaire for hip replacements. 
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4. In the event of more than 1 JR, imaging assessments should be repeated if it has been 
>60 days since the joints were last imaged. If it has been ≤60 days since imaging 
assessments were completed, imaging assessments may be completed at the discretion of 
the investigator. An MRI may be requested by the imaging vendor after review of the 
X-rays.  
5. Imaging will be done at week 4 if not done pre-operatively. 
6. Imaging may be performed on any joint following a report of clinically significant 
worsening or exacerbation of pain in that joint. 
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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 4: 
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. 
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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 
Conjugated 
Bilirubin 
(Direct Bilirubin >35% Total Bilirubin and Total 
Bilirubin >1.5 ULN) and (Direct Bilirubin 
<=35% Total Bilirubin or Total Bilirubin <=1.5 
ULN) at baseline 
Conjugated bilirubin dosed on a case-by-case 
basis. 
ALT/AST and 
Total Bilirubin 
(ALT >3 ULN and TBILI>2 ULN) and baseline 
(ALT <=3 ULN or TBILI <=2 ULN) 
(AST >3 ULN and TBILI>2 ULN) and baseline 
(AST <=3 ULN or TBILI <=2 ULN) 
(ALT >3 ULN and TBILI>1.5 ULN) and 
baseline (ALT <=3 ULN or TBILI <=1.5 ULN) 
(AST >3 ULN and TBILI>1.5 ULN) and 
baseline (AST <=3 ULN or TBILI <=1.5 ULN) 
FDA DILI Guidance July 2009. 
ALT/AST and 
Total Bilirubin and 
ALP 
(ALT >3 ULN and TBILI>2 ULN and ALP < 2 
ULN) and baseline (ALT <=3 ULN or TBILI 
<=2 ULN or ALP >=2 ULN) 
(AST>3 ULN and TBILI>2 ULN and ALP < 2 
ULN) and baseline (AST <=3 ULN or TBILI 
<=2 ULN or ALP >=2 ULN) 
FDA DILI Guidance July 2009. 
 
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Parameter 
Treatment Emergent PCSV 
Comments 
CPK* 
>3 and ≤ 10 ULN and baseline ≤ 3ULN* 
>10 ULN and baseline ≤ 10ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
* At least one level is required; multiple levels 
are optional for phase 2/3 studies. If it is 
desirable to get the distribution of significant 
level, additional shift table on ≤3, >3 to ≤10, 
and > 10 category for baseline vs. post 
baseline may be provided 
Creatinine 
≥150 μmol/L (Adults) and baseline < 150 
μmol/L 
>=30% change from baseline and <100% 
change from baseline 
≥100% change from baseline 
Benichou C., 1994 
3 independent criteria  
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 μmol/L and <=408 μmol/L at baseline 
<120 μmol/L and >= 120 μmol/L at baseline 
Harrison - Principles of internal Medicine 17th 
Ed., 2008. 
Two independent criteria 
Blood Urea 
Nitrogen 
≥17 mmol/L and <17 mmol/L at baseline 
Two independent criteria 
Chloride 
Hypochloremia 
Hyperchloremia 
 
<80 mmol/L and baseline ≥ 80 mmol/L  
>115 mmol/L and baseline ≤ 115 mmol/L  
Two independent criteria  
Sodium 
Hyponatremia 
Hypernatremia 
 
≤129 mmol/L and baseline > 129 mmol/L  
≥160 mmol/L and baseline <160 mmol/L  
Two independent criteria 
Potassium 
Hypokalaemia 
Hyperkalaemia 
 
<3 mmol/L and baseline ≥ 3 mmol/L  
≥5.5 mmol/L and baseline <5.5 mmol/L  
FDA Feb 2005. 
Two independent criteria 
Total Cholesterol 
≥7.74 mmol/L and < 7.74 mmol/L at baseline 
Threshold for therapeutic intervention. 
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Parameter 
Treatment Emergent PCSV 
Comments 
Triglycerides 
≥4.6 mmol/L and < 4.6 mmol/L at baseline 
Threshold for therapeutic intervention. 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
(≤3.9 mmol/L and <LLN) and (>3.9 mmol/L or 
>=LLN) at baseline 
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) 
and < 11.1 mmol/L (unfasted); <7 mmol/L 
(fasted) at baseline 
 
ADA May 2005. 
ADA Jan 2008. 
HbA1c 
>8% and <= 8% at baseline 
 
Albumin 
≤25 g/L and >25 g/L at baseline 
 
hs-CRP 
2 ULN or > 10 mg/L  
(if ULN not provided) 
FDA Sept. 2005 
Hematology 
WBC 
<3.0 Giga/L and >=3.0 Giga/L at baseline (Non-
Black);  
<2.0 Giga/L and >=2.0 Giga/L at baseline 
(Black) 
≥16.0 Giga/L and < 16 Giga/L at baseline 
Increase in WBC: not relevant. 
 
 
To be interpreted only if no differential count 
available. 
Lymphocytes 
>4.0 Giga/L and <= 4.0 Giga/L at baseline 
 
Neutrophils 
<1.5 Giga/L and >=1.5 Giga/L at baseline (Non-
Black);  
<1.0 Giga/L and >=1.0 Giga/L at baseline 
(Black) 
International Consensus meeting on 
drug-induced blood cytopenias, 1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L <= 0.7 Giga/L at baseline 
 
Basophils 
>0.1 Giga/L <= 0.1 Giga/L at baseline 
 
Eosinophils 
(>0.5 Giga/L and >ULN) and (<=0.5 Giga/L or 
<= ULN at baseline) 
Harrison - Principles of internal Medicine 17th 
Ed., 2008. 
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Parameter 
Treatment Emergent PCSV 
Comments 
Hemoglobin 
≤115 g/L and > 115 g/L at baseline for male; 
≤95 g/L and> 95 g/L at baseline for Female. 
≥185 g/L and <185 g/L at baseline for Male; 
≥165 g/L and < 165 g/L at baseline for Female 
Decrease from Baseline ≥20 g/L 
Three criteria are independent. 
 
 
Criteria based upon decrease from baseline 
are more relevant than based on absolute 
value. Other categories for decrease from 
baseline can be used (≥30 g/L, ≥40 g/L, 
≥50 g/L). 
Hematocrit 
≤0.37 v/v and > 0.37 v/v at baseline for Male; 
≤0.32 v/v and > 0.32 v/v at baseline forFemale 
≥0.55 v/v and < 0.55 v/v at baseline for Male; 
≥0.5 v/v and < 0.5 v/v at baseline for Female 
Two Criteria are independent 
RBC 
Female 
<3 Tera/L and baseline ≥3 Tera/L 
≥6 Tera/L and baseline < 6 Tera/L  
Male 
<4 Tera/L and baseline ≥4 Tera/L 
≥7 Tera/L and baseline < 7 Tera/L 
Unless specifically required for particular 
drug development, the analysis is redundant 
with that of Hb. 
Otherwise, consider FDA criteria. 
Platelets 
<100 Giga/L and >=100 Giga/L at baseline 
≥700 Giga/L and < 700 Giga/L at baseline 
International Consensus meeting on 
drug-induced blood cytopenias, 1991. 
Two independent criteria 
Urinalysis 
pH 
≤4.6 and > 4.6 at baseline 
≥8 and < 8 at baseline 
Two independent criteria 
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. 
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Parameter 
Treatment Emergent PCSV 
Comments 
SBP 
≤95 mmHg and decrease from baseline 
≥20mmHg 
≥160 mmHg and increase from baseline ≥20 
mmHg 
To be applied for all positions (including 
missing) except STANDING. 
DBP 
≤45 mmHg and decrease from baseline ≥10 
mmHg 
≥110 mmHg and increase from baseline ≥10 
mmHg 
To be applied for all positions (including 
missing) except STANDING. 
Orthostatic 
Hypotension 
Su SBP < 160 mmHg - 
SBP St – Su  - 20 mmHg 
DBP St – Su  - 10 mmHg 
Su SBP  160 mmHg - 
SBP St – Su  - 30 mmHg 
DBP St – Su  - 15 mmHg 
 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 
ECG 
Ref.: CPMP 1997 guideline. ICH E14 2005 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline ≥20 bpm 
 
PR 
≥220 ms and increase from baseline ≥20 ms 
 
QRS 
≥120 ms & < 120 ms at baseline 
 
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Parameter 
Treatment Emergent PCSV 
Comments 
QTc 
Absolute values (ms) 
>450 ms and baseline <=450 ms 
>480 ms and baseline <=480 ms 
>500 ms and <= 500 ms at baseline 
 
Increase from baseline 
Increase from baseline 30-60 ms 
Increase from baseline >60 ms 
To be applied to any kind of QT correction 
formula.  
 
 
 
QTc>60 ms are the PCSA to be identified in 
individual subjects/patients’ listings. 
 
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11.3. 
Prohibited Non-Steroidal Anti-Inflammatory Drug (NSAID) 
Medication List 
Table 5 
List of Prohibited Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) 
 
 
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Signature Page for VV-RIM-00064748 v2.0
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ESig Approval
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07-Dec-2018 20:30:46 GMT+0000
ESig Approval
07-Dec-2018 20:37:30 GMT+0000
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07-Dec-2018 20:39:37 GMT+0000
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07-Dec-2018 21:18:28 GMT+0000
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                                        VV-RIM-00064748-2.0 Approved - 10 Dec 2018 GMT-5:00