A Randomized, Double-blind, Placebo-controlled, Parallel-group Study to Evaluate the Efficacy and Safety of Evinacumab in Patients With Homozygous Familial Hypercholesterolemia
Phase: PHASE3
Conditions: Homozygous Familial Hypercholesterolemia
Sponsor: Regeneron Pharmaceuticals

IND Number: 116,398 
Eudract Number: 2017-001388-19 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP STUDY TO EVALUATE THE EFFICACY AND 
SAFETY OF EVINACUMAB IN PATIENTS WITH HOMOZYGOUS 
FAMILIAL HYPERCHOLESTEROLEMIA 
Compound: 
Evinacumab (REGN1500) 
Clinical Phase: 
3 
Protocol Number:
R1500-CL-1629  
Protocol Version:
R1500-CL-1629 Amendment 4A 
Amendment 4A Date of Issue 
See appended electronic signature page 
Amendment 3A Date of Issue:
25 Jun 2018 
Amendment 2A Date of Issue: 
04 Dec 2017 
Amendment 1 Date of Issue: 
21 Sep 2017 
Original Date of Issue: 
17 May 2017 
Scientific/Medical Monitor:
 
Director, Clinical Sciences 
Cardiovascular and Metabolism 
Clinical Development and Regulatory Affairs 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
 
VV-RIM-00089245-1.0 Approved - 11 Oct 2019 GMT-5:00
NCT03399786

Clinical Study Protocol 
 
R1500-CL-1629 Amendment 4A 
Regeneron Pharmaceuticals, Inc. 
 
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AMENDMENT HISTORY 
Amendment 4A 
The protocol was amended in response to recent nonclinical findings in the rabbit. The table 
below summarizes the changes and the affected sections:  
Change 
Sections Changed  
In an embryofetal development toxicology 
study in rabbits, incomplete ossification of 
the 15th vertebra was observed in some 
fetuses resulting from the mating of male 
rabbits exposed to evinacumab with female 
rabbits not exposed to evinacumab. In male 
rabbits, there were measurable levels of 
evinacumab in seminal fluid and, as a safety 
measure, the current clinical study is 
amended to require  consistent use of a 
condom for all sexually active males. 
Section 6.2.2 Exclusion Criteria #23 
Table 3 Schedule of Events, Baseline, Double-Blind 
Treatment Period, and Open-Label Treatment Period 
Table 4 Schedule of Events – Follow-up Period 
Updated Scientific/Medical Monitor 
Title Page 
Added abbreviation for WOCBP 
List of Abbreviations 
 
Amendment 3A 
The table below summarizes the changes to the protocol and the affected sections: 
Rationale for Change 
Sections Changed  
Expanded Risk/Benefit section to include 
risk/benefit assessment of the 
combination of evinacumab and PCSK9 
inhibitors, including alirocumab for the 
treatment of patients with homozygous 
familial hypercholesterolemia (HoFH). 
Section 3.2.3 Risk/Benefit Assessment 
Section 21 References 
Clarified the eligibility requirements by 
requiring that patients entering this study 
from R727-CL-1628 meet all of the 
eligibility criteria for this study. 
Clarified that patients enrolling from 
R727-CL1628 will continue to receive 
alirocumab 150 mg every 2 weeks 
(Q2W). 
Clinical Study Protocol Synopsis: Study Design 
Clinical Study Protocol Synopsis: Treatment(s) 
Section 5.1 Study Description and Duration 
Section 7.3 Background Treatment 
 
To be consistent with the 
recommendations from the Clinical Trial 
Facilitation Group (CTFG) on 
contraception and pregnancy testing in 
clinical trials, added “True abstinence: 
When this is in line with the preferred 
Section 6.2.2 Exclusion Criterion #22 
 
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CONFIDENTIAL 
Rationale for Change 
Sections Changed  
and usual lifestyle of the patient. Periodic 
abstinence (calendar, symptothermal, 
post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, 
and lactational amenorrhea method 
(LAM) are not acceptable methods of 
contraception.” 
 
Added exclusion criteria for patients 
housed in an institution on the basis of an 
administrative or judicial order and 
patients who are dependent on the 
sponsor, investigator, or the study site. 
Section 6.2.2 Exclusion Criterion #24, #25 
Editorial or administrative edits 
Section 5.1 Study Description and Duration 
Section 5.3.1 Independent Data Monitoring Committee 
Section 5.3.2 Clinical Events Committee 
Section 6.2.1 Inclusion Criteria #3 
Section 7.6.1 Blinding 
Section 7.8.1 Prohibited Medications and Procedures 
Table 3 Schedule of Events – Baseline, Double-Blind 
Treatment Period 
Table 4 Schedule of Events – Follow-up Period 
Section 8.2.2 Efficacy Procedures 
Section 14.1 Good Clinical Practice Statement 
Section 14.2 Informed Consent 
 
Amendment 2A 
This version of the protocol replaces the previous US-specific amendment 1.  
The table below summarizes the changes to the protocol and the affected sections: 
Rationale for Change 
Sections Changed  
The US-specific version is no longer a 
country-specific version of the protocol, 
and is now designated amendment 2A 
Cover page and header. 
Added a Risk/Benefit section for 
consistency with the sister protocol (2B) 
Section 3.2.3 Risk/Benefit Assessment 
Clarified confirmation of patient’s HoFH 
status and added text for genotyping, as 
well as a DNA sample for genotyping in 
the schedule of events 
Section 5.1 Study Description and Duration 
Table 3 Schedule of Events – Baseline, Double-Blind 
Treatment Period, and Open-Label Treatment Period 
Clarified text for patients who transition 
from study R727-CL-1628 to this study 
Clinical Study Protocol Synopsis: Study Design 
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Regeneron Pharmaceuticals, Inc. 
 
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CONFIDENTIAL 
Rationale for Change 
Sections Changed  
and added a footnote to Table 3. Added 
consent and pharmacogenomics consent 
to schedule of events table. 
Section 5.1 Study Description and Duration 
Table 3 Schedule of Events – Baseline, Double-Blind 
Treatment Period, and Open-Label Treatment Period 
Section 8.1.3 Footnotes for Schedule of Events Table 3: #1 
Clarified language for apheresis 
requirements and collection of clinical 
laboratory samples relative to the timing 
of apheresis procedures, administration 
of PCSK9 inhibitor or mipomersen 
Section 5.1 Study Description and Duration 
Section 8.1.3 Footnotes for Schedule of Events Table 3: #2 
Clarified that patients should be on a 
maximally tolerated regimen of lipid 
modifying therapy 
Clinical Study Protocol Synopsis: Population 
Section 6.2 Study Population 
Section 7.3 Background Treatment 
Added a footnote for timing of collection 
of vital signs on dosing days 
Section 8.1.3 Footnotes for Schedule of Events Table 3: #5 
Added Lipid Panel and  Specialty Lipid 
Panel assessment and assessments of 
hematology, blood chemistry, and 
creatinine phosphokinase for the follow-
up period 
Table 4 Schedule of Events – Follow-up Period 
Added “Query LMT compliance” to SoE 
tables 
Table 1 Schedule of Events – Run-in and Screening 
Table 2 Schedule of Events – Screening for Patients with No 
Run-in Table 3 Schedule of Events – Baseline, Double-Blind 
Treatment Period, and Open-Label Treatment Period 
Table 4 Schedule of Events – Follow-up Period 
Edits/Clarifications 
Clinical Study Protocol Synopsis: Study Design 
Clinical Study Protocol Synopsis: Procedures and 
Assessments 
Section 6.2.2 Exclusion Criteria 
Section 7.8.1 Prohibited Medications and Procedures 
Section 8.1.1 Footnotes for Schedule of Events Table 1 
Section 8.2.7.2 DNA Sample for HoFH Genotyping 
Section 10.4.3.2 Secondary Efficacy Analysis 
US Amendment 1 
The table below summarizes the changes to the protocol and the affected sections: 
Rationale for Change 
Sections Changed  
Added EQ-5D and HADS QOL 
questionnaires and an EQ-5D and HADS 
objective and exploratory endpoint to allow 
assessment of quality of life in this 
population 
Section 2.3  Other Objective 
Section 4.2.4 Other Endpoints 
Table 3: Schedule of Events – Baseline, Double-Blind 
Treatment Period, and Open-Label Treatment Period  
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Rationale for Change 
Sections Changed  
Section 8.1.3  Footnotes for Schedule of Events Table 3: 
footnote #12 
Section 8.2.3 Quality of Life Procedures 
Clarified language for apheresis 
requirements and collection of clinical 
laboratory samples relative to the timing of 
apheresis procedures 
Section 5.1 Study Description and Duration 
Section 6.2.1 Inclusion Criteria #3 
Section 8.1.3 Footnotes for Schedule of Events Table 3 
#1 
Added a criterion excluding patients with 
LDL-C level <70 mg/dL as this is the goal 
for FH patients. Consequently, patients 
already at goal will be excluded. 
Update efficacy procedure for lipids 
Added criterion excluding members of the 
clinical site study team and/or his/her 
immediate family 
Section 6.2.2 Exclusion Criteria #1 and #20 
Section 8.2.2 Efficacy Procedures - (added LDL-C values 
below 25 mg/dL) 
Clarified LDL apheresis therapy during the 
run-in period 
Section 6.2.2 Exclusion Criteria #3 
Section 7.2 Run-in Treatment(s) 
Updated anti-drug antibody  (ADA) 
variables and added a statement for follow-
up of patients positive in the ADA assay 
Section 4.4 Anti-Drug Antibody Variables 
Section 8.2.5.2 Anti-Drug Antibody Measurements and 
Samples 
Added a section on pregnancy testing 
Section 8.2.4.5 Pregnancy Testing 
Clarified collection of data regarding lipid 
modifying therapy 
Clinical Study Protocol Synopsis 
Section 6.2 Study Population 
Section 7.3  Background Treatment(s) 
Added week 4 for ADA sampling 
Removed body weight measurement Day 15 
Removed height measurement at Day 337 
Table 3: Schedule of Events – Baseline, Double-Blind 
Treatment Period, and Open-Label Treatment Period   
Provided a definition for “new onset 
diabetes” as this is an adverse event of 
special interest (AESI) and expanded the list 
of AESIs for evinacumab 
Section 9.4.3 Other Events that Require Accelerated 
Reporting 
Clarified intent to treat population and 
updated methods of analysis to account for 
missing data 
Section 10.3.1.1 Intent-to-Treat 
Section 10.4.3.1 Primary Efficacy Analysis 
Edits/Clarifications 
Clinical Study Protocol Synopsis: Study Design  
Clinical Study Protocol Synopsis: Duration  
Clinical Study Protocol Synopsis: Population  
Section 1 Introduction  
Section 3.2.1 Rationale for Study Design 
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Rationale for Change 
Sections Changed  
Section 5.1 Study Description and Duration and 
Synopsis, Study Duration 
Figure 1: Study Flow Diagram 
Section 6.2 Study Population 
Section 7.3 Background Treatment(s) 
Section 7.4.2 Study Drug Discontinuation 
Section 7.6 Method of Treatment Assignment 
Section 7.7.1 Packaging, Labeling, and Storage 
Section 7.8.2 Permitted Medications and Procedures 
Table 1: Schedule of Events – Run-in and Screening 
Table 2: Schedule of Events – Screening for Patients with 
no Run-in 
Table 3:Schedule of Events – Baseline, Double-Blind 
Treatment Period, and Open-Label Treatment Period 
Table 4: Follow-up Period 
Section 8.1.1 Footnotes for Schedule of Events Table 1: 
#2 
Section 8.1.2 Footnotes for Schedule of Events Table 2: 
#2 
Section 8.1.3 Footnotes for Schedule of Events Table 3: 
#2 and  #3 
Section 8.2.2 Efficacy Procedures - lipid panel 
Section 8.1.5 Early Termination Visit 
Section 8.2.2 Efficacy Procedures 
Section 8.2.4.1 Vital Signs 
Section 8.2.7.2 DNA Sample and HoFH Genotyping 
Section 10.4.4.1 Adverse Events 
 
 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................13 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................18 
1. 
INTRODUCTION ......................................................................................................21 
2. 
STUDY OBJECTIVES ..............................................................................................24 
2.1. 
Primary Objective .......................................................................................................24 
2.2. 
Secondary Objective(s) ...............................................................................................24 
2.3. 
Other Objective ...........................................................................................................24 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................24 
3.1. 
Hypothesis ..................................................................................................................24 
3.2. 
Rationale .....................................................................................................................24 
3.2.1. 
Rationale for Study Design .........................................................................................24 
3.2.2. 
Rationale for Dose Selection ......................................................................................25 
3.2.3. 
Risk/Benefit Assessment ............................................................................................25 
4. 
STUDY VARIABLES................................................................................................27 
4.1. 
Demographic and Baseline Characteristics ................................................................27 
4.2. 
Primary and Secondary Endpoints..............................................................................27 
4.2.1. 
Primary Efficacy Endpoint .........................................................................................27 
4.2.2. 
Key Secondary Efficacy Endpoints ............................................................................28 
4.2.3. 
Other Secondary Efficacy Endpoints ..........................................................................28 
4.2.4. 
Other Endpoints ..........................................................................................................29 
4.3. 
Pharmacokinetic Variables .........................................................................................29 
4.4. 
Anti-Drug Antibody Variables ...................................................................................29 
5. 
STUDY DESIGN .......................................................................................................30 
5.1. 
Study Description and Duration .................................................................................30 
5.1.1. 
End of Study Definition ..............................................................................................33 
5.2. 
Planned Interim Analysis ............................................................................................33 
5.3. 
Study Committees .......................................................................................................33 
5.3.1. 
Independent Data Monitoring Committee ..................................................................33 
5.3.2. 
Clinical Events Committee .........................................................................................33 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............34 
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6.1. 
Number of Patients Planned .......................................................................................34 
6.2. 
Study Population .........................................................................................................34 
6.2.1. 
Inclusion Criteria ........................................................................................................35 
6.2.2. 
Exclusion Criteria .......................................................................................................35 
6.3. 
Premature Withdrawal from the Study .......................................................................38 
6.4. 
Replacement of Patients .............................................................................................39 
6.5. 
Rescreening of Patients ...............................................................................................39 
7. 
STUDY TREATMENTS............................................................................................39 
7.1. 
Investigational and Reference Treatments ..................................................................39 
7.2. 
Run-in Treatment(s) ....................................................................................................40 
7.3. 
Background Treatment(s) ...........................................................................................40 
7.4. 
Dose Modification and Study Treatment Discontinuation Rules ...............................40 
7.4.1. 
Dose Modification ......................................................................................................40 
7.4.2. 
Study Drug Discontinuation .......................................................................................40 
7.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................41 
7.5. 
Management of Acute Reactions ................................................................................41 
7.5.1. 
Acute Infusion Reactions ............................................................................................41 
7.5.1.1. 
Interruption of the Infusion .........................................................................................42 
7.5.1.2. 
Termination of the Infusion ........................................................................................42 
7.6. 
Method of Treatment Assignment ..............................................................................43 
7.6.1. 
Blinding ......................................................................................................................43 
7.6.2. 
Emergency Unblinding ...............................................................................................43 
7.7. 
Treatment Logistics and Accountability .....................................................................44 
7.7.1. 
Packaging, Labeling, and Storage ..............................................................................44 
7.7.2. 
Supply and Disposition of Treatments .......................................................................44 
7.7.3. 
Treatment Accountability ...........................................................................................44 
7.7.4. 
Treatment Compliance ................................................................................................44 
7.8. 
Concomitant Medications and Procedures .................................................................44 
7.8.1. 
Prohibited Medications and Procedures .....................................................................44 
7.8.2. 
Permitted Medications and Procedures ......................................................................45 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................46 
8.1. 
Schedule of Events .....................................................................................................46 
8.1.1. 
Footnotes for Schedule of Events Table 1 ..................................................................51 
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8.1.2. 
Footnotes for Schedule of Events Table 2 ..................................................................51 
8.1.3. 
Footnotes for Schedule of Events Table 3 ..................................................................51 
8.1.4. 
Footnotes for Schedule of Events Table 4 ..................................................................52 
8.1.5. 
Early Termination Visit ..............................................................................................53 
8.1.6. 
Unscheduled Visits .....................................................................................................53 
8.2. 
Study Procedures ........................................................................................................53 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................53 
8.2.2. 
Efficacy Procedures ....................................................................................................53 
8.2.2.1. 
Lipid Panel ..................................................................................................................54 
8.2.2.2. 
Specialty Lipid Panel ..................................................................................................54 
8.2.3. 
Quality of Life Procedures ..........................................................................................54 
8.2.3.1. 
EuroQol-5 Questionnaire ............................................................................................54 
8.2.3.2. 
Patient Assessed Hospital Anxiety and Depression Scale ..........................................54 
8.2.4. 
Safety Procedures .......................................................................................................55 
8.2.4.1. 
Vital Signs ..................................................................................................................55 
8.2.4.2. 
Physical Examination .................................................................................................55 
8.2.4.3. 
Electrocardiogram .......................................................................................................55 
8.2.4.4. 
Laboratory Testing ......................................................................................................55 
8.2.4.5. 
Pregnancy Testing ......................................................................................................57 
8.2.5. 
Pharmacokinetic and Anti-Drug Antibody Procedures ..............................................57 
8.2.5.1. 
Drug Concentration Measurements and Samples .......................................................57 
8.2.5.2. 
Anti-Drug Antibody Measurements and Samples ......................................................57 
8.2.5.3. 
Statin Concentrations ..................................................................................................57 
8.2.6. 
Pharmacodynamic Procedures ....................................................................................57 
8.2.7. 
Other Assessments ......................................................................................................57 
8.2.7.1. 
Review of Diet ............................................................................................................57 
8.2.7.2. 
DNA Sample for HoFH Genotyping ..........................................................................58 
8.2.7.3. 
LDLR Function ...........................................................................................................58 
 
 
 
 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................58 
9.1. 
Obligations of Investigator .........................................................................................58 
9.2. 
Obligations of Sponsor ...............................................................................................59 
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9.3. 
Definitions ..................................................................................................................59 
9.3.1. 
Adverse Event .............................................................................................................59 
9.3.2. 
Serious Adverse Event ................................................................................................59 
9.3.3. 
Adverse Events of Special Interest .............................................................................60 
9.3.4. 
Infusion Reactions ......................................................................................................60 
9.4. 
Recording and Reporting Adverse Events ..................................................................60 
9.4.1. 
Adverse Events ...........................................................................................................60 
9.4.2. 
Serious Adverse Events ..............................................................................................60 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor ...................................61 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................62 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results .............................62 
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 .......................................................................................................65 
9.7. 
Investigator Alert Notification ....................................................................................65 
10. 
STATISTICAL PLAN................................................................................................65 
10.1. 
Statistical Hypothesis ..................................................................................................66 
10.2. 
Justification of Sample Size........................................................................................66 
10.3. 
Analysis Sets ...............................................................................................................66 
10.3.1. 
Efficacy Analysis Sets ................................................................................................66 
10.3.1.1. 
Intent-to-Treat .............................................................................................................66 
10.3.1.2. 
Modified Intent-to-Treat .............................................................................................66 
10.3.2. 
Safety Analysis Sets ...................................................................................................67 
10.3.2.1. 
Double-Blind Safety Analysis Set ..............................................................................67 
10.3.2.2. 
Open-Label Safety Analysis Set .................................................................................67 
10.3.3. 
Other Analysis Sets .....................................................................................................67 
10.4. 
Statistical Methods ......................................................................................................67 
10.4.1. 
Patient Disposition ......................................................................................................67 
10.4.2. 
Demography and Baseline Characteristics .................................................................68 
10.4.3. 
Efficacy Analyses .......................................................................................................68 
10.4.3.1. 
Primary Efficacy Analysis ..........................................................................................68 
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10.4.3.2. 
Secondary Efficacy Analysis ......................................................................................69 
10.4.3.3. 
Multiplicity Considerations ........................................................................................70 
10.4.3.4. 
Other Efficacy Endpoints ...........................................................................................71 
10.4.3.5. 
Subgroup Analyses for the Primary Efficacy Endpoint .............................................71 
10.4.3.6. 
On-Treatment Efficacy Analyses ...............................................................................71 
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 ....................................................................................................74 
10.4.4.4. 
Treatment Compliance ................................................................................................75 
10.4.5. 
Analysis of Drug Concentration and Target Concentration Data ...............................75 
10.4.6. 
Analysis of Anti-Drug Antibody Data ........................................................................75 
10.4.7. 
Analysis of Statin Concentration ................................................................................75 
 
 
10.4.9. 
Timing of Statistical Analyses ....................................................................................75 
10.4.9.1. 
First Step: Main Efficacy and Safety Analysis ...........................................................75 
10.4.9.2. 
Second Step: Final Safety Analysis ............................................................................76 
10.5. 
Additional Statistical Data Handling Conventions .....................................................76 
10.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .........76 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS .....................................76 
11.1. 
Data Management .......................................................................................................76 
11.2. 
Electronic Systems ......................................................................................................76 
12. 
STUDY MONITORING ............................................................................................77 
12.1. 
Monitoring of Study Sites ...........................................................................................77 
12.2. 
Source Document Requirements ................................................................................77 
12.3. 
Case Report Form Requirements ................................................................................77 
13. 
AUDITS AND INSPECTIONS .................................................................................77 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................78 
14.1. 
Good Clinical Practice Statement ...............................................................................78 
14.2. 
Informed Consent .......................................................................................................78 
14.3. 
Patient Confidentiality and Data Protection ...............................................................78 
14.4. 
Institutional Review Board/Ethics Committee ...........................................................79 
15. 
PROTOCOL AMENDMENTS ..................................................................................79 
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16. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................79 
16.1. 
Premature Termination of the Study ...........................................................................79 
16.2. 
Close-out of a Site ......................................................................................................80 
17. 
STUDY DOCUMENTATION ...................................................................................80 
17.1. 
Certification of Accuracy of Data ...............................................................................80 
17.2. 
Retention of Records ..................................................................................................80 
18. 
CONFIDENTIALITY ................................................................................................81 
19. 
FINANCING AND INSURANCE .............................................................................81 
20. 
PUBLICATION POLICY ..........................................................................................81 
21. 
REFERENCES ...........................................................................................................82 
22. 
INVESTIGATOR’S AGREEMENT ..........................................................................84 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................87 
 
LIST OF TABLES 
Table 1: 
Schedule of Events – Run-in and Screening ...............................................................46 
Table 2: 
Schedule of Events – Screening for Patients with No Run-in ....................................47 
Table 3: 
Schedule of Events – Baseline, Double-Blind Treatment Period, and Open-
Label Treatment Period ..............................................................................................48 
Table 4: 
Schedule of Events – Follow-up Period .....................................................................50 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................33 
 
LIST OF APPENDICES 
Appendix 1. Factors to Consider in Assessing the Relationship of Adverse Events to 
Study Drug and Study Conduct or Study Procedure or Background 
Treatment, etc. .......................................................................................................85 
Appendix 2. Summary of TLC Diet for High Cholesterol ..........................................................86 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A randomized, double-blind, placebo-controlled, parallel-group study to 
evaluate the efficacy and safety of evinacumab in patients with homozygous 
familial hypercholesterolemia 
Site Location(s) 
 
Principal Investigator 
Approximately 30 sites multinationally  
Multi-center  
Objective(s) 
The primary objective of the study is: 
 
To demonstrate the reduction of low-density lipoprotein 
cholesterol (LDL-C) by evinacumab 15 mg/kg intravenously 
(IV) in comparison to placebo after 24 weeks in patients with 
homozygous familial hypercholesterolemia (HoFH). 
The secondary objectives of the study are: 
 
To evaluate the effect of evinacumab 15 mg/kg IV on other 
lipid 
parameters 
(ie, 
apolipoprotein 
B 
[Apo 
B], 
non-high-density 
lipoprotein 
cholesterol 
[HDL-C], 
total-cholesterol [TC]) in patients with HoFH 
 
To evaluate the effect of evinacumab on LDL-C goal 
attainment 
 
To assess the effect of evinacumab on eligibility for apheresis 
(using German and US apheresis criteria) 
 
To evaluate the safety and tolerability of evinacumab 15 
mg/kg in patients with HoFH 
 
To assess the pharmacokinetics (PK) of evinacumab in 
patients with HoFH 
 
To evaluate the potential development of anti-evinacumab 
antibodies 
Study Design 
The study consists of the following periods: up to 8-week run-in period (for 
patients who may require HoFH genotyping, for patients whose background 
medical lipid modifying therapy [LMT] has not been stable prior to 
screening or whose apheresis settings and/or schedule have not been stable 
for at least 8 weeks prior to screening), a 2-week screening period, a 24-
week double-blind treatment period (DBTP), and a 24-week open-label 
treatment period (OLTP), and a 24-week follow-up period after the last dose 
of study drug for those patients who choose not to enter the optional open-
label study. 
Patients who are not undergoing apheresis therapy, patients who have been 
on a stable apheresis schedule for at least 8 weeks before the screening visit, 
and patients on stable background medical LMT (as applicable) for at least 
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4 weeks (6 weeks for fibrates, 8 weeks for proprotein convertase 
subtilisin/kexin type 9 [PCSK9] inhibitor antibodies, 12 weeks for 
lomitapide, 24 weeks for mipomersen) before the screening visit, will enter 
a 2-week screening period. 
Patients who participated in the R727-CL-1628 study may enter the run-in 
or screening period or enroll directly into this study. Patients who completed 
the R727-CL-1628 study and fulfill all of the eligibility criteria can be 
enrolled directly into this study.  Data collected during the R727-CL-1628 
study (ie, lab test results) can be used to assess eligibility criteria for these 
patients. If these patients meet all the eligibility criteria and if approved by 
the sponsor, the patients may not have to undergo the screening visit in this 
study. In this case, overlapping assessments completed at the end-of-open-
label treatment visit in R727-CL-1628 do not need to be repeated during the 
R1500-CL-1629 baseline visit.  The baseline/day 1 visit can occur 
immediately after the end of the open-label treatment visit in the R727-CL-
1628 study. To ensure continuity of treatment with alirocumab, all patients 
from R727-CL-1628 entering this study will be provided alirocumab. 
Patients who meet all the inclusion criteria and none of the exclusion criteria 
will be randomized 2:1 to receive evinacumab 15 mg/kg IV every 4 weeks 
(Q4W) or matching placebo IV Q4W for the double-blind portion of the 
study (24 weeks). Randomization will be stratified by apheresis treatment 
(Yes, No) and by region (Japan, Rest of World). 
After completion of the DBTP, all patients will enter a 24-week OLTP and 
receive open-label evinacumab 15 mg/kg IV Q4W. 
After completion of the 24-week OLTP, all patients who have successfully 
completed this study might have the opportunity to participate in a separate 
open-label (OL) study.  All patients that enroll in the separate OL study will 
continue to receive open-label evinacumab at a dose of 15 mg/kg IV Q4W.  
Those patients who do not participate in the separate OL study will undergo 
a 24-week follow-up after the last dose of study drug. 
Study Duration 
The duration of the study including run-in (8 weeks), screening (2 weeks), 
DBTP and OLTP (48 weeks), and follow-up (20 weeks) may be up to 
78 weeks. 
Population 
 
 
Sample Size: 
Approximately 57 patients will be randomized at approximately 
30 multinational sites 
 
Target Population: 
The study population will consist of males and females ≥18 years of age 
diagnosed with homozygous FH (HoFH), receiving stable lipid modifying 
therapy (LMT), as applicable.  Patients should be on a maximally tolerated 
daily statin, ezetimibe, and a PCSK9 inhibitor antibody unless the patient 
has a documented history of tolerability issues, little or no response to 
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therapy or other documented reason.  Lipid modifying therapies may also 
include other lipid lowering therapies, including low-density lipoprotein 
(LDL)-apheresis. 
Treatment(s) 
 
 
Study Drug 
 
Dose/Route/Schedule: 
In the double-blind treatment period, eligible patients will be enrolled to 
receive evinacumab 15 mg/kg IV Q4W 
In the open-label portion of the study, all patients will receive evinacumab 
15 mg/kg IV Q4W starting at week 24 
 
Placebo 
 
Route/Schedule: 
In the double-blind treatment period, placebo matching IV evinacumab 
Q4W 
 
Background Treatment 
 
Dose/Route/Schedule: 
Patients who are on LMT or who are undergoing apheresis should maintain 
stable LMT and a stable apheresis schedule (as applicable) throughout the 
duration of the study, from screening to the end of double-blind treatment 
period visit (week 24), and continuing through week 48 of the open-label 
treatment period. 
Patients who enter this study after completing study R727-CL-1628 will 
continue to receive alirocumab 150 mg subcutaneous (SC) every 2 weeks 
(Q2W) for the duration of the study. 
Endpoint(s) 
 
 
Primary: 
The primary endpoint is the percent change in calculated LDL-C from 
baseline to week 24. 
 
Secondary: 
 
The percent change in Apo B from baseline to week 24 
 
The percent change in non-HDL-C from baseline to week 24 
 
The percent change in TC from baseline to week 24 
 
The proportion of patients with ≥30% reduction in LDL-C at 
week 24 
 
The proportion of patients with ≥50% reduction in LDL-C at 
week 24 
 
The proportion of patients with LDL-C <100 mg/dL 
(2.59 mmol/L) at week 24 
 
The change in calculated LDL-C from baseline to week 24 
 
The proportion of patients who meet EU apheresis eligibility 
criteria (see German Apheresis Working Group) from 
baseline to week 24 
 
The proportion of patients who meet US apheresis eligibility 
criteria (see US [National Lipid Association] Lipid Apheresis 
Criteria) from baseline to week 24 
Procedures and Assessments 
The efficacy of evinacumab will be assessed by clinical laboratory 
evaluation of lipid levels at pre-specified time points throughout the study. 
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Overall safety will be assessed by monitoring/evaluation of treatment-
emergent adverse events (TEAEs), physical examinations, vital signs, 
electrocardiogram (ECG), and clinical safety laboratory tests at pre-
specified time points. 
The potential emergence of anti-evinacumab antibodies will also be 
evaluated. 
Statistical Plan 
Sample Size Determination For the primary efficacy hypothesis during the 
double-blind treatment period, a total sample size of 57 patients (38 on 
evinacumab and 19 on placebo) will have 90% power to detect a treatment 
group difference in mean percent change LDL-C of 38% with a 0.05 
two-sided significance level and assuming a common standard deviation of 
35%. This sample size has been adjusted for a 5% non-evaluable patient rate 
for the primary efficacy endpoint, and a 15% dropout rate. 
Primary Efficacy Analysis The double-blind primary efficacy analysis will 
compare the evinacumab 15 mg/kg IV treatment group to placebo at 
week 24. The primary efficacy endpoint is the percent change in calculated 
LDL-C from baseline to week 24. The percent change from baseline in 
calculated LDL-C will be analyzed in the ITT (intent-to-treat) population 
(defined as all randomized patients who had an evaluable primary endpoint, 
regardless of adherence to study treatment) using a mixed-effect model with 
repeated measures (MMRM) approach. All post-baseline data available 
within week 2 to week 24 analysis windows will be used and missing data 
are accounted for by the MMRM model. The model will include the fixed 
categorical effects of treatment group (placebo versus evinacumab), 
randomization strata, time point, strata-by-time point interaction, and 
treatment by time point interaction, as well as the continuous fixed 
covariates of baseline LDL-C value and baseline value-by-time point 
interaction. The statistical testing of the comparison for the primary measure 
will be evaluated at a 2-sided significance level of 0.05. 
Subgroup Analyses for the Primary Efficacy Endpoint. Analyses are 
planned on the primary efficacy endpoint to access the homogeneity of 
evinacumab treatment effect across various patient subgroups in the ITT 
population, including the 2 stratification factors LDL-C apheresis and 
region, and patients with or without receptor-negative mutations in both 
low-density lipoprotein receptor (LDLR) alleles. Statistical analysis 
methods will be provided in the statistical analysis plan (SAP) 
Statistical analyses will be conducted in 2 steps. The first analysis will be 
conducted as soon as all patients have been randomized and all data through 
week 24 (double-blind period) have been collected and validated. This first 
analysis will consist of the final analysis of the primary and secondary 
efficacy endpoints. The results of the first analysis will not be used to change 
the conduct of the ongoing study in any aspect. Since data collection for the 
double-blind primary efficacy measure and key secondary efficacy 
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measures will have been concluded at the time of this first analysis, the 
significance level for the study remains at 0.05. 
The second analysis will be conducted at the end of the open-label treatment 
period (end of study) and will consist of the final analysis for safety and 
open-label treatment period exploratory efficacy measures. 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANGPTL3 
Angiopoietin-like 3 
Apo A-1 
Apolipoprotein A-1 
Apo B 
Apolipoprotein B 
ApoCIII 
Apolipoprotein CIII 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CEC 
Clinical Events Committee 
CI 
Confidence interval 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
CV 
Cardiovascular 
CVD 
Cardiovascular disease 
DBTP 
Double-blind treatment period 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EOT 
End of treatment 
EDC 
Electronic data capture 
FH 
Familial hypercholesterolemia 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
HDL 
High-density lipoprotein 
HDL-C 
High-density lipoprotein cholesterol 
HoFH 
Homozygous familial hypercholesterolemia 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IRB 
Institutional Review Board 
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ITT 
Intent-to-treat 
IV 
Intravenously 
IVRS 
Interactive voice response system 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LDL-C 
Low-density lipoprotein cholesterol 
LDLR 
Low-density lipoprotein receptor 
LDLRAP1 
Low-density lipoprotein receptor adaptor protein 1 
LMT 
Lipid modifying therapy 
LOF 
Loss-of-function 
Lp(a) 
Lipoprotein a 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 
MMRM 
Mixed-effect model with repeated measures 
MTD 
Maximum tolerated dose 
OL 
Open-label 
OLTP 
Open-label treatment period 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PMM 
Pattern Mixture Model 
PT 
Preferred term 
Q2W 
Every 2 weeks 
Q4W 
Every 4 weeks 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SD 
Standard deviation 
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SE 
Standard error 
SMT 
Safety monitoring team 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TC 
Total cholesterol 
TEAE 
Treatment-emergent adverse event 
TG 
Triglyceride 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WOCBP 
Women of child bearing potential 
 
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1. 
INTRODUCTION 
Homozygous familial hypercholesterolemia (HoFH) is a rare and serious genetic condition 
resulting in severely elevated low-density lipoprotein cholesterol (LDL-C) and accelerated 
cardiovascular disease (CVD). Familial hypercholesterolemia results from mutations in the 
low-density lipoprotein receptor (LDLR), or in 3 associated genes: proprotein convertase 
subtilisin/kexin type 9 (PCSK9), apolipoprotein B (Apo B), and LDLR adaptor protein 1 
(LDLRAP1). Regardless of the underlying mutations, patients with familial hypercholesterolemia 
(FH) are phenotypically similar, but vary with respect to severity of the condition. Mutations in 
LDLR, PCSK9, and Apo B have a dominant mode of transmission, while mutations in LDLRAP1 
have 
a 
recessive 
mode 
of 
transmission 
(http://omim.org/entry/143890; 
http://omim.org/entry/603813). The vast majority of mutations that lead to FH derive from 
mutations in the LDLR (between 60-80%) (Youngblom 1993). 
Homozygous FH is frequently caused by mutations in both alleles of the LDLR gene and results 
in the decreased clearance of LDL particles from plasma. Patients with HoFH have severe 
hypercholesterolemia, often 3 to 6 times normal (500 to 1000 mg/dL), which can lead to an 
exceedingly high risk of developing premature atherosclerosis, as well as valvular and 
supravalvular stenosis. In children as young as 7 years of age, mild coronary atherosclerosis can 
be evident even without any clinically apparent coronary artery disease. This accelerated 
atherosclerosis results in premature CVD and an increased risk of a cardiovascular (CV) event. A 
recent observational study of HoFH patients demonstrated that the mean age for first major CV 
event was 20 years (Goldstein 2001, Kolansky 2008, Macchiaiolo 2012, Rader 2003). 
Patients with HoFH tend to be treated with multiple lipid-lowering medications in order to try and 
attain LDL-C levels that are closer to optimal for adults. Consensus statements recommend starting 
drug treatment as soon as possible and targeting LDL-C goals of <70 mg/dL or <100 mg/dL 
depending on risk (Cuchel 2014, France 2016). Many of the therapies for hypercholesterolemia 
are dependent on their stimulating an increase in activity of the LDLR. Part of the basis for the 
refractory nature of treatments is linked to the mutations in the LDLR that are the driver of HoFH. 
Low-density lipoprotein cholesterol-lowering therapies in patients with HeFH and a single 
mutation in the LDLR can rely on the normally functioning LDLR allele to provide similar efficacy 
as in non-FH patients. However, the presence of mutations in both LDLR alleles can result in far 
less efficacy for therapies that rely on the LDLR as part of their mechanism of action. Examples 
of such therapies include statins and PCSK9 inhibitor antibodies. Mutations in the LDLR can range 
from being defective (where the LDLR retains some LDL-binding functionality) to null or negative 
mutations where no functioning LDLR is expressed. Residual LDLR activity ranges from <2% for 
patients who are receptor negative to 2-25% for patients who are LDLR defective (Cuchel 2014). 
In the most extreme cases are patients with two null/negative LDLR mutations. These patients tend 
to have higher LDL-C levels and worse clinical outcome than patients who are LDLR defective 
(Kolansky 2008, Moorjani 1993). Patients who are LDLR negative develop xanthomas sooner 
than patients who are LDLR defective, and untreated patients who are LDLR negative rarely live 
past the second decade (Kolansky 2008, Moorjani 1993). These patients tend to have untreated 
LDL-C levels at the highest end of the range and in many cases see no efficacy from drugs such 
as statins or PCSK9 inhibitor antibodies because of their near total lack of functional LDLRs 
(Marais 2008, Raal 2000, Raal 1997). 
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While statins can reduce LDL-C by more than 50% in patients with HeFH or with polygenic forms 
of hypercholesterolemia, in HoFH patients, statins may provide a decrease of <15 to 30% 
(Crestor 2003, Lipitor 1996, Zocor 1991). When ezetimibe is added to a statin, LDL-C may be 
reduced by 21 to 27% (Zetia 2002), but many patients with HoFH treated with a high-dose statin 
and ezetimibe remain far from their LDL-C goal. In patients with little or no LDLR activity, 
including patients with null/null mutations, statins provide minimal efficacy. Some patients who 
are receptor-negative (LDLR activity <2%) may respond to statin therapy (Raal 2000), but the 
degree of response tends to be less than those patients with residual LDLR function (Rader 2003). 
Although anti-PCSK9 therapy provides an effective treatment in patients with HeFH and 
polygenic causes of hypercholesterolemia, it appears to be minimally effective in the HoFH 
patient. In the recent TESLA study in patients with HoFH, evolocumab therapy resulted in a mean 
percent reduction in LDL-C of 23.1% (Raal 2015). In the subset of patients known to have two 
LDLR negative alleles, no response was observed with evolocumab (Repatha 2015). 
Other therapies for HoFH, mipomersen and lomitapide, can provide an additional ~25% and 40% 
reduction in LDL-C, respectively. However, these therapies are associated with high rates of 
gastrointestinal side effects (lomitapide), hepatic abnormalities including hepatic steatosis and 
increases in liver function tests (lomitapide and mipomersen) and frequent injection site reactions 
(mipomersen) (Cuchel 2013, Raal 2010). 
High-dose statins, ezetimibe, anti-PCSK9 monoclonal antibodies (mAb), mipomersen, and 
lomitapide may be effective in some patients with HoFH, but many patients still require lipid 
apheresis (Goldberg 2011). Lipid apheresis can be effective, but entails treatments lasting several 
hours multiple times a month, is both costly and associated with a risk of infections (Vella 2001, 
Kajinami 1999), and is not routinely available in all geographical areas (Thompson 2010). 
Despite treatment with lipid modifying therapies (LMTs), such as pharmacological agents, as well 
as mechanical removal by lipid apheresis, many patients with HoFH remain far from their LDL-C 
treatment goal. Therefore, the need for more intensive treatment in HoFH, especially those patients 
with double null mutations remains. 
Angiopoietin-like 3 (ANGPTL3) has recently emerged as a potential target for the treatment of 
elevated levels of triglycerides (TGs) and for the treatment of elevated levels of LDL-C, both risk 
factors for the development of CVD. ANGPTL3 acts as a natural inhibitor of lipoprotein lipase, 
an endothelial-bound enzyme involved in the hydrolysis of the TG content of very-low-density 
lipoproteins and chylomicron lipoproteins. Patients who are homozygous for loss-of-function 
(LOF) mutations in ANGPTL3 have lower levels of LDL-C (mean difference of 48% versus 
control family members). The mechanism by which ANGPTL3 LOF mutations result in lowered 
LDL-C levels is not fully understood, but appears to be independent of the effects on TGs and 
independent of the LDLR. It is noteworthy that patients with one or two ANGPTL3 LOF alleles 
also have reported reductions in serum high-density lipoprotein (HDL) cholesterol (HDL-C) 
levels. The mechanism for this may be related to the inhibitory effect of ANGPTL3 on endothelial 
lipase, which is involved in the hydrolysis of HDL phospholipids. Importantly, no health deficits 
have been reported in the relatively small number of patients who are homozygous for ANGPTL3 
LOF mutations. These data suggest that inhibiting ANGPTL3 may be a meaningful and well-
tolerated strategy for lowering serum LDL-C and TGs. 
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Evinacumab (REGN1500) is a fully human mAb, created with Regeneron’s VelocImmune 
technology platform, which specifically binds to ANGPTL3. Experiments performed in animals 
demonstrate that the administration of evinacumab results in a reduction of serum LDL-C and 
serum TGs. In hyperlipemic mice models (ApoE -/-, Ldlr -/-, db/db), single administrations of 
evinacumab led to reductions in LDL-C, TGs, and HDL-C up to 49%, 72%, and 39%, respectively. 
Specifically in mice that have absent LDLR function (Ldlr -/- mice), administration of evinacumab 
resulted in a 23% reduction in LDL-C. Therefore, it appears that ANGPTL3 inhibition lowers 
LDL-C through an LDLR-independent mechanism. 
In a phase 1, first-in-human, placebo-controlled, double-blind, ascending single-dose study 
(R1500-HV-1214) of the safety, tolerability, and bioeffect of evinacumab administered 
subcutaneously (SC) or intravenously (IV) in healthy volunteers with modest elevations in TGs 
and/or LDL-C at baseline, 99 subjects received placebo or evinacumab at 1 of the following dose 
levels: 75 mg SC, 150 mg SC, 250 mg SC, 5 mg/kg IV, 10 mg/kg IV, or 20 mg/kg IV. Among 
these subjects with elevations of TG levels 150 to 450 mg/dL (1.69 mmol/L to 5.09 mmol/L) 
and/or LDL-C ≥100 mg/dL (2.59 mmol/L), the maximal mean percent LDL-C decrease from 
baseline of 27.8% was observed on day 15 in the 20 mg/kg IV group (n=11) compared to a decrease 
of 4.5% in the placebo IV group (n=12). A maximal mean percent HDL-C decrease from baseline 
of 27.3% was observed on day 15 in the 10 mg/kg IV group (n=9) compared to a 1.8% decrease 
in the placebo IV group (n=12). For all subjects in the 20 mg/kg IV group (n=11), the median 
percent decrease in TG from baseline on day 4 was 75.0% vs an increase of 9% in the placebo IV 
group (n=12). Evinacumab was well tolerated at all dose levels. 
In a randomized, double-blind, placebo-controlled, multiple ascending dose study 
(R1500-CL-1321) of the safety, tolerability, pharmacokinetics (PK), immunogenicity, and 
pharmacodynamic (PD) effects of evinacumab in subjects with mixed dyslipidemia (TGs 150-500 
mg/dL [1.69 mmol/L to 5.09 mmol/L] and LDL-C ≥100 mg/dL [2.59 mmol/L]), subjects who 
received evinacumab 20 mg/kg IV every 4 weeks (Q4W) achieved a mean percent reduction from 
baseline in LDL-C of 34.7% at day 57. Those patients who received evinacumab 300 mg SC every 
2 weeks (Q2W) achieved a mean percent reduction in LDL-C of 33.4% from baseline. Evinacumab 
was well tolerated in doses up to 20 mg/kg IV Q4W. 
In an open-label, single-arm, proof-of-concept study in patients with HoFH, (Study 
R1500-CL-1331), evinacumab demonstrated a mean percent reduction from baseline of 49.2% 
(n=9) at week 4, with a duration of effect of at least 10 weeks after a 15 mg/kg IV dose (n=7).  A 
peak mean reduction of 52.1% was observed at week 6. Three patients enrolled in Study 
R1500-CL-1331 are homozygous for null mutations in the LDLR. Evinacumab provided 
meaningful reductions in LDL-C in these 3 null/null HoFH patients (26-44% percent change in 
LDL-C by week 4). Evinacumab has been well tolerated in this proof-of-concept study.  
Additional background information on the study drug and development program can be found in 
the Investigator’s Brochure. 
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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of the study is to demonstrate the reduction of LDL-C by evinacumab 
15 mg/kg IV in comparison to placebo after 24 weeks in patients with HoFH. 
2.2. 
Secondary Objective(s) 
The secondary objectives of the study are: 
 To evaluate the effect of evinacumab 15 mg/kg IV on other lipid parameters 
(ie, Apo B, non-HDL-C, total cholesterol [TC]) in patients with HoFH 
 To evaluate the effect of evinacumab on LDL-C goal attainment 
 To assess the effect of evinacumab on eligibility for apheresis (using German and US 
apheresis criteria) 
 To evaluate the safety and tolerability of evinacumab 15 mg/kg in patients with 
HoFH 
 To determine concentrations of evinacumab in patients with HoFH 
 To evaluate the potential development of anti-evinacumab antibodies 
2.3. 
Other Objective 
 Genotyping will be performed for all patients to identify mutations causing HoFH and 
to characterize LDLR function, in order to explore potential differences in efficacy 
and safety. 
 To assess the effect of evinacumab on quality of life using the EQ-5D and HADS 
QOL questionnaires 
3. 
HYPOTHESIS AND RATIONALE  
3.1. 
Hypothesis 
Blockade of ANGPTL3 with evinacumab will reduce LDL-C in patients with HoFH. 
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
This study is intended to demonstrate efficacy and safety of evinacumab in the treatment of HoFH.  
Diagnosis of HoFH will be based on either genotyping or clinical criteria. The genetic definition 
will include all individuals considered to be FH homozygotes, which is defined by the presence of 
the same mutation(s) in both LDLRs, Apo B, PCSK9 or LDLRAP1 alleles, or individuals 
considered to be compound heterozygotes, defined by the presence of different mutations in the 
same allele, or double heterozygotes, defined as mutations in different genes. 
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The percent change in LDL-C from baseline to week 24 will be the primary endpoint. LDL-C is 
an accepted surrogate endpoint for CV risk, and has repeatedly been used as the primary endpoint 
for approval of multiple other HoFH treatments. This study is designed as a placebo-controlled 
trial with the addition of evinacumab on top of patients’ existing treatment regimens of maximally 
tolerated LMT, including lipid apheresis. This study will utilize a run-in period for those patients 
whose LMT regimen is not stable. This “add-on” design is appropriate because removal of any 
therapies from patients’ existing treatment regimen will lead to an increase in LDL-C and possibly 
contribute to the serious CV sequelae seen in this severe disease with high CV risk.  
The study consists of 4 periods: run-in (for patients whose background medical LMT has not been 
stable for at least 4 weeks prior to screening or whose apheresis settings and/or schedule have not 
been stable for at least 8 weeks prior to screening), screening, double-blind treatment, and open-
label treatment. In the 24-week double-blind treatment period (DBTP), patients will receive 
evinacumab 15 mg/kg IV Q4W or matching placebo IV Q4W. 
In order to provide additional safety, PK, and long term efficacy information on evinacumab in 
this rare patient population, after completion of the DBTP, all patients will enter a 24-week open-
label treatment period (OLTP). During the OLTP portion of the study, all patients, regardless of 
treatment assignment in the DBTP, will receive evinacumab 15 mg/kg IV every month. 
3.2.2. 
Rationale for Dose Selection 
The 15 mg/kg IV dose is selected based on safety and the substantial LDL-C reduction observed 
in HoFH patients in study R1500-CL-1331. The higher dose regimen of 20 mg/kg IV Q4W 
demonstrated favorable tolerability when given as an 8-week treatment in otherwise healthy 
subjects (R1500-CL-1321) and so the 15 mg/kg IV Q4W regimen is expected to also demonstrate 
favorable tolerability, because the evinacumab exposure within each dosing interval is expected to 
be lower and the accumulation of serum concentration with a monthly dosing frequency is 
predicted to be minimal. From an efficacy perspective, the 15 mg/kg IV dose has previously 
demonstrated evinacumab concentrations above 100 mg/L for approximately 4 weeks; an 
exposure threshold associated with target saturation and maximal effect on TG reduction (R1500-
CL-1321 and R1500-HV-1214). Based on these PK/PD data, combined with the efficacy data from 
the proof-of-concept study in HoFH (R1500-CL-1331), 15 mg/kg IV is expected to maintain target 
saturation and thereby to provide maximal benefit during the monthly dosing interval. 
3.2.3. 
Risk/Benefit Assessment 
Patients with HoFH have extremely high LDL-C levels, are far from their target level and will 
require significant reductions to get to their goal. Despite the approval of newer treatments 
including evolocumab, lomitapide and mipomersen, the need for more intensive therapies remains. 
Evinacumab could be a new addition to the armamentarium of LMT that could contribute to 
lowering the LDL-C of patients with HoFH. In study R1500-CL-1331, evinacumab demonstrated 
a mean percent reduction from baseline of 49.2% (n=9) at week 4, with a duration of effect of at 
least 10 weeks after a 15 mg/kg IV dose (n=7). A peak mean reduction of 52.1% was observed at 
week 6. Three patients in the study are homozygous for null mutations in the LDLR. Treatment 
with evinacumab in these difficult-to-treat patients reduced LDL-C by an average of 37.3% at 
week 4 with peak reductions up to 59.5%. Based on these data, it is expected that the addition of 
evinacumab to existing treatments will lead to significant LDL-C reductions in the HoFH 
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population. The body of evidence from the statin literature shows that the relationship between 
LDL-C reduction and CV event reduction is approximately linear and for every 1 mmol/L (38.7 
mg/dL) reduction in LDL-C there is a corresponding 22% risk reduction in CV events 
(Cholestrol Treatment Trialists’ Collaboration 2010). Moreover, the results from the recent 
outcomes trials with ezetimibe (IMPROVE-IT [Cannon 2015]), alirocumab (ODYSSEY 
OUTCOMES [Steg 2018]) and evolocumab (FOURIER [Sabatine 2017]) reinforce this concept, 
providing additional evidence for the relationship between LDL-C lowering and reductions in CV 
events and the importance for patients to achieve their target LDL-C. Within the context of this 
study in the HoFH patient population, additional reduction in LDL-C may get patients closer their 
LDL-C target, which could translate into significant benefits.  
It is also expected that treatment with evinacumab will be well tolerated and have an acceptable 
safety profile. The accumulated safety information from the completed and ongoing clinical 
studies is marked by the absence of any important identified risks. There are potential risks that 
include systemic hypersensitivity reactions, immunogenicity, and embryofetal toxicity. These 
risks will be managed through careful patient selection and monitoring. For the potential 
embryofetal toxicity risk, there is a strict risk mitigation plan, including requirements for consistent 
use of contraception for sexually active male study participants and sexually active female study 
participants of child-bearing potential. 
Patients entering this study should be on a background statin, ezetimibe, and a PCSK9 inhibitor, 
unless they have a documented history of tolerability issues, lack of efficacy, or other reason.  
Patients should be on these lipid lowering drugs because of the above mentioned proven CV risk 
reduction demonstrated in recent CV outcomes trials (ODYSSEY OUTCOMES, FOURIER, 
IMPROVE-IT).  There are 2 PCSK9 inhibitors on the market; evolocumab is approved for use in 
patients with HoFH in most countries, and alirocumab is currently being evaluated in a double-
blind placebo-controlled study in patients with HoFH (study R727-CL-1628, ODYSSEY HoFH).  
Patients entering this study may be taking either evolocumab or alirocumab.  Patients who 
complete study R727-CL-1628 (ODYSSEY HoFH) with alirocumab are permitted to participate 
in this study and will continue to receive alirocumab as part of their background LMT.  The 
concurrent use of evinacumab with alirocumab is considered to have an acceptable benefit/risk 
profile because it could be beneficial and is not considered to pose any safety concerns. 
Evinacumab and alirocumab have different mechanisms of action and concomitant administration 
of both agents is not expected to perturb the action of the other.  Rather, their distinct mechanisms 
of action are anticipated to complement each other to lower LDL-C since they work at different 
sites of action. 
The safety profile of each agent is considered acceptable and the concurrent use of the 2 agents 
together is not expected to augment or exacerbate potential adverse events (AEs).  Concomitant 
use of evinacumab and evolocumab was found to have an acceptable safety profile in 4 patients in 
the R1500-CL-1331 study, a study evaluating evinacumab in 9 patients with HoFH (details of the 
study are provided in the evinacumab Investigator’s Brochure and the Introduction [Section 1]).  
No safety signals or adverse effects related to the concomitant use of both agents have been 
observed.  The safety of the use of evinacumab along with alirocumab will be carefully monitored 
in this study. Safety monitoring will include ongoing reviews by an unblinded Independent Data 
Monitoring Committee (IDMC), by the sponsor’s blinded safety monitoring team (SMT), and by 
the blinded clinical study team.  If significant safety trends or findings are identified by either the 
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IDMC or the sponsor’s blinded study team or SMT, they will be escalated and appropriately 
evaluated to understand the best course of action. 
From the perspective of PK drug-drug interactions, co-administration of evinacumab, alirocumab, 
and the other possible background LMT (statin, ezetimibe, etc) is not expected to result in drug-
drug interactions with each other or other drugs. Evinacumab and alirocumab are both eliminated 
via a combination of non-saturable, linear, proteolytic degradation and saturable, non-linear target-
mediated clearance. The 2 molecules bind to different targets and the target-mediated pathways 
are entirely independent. Neither evinacumab nor alirocumab are a cytokine or cytokine 
modulator; therefore, it is not anticipated to interact directly or indirectly with cytochrome P450 
enzymes, other drug metabolizing enzymes or drug transporters, which are known to influence the 
disposition of statins.  Conversely, the PK of evinacumab is not expected to be impacted by statins, 
due to its elimination pathways. 
Indeed, the concomitant administration of 2 fully human monoclonal antibodies may be a new 
treatment paradigm in CV medicine, but not uncommon in other therapeutic areas such as 
autoimmune disease or oncology.  Experience in those areas has demonstrated the use of multiple 
biologic agents to be acceptable from a safety and tolerability perspective. 
For the reasons stated above, the benefit/risk profile for the concurrent use of evinacumab and 
PCSK9 inhibitor antibodies or the use of evinacumab in the absence of a PCSK9 inhibitor antibody 
as part of the background LMT is considered favorable. 
4. 
STUDY VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height), lipid 
levels, medical history (including allergic history), mutation status, medication history, and 
apheresis schedule (if applicable) for each patient. Patients’ history on other medications for 
treatment of HoFH will be documented on a specific page of the case report form (CRF). 
4.2. 
Primary and Secondary Endpoints 
4.2.1. 
Primary Efficacy Endpoint 
The primary endpoint is the percent change in calculated LDL-C from baseline to week 24. The 
primary endpoint is defined as:  100x (calculated LDL-C value at week 24 - calculated LDL-C 
value at baseline)/calculated LDL-C value at baseline. 
The baseline LDL-C value will be the last calculated LDL-C value obtained before the first dose 
of double-blind-study drug. The calculated LDL-C at week 24 will be the LDL-C value obtained 
within the week 24 analysis window, regardless of adherence to treatment and subsequent 
therapies (intent-to-treat [ITT] estimand). 
All calculated LDL-C values (scheduled or unscheduled, fasting or not fasting) may be used to 
provide a value for the primary efficacy endpoint, if appropriate, according to the above definition. 
The analysis window used to allocate a time point to a measurement will be defined in the 
statistical analysis plan (SAP). 
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4.2.2. 
Key Secondary Efficacy Endpoints  
The key secondary endpoints are:   
 The percent change in Apo B from baseline to week 24 (ITT estimand) 
 The percent change in non-HDL-C from baseline to week 24 (ITT estimand) 
 The percent change in TC from baseline to week 24 (ITT estimand) 
 The proportion of patients with ≥30% reduction in calculated LDL-C at week 24 
(ITT estimand) 
 The proportion of patients with ≥50% reduction in calculated LDL-C at week 24 
(ITT estimand) 
 The proportion of patients with LDL-C <100 mg/dL [2.59 mmol/L] at week 24 
(ITT estimand) 
 The change in calculated LDL-C from baseline to week 24 (ITT estimand) 
 The proportion of patients who meet EU apheresis eligibility criteria (see German 
Apheresis Working Group) at week 24 (ITT estimand) 
 The proportion of patients who meet US apheresis eligibility criteria (see US 
[National Lipid Association] Lipid Apheresis Criteria) at week 24 (ITT estimand) 
4.2.3. 
Other Secondary Efficacy Endpoints 
 The percent change in TG from baseline to week 24 (ITT estimand) 
 The change in Apo B from baseline to week 24 (ITT estimand) 
 The change in non-HDL-C from baseline to week 24 (ITT estimand) 
 The change in TC from baseline to week 24 (ITT estimand)  
 The percent change in lipoprotein a [Lp(a)] from baseline to week 24 (ITT estimand) 
 The proportion of patients with LDL-C <70 mg/dL [1.81 mmol/L] at week 24 
(ITT estimand) 
 The percent change in apolipoprotein CIII (Apo CIII) from baseline to week 24 
(ITT estimand) 
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National Lipid Association (US) 
[Goldberg 2011] 
German Apheresis Working Group (EU) 
[Schettler 2012] 
 
Patients have inadequate response to 
diet and LMTs after 6 months of 
treatment 
 
Functional HoFH or HeFH (with 0-1 
risk factor) with LDL-C >300 mg/dL 
(7.77 mmol/L)1 
 
Patients have inadequate response to diet and 
LMTs after 3 months of treatment 
 
Primary prevention – FH with LDL-C 
>160 mg/dL (4.2 mmol/L) and CV events in 
close relatives 
 
Secondary prevention – Patients with 
progressive CV events with LDL-C >120 to 
130 mg/dL (3.1-3.4 mmol/L) 
1 Risk factors include age, elevated TC and LDL-C, low HDL-C, male sex, smoking, metabolic syndrome, diabetes, 
hypertension, and family history of CVD 
4.2.4. 
Other Endpoints 
 The change in hemoglobin A1c (HbA1c [%]) from baseline to week 24 
 Response of each EQ-5D item, index score, and change of index score from baseline 
through week 24 
 Response on Hospital Anxiety and Depression Scale (HADS) from baseline through 
week 48. 
4.3. 
Pharmacokinetic Variables 
The PK variable is total evinacumab concentration in serum. 
4.4. 
Anti-Drug Antibody Variables 
Anti-drug antibody (ADA) status will be assessed.  
 Treatment emergent response - defined as a positive response post-first dose in the 
ADA assay when baseline ADA results are negative or missing 
 Treatment-boosted response – defined as a positive response post-first dose in the 
ADA assay that is at least 9-fold over baseline titer levels, when baseline ADA results 
are positive. 
The definition of persistent and transient ADA will be defined a priori in the SAP. 
Samples positive in the ADA assay will be assessed for titer: 
 Titer category 
 Low (titer <1,000) 
 Moderate (1,000≤ titer ≤10,000) 
 High (titer >10,000) 
Samples positive in the ADA assay will be assessed for neutralizing activity. 
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5. 
STUDY DESIGN 
5.1. 
Study Description and Duration 
This phase 3 study consists of the following periods: an up to 8-week run-in period (for patients 
who may require genotyping, for patients whose background medical LMT has not been stable 
prior to screening or whose apheresis settings and/or schedule have not been stable for at least 8 
weeks prior to screening), a 2-week screening period, a 24-week DBTP, a 24-week OLTP, and a 
follow-up period for 24 weeks, after the last dose of study drug, for those patients who decide not 
to enter an optional open-label study (Figure 1). The total duration of the run-in, screening, DBTP 
and OLTP may be up to may be up 78 weeks. 
Run-In:   
Apheresis therapy - Patients who are undergoing apheresis therapy must be on a stable weekly 
(every 7±1 days) or every other week (every 14±2 days) schedule. Patients whose schedule and/or 
apheresis settings, which have not been stable for at least 8 weeks before the screening visit, will 
enter an 8-week run-in period before the screening period. After the 8-week run-in period, patients 
whose lipid apheresis schedule remains stable will be eligible to enter the 2-week screening period. 
Lipid modifying therapy - Patients who are on background LMT (excluding lomitapide and 
mipomersen) that has not been stable for at least 4 weeks (6 weeks for fibrates, 8 weeks for PCSK9 
inhibitor antibody) before the screening visit will enter a 4-week (6 weeks for fibrates, 8 weeks for 
PCSK9 inhibitor antibody) run-in period to stabilize their LMT before entering the screening 
period. For patients taking mipomersen or lomitapide, patients who have not been on a stable dose 
of mipomersen for 24 weeks prior to screening or on a maximum tolerated dose (MTD) of 
lomitapide for 12 weeks prior to screening are excluded. 
Genotyping – Confirmation of patient’s HoFH status can be made by either genetic or clinical 
criteria. If HoFH diagnosis cannot be confirmed by the clinical criteria listed or from previous 
genotyping results, patients can enter the run-in period to determine their mutation status in 
advance of screening, if deemed appropriate by the investigator. 
Screening:   
Patients who are not undergoing apheresis therapy, patients who have been on a stable apheresis 
schedule for at least 8 weeks before the screening visit, and patients on stable background medical 
LMT (as applicable) for at least 4 weeks (6 weeks for fibrates, 8 weeks for PCSK9 inhibitor 
antibodies, 12 weeks for lomitapide, 24 weeks for mipomersen) before the screening visit, will 
enter a 2-week screening period. 
Patients who participated in the R727-CL-1628 study may enter the run-in or screening period or 
enroll directly into this study. Patients who completed the R727-CL-1628 study and fulfill all of 
the eligibility criteria can be enrolled directly into this study. Data collected during the R727-CL-
1628 study (ie, lab test results) can be used to assess eligibility criteria for these patients. If these 
patients meet all the eligibility criteria and if approved by the sponsor, the patients may not have 
to undergo the screening visit in this study.  In this case, overlapping assessments completed at the 
end of the open-label treatment visit in R727-CL-1628  do not need to be repeated during the 
R1500-CL-1629 baseline visit.  The baseline/day 1 visit can occur immediately after the end of 
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the open-label treatment visit in the R727-CL-1628 study.  To ensure continuity of treatment with 
alirocumab, all patients from R727-CL-1628 entering this study will be provided alirocumab.  
Double-Blind Treatment: 
Patients who meet all the inclusion criteria and none of the exclusion criteria will be randomized 
2:1 to receive:  
 evinacumab 15 mg/kg IV Q4W 
OR 
 matching placebo IV Q4W 
Randomization will be stratified by apheresis treatment (Yes, No) and by geographical region 
(Japan, Rest of World). 
Study drug administration during the DBTP will take place at the site, starting on the day of 
randomization (day 1), and will be administered immediately after completion of the 
LDL-apheresis procedure (if applicable). For those patients not undergoing LDL-apheresis, study 
drug must be administered after all samples for clinical laboratory evaluation have been obtained. 
The last dose of double-blind study drug will be administered at week 20. 
Patients who are on LMT or who are undergoing LDL-apheresis should maintain stable LMT and 
a stable apheresis schedule (as applicable) throughout the duration of the study, from screening to 
the end of DBTP visit (week 24), and continuing through the end of the OLTP.  All patients who 
enter this study from R727-CL-1628 will continue to receive alirocumab 150 mg SC Q2W for the 
duration of this study.  Alirocumab should continue to be administered after LDL-apheresis (if 
applicable). On days with concomitant alirocumab and evinacumab administration, the 
recommendation is to administer alirocumab after the end of the evinacumab post-infusion 
observation period.  
Open-Label Treatment:   
After completion of the DBTP, all patients will enter an OLTP. Starting at week 24, all patients, 
regardless of treatment assignment in the DBTP, will receive open-label evinacumab 15 mg/kg IV 
Q4W for the 24-week OLTP. The last dose of open-label study drug will be at week 44. 
Patients who are on LMT or apheresis must continue their stable dose and regimen through the 
end of the OLTP (through week 48).  All patients who enter this study from R727-CL-1628 will 
continue to receive alirocumab. 
Throughout the Study:   
For all patients undergoing LDL-apheresis, all samples for clinical laboratory evaluation must be 
obtained immediately prior to the LDL-apheresis procedure and prior to administration of study 
drug. Given the impact of LDL apheresis, PCSK9 inhibitors, and mipomersen on lipid parameters, 
it is important to match the time of the baseline activities with the timing of the week 24 activities. 
This would mean that the timing between the baseline sample collection relative to the most 
recently completed LDL apheresis procedure, administration of a PCSK9 inhibitor or mipomersen 
should match the timing of the week 24 sample collection relative to the most recently completed 
LDL apheresis procedure, administration of a PCSK9 inhibitor or mipomersen. For all patients 
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who are not undergoing apheresis, all samples for clinical laboratory evaluation must be obtained 
prior to administration of study drug. 
The efficacy of evinacumab in this population will be assessed by clinical laboratory evaluation of 
lipid levels at pre-specified time points throughout the study. Overall safety will be assessed by 
monitoring/evaluation of treatment-emergent adverse events (TEAEs), physical examinations, 
electrocardiogram (ECG), and clinical safety laboratory tests at pre-specified time points. The 
potential emergence of anti-evinacumab antibodies will also be evaluated. Patients who experience 
an ongoing serious adverse event (SAE) at the pre-specified study end-date should be followed 
until resolution, stabilization, or collection of outcome and related data. 
For all patients undergoing LDL-apheresis, the apheresis schedule and apheresis settings should 
remain stable throughout the duration of the DBTP and through the end of the OLTP (week 48). 
The use of all medications and nutritional supplements known to alter serum lipids, including (but 
not limited to) statins, ezetimibe, PCSK9 inhibitor antibody, mipomersen, lomitapide, fibrates, 
niacin, and bile acid resins is permitted as long as that therapy has been stable for at least 4 weeks 
(6 weeks for fibrates, 8 weeks for PCSK9 inhibitor antibodies, 12 weeks for the MDT of 
lomitapide, 24 weeks for mipomersen) prior to the screening visit. Patients should continue taking 
their LMT throughout the duration of the DBTP, starting at screening, and through the end of the 
OLTP (week 48). 
Patients should be on a stable low fat or heart-healthy diet. 
Patients’ exercise regimen should remain stable throughout the duration of the study, from 
screening through the OLTP. 
After completion of the 24-week OLTP, all patients who have successfully completed this study 
may have the opportunity to participate in a separate open-label (OL) study, R1500-CL-1719.  All 
patients who enroll in the separate OL study will continue to receive open-label evinacumab at a 
dose of 15 mg/kg IV Q4W. 
Follow-up Period (if applicable):   
Patients not consenting to participate in the optional OL study (R1500-CL-1719) will enter a 
follow-up period for 24 weeks after completion of the OLTP. A follow-up period of 24 weeks after 
the last dose of study drug will be required for patients who prematurely discontinue study 
treatment. 
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Figure 1: 
Study Flow Diagram 
 
Run-in1 
Screening 
Double-Blind Treatment2 
Open-Label Treatment3 
Follow-up4 
 
 
 
 
 
 
 
 
V1a 
Day -
70 
 
V1 
Day -14 
 
V2 
Day 1 
 
V3 to V9 
Wk 2 to 24 
End of 
DBTP3 
V10 to V15  
Wk 28 to 48 
End of 
OLTP 
V16 to V20  
Wk  52 to 68 
 
 
 
Baseline 
 
 
 
 
 
EOS 
1 Patients who are undergoing apheresis therapy with a schedule and/or apheresis settings that have not been stable 
for at least 8 weeks before the screening visit will enter a run-in period before the screening period. Patients who 
are on background LMT that has not been stable for at least 4 weeks (6 weeks for fibrates, 8 weeks for PCSK9 
inhibitor antibodies) before the screening visit will enter the run-in period to stabilize their LMT before entering 
the screening period. Patients who have completed the R727-CL-1628 study and meet all the eligibility criteria for 
this study can be enrolled directly. The end of the open-label treatment visit from the R727-CL-1628 study can 
serve as the baseline/day 1 visit for this study. 
2 Patients will receive study drug IV Q4W starting at day 1. 
3 The open-label period begins at week 24 (day 169) when all patients will receive evinacumab 15 mg/kg IV Q4W. 
The last dose of evinacumab will be at week 44. 
4 Follow-up only for patients who do not enter a separate, optional OL study, R1500-CL-1719 or prematurely 
discontinue study treatment in this study. 
5.1.1. 
End of Study Definition 
The end of study is defined as last visit of the last patient. 
5.2. 
Planned Interim Analysis 
No interim analysis is planned. 
5.3. 
Study Committees 
5.3.1. 
Independent Data Monitoring Committee 
An IDMC, composed of members who are independent from the sponsor and the study 
investigators, will monitor patient safety by conducting formal reviews of accumulated safety data 
that will be blinded by treatment group; if requested, the IDMC may have access to the treatment 
allocation code or any other requested data for the purposes of a risk-benefit assessment (eg, lipid 
efficacy data). 
The IDMC will provide the sponsor with appropriate recommendations on the conduct of the 
clinical study to ensure the protection and safety of the patients enrolled in the study. The IDMC 
will also institute any measures that may be required for ensuring the integrity of the study results 
during the study execution. 
All activities and responsibilities of the IDMC are described in the IDMC charter. 
5.3.2. 
Clinical Events Committee 
The Clinical Events Committee (CEC) is composed of experts in the field of CVD, independent 
of the sponsor and the investigators. This committee will be responsible for defining, validating, 
and classifying (in a blinded fashion) pre-specified CV events and all deaths. 
Patients with suspected or confirmed CV events that occur in the time period from randomization 
until the end of the study will have a corresponding adjudication package prepared and submitted 
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to the CEC. The events should also be reported as SAEs, as appropriate. Adjudicated CV events 
include all CV AEs positively adjudicated. The adjudication categories include:   
 Coronary heart disease death 
 Nonfatal myocardial infarction (MI) 
 Fatal and nonfatal ischemic stroke 
 Unstable angina requiring hospitalization 
 Congestive heart failure requiring hospitalization 
In addition, other deaths (besides coronary heart disease deaths) will be classified by the CEC. All 
coronary revascularizations (percutaneous coronary intervention, coronary artery bypass graft 
surgery) will be submitted to the CEC and analyzed. 
A charter and an adjudication operational manual will specify additional details regarding the 
procedures, criteria, and classification used for adjudication of these events. 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
6.1. 
Number of Patients Planned 
Approximately 57 patients will be randomized at approximately 30 multinational sites. 
6.2. 
Study Population 
The study population will consist of males and females ≥18 years of age diagnosed with HoFH, 
receiving stable LMT, as applicable.  
Patients should be on a maximally tolerated daily statin, ezetimibe and PCSK9 inhibitor antibody 
unless the patient has a documented history of tolerability issues, little or no response to therapy 
or other documented reason. Lipid modifying therapy may also include other lipid lowering 
therapies, including LDL-apheresis.  Whether or not a patient is considered to be on a maximum 
tolerated regimen of lipid modifying treatments (statin, PCSK9 inhibitor antibody, ezetimibe, 
lomitapide, mipomersen, probucol, etc), reasons why or why not (eg, due to intolerance, lack of 
efficacy, etc) the patient is taking/not taking the various treatments will need to be documented in 
the CRF. 
HoFH is defined by having at least one of the following (either genetic or clinical criteria):   
Genetic criteria:   
1. Documented functional mutation or mutations in both LDLR alleles 
 Note: patients who have null receptor mutations on both LDLR alleles, ie, double 
null, are eligible 
OR 
2. Documented homozygous or compound heterozygous mutations in Apo B or PCSK9 
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 Note: patients who are double heterozygous, ie, mutations on different genes (eg, 
LDLR/PCSK9) and patients with homozygous LDLRAP1 mutations are eligible 
Clinical Criteria:   
Untreated TC >500 mg/dL (12.93 mmol/L) and TGs <300 mg/dL (3.39 mmol/L)  
AND  
both parents with documented TC >250 mg/dL (6.47 mmol/L) OR cutaneous or 
tendinous xanthoma before the age of 10 years 
6.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Male or female ≥18 years of age at the time of the screening visit 
2. Diagnosis of functional HoFH by at least 1 of the following:   
a. Documented functional mutation or mutations in both LDLR alleles 
Note: patients who have null receptor mutations on both LDLR alleles, ie, double 
null, are eligible 
b. Presence of homozygous or compound heterozygous mutations in Apo B or PCSK9 
Note: patients who are double heterozygous, ie, mutations on different genes (eg, 
LDLR/PCSK9) and patients with homozygous LDLRAP1 mutations are eligible 
c. Untreated TC >500 mg/dL (12.93 mmol/L) and TG <300 mg/dL (3.39 mmol/L)  
AND 
both parents with documented TC >250 mg/dL (6.47 mmol) 
OR cutaneous or tendinous xanthoma before the age of 10 years 
3. If undergoing LDL apheresis, must have initiated LDL apheresis at least 3 months prior 
to screening and must have been on a stable weekly (every 7±1 days) or every other week 
(every 14±2 days) schedule and stable settings for at least 8 weeks 
4. Willing and able to comply with clinic visits and study-related procedures 
5. Willing to consistently maintain his/her usual low fat or heart-healthy diet for the 
duration of the study 
6. Provide signed informed consent or assent 
6.2.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. LDL-C level <70 mg/dL (1.81 mmol/L) at the screening visit. 
2. Background medical LMT (if applicable) that has not been stable for at least 4 weeks 
(6 weeks for fibrates, 8 weeks for PCSK9 inhibitor antibodies, 12 weeks for MTD of 
lomitapide, 24 weeks for mipomersen) before the screening visit 
3. Lipid-apheresis schedule (every 7 or 14 days)/apheresis settings (if applicable) that have 
not been stable for at least 8 weeks before the screening visit or an apheresis schedule 
that is not anticipated to be stable over the next 48 weeks.  Plasma exchange is excluded. 
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4. Use of nutraceuticals or over-the-counter therapies known to affect lipids, at a 
dose/amount that has not been stable for at least 4 weeks prior to the screening visit or 
between the screening and randomization visits 
5. Presence of any clinically significant uncontrolled endocrine disease known to influence 
serum lipids or lipoproteins 
Note: patients on thyroid replacement therapy can be included if the dosage of 
replacement therapy has been stable for at least 12 weeks prior to screening and the 
thyroid stimulating hormone (TSH) level is within the normal range of the central 
laboratory at the screening visit. 
6. Newly diagnosed (within 3 months prior to randomization visit [week 0/day 1]) diabetes 
mellitus or poorly controlled (HbA1c >9%) diabetes 
7. Unstable weight (variation >5 kg) within 2 months prior to the screening visit (week -2) 
8. Initiation of a new diet or major change to a previous diet within 4 weeks prior to 
screening 
9. Use of systemic corticosteroids, unless used as replacement therapy for pituitary/adrenal 
disease with a stable regimen for at least 6 weeks prior to screening 
Note: topical, intra-articular, nasal, inhaled and ophthalmic steroid therapies are not 
considered as ‘systemic’ and are allowed 
10. Use of estrogen or testosterone therapy unless the regimen has been stable 6 weeks prior 
to the screening visit and no plans to change the regimen during the study 
11. Systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg at the 
screening visit or time of randomization (week 0/day 1) 
12. History of a MI, unstable angina leading to hospitalization, coronary artery bypass graft 
surgery, percutaneous coronary intervention, uncontrolled cardiac arrhythmia, carotid 
surgery or stenting, stroke, transient ischemic attack, valve replacement surgery, carotid 
revascularization, endovascular procedure or surgical intervention for peripheral vascular 
disease within 3 months prior to the screening visit 
13. History of New York Heart Association (NYHA) Class IV heart failure within 12 months 
before screening. 
14. Age <18 years at the screening visit 
15. History of cancer within the past 5 years, except for adequately treated basal cell skin 
cancer, squamous cell skin cancer, or in situ cervical cancer 
16. Use of any active investigational drugs (except alirocumab) within 1 month or 5 
half-lives prior to the screening visit, whichever is longer 
17. Conditions/situations such as: 
a. Any clinically significant abnormality identified at the time of screening that, in the 
judgment of the investigator or any sub-investigator, would preclude safe completion 
of the study or constrain endpoints assessment; eg, major systemic diseases, patients 
with short life expectancy 
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b. Considered by the investigator or any sub-investigator as inappropriate for this study 
for any reason, eg: 
 Deemed unable to meet specific protocol requirements, such as scheduled visits 
 Investigator or any sub-investigator, pharmacist, study coordinator, other study 
staff or relative thereof directly involved in the conduct of the protocol, etc 
 Presence of any other conditions (eg, geographic or social), either actual or 
anticipated, which the investigator feels would restrict or limit the patient’s 
participation for the duration of the study 
18. Laboratory findings during the screening period (not including randomization labs): 
 Positive test for hepatitis B surface antigen and/or hepatitis C antibody (associated 
with a positive HCV RNA polymerase chain reaction) 
 Positive serum beta-human chorionic gonadotropin or urine pregnancy test in women 
of childbearing potential (WOCBP) 
 eGFR <30 mL/min/1.73 m2 (calculated by central lab)  
 Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 x upper 
limit of normal (ULN) (1 repeat lab is allowed) 
 CPK >3 x ULN (1 repeat lab is allowed) 
 TSH >1.5 x ULN of the central laboratory (1 repeat lab is allowed) for patients not on 
thyroid replacement therapy 
19. Known hypersensitivity to mAb therapeutics 
20. Member of the clinical site study team and/or his/her immediate family 
21. Pregnant or breastfeeding women 
22. Sexually active WOCBP*, who are unwilling to practice a highly effective birth control 
method prior to the initial dose, during the study, and for 24 weeks after the last dose of 
study drug. Highly effective contraceptive measures include: 
 Stable use of combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation initiated 2 or more menstrual 
cycles prior to screening 
o oral  
o intravaginal 
o transdermal 
 Stable use of progestogen-only hormonal contraception associated with inhibition of 
ovulation initiated 2 or more menstrual cycles prior to screening: 
o oral 
o injectable 
o implantable 
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 Intrauterine device 
 Intrauterine hormone-releasing system  
 Bilateral tubal ligation 
 Vasectomized partner. Note:  vasectomized partner is a highly effective birth control 
method provided that the partner is the sole sexual partner of the WOCBP trial 
participant and that the vasectomized partner has received medical assessment of the 
surgical success  
Sexual abstinence. Note:  Sexual abstinence is considered a highly effective method only 
if defined as refraining from heterosexual intercourse during the entire period of risk 
associated with study treatments. True abstinence: When this is in line with the preferred 
and usual lifestyle of the patient. Periodic abstinence (calendar, symptothermal, post-
ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhea method (LAM) are not acceptable methods of contraception.   
*Postmenopausal women must be amenorrheic for at least 12 months in order not to be 
considered of childbearing potential. Postmenopausal status will be confirmed by 
measurement of follicle-stimulating hormone (FSH). Pregnancy testing and contraception 
are not required for women with documented hysterectomy and/or oophorectomy. 
23. Men who are sexually active with WOCBP and are unwilling to consistently use 
condoms during the study drug treatment period and for 24 weeks after the last dose of 
study drug regardless of vasectomy status.  Sperm donation is prohibited during the study 
and for up to 24 weeks after the last injection of study drug. 
24. Housed in an institution on the basis of an administrative or judicial order. 
25. Dependent on the sponsor, investigator, or the study site. 
 
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 8.1.5. 
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 7.4.2. 
 
 
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Early Termination from the Study 
If for any reason the patient withdraws from the study prematurely, the patient should undergo an 
unscheduled visit with assessments normally planned at the end of the double-blind treatment visit 
if the patient is in the DBTP, or the end of the open-label treatment visit, if the patient is in the 
OLTP. The visit should take place within 5 days of treatment discontinuation. The assessments 
completed should include pregnancy testing for WOCBP. The patient should be followed for at 
least 24 weeks from the last dose of study drug or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. A final end of study visit should 
take place with assessments as specified in the end of study visit (ie, follow up visit) at 24 weeks 
after the premature discontinuation of study drug. 
Sexually active WOCBP who discontinue the study prematurely should be reminded at the 
unscheduled visit following treatment discontinuation to maintain highly effective contraceptive 
measures for 24 weeks after the last dose of study drug. At this visit, the patient will be provided 
5 urine pregnancy tests with instructions to test for pregnancy 4 weeks after this visit and Q4W 
thereafter. The patient will also be notified of Q4W follow-up phone calls to confirm continued 
contraception use and pregnancy reporting and to obtain the results of the urine pregnancy test. 
The investigator should make the best effort to contact any patient (eg, contacting patient’s family 
or private physician, review available registries or health care database) who fails to return to the 
site, and to determine health status. Attempts to contact such patients must be documented in the 
patient’s records (eg, times and dates of attempted telephone contact, receipt for sending a 
registered letter).  The site will be provided a retention manual outlining the best practices for 
patient retention. 
6.4. 
Replacement of Patients 
Patients prematurely discontinued from the study drug will not be replaced. 
6.5. 
Rescreening of Patients 
Patients who do not meet eligibility criteria during the initial screening may re-screen only once. 
Patients who are re-screened after the screening window ends must re-consent for study 
participation and repeat all screening procedures. 
Patients who do not meet all eligibility criteria during the initial screening, and are still within the 
screening window, may retest once for the assessments that did not meet eligibility criteria. 
7. 
STUDY TREATMENTS 
7.1. 
Investigational and Reference Treatments 
Evinacumab or placebo IV infusion. 
In the DBTP, eligible patients will be enrolled to receive an IV dose of evinacumab 15 mg/kg 
Q4W or matching placebo, starting on day 1. The last dose of double-blind study drug will be at 
week 20. 
In the open-label portion of the study, patients will receive  
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 Evinacumab at 15 mg/kg IV Q4W starting at week 24 (day 169) with the last dose at 
week 44 (day 309) 
Dosing should fall within a window of ±7 days; if >14 days has passed, skip the dose and return 
to the original schedule. 
Instructions on dose preparation and administration are provided in the pharmacy manual. 
Instructions on management of infusion reactions are provided in Section 7.5.1. 
Sterile alirocumab drug product will be supplied at a concentration of 150 mg/mL in a prefilled 
pen for patients from study R727-CL-1628 who enroll in this study. 
7.2. 
Run-in Treatment(s) 
Patients who are undergoing apheresis therapy must have initiated LDL apheresis at least 3 months 
prior to screening and must be on a stable weekly (every 7 days) or every other week (every 14 
days) schedule and/or stable settings for at least 8 weeks prior to screening.  Patients with a 
schedule and/or apheresis settings that have not been stable for at least 8 weeks before the 
screening visit will enter an 8-week run-in period before the screening period. 
Patients who are on background LMT that has not been stable for at least 4 weeks (6 weeks for 
fibrates, 8 weeks for PCSK9 inhibitor antibodies) before the screening visit will enter a 4-week 
(6 weeks for fibrates, 8 weeks for PCSK9 inhibitor antibodies) run-in period to stabilize their LMT 
before entering the screening period. 
7.3. 
Background Treatment(s) 
Patients who are receiving background LMT or who are undergoing apheresis should maintain 
stable LMT and a stable apheresis schedule (as applicable) throughout the duration of the study, 
from screening to the end of DBTP visit (week 24), and continuing through the end of the OLTP. 
For all patients who enter this study from R727-CL-1628, alirocumab will be provided and patients 
will administer alirocumab 150 mg SC Q2W for the duration of the study.  
Patients should be on a maximally tolerated LMT regimen. Whether or not a patient is considered 
to be on a maximum tolerated regimen of LMT (statin, PCSK9 inhibitor antibody, ezetimibe, 
lomitapide, mipomersen, probucol, etc), reasons why or why not (eg, due to intolerance, lack of 
efficacy) the patient is taking/not taking the various treatments will need to be documented in the 
CRF. 
7.4. 
Dose Modification and Study Treatment Discontinuation Rules 
7.4.1. 
Dose Modification 
Dose modification for an individual patient is not allowed. 
7.4.2. 
Study Drug Discontinuation 
During the DBTP, study drug should be continued whenever possible. In the event study drug 
dosing is stopped, it should be determined if the stop can be made temporarily; permanent 
discontinuation should be a last resort. Regardless, the patient should remain in the DBTP as long 
as possible. 
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Patients who permanently discontinue study drug during the DBTP should remain in the study and 
undergo all double-blind study visits and procedures with the exception of dosing with study drug. 
At the time of study drug discontinuation, the patient should have, as soon as possible, an 
unscheduled visit with assessments normally planned at end of the double-blind treatment visit 
(this should take place within 5 days of discontinuation of study drug, if possible) and then resume 
the original study schedule until end of the DBTP. In case of early discontinuation before week 
24, all efforts should be made to perform the week 24 assessments at week 24. 
Patients who permanently discontinue study drug during the OLTP should have, as soon as 
possible, an unscheduled visit with assessments normally planned at the end of the OLTP (this 
should take place within 5 days of discontinuation of study drug, if possible) and then have 
end-of-study assessments at least 24 weeks after their last dose of study drug. 
Patients who permanently discontinue study drug and who opt to withdraw from the study will be 
asked to complete study assessments, per Section 8.1.5. 
Sexually active WOCBP who discontinue the study prematurely should be reminded at the 
unscheduled visit following treatment discontinuation to maintain highly effective contraceptive 
measures for 24 weeks after the last dose of study drug. At this visit, the patient will be provided 
5 urine pregnancy tests with instructions to test for pregnancy 4 weeks after this visit and Q4W 
thereafter. The patient will also be notified of Q4W follow-up phone calls to confirm continued 
contraception use and pregnancy reporting and to obtain the results of the urine pregnancy test. 
7.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
Study drug dosing will be permanently stopped in the event of the following but not limited to:   
 Evidence of pregnancy 
 Acute systemic infusion reactions with AEs including, but not limited to, anaphylaxis, 
laryngeal/pharyngeal edema, severe bronchospasm, chest pain, seizure, or severe 
hypotension 
 Patient requires a prohibited concomitant medication during the DBTP. The principal 
investigator should contact the Regeneron study monitor. Based on the discussion, 
study drug may be continued, or may be temporarily or permanently discontinued 
 Patient withdraws consent 
The investigator may permanently discontinue study drug dosing at any time, even without 
consultation with the medical monitor if the urgency of the situation requires immediate action 
and if this is determined to be in the patient’s best interest. However, the medical monitor should 
be contacted as soon as possible in any case of permanent study drug discontinuation. 
7.5. 
Management of Acute Reactions  
7.5.1. 
Acute Infusion Reactions 
Emergency equipment and medication for the treatment of infusion reactions must be available for 
immediate use. All infusion reactions must be reported as AEs (as defined in Section 9.4.1) and 
graded using the grading scales as instructed in Section 9.5.1. 
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7.5.1.1. 
Interruption of the Infusion 
The infusion should be interrupted if any of the following AEs are observed: 
 Cough 
 Rigors/chills 
 Rash, pruritus (itching) 
 Urticaria (hives, welts, wheals) 
 Diaphoresis (sweating) 
 Hypotension 
 Dyspnea (shortness of breath) 
 Vomiting 
 Flushing 
The reaction(s) should be treated symptomatically, and the infusion may be restarted at 50% of the 
original rate. 
If investigators feel there is a medical need for treatment or discontinuation of the infusion other 
than described above, they should use clinical judgment to provide the appropriate response 
according to typical clinical practice. 
7.5.1.2. 
Termination of the Infusion 
The infusion should be terminated and NOT restarted if any of the following AEs occur: 
 anaphylaxis* 
 laryngeal/pharyngeal edema 
 severe bronchospasm 
 chest pain 
 seizure 
 severe hypotension 
 other neurological symptoms (confusion, loss of consciousness, parathesia, paralysis, 
etc) 
 any other symptom or sign that, in the opinion of the investigator, warrants 
discontinuation of the infusion. 
*Consider anaphylaxis if the following is observed (Sampson 2006):  acute onset of an illness 
(minutes to several hours) with the involvement of the skin, mucosal tissue, or both (eg, 
generalized hives, pruritus or flushing, swollen lips-tongue-uvula AND AT LEAST ONE OF THE 
FOLLOWING:   
a. respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia);  
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b. reduced blood pressure or associated symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, incontinence). 
7.6. 
Method of Treatment Assignment 
Approximately 57 patients will be randomized in a 2:1 ratio to receive either 15 mg/kg IV 
evinacumab or matching placebo according to a central randomization scheme provided by an 
interactive web response system (IWRS) to the designated study pharmacist (or qualified 
designee). Randomization will be stratified by apheresis treatment (Yes/No) and by geographical 
region (Japan, Rest of World). 
In the OLTP of the study, all patients will receive evinacumab as described in Section 7.1. 
7.6.1. 
Blinding 
Study patients, the principal investigators, and study site personnel will remain blinded to all 
randomization assignments throughout the DBTP (up to week 24). The Regeneron Study Director, 
Medical Monitor, Study Monitor, and any other Regeneron and contract research organization 
(CRO) personnel who are in regular contact with the study site will remain blinded to all patient 
randomization assignments. 
Lipid results from blood samples collected after the randomization visit will not be communicated 
to the sites, and the sponsor’s operational team will not have access to these laboratory results until 
after completion of the DBTP and the first-step analysis. 
Although there is a slight color difference between the drug product and placebo product for IV 
infusion bag preparation, the color difference is not detectable when the investigational product is 
added to the IV infusion bag.  
Further details are provided in the pharmacy manual. 
After the end of the DBTP visit at week 24, the study becomes an open-label study. 
7.6.2. 
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: 
o Only the investigator will make the decision to unblind the treatment assignment. 
o Only the affected patient will be unblinded. 
o 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. 
o 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 
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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. 
7.7. 
Treatment Logistics and Accountability 
7.7.1. 
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. 
7.7.2. 
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 opened and unopened study drug will be returned to the sponsor or designee. 
7.7.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug. These records 
should contain the dates, quantity, and study medication: 
 dispensed to each patient, 
 returned from each patient (if applicable), and 
 disposed of at the site or returned to the sponsor or designee. 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
7.7.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the sponsor 
and regulatory agency inspectors. 
7.8. 
Concomitant Medications and Procedures 
Any treatment administered, including apheresis, from the time of informed consent to the end of 
the treatment period/final study visit will be considered concomitant medication. This includes 
medications that were started before the study and are ongoing during the study. 
7.8.1. 
Prohibited Medications and Procedures 
The following concomitant medications and procedures are prohibited through the end of the 
DBTP (week 24) and continuing through the end of the OLTP (week 48):   
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 Background medical LMT (if applicable) that has not been stable for at least 4 weeks 
(6 weeks for fibrates) before the screening visit (week -2) (unless participating in the 
run-in period to stabilize) 
 Background mipomersen treatment that has not been stable for 24 weeks before the 
screening visit (week -2) 
 Background lomitapide at a MTD that has not been stable for 12 weeks before the 
screening visit (week -2) 
 Recent discontinuation of lomitapide that has not been washed out for at least 8 
weeks before the screening visit (week -2). 
 Background PCSK9 inhibitor antibody that has not been stable for at least 8 weeks 
prior to the screening visit (week -2) 
 Lipid apheresis schedule that is not an every 7 day (±1 day) or an every 14 day 
(±2 days) regimen or has not been stable for at least 8 weeks prior to screening 
(week -2) 
 Plasma exchange 
 Nutraceuticals or over-the-counter therapies known to affect lipids, at a dose/amount 
that has not been stable for at least 4 weeks prior to the screening visit (week -2) 
 Systemic corticosteroids, unless used as replacement therapy for pituitary/adrenal 
disease with a stable regimen for at least 6 weeks prior to the screening visit (week-2) 
 Thyroid replacement therapy, unless the dosage of replacement therapy has been 
stable for at least 12 weeks prior to the screening visit (week -2). 
7.8.2. 
Permitted Medications and Procedures 
The use of all medications and nutritional supplements known to alter serum lipids, including (but 
not limited to) statins, ezetimibe, fibrates, niacin, bile acid resins, red yeast rice, lomitapide, 
mipomersen, and PCSK9 inhibitor antibodies is permitted as long as that therapy has been stable 
for at least 4 weeks (6 weeks for fibrates, 8 weeks for PCSK9 inhibitor antibodies, 12 weeks for 
lomitapide, 24 weeks for mipomersen) prior to the screening visit (week-2). Patients should 
continue taking their background medical LMT for the duration of the study starting at screening 
and through the end of the OLTP (week 48). Similarly, patients should maintain their apheresis 
regimen (if applicable) starting at screening and through the end of the OLTP (week 48).  
Patients on thyroid replacement therapy can be included if the dosage has been stable for at least 
12 weeks prior to the screening visit (week -2). 
Topical, intra-articular, nasal, inhaled and ophthalmic steroid therapies are not considered as 
‘systemic’ and are allowed. 
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8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
8.1. 
Schedule of Events 
Study assessments and procedures are presented by study period and visit in Table 1, Table 2, 
Table 3, and Table 4. 
Table 1: 
Schedule of Events – Run-in and Screening 
Study Procedure 
Run-in6  
Screening 
Visit  
1a 
1 
Day 
-70 to -14 
-14 to -1 
Visit Window (Day) 
 
 
Week 
-10 to -2 
-2 to -1 
Screening/Baseline: 
Informed Consent 
X 
 
Pharmacogenomics Consent 
 
X 
Inclusion/Exclusion 
 
X 
Medical/Surgical History, Alcohol/Smoking Habits 
 
X 
Medication History 
 
X 
Demographics 
 
X 
Treatment: 
Concomitant Medications (including LMT and apheresis) 
X 
X 
Query LMT compliance 
X 
X 
Efficacy: 
Lipid Panel1 ,2   
 
X 
Safety: 
Adverse Events 
X 
X 
Physical Examination 
 
X 
Measured Height 
 
X 
Body Weight 
 
X 
Vital Signs (pulse rate, BP) 
X 
X 
Electrocardiogram3  
 
X 
Laboratory Testing4 : 
Hematology 
 
X 
Blood Chemistry 
 
X 
Creatine Phosphokinase 
 
X 
Hepatitis B Surface Antigen 
 
X 
Hepatitis C Antibody 
 
X 
Serum Pregnancy Test5  
 
X 
Urine Pregnancy Test5  
X 
 
FSH 
X 
 
Urinalysis 
 
X 
TSH 
 
X 
DNA sample for HoFH genotyping 
X 
Other: 
Review of diet 
X 
X 
 
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Table 2: 
Schedule of Events – Screening for Patients with No Run-in 
Study Procedure 
Screening 
Visit  
1 
Day 
-14 to -1 
Visit Window (Day) 
 
Week 
-2 to -1 
Screening/Baseline: 
Informed Consent 
X 
Pharmacogenomics Consent 
X 
Inclusion/Exclusion 
X 
Medical/Surgical History, Alcohol/Smoking Habits 
X 
Medication History 
X 
Demographics 
X 
Treatment: 
Concomitant Medications (including LMT and 
apheresis) 
X 
Query LMT compliance 
X 
Efficacy: 
Lipid Panel1 ,2  
X 
Safety: 
Adverse Events 
X 
Physical Examination 
X 
Measured Height 
X 
Body Weight 
X 
Vital Signs (pulse rate, BP) 
X 
Electrocardiogram3  
X 
Laboratory Testing4 : 
Hematology 
X 
Blood Chemistry 
X 
Creatine Phosphokinase 
X 
Hepatitis B Surface Antigen 
X 
Hepatitis C Antibody 
X 
Serum Pregnancy Test5  
X 
Urine Pregnancy Test5 
 
FSH 
X 
Urinalysis 
X 
TSH 
X 
DNA sample for HoFH genotyping 
X 
Other: 
Review of diet 
X 
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Table 3: 
Schedule of Events – Baseline, Double-Blind Treatment Period, and Open-Label Treatment Period 
Study Procedure 
Double-Blind Treatment Period 
Open-Label Treatment Period 
Visit  
2 
3 
4 
5 
6 
7 
8 
9 
End 
DBTP 1
3 
10 
11 
12 
13 
14 
15 
End of 
OLTP 
Day 
1 
15 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
Visit Window (Day) 
±1 
±3 
±3 
±3 
±3 
±5 
±5 
±1 
±5 
±5 
±5 
±5 
±5 
±5 
Week 
0 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
Baseline: 
Informed Consent 
X1  
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacogenomics Consent 
X1  
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment: 
 
Randomization 
X1  
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer IV Double-Blind 
Study Drug 
X1  
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Administer IV Open-Label Study 
Drug 
 
 
 
 
 
 
 
X10  
X 
X 
X 
X 
X 
 
Concomitant Medications 
(including LMT and apheresis) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Query LMT compliance 
X1  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy: 
Lipid Panel2 ,3  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Specialty Lipid Panel2 ,4  
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
Safety: 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
Measured Height 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs (pulse rate, BP)5  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram6  
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Confirm contraception use and 
reminder of pregnancy reporting 
X1  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Remind male patients to use 
condoms 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing7 : 
Hematology 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
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Study Procedure 
Double-Blind Treatment Period 
Open-Label Treatment Period 
Visit  
2 
3 
4 
5 
6 
7 
8 
9 
End 
DBTP 1
3 
10 
11 
12 
13 
14 
15 
End of 
OLTP 
Day 
1 
15 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
Visit Window (Day) 
±1 
±3 
±3 
±3 
±3 
±5 
±5 
±1 
±5 
±5 
±5 
±5 
±5 
±5 
Week 
0 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
Blood Chemistry 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
Creatine Phosphokinase 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
Serum Pregnancy Test8  
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Urine Pregnancy Test8  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
hs-CRP 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
HbA1C 
X1  
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
LDLR function 
X1  
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Samples 
X1  
 
X 
X 
 
X 
 
X 
X 
 
 
 
 
 
PK and PD Samples 
ADA Sample9  
X1  
 
X 
 
X 
 
 
X 
 
 
 
 
 
X 
PK (evinacumab, alirocumab), 
ANGPTL3, PCSK9 samples10 ,11  
X1  
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
PK of statin10  
X1  
 
 
 
 
X 
 
 
 
 
 
 
 
 
DNA sample for HoFH 
genotyping 
X1  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
X1  
 
 
 
 
 
 
 
 
 
 
 
 
 
Other: 
EQ-5D 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
HADS 
X1  
 
 
 
 
 
 
X 
 
 
 
X14  
 
X14  
Review of diet 
X1  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Table 4: 
Schedule of Events – Follow-up Period 
Study Procedure 
Follow-up Period5 
Visit  
164  
PV174 ,5  
184  
PV194 ,5  
EOS 
20 
Day 
365 
393 
421 
449 
477 
Visit Window (Day) 
±5 
±5 
±5 
±5 
±5 
Week 
52 
56 
60 
64 
68 
Treatment: 
 
Concomitant Medications (including LMT and 
apheresis) 
X 
X 
X 
X 
X 
Query LMT compliance 
X 
X 
X 
X 
X 
Safety: 
Adverse Events 
X 
X 
X 
X 
X 
Physical Examination 
 
 
 
 
X 
Measured Height 
 
 
 
 
 
Body Weight 
 
 
 
 
X 
Vital Signs (pulse rate, BP) 
 
 
 
 
X 
Electrocardiogram1  
 
 
 
 
X 
Confirm contraception use and reminder of pregnancy 
reporting 
X 
X 
X 
X 
X 
Remind male patients to use condoms 
X 
X 
X 
X 
 
Laboratory Testing: 
Lipid Panel 
X 
 
X 
 
X 
Specialty Lipid Panel 
X 
 
X 
 
X 
Hematology 
X 
 
X 
 
X 
Blood Chemistry 
X 
 
X 
 
X 
Creatine Phosphokinase 
X 
 
X 
 
X 
Serum Pregnancy Test2  
 
 
 
 
X 
Urine Pregnancy Test2  
X 
X 
X 
X 
 
Urinalysis 
 
 
 
 
X 
hs-CRP 
 
 
 
 
X 
HbA1C 
 
 
X 
 
X 
PK and PD Samples 
ADA Sample 
 
 
 
 
X 
PK (evinacumab, alirocumab), ANGPTL3 samples3  
 
 
 
 
X 
Other: 
Review of diet 
 
 
 
 
X 
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8.1.1. 
Footnotes for Schedule of Events Table 1  
1. Study assessments are to be performed and blood samples are to be collected before the 
dose of study drug in all patients. For patients undergoing apheresis:  Study assessments 
are to be performed and blood samples are to be collected immediately before the 
lipid-apheresis procedure; study drug will be administered after the apheresis procedure. 
2. Fasting sample will be collected for the lipid panel: TC, calculated LDL-C, HDL-C, TG, 
non-HDL-C 
3. ECG should be performed before blood samples are collected at visits requiring blood 
draws. 
4. All laboratory samples should be collected before administration of study drug. 
5. WOCBP only, confirm required contraception use and reminder pregnancy reporting 
6. For patients who require HoFH genotyping, stabilization of their lipid-apheresis schedule 
or stabilization of their background medical LMT, ie, stable lipid-apheresis for at least 8 
weeks before screening and stable background medical LMT for at least 4 weeks 
(6 weeks for fibrates, 8 weeks for PCSK9 inhibitor antibodies) 
8.1.2. 
Footnotes for Schedule of Events Table 2 
1. Study assessments are to be performed and blood samples are to be collected before the 
dose of study drug in all patients. For patients undergoing apheresis:  Study assessments 
are to be performed and blood samples are to be collected immediately before the 
lipid-apheresis procedure; study drug will be administered after the apheresis procedure. 
2. Fasting sample will be collected for the lipid panel: total-C, calculated LDL-C, HDL-C, 
TG, non-HDL-C 
3. ECG should be performed before blood samples are collected at visits requiring blood 
draws. 
4. All laboratory samples should be collected before administration of study drug. 
5. WOCBP only, confirm required contraception use and reminder pregnancy reporting 
8.1.3. 
Footnotes for Schedule of Events Table 3 
1. For those patients enrolling directly from the R727-CL-1628 study and do not complete 
the R1500-CL-1629 run-in or screening period, the informed consent forms should be 
signed at the baseline visit.  Overlapping assessments completed at the R727-CL-1628 
open-label EOT visit do not need to be repeated during the R1500-CL-1629 baseline visit; 
only assessments footnoted will need to be performed. 
2. Study assessments are to be performed and blood samples are to be collected before the 
dose of study drug in all patients. For patients undergoing apheresis:  Study assessments 
are to be performed and blood samples are to be collected immediately before the 
lipid-apheresis procedure; study drug will be administered after the apheresis procedure. 
The timing between the baseline sample collection relative to the most recently completed 
LDL apheresis procedure, administration of a PCSK9 inhibitor or mipomersen should 
match the timing of the week 24 sample collection relative to the most recently completed 
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LDL apheresis procedure, administration of a PCSK9 inhibitor or mipomersen. Depending 
on the duration between the LDL apheresis procedure and sample collection, the visit 
window may not apply. 
3. Fasting sample will be collected for the lipid panel: total-C, calculated LDL-C, HDL-C, 
TG, non-HDL-C 
4. Fasting sample will be collected for specialty lipid panel: Apo B, Apo A-1, and Lp(a) 
5. On dosing days, vital signs should be recorded prior to IV infusion, and 30 minutes and 
60 minutes post-IV infusion 
6. ECG should be performed before blood samples are collected at visits requiring blood 
draws. 
7. All laboratory samples should be collected before administration of study drug 
8. WOCBP only, confirm required contraception use and reminder pregnancy reporting 
9. The ADA sample should be drawn before study drug administration 
10. For patients who are not undergoing apheresis, the PK sample should be drawn before the 
dose of study drug and at the end of the infusion. For patients undergoing apheresis, a PK 
sample should be collected immediately before the apheresis procedure and a PK sample 
should be collected immediately after the apheresis procedure, prior to administration of 
study drug, and, again at the end of the infusion of study drug.  
11. Including assay of total ANGPTL3 
 
13. All end of treatment (EOT) assessments are to be performed and blood samples are to be 
collected before the dose of open-label study drug in all patients. For patients undergoing 
apheresis:  Study assessments are to be performed and blood samples are to be collected 
immediately before the lipid-apheresis procedure; open-label study drug will be 
administered after the apheresis procedure. 
14. In the OLTP, the HADS should be administered after the patients have been informed of 
their lipid results 
8.1.4. 
Footnotes for Schedule of Events Table 4 
1. ECG should be performed before blood samples are collected at visits requiring blood 
draws 
2. WOCBP only, confirm required contraception use and reminder pregnancy reporting. 
3. Including assay of total ANGPTL3 
4. For patients who discontinue prematurely or who opt out of the OL study 
5. Phone visits (PV) at weeks 56 and 64 to confirm required contraception use and obtain 
results of the home urine pregnancy test.  Adverse events and concomitant medications 
will be collected 
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8.1.5. 
Early Termination Visit  
In the case a patient prematurely discontinues study treatment, an unscheduled visit should occur 
with assessments normally planned at the (EOT) visit (it should take place within 5 days of 
treatment discontinuation, if possible). Patients who permanently discontinue study drug during 
the DBTP should then resume the original study schedule (except for study treatment 
administration) until end of the DBTP, and all efforts should be made to perform the week 24 
assessments at week 24 (regardless of study treatment administration). All patients who 
prematurely discontinue study treatment (either in the double-blind period or the open-label 
period) should be followed for at least 24 weeks from the last dose of study drug, and a final end 
of study visit can take place with assessments as specified in the end of study visit (ie, follow up 
visit). 
Sexually active WOCBP who discontinue the study prematurely should be reminded at the 
unscheduled visit following treatment discontinuation to maintain highly effective contraceptive 
measures for 24 weeks after the last dose of study drug. At this visit, the patient will be provided 
5 urine pregnancy tests with instructions to test for pregnancy 4 weeks after this visit and Q4W 
thereafter. The patient will also be notified of Q4W follow-up phone calls to confirm continued 
contraception use and pregnancy reporting and to obtain the results of the urine pregnancy test. 
If a WOCBP is lost to follow-up, sites should attempt a minimum of 2 telephone calls. If the patient 
cannot be reached on the second attempt, a formal letter will be issued from the site to the patient 
that reminds the patient of the importance of continued use of highly effective contraception use 
for at least 6 months after the last dose of study drug. 
8.1.6. 
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 for the sole purpose of determining study eligibility 
or characterizing the baseline population:   
 Hepatitis B Surface Antigen 
 Hepatitis C Antibody 
 TSH 
 FSH 
8.2.2. 
Efficacy Procedures 
All laboratory samples will be collected before the dose of study drug is administered. 
Blood samples for lipid panels should be collected in the morning, in fasting condition 
(ie, overnight, at least 8 hours fast, only water) for all clinic visits. Alcohol consumption within 
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48 hours, and smoking or intense physical exercise within 24 hours, preceding blood sampling are 
discouraged. 
Total-C, HDL-C, TG, Apo B, Apo A-1, Lp(a), and Apo CIII will be directly measured by the 
central laboratory. LDL-C will be calculated using the Friedewald formula. If TG values exceed 
400 mg/dL (4.52 mmol/L) or if calculated LDL-C values are below 25 mg/dL (0.65 mmol/L), 
LDL-C will be measured via the beta quantification method (rather than via the Friedewald 
formula). Non-HDL-C will be calculated by subtracting HDL-C from the total-C. Ratio Apo 
B/Apo A-1 will be calculated. All lipid results will be blinded from after the randomization visit 
until the week 36 visit. Every effort should be made to continue to keep the sponsor blinded to all 
lipid parameters for the duration of the study. No attempts should be made by the investigator or 
patient to have the patient’s lipid values independently evaluated after randomization until after 
the end of study visit. 
Detailed procedures of sample preparation, storage, and shipment are provided in the laboratory 
manual. 
8.2.2.1. 
Lipid Panel 
Fasting (at least 8 hours) blood samples will be collected at specified time points shown in 
Section 8.1 for assessment of the lipid profile, comprising calculated LDL-C, HDL-C, 
non-HDL-C, total-C, and TGs. These samples will also be used for specialty lipid panel assessment 
when it is scheduled at the same time as the lipid panel assessment. 
8.2.2.2. 
Specialty Lipid Panel 
Fasting (at least 8 hours) blood samples will be collected at specified time points shown in 
Section 8.1 for assessment of the specialty lipid profile, comprising Apo B, Apo A-1, ratio of Apo 
B/Apo A-1, and Lp(a) as well as for Apo CIII. The specialty lipid panels will be assessed in the 
same sample that is collected for the lipid panel. 
8.2.3. 
Quality of Life Procedures 
8.2.3.1. 
EuroQol-5 Questionnaire 
The EQ-5D is a standardized measure of health status developed by the EuroQol Group in order 
to provide a simple, generic measure of health for clinical and economic appraisal. The EQ-5D as 
a measure of health related quality of life, defines health in terms of 5 dimensions: mobility, self-
care, usual activities, pain/discomfort, anxiety/depression. Each dimension has 3 ordinal levels of 
severity: “no problem” (1), “some problems” (2), “severe problems” (3). 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, where 0 represents “death” 
and 1 represents “perfect health.” 
8.2.3.2. 
Patient Assessed Hospital Anxiety and Depression Scale 
The HADS is an instrument for screening anxiety and depression in non-psychiatric populations; 
repeated administration also provides information about changes to a patient’s emotional state 
(Zigmond 1983, Herrmann 1997). The HADS consists of 14 items, 7 each for anxiety and 
depression symptoms; possible scores range from 0 to 21 for each subscale. The following cut-off 
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scores are recommended for both subscales: 7 to 8 for possible presence, 10 to 11 for probable 
presence, and 14 to 15 for severe anxiety or depression. 
8.2.4. 
Safety Procedures 
8.2.4.1. 
Vital Signs 
Vital signs, including temperature, sitting blood pressure and pulse and respiration rate, will be 
collected predose at time points according to Table 1, Table 2, Table 3, and Table 4. On dosing 
days, vital signs consisting of blood pressure and pulse rate will also be collected pre-dose and 30 
minutes and 60 minutes after completion of the IV infusion. 
Blood pressure should be measured in the same arm throughout the study after the patient has been 
resting quietly for at least 5 minutes. Pulse rate will be measured at the time of the measurement 
of blood pressure. 
8.2.4.2. 
Physical Examination 
A thorough and complete physical examination will be performed at time points according to 
Table 1, Table 2, Table 3, and Table 4. Care should be taken to examine and assess any 
abnormalities that may be present, as indicated by the patient’s medical history. 
8.2.4.3. 
Electrocardiogram 
Electrocardiograms should be performed before blood is drawn during visits that require blood 
draws. A standard 12-lead ECG will be performed at time points according to Table 1, Table 2, 
Table 3, and Table 4.  
The 12-lead ECGs should be performed in the supine position after resting for at least 10 minutes. 
For each ECG recording throughout the study, the electrodes should be positioned at the same 
place as much as possible. The ECG will be interpreted locally by the investigator. Any new and/or 
clinically significant changes in ECG parameters should be immediately rechecked for 
confirmation before making any decision for the concerned patient. 
Any clinically significant abnormality should be documented as an AE/SAE, as applicable (see 
Section 9.4.5). Each ECG tracing will be analyzed in comparison with the screening recorded 
trace. All ECG tracings will be kept as source data.  
8.2.4.4. 
Laboratory Testing 
All laboratory samples will be collected before the dose of study drug is administered. 
Samples for laboratory testing will be collected at visits according to Table 1, Table 2, Table 3, 
and Table 4 and analyzed by a central laboratory. Detailed instructions for blood sample collection 
are in the laboratory manual provided to study sites and specific tests are listed below. 
Tests will include: 
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Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin 
Potassium 
Creatinine 
 
Chloride 
Blood urea nitrogen (BUN) 
 
Carbon dioxide 
AST 
Uric acid 
Calcium 
ALT 
CPK 
Glucose 
Alkaline phosphatase 
 
Albumin 
Lactate dehydrogenase (LDH) 
 
 
Hematology 
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
Urinalysis 
Color 
Glucose 
RBC 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBC 
Yeast 
Other Laboratory Tests 
Other laboratory tests will be performed at time points shown in Table 1, Table 2, Table 3, and 
Table 4 and are as follows:  FSH, TSH, high sensitivity C-reactive protein (hs-CRP), HbA1c, and 
serum and urine pregnancy test. 
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. 
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8.2.4.5. 
Pregnancy Testing 
Women of childbearing potential will undergo pregnancy testing approximately every 4 weeks 
throughout the study from baseline through EOS.  Pregnancy testing will be via a urine pregnancy 
test, except for the screening visit and EOS visit, which will be via a serum pregnancy test.  During 
some follow-up visits, and in case of early termination, pregnancy testing may occur at home via 
a urine pregnancy test where the results will be reported to the clinical site by the patient. 
8.2.5. 
Pharmacokinetic and Anti-Drug Antibody Procedures 
8.2.5.1. 
Drug Concentration Measurements and Samples 
Samples for assessment of evinacumab and alirocumab concentration will be collected at time 
points listed in Table 3 and Table 4. They will be collected predose and at the end of the IV 
infusion on days when study drug is administered.  
 
. 
8.2.5.2. 
Anti-Drug Antibody Measurements and Samples 
Samples for ADA assessment will be collected at time points listed in Table 3 and Table 4. They 
will be collected predose on days when study drug is administered. 
Patients who exhibit a treatment-emergent or treatment-boosted positive ADA assay response with 
a titer greater than 240 in their last sample analyzed and who do not participate in an open-label 
study will be followed until the titers are <240 or within two dilution steps from their baseline titer 
levels. 
 
 
8.2.5.3. 
Statin Concentrations 
Samples for statin concentration will be collected at time points shown in Table 3. 
8.2.6. 
Pharmacodynamic Procedures 
Total ANGPTL3 and total PCSK9 concentrations in serum will be measured using the PK samples 
collected at the time points listed in Table 3 and Table 4. 
8.2.7. 
Other Assessments 
8.2.7.1. 
Review of Diet 
Patients will be following a low fat or heart-healthy diet at the screening visit and will be asked to 
continue the low fat or heart-healthy diet until the last study visit. Patients will be queried on 
compliance with their diet during the DBTP and OLTP, at time points according to Section 8.1. 
Details are provided in Appendix 2. 
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8.2.7.2. 
DNA Sample for HoFH Genotyping 
A required blood sample for DNA extraction will be collected from all patients to identify or 
confirm a known mutation in PCSK9, LDLR, Apo B gene, and/or LDLRAP1 gene.  
8.2.7.3. 
LDLR Function 
A blood sample for LDLR function testing will be collected from all patients at time points 
according to Section 8.1, in order to characterize LDLR function and explore potential differences 
in patient efficacy and safety. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
9.1. 
Obligations of Investigator 
The investigator must promptly report to the Institutional Review Board (IRB)/Ethics Committee 
(EC) all unanticipated problems involving risks to patients. This includes death from any cause 
and all SAEs related to the use of the study drug. It is recommended that all SAEs be reported to 
the IRB/EC, regardless of assessed causality. 
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9.2. 
Obligations of Sponsor 
During the course of the study, the sponsor will report in an expedited manner all SAEs that are 
both unexpected and at least reasonably related to the study drug (suspected unexpected serious 
adverse reaction [SUSAR]), to the health authorities, ECs/IRBs as appropriate, and to the 
investigators.  
Any AE not listed as an expected event in the Investigator’s Brochure or in this protocol will be 
considered as unexpected. Any worsening of or new onset of symptoms related to 
hypercholesterolemia which occur during the screening/washout period prior to study drug 
administration will be considered expected. 
In addition, the sponsor will report in an expedited manner all SAEs that are expected and at least 
reasonably related to evinacumab 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 ECs/IRB as appropriate. 
9.3. 
Definitions 
9.3.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug, which may or 
may not have a causal relationship with the study drug. Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease, which is 
temporally associated with the use of a study drug, whether or not considered related to the study 
drug. 
An AE also includes any worsening (ie, any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug. 
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 
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 Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent one of the other serious outcomes listed above 
(eg, intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development 
of drug dependency or drug abuse). 
9.3.3. 
Adverse Events of Special Interest 
An AE of special interest (AESI; serious or non-serious) is one of scientific and medical concern 
specific to the sponsor’s product or program, for which ongoing monitoring and rapid 
communication by the investigator to the sponsor can be appropriate. Such an event might warrant 
further investigation in order to characterize and understand it. Depending on the nature of the 
event, rapid communication by the trial sponsor to other parties (eg, regulators) might also be 
warranted (Section 9.4.3). 
9.3.4. 
Infusion Reactions 
Infusion reactions are defined as any AE that occurs during the infusion or within 2 hours after the 
infusion is completed. All infusion reactions must be reported as AEs (defined in Section 9.4.1) 
and graded using the grading scales as instructed in Section 9.5.1. 
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 study. Refer to the study reference manual for the procedures to be 
followed. 
Information on follow-up for AEs is provided in Section 9.4.6.  Laboratory, vital signs, or ECG 
abnormalities are to be recorded as AEs as outlined in Section 9.4.5. 
9.4.2. 
Serious Adverse Events 
All SAEs, regardless of assessment of causal relationship to study drug, must be reported to the 
sponsor (or designee) within 24 hours. Refer to the study reference manual for the procedure to be 
followed. 
Information not available at the time of the initial report must be documented in a follow-up report. 
Substantiating data such as relevant hospital or medical records and diagnostic test reports may 
also be requested. 
In the event the investigator is informed of an SAE after the patient completes the study, the 
following will apply: 
 SAE with an onset within 30 days of the end of study or within 168 days (24 weeks) 
of last study drug administration if the patient prematurely discontinued from the 
study - the SAE will be reported to the sponsor. The investigator should make every 
effort to obtain follow-up information on the outcome until the event is considered 
chronic and/or stable. 
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 SAE with an onset day greater than 30 days from the end of study/early termination 
visit - only fatal SAEs and those deemed by the investigator to be drug-related SAEs 
will be reported to the sponsor. The investigator should make every effort to obtain 
follow-up information on the outcome of a drug-related SAE until the event is 
considered chronic and/or stable. 
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 24 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 AESIs, serious and nonserious, 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 (serious or non-serious) for evinacumab include the following: 
 Anaphylactic reactions 
 Allergic reactions and/or local injection site reactions that require consultation with 
another physician for further evaluation or requiring medical treatment 
 Increase in ALT or AST: ≥3 x ULN (if baseline <ULN), or ≥2 times the baseline 
value (if baseline ≥ ULN) 
 Pregnancy 
 Symptomatic overdose with investigational medicinal product 
 Neurocognitive events 
 New onset of diabetes (see definition below) 
 Pancreatitis 
Adverse events of special interest for alirocumab include the following:   
 Increase in ALT: ALT ≥3 x ULN (if baseline ALT <ULN), or ALT ≥2 times the 
baseline value (if baseline ALT ≥ ULN) 
 Allergic events and/or local injection site reactions that require consultation with 
another physician for further evaluation 
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 Pregnancy 
 Symptomatic overdose with investigational medicinal product 
 Neurologic events that require additional examinations/procedures and/or referral to a 
specialist 
 Neurocognitive events 
 Cataracts 
 New onset of diabetes: The definition of new onset of diabetes (NOD) will be the 
following: 
 Type 1 or type 2 diabetes TEAE (grouping of Medical Dictionary for Regulatory 
Activities [MedDRA®] terms will be specified in the SAP) 
and/or 
 At least 2 values of HbA1c ≥6.5% during the TEAE period. NOTE: For patients 
with only a single measurement available during the TEAE period, a single value 
≥6.5% will be considered and qualify the patient as NOD by default. For patients 
with several HbA1c measurements but only with the last one ≥6.5%, this single 
value ≥6.5% will be considered and qualify the patient as NOD by default. 
and/or 
 At least 2 values of fasting glucose ≥126 mg/dL (7.0 mmol/L). NOTE: For 
patients with only a single measurement available during the TEAE period, a 
single value ≥126 mg/dL (7.0 mmol/L) will NOT be considered and will NOT 
qualify the patient as NOD. For patients with several fasting glucose 
measurements but only with the last one ≥126 mg/dL (7.0 mmol/L), this single 
value ≥126 mg/dL (7.0 mmol/L) will NOT be considered and will NOT qualify 
the patient as NOD. 
Refer to the study manual for the procedures to be followed. 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study 
All AEs that lead to a patient’s withdrawal from the study must be reported to the sponsor’s 
medical monitor within 30 days. 
Refer to the study 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 
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 the test result leads to a change in dosing (outside of protocol-stipulated dose 
adjustments), discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy 
Contact the medical monitor in the event the investigator feels that an abnormal test finding should 
be reported as an AE, although it does not meet any of the above criteria. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an 
AE. Any abnormal test result that is determined to be an error does not require reporting as an AE. 
Evaluation of severity of laboratory abnormalities will be assessed according to the scale outlined 
in Section 9.5.1. 
9.4.6. 
Follow-up 
Adverse event information will be collected until the patient’s last study visit. 
Serious adverse event information will be collected until the event is considered chronic and/or 
stable. 
9.5. 
Evaluation of Severity and Causality 
9.5.1. 
Evaluation of Severity 
The severity of AEs will be graded according to the following scale: 
 Mild:  Does not interfere in a significant manner with the patient’s normal functioning 
level. It may be an annoyance. Prescription drugs are not ordinarily needed for relief of 
symptoms, but may be given because of personality of the patient. 
 Moderate:  Produces some impairment of functioning but is not hazardous to health. 
It is uncomfortable or an embarrassment. Treatment for symptom may be needed. 
 Severe:  Produces significant impairment of functioning or incapacitation and is a 
definite hazard to the patient’s health. Treatment for symptom may be given and/or 
patient hospitalized. 
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
Infusion Reactions 
The severity of infusion reactions will be graded according to the following scale (semi-colon 
indicates “or” within description of the grade): 
 Mild:  Mild transient reaction; infusion interruption not indicated; intervention not 
indicated. 
 Moderate:  Therapy or infusion interruption indicated but responds promptly to 
symptomatic treatment (eg, antihistamines, nonsteroidal anti-inflammatory drugs, 
narcotics, IV fluids); prophylactic medications indicated for ≤24 hours. 
 Severe:  Prolonged (eg, not rapidly responsive to symptomatic medication and/or brief 
interruption of infusion); recurrence of symptoms following initial improvement; 
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hospitalization indicated for clinical sequelae; life-threatening consequences; urgent 
intervention indicated; death. 
9.5.2. 
Evaluation of Causality 
Relationship of AEs to Blinded IV Study Drug: 
The relationship of AEs to study drug will be assessed by the 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 
A list of factors to consider when assessing the relationship of AEs to study drug is provided in 
Appendix 1. 
The investigator should justify the causality assessment of each SAE. 
Relationship of AEs to SC PCSK9 Inhibitor Antibody (if applicable): 
The relationship of AEs to a PCSK9 inhibitor antibody (if applicable) will be assessed by the 
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 PCSK9 inhibitor 
antibody? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by the 
PCSK9 inhibitor antibody 
Related: 
There is a reasonable possibility that the event may have been caused by the PCSK9 
inhibitor antibody 
A list of factors to consider when assessing the relationship of AEs to a drug is provided in 
Appendix 1. 
The investigator should justify the causality assessment of each SAE. 
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Relationship of Adverse Events to Study Conduct: 
The relationship of AEs to study conduct will be assessed by the investigator, and will be a clinical 
decision based on all available information. The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by study conduct? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by study 
conduct 
Related: 
There is a reasonable possibility that the event may have been caused by study 
conduct 
A list of factors to consider when assessing the relationship of AEs to study conduct is provided 
in Appendix 1. 
The investigator should justify the causality assessment of each SAE. 
9.6. 
Safety Monitoring 
The investigator will monitor the safety of study patients at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP). Any questions or 
concerns should be discussed with the sponsor in a timely fashion. The sponsor will monitor the 
safety data from across all study sites. The medical monitor will have primary responsibility for 
the emerging safety profile of the compound, but will be supported by other departments (eg, 
Pharmacovigilance and Risk Management; Biostatistics and Data Management). Safety 
monitoring will be performed on an ongoing basis (eg, individual review of SAEs) and on a 
periodic cumulative aggregate basis. 
9.7. 
Investigator Alert Notification 
Regeneron (or designee) will inform all investigators participating in this clinical trial, as well as 
in any other clinical trial using the same investigational drug (evinacumab), 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 at the time of the double-blind period completion (ie, 
first-step analysis). 
Analysis variables are listed in Section 4. 
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10.1. 
Statistical Hypothesis 
Let μ0 and μ1 be the population means of the percent change from baseline in calculated LDL-C 
at week 24 under placebo and evinacumab, respectively. The following null hypothesis and 
alternative will be tested: 
H0 : μ0 = μ1 
versus 
H1 : μ0 ≠ μ1 
LDL-apheresis treatment (Yes/No), and geographical region (Japan, Rest of World) will be the 
2 stratification factors for patient randomization, and will be accounted for in the statistical 
modeling for efficacy. 
10.2. 
Justification of Sample Size 
For the primary efficacy hypothesis during the DBTP, a total sample size of 57 patients (38 on 
evinacumab and 19 on placebo) will have 90% power to detect a treatment group difference in 
mean percent change LDL-C of 38% with a 0.05 two-sided significance level and assuming a 
common standard deviation (SD) of 35%. This sample size has been adjusted for a 5% 
non-evaluable patient rate for the primary efficacy endpoint, and a 15% dropout rate. 
To gain experience with evinacumab in the population of Japanese patients, this study will plan to 
enroll up to 9 patients in Japan. Due to the rare patient population planned for evaluation, the 
sample size of 9 patients (15% of the planned study sample size) was chosen for practical reasons, 
centered on the feasibility to identify and enroll these patients into the trial. Based on the Ministry 
of Health, Labor, and Welfare 2007 “Basic Principles on Global Clinical Trials” method 1, a 
sample size of 12 (21%) will be needed to achieve 80% probability that the effect in Japan is at 
least ½ of the global effect. A sample size of 9 provides approximately 77% probability. 
10.3. 
Analysis Sets 
10.3.1. 
Efficacy Analysis Sets 
10.3.1.1. Intent-to-Treat 
The ITT population is defined as all randomized patients who received at least one dose or part of 
a dose of double blind study drug. Patients in the ITT population will be analyzed according to the 
treatment group allocated by randomization (ie, as randomized patient group): 
10.3.1.2. Modified Intent-to-Treat 
The modified ITT (mITT) population is defined as the all randomized population who took at least 
1 dose or part of a dose of study drug and have an evaluable primary endpoint. The endpoint is 
considered as evaluable when both of the following conditions are met: 
 Availability of at least 1 measurement value for calculated LDL-C before first dose of 
study drug (ie, baseline). 
 Availability of at least 1 calculated LDL-C value during the efficacy treatment period 
and within one of the analysis windows in the DBTP up to week 24. The efficacy 
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treatment period is defined as the time from the first double-blind study drug 
administration up to 35 days after the last double-blind study drug administration, or 
up to the first dose of the open-label study drug, whichever is earlier. 
Patients in the mITT population will be analyzed according to the treatment group allocated by 
randomization. 
10.3.2. 
Safety Analysis Sets 
10.3.2.1. Double-Blind Safety Analysis Set 
The double-blind safety analysis set (SAF) considered for safety analyses will be the randomized 
population who received at least 1 dose or part of a dose of double-blind study drug. Patients will 
be analyzed according to the treatment received (placebo or evinacumab). In addition:   
 Randomized patients for whom it is unclear whether they took the study drug will be 
included in the safety population as randomized. 
 For patients receiving study drug from more than 1 treatment group during the trial, 
the treatment group allocation for as-treated analysis will be the one in which the 
patient was treated with the highest number of infusions. 
10.3.2.2. Open-Label Safety Analysis Set 
The open-label SAF considered for safety analyses will be the randomized population who 
received at least 1 dose or part of a dose of open-label study drug. 
10.3.3. 
Other Analysis Sets 
The PK and the ADA analyses will be performed on all randomized patients who received any 
study drug, and further:   
 The PK analysis set will also require for each patient at least 1 non-missing 
post-baseline measurement of evinacumab concentration. Treatment assignments 
are based on the treatment received (placebo or evinacumab). 
 The ADA analysis set will also require for each patient at least 1 evaluable ADA 
result collected after the first dose of study treatment. Treatment assignments are 
based on the treatment received (placebo or evinacumab). 
10.4. 
Statistical Methods 
10.4.1. 
Patient Disposition 
The following data will be summarized: 
 The total number of screened patients, defined as originally having met the inclusion 
criteria and signed the ICF.  
 The total number of randomized patients, defined as all screened patients with a 
double-blind treatment kit number allocated and recorded in the IVRS database, 
regardless of whether the treatment kit was used. 
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For any patient randomized more than once, safety data from the first randomization 
will be included in the SAF, with safety data associated with the later randomization 
reported separately. Since this is expected to be a rare event, inclusion of efficacy 
data from the patient randomized more than once in the efficacy population will be 
decided on a case-by-case basis prior to the unblinding of treatment assignments and 
will be documented in the clinical study report. 
 The total number of patients randomized but not receiving study treatment. 
 The total number of patients randomized and receiving study treatment. 
 The total number of patients who completed the DBTP, defined as at least 20 weeks 
of study treatment exposure and visit week 24 performed. 
 The total number of patients who completed the OLTP, defined as at least 44 weeks 
of study treatment exposure and visit week 48 performed. 
 The total number of patients who prematurely discontinued study treatment during 
the double-blind period, and the reasons for discontinuation. 
 The total number of patients who prematurely discontinued study treatment during 
the open-label period, and the reasons for discontinuation. 
 The total number of patients who did not complete the study follow-up period, 
defined as the last visit performed less than 23 weeks after the last study treatment 
infusion. Patients who died during the study are excluded. 
 The total number of patients in each analysis set. 
 A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized. 
 A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation. 
10.4.2. 
Demography and Baseline Characteristics 
For the DBTP, demographic and baseline characteristics will be summarized descriptively by 
treatment group for patients in the ITT population. For the open-label period, demographic and 
baseline characteristics will be summarized descriptively by treatment group assigned in the 
double-blind period, as well as for patient total, for patients in the open-label SAF. Continuous 
variables will be descriptively summarized with mean, median, SD, minimum, and maximum. 
Categorical variables will be descriptively summarized with frequency and percentage.  
10.4.3. 
Efficacy Analyses 
10.4.3.1. Primary Efficacy Analysis 
The double-blind primary efficacy analysis will compare the evinacumab treatment group to 
placebo at week 24. The primary efficacy endpoint is the percent change in calculated LDL-C from 
baseline to week 24 (ITT estimand). The percent change from baseline in calculated LDL-C will 
be analyzed in the ITT population using a mixed-effect model with repeated measures (MMRM) 
approach. All post-baseline data available within week 2 to week 24 analysis windows will be used 
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and missing data are accounted for by the MMRM model. The model will include the fixed 
categorical effects of treatment group (placebo versus evinacumab), randomization strata 
(apheresis [Yes/No] and region [Japan, Rest of World]), time point (weeks 2, 4, 8, 12, 16, 20, 24), 
strata-by-time point interaction, and treatment by time point interaction, as well as, the continuous 
fixed covariates of baseline calculated LDL-C value and baseline value-by-time point interaction. 
The statistical testing of the comparison for the primary measure will be evaluated at a 2-sided 
significance level of 0.05. Model assumptions for distribution normality and equal variances 
between treatment groups will be explored prior to the analysis testing. 
This model will be run using Statistical Analysis System (SAS) Mixed procedure with an 
unstructured correlation matrix to model the within-patient errors. Parameters will be estimated 
using restricted maximum likelihood method with the Newton-Raphson algorithm. Denominator 
degrees of freedom will be estimated using Satterthwaite’s approximation. This model will provide 
baseline adjusted least squares means estimates at week 24 for both treatment groups with their 
corresponding standard errors (SEs). 
Robustness of the primary analysis statistical methods will be assessed through sensitivity analyses 
detailed in the SAP, including an on-treatment analysis of the percent change in calculated LDL-
C from baseline to week 24 (ie, mITT patient population using calculated LDL-C values collected 
during the efficacy treatment period [on-treatment estimand]), and a different methodology for 
missing data. Specifically, a pattern mixture model (PMM) will be employed to assess the potential 
violation of the missing at random assumption. For the PMM, the imputation model will account 
for the differing missing value patterns based on calculated LDL-C collected in the presence or 
absence of study treatment administration for those patients randomized into the study. 
10.4.3.2. Secondary Efficacy Analysis 
For the key secondary efficacy endpoints (defined in Section 4.2.2) and other secondary efficacy 
endpoints (described in Section 4.2.3) collected in the DBTP, descriptive summaries and analyses 
will be performed in the ITT population, using values obtained regardless of adherence to study 
treatment and subsequent therapies (ITT estimand). 
For descriptive summaries, percent change, and when appropriate change from baseline, in 
calculated LDL-C, total-C, TG, non-HDL-C, Apo B, Lp(a), and Apo CIII will be provided at each 
time point. All measurements, scheduled or unscheduled, will be assigned to analysis windows 
defined in the SAP in order to provide an assessment for these time points. Laboratory assessments 
other than the ones provided by the central laboratory will be excluded. For TG, measurements on 
non-fasting patients will be excluded. The time profile of each parameter will be plotted by 
treatment group with the corresponding SEs. 
Multiple types of measurements are planned to be analyzed during differing time points in the trial, 
specifically continuous measurements expected to have a normal distribution (example:  percent 
change in calculated LDL-C), continuous measurements expected to have a non-normal 
distribution (example: TG), and binary measurements (example:  proportion of patients reaching 
LDL-C <100mg/dL). 
I. Continuous endpoints anticipated to have a normal distribution 
Continuous secondary variables defined in Section 4.2.2 and Section 4.2.3 anticipated to have a 
normal distribution (ie, lipids other than TG and Lp[a]) will be analyzed using the same MMRM 
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model as for the primary endpoint. Specifically, the model will contain fixed categorical effects of 
treatment group, randomization strata, planned time points up to the time point of interest, strata-
by-time point interaction and treatment-by-time point interaction, as well as the continuous fixed 
covariates of corresponding baseline value and baseline value-by-time point interaction. 
II. Continuous endpoints anticipated to have a non-normal distribution 
Continuous secondary efficacy endpoints defined in Section 4.2.2 and Section 4.2.3 anticipated to 
have a non-normal distribution (ie, TG and Lp[a]), will be analyzed using a robust regression 
model (ie, ROBUSTREG SAS procedure with M-estimation option) with treatment group and 
randomization stratum as main effect and corresponding baseline value(s) as a covariate. Missing 
values will be addressed using a multiple imputation approach, which will be described in the SAP. 
The variables in the multiple imputation model will at least include the same variables as used in 
the robust regression model. The treatment group combined means will be provided with 
respective SE estimates. The combined mean difference between the treatment groups will be 
provided with the SE, 95% confidence interval (CI) and p-value. 
III. Binary endpoints 
Binary secondary efficacy endpoints defined in Section 4.2.2 and Section 4.2.3 will be analyzed 
using stratified logistic regression (using the strata option of the SAS logistic procedure) with 
treatment group and randomization stratum as main effect and corresponding baseline value(s) as 
a covariate. Missing values will be addressed using a multiple imputation approach, which will be 
described in the SAP. The variables in the multiple imputation model will at least include the same 
variables as used in the logistic regression model. Treatment effects will be compared and the 
combined odds ratio estimate between the treatment groups, with their corresponding 95% CI and 
p-value will be provided. 
In the data dependent case that the logistic regression method is not applicable (eg, the response 
rate is zero in one treatment arm and thus the maximum likelihood estimate may not exist), the last 
observation carried forward (LOCF) approach would be used for handling of missing values and 
an exact conditional logistic regression would be performed to compare treatment effects. The 
LOCF imputation method will consist of using the last value obtained up to the week 24 time 
window to impute the missing week 24 value. 
10.4.3.3. Multiplicity Considerations 
In order to address multiple key secondary efficacy endpoints (ie, other lipid parameters) collected 
in the double-blind period (Section 4.2.2 and Section 4.2.3) , the overall type-I error will be 
controlled by the use of a hierarchical inferential approach. Statistical significance of the primary 
parameter is required before drawing inferential conclusions about the first key secondary 
parameter at the 0.05 alpha level. Inferential conclusions about successive key secondary 
parameters require statistical significance of the prior parameter within the hierarchy. The 
hierarchy testing sequence will be provided in the SAP, prior to treatment unblinding. This fixed 
hierarchical approach will ensure a strong control of the overall type-I error rate at the 0.05 level. 
No further adjustments will be made for other secondary endpoints, for which p-values will be 
provided for descriptive purposes only. 
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No adjustment will be made for the first step (Section 10.4.9.1) and second step (Section 10.4.9.2) 
statistical analyses, since the primary and key secondary efficacy endpoints will have been 
concluded at the time of the first step analysis. 
10.4.3.4. Other Efficacy Endpoints 
During the OLTP, efficacy variables will be explored through descriptive statistics at each 
scheduled visit for the total patients administered open-label study treatment (total), as well as by 
the patient subgroups of study treatment received in the DBTP (ie, evinacumab, placebo). Formal 
statistical testing is not planned. Descriptive statistics will include the same parameters as 
described for each variable in the DBTP. 
For patients receiving evinacumab in the DBTP, a combined summary including both the double-
blind and OLTP assessments may be considered, referencing the double-blind baseline for variable 
calculations. Prolonged time between last dose of double-blind treatment and first dose of open-
label treatment will need to be taken into consideration when combining longitudinal efficacy data. 
Formal statistical testing is not planned. 
10.4.3.5. Subgroup Analyses for the Primary Efficacy Endpoint 
Analyses are planned on the primary efficacy endpoint to access the homogeneity of evinacumab 
treatment effect across various patient subgroups in the ITT population, including the 
2 stratification factors LDL-C apheresis and region, and patients with or without receptor-negative 
mutations in both LDLR alleles. Statistical analysis methods will be provided in the SAP. 
With respect to the subgroup analysis for region, the primary efficacy analysis MMRM model will 
be used to evaluate treatment effect in Japanese patients (as recorded in the electronic data capture 
[EDC] system) by adding the variables of treatment-by-region strata and treatment-by time point-
by region strata interaction terms to the model. With this subgroup specific MMRM model, the 
primary efficacy endpoint LS mean at week 24 for the evinacumab treatment group will be 
provided for the Japanese patients, along with the corresponding SE and 95% CI. Due to the few 
Japanese patients (3) expected to be randomized to the placebo group, the evinacumab group LS 
mean point estimate will be used to access consistency of evinacumab effect between the Japanese 
patients and all evinacumab treated patients in this global study (provided by the primary efficacy 
analysis described in Section 10.4.3.1). The evinacumab primary efficacy endpoint LS mean point 
estimate for the Japanese patients is considered to show consistent efficacy results with the global 
study point estimate when the Japanese patient’s LS mean point estimate is greater by a pre-
specified amount (to be provided in the SAP) than the corresponding global study point estimate 
(ie, ratio of point estimate for Japanese patients divided by point estimate for the global study). 
10.4.3.6. On-Treatment Efficacy Analyses 
For key secondary efficacy endpoints (defined in Section 4.2.2) collected in the DBTP, descriptive 
summaries and analyses comparing treatment groups will be performed in the mITT population, 
using values obtained during the efficacy treatment period (on-treatment estimand). Statistical 
methods described above will be used to analyze each key secondary efficacy endpoint. P-values 
will be provided for descriptive purposes only. 
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10.4.4. 
Safety Analysis 
For the double-blind period, summaries of safety results will be presented by treatment group for 
patients in the double-blind SAF. Summaries of safety results for the open-label period will be 
presented for patients in the open-label SAF, by the total patients administered open-label study 
treatment (total), as well as by the patient subgroups of study treatment received in the DBTP 
(ie, evinacumab, placebo). No formal inferential testing will be performed. Summaries will be 
descriptive in nature. 
All safety analyses will be performed using the following common rule: 
 The baseline value is defined as the last available value before the first dose of 
double-blind study treatment. 
10.4.4.1. Adverse Events 
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®). The verbatim text, the preferred term (PT), and 
the system organ class (SOC) will be provided in patient listings. 
Definitions 
For safety variables, the following observation periods are defined: 
 The pretreatment period is defined from the day the ICF is signed to the day before 
the first dose of double-blind study treatment. 
 The double-blind TEAE observation period is defined from the day of the first dose 
of double-blind study treatment to the day of the last dose of double-blind study 
treatment + 168 days (24 weeks) (residual effect of treatment for IV dose regimen is 
expected until 24 weeks after the last dose of study drug) for those patients not 
proceeding into the OLTP, or up to the day before the first dose of open-label study 
treatment administration for those patients proceeding into the OLTP.  
 The open-label TEAE observation period is defined from the day of the first 
open-label study treatment administration to the day of the last open-label study 
treatment administration + 168 days.  
 The post-treatment observation period is defined as the time from the day after the 
end of the respective TEAE periods to the last study visit. 
Double-blind TEAEs are defined as those events that developed, worsened, or became serious 
during the double-blind TEAE period. Open-label TEAEs are defined as those events that 
developed, worsened, or became serious during the open-label TEAE period. 
Analysis 
Adverse event incidence tables will present data by SOC sorted alphabetically and PT sorted by 
decreasing frequency, and summarize the number (n) and percentage (%) of patients experiencing 
an AE. Multiple occurrences of the same event in the same patient will be counted only once in 
the tables. Data conventions for missing or partial AE dates will be addressed in the SAP. The 
denominator for computation of percentages is the respective SAF populations (ie, double-blind 
SAF or open-label SAF) within each treatment group. 
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Summaries of TEAEs incidences will include: 
 All TEAEs (and patient listing) 
 All treatment-emergent SAEs, including patient deaths (and patient listing) 
 All TEAEs of special interest for alirocumab treatment (ie, increase in ALT, etc) 
 All TEAEs of special interest for evinacumab treatment (anaphylactic reaction, etc) 
 TEAEs by severity (according to the grading scale outlined in Section 9.5.1), 
depicting the worse TEAE severity for those patients with multiple occurrences of the 
same event  
 All TEAEs leading to permanent treatment discontinuation (and patient listing) 
An AE patient listing will be provided for all patient deaths occurring during the respective TEAE 
periods (ie, double-blind and open-label) and the post-treatment period. 
10.4.4.2. Other Safety 
Definitions 
The following definitions will be applied to laboratory parameters and vital signs: 
 The potentially clinically significant value (PCSV) criteria are defined as abnormal 
values considered medically important by the sponsor according to predefined 
criteria/thresholds based on literature review and defined by the sponsor for clinical 
laboratory tests and vital signs. PCSV criteria will be provided in the SAP. 
 PCSV criteria will determine which patients had at least 1 PCSV during the 
respective TEAE periods (double-blind and open-label), taking into account all 
evaluations performed during the respective TEAE periods, including unscheduled or 
repeated evaluations. The number of all such patients will be the numerator for the 
PCSV percentage. 
 Double-blind treatment period:  The treatment period used for the quantitative 
analysis of laboratory and vital signs data in the double-blind period is defined from 
the day after the first dose of double blind study treatment to the day of the last dose 
of double-blind study treatment + 28 days for those patients not proceeding into the 
OLTP, or up to the day of the first dose of open-label study treatment administration 
for those patients proceeding into the OLTP. 
 Open-label treatment period:  The treatment period used for quantitative analysis of 
laboratory and vital signs data in the open-label study period is defined from the day 
after the first dose of open-label study treatment to the day of the last dose of 
open-label study treatment + 28 days. 
Analysis 
Summary statistics of all laboratory variables (including lipid HDL-C) and all vital signs 
parameters (raw data and changes from baseline) will be calculated for each protocol scheduled 
visit assessed during the respective treatment periods. For selected parameters, mean changes from 
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baseline with the corresponding SE may be plotted over time (at same time points) in each 
treatment group. 
The incidence of PCSVs at any time during the respective TEAE periods will be summarized 
regardless of the baseline level, and again according to the following baseline categories: 
 Normal/missing 
 Abnormal according to PCSV criterion or criteria 
For laboratory parameters for which a PCSV criterion is not defined, similar table(s) using the 
normal range will be provided, regardless of baseline level. 
Listings will be provided with flags indicating the laboratory values meeting PCSV criteria. 
10.4.4.3. Treatment Exposure 
The duration of study treatment exposure for the double-blind period will be calculated as: 
 Patient duration of study treatment exposure in weeks: (last double-blind study 
treatment administration date + 28 – first double-blind study treatment administration 
date +1 day)/7, regardless of unplanned intermittent discontinuations. 
 The total number of double-blind treatment infusions by patient. 
The duration of evinacumab exposure for the open-label period will be calculated as: 
 Patient duration of evinacumab exposure in weeks: (last open-label evinacumab 
administration date + 28 – first open-label evinacumab treatment administration 
date)/7, regardless of unplanned intermittent discontinuations. 
 The total number of open-label evinacumab infusions by patient. 
The duration of evinacumab cumulative exposure in the double-blind and open-label periods will 
be calculated as: 
 Combined patient duration of evinacumab exposure in weeks: double-blind 
evinacumab treatment duration + open-label evinacumab treatment duration, 
regardless of unplanned intermittent discontinuations. 
 Combined total number of evinacumab treatment infusions by patient defined as: total 
number of double-blind evinacumab infusions + total number of open-label 
evinacumab infusions. 
The durations of study treatment exposure (double-blind, open-label, and cumulative across the 
study), measured in weeks, will be summarized by at least; mean, median, SD, and 
minimum/maximum. The categorical data for number of study treatment infusions (double-blind, 
open-label, and cumulative across the study) will be summarized by patient counts and 
percentages. 
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10.4.4.4. Treatment Compliance 
Compliance during the double-blind period will be assessed by infusion frequency, specifically: 
 Defined for each patient as the average number of days between 2 infusions: (last 
double-blind dose date – first double-blind dose date) / (number of infusions in 
double-blind -1), for patients receiving at least 2 infusions. 
Infusion frequency for the double-blind period will be summarized by at least; mean, median, SD, 
and minimum/maximum. 
10.4.5. 
Analysis of Drug Concentration and Target Concentration Data 
Descriptive statistics of evinacumab concentrations and total ANGPTL3 concentration and 
alirocumab and PCSK9 concentration at each sampling time will be provided by treatment group. 
Plots of mean concentrations (linear and log scales) versus time will be presented. 
10.4.6. 
Analysis of Anti-Drug Antibody Data 
Listings of ADA positivity and titers presented by patient, time point, and study treatment received 
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 treatment received. 
The influence of ADA on drug concentrations will be evaluated. Assessment of impact of ADA 
on safety and efficacy may be provided. 
10.4.7. 
Analysis of Statin Concentration 
Descriptive statistics at each sampling time. The ratio of concentration at week 24 over baseline 
for individual patient will be presented, when available. 
 
 
 
 
 
 
10.4.9. 
Timing of Statistical Analyses 
The analyses will be conducted in 2 steps: 
10.4.9.1. First Step: Main Efficacy and Safety Analysis 
The first analysis will be conducted as soon as all patients have been randomized and all data 
through week 24 (double-blind period) has been collected and validated. This first analysis will 
consist of the final analysis of the primary and secondary efficacy endpoints. The safety analysis 
will be performed on all safety data collected and validated at the time of the first analysis. 
The results of the first analysis will not be used to change the conduct of the ongoing study in any 
aspect. Since data collection for the double-blind primary efficacy measure and key secondary 
efficacy measures will have been concluded at the time of this first analysis, the significance level 
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for the study remains at 0.05. This first analysis maybe used for the submission dossier to health 
authorities. 
Individuals involved in the first step analysis of the study will not be involved in the conduct of 
the study afterwards; individual patient identification will not be released to anyone who is directly 
involved in the conduct of the study. The first step analysis process, the measures used to protect 
the blind and the integrity of the study, the communication plan, and the confidentiality agreement 
will be described in a separate document. 
10.4.9.2. Second Step: Final Safety Analysis 
The second analysis will be conducted at the end of the OLTP (end of study) and will consist of 
the final analysis for safety and the OLTP exploratory efficacy measures. 
10.5. 
Additional Statistical Data Handling Conventions 
Additional analysis and data conventions will be provided in the SAP, including the definitions 
for the analysis windows around each planned visit. 
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 EDC tool, iMedidata Rave. 
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 
 EDC system – data capture 
 SAS – statistical review and analysis 
 Pharmacovigilance safety database 
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12. 
STUDY MONITORING 
12.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, CRO monitor) will visit each site prior to enrollment of 
the first patient, and periodically during the study. 
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. 
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/EC files, documentation of certification and quality 
control of supporting laboratories, and records relevant to the study maintained in any supporting 
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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 (refer to current version), 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/EC. A copy of the IRB/EC-approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient prior to his/her participation in the study and after the 
aims, methods, objectives, and potential hazards of the study have been explained to the patient in 
language that he/she can understand. The ICF should be signed and dated by the patient and by the 
investigator or authorized designee who reviewed the ICF with the patient. 
 Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
 Patients who can understand but who can neither write nor read will have the ICF 
read to them in presence of an impartial witness. The patient will give oral consent 
and the impartial witness 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. 
Patient Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained. Patients should be identified by their patient identification number, 
only, on CRFs or other documents submitted to the sponsor. Documents that will not be submitted 
to the sponsor (eg, signed ICF) must be kept in strict confidence. 
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The patient's and investigator's personal data, which may be included in the sponsor database, will 
be treated in compliance with all applicable laws and regulations. The sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third party. 
14.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve: 
 The protocol, ICF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
 Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patients, in 
which case the IRB/EC should be informed as soon as possible  
 Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
In addition, the IRB/EC should be informed of any event likely to affect the safety of patients or 
the continued conduct of the clinical study. 
A copy of the IRB/EC approval letter with a current list of the IRB/EC members and their functions 
must be received by the sponsor prior to shipment of drug supplies to the investigator. The approval 
letter should include the study number and title, the documents reviewed, and the date of the 
review. 
Records of the IRB/EC review and approval of all study documents (including approval of ongoing 
studies) must be kept on file by the investigator. 
15. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an IRB/EC-
approved amendment. Regulatory approvals will also be sought where applicable under local 
regulations. 
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. 
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16.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
Investigator’s Decision 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at least 
30 days’ notice. The final decision should be made through mutual agreement with the sponsor. 
Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing. Reasons 
may include the following, among others:  
 The investigator has received all items and information necessary to perform the 
study, but has not enrolled any patient within a reasonable period of time 
 The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines  
 The total number of patients required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB/EC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection of 
the patients’ interests. 
17. 
STUDY DOCUMENTATION 
17.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the CRF must be signed 
electronically by the investigator. This signed declaration accompanies each set of patient final 
eCRFs 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. 
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18. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
19. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
20. 
PUBLICATION POLICY 
The publication policy is provided as a separate agreement. 
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Cuchel M, Bruckert E, Ginsberg HN, et al. Homozygous familial hypercholesterolaemia: new 
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Goldberg AC, Hopkins PN, Toth PP et al., Familial hypercholesterolemia: screening, diagnosis 
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Marais AD, Raal FJ, Stein EA, et al. A dose-titration and comparative study of rosuvastatin and 
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Raal FJ, Pilcher GJ, Illingworth DR, et al. Expanded-dose simvastatin is effective in homozygous 
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22. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: “A randomized, double-blind, placebo-controlled, parallel-group 
study to evaluate the efficacy and safety of evinacumab in patients with homozygous familial 
hypercholesterolemia”, and agree to abide by all provisions set forth therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, state, 
or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor or a partnership 
in which the sponsor is involved. I will immediately disclose it in writing to the sponsor if any 
person who is involved in the study is debarred, or if any proceeding for debarment is pending, or, 
to the best of my knowledge, threatened. 
This document contains confidential information of the sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the IRB/EC. I agree to ensure that this 
information will not be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the sponsor. 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
 
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APPENDIX 1. FACTORS TO CONSIDER IN ASSESSING THE 
RELATIONSHIP OF ADVERSE EVENTS TO STUDY 
DRUG AND STUDY CONDUCT OR STUDY PROCEDURE 
OR BACKGROUND TREATMENT, ETC. 
Is there a reasonable possibility that the event may have been caused by the study drug or study 
conduct or study procedure or background treatment, etc? 
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 study procedure or background treatment, etc. 
 do not reappear or worsen when dosing with study drug or study procedure or 
background treatment, etc is resumed 
 are not a suspected response to the study drug or 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 
 follow a reasonable temporal sequence following the time of administration of the 
dose of study drug or study procedure or background treatment, etc. 
 resolve or improve after discontinuation of study drug or study procedure or 
background treatment, etc. 
 reappear or worsen when dosing with study drug or study procedure or background 
treatment, etc is resumed 
 are known or suspected to be a response to the study drug or study procedure or 
background treatment, etc, based upon preclinical data or prior clinical data 
NOTE:  This list is not exhaustive. 
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CONFIDENTIAL 
APPENDIX 2. SUMMARY OF TLC DIET FOR HIGH CHOLESTEROL 
Total Fat 
25% - 35% total calories* 
Saturated fat* 
<7% total calories 
Polyunsaturated fat 
up to 10% total calories 
Monounsaturated fat 
up to 20% total calories 
Carbohydrates† 
50% - 60% total calories* 
Protein 
~15% total calories 
Cholesterol 
<200 mg/dL (5.172 mmol/l) 
Plant Sterols 
2g 
Soluble Fiber such as psyllium 
10g - 25g 
* ATP III allows an increase of total fat to 35 percent of total calories and a reduction in carbohydrate to 50 percent for persons with the 
metabolic syndrome. Any increase in fat intake should be in the form of either polyunsaturated or monounsaturated fat. Trans-fatty acids 
are another LDL-raising fat that should be kept at a low intake. 
† Carbohydrate should derive predominantly from foods rich in complex carbohydrates including grains—especially whole grains—fruits, 
and vegetables. 
 
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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 protocol accurately describes the conduct of the study. 
Study Title: 
A randomized, double-blind, placebo-controlled, parallel-group study to evaluate 
the efficacy and safety of evinacumab in patients with homozygous familial 
hypercholesterolemia 
Protocol Number: 
R1500-CL-1629 
Protocol Version: 
R1500-CL-1629 Amendment 4A 
 
See appended electronic signature page 
Sponsor’s Responsible Scientific/Medical Monitor 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Representative 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Team Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
                                        VV-RIM-00089245-1.0 Approved - 11 Oct 2019 GMT-5:00

Signature Page for VV-RIM-00089245 v1.0
Signature Page for VV-RIM-00089245 v1.0 Approved
ESig Approval
nt
10-Oct-2019 22:25:00 GMT+0000
ESig Approval
11-Oct-2019 01:49:52 GMT+0000
ESig Approval
11-Oct-2019 10:28:39 GMT+0000
ESig Approval
2019 19:04:57 GMT+0000
                                        VV-RIM-00089245-1.0 Approved - 11 Oct 2019 GMT-5:00

Eudract Number: 2017-001388-19 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP STUDY TO EVALUATE THE EFFICACY AND 
SAFETY OF EVINACUMAB IN PATIENTS WITH HOMOZYGOUS 
FAMILIAL HYPERCHOLESTEROLEMIA 
Compound: 
Evinacumab (REGN1500) 
Clinical Phase: 
3 
Protocol Number: 
R1500-CL-1629 
Protocol Version: 
R1500-CL-1629 Amendment 4B 
Amendment 4B Date of Issue 
See appended electronic signature page 
Amendment 3B Date of Issue: 
22 Jun 2018 
Amendment 2B Date of Issue: 
08 Dec 2017 
Original Date of Issue: 
07 May 2017 
Scientific/Medical Monitor: 
 
Director, Clinical Sciences 
Cardiovascular and Metabolism 
Clinical Development and Regulatory Affairs 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
 
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NCT03399786

Clinical Study Protocol 
 
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CONFIDENTIAL 
 
AMENDMENT HISTORY 
Amendment 4B 
The protocol was amended in response to recent nonclinical findings in the rabbit. The table 
below summarizes the changes and the affected sections:  
Change 
Sections Changed  
In an embryofetal development toxicology 
study in rabbits, incomplete ossification of 
the 15th vertebra was observed in some 
fetuses resulting from the mating of male 
rabbits exposed to evinacumab with female 
rabbits not exposed to evinacumab. In male 
rabbits, there were measurable levels of 
evinacumab in seminal fluid and, as a safety 
measure, the current clinical study is 
amended to require consistent use of a 
condom for all sexually active males.  
Section 3.2.3 Risk/Benefit Assessment 
Section 6.2.2 Exclusion Criteria #24 
Table 3 Schedule of Events – Baseline, Double-Blind 
Treatment Period, and Open-Label Treatment Period. 
Table 4 Schedule of Events – Follow-up Period 
Updated Scientific/Medical monitorr 
Title page 
Added abbreviation for women of child 
bearing potential 
List of abbreviations 
Amendment 3B 
The table below summarizes the changes to the protocol and the affected sections:   
Rationale for Change 
Sections Changed  
Expanded Risk/Benefit section to include 
risk/benefit assessment of the combination 
of evinacumab and PCSK9 inhibitors, 
including alirocumab for the treatment of 
patients with homozygous familial 
hypercholesterolemia (HoFH). 
Section 3.2.3 Risk/Benefit Assessment 
Section 21 References 
Clarified the eligibility requirements by 
requiring that patients entering this study 
from R727-CL-1628 meet all of the 
eligibility criteria for this study. 
Clarified that patients enrolling from R727-
CL1628 will continue to receive alirocumab 
150 mg every 2 weeks (Q2W). 
Clinical Study Protocol Synopsis: Study Design 
Clinical Study Protocol Synopsis: Treatment(s) 
Section 5.1 Study Description and Duration 
Section 7.3 Background Treatments 
To be consistent with the recommendations 
from the Clinical Trial Facilitation Group 
(CTFG) on contraception and pregnancy 
testing in clinical trials, added “True 
abstinence: When this is in line with the 
preferred and usual lifestyle of the patient. 
Periodic abstinence (calendar, 
symptothermal, post-ovulation methods), 
withdrawal (coitus interruptus), spermicides 
Section 6.2.2 Exclusion Criteria #23 
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Rationale for Change 
Sections Changed  
only, and lactational amenorrhea method 
(LAM) are not acceptable methods of 
contraception.” 
Added exclusion criteria for patients housed 
in an institution on the basis of an 
administrative or judicial order and patients 
who are dependent on the sponsor, 
investigator or the study site. 
Section 6.2.2 Exclusion Criteria #25, #26 
Editorial or administrative edits 
Section 5.1 Study Description and Duration 
Section 5.3.1 Independent Data Monitoring Committee 
Section 5.3.2 Clinical Events Committee 
Section 6.2.1 Inclusion Criteria #3 
Section 7.6.1 Blinding 
Section 7.8.1 Prohibited Medications and Procedures 
Section 8.2.2 Efficacy Procedures 
Section 14.1 Good Clinical Practice Statement 
Section 14.2 Informed Consent 
Amendment 2B 
This replaces the Global protocol. The table below summarizes the changes to the protocol and 
the affected sections:   
Rationale for Change 
Sections Changed  
Added a section on Risk/Benefit 
Section 3.2.3 Risk/Benefit Assessment (new) 
Added EQ-5D and HADS QOL 
questionnaires and an EQ-5D and HADS 
objective and exploratory endpoint to allow 
assessment of quality of life in this 
population 
Section 2.3 Other Objectives 
Section 4.2.4 Other Endpoints 
Table 3 Schedule of Events - Baseline, Double-Blind Treatment 
Period, and Open-Label Treatment Period 
Section 8.1.3 Footnotes for Schedule of Events Table 3 
Section 8.2.3 Quality of Life Procedures (new) 
Section 8.2.3.1 EuroQol-5Questionnaire 
Section 8.2.3.2 Patient Assessed Hospital Anxiety and Depression 
Scale 
Clarified language for apheresis 
requirements and collection of clinical 
laboratory samples relative to the timing of 
apheresis procedures, administration of 
PCSK9 inhibitor or mipomersen 
Section 5.1 Study Description and Duration 
Section 6.2.1 Inclusion Criteria: #3 
Section 8.1.3 Footnotes for Schedule of Events Table 3: #2 
Clarified confirmation of patients HoFH 
status and added text for genotyping as well 
as a DNA sample for genotyping in the 
schedule of events 
Section 5.1 Study Description and Duration 
Table 3 Schedule of Events - Baseline, Double-Blind Treatment 
Period, and Open-Label Treatment Period 
Clarified text for patients who transition 
from study R727-CL-1628 to this study and 
Clinical Study Protocol Synopsis: Study Design 
Section 5.1 Study Description and Duration 
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Rationale for Change 
Sections Changed  
added a footnote to Table 3. Added consent 
and pharmacogenomics consent to schedule 
of events table 
Table 3 Schedule of Events - Baseline, Double-Blind Treatment 
Period, and Open-Label Treatment Period 
Section 8.1.3 Footnotes for Schedule of Events Table 3: #1 
Clarified that patients should be on a 
maximally tolerated regimen of lipid 
modifying therapy 
Clinical Study Protocol Synopsis: Population 
Section 6.2 Study Population 
Section 7.3 Background Treatment(s) 
Added a footnote for timing of collection of 
vital signs on dosing days 
Section 8.1.3 Footnotes for Schedule of Events Table 3: #5 
Added Lipid Panel and Specialty Lipid 
Panel assessments and assessments of 
hematology, blood chemistry, and creatinine 
phosphokinase for the follow-up period 
Table 4 Schedule of Events – Follow-up Period 
Added a criterion excluding patients with 
LDL-C level <70 mg/dL as this is the goal 
for FH patients. Consequently, patients 
already at goal will be excluded. 
Update efficacy procedure for lipids 
Added criterion excluding members of the 
clinical site study team and/or his/her 
immediate family 
Section 6.2.2 Exclusion Criteria: #1, #21 
Section 8.2.2 Efficacy Procedures – (added LDL-C values below 
25 mg/dL) 
Clarified LDL apheresis therapy during the 
run-in period 
Section 6.2.2 Exclusion Criteria: #3 
Section 7.2 Run-in Treatments 
Updated anti-drug antibody  (ADA) 
variables and added a statement for follow-
up of patients positive in the ADA assay 
Added ADA sample at week 4 
Section 4.4 Anti-Drug Antibody Variables 
Section 8.2.5.2 Anti-Drug Antibody Measurements and Samples 
Table 3 Schedule of Events - Baseline, Double-Blind Treatment 
Period, and Open-Label Treatment Period 
Clarified collection of data regarding lipid 
modifying therapy 
Section 6.2 Study Population 
Section 7.3 Background Treatment(s) 
Modified text for lipid results  
Section 8.2.2 Efficacy Procedures 
Added a section of pregnancy testing  
Section 8.2.4.6 Pregnancy Testing 
Added sex hormones to assessments for 
adolescents 
Table 1 Schedule of Events – Run-in and Screening 
Table 2 Schedule of Events – Screening for Patients with No Run-
in  
Table 3 Schedule of Events - Baseline, Double-Blind Treatment 
Period, and Open-Label Treatment Period 
Table 4 Schedule of Events – Follow-up Period 
Section 8.1.1 Footnotes for Schedule of Events Table 1: #4 
Section 8.1.2 Footnotes for Schedule of Events Table 2: #4 
Section 8.1.3 Footnotes for Schedule of Events Table 3: #6 
Section 8.1.4 Footnotes for Schedule of Events Table 4: #2 
Section 8.2.4.5 Laboratory Testing 
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Rationale for Change 
Sections Changed  
Modified timing of one assessments for 
weight and one assessment for PK 
Table 3 Schedule of Events - Baseline, Double-Blind Treatment 
Period, and Open-Label Treatment Period 
Provided a definition for “new onset 
diabetes” as this is an adverse event of 
special interest (AESI) and expanded the list 
of AESIs for evinacumab 
Section 9.4.3 Other Events that Require Accelerated Reporting 
Clarified intent to treat population and 
updated methods of analysis to account for 
missing data 
Section 10.3.1.1 Intent-to-Treat  
Section 10.4.3.1 Primary Efficacy Analysis 
Query LMT Compliance added to the 
schedule of events tables 
Table 1 Schedule of Events – Run-in and Screening 
Table 2 Schedule of Events – Screening for Patients with No 
Run-in  
Table 3 Schedule of Events - Baseline, Double-Blind Treatment 
Period, and Open-Label Treatment Period 
Table 4 Schedule of Events – Follow-up Period 
Edits/Clarifications 
Clinical Study Protocol Synopsis: Study Design 
Clinical Study Protocol Synopsis: Duration 
Clinical Study Protocol Synopsis: Population 
Section 1 Introduction 
Section 3.2.1 Rationale for Study Design 
Section 4.2.1 Primary Efficacy Endpoint 
Section 5.1 Study Description and Duration and Synopsis, Study 
Duration 
Figure 1 Study Flow Diagram 
Section 6.2.2 Exclusion Criteria 
Section 7.4.2 Study Drug Discontinuation 
Section 7.6 Method of Treatment Assignment 
Section 7.6.1 Blinding 
Section 7.7.1 Packaging, Labeling, and Storage 
Section 7.8.1 Prohibited Medications and Procedures 
Section 7.8.2 Permitted Medications and Procedures 
Section 8.1 Schedule of Events (Tables) 
Section 8.1.1 Footnotes for Schedule of Events Table 1: #2, #7 
Section 8.1.2 Footnotes for Schedule of Events Table 2: #2 
Section 8.1.3 Footnotes for Schedule of Events Table 3: #2, #3 
Section 8.1.5 Early Termination Visit 
Section 8.2.4.1 Vital Signs 
Section 8.2.7.2 DNA Sample and HoFH Genotyping 
Section 10.4.3.2 Secondary Efficacy Analysis 
Section 10.4.4.1 Adverse Events 
 
 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................17 
1. 
INTRODUCTION ......................................................................................................20 
2. 
STUDY OBJECTIVES ..............................................................................................23 
2.1. 
Primary Objective .......................................................................................................23 
2.2. 
Secondary Objectives .................................................................................................23 
2.3. 
Other Objective ...........................................................................................................23 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................23 
3.1. 
Hypothesis ..................................................................................................................23 
3.2. 
Rationale .....................................................................................................................23 
3.2.1. 
Rationale for Study Design .........................................................................................23 
3.2.2. 
Rationale for Dose Selection ......................................................................................24 
3.2.3. 
Risk / Benefit Assessment ..........................................................................................25 
4. 
STUDY VARIABLES................................................................................................27 
4.1. 
Demographic and Baseline Characteristics ................................................................27 
4.2. 
Primary and Secondary Endpoints..............................................................................27 
4.2.1. 
Primary Efficacy Endpoint .........................................................................................27 
4.2.2. 
Key Secondary Efficacy Endpoints ............................................................................27 
4.2.3. 
Other Secondary Efficacy Endpoints ..........................................................................28 
4.2.4. 
Other Endpoints ..........................................................................................................28 
4.3. 
Pharmacokinetic Variables .........................................................................................28 
4.4. 
Anti-Drug Antibody Variables ...................................................................................28 
5. 
STUDY DESIGN .......................................................................................................29 
5.1. 
Study Description and Duration .................................................................................29 
5.1.1. 
End of Study Definition ..............................................................................................33 
5.2. 
Planned Interim Analysis ............................................................................................33 
5.3. 
Study Committees .......................................................................................................33 
5.3.1. 
Independent Data Monitoring Committee ..................................................................33 
5.3.2. 
Clinical Events Committee .........................................................................................33 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............34 
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6.1. 
Number of Patients Planned .......................................................................................34 
6.2. 
Study Population .........................................................................................................34 
6.2.1. 
Inclusion Criteria ........................................................................................................35 
6.2.2. 
Exclusion Criteria .......................................................................................................35 
6.3. 
Premature Withdrawal from the Study .......................................................................38 
6.4. 
Replacement of Patients .............................................................................................39 
6.5. 
Rescreening of Patients ...............................................................................................39 
7. 
STUDY TREATMENTS............................................................................................40 
7.1. 
Investigational and Reference Treatments ..................................................................40 
7.2. 
Run-in Treatments ......................................................................................................40 
7.3. 
Background Treatments ..............................................................................................40 
7.4. 
Dose Modification and Study Treatment Discontinuation Rules ...............................41 
7.4.1. 
Dose Modification ......................................................................................................41 
7.4.2. 
Study Drug Discontinuation .......................................................................................41 
7.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................41 
7.5. 
Management of Acute Reactions ................................................................................42 
7.5.1. 
Acute Infusion Reactions ............................................................................................42 
7.5.1.1. 
Interruption of the Infusion .........................................................................................42 
7.5.1.2. 
Termination of the Infusion ........................................................................................42 
7.6. 
Method of Treatment Assignment ..............................................................................43 
7.6.1. 
Blinding ......................................................................................................................43 
7.6.2. 
Emergency Unblinding ...............................................................................................43 
7.7. 
Treatment Logistics and Accountability .....................................................................44 
7.7.1. 
Packaging, Labeling, and Storage ..............................................................................44 
7.7.2. 
Supply and Disposition of Treatments .......................................................................44 
7.7.3. 
Treatment Accountability ...........................................................................................44 
7.7.4. 
Treatment Compliance ................................................................................................45 
7.8. 
Concomitant Medications and Procedures .................................................................45 
7.8.1. 
Prohibited Medications and Procedures .....................................................................45 
7.8.2. 
Permitted Medications and Procedures ......................................................................45 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................46 
8.1. 
Schedule of Events .....................................................................................................46 
8.1.1. 
Footnotes for Schedule of Events Table 1 ..................................................................52 
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8.1.2. 
Footnotes for Schedule of Events Table 2 ..................................................................52 
8.1.3. 
Footnotes for Schedule of Events Table 3 ..................................................................52 
8.1.4. 
Footnotes for Schedule of Events Table 4 ..................................................................54 
8.1.5. 
Early Termination Visit ..............................................................................................54 
8.1.6. 
Unscheduled Visits .....................................................................................................54 
8.2. 
Study Procedures ........................................................................................................55 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................55 
8.2.2. 
Efficacy Procedures ....................................................................................................55 
8.2.2.1. 
Lipid Panel ..................................................................................................................55 
8.2.2.2. 
Specialty Lipid Panel ..................................................................................................55 
8.2.3. 
Quality of Life Procedures ..........................................................................................56 
8.2.3.1. 
EuroQol-5 Questionnaire ............................................................................................56 
8.2.3.2. 
Patient Assessed Hospital Anxiety and Depression Scale ..........................................56 
8.2.4. 
Safety Procedures .......................................................................................................56 
8.2.4.1. 
Vital Signs ..................................................................................................................56 
8.2.4.2. 
Physical Examination .................................................................................................56 
8.2.4.3. 
Tanner Stages ..............................................................................................................56 
8.2.4.4. 
Electrocardiogram .......................................................................................................57 
8.2.4.5. 
Laboratory Testing ......................................................................................................57 
8.2.4.6. 
Pregnancy Testing ......................................................................................................58 
8.2.5. 
Pharmacokinetic and Anti-Drug Antibody Procedures ..............................................58 
8.2.5.1. 
Drug Concentration Measurements and Samples .......................................................58 
8.2.5.2. 
Anti-Drug Antibody Measurements and Samples ......................................................59 
8.2.5.3. 
Statin Concentrations ..................................................................................................59 
8.2.6. 
Pharmacodynamic Procedures ....................................................................................59 
8.2.7. 
Other Assessments ......................................................................................................59 
8.2.7.1. 
Review of Diet ............................................................................................................59 
8.2.7.2. 
DNA Sample for HoFH Genotyping ..........................................................................59 
8.2.7.3. 
LDLR Function ...........................................................................................................59 
 
 
 
 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................60 
9.1. 
Obligations of Investigator .........................................................................................60 
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9.2. 
Obligations of Sponsor ...............................................................................................60 
9.3. 
Definitions ..................................................................................................................61 
9.3.1. 
Adverse Event .............................................................................................................61 
9.3.2. 
Serious Adverse Event ................................................................................................61 
9.3.3. 
Adverse Events of Special Interest .............................................................................61 
9.3.4. 
Infusion Reactions ......................................................................................................62 
9.4. 
Recording and Reporting Adverse Events ..................................................................62 
9.4.1. 
Adverse Events ...........................................................................................................62 
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 ...........................64 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results .............................64 
9.4.6. 
Follow-up ....................................................................................................................64 
9.5. 
Evaluation of Severity and Causality .........................................................................65 
9.5.1. 
Evaluation of Severity ................................................................................................65 
9.5.2. 
Evaluation of Causality ...............................................................................................65 
9.6. 
Safety Monitoring .......................................................................................................66 
9.7. 
Investigator Alert Notification ....................................................................................67 
10. 
STATISTICAL PLAN................................................................................................67 
10.1. 
Statistical Hypothesis ..................................................................................................67 
10.2. 
Justification of Sample Size........................................................................................67 
10.3. 
Analysis Sets ...............................................................................................................68 
10.3.1. 
Efficacy Analysis Sets ................................................................................................68 
10.3.1.1. 
Intent-to-Treat .............................................................................................................68 
10.3.1.2. 
Modified Intent-to-Treat .............................................................................................68 
10.3.2. 
Safety Analysis Sets ...................................................................................................68 
10.3.2.1. 
Double-Blind Safety Analysis Set ..............................................................................68 
10.3.2.2. 
Open-Label Safety Analysis Set .................................................................................68 
10.3.3. 
Other Analysis Sets .....................................................................................................69 
10.4. 
Statistical Methods ......................................................................................................69 
10.4.1. 
Patient Disposition ......................................................................................................69 
10.4.2. 
Demography and Baseline Characteristics .................................................................70 
10.4.3. 
Efficacy Analyses .......................................................................................................70 
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10.4.3.1. 
Primary Efficacy Analysis ..........................................................................................70 
10.4.3.2. 
Secondary Efficacy Analysis ......................................................................................71 
10.4.3.3. 
Multiplicity Considerations ........................................................................................72 
10.4.3.4. 
Other Efficacy Endpoints ...........................................................................................72 
10.4.3.5. 
Subgroup Analyses for the Primary Efficacy Endpoint .............................................72 
10.4.3.6. 
On-Treatment Efficacy Analyses ...............................................................................73 
10.4.4. 
Safety Analysis ...........................................................................................................73 
10.4.4.1. 
Adverse Events ...........................................................................................................73 
10.4.4.2. 
Other Safety ................................................................................................................74 
10.4.4.3. 
Treatment Exposure ....................................................................................................75 
10.4.4.4. 
Treatment Compliance ................................................................................................76 
10.4.5. 
Analysis of Drug Concentration and Target Concentration Data ...............................76 
10.4.6. 
Analysis of Anti-Drug Antibody Data ........................................................................76 
10.4.7. 
Analysis of Statin Concentration ................................................................................77 
 
 
10.4.9. 
Timing of Statistical Analyses ....................................................................................77 
10.4.9.1. 
First Step: Main Efficacy and Safety Analysis ...........................................................77 
10.4.9.2. 
Second Step: Final Safety Analysis ............................................................................77 
10.5. 
Additional Statistical Data Handling Conventions .....................................................77 
10.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .........77 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS .....................................78 
11.1. 
Data Management .......................................................................................................78 
11.2. 
Electronic Systems ......................................................................................................78 
12. 
STUDY MONITORING ............................................................................................78 
12.1. 
Monitoring of Study Sites ...........................................................................................78 
12.2. 
Source Document Requirements ................................................................................78 
12.3. 
Case Report Form Requirements ................................................................................78 
13. 
AUDITS AND INSPECTIONS .................................................................................79 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................79 
14.1. 
Good Clinical Practice Statement ...............................................................................79 
14.2. 
Informed Consent .......................................................................................................80 
14.3. 
Patient Confidentiality and Data Protection ...............................................................81 
14.4. 
Institutional Review Board/Ethics Committee ...........................................................81 
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15. 
PROTOCOL AMENDMENTS ..................................................................................82 
16. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................82 
16.1. 
Premature Termination of the Study ...........................................................................82 
16.2. 
Close-out of a Site ......................................................................................................82 
17. 
STUDY DOCUMENTATION ...................................................................................83 
17.1. 
Certification of Accuracy of Data ...............................................................................83 
17.2. 
Retention of Records ..................................................................................................83 
18. 
CONFIDENTIALITY ................................................................................................83 
19. 
FINANCING AND INSURANCE .............................................................................83 
20. 
PUBLICATION POLICY ..........................................................................................83 
21. 
REFERENCES ...........................................................................................................84 
22. 
INVESTIGATOR’S AGREEMENT ..........................................................................86 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................89 
 
LIST OF TABLES 
Table 1: 
Schedule of Events – Run-in and Screening ...............................................................47 
Table 2: 
Schedule of Events – Screening for Patients with No Run-in ....................................48 
Table 3: 
Schedule of Events – Baseline, Double-Blind Treatment Period, and Open-
Label Treatment Period ..............................................................................................49 
Table 4: 
Schedule of Events – Follow-up Period .....................................................................51 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................33 
 
LIST OF APPENDICES 
Appendix 1. Factors to Consider in Assessing the Relationship of Adverse Events to 
Study Drug and Study Conduct or Study Procedure or Background 
Treatment, etc. ............................................................................................................87 
Appendix 2. Summary of TLC Diet for High Cholesterol ..........................................................88 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A randomized, double-blind, placebo-controlled, parallel-group study to 
evaluate the efficacy and safety of evinacumab in patients with homozygous 
familial hypercholesterolemia 
Site Location(s) 
 
Principal Investigator 
Approximately 30 sites multinationally  
Multi-center  
Objective(s) 
The primary objective of the study is: 
 
To demonstrate the reduction of low-density lipoprotein 
cholesterol (LDL-C) by evinacumab 15 mg/kg intravenously 
(IV) in comparison to placebo after 24 weeks in patients with 
homozygous familial hypercholesterolemia (HoFH). 
The secondary objectives of the study are: 
 
To evaluate the effect of evinacumab 15 mg/kg IV on other 
lipid parameters (ie, apolipoprotein B [Apo B], non-high-
density lipoprotein cholesterol [HDL-C], total-cholesterol 
[TC]) in patients with HoFH 
 
To evaluate the effect of evinacumab on LDL-C goal 
attainment 
 
To assess the effect of evinacumab on eligibility for apheresis 
(using German and US apheresis criteria) 
 
To evaluate the safety and tolerability of evinacumab 15 mg/kg 
in patients with HoFH 
 
To assess the pharmacokinetics (PK) of evinacumab in patients 
with HoFH 
 
To evaluate the potential development of anti-evinacumab 
antibodies 
Study Design 
The study consists of the following periods:  up to 8-week run-in period (for 
patients who may require HoFH genotyping, for patients whose background 
medical lipid modifying therapy (LMT) has not been stable prior to 
screening or whose apheresis settings and/or schedule have not been stable 
for at least 8 weeks prior to screening), a 2-week screening period, a 24-
week double-blind treatment period (DBTP), and a 24-week open-label 
treatment period (OLTP), and a 24-week follow-up period after the last dose 
of study drug for those patients who choose not to enter the open-label study. 
Patients who are not undergoing apheresis therapy, patients who have been 
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on a stable apheresis schedule for at least 8 weeks before the screening visit, 
and patients on stable background medical LMT (as applicable) for at least 
4 weeks (6 weeks for fibrates, 8 weeks for proprotein convertase 
subtilisin/kexin type 9 [PCSK9] inhibitor antibodies, 12 weeks for 
lomitapide, 24 weeks for mipomersen) before the screening visit, will enter a 
2-week screening period. 
Patients who participated in the R727-CL-1628 study may enter the run-in or 
screening period or enroll directly into this study. Patients who completed 
the R727-CL-1628 study and fulfill all of the eligibility criteria can be 
enrolled directly into this study. Data collected during the R727-CL-1628 
study (ie, lab test results) can be used to assess eligibility criteria for these 
patients. If these patients meet all the eligibility criteria and if approved by 
the sponsor, the patients may not have to undergo the screening visit in this 
study. 
In 
this 
case, 
overlapping 
assessments 
completed 
at 
the 
end-of-open-label treatment visit in R727-CL-1628 do not need to be 
repeated during the R1500-CL-1629 baseline visit. The baseline/day 1 visit 
can occur immediately after the end of the open-label treatment visit in the 
R727-CL-1628 study. To ensure continuity of treatment with alirocumab, all 
patients from R727-CL-1628 entering this study will be provided 
alirocumab. 
Patients who meet all the inclusion criteria and none of the exclusion criteria 
will be randomized 2:1 to receive evinacumab 15 mg/kg IV every 4 weeks 
(Q4W) or matching placebo IV Q4W for the double-blind portion of the 
study (24 weeks). Randomization will be stratified by apheresis treatment 
(Yes, No) and by region (Japan, Rest of World). 
After completion of the DBTP, all patients will enter a 24-week OLTP and 
receive open-label evinacumab 15 mg/kg IV Q4W. 
After completion of the 24-week OLTP, all patients who have successfully 
completed this study might have the opportunity to participate in a separate 
open-label (OL) study.  All patients that enroll in the separate OL study will 
continue to receive open-label evinacumab at a dose of 15 mg/kg IV Q4W.  
Those patients who do not participate in the separate open-label study will 
undergo a 24-week follow-up after the last dose of study drug. 
Study Duration 
The duration of the study including run-in (8 weeks), screening (2 weeks), 
DBTP and OLTP (48 weeks), and follow-up (20 weeks) periods may be up 
to 78 weeks. 
Population 
 
 
Sample Size: 
Approximately 57 patients will be randomized at approximately 
30 multinational sites 
 
Target Population: 
The study population will consist of males and females ≥12 years of age 
diagnosed with homozygous FH (HoFH), receiving stable lipid modifying 
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therapy (LMT), as applicable.  Patients should be on a maximally tolerated 
daily statin, ezetimibe, and a PCSK9 inhibitor antibody unless the patient has 
a documented history of tolerability issues, little to no response to therapy or 
other documented reason.  Lipid modifying therapies may also include other 
lipid lowering therapies, including low-density lipoprotein (LDL)-apheresis. 
Treatment(s) 
 
 
Study Drug 
 
Dose/Route/Schedule: 
In the double-blind treatment period, eligible patients will be enrolled to 
receive evinacumab 15 mg/kg IV Q4W 
In the open-label portion of the study, all patients will receive evinacumab 
15 mg/kg IV Q4W starting at week 24 
 
Placebo 
 
Route/Schedule: 
In the double-blind treatment period, placebo matching IV evinacumab Q4W 
 
Background Treatment 
 
Dose/Route/Schedule: 
Patients who are on LMT or who are undergoing apheresis should maintain 
stable LMT and a stable apheresis schedule (as applicable) throughout the 
duration of the study, from screening to the end of double-blind treatment 
period visit (week 24), and continuing through week 48 of the open-label 
treatment period. 
Patients who enter this study after completing study R727-CL-1628 will 
continue to receive alirocumab 150 mg subcutaneous (SC) every 2 weeks 
(Q2W) for the duration of the study. 
Endpoint(s) 
 
 
Primary: 
The primary endpoint is the percent change in calculated LDL-C from 
baseline to week 24. 
 
Secondary: 
 
The percent change in Apo B from baseline to week 24 
 
The percent change in non-HDL-C from baseline to week 24 
 
The percent change in TC from baseline to week 24 
 
The proportion of patients with ≥30% reduction in LDL-C at 
week 24 
 
The proportion of patients with ≥50% reduction in LDL-C at 
week 24 
 
The proportion of patients with LDL-C <100 mg/dL 
(2.59 mmol/L) at week 24 
 
The change in calculated LDL-C from baseline to week 24 
 
The proportion of patients who meet EU apheresis eligibility 
criteria (see German Apheresis Working Group) from baseline 
to week 24 
 
The proportion of patients who meet US apheresis eligibility 
criteria (see US [National Lipid Association] Lipid Apheresis 
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Criteria) from baseline to week 24 
Procedures and Assessments 
The efficacy of evinacumab will be assessed by clinical laboratory evaluation 
of lipid levels at pre-specified time points throughout the study. 
Overall 
safety 
will 
be 
assessed 
by 
monitoring/evaluation 
of 
treatment-emergent adverse events (TEAEs), physical examinations, vital 
signs, electrocardiogram (ECG), Tanner stage (for adolescents only), and 
clinical safety laboratory tests at pre-specified time points. 
The potential emergence of anti-evinacumab antibodies will also be evaluated. 
Statistical Plan 
Sample Size Determination For the primary efficacy hypothesis during the 
double-blind treatment period, a total sample size of 57 patients (38 on 
evinacumab and 19 on placebo) will have 90% power to detect a treatment 
group difference in mean percent change LDL-C of 38% with a 0.05 
two-sided significance level and assuming a common standard deviation of 
35%. This sample size has been adjusted for a 5% non-evaluable patient rate 
for the primary efficacy endpoint, and a 15% dropout rate. 
Primary Efficacy Analysis The double-blind primary efficacy analysis will 
compare the evinacumab 15 mg/kg IV treatment group to placebo at 
week 24. The primary efficacy endpoint is the percent change in calculated 
LDL-C from baseline to week 24. The percent change from baseline in 
calculated LDL-C will be analyzed in the ITT (intent-to-treat) population 
(defined as all randomized patients who had an evaluable primary endpoint, 
regardless of adherence to study treatment) using a mixed-effect model with 
repeated measures (MMRM) approach. All post-baseline data available 
within week 2 to week 24 analysis windows will be used and missing data 
are accounted for by the MMRM model. The model will include the fixed 
categorical effects of treatment group (placebo versus evinacumab), 
randomization strata, time point, strata-by-time point interaction, and 
treatment by time point interaction, as well as the continuous fixed 
covariates of baseline LDL-C value and baseline value-by-time point 
interaction. The statistical testing of the comparison for the primary measure 
will be evaluated at a 2-sided significance level of 0.05. 
Subgroup Analyses for the Primary Efficacy Endpoint. Analyses are 
planned on the primary efficacy endpoint to access the homogeneity of 
evinacumab treatment effect across various patient subgroups in the ITT 
population, including the 2 stratification factors LDL-C apheresis and 
region, and patients with or without receptor-negative mutations in both 
low-density lipoprotein receptor (LDLR) alleles. Statistical analysis methods 
will be provided in the statistical analysis plan (SAP) 
Statistical analyses will be conducted in 2 steps. The first analysis will be 
conducted as soon as all patients have been randomized and all data through 
week 24 (double-blind period) have been collected and validated. This first 
analysis will consist of the final analysis of the primary and secondary 
efficacy endpoints. The results of the first analysis will not be used to change 
the conduct of the ongoing study in any aspect. Since data collection for the 
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double-blind primary efficacy measure and key secondary efficacy measures 
will have been concluded at the time of this first analysis, the significance 
level for the study remains at 0.05. 
The second analysis will be conducted at the end of the open-label treatment 
period (end of study) and will consist of the final analysis for safety and 
open-label treatment period exploratory efficacy measures. 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANGPTL3 
Angiopoietin-like 3 
Apo A-1 
Apolipoprotein A-1 
Apo B 
Apolipoprotein B 
ApoCIII 
Apolipoprotein CIII 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CEC 
Clinical Events Committee 
CI 
Confidence interval 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
CV 
Cardiovascular 
CVD 
Cardiovascular disease 
DBTP 
Double-blind treatment period 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EOT 
End of treatment 
EDC 
Electronic data capture 
FH 
Familial hypercholesterolemia 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
HDL 
High-density lipoprotein 
HDL-C 
High-density lipoprotein cholesterol 
HoFH 
Homozygous familial hypercholesterolemia 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IV 
Intravenously 
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IVRS 
Interactive voice response system 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LDL-C 
Low-density lipoprotein cholesterol 
LDLR 
Low-density lipoprotein receptor 
LDLRAP1 
Low-density lipoprotein receptor adaptor protein 1 
LMT 
Lipid modifying therapy 
LOF 
Loss-of-function 
Lp(a) 
Lipoprotein a 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 
MMRM 
Mixed-effect model with repeated measures 
MTD 
Maximum tolerated dose 
OL 
Open-label 
OLTP 
Open-label treatment period 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PMM 
Pattern Mixture Model 
PT 
Preferred term 
Q2W 
Every 2 weeks 
Q4W 
Every 4 weeks 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SD 
Standard deviation 
SE 
Standard error 
SMT 
Safety Monitoring Team 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TC 
Total cholesterol 
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TEAE 
Treatment-emergent adverse event 
TG 
Triglyceride 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WOCBP 
Women of child bearing potential 
 
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1. 
INTRODUCTION 
Homozygous familial hypercholesterolemia (HoFH) is a rare and serious genetic condition 
resulting in severely elevated low-density lipoprotein cholesterol (LDL-C) and accelerated 
cardiovascular disease (CVD). Familial hypercholesterolemia results from mutations in the 
low-density lipoprotein receptor (LDLR), or in 3 associated genes: proprotein convertase 
subtilisin/kexin type 9 (PCSK9), apolipoprotein B (Apo B), and LDLR adaptor protein 1 
(LDLRAP1). 
Regardless 
of 
the 
underlying 
mutations, 
patients 
with 
familial 
hypercholesterolemia (FH) are phenotypically similar, but vary with respect to severity of the 
condition. Mutations in LDLR, PCSK9, and Apo B have a dominant mode of transmission, while 
mutations in LDLRAP1 have a recessive mode of transmission (http://omim.org/entry/143890, 
http://omim.org/entry/603813). The vast majority of mutations that lead to FH derive from 
mutations in the LDLR (between 60-80%) (Youngblom 1993). 
Homozygous FH is frequently caused by mutations in both alleles of the LDLR gene and results 
in the decreased clearance of LDL particles from plasma. Patients with HoFH have severe 
hypercholesterolemia, often 3 to 6 times normal (500 to 1000 mg/dL), which can lead to an 
exceedingly high risk of developing premature atherosclerosis, as well as valvular and 
supravalvular stenosis. In children as young as 7 years of age, mild coronary atherosclerosis can 
be evident even without any clinically apparent coronary artery disease. This accelerated 
atherosclerosis results in premature CVD and an increased risk of a cardiovascular (CV) event. A 
recent observational study of HoFH patients demonstrated that the mean age for first major CV 
event was 20 years (Goldstein 2001, Kolansky 2008, Macchiaiolo 2012, Rader 2003). 
Patients with HoFH tend to be treated with multiple lipid-lowering medications in order to try 
and attain LDL-C levels that are closer to optimal for adults. Consensus statements recommend 
starting drug treatment as soon as possible and targeting LDL-C goals of <70 mg/dL or 
<100 mg/dL depending on risk (Cuchel 2014, France 2016). Many of the therapies for 
hypercholesterolemia are dependent on their stimulating an increase in activity of the LDLR. 
Part of the basis for the refractory nature of treatments is linked to the mutations in the LDLR 
that are the driver of HoFH. 
Low-density lipoprotein cholesterol-lowering therapies in patients with HeFH and a single 
mutation in the LDLR can rely on the normally functioning LDLR allele to provide similar 
efficacy as in non-FH patients. However, the presence of mutations in both LDLR alleles can 
result in far less efficacy for therapies that rely on the LDLR as part of their mechanism of 
action. Examples of such therapies include statins and PCSK9 inhibitor antibodies. Mutations in 
the LDLR can range from being defective (where the LDLR retains some LDL-binding 
functionality) to null or negative mutations where no functioning LDLR is expressed. Residual 
LDLR activity ranges from <2% for patients who are receptor negative to 2-25% for patients 
who are LDLR defective (Cuchel 2014). In the most extreme cases are patients with two 
null/negative LDLR mutations. These patients tend to have higher LDL-C levels and worse 
clinical outcome than patients who are LDLR defective (Kolansky 2008, Moorjani 1993). 
Patients who are LDLR negative develop xanthomas sooner than patients who are LDLR 
defective, and untreated patients who are LDLR negative rarely live past the second decade 
(Kolansky 2008, Moorjani 1993). These patients tend to have untreated LDL-C levels at the 
highest end of the range and in many cases see no efficacy from drugs such as statins or PCSK9 
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inhibitor antibodies because of their near total lack of functional LDLRs (Marais 2008, 
Raal 2000, Raal 1997). 
While statins can reduce LDL-C by more than 50% in patients with HeFH or with polygenic 
forms of hypercholesterolemia, in HoFH patients, statins may provide a decrease of <15 to 30% 
(Crestor 2003, Lipitor 1996, Zocor 1991). When ezetimibe is added to a statin, LDL-C may be 
reduced by 21 to 27% (Zetia 2002), but many patients with HoFH treated with a high-dose statin 
and ezetimibe remain far from their LDL-C goal. In patients with little or no LDLR activity, 
including patients with null/null mutations, statins provide minimal efficacy. Some patients who 
are receptor-negative (LDLR activity<2%) may respond to statin therapy (Raal 2000), but the 
degree of response tends to be less than those patients with residual LDLR function 
(Rader 2003). 
Although anti-PCSK9 therapy provides an effective treatment in patients with HeFH and 
polygenic causes of hypercholesterolemia, it appears to be minimally effective in the HoFH 
patient. In the recent TESLA study in patients with HoFH, evolocumab therapy resulted in a 
mean percent reduction in LDL-C of 23.1% (Raal 2015). In the subset of patients known to have 
two LDLR negative alleles, no response was observed with evolocumab (Repatha 2015). 
Other therapies for HoFH, mipomersen and lomitapide, can provide an additional ~25% and 
40% reduction in LDL-C, respectively. However, these therapies are associated with high rates 
of gastrointestinal side effects (lomitapide), hepatic abnormalities including hepatic steatosis and 
increases in liver function tests (lomitapide and mipomersen) and frequent injection site reactions 
(mipomersen) (Cuchel 2013, Raal 2010). 
High-dose statins, ezetimibe, anti-PCSK9 monoclonal antibodies (mAb), mipomersen, and 
lomitapide may be effective in some patients with HoFH, but many patients still require lipid 
apheresis (Goldberg 2011). Lipid apheresis can be effective, but entails treatments lasting several 
hours multiple times a month, is both costly and associated with a risk of infections (Vella 2001, 
Kajinami 1999), and is not routinely available in all geographical areas (Thompson 2010). 
Despite treatment with lipid modifying therapies (LMTs), such as pharmacological agents, as 
well as mechanical removal by lipid apheresis, many patients with HoFH remain far from their 
LDL-C treatment goal. Therefore, the need for more intensive treatment in HoFH, especially 
those patients with double null mutations remains. 
Angiopoietin-like 3 (ANGPTL3) has recently emerged as a potential target for the treatment of 
elevated levels of triglycerides (TGs) and for the treatment of elevated levels of LDL-C, both 
risk factors for the development of CVD. ANGPTL3 acts as a natural inhibitor of lipoprotein 
lipase, an endothelial-bound enzyme involved in the hydrolysis of the TG content of 
very-low-density lipoproteins and chylomicron lipoproteins. Patients who are homozygous for 
loss-of-function (LOF) mutations in ANGPTL3 have lower levels of LDL-C (mean difference of 
48% versus control family members). The mechanism by which ANGPTL3 LOF mutations 
result in lowered LDL-C levels is not fully understood, but appears to be independent of the 
effects on TGs and independent of the LDLR. It is noteworthy that patients with one or two 
ANGPTL3 LOF alleles also have reported reductions in serum high-density lipoprotein (HDL) 
cholesterol (HDL-C) levels. The mechanism for this may be related to the inhibitory effect of 
ANGPTL3 on endothelial lipase, which is involved in the hydrolysis of HDL phospholipids. 
Importantly, no health deficits have been reported in the relatively small number of patients who 
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are homozygous for ANGPTL3 LOF mutations. These data suggest that inhibiting ANGPTL3 
may be a meaningful and well-tolerated strategy for lowering serum LDL-C and TGs. 
Evinacumab (REGN1500) is a fully human mAb, created with Regeneron’s VelocImmune 
technology platform, which specifically binds to ANGPTL3. Experiments performed in animals 
demonstrate that the administration of evinacumab results in a reduction of serum LDL-C and 
serum TGs. In hyperlipemic mice models (ApoE -/-, Ldlr -/-, db/db), single administrations of 
evinacumab led to reductions in LDL-C, TGs, and HDL-C up to 49%, 72%, and 39%, 
respectively. Specifically in mice that have absent LDLR function (Ldlr -/- mice), administration 
of evinacumab resulted in a 23% reduction in LDL-C. Therefore, it appears that ANGPTL3 
inhibition lowers LDL-C through an LDLR-independent mechanism. 
In a phase 1, first-in-human, placebo-controlled, double-blind, ascending single-dose study 
(R1500-HV-1214) of the safety, tolerability, and bioeffect of evinacumab administered 
subcutaneously (SC) or intravenously (IV) in healthy volunteers with modest elevations in TGs 
and/or LDL-C at baseline, 99 subjects received placebo or evinacumab at 1 of the following dose 
levels: 75 mg SC, 150 mg SC, 250 mg SC, 5 mg/kg IV, 10 mg/kg IV, or 20 mg/kg IV. Among 
these subjects with elevations of TG levels 150 to 450 mg/dL (1.69 mmol/L to 5.09 mmol/L) 
and/or LDL-C ≥ 100 mg/dL (2.59 mmol/L), the maximal mean percent LDL-C decrease from 
baseline of 27.8% was observed on day 15 in the 20 mg/kg IV group (n=11) compared to a 
decrease of 4.5% in the placebo IV group (n=12). A maximal mean percent HDL-C decrease 
from baseline of 27.3% was observed on day 15 in the 10 mg/kg IV group (n=9) compared to a 
1.8% decrease in the placebo IV group (n=12). For all subjects in the 20 mg/kg IV group (n=11), 
the median percent decrease in TG from baseline on day 4 was 75.0% vs an increase of 9% in the 
placebo IV group (n=12). Evinacumab was well tolerated at all dose levels. 
In a randomized, double-blind, placebo-controlled, multiple ascending dose study 
(R1500-CL-1321) of the safety, tolerability, pharmacokinetics (PK), immunogenicity, and 
pharmacodynamic (PD) effects of evinacumab in subjects with mixed dyslipidemia (TGs 
150-500 mg/dL [1.69 mmol/L to 5.09 mmol/L] and LDL-C ≥ 100 mg/dL [2.59 mmol/L]), 
subjects who received evinacumab 20 mg/kg IV every 4 weeks (Q4W) achieved a mean percent 
reduction from baseline in LDL-C of 34.7% at day 57. Those patients who received evinacumab 
300 mg SC every 2 weeks (Q2W) achieved a mean percent reduction in LDL-C of 33.4% from 
baseline. Evinacumab was well tolerated in doses up to 20 mg/kg IV Q4W. 
In 
an 
open-label, 
single-arm, 
proof-of-concept 
study 
in 
patients 
with 
HoFH, 
(Study R1500-CL-1331), evinacumab demonstrated a mean percent reduction from baseline of 
49.2% (n=9) at week 4, with a duration of effect of at least 10 weeks after a 15 mg/kg IV dose 
(n=7).  A peak mean reduction of 52.1% was observed at week 6. Three patients enrolled in 
Study R1500-CL-1331 are homozygous for null mutations in the LDLR. Evinacumab provided 
meaningful reductions in LDL-C in these 3 null/null HoFH patients (26-44% percent change in 
LDL-C by week 4). Evinacumab has been well tolerated in this proof-of-concept study.  
Additional background information on the study drug and development program can be found in 
the Investigator’s Brochure. 
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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of the study is to demonstrate the reduction of LDL-C by evinacumab 
15 mg/kg IV in comparison to placebo after 24 weeks in patients with HoFH. 
2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
 To evaluate the effect of evinacumab 15 mg/kg IV on other lipid parameters 
(ie, Apo B, non-HDL-C, total cholesterol [TC]) in patients with HoFH 
 To evaluate the effect of evinacumab on LDL-C goal attainment 
 To assess the effect of evinacumab on eligibility for apheresis (using German and US 
apheresis criteria) 
 To evaluate the safety and tolerability of evinacumab 15 mg/kg in patients with 
HoFH 
 To determine concentrations of evinacumab in patients with HoFH 
 To evaluate the potential development of anti-evinacumab antibodies 
2.3. 
Other Objective 
 Genotyping will be performed for all patients to identify mutations causing HoFH and 
to characterize LDLR function, in order to explore potential differences in efficacy 
and safety. 
 To assess the effect of evinacumab on quality of life using the EQ-5D and HADS 
QOL questionnaires 
3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypothesis 
Blockade of ANGPTL3 with evinacumab will reduce LDL-C in patients with HoFH. 
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
This study is intended to demonstrate efficacy and safety of evinacumab in the treatment of 
HoFH. The study population will include individuals ≥12 years of age. Because this disease is 
characterized by severe hypercholesterolemia from birth and, subsequently, the onset of 
premature CVD during childhood, the HoFH population includes children and adolescents. 
Allowing individuals ≥12 years of age to enroll in this study will ensure the study population is 
reflective of the patient population manifesting disease in adolescence and adulthood. Diagnosis 
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of HoFH will be based on either genotyping or clinical criteria. The genetic definition will 
include all individuals considered to be FH homozygotes, which is defined by the presence of the 
same mutation(s) in both LDLRs, Apo B, PCSK9, or LDLRAP1 alleles, or individuals 
considered to be compound heterozygotes, defined by the presence of different mutations in the 
same allele, or double heterozygotes, defined as mutations in different genes. 
The percent change in LDL-C from baseline to week 24 will be the primary endpoint. LDL-C is 
an accepted surrogate endpoint for CV risk, and has repeatedly been used as the primary 
endpoint for approval of multiple other HoFH treatments. This study is designed as a 
placebo-controlled trial with the addition of evinacumab on top of patients’ existing treatment 
regimens of maximally tolerated LMT, including lipid apheresis. This study will utilize a run-in 
period for those patients whose LMT regimen is not stable. This “add-on” design is appropriate 
because removal of any therapies from patients’ existing treatment regimen will lead to an 
increase in LDL-C and possibly contribute to the serious CV sequelae seen in this severe disease 
with high CV risk. 
The study consists of 4 periods: screening, run-in (for patients whose background medical LMT 
has not been stable for at least 4 weeks prior to screening or whose apheresis settings and/or 
schedule have not been stable for at least 8 weeks prior to screening), double-blind treatment, 
and open-label treatment. In the 24-week double-blind treatment period (DBTP), patients will 
receive evinacumab 15 mg/kg IV Q4W or matching placebo IV Q4W. 
In order to provide additional safety, PK, and long term efficacy information on evinacumab in 
this rare patient population, after completion of the DBTP, all patients will enter a 24-week 
open-label treatment period (OLTP). During the OLTP portion of the study, all patients, 
regardless of treatment assignment in the DBTP, will receive evinacumab 15 mg/kg IV every 
month. 
3.2.2. 
Rationale for Dose Selection 
The 15 mg/kg IV dose is selected based on safety and the substantial LDL-C reduction observed 
in HoFH patients in study R1500-CL-1331. The higher dose regimen of 20 mg/kg IV Q4W 
demonstrated favorable tolerability when given as an 8-week treatment in otherwise healthy 
subjects (R1500-CL-1321) and so the 15 mg/kg IV Q4W regimen is expected to also 
demonstrate favorable tolerability, because the evinacumab exposure within each dosing interval 
is expected to be lower and the accumulation of serum concentration with a monthly dosing 
frequency is predicted to be minimal. From an efficacy perspective, the 15 mg/kg IV dose has 
previously demonstrated evinacumab concentrations above 100 mg/L for approximately 
4 weeks; an exposure threshold associated with target saturation and maximal effect on TG 
reduction (R1500-CL-1321 and R1500-HV-1214). Based on these PK/PD data, combined with 
the efficacy data from the proof-of-concept study in HoFH (R1500-CL-1331), 15 mg/kg IV is 
expected to maintain target saturation and thereby to provide maximal benefit during the 
monthly dosing interval. 
Evinacumab has not previously been administered to patients aged 12 to 17 years. In adults, its 
PK profile indicates that systemic elimination is the result of a combination of 
concentration-independent 
(linear) 
clearance 
and 
concentration-dependent 
(nonlinear) 
target-mediated clearance. Typically, linear clearance for immunoglobulin G antibodies is 
similar between adults and adolescents, after adjusting for body weight. The comparison of 
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nonlinear clearance between adolescents and adults is less well understood. However, at the 
proposed dose of 15 mg/kg IV, it is expected that the target will be essentially saturated, hence 
linear clearance will be the main determinant of evinacumab exposure. Therefore, the 15 mg/kg 
dose is expected to yield exposure in the adolescent patients that is similar to what has been 
shown to be associated with efficacy and tolerability in adults.  
3.2.3. 
Risk / Benefit Assessment 
Patients with HoFH have extremely high LDL-C levels, are far from their target level and will 
require significant reductions to get to their goal. Despite the approval of newer treatments 
including evolocumab, lomitapide and mipomersen, the need for more intensive therapies 
remains. Evinacumab could be a new addition to the armamentarium of LMT that could 
contribute to lowering the LDL-C of patients with HoFH. As mentioned above, in study 
R1500-CL-1331, evinacumab demonstrated a mean percent reduction from baseline of 49.2% 
(n=9) at week 4, with a duration of effect of at least 10 weeks after a 15 mg/kg IV dose (n=7). A 
peak mean reduction of 52.1% was observed at week 6. Three patients in the study are 
homozygous for null mutations in the LDLR. Treatment with evinacumab in these difficult-to-
treat patients reduced LDL-C by an average of 37.3% at week 4 with peak reductions up to 
59.5%. Based on these data, it is expected that the addition of evinacumab to existing treatments 
will lead to significant LDL-C reductions in the HoFH population. The body of evidence from 
the statin literature shows that the relationship between LDL-C reduction and CV event 
reduction is approximately linear and for every 1 mmol/L (38.7 mg/dL) reduction in LDL-C 
there is a corresponding 22% risk reduction in CV events (Cholesterol Treatment Trialists’ 
Collaboration 2010). Moreover, the results from the recent outcomes trials with ezetimibe 
(IMPROVE-IT [Cannon 2015]), alirocumab (ODYSSEY OUTCOMES [Steg 2018]) and 
evolocumab (FOURIER [Sabatine 2017]) reinforce this concept, providing additional evidence 
for the relationship between LDL-C lowering and reductions in CV events and the importance 
for patients to achieve their target LDL-C. Within the context of this study in the HoFH patient 
population, additional reduction in LDL-C may get patients closer their LDL-C target, which 
could translate into significant benefits. 
It is also expected that treatment with evinacumab will be well tolerated and have an acceptable 
safety profile. The accumulated safety information from the completed and ongoing clinical 
studies is marked by the absence of any important identified risks. There are potential risks that 
include systemic hypersensitivity reactions, immunogenicity, and embryofetal toxicity. These 
risks will be managed through careful patient selection and monitoring. For the potential 
embryofetal toxicity risk, there is a strict risk mitigation plan, including requirements for 
consistent use of contraception for sexually active male study participants and sexually active 
female study participants of child bearing potential. 
Patients entering this study should be on a background statin, ezetimibe, and a PCSK9 inhibitor, 
unless they have a documented history of tolerability issues, lack of efficacy, or other reason.  
Patients should be on these lipid lowering drugs because of the above mentioned proven CV risk 
reduction demonstrated in recent CV outcomes trials (ODYSSEY OUTCOMES, FOURIER, 
IMPROVE-IT).  There are 2 PCSK9 inhibitors on the market; evolocumab is approved for use in 
patients with HoFH in most countries, and alirocumab is currently being evaluated in a 
double-blind placebo-controlled study in patients with HoFH (study R727-CL-1628, ODYSSEY 
HoFH).  Patients entering this study may be taking either evolocumab or alirocumab.  Patients 
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who complete study R727-CL-1628 (ODYSSEY HoFH) with alirocumab are permitted to 
participate in this study and will continue to receive alirocumab as part of their background 
LMT.  The concurrent use of evinacumab with alirocumab is considered to have an acceptable 
benefit/risk profile because it could be beneficial and is not considered to pose any safety 
concerns. 
Evinacumab and alirocumab have different mechanisms of action and concomitant 
administration of both agents is not expected to perturb the action of the other.  Rather, their 
distinct mechanisms of action are anticipated to complement each other to lower LDL-C since 
they work at different sites of action. 
The safety profile of each agent is considered acceptable and the concurrent use of the 2 agents 
together is not expected to augment or exacerbate potential adverse events (AEs).  Concomitant 
use of evinacumab and evolocumab was found to have an acceptable safety profile in 4 patients 
in the R1500-CL-1331 study, a study evaluating evinacumab in 9 patients with HoFH (details of 
the study are provided in the evinacumab Investigator’s Brochure and the Introduction [Section 
1]).  No safety signals or adverse effects related to the concomitant use of both agents have been 
observed.  The safety of the use of evinacumab along with alirocumab will be carefully 
monitored in this study. Safety monitoring will include ongoing reviews by an unblinded 
Independent Data Monitoring Committee (IDMC), by the sponsor’s blinded safety monitoring 
team (SMT), and by the blinded clinical study team.  If significant safety trends or findings are 
identified by either the IDMC or the sponsor’s blinded study team or SMT, they will be escalated 
and appropriately evaluated to understand the best course of action. 
From the perspective of PK drug-drug interactions, co-administration of evinacumab, 
alirocumab, and the other possible background LMT (statin, ezetimibe, etc) is not expected to 
result in drug-drug interactions with each other or other drugs. Evinacumab and alirocumab are 
both eliminated via a combination of non-saturable, linear, proteolytic degradation and saturable, 
non-linear target-mediated clearance. The 2 molecules bind to different targets and the 
target-mediated pathways are entirely independent. Neither evinacumab nor alirocumab are a 
cytokine or cytokine modulator; therefore, it is not anticipated to interact directly or indirectly 
with cytochrome P450 enzymes, other drug metabolizing enzymes or drug transporters, which 
are known to influence the disposition of statins.  Conversely, the PK of evinacumab is not 
expected to be impacted by statins, due to its elimination pathways. 
Indeed, the concomitant administration of 2 fully human monoclonal antibodies may be a new 
treatment paradigm in CV medicine, but not uncommon in other therapeutic areas such as 
autoimmune disease or oncology.  Experience in those areas has demonstrated the use of 
multiple biologic agents to be acceptable from a safety and tolerability perspective. 
For the reasons stated above, the benefit/risk profile for the concurrent use of evinacumab and 
PCSK9 inhibitor antibodies or the use of evinacumab in the absence of a PCSK9 inhibitor 
antibody as part of the background LMT is considered favorable. 
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4. 
STUDY VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height), lipid 
levels, medical history (including allergic history), mutation status, medication history, and 
apheresis schedule (if applicable) for each patient. Patients’ history on other medications for 
treatment of HoFH will be documented on a specific page of the case report form (CRF). 
4.2. 
Primary and Secondary Endpoints 
4.2.1. 
Primary Efficacy Endpoint 
The primary endpoint is the percent change in calculated LDL-C from baseline to week 24. The 
primary endpoint is defined as:  100x (calculated LDL-C value at week 24 - calculated LDL-C 
value at baseline)/calculated LDL-C value at baseline. 
The baseline LDL-C value will be the last calculated LDL-C value obtained before the first dose 
of double-blind-study drug. The calculated LDL-C at week 24 will be the LDL-C value obtained 
within the week 24 analysis window, regardless of adherence to treatment and subsequent 
therapies (intent-to-treat [ITT] estimand). 
All calculated LDL-C values (scheduled or unscheduled, fasting or not fasting) may be used to 
provide a value for the primary efficacy endpoint, if appropriate, according to the above 
definition. The analysis window used to allocate a time point to a measurement will be defined in 
the statistical analysis plan (SAP). 
4.2.2. 
Key Secondary Efficacy Endpoints 
The key secondary endpoints are:   
 The percent change in Apo B from baseline to week 24 (ITT estimand) 
 The percent change in non-HDL-C from baseline to week 24 (ITT estimand) 
 The percent change in TC from baseline to week 24 (ITT estimand) 
 The proportion of patients with ≥ 30% reduction in calculated LDL-C at week 24 
(ITT estimand) 
 The proportion of patients with ≥ 50% reduction in calculated LDL-C at week 24 
(ITT estimand) 
 The proportion of patients with LDL-C <100 mg/dL [2.59 mmol/L] at week 24 
(ITT estimand) 
 The change in calculated LDL-C from baseline to week 24 (ITT estimand) 
 The proportion of patients who meet EU apheresis eligibility criteria (see German 
Apheresis Working Group) at week 24 (ITT estimand) 
 The proportion of patients who meet US apheresis eligibility criteria (see US 
[National Lipid Association] Lipid Apheresis Criteria) at week 24 (ITT estimand) 
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4.2.3. 
Other Secondary Efficacy Endpoints 
 The percent change in TG from baseline to week 24 (ITT estimand) 
 The change in Apo B from baseline to week 24 (ITT estimand) 
 The change in non-HDL-C from baseline to week 24 (ITT estimand) 
 The change in TC from baseline to week 24 (ITT estimand)  
 The percent change in lipoprotein a [Lp(a)] from baseline to week 24 (ITT estimand) 
 The proportion of patients with LDL-C <70 mg/dL [1.81 mmol/L] at week 24 
(ITT estimand) 
 The percent change in apolipoprotein CIII (Apo CIII) from baseline to week 24 
(ITT estimand) 
National Lipid Association (US) 
[Goldberg 2011] 
German Apheresis Working Group (EU) 
[Schettler 2012] 
 
Patients have inadequate response to diet and 
LMTs after 6 months of treatment 
 
Functional HoFH or HeFH (with 0-1 risk 
factor) with LDL-C >300 mg/dL 
(7.77 mmol/L)1 
 
Patients have inadequate response to diet and 
LMTs after 3 months of treatment 
 
Primary prevention – FH with LDL-C 
>160 mg/dL (4.2 mmol/L) and CV events in 
close relatives 
 
Secondary prevention – Patients with 
progressive CV events with LDL-C >120 to 
130 mg/dL (3.1-3.4 mmol/L) 
1 Risk factors include age, elevated TC and LDL-C, low HDL-C, male sex, smoking, metabolic syndrome, diabetes, 
hypertension, and family history of CVD 
4.2.4. 
Other Endpoints 
 The change in hemoglobin A1c (HbA1c [%]) from baseline to week 24 
 Response of each EQ-5D item, index score, and change of index score from baseline 
through week 24. 
 Response on Hospital Anxiety and Depression Scale (HADS) from baseline through 
week 48. 
4.3. 
Pharmacokinetic Variables 
The PK variable is total evinacumab concentration in serum. 
4.4. 
Anti-Drug Antibody Variables 
Anti-drug antibody (ADA) status will be assessed.  
 Treatment emergent response - defined as a positive response post-first dose in the 
ADA assay when baseline ADA results are negative or missing 
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 Treatment-boosted response – defined as a positive response post-first dose in the 
ADA assay that is at least 9-fold over the baseline titer levels when baseline ADA 
results are positive. 
The definition of persistent and transient ADA will be defined a priori in the SAP. 
Samples positive in the ADA assay will be assessed for titer: 
 Titer category 
 Low (titer <1,000) 
 Moderate (1,000≤ titer ≤10,000) 
 High (titer >10,000) 
Samples positive in the ADA assay will be assessed for neutralizing activity. 
5. 
STUDY DESIGN 
5.1. 
Study Description and Duration 
This phase 3 study consists of the following periods:  an up to 8-week run-in period (for patients 
who may require HoFH genotyping, for patients whose background medical LMT has not been 
stable prior to screening or whose apheresis settings and/or schedule have not been stable for at 
least 8 weeks prior to screening), a 2-week screening period, a 24-week DBTP, a 24-week 
OLTP, and a follow-up period for 24 weeks after the last dose of study drug, for those patients 
who decide not to enter an optional open-label study (Figure 1). The total duration of the run-in, 
screening, DBTP and OLTP may be up to 78 weeks . 
Run-In: 
Apheresis therapy - Patients who are undergoing apheresis therapy must be on a stable weekly 
(every 7±1 days) or every other week (every 14±2 days) schedule. Patients whose schedule 
and/or apheresis settings have not been stable for at least 8 weeks before the screening visit, will 
enter an 8-week run-in period before the screening period. After the 8-week run-in period, 
patients whose lipid apheresis schedule remains stable will be eligible to enter the 2-week 
screening period. 
Lipid modifying therapy - Patients who are on background LMT (excluding lomitapide and 
mipomersen) that has not been stable for at least 4 weeks (6 weeks for fibrates, 8 weeks for 
PCSK9 inhibitor antibody) before the screening visit will enter a 4-week (6 weeks for fibrates, 
8 weeks for PCSK9 inhibitor antibody) run-in period to stabilize their LMT before entering the 
screening period. For patients taking mipomersen or lomitapide, patients who have not been on a 
stable dose of mipomersen for 24 weeks prior to screening or on a maximum tolerated dose 
(MTD) of lomitapide for 12 weeks prior to screening are excluded. 
Genotyping – Confirmation of a patient’s HoFH status can be made by either genetic or clinical 
criteria.  If HoFH diagnosis cannot be confirmed by the clinical criteria listed or from previous 
genotyping results, patients can enter the run-in period to determine their mutation status in 
advance of screening, if deemed appropriate by the investigator.  
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Screening:   
Patients who are not undergoing apheresis therapy, patients who have been on a stable apheresis 
schedule for at least 8 weeks before the screening visit, and patients on stable background 
medical LMT (as applicable) for at least 4 weeks (6 weeks for fibrates, 8 weeks for PCSK9 
inhibitor antibodies, 12 weeks for lomitapide, 24 weeks for mipomersen) before the screening 
visit, will enter a 2-week screening period.   
Patients who participated in the R727-CL-1628 study may enter the run-in or screening period or 
enroll directly into this study. Patients who completed the R727-CL-1628 study and fulfill all of 
the eligibility criteria can be enrolled directly into this study. Data collected during the 
R727-CL-1628 study (ie, lab test results) can be used to assess eligibility criteria for these 
patients. If these patients meet all the eligibility criteria and if approved by the sponsor, the 
patients may not have to undergo the screening visit in this study.  In this case, overlapping 
assessments completed at the end of the open-label treatment visit in R727-CL-1628 do not need 
to be repeated during the R1500-CL-1629 baseline visit.  The baseline/day 1 visit can occur 
immediately after the end of the open-label treatment visit in the R727-CL-1628 study.  To 
ensure continuity of treatment with alirocumab, all patients from R727-CL-1628 entering this 
study will be provided alirocumab. 
Double-Blind Treatment:   
Patients who meet all the inclusion criteria and none of the exclusion criteria will be randomized 
2:1 to receive:  
 evinacumab 15 mg/kg IV Q4W 
OR 
 matching placebo IV Q4W 
Randomization will be stratified by apheresis treatment (Yes, No) and by geographical region 
(Japan, Rest of World). 
Study drug administration during the DBTP will take place at the site, starting on the day of 
randomization (day 1), and will be administered immediately after completion of the 
LDL-apheresis procedure (if applicable). For those patients not undergoing LDL-apheresis, study 
drug must be administered after all samples for clinical laboratory evaluation have been 
obtained. The last dose of double-blind study drug will be administered at week 20. 
Patients who are on LMT or who are undergoing LDL-apheresis should maintain stable LMT 
and a stable apheresis schedule (as applicable) throughout the duration of the study, from 
screening to the end of DBTP visit (week 24), and continuing through the end of the OLTP. All 
patients who enter this study from R727-CL-1628 will continue to receive alirocumab 150 mg 
SC Q2W for the duration of this study.  Alirocumab should continue to be administered after 
LDL-apheresis (if applicable). On days with concomitant alirocumab and evinacumab 
administration, the recommendation is to administer alirocumab after the end of the evinacumab 
post-infusion observation period. 
Open-Label Treatment: 
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After completion of the DBTP, all patients will enter an OLTP. Starting at week 24, all patients, 
regardless of treatment assignment in the DBTP, will receive open-label evinacumab 15 mg/kg 
IV Q4W for the 24-week OLTP. The last dose of open-label study drug will be at week 44. 
Patients who are on LMT or apheresis must continue their stable dose and regimen through the 
end of the OLTP (through week 48). All patients who enter this study from R727-CL-1628 will 
continue to receive alirocumab. 
Throughout the Study: 
For all patients undergoing LDL-apheresis, all samples for clinical laboratory evaluation must be 
obtained immediately prior to the LDL-apheresis procedure and prior to administration of study 
drug. Given the impact of LDL apheresis, PCSK9 inhibitors, and mipomersen on lipid 
parameters, it is important to match the time of the baseline activities with the timing of the 
week 24 activities. This would mean that the timing between the baseline sample collection 
relative to the most recently completed LDL apheresis procedure, administration of a PCSK9 
inhibitor or mipomersen should match the timing of the week 24 sample collection relative to the 
most recently completed LDL apheresis procedure, administration of a PCSK9 inhibitor or 
mipomersen. For all patients who are not undergoing apheresis, all samples for clinical 
laboratory evaluation must be obtained prior to administration of study drug. 
The efficacy of evinacumab in this population will be assessed by clinical laboratory evaluation 
of lipid levels at pre-specified time points throughout the study. Overall safety will be assessed 
by monitoring/evaluation of treatment-emergent adverse events (TEAEs), physical examinations, 
electrocardiogram (ECG), and clinical safety laboratory tests at pre-specified time points. The 
potential emergence of anti-evinacumab antibodies will also be evaluated. Patients who 
experience an ongoing serious adverse event (SAE) at the pre-specified study end-date should be 
followed until resolution, stabilization, or collection of outcome and related data. 
For all patients undergoing LDL-apheresis, the apheresis schedule and apheresis settings should 
remain stable throughout the duration of the DBTP and through the end of the OLTP (week 48). 
The use of all medications and nutritional supplements known to alter serum lipids, including 
(but not limited to) statins, ezetimibe, PCSK9 inhibitor antibody, mipomersen, lomitapide, 
fibrates, niacin, and bile acid resins is permitted as long as that therapy has been stable for at 
least 4 weeks (6 weeks for fibrates, 8 weeks for PCSK9 inhibitor antibodies, 12 weeks for the 
MTD of lomitapide, 24 weeks for mipomersen) prior to the screening visit. Patients should 
continue taking their LMT throughout the duration of the DBTP, starting at screening, and 
through the end of the OLTP (week 48). 
Patients should be on a stable low fat or heart-healthy diet. 
Patients’ exercise regimen should remain stable throughout the duration of the study, from 
screening through the OLTP. 
After completion of the 24-week OLTP, all patients who have successfully completed this study 
may have the opportunity to participate in a separate open-label (OL) study, R1500-CL-1719.  
All patients who enroll in the separate OL study will continue to receive open-label evinacumab 
at a dose of 15 mg/kg IV Q4W. 
Follow-up Period (if applicable):  
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Patients not consenting to participate in the optional OL study (R1500-CL-1719) will enter a 
follow-up period for 24 weeks after completion of the OLTP. A follow-up period of 24 weeks 
after the last dose of study drug will be required for patients who prematurely discontinue study 
treatment. 
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Figure 1: 
Study Flow Diagram 
 
Run-in1 
Screening 
Double-Blind Treatment2 
Open-Label Treatment3 
Follow-up4 
 
 
 
 
 
 
 
 
V1a 
Day -70 
 
V1 
Day -14 
 
V2 
Day 1 
 
V3 to V9 
Wk 2 to 24 
End of 
DBTP3 
V10 to V15  
Wk 28 to 48 
End of 
OLTP 
V16 to V20  
Wk  52 to 68 
 
 
 
Baseline 
 
 
 
 
 
EOS 
1 Patients who are undergoing apheresis therapy with a schedule and/or apheresis settings that have not been stable 
for at least 8 weeks before the screening visit will enter a run-in period before the screening period. Patients who 
are on background LMT that has not been stable for at least 4 weeks (6 weeks for fibrates, 8 weeks for PCSK9 
inhibitor antibodies) before the screening visit will enter the run-in period to stabilize their LMT before entering 
the screening period. Patients who have completed the R727-CL-1628 study and meet all the eligibility criteria for 
this study can be enrolled directly. The end of the open-label treatment visit from the R727-CL-1628 study can 
serve as the baseline/day 1 visit for this study. 
2 Patients will receive study drug IV Q4W starting at day 1. 
3 The open-label period begins at week 24 (day 169) when all patients will receive evinacumab 15 mg/kg IV Q4W. 
The last dose of evinacumab will be at week 44. 
4 Follow-up only for patients who do not enter a separate, optional OL study, R1500-CL-1719 or prematurely 
discontinue study treatment in this study. 
5.1.1. 
End of Study Definition 
The end of study is defined as last visit of the last patient. 
5.2. 
Planned Interim Analysis 
No interim analysis is planned. 
5.3. 
Study Committees 
5.3.1. 
Independent Data Monitoring Committee 
An IDMC, composed of members who are independent from the sponsor and the study 
investigators, will monitor patient safety by conducting formal reviews of accumulated safety 
data that will be blinded by treatment group; if requested, the IDMC may have access to the 
treatment allocation code or any other requested data for the purposes of a risk-benefit 
assessment (eg, lipid efficacy data). 
The IDMC will provide the sponsor with appropriate recommendations on the conduct of the 
clinical study to ensure the protection and safety of the patients enrolled in the study. The IDMC 
will also institute any measures that may be required for ensuring the integrity of the study 
results during the study execution. 
All activities and responsibilities of the IDMC are described in the IDMC charter. 
5.3.2. 
Clinical Events Committee 
The Clinical Events Committee (CEC) is composed of experts in the field of CVD, independent 
of the sponsor and the investigators. This committee will be responsible for defining, validating, 
and classifying (in a blinded fashion) pre-specified CV events and all deaths. 
Patients with suspected or confirmed CV events that occur in the time period from randomization 
until the end of the study will have a corresponding adjudication package prepared and submitted 
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to the CEC. The events should also be reported as SAEs, as appropriate. Adjudicated CV events 
include all CV AEs positively adjudicated. The adjudication categories include:   
 Coronary heart disease death 
 Nonfatal myocardial infarction (MI) 
 Fatal and nonfatal ischemic stroke 
 Unstable angina requiring hospitalization 
 Congestive heart failure requiring hospitalization 
In addition, other deaths (besides coronary heart disease deaths) will be classified by the CEC. 
All coronary revascularizations (percutaneous coronary intervention, coronary artery bypass 
graft surgery) will be submitted to the CEC and analyzed. 
A charter and an adjudication operational manual will specify additional details regarding the 
procedures, criteria, and classification used for adjudication of these events. 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
6.1. 
Number of Patients Planned 
Approximately 57 patients will be randomized at approximately 30 multinational sites. 
6.2. 
Study Population 
The study population will consist of males and females ≥12 years of age diagnosed with HoFH, 
receiving stable LMT, as applicable.  
Patients should be on a maximally tolerated daily statin, ezetimibe and a PCSK9 inhibitor 
antibody (evolocumab or alirocumab) unless the patient has a documented history of tolerability 
issues, little to no response to therapy or other documented reason.  Lipid modifying therapy may 
also include other lipid lowering therapies, including LDL-apheresis. Whether or not a patient is 
considered to be on a maximum tolerated regimen of lipid modifying treatments (statin, PCSK9 
inhibitor antibody, ezetimibe, lomitapide, mipomersen, probucol, etc) reasons why or why not 
(eg, due to intolerance, lack of efficacy, etc) the patient is taking/not taking the various 
treatments will need to be documented in the CRF. 
HoFH is defined by having at least one of the following (either genetic or clinical criteria):   
Genetic criteria:   
1. Documented functional mutation or mutations in both LDLR alleles 
 Note: patients who have null receptor mutations on both LDLR alleles, ie, double 
null, are eligible 
OR 
2. Documented homozygous or compound heterozygous mutations in Apo B or PCSK9 
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 Note: patients who are double heterozygous, ie, mutations on different genes 
(eg, LDLR/PCSK9) and patients with homozygous LDLRAP1 mutations are eligible 
Clinical Criteria:   
Untreated TC > 500 mg/dL (12.93 mmol/L) and TGs <300 mg/dL (3.39 mmol/L)  
AND  
Both parents with documented TC > 250 mg/dL (6.47 mmol/L) OR cutaneous or 
tendinous xanthoma before the age of 10 years 
6.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Male or female ≥12 years of age at the time of the screening visit 
2. Diagnosis of functional HoFH by at least 1 of the following:   
a. Documented functional mutation or mutations in both LDLR alleles 
Note: patients who have null receptor mutations on both LDLR alleles, ie, double null, 
are eligible 
b. Presence of homozygous or compound heterozygous mutations in Apo B or PCSK9 
Note: patients who are double heterozygous, ie, mutations on different genes (eg, 
LDLR/PCSK9) and patients with homozygous LDLRAP1 mutations are eligible 
c. Untreated TC > 500 mg/dL (12.93 mmol/L) and TG <300 mg/dL (3.39 mmol/L)  
AND 
both parents with documented TC > 250 mg/dL (6.47 mmol) 
OR cutaneous or tendinous xanthoma before the age of 10 years 
3. If undergoing LDL apheresis, must have initiated LDL apheresis at least 3 months prior 
to screening and must have been on a stable weekly (every 7±1 days) or every other week 
(every 14±2 days) schedule and stable settings for at least 8 weeks 
4. Willing and able to comply with clinic visits and study-related procedures 
5. Willing to consistently maintain his/her usual low fat or heart-healthy diet for the 
duration of the study 
6. Provide signed informed consent or assent 
6.2.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. LDL-C level <70 mg/dL (1.81 mmol/L) at the screening visit. 
2. Background medical LMT (if applicable) that has not been stable for at least 4 weeks 
(6 weeks for fibrates, 8 weeks for PCSK9 inhibitor antibodies, 12 weeks for MTD of 
lomitapide, 24 weeks for mipomersen) before the screening visit 
3. Lipid-apheresis schedule (every 7 or 14 days)/apheresis settings (if applicable) that have 
not been stable for at least 8 weeks before the screening visit or an apheresis schedule 
that is not anticipated to be stable over the next 48 weeks.  Plasma exchange is excluded 
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4. Use of nutraceuticals or over-the-counter therapies known to affect lipids, at a 
dose/amount that has not been stable for at least 4 weeks prior to the screening visit or 
between the screening and randomization visits 
5. Presence of any clinically significant uncontrolled endocrine disease known to influence 
serum lipids or lipoproteins 
Note: patients on thyroid replacement therapy can be included if the dosage of 
replacement therapy has been stable for at least 12 weeks prior to screening and the 
thyroid stimulating hormone (TSH) level is within the normal range of the central 
laboratory at the screening visit. 
6. Newly diagnosed (within 3 months prior to randomization visit [week 0/day 1]) diabetes 
mellitus or poorly controlled (HbA1c >9%) diabetes 
7. Unstable weight (variation >5 kg) within 2 months prior to the screening visit (week -2) 
8. Initiation of a new diet or major change to a previous diet within 4 weeks prior to 
screening 
9. Use of systemic corticosteroids, unless used as replacement therapy for pituitary/adrenal 
disease with a stable regimen for at least 6 weeks prior to screening 
Note: topical, intra-articular, nasal, inhaled and ophthalmic steroid therapies are not 
considered as ‘systemic’ and are allowed 
10. Use of estrogen or testosterone therapy unless the regimen has been stable 6 weeks prior 
to the screening visit and no plans to change the regimen during the study 
11. Systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg at the 
screening visit or time of randomization (week 0/day 1) 
12. History of a MI, unstable angina leading to hospitalization, coronary artery bypass graft 
surgery, percutaneous coronary intervention, uncontrolled cardiac arrhythmia, carotid 
surgery or stenting, stroke, transient ischemic attack, valve replacement surgery, carotid 
revascularization, endovascular procedure or surgical intervention for peripheral vascular 
disease within 3 months prior to the screening visit 
13. History of New York Heart Association (NYHA) Class IV heart failure within 12 months 
before screening. 
14. Age <12 years at the screening visit 
15. Tanner stage <2 at the screening visit 
16. History of cancer within the past 5 years, except for adequately treated basal cell skin 
cancer, squamous cell skin cancer, or in situ cervical cancer 
17. Use of any active investigational drugs (except alirocumab) within 1 month or 5 
half-lives prior to the screening visit, whichever is longer 
18. Conditions/situations such as: 
a. Any clinically significant abnormality identified at the time of screening that, in the 
judgment of the investigator or any sub-investigator, would preclude safe completion 
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of the study or constrain endpoints assessment; eg, major systemic diseases, patients 
with short life expectancy 
b. Considered by the investigator or any sub-investigator as inappropriate for this study 
for any reason, eg: 
 Deemed unable to meet specific protocol requirements, such as scheduled visits 
 Investigator or any sub-investigator, pharmacist, study coordinator, other study 
staff or relative thereof directly involved in the conduct of the protocol, etc 
 Presence of any other conditions (eg, geographic or social), either actual or 
anticipated, which the investigator feels would restrict or limit the patient’s 
participation for the duration of the study 
19. Laboratory findings during the screening period (not including randomization labs): 
 Positive test for Hepatitis B surface antigen and/or Hepatitis C antibody (associated 
with a positive HCV RNA polymerase chain reaction) 
 Positive serum beta-human chorionic gonadotropin or urine pregnancy test in women 
of childbearing potential (WOCBP) 
 eGFR <30 mL/min/1.73 m2 (calculated by central lab)  
 Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 x upper 
limit of normal (ULN) (1 repeat lab is allowed) 
 CPK >3 x ULN (1 repeat lab is allowed) 
 TSH >1.5 x ULN of the central laboratory (1 repeat lab is allowed) for patients not on 
thyroid replacement therapy 
20. Known hypersensitivity to mAb therapeutics 
21. Member of the clinical site study team and/or his/her immediate family 
22. Pregnant or breastfeeding women 
23. Sexually active WOCBP*, who are unwilling to practice a highly effective birth control 
method prior to the initial dose, during the study, and for 24 weeks after the last dose of 
study drug. Highly effective contraceptive measures include: 
 Stable use of combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation initiated 2 or more menstrual 
cycles prior to screening 
 oral  
 intravaginal 
 transdermal 
 Stable use of progestogen-only hormonal contraception associated with inhibition of 
ovulation initiated 2 or more menstrual cycles prior to screening: 
 oral 
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 injectable 
 implantable 
 Intrauterine device 
 Intrauterine hormone-releasing system  
 Bilateral tubal ligation 
 Vasectomized partner. Note:  vasectomized partner is a highly effective birth control 
method provided that the partner is the sole sexual partner of the WOCBP trial 
participant and that the vasectomized partner has received medical assessment of the 
surgical success  
 Sexual abstinence. Note:  Sexual abstinence is considered a highly effective method 
only if defined as refraining from heterosexual intercourse during the entire period of 
risk associated with study treatments. True abstinence: When this is in line with the 
preferred and usual lifestyle of the patient. Periodic abstinence (calendar, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method (LAM) are not acceptable methods of 
contraception. 
 *Postmenopausal women must be amenorrheic for at least 12 months in order not 
to be considered of childbearing potential. Postmenopausal status will be 
confirmed by measurement of follicle-stimulating hormone (FSH). Pregnancy 
testing and contraception are not required for women with documented 
hysterectomy and/or oophorectomy. 
24. Men who are sexually active with WOCBP and are unwilling to consistently use 
condoms during the study drug treatment period and for 24 weeks after the last dose of 
study drug regardless of vasectomy status. Sperm donation is prohibited during the study 
and for up to 24 weeks after the last injection of study drug. 
25. Housed in an institution on the basis of an administrative or judicial order. 
26. Dependent on the sponsor, investigator or the study site. 
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 8.1.5. 
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Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 7.4.2. 
Early Termination from the Study 
If for any reason the patient withdraws from the study prematurely, the patient should undergo an 
unscheduled visit with assessments normally planned at the end of the double-blind treatment 
visit if the patient is in the DBTP, or the end of the open-label treatment visit, if the patient is in 
the OLTP. The visit should take place within 5 days of treatment discontinuation. The 
assessments completed should include pregnancy testing for WOCBP. The patient should be 
followed for at least 24 weeks from the last dose of study drug or up to recovery or stabilization 
of any AE to be followed-up as specified in this protocol, whichever comes last. A final end of 
study visit should take place with assessments as specified in the end of study visit (ie, follow up 
visit) at 24 weeks after the premature discontinuation of study drug. 
Sexually active WOCBP who discontinue the study prematurely should be reminded at the 
unscheduled visit following treatment discontinuation to maintain highly effective contraceptive 
measures for 24 weeks after the last dose of study drug. At this visit, the patient will be provided 
5 urine pregnancy tests with instructions to test for pregnancy 4 weeks after this visit and Q4W 
thereafter. The patient will also be notified of Q4W follow-up phone calls to confirm continued 
contraception use and pregnancy reporting and to obtain the results of the urine pregnancy test. 
The investigator should make the best effort to contact any patient (eg, contacting patient’s 
family or private physician, review available registries or health care database) who fails to 
return to the site, and to determine health status. Attempts to contact such patients must be 
documented in the patient’s records (eg, times and dates of attempted telephone contact, receipt 
for sending a registered letter).  The site will be provided a retention manual outlining the best 
practices for patient retention. 
6.4. 
Replacement of Patients 
Patients prematurely discontinued from the study drug will not be replaced. 
6.5. 
Rescreening of Patients 
Patients who do not meet eligibility criteria during the initial screening may re-screen only once. 
Patients who are re-screened after the screening window ends must re-consent for study 
participation and repeat all screening procedures. 
Patients who do not meet all eligibility criteria during the initial screening, and are still within 
the screening window, may retest once for the assessments that did not meet eligibility criteria. 
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7. 
STUDY TREATMENTS 
7.1. 
Investigational and Reference Treatments 
Evinacumab or placebo IV infusion. 
In the DBTP, eligible patients will be enrolled to receive an IV dose of evinacumab 15 mg/kg 
Q4W or matching placebo, starting on day 1. The last dose of double-blind study drug will be at 
week 20. 
In the open-label portion of the study, patients will receive  
 Evinacumab at 15 mg/kg IV Q4W starting at week 24 (day 169) with the last dose at 
week 44 (day 309) 
Dosing should fall within a window of ±7 days; if >14 days has passed, skip the dose and return 
to the original schedule. 
Instructions on dose preparation and administration are provided in the pharmacy manual. 
Instructions on management of infusion reactions are provided in Section 7.5.1. 
Sterile alirocumab drug product will be supplied at a concentration of 150 mg/mL in a prefilled 
pen for patients from study R727-CL-1628 who enroll in this study. 
7.2. 
Run-in Treatments 
Patients who are undergoing apheresis therapy must have initiated LDL apheresis at least 
3 months prior to screening and must be on a stable weekly (every 7 days) or every other week 
(every 14 days) schedule and/or stable settings for at least 8 weeks prior to screening.  Patients 
with a schedule and/or apheresis settings, which have not been stable for at least 8 weeks before 
the screening visit will enter an 8-week run-in period before the screening period. 
Patients who are on background LMT that has not been stable for at least 4 weeks (6 weeks for 
fibrates, 8 weeks for PCSK9 inhibitor antibodies) before the screening visit will enter a 4-week 
(6 weeks for fibrates, 8 weeks for PCSK9 inhibitor antibodies) run-in period to stabilize their 
LMT before entering the screening period. 
7.3. 
Background Treatments 
Patients who are receiving background LMT or who are undergoing apheresis should maintain 
stable LMT and a stable apheresis schedule (as applicable) throughout the duration of the study, 
from screening to the end of DBTP visit (week 24), and continuing through the end of the OLTP. 
For all patients who enter this study from R727-CL-1628, alirocumab will be provided and 
patients will administer alirocumab 150 mg SC Q2W for the duration of the study. 
Patients should be on a maximally tolerated LMT regimen. Whether or not a patient is 
considered to be on a maximum tolerated regimen of LMT (statin, PCSK9 inhibitor antibody, 
ezetimibe, lomitapide, mipomersen, probucol, etc), reasons why or why not (eg, due to 
intolerance, lack of efficacy, etc) the patient is taking/not taking the various treatments will need 
to be documented in the CRF. 
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7.4. 
Dose Modification and Study Treatment Discontinuation Rules 
7.4.1. 
Dose Modification 
Dose modification for an individual patient is not allowed. 
7.4.2. 
Study Drug Discontinuation 
During the DBTP, study drug should be continued whenever possible. In the event study drug 
dosing is stopped, it should be determined if the stop can be made temporarily; permanent 
discontinuation should be a last resort. Regardless, the patient should remain in the DBTP as 
long as possible. 
Patients who permanently discontinue study drug during the DBTP should remain in the study 
and undergo all double-blind study visits and procedures with the exception of dosing with study 
drug. At the time of study drug discontinuation, the patient should have, as soon as possible, an 
unscheduled visit with assessments normally planned at end of the double-blind treatment visit 
(this should take place within 5 days of discontinuation of study drug, if possible) and then 
resume the original study schedule until end of the DBTP. In case of early discontinuation before 
week 24, all efforts should be made to perform the week 24 assessments at week 24. 
Patients who permanently discontinue study drug during the OLTP should have, as soon as 
possible, an unscheduled visit with assessments normally planned at the end of the OLTP (this 
should take place within 5 days of discontinuation of study drug, if possible) and then have 
end-of-study assessments at least 24 weeks after their last dose of study drug. 
Patients who permanently discontinue study drug and who opt to withdraw from the study will 
be asked to complete study assessments, per Section 8.1.5. 
Sexually active WOCBP who discontinue the study prematurely should be reminded at the 
unscheduled visit following treatment discontinuation to maintain highly effective contraceptive 
measures for 24 weeks after the last dose of study drug. At this visit, the patient will be provided 
5 urine pregnancy tests with instructions to test for pregnancy 4 weeks after this visit and Q4W 
thereafter. The patient will also be notified of Q4W follow-up phone calls to confirm continued 
contraception use and pregnancy reporting and to obtain the results of the urine pregnancy test. 
7.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
Study drug dosing will be permanently stopped in the event of the following but not limited to:   
 Evidence of pregnancy 
 Acute systemic infusion reactions with AEs including, but not limited to, anaphylaxis, 
laryngeal/pharyngeal edema, severe bronchospasm, chest pain, seizure, or severe 
hypotension 
 Patient requires a prohibited concomitant medication during the DBTP. The principal 
investigator should contact the Regeneron study monitor. Based on the discussion, 
study drug may be continued, or may be temporarily or permanently discontinued 
 Patient withdraws consent 
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The investigator may permanently discontinue study drug dosing at any time, even without 
consultation with the medical monitor if the urgency of the situation requires immediate action 
and if this is determined to be in the patient’s best interest. However, the medical monitor should 
be contacted as soon as possible in any case of permanent study drug discontinuation. 
7.5. 
Management of Acute Reactions 
7.5.1. 
Acute Infusion Reactions 
Emergency equipment and medication for the treatment of infusion reactions must be available 
for immediate use. All infusion reactions must be reported as AEs (as defined in Section 9.4.1) 
and graded using the grading scales as instructed in Section 9.5.1. 
7.5.1.1. 
Interruption of the Infusion 
The infusion should be interrupted if any of the following AEs are observed: 
 Cough 
 Rigors/chills 
 Rash, pruritus (itching) 
 Urticaria (hives, welts, wheals) 
 Diaphoresis (sweating) 
 Hypotension 
 Dyspnea (shortness of breath) 
 Vomiting 
 Flushing 
The reaction(s) should be treated symptomatically, and the infusion may be restarted at 50% of 
the original rate. 
If investigators feel there is a medical need for treatment or discontinuation of the infusion other 
than described above, they should use clinical judgment to provide the appropriate response 
according to typical clinical practice. 
7.5.1.2. 
Termination of the Infusion 
The infusion should be terminated and NOT restarted if any of the following AEs occur: 
 anaphylaxis* 
 laryngeal/pharyngeal edema 
 severe bronchospasm 
 chest pain 
 seizure 
 severe hypotension 
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 other neurological symptoms (confusion, loss of consciousness, parathesia, paralysis, 
etc.) 
 any other symptom or sign that, in the opinion of the investigator, warrants 
discontinuation of the infusion. 
*Consider anaphylaxis if the following is observed (Sampson 2006):  acute onset of an illness 
(minutes to several hours) with the involvement of the skin, mucosal tissue, or both 
(eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula AND AT LEAST ONE 
OF THE FOLLOWING:   
a) respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia);  
b) reduced blood pressure or associated symptoms of end-organ dysfunction 
(eg, hypotonia [collapse], syncope, incontinence). 
7.6. 
Method of Treatment Assignment 
Approximately 57 patients will be randomized in a 2:1 ratio to receive either 15 mg/kg IV 
evinacumab or matching placebo according to a central randomization scheme provided by an 
interactive web response system (IWRS) to the designated study pharmacist (or qualified 
designee). Randomization will be stratified by apheresis treatment (Yes/No) and by geographical 
region (Japan, Rest of World). 
In the OLTP of the study, all patients will receive evinacumab as described in Section 7.1. 
7.6.1. 
Blinding 
Study patients, the principal investigators, and study site personnel will remain blinded to all 
randomization assignments throughout the DBTP (up to week 24). The Regeneron Study 
Director, Medical Monitor, Study Monitor, and any other Regeneron and contract research 
organization (CRO) personnel who are in regular contact with the study site will remain blinded 
to all patient randomization assignments. 
Lipid results from blood samples collected after the randomization visit will not be 
communicated to the sites, and the sponsor’s operational team will not have access to these 
laboratory results until after completion of the DBTP and the first-step analysis. 
Although there is a slight color difference between the drug product and placebo product for IV 
infusion bag preparation, the color difference is not detectable when the investigational product 
is added to the IV infusion bag.  
Further details are provided in the pharmacy manual. 
After the end of the DBTP visit at week 24, the study becomes an open-label study. 
7.6.2. 
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). 
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 If unblinding is required: 
 Only the investigator will make the decision to unblind the treatment assignment. 
 Only the affected patient will be unblinded. 
 The designated study pharmacist(s)/designee at the study site will provide the 
treatment assignment to the investigator. If there is no study pharmacist, the 
investigator for the site will unblind the patient. 
 The investigator will notify Regeneron and/or designee before unblinding the 
patient, whenever possible 
Treatment assignment is not to be provided to site personnel, other than the unblinded study 
pharmacist (when applicable), at any time during the conduct of the study, except in the case of a 
true emergency. In the event that there is no study pharmacist, the individual at the site fulfilling 
that role will be the only unblinded member of the site personnel. 
7.7. 
Treatment Logistics and Accountability 
7.7.1. 
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. 
7.7.2. 
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 opened and unopened study drug will be returned to 
the sponsor or designee. 
7.7.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug. These records 
should contain the dates, quantity, and study medication: 
 dispensed to each patient, 
 returned from each patient (if applicable), and 
 disposed of at the site or returned to the sponsor or designee. 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
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7.7.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the 
sponsor and regulatory agency inspectors. 
7.8. 
Concomitant Medications and Procedures 
Any treatment administered, including apheresis, from the time of informed consent to the end of 
the treatment period/final study visit will be considered concomitant medication. This includes 
medications that were started before the study and are ongoing during the study. 
7.8.1. 
Prohibited Medications and Procedures 
The following concomitant medications and procedures are prohibited through the end of the 
DBTP (week 24) and continuing through the end of the OLTP (week 48):   
 Background medical LMT (if applicable) that has not been stable for at least 4 weeks 
(6 weeks for fibrates) before the screening visit (week -2) (unless participating in the 
run-in period to stabilize) 
 Background mipomersen treatment that has not been stable for 24 weeks before the 
screening visit (week -2) 
 Background lomitapide at a MTD that has not been stable for 12 weeks before the 
screening visit (week -2) 
 Recent discontinuation of lomitapide that has not been washed out for at least 8 
weeks before the screening visit (week -2). 
 Background PCSK9 inhibitor antibody that has not been stable for at least 8 weeks 
prior to the screening visit (week -2) 
 Lipid apheresis schedule that is not an every 7 day (+/- 1 day) or an every 14 day (+/-
 2 days) regimen or that has been stable for at least 8 weeks prior to screening (week -
2)  
 Plasma exchange 
 Nutraceuticals or over-the-counter therapies known to affect lipids, at a dose/amount 
that has not been stable for at least 4 weeks prior to the screening visit (week -2) 
 Systemic corticosteroids, unless used as replacement therapy for pituitary/adrenal 
disease with a stable regimen for at least 6 weeks prior to the screening visit (week-2) 
 Thyroid replacement therapy, unless the dosage of replacement therapy has been 
stable for at least 12 weeks prior to the screening visit (week -2). 
7.8.2. 
Permitted Medications and Procedures 
The use of all medications and nutritional supplements known to alter serum lipids, including 
(but not limited to) statins, ezetimibe, fibrates, niacin, bile acid resins, red yeast rice, lomitapide, 
mipomersen, and PCSK9 inhibitor antibodies is permitted as long as that therapy has been stable 
for at least 4 weeks (6 weeks for fibrates, 8 weeks for PCSK9 inhibitor antibodies, 12 weeks for 
lomitapide, 24 weeks for mipomersen) prior to the screening visit (week-2). Patients should 
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continue taking their background medical LMT for the duration of the study starting at screening 
and through the end of the OLTP (week 48). Similarly, patients should maintain their apheresis 
regimen (if applicable) starting at screening and through the end of the OLTP (week 48).  
Patients on thyroid replacement therapy can be included if the dosage has been stable for at least 
12 weeks prior to the screening visit (week -2). 
Topical, intra-articular, nasal, inhaled and ophthalmic steroid therapies are not considered as 
‘systemic’ and are allowed. 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
8.1. 
Schedule of Events 
Study assessments and procedures are presented by study period and visit in Table 1, Table 2, 
Table 3, and Table 4. 
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Table 1: 
Schedule of Events – Run-in and Screening 
Study Procedure 
Run-in7 
Screening 
Visit  
1a 
1 
Day 
-70 to -14 
-14 to -1 
Visit Window (Day) 
 
 
Week 
-10 to -2 
-2 to -1 
Screening/Baseline: 
Informed Consent 
X 
 
Pharmacogenomics Consent 
 
X 
Inclusion/Exclusion 
 
X 
Medical/Surgical History, Alcohol/Smoking Habits 
 
X 
Medication History 
 
X 
Demographics 
 
X 
Treatment: 
Concomitant Medications (including LMT and apheresis) 
X 
X 
Query LMT Compliance  
X 
X 
Efficacy: 
Lipid Panel1,2  
 
X 
Safety: 
Adverse Events 
X 
X 
Physical Examination 
 
X 
Measured Height 
 
X 
Body Weight 
 
X 
Vital Signs (pulse rate, BP) 
X 
X 
Electrocardiogram3 
 
X 
Tanner stage4 
 
X 
Laboratory Testing5: 
Hematology 
 
X 
Blood Chemistry 
 
X 
Creatine Phosphokinase 
 
X 
Hepatitis B Surface Antigen 
 
X 
Hepatitis C Antibody 
 
X 
Serum Pregnancy Test6 
 
X 
Urine Pregnancy Test6 
X 
 
FSH 
X 
 
Sex Hormones4 
 
X 
Urinalysis 
 
X 
TSH 
 
X 
DNA sample for HoFH genotyping 
X 
Other: 
Review of diet 
X 
X 
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Table 2: 
Schedule of Events – Screening for Patients with No Run-in 
Study Procedure 
Screening 
Visit  
1 
Day 
-14 to -1 
Visit Window (Day) 
 
Week 
-2 to -1 
Screening/Baseline: 
Informed Consent 
X 
Pharmacogenomics Consent 
X 
Inclusion/Exclusion 
X 
Medical/Surgical History, Alcohol/Smoking Habits 
X 
Medication History 
X 
Demographics 
X 
Treatment: 
Concomitant Medications (including LMT and apheresis) 
X 
Query LMT Compliance  
X  
Efficacy: 
Lipid Panel1,2 
X 
Safety: 
Adverse Events 
X 
Physical Examination 
X 
Measured Height 
X 
Body Weight 
X 
Vital Signs (pulse rate, BP) 
X 
Electrocardiogram3 
X 
Tanner stage4 
X 
Laboratory Testing5: 
Hematology 
X 
Blood Chemistry 
X 
Creatine Phosphokinase 
X 
Hepatitis B Surface Antigen 
X 
Hepatitis C Antibody 
X 
Serum Pregnancy Test6 
X 
Urine Pregnancy Test6 
 
Sex Hormones4 
X 
FSH 
X 
Urinalysis 
X 
TSH 
X 
DNA sample for HoFH genotyping 
X 
Other: 
Review of diet 
X 
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Table 3: 
Schedule of Events – Baseline, Double-Blind Treatment Period, and Open-Label Treatment Period 
Study Procedure 
Double-Blind Treatment Period 
Open-Label Treatment Period 
Visit  
2 
3 
4 
5 
6 
7 
8 
9 
End 
DBTP14 
10 
11 
12 
13 
14 
15 
End of 
OLTP 
Day 
1 
15 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
Visit Window (Day) 
±1 
±3 
±3 
±3 
±3 
±5 
±5 
±1 
±5 
±5 
±5 
±5 
±5 
±5 
Week 
0 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
Baseline: 
Informed Consent 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacogenomics Consent 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment: 
Randomization 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer IV Double-Blind Study 
Drug 
X1 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Administer IV Open-Label Study 
Drug 
 
 
 
 
 
 
 
X10 
X 
X 
X 
X 
X 
 
Concomitant Medications 
(including LMT and apheresis) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Query LMT Compliance 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy: 
Lipid Panel2,3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Specialty Lipid Panel2,4 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
Safety: 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
Measured Height 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Body Weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs (pulse rate, BP)5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram6 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Tanner stage7 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Confirm contraception use and 
reminder of pregnancy reporting 
X1 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Remind male patients to use 
condoms 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing8: 
Hematology 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
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Study Procedure 
Double-Blind Treatment Period 
Open-Label Treatment Period 
Visit  
2 
3 
4 
5 
6 
7 
8 
9 
End 
DBTP14 
10 
11 
12 
13 
14 
15 
End of 
OLTP 
Day 
1 
15 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
Visit Window (Day) 
±1 
±3 
±3 
±3 
±3 
±5 
±5 
±1 
±5 
±5 
±5 
±5 
±5 
±5 
Week 
0 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
Blood Chemistry 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
Creatine Phosphokinase 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
Serum Pregnancy Test9 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Urine Pregnancy Test9 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Sex Hormones7 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Urinalysis 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
hs-CRP 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
HbA1C 
X1 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
LDLR function 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Samples 
X1 
 
X 
X 
 
X 
 
X 
X 
 
 
 
 
 
PK and PD Samples 
ADA Sample10 
X1 
 
X 
 
X 
 
 
X 
 
 
 
 
 
X 
PK (evinacumab, alirocumab), 
ANGPTL3, PCSK9 Samples11,12 
X1 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
PK of statin11 
X1 
 
 
 
 
X 
 
 
 
 
 
 
 
 
DNA sample for HoFH genotyping 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other: 
EQ-5D  
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
HADS 
X1 
 
 
 
 
 
 
X 
 
 
 
X15 
 
X15 
Review of diet 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Table 4: 
Schedule of Events – Follow-up Period 
Study Procedure 
Follow-up Period5 
Visit  
165 
PV175,6 
185 
PV195,6 
EOS 
20 
Day 
365 
393 
421 
449 
477 
Visit Window (Day) 
±5 
±5 
±5 
±5 
±5 
Week 
52 
56 
60 
64 
68 
Treatment: 
 
Concomitant Medications (including LMT and 
apheresis) 
X 
X 
X 
X 
X 
Query LMT Compliance 
X 
X 
X 
X 
X 
Safety: 
Adverse Events 
X 
X 
X 
X 
X 
Physical Examination 
 
 
 
 
X 
Measured Height 
 
 
 
 
 
Body Weight 
 
 
 
 
X 
Vital Signs (pulse rate, BP) 
 
 
 
 
X 
Electrocardiogram1 
 
 
 
 
X 
Tanner stage2 
 
 
 
 
X 
Confirm contraception use and reminder of 
pregnancy reporting 
X 
X 
X 
X 
X 
Remind male patients to use condoms 
X 
X 
X 
X 
 
Laboratory Testing: 
Lipid Panel 
X 
 
X 
 
X 
Specialty Lipid Panel 
X 
 
X 
 
X 
Hematology 
X 
 
X 
 
X 
Blood Chemistry 
X 
 
X 
 
X 
Creatine Phosphokinase 
X 
 
X 
 
X 
Serum Pregnancy Test3 
 
 
 
 
X 
Urine Pregnancy Test3 
X 
X 
X 
X 
 
Sex Hormones2 
 
 
 
 
X 
Urinalysis 
 
 
 
 
X 
hs-CRP 
 
 
 
 
X 
HbA1C 
 
 
X 
 
X 
PK and PD Samples 
ADA Sample 
 
 
 
 
X 
PK (evinacumab, alirocumab), ANGPTL3 
Samples4 
 
 
 
 
X 
Other: 
Review of diet 
 
 
 
 
X 
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8.1.1. 
Footnotes for Schedule of Events Table 1 
1. Study assessments are to be performed and blood samples are to be collected before the 
dose of study drug in all patients. For patients undergoing apheresis:  Study assessments 
are to be performed and blood samples are to be collected immediately before the 
lipid-apheresis procedure; study drug will be administered after the apheresis procedure. 
2. Fasting sample will be collected for the lipid panel: TC, calculated LDL-C, HDL-C, TG, 
non-HDL-C 
3. ECG should be performed before blood samples are collected at visits requiring blood 
draws. 
4. Assessment of Tanner Stage and sex hormones (includes luteinizing hormone, follicle 
stimulating hormone, estradiol, total testosterone) only applicable to patients <18 years 
old. 
5. All laboratory samples should be collected before administration of study drug. 
6. WOCBP only, confirm required contraception use and reminder pregnancy reporting 
7. For patients who require HoFH genotyping, stabilization of their lipid-apheresis schedule 
or stabilization of their background medical LMT, ie, stable lipid-apheresis for at least 
8 weeks before screening and stable background medical LMT for at least 4 weeks 
(6 weeks for fibrates, 8 weeks for PCSK9 inhibitor antibodies) 
8.1.2. 
Footnotes for Schedule of Events Table 2 
1. Study assessments are to be performed and blood samples are to be collected before the 
dose of study drug in all patients. For patients undergoing apheresis:  Study assessments 
are to be performed and blood samples are to be collected immediately before the 
lipid-apheresis procedure; study drug will be administered after the apheresis procedure. 
2. Fasting sample will be collected for the lipid panel: total-C, calculated LDL-C, HDL-C, 
TG, non-HDL-C 
3. ECG should be performed before blood samples are collected at visits requiring blood 
draws. 
4. Assessment of Tanner Stage and sex hormones (includes luteinizing hormone, follicle 
stimulating hormone, estradiol, total testosterone) only applicable to patients <18 years 
old. 
5. All laboratory samples should be collected before administration of study drug. 
6. WOCBP only, confirm required contraception use and reminder pregnancy reporting 
8.1.3. 
Footnotes for Schedule of Events Table 3 
1. For those patients enrolling directly from the R727-CL-1628 study and do not complete 
the R1500-CL-1629 run-in or screening period, the informed consent forms should be 
signed at the baseline visit.  Overlapping assessments completed at the R727-CL-1628 
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open-label EOT visit do not need to be duplicated during the R1500-CL-1629 baseline 
visit; only assessments footnoted will need to be performed. 
2. Study assessments are to be performed and blood samples are to be collected before the 
dose of study drug in all patients. For patients undergoing apheresis:  Study assessments 
are to be performed and blood samples are to be collected immediately before the 
lipid-apheresis procedure; study drug will be administered after the apheresis procedure. 
The timing between the baseline sample collection relative to the most recently 
completed LDL apheresis procedure, administration of a PCSK9 inhibitor or mipomersen 
should match the timing of the week 24 sample collection relative to the most recently 
completed LDL apheresis procedure, administration of a PCSK9 inhibitor or 
mipomersen. Depending on the duration between the LDL apheresis procedure and 
sample collection, the visit window may not apply.  
3. Fasting sample will be collected for the lipid panel: total-C, calculated LDL-C, HDL-C, 
TG, non-HDL-C 
4. Fasting sample will be collected for specialty lipid panel: Apo B, Apo A-1, and Lp(a) 
5. On dosing days, vital signs should be recorded prior to IV infusion, and 30 minutes and 
60 minutes post-IV infusion 
6. ECG should be performed before blood samples are collected at visits requiring blood 
draws. 
7. Assessment of Tanner Stage and sex hormones (includes luteinizing hormone, follicle 
stimulating hormone, estradiol, total testosterone) only applicable to patients <18 years 
old. 
8. All laboratory samples should be collected before administration of study drug. 
9. WOCBP only, confirm required contraception use and reminder pregnancy reporting 
10. The ADA sample should be drawn before study drug administration 
11. For patients who are not undergoing apheresis, the PK sample should be drawn before the 
dose of study drug and at the end of the infusion. For patients undergoing apheresis, a PK 
sample should be collected immediately before the apheresis procedure and a PK sample 
should be collected immediately after the apheresis procedure, prior to administration of 
study drug, and, again at the end of the infusion of study drug.  
12. Including assay of total ANGPTL3. 
 
14. All end of treatment (EOT) assessments are to be performed and blood samples are to be 
collected before the dose of open-label study drug in all patients. For patients undergoing 
apheresis:  Study assessments are to be performed and blood samples are to be collected 
immediately before the lipid-apheresis procedure; open-label study drug will be 
administered after the apheresis procedure. 
15. In the OLTP, the HADS should be administered after the patients have been informed of 
their lipid results. 
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8.1.4. 
Footnotes for Schedule of Events Table 4 
1. ECG should be performed before blood samples are collected at visits requiring blood 
draws. 
2. Assessment of Tanner Stage and sex hormones (includes luteinizing hormone, follicle 
stimulating hormone, estradiol, total testosterone) only applicable to patients <18 years 
old. 
3. WOCBP only, confirm required contraception use and reminder pregnancy reporting.  
4. Including assay of total ANGPTL3. 
5. For patients who discontinue prematurely or who opt out of the OL study. 
6. Phone visits (PV) at weeks 56 and 64 to confirm required contraception use and obtain 
results of the home urine pregnancy test.  Adverse events and concomitant medications 
will be collected. 
8.1.5. 
Early Termination Visit 
In the case a patient prematurely discontinues study treatment, an unscheduled visit should occur 
with assessments normally planned at the (EOT) visit (it should take place within 5 days of 
treatment discontinuation, if possible). Patients who permanently discontinue study drug during 
the DBTP should then resume the original study schedule (except for study treatment 
administration) until end of the DBTP, and all efforts should be made to perform the week 24 
assessments at week 24 (regardless of study treatment administration). All patients who 
prematurely discontinue study treatment (either in the double-blind period or the open-label 
period) should be followed for at least 24 weeks from the last dose of study drug, and a final end 
of study visit can take place with assessments as specified in the end of study visit (ie, follow up 
visit). 
Sexually active WOCBP who discontinue the study prematurely should be reminded at the 
unscheduled visit following treatment discontinuation to maintain highly effective contraceptive 
measures for 24 weeks after the last dose of study drug. At this visit, the patient will be provided 
5 urine pregnancy tests with instructions to test for pregnancy 4 weeks after this visit and Q4W 
thereafter. The patient will also be notified of Q4W follow-up phone calls to confirm continued 
contraception use and pregnancy reporting and to obtain the results of the urine pregnancy test. 
If a WOCBP is lost to follow-up, sites should attempt a minimum of 2 telephone calls. If the 
patient cannot be reached on the second attempt, a formal letter will be issued from the site to the 
patient that reminds the patient of the importance of continued use of highly effective 
contraception use for at least 6 months after the last dose of study drug. 
8.1.6. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule. Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for 
any other reason, as warranted. 
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8.2. 
Study Procedures 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed for the sole purpose of determining study eligibility 
or characterizing the baseline population:   
 Hepatitis B Surface Antigen 
 Hepatitis C Antibody 
 TSH 
 FSH 
8.2.2. 
Efficacy Procedures 
All laboratory samples will be collected before the dose of study drug is administered. 
Blood samples for lipid panels should be collected in the morning, in fasting condition 
(ie, overnight, at least 8 hours fast, only water) for all clinic visits. Alcohol consumption within 
48 hours, and smoking or intense physical exercise within 24 hours, preceding blood sampling 
are discouraged. 
Total-C, HDL-C, TG, Apo B, Apo A-1, Lp(a), and Apo CIII will be directly measured by the 
central laboratory. LDL-C will be calculated using the Friedewald formula. If TG values exceed 
400 mg/dL (4.52 mmol/L) or if calculated LDL-C values are below 25 mg/dL (0.65 mmol/L), 
LDL-C will be measured via the beta quantification method (rather than via the Friedewald 
formula). Non-HDL-C will be calculated by subtracting HDL-C from the total-C. Ratio Apo 
B/Apo A-1 will be calculated. All lipid results will be blinded from after the randomization visit 
until the week 36 visit. Every effort should be made to continue to keep the sponsor blinded to 
all lipid parameters for the duration of the study. No attempts should be made by the investigator 
or patient to have the patient’s lipid values independently evaluated after randomization until 
after the end of study visit. 
Detailed procedures of sample preparation, storage, and shipment are provided in the laboratory 
manual. 
8.2.2.1. 
Lipid Panel 
Fasting (at least 8 hours) blood samples will be collected at specified time points shown in 
Section 8.1 for assessment of the lipid profile, comprising calculated LDL-C, HDL-C, 
non-HDL-C, total-C, and TGs. These samples will also be used for specialty lipid panel 
assessment when it is scheduled at the same time as the lipid panel assessment. 
8.2.2.2. 
Specialty Lipid Panel 
Fasting (at least 8 hours) blood samples will be collected at specified time points shown in 
Section 8.1 for assessment of the specialty lipid profile, comprising Apo B, Apo A-1, ratio of 
Apo B/Apo A-1, and Lp(a) as well as for Apo CIII. The specialty lipid panels will be assessed in 
the same sample that is collected for the lipid panel. 
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8.2.3. 
Quality of Life Procedures 
8.2.3.1. 
EuroQol-5 Questionnaire 
The EQ-5D is a standardized measure of health status developed by the EuroQol Group in order 
to provide a simple, generic measure of health for clinical and economic appraisal. The EQ-5D 
as a measure of health related quality of life, defines health in terms of 5 dimensions: mobility, 
self-care, usual activities, pain/discomfort, anxiety/depression. Each dimension has 3 ordinal 
levels of severity: “no problem” (1), “some problems” (2), “severe problems” (3). 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, where 0 represents 
“death” and 1 represents “perfect health.” 
8.2.3.2. 
Patient Assessed Hospital Anxiety and Depression Scale 
The HADS is an instrument for screening anxiety and depression in non-psychiatric populations; 
repeated administration also provides information about changes to a patient’s emotional state 
(Zigmond 1983, Herrmann 1997). The HADS consists of 14 items, 7 each for anxiety and 
depression symptoms; possible scores range from 0 to 21 for each subscale. The following cut-
off scores are recommended for both subscales: 7 to 8 for possible presence, 10 to 11 for 
probable presence, and 14 to 15 for severe anxiety or depression. 
8.2.4. 
Safety Procedures 
8.2.4.1. 
Vital Signs 
Vital signs, including temperature, sitting blood pressure and pulse and respiration rate, will be 
collected predose at time points according to Table 1, Table 2, Table 3, and Table 4. On dosing 
days, vital signs consisting of blood pressure and pulse rate will also be collected  30 minutes 
and 60 minutes after completion of the IV infusion. 
Blood pressure should be measured in the same arm throughout the study after the patient has 
been resting quietly for at least 5 minutes. Pulse rate will be measured at the time of the 
measurement of blood pressure. 
8.2.4.2. 
Physical Examination 
A thorough and complete physical examination will be performed at time points according to 
Table 1, Table 2, Table 3, and Table 4. Care should be taken to examine and assess any 
abnormalities that may be present, as indicated by the patient’s medical history. 
8.2.4.3. 
Tanner Stages 
The Tanner stages will be assessed throughout the study for all patients <18 years old according 
to Table 1, Table 2, Table 3, and Table 4. If possible, for each adolescent patient, the Tanner 
stages assessment should be performed by the same investigator/designee trained to assess 
pubertal development. 
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8.2.4.4. 
Electrocardiogram 
Electrocardiograms should be performed before blood is drawn during visits that require blood 
draws. A standard 12-lead ECG will be performed at time points according to Table 1, Table 2, 
Table 3, and Table 4.  
The 12-lead ECGs should be performed in the supine position after resting for at least 
10 minutes. For each ECG recording throughout the study, the electrodes should be positioned at 
the same place as much as possible. The ECG will be interpreted locally by the investigator. Any 
new and/or clinically significant changes in ECG parameters should be immediately rechecked 
for confirmation before making any decision for the concerned patient. 
Any clinically significant abnormality should be documented as an AE/SAE, as applicable (see 
Section 9.4.5). Each ECG tracing will be analyzed in comparison with the screening recorded 
trace. All ECG tracings will be kept as source data.  
8.2.4.5. 
Laboratory Testing 
All laboratory samples will be collected before the dose of study drug is administered. 
Samples for laboratory testing will be collected at visits according to Table 1, Table 2, Table 3, 
and Table 4 and analyzed by a central laboratory. Detailed instructions for blood sample 
collection are in the laboratory manual provided to study sites and specific tests are listed below. 
Tests will include: 
Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin 
Potassium 
Creatinine 
 
Chloride 
Blood urea nitrogen (BUN) 
 
Carbon dioxide 
AST 
Uric acid 
Calcium 
ALT 
CPK 
Glucose 
Alkaline phosphatase 
 
Albumin 
Lactate dehydrogenase (LDH) 
 
 
Hematology 
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
 
 
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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 
Other Laboratory Tests 
Other laboratory tests will be performed at time points shown in Table 1, Table 2, Table 3, and 
Table 4 and are as follows:  FSH, TSH, high sensitivity C-reactive protein (hs-CRP), HbA1c, 
serum and urine pregnancy test, and sex hormones (for adolescents only and includes luteinizing 
hormone, follicle stimulating hormone, estradiol, total testosterone). 
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. 
8.2.4.6. 
Pregnancy Testing 
Women of childbearing potential will undergo pregnancy testing approximately every 4 weeks 
throughout the study from baseline through EOS.  Pregnancy testing will be via a urine 
pregnancy test, except for the screening visit and EOS visit, which will be via a serum pregnancy 
test.  During some follow-up visits, and in case of early termination, pregnancy testing may 
occur at home via a urine pregnancy test where the results will be reported to the clinical site by 
the patient. 
8.2.5. 
Pharmacokinetic and Anti-Drug Antibody Procedures 
8.2.5.1. 
Drug Concentration Measurements and Samples 
Samples for assessment of evinacumab and alirocumab concentration will be collected at time 
points listed in Table 3, and Table 4. They will be collected predose and at the end of the IV 
infusion on days when study drug is administered.  
 
 
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8.2.5.2. 
Anti-Drug Antibody Measurements and Samples 
Samples for ADA assessment will be collected at time points listed in Table 3, and Table 4. They 
will be collected predose on days when study drug is administered. 
Patients who exhibit a treatment-emergent or treatment-boosted positive ADA assay response 
with a titer greater than 240 in their last sample analyzed and who do not participate in an 
open-label study will be followed until the titers are <240 or within  two dilution steps from their 
baseline titer levels. 
 
. 
8.2.5.3. 
Statin Concentrations 
Samples for statin concentration will be collected at time points shown in Table 3. 
8.2.6. 
Pharmacodynamic Procedures 
Total ANGPTL3 and total PCSK9 concentrations in serum will be measured using the PK 
samples collected at the time points listed in Table 3, and Table 4. 
8.2.7. 
Other Assessments 
8.2.7.1. 
Review of Diet 
Patients will be following a low fat or heart-healthy diet at the screening visit and will be asked 
to continue the low fat or heart-healthy diet until the last study visit. Patients will be queried on 
compliance with their diet during the DBTP and OLTP, at time points according to Table 1, 
Table 2, Table 3, and Table 4. 
Details are provided in Appendix 2. 
8.2.7.2. 
DNA Sample for HoFH Genotyping 
A required blood sample for DNA extraction will be collected from all patients to identify or 
confirm a known mutation in PCSK9, LDLR, Apo B gene, and/or LDLRAP1 gene.  
8.2.7.3. 
LDLR Function 
A blood sample for LDLR function testing will be collected from all patients at time points 
according to Table 3, in order to characterize LDLR function and explore potential differences in 
patient efficacy and safety. 
 
 
 
 
 
 
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9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
9.1. 
Obligations of Investigator 
The investigator must promptly report to the Institutional Review Board (IRB)/Ethics Committee 
(EC) all unanticipated problems involving risks to patients. This includes death from any cause 
and all SAEs related to the use of the study drug. It is recommended that all SAEs be reported to 
the IRB/EC, regardless of assessed causality. 
9.2. 
Obligations of Sponsor 
During the course of the study, the sponsor will report in an expedited manner all SAEs that are 
both unexpected and at least reasonably related to the study drug (suspected unexpected serious 
adverse reaction [SUSAR]), to the health authorities, ECs/IRBs as appropriate, and to the 
investigators.  
Any AE not listed as an expected event in the Investigator’s Brochure or in this protocol will be 
considered as unexpected. Any worsening of or new onset of symptoms related to 
hypercholesterolemia which occur during the screening/washout period prior to study drug 
administration will be considered expected. 
In addition, the sponsor will report in an expedited manner all SAEs that are expected and at 
least reasonably related to evinacumab 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 ECs/IRB as appropriate. 
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9.3. 
Definitions 
9.3.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug, which may or 
may not have a causal relationship with the study drug. Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease, which is 
temporally associated with the use of a study drug, whether or not considered related to the study 
drug. 
An AE also includes any worsening (ie, any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug. 
9.3.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death – includes all deaths, even those that appear to be completely 
unrelated to study drug (eg, a car accident in which a patient is a passenger). 
 Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event. This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
 Requires in-patient hospitalization or prolongation of existing hospitalization. In-
patient hospitalization is defined as admission to a hospital or an emergency room for 
longer than 24 hours. Prolongation of existing hospitalization is defined as a hospital 
stay that is longer than was originally anticipated for the event, or is prolonged due to 
the development of a new AE as determined by the investigator or treating physician. 
 Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions). 
 Is a congenital anomaly/birth defect 
 Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent one of the other serious outcomes listed above 
(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 AE of special interest (AESI; serious or non-serious) is one of scientific and medical concern 
specific to the sponsor’s product or program, for which ongoing monitoring and rapid 
communication by the investigator to the sponsor can be appropriate. Such an event might 
warrant further investigation in order to characterize and understand it. Depending on the nature 
of the event, rapid communication by the trial sponsor to other parties (eg, regulators) might also 
be warranted (Section 9.4.3). 
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9.3.4. 
Infusion Reactions 
Infusion reactions are defined as any AE that occurs during the infusion or within 2 hours after 
the infusion is completed. All infusion reactions must be reported as AEs (defined in 
Section 9.4.1) and graded using the grading scales as instructed in Section 9.5.1. 
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 study. Refer to the study reference manual for the procedures to be 
followed. 
Information on follow-up for AEs is provided in Section 9.4.6. Laboratory, vital signs, or ECG 
abnormalities are to be recorded as AEs as outlined in Section 9.4.5. 
9.4.2. 
Serious Adverse Events 
All SAEs, regardless of assessment of causal relationship to study drug, must be reported to the 
sponsor (or designee) within 24 hours. Refer to the study reference manual for the procedure to 
be followed. 
Information not available at the time of the initial report must be documented in a follow-up 
report. Substantiating data such as relevant hospital or medical records and diagnostic test reports 
may also be requested. 
In the event the investigator is informed of an SAE after the patient completes the study, the 
following will apply: 
 SAE with an onset within 30 days of the end of study or within 168 days (24 weeks) 
of last study drug administration if the patient prematurely discontinued from the 
study - the SAE will be reported to the sponsor. The investigator should make every 
effort to obtain follow-up information on the outcome until the event is considered 
chronic and/or stable. 
 SAE with an onset day greater than 30 days from the end of study/early termination 
visit - only fatal SAEs and those deemed by the investigator to be drug-related SAEs 
will be reported to the sponsor. The investigator should make every effort to obtain 
follow-up information on the outcome of a drug-related SAE until the event is 
considered chronic and/or stable. 
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. 
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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 24 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 AESIs, serious and nonserious, 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 (serious or non-serious) for evinacumab include the following: 
 Anaphylactic reactions 
 Allergic reactions and/or local injection site reactions that require consultation with 
another physician for further evaluation or requiring medical treatment  
 Increase in ALT or AST: ≥3 x ULN (if baseline <ULN), or ≥2 times the baseline 
value (if baseline ≥ ULN) 
 Pregnancy 
 Symptomatic overdose with investigational medicinal product 
 Neurocognitive events 
 New onset of diabetes (see definition below) 
 Pancreatitis 
Adverse events of special interest for alirocumab include the following:   
 Increase in ALT: ALT ≥3 x ULN (if baseline ALT <ULN), or ALT ≥2 times the 
baseline value (if baseline ALT ≥ ULN) 
 Allergic events and/or local injection site reactions that require consultation with 
another physician for further evaluation 
 Pregnancy 
 Symptomatic overdose with investigational medicinal product 
 Neurologic events that require additional examinations/procedures and/or referral to a 
specialist 
 Neurocognitive events 
 Cataracts 
 New onset of diabetes: The definition of new onset of diabetes (NOD) will be the 
following: 
 Type 1 or type 2 diabetes TEAE (grouping of Medical Dictionary for Regulatory 
Activities [MedDRA®] terms will be specified in the SAP) 
and/or 
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 At least 2 values of HbA1c ≥6.5% during the TEAE period. NOTE: For patients 
with only a single measurement available during the TEAE period, a single value 
≥6.5% will be considered and qualify the patient as NOD by default. For patients 
with several HbA1c measurements but only with the last one ≥6.5%, this single 
value ≥6.5% will be considered and qualify the patient as NOD by default. 
and/or 
 At least 2 values of fasting glucose ≥126 mg/dL (7.0 mmol/L). NOTE: For 
patients with only a single measurement available during the TEAE period, a 
single value ≥126 mg/dL (7.0 mmol/L) will NOT be considered and will NOT 
qualify the patient as NOD. For patients with several fasting glucose 
measurements but only with the last one ≥126 mg/dL (7.0 mmol/L), this single 
value ≥ 126 mg/dL (7.0 mmol/L) will NOT be considered and will NOT qualify 
the patient as NOD. 
Refer to the study manual for the procedures to be followed. 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study 
All AEs that lead to a patient’s withdrawal from the study must be reported to the sponsor’s 
medical monitor within 30 days. 
Refer to the study 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 monitor in the event the investigator feels that an abnormal test finding 
should be reported as an AE, although it does not meet any of the above criteria. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an 
AE. Any abnormal test result that is determined to be an error does not require reporting as an 
AE. 
Evaluation of severity of laboratory abnormalities will be assessed according to the scale 
outlined in Section 9.5.1. 
9.4.6. 
Follow-up 
Adverse event information will be collected until the patient’s last study visit. 
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Serious adverse event information will be collected until the event is considered chronic and/or 
stable. 
9.5. 
Evaluation of Severity and Causality 
9.5.1. 
Evaluation of Severity 
The severity of AEs will be graded according to the following scale: 
 Mild:  Does not interfere in a significant manner with the patient’s normal 
functioning level. It may be an annoyance. Prescription drugs are not ordinarily 
needed for relief of symptoms, but may be given because of personality of the patient. 
 Moderate:  Produces some impairment of functioning but is not hazardous to health. 
It is uncomfortable or an embarrassment. Treatment for symptom may be needed. 
 Severe:  Produces significant impairment of functioning or incapacitation and is a 
definite hazard to the patient’s health. Treatment for symptom may be given and/or 
patient hospitalized. 
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
Infusion Reactions 
The severity of infusion reactions will be graded according to the following scale (semi-colon 
indicates “or” within description of the grade): 
 Mild:  Mild transient reaction; infusion interruption not indicated; intervention not 
indicated. 
 Moderate:  Therapy or infusion interruption indicated but responds promptly to 
symptomatic treatment (eg, antihistamines, nonsteroidal anti-inflammatory drugs, 
narcotics, IV fluids); prophylactic medications indicated for ≤24 hours. 
 Severe:  Prolonged (eg, not rapidly responsive to symptomatic medication and/or 
brief interruption of infusion); recurrence of symptoms following initial 
improvement; hospitalization indicated for clinical sequelae; life-threatening 
consequences; urgent intervention indicated; death. 
9.5.2. 
Evaluation of Causality 
Relationship of AEs to Blinded IV Study Drug: 
The relationship of AEs to study drug will be assessed by the 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 
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Related: 
There is a reasonable possibility that the event may have been caused by the study 
drug 
A list of factors to consider when assessing the relationship of AEs to study drug is provided in 
Appendix 1. 
The investigator should justify the causality assessment of each SAE. 
Relationship of AEs to SC PCSK9 Inhibitor Antibody (if applicable): 
The relationship of AEs to a PCSK9 inhibitor antibody (if applicable) will be assessed by the 
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 PCSK9 inhibitor 
antibody? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by the 
PCSK9 inhibitor antibody 
Related: 
There is a reasonable possibility that the event may have been caused by the 
PCSK9 inhibitor antibody 
A list of factors to consider when assessing the relationship of AEs to a drug is provided in 
Appendix 1. 
The investigator should justify the causality assessment of each SAE. 
Relationship of Adverse Events to Study Conduct: 
The relationship of AEs to study conduct will be assessed by the investigator, and will be a 
clinical decision based on all available information. The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by study conduct? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by study 
conduct 
Related: 
There is a reasonable possibility that the event may have been caused by study 
conduct 
A list of factors to consider when assessing the relationship of AEs to study conduct is provided 
in Appendix 1. 
The investigator should justify the causality assessment of each SAE. 
9.6. 
Safety Monitoring 
The investigator will monitor the safety of study patients at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP). Any questions or 
concerns should be discussed with the sponsor in a timely fashion. The sponsor will monitor the 
safety data from across all study sites. The medical monitor will have primary responsibility for 
the emerging safety profile of the compound, but will be supported by other departments (eg, 
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Pharmacovigilance and Risk Management; Biostatistics and Data Management). Safety 
monitoring will be performed on an ongoing basis (eg, individual review of SAEs) and on a 
periodic cumulative aggregate basis. 
9.7. 
Investigator Alert Notification 
Regeneron (or designee) will inform all investigators participating in this clinical trial, as well as 
in any other clinical trial using the same investigational drug (evinacumab), 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 at the time of the double-blind period 
completion (ie first-step analysis). 
Analysis variables are listed in Section 4. 
10.1. 
Statistical Hypothesis 
Let μ0 and μ1 be the population means of the percent change from baseline in calculated LDL-C 
at week 24 under placebo and evinacumab, respectively. The following null hypothesis and 
alternative will be tested: 
H0 : μ0 = μ1 
versus 
H1 : μ0 ≠ μ1 
LDL-apheresis treatment [Yes/No], and geographical region [Japan, Rest of World] will be the 
2 stratification factors for patient randomization, and will be accounted for in the statistical 
modeling for efficacy. 
10.2. 
Justification of Sample Size 
For the primary efficacy hypothesis during the DBTP, a total sample size of 57 patients (38 on 
evinacumab and 19 on placebo) will have 90% power to detect a treatment group difference in 
mean percent change LDL-C of 38% with a 0.05 two-sided significance level and assuming a 
common standard deviation (SD) of 35%. This sample size has been adjusted for a 5% 
non-evaluable patient rate for the primary efficacy endpoint, and a 15% dropout rate. 
To gain experience with evinacumab in the population of Japanese patients, this study will plan 
to enroll up to 9 patients in Japan. Due to the rare patient population planned for evaluation, the 
sample size of 9 patients (15% of the planned study sample size) was chosen for practical 
reasons, centered on the feasibility to identify and enroll these patients into the trial. Based on the 
Ministry of Health, Labor, and Welfare 2007 “Basic Principles on Global Clinical Trials” 
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method 1, a sample size of 12 (21%) will be needed to achieve 80% probability that the effect in 
Japan is at least ½ of the global effect. A sample size of 9 provides approximately 77% 
probability. 
10.3. 
Analysis Sets 
10.3.1. 
Efficacy Analysis Sets 
10.3.1.1. Intent-to-Treat 
The ITT population is defined as all randomized patients who received at least one dose or part 
of a dose of double blind study drug. Patients in the ITT population will be analyzed according to 
the treatment group allocated by randomization (ie, as randomized patient group).  
10.3.1.2. Modified Intent-to-Treat 
The modified ITT (mITT) population is defined as the all randomized population who took at 
least 1 dose or part of a dose of study drug and have an evaluable primary endpoint. The 
endpoint is considered as evaluable when both of the following conditions are met: 
 Availability of at least 1 measurement value for calculated LDL-C before first dose of 
study drug (ie, baseline). 
 Availability of at least 1 calculated LDL-C value during the efficacy treatment period 
and within one of the analysis windows in the DBTP up to week 24. The efficacy 
treatment period is defined as the time from the first double-blind study drug 
administration up to 35 days after the last double-blind study drug administration, or 
up to the first dose of the open-label study drug, whichever is earlier. 
Patients in the mITT population will be analyzed according to the treatment group allocated by 
randomization. 
10.3.2. 
Safety Analysis Sets 
10.3.2.1. Double-Blind Safety Analysis Set 
The double-blind safety analysis set (SAF) considered for safety analyses will be the randomized 
population who received at least 1 dose or part of a dose of double-blind study drug. Patients will 
be analyzed according to the treatment received (placebo or evinacumab). In addition:   
 Randomized patients for whom it is unclear whether they took the study drug will be 
included in the safety population as randomized. 
 For patients receiving study drug from more than 1 treatment group during the trial, 
the treatment group allocation for as-treated analysis will be the one in which the 
patient was treated with the highest number of infusions. 
10.3.2.2. Open-Label Safety Analysis Set 
The open-label SAF considered for safety analyses will be the randomized population who 
received at least 1 dose or part of a dose of open-label study drug. 
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10.3.3. 
Other Analysis Sets 
The PK and the ADA analyses will be performed on all randomized patients who received any 
study drug, and further:   
 The PK analysis set will also require for each patient at least 1 non-missing 
post-baseline measurement of evinacumab concentration. Treatment assignments are 
based on the treatment received (placebo or evinacumab). 
 The ADA analysis set will also require for each patient at least 1 evaluable ADA 
result collected after the first dose of study treatment. Treatment assignments are 
based on the treatment received (placebo or evinacumab). 
10.4. 
Statistical Methods 
10.4.1. 
Patient Disposition 
The following data will be summarized: 
 The total number of screened patients, defined as originally having met the inclusion 
criteria and signed the ICF.  
 The total number of randomized patients, defined as all screened patients with a 
double-blind treatment kit number allocated and recorded in the IVRS database, 
regardless of whether the treatment kit was used. 
For any patient randomized more than once, safety data from the first randomization 
will be included in the SAF, with safety data associated with the later randomization 
reported separately. Since this is expected to be a rare event, inclusion of efficacy 
data from the patient randomized more than once in the efficacy population will be 
decided on a case-by-case basis prior to the unblinding of treatment assignments and 
will be documented in the clinical study report. 
 The total number of patients randomized but not receiving study treatment. 
 The total number of patients randomized and receiving study treatment. 
 The total number of patients who completed the DBTP, defined as at least 20 weeks 
of study treatment exposure and visit week 24 performed. 
 The total number of patients who completed the OLTP, defined as at least 44 weeks 
of study treatment exposure and visit week 48 performed. 
 The total number of patients who prematurely discontinued study treatment during 
the double-blind period, and the reasons for discontinuation. 
 The total number of patients who prematurely discontinued study treatment during 
the open-label period, and the reasons for discontinuation. 
 The total number of patients who did not complete the study follow-up period, 
defined as the last visit performed less than 23 weeks after the last study treatment 
infusion. Patients who died during the study are excluded. 
 The total number of patients in each analysis set. 
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 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 
For the DBTP, demographic and baseline characteristics will be summarized descriptively by 
treatment group for patients in the ITT population. For the open-label period, demographic and 
baseline characteristics will be summarized descriptively by treatment group assigned in the 
double-blind period, as well as for patient total, for patients in the open-label SAF. Continuous 
variables will be descriptively summarized with mean, median, SD, minimum, and maximum. 
Categorical variables will be descriptively summarized with frequency and percentage.  
10.4.3. 
Efficacy Analyses 
10.4.3.1. Primary Efficacy Analysis 
The double-blind primary efficacy analysis will compare the evinacumab treatment group to 
placebo at week 24. The primary efficacy endpoint is the percent change in calculated LDL-C 
from baseline to week 24 (ITT estimand). The percent change from baseline in calculated 
LDL-C will be analyzed in the ITT population using a mixed-effect model with repeated 
measures (MMRM) approach. All post-baseline data available within week 2 to week 24 analysis 
windows will be used and missing data are accounted for by the MMRM model. The model will 
include the fixed categorical effects of treatment group (placebo versus evinacumab), 
randomization strata (apheresis [Yes/No] and region [Japan, Rest of World]), time point (weeks 
2, 4, 8, 12, 16, 20, 24), strata-by-time point interaction, and treatment by time point interaction, 
as well as, the continuous fixed covariates of baseline calculated LDL-C value and baseline 
value-by-time point interaction. The statistical testing of the comparison for the primary measure 
will be evaluated at a 2-sided significance level of 0.05. Model assumptions for distribution 
normality and equal variances between treatment groups will be explored prior to the analysis 
testing. 
This model will be run using Statistical Analysis System (SAS) Mixed procedure with an 
unstructured correlation matrix to model the within-patient errors. Parameters will be estimated 
using restricted maximum likelihood method with the Newton-Raphson algorithm. Denominator 
degrees of freedom will be estimated using Satterthwaite’s approximation. This model will 
provide baseline adjusted least squares means estimates at week 24 for both treatment groups 
with their corresponding standard errors (SEs). 
Robustness of the primary analysis statistical methods will be assessed through sensitivity 
analyses detailed in the SAP, including an on-treatment analysis of the percent change in 
calculated LDL-C from baseline to week 24 (ie, mITT patient population using calculated 
LDL-C values collected during the efficacy treatment period [on-treatment estimand]), and a 
different methodology for missing data. Specifically, a pattern mixture model (PMM) will be 
employed to assess the potential violation of the missing at random assumption. For the PMM, 
the imputation model will account for the differing missing value patterns based on calculated 
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LDL-C collected in the presence or absence of study treatment administration for those patients 
randomized into the study. 
10.4.3.2. Secondary Efficacy Analysis 
For the key secondary efficacy endpoints (defined in Section 4.2.2) and other secondary efficacy 
endpoints (described in Section 4.2.3) collected in the DBTP, descriptive summaries and 
analyses will be performed in the ITT population, using values obtained regardless of adherence 
to study treatment and subsequent therapies (ITT estimand). 
For descriptive summaries, percent change, and when appropriate change from baseline, in 
calculated LDL-C, total-C, TG, non-HDL-C, Apo B, Lp(a), and Apo CIII will be provided at 
each time point. All measurements, scheduled or unscheduled, will be assigned to analysis 
windows defined in the SAP in order to provide an assessment for these time points. Laboratory 
assessments other than the ones provided by the central laboratory will be excluded. For TG, 
measurements on non-fasting patients will be excluded. The time profile of each parameter will 
be plotted by treatment group with the corresponding SEs. 
Multiple types of measurements are planned to be analyzed during differing time points in the 
trial, specifically continuous measurements expected to have a normal distribution (example:  
percent change in calculated LDL-C), continuous measurements expected to have a non-normal 
distribution (example: TG), and binary measurements (example:  proportion of patients reaching 
LDL-C <100mg/dL). 
I. Continuous endpoints anticipated to have a normal distribution 
Continuous secondary variables defined in Section 4.2.2 and Section 4.2.3 anticipated to have a 
normal distribution (ie, lipids other than TG and Lp[a]) will be analyzed using the same MMRM 
model as for the primary endpoint. Specifically, the model will contain fixed categorical effects 
of treatment group, randomization strata, planned time points up to the time point of interest, 
strata-by-time point interaction and treatment-by-time point interaction, as well as the continuous 
fixed covariates of corresponding baseline value and baseline value-by-time point interaction. 
II. Continuous endpoints anticipated to have a non-normal distribution 
Continuous secondary efficacy endpoints defined in Section 4.2.2 and Section 4.2.3 anticipated 
to have a non-normal distribution (ie, TG and Lp[a]), will be analyzed using a robust regression 
model (ie, ROBUSTREG SAS procedure with M-estimation option) with treatment group and 
randomization stratum as main effect and corresponding baseline value(s) as a covariate. Missing 
values will be addressed using a multiple imputation approach, which will be described in the 
SAP. The variables in the multiple imputation model will at least include the same variables as 
used in the robust regression model. The treatment group combined means will be provided with 
respective SE estimates. The combined mean difference between the treatment groups will be 
provided with the SE, 95% confidence interval (CI) and p-value. 
III. Binary endpoints 
Binary secondary efficacy endpoints defined in Section 4.2.2 and Section 4.2.3 will be analyzed 
using stratified logistic regression (using the strata option of the SAS logistic procedure) with 
treatment group and randomization stratum as main effect and corresponding baseline value(s) as 
a covariate. Missing values will be addressed using a multiple imputation approach, which will 
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be described in the SAP. The variables in the multiple imputation model will at least include the 
same variables as used in the logistic regression model. Treatment effects will be compared and 
the combined odds ratio estimate between the treatment groups, with their corresponding 95% CI 
and p-value will be provided. 
In the data dependent case that the logistic regression method is not applicable (eg, the response 
rate is zero in one treatment arm and thus the maximum likelihood estimate may not exist), the 
last observation carried forward (LOCF) approach would be used for handling of missing values 
and an exact conditional logistic regression would be performed to compare treatment effects. 
The LOCF imputation method will consist of using the last value obtained up to the week 24 
time window to impute the missing week 24 value. 
10.4.3.3. Multiplicity Considerations 
In order to address multiple key secondary efficacy endpoints (ie, other lipid parameters) 
collected in the double-blind period (Section 4.2.2 and Section 4.2.3) , the overall type-I error 
will be controlled by the use of a hierarchical inferential approach. Statistical significance of the 
primary parameter is required before drawing inferential conclusions about the first key 
secondary parameter at the 0.05 alpha level. Inferential conclusions about successive key 
secondary parameters require statistical significance of the prior parameter within the hierarchy. 
The hierarchy testing sequence will be provided in the SAP, prior to treatment unblinding. This 
fixed hierarchical approach will ensure a strong control of the overall type-I error rate at the 0.05 
level. 
No further adjustments will be made for other secondary endpoints, for which p-values will be 
provided for descriptive purposes only. 
No adjustment will be made for the first step (Section 10.4.9.1) and second step 
(Section 10.4.9.2) statistical analyses, since the primary and key secondary efficacy endpoints 
will have been concluded at the time of the first step analysis. 
10.4.3.4. Other Efficacy Endpoints 
During the OLTP, efficacy variables will be explored through descriptive statistics at each 
scheduled visit for the total patients administered open-label study treatment (total), as well as by 
the patient subgroups of study treatment received in the DBTP (ie, evinacumab, placebo). Formal 
statistical testing is not planned. Descriptive statistics will include the same parameters as 
described for each variable in the DBTP. 
For patients receiving evinacumab in the DBTP, a combined summary including both the 
double-blind and OLTP assessments may be considered, referencing the double-blind baseline 
for variable calculations. Prolonged time between last dose of double-blind treatment and first 
dose of open-label treatment will need to be taken into consideration when combining 
longitudinal efficacy data. Formal statistical testing is not planned. 
10.4.3.5. Subgroup Analyses for the Primary Efficacy Endpoint 
Analyses are planned on the primary efficacy endpoint to access the homogeneity of evinacumab 
treatment effect across various patient subgroups in the ITT population, including the 
2 stratification factors LDL-C apheresis and region, and patients with or without 
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receptor-negative mutations in both LDLR alleles. Statistical analysis methods will be provided 
in the SAP. 
With respect to the subgroup analysis for region, the primary efficacy analysis MMRM model 
will be used to evaluate treatment effect in Japanese patients (as recorded in the electronic data 
capture [EDC] system) by adding the variables of treatment-by-region strata and treatment-by 
time point-by region strata interaction terms to the model. With this subgroup specific MMRM 
model, the primary efficacy endpoint LS mean at week 24 for the evinacumab treatment group 
will be provided for the Japanese patients, along with the corresponding SE and 95% CI. Due to 
the few Japanese patients (3) expected to be randomized to the placebo group, the evinacumab 
group LS mean point estimate will be used to access consistency of evinacumab effect between 
the Japanese patients and all evinacumab treated patients in this global study (provided by the 
primary efficacy analysis described in Section 10.4.3.1). The evinacumab primary efficacy 
endpoint LS mean point estimate for the Japanese patients is considered to show consistent 
efficacy results with the global study point estimate when the Japanese patient’s LS mean point 
estimate is greater by a pre-specified amount (to be provided in the SAP) than the corresponding 
global study point estimate (ie, ratio of point estimate for Japanese patients divided by point 
estimate for the global study). 
10.4.3.6. On-Treatment Efficacy Analyses 
For key secondary efficacy endpoints (defined in Section 4.2.2) collected in the DBTP, 
descriptive summaries and analyses comparing treatment groups will be performed in the mITT 
population, using values obtained during the efficacy treatment period (on-treatment estimand). 
Statistical methods described above will be used to analyze each key secondary efficacy 
endpoint. P-values will be provided for descriptive purposes only. 
10.4.4. 
Safety Analysis 
For the double-blind period, summaries of safety results will be presented by treatment group for 
patients in the double-blind SAF. Summaries of safety results for the open-label period will be 
presented for patients in the open-label SAF, by the total patients administered open-label study 
treatment (total), as well as by the patient subgroups of study treatment received in the DBTP (ie, 
evinacumab, placebo). No formal inferential testing will be performed. Summaries will be 
descriptive in nature. 
All safety analyses will be performed using the following common rule: 
 The baseline value is defined as the last available value before the first dose of 
double-blind study treatment. 
10.4.4.1. Adverse Events 
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®). The verbatim text, the preferred term (PT), 
and the system organ class (SOC) will be provided in patient listings. 
Definitions 
For safety variables, the following observation periods are defined: 
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 The pretreatment period is defined from the day the ICF is signed to the day before 
the first dose of double-blind study treatment. 
 The double-blind TEAE observation period is defined from the day of the first dose 
of double-blind study treatment to the day of the last dose of double-blind study 
treatment + 168 days (24 weeks) (residual effect of treatment for IV dose regimen is 
expected until 24 weeks after the last dose of study drug) for those patients not 
proceeding into the OLTP, or up to the day before the first dose of open-label study 
treatment administration for those patients proceeding into the OLTP.  
 The open-label TEAE observation period is defined from the day of the first 
open-label study treatment administration to the day of the last open-label study 
treatment administration + 168 days.  
 The post-treatment observation period is defined as the time from the day after the 
end of the respective TEAE periods to the last study visit. 
Double-blind TEAEs are defined as those events that developed, worsened, or became serious 
during the double-blind TEAE period. Open-label TEAEs are defined as those events that 
developed, worsened, or became serious during the open-label TEAE period. 
Analysis 
Adverse event incidence tables will present data by SOC sorted alphabetically and PT sorted by 
decreasing frequency, and summarize the number (n) and percentage (%) of patients 
experiencing an AE. Multiple occurrences of the same event in the same patient will be counted 
only once in the tables. Data conventions for missing or partial AE dates will be addressed in the 
SAP. The denominator for computation of percentages is the respective SAF populations (ie 
double-blind SAF or open-label SAF) within each treatment group. 
Summaries of TEAEs incidences will include: 
 All TEAEs (and patient listing) 
 All treatment-emergent SAEs, including patient deaths (and patient listing) 
 All TEAEs of special interest for alirocumab treatment (ie, increase in ALT etc) 
 All TEAEs of special interest for evinacumab treatment (anaphylactic reaction etc) 
 TEAEs by severity (according to the grading scale outlined in Section 9.5.1), 
depicting the worse TEAE severity for those patients with multiple occurrences of the 
same event  
 All TEAEs leading to permanent treatment discontinuation (and patient listing) 
An AE patient listing will be provided for all patient deaths occurring during the respective 
TEAE periods (ie double-blind and open-label) and the post-treatment period. 
10.4.4.2. Other Safety 
Definitions 
The following definitions will be applied to laboratory parameters and vital signs: 
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 The potentially clinically significant value (PCSV) criteria are defined as abnormal 
values considered medically important by the sponsor according to predefined 
criteria/thresholds based on literature review and defined by the sponsor for clinical 
laboratory tests and vital signs. PCSV criteria will be provided in the SAP. 
 PCSV criteria will determine which patients had at least 1 PCSV during the 
respective TEAE periods (double-blind and open-label), taking into account all 
evaluations performed during the respective TEAE periods, including unscheduled or 
repeated evaluations. The number of all such patients will be the numerator for the 
PCSV percentage. 
 Double-blind treatment period:  The treatment period used for the quantitative 
analysis of laboratory and vital signs data in the double-blind period is defined from 
the day after the first dose of double blind study treatment to the day of the last dose 
of double-blind study treatment + 28 days for those patients not proceeding into the 
OLTP, or up to the day of the first dose of open-label study treatment administration 
for those patients proceeding into the OLTP. 
 Open-label treatment period:  The treatment period used for quantitative analysis of 
laboratory and vital signs data in the open-label study period is defined from the day 
after the first dose of open-label study treatment to the day of the last dose of open-
label study treatment + 28 days. 
Analysis 
Summary statistics of all laboratory variables (including lipid HDL-C) and all vital signs 
parameters (raw data and changes from baseline) will be calculated for each protocol scheduled 
visit assessed during the respective treatment periods. For selected parameters, mean changes 
from baseline with the corresponding SE may be plotted over time (at same time points) in each 
treatment group. 
The incidence of PCSVs at any time during the respective TEAE periods will be summarized 
regardless of the baseline level, and again according to the following baseline categories: 
 Normal/missing 
 Abnormal according to PCSV criterion or criteria 
For laboratory parameters for which a PCSV criterion is not defined, similar table(s) using the 
normal range will be provided, regardless of baseline level. 
Listings will be provided with flags indicating the laboratory values meeting PCSV criteria. 
10.4.4.3. Treatment Exposure 
The duration of study treatment exposure for the double-blind period will be calculated as: 
 Patient duration of study treatment exposure in weeks: (last double-blind study 
treatment administration date + 28 – first double-blind study treatment administration 
date +1 day)/7, regardless of unplanned intermittent discontinuations. 
 The total number of double-blind treatment infusions by patient. 
The duration of evinacumab exposure for the open-label period will be calculated as: 
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 Patient duration of evinacumab exposure in weeks: (last open-label evinacumab 
administration date + 28 – first open-label evinacumab treatment administration 
date)/7, regardless of unplanned intermittent discontinuations. 
 The total number of open-label evinacumab infusions by patient. 
The duration of evinacumab cumulative exposure in the double-blind and open-label periods will 
be calculated as: 
 Combined patient duration of evinacumab exposure in weeks: double-blind 
evinacumab treatment duration + open-label evinacumab treatment duration, 
regardless of unplanned intermittent discontinuations. 
 Combined total number of evinacumab treatment infusions by patient defined as: total 
number of double-blind evinacumab infusions + total number of open-label 
evinacumab infusions. 
The durations of study treatment exposure (double-blind, open-label, and cumulative across the 
study), measured in weeks, will be summarized by at least; mean, median, SD, and 
minimum/maximum. The categorical data for number of study treatment infusions (double-blind, 
open-label, and cumulative across the study) will be summarized by patient counts and 
percentages. 
10.4.4.4. Treatment Compliance 
Compliance during the double-blind period will be assessed by infusion frequency, specifically: 
 Defined for each patient as the average number of days between 2 infusions: (last 
double-blind dose date – first double-blind dose date) / (number of infusions in 
double-blind -1), for patients receiving at least 2 infusions. 
Infusion frequency for the double-blind period will be summarized by at least; mean, median, 
SD, and minimum/maximum. 
10.4.5. 
Analysis of Drug Concentration and Target Concentration Data 
Descriptive statistics of evinacumab concentrations and total ANGPTL3 concentration and 
alirocumab and PCSK9 concentration at each sampling time will be provided by treatment 
group. Plots of mean concentrations (linear and log scales) versus time will be presented. 
10.4.6. 
Analysis of Anti-Drug Antibody Data 
Listings of ADA positivity and titers presented by patient, time point, and study treatment 
received 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 treatment 
received. 
The influence of ADA on drug concentrations will be evaluated. Assessment of impact of ADA 
on safety and efficacy may be provided. 
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10.4.7. 
Analysis of Statin Concentration 
Descriptive statistics at each sampling time. The ratio of concentration at week 24 over baseline 
for individual patient will be presented, when available. 
 
 
 
 
 
 
10.4.9. 
Timing of Statistical Analyses 
The analyses will be conducted in 2 steps: 
10.4.9.1. First Step: Main Efficacy and Safety Analysis 
The first analysis will be conducted as soon as all patients have been randomized and all data 
through week 24 (double-blind period) has been collected and validated. This first analysis will 
consist of the final analysis of the primary and secondary efficacy endpoints. The safety analysis 
will be performed on all safety data collected and validated at the time of the first analysis. 
The results of the first analysis will not be used to change the conduct of the ongoing study in 
any aspect. Since data collection for the double-blind primary efficacy measure and key 
secondary efficacy measures will have been concluded at the time of this first analysis, the 
significance level for the study remains at 0.05. This first analysis maybe used for the submission 
dossier to health authorities. 
Individuals involved in the first step analysis of the study will not be involved in the conduct of 
the study afterwards; individual patient identification will not be released to anyone who is 
directly involved in the conduct of the study. The first step analysis process, the measures used to 
protect the blind and the integrity of the study, the communication plan, and the confidentiality 
agreement will be described in a separate document. 
10.4.9.2. Second Step: Final Safety Analysis 
The second analysis will be conducted at the end of the OLTP (end of study) and will consist of 
the final analysis for safety and the OLTP exploratory efficacy measures. 
10.5. 
Additional Statistical Data Handling Conventions 
Additional analysis and data conventions will be provided in the SAP, including the definitions 
for the analysis windows around each planned visit. 
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. 
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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 EDC tool, iMedidata Rave. 
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 
 EDC system – data capture 
 SAS – statistical review and analysis 
 Pharmacovigilance safety database 
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. 
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 
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retained by the investigator as part of the study record and must be available at all times for 
inspection by authorized representatives of the sponsor and regulatory authorities. 
Corrections to the CRF will be entered in the CRF by the investigator or an authorized designee. 
All changes, including date and person performing corrections, will be available via the audit 
trail, which is part of the EDC system. For corrections made via data queries, a reason for any 
alteration must be provided. 
13. 
AUDITS AND INSPECTIONS 
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities. Should this occur, the investigator is responsible for: 
 Informing the sponsor of a planned inspection by the authorities as soon as 
notification is received, and authorizing the sponsor’s participation in the inspection 
 Providing access to all necessary facilities, study data, and documents for the 
inspection or audit 
 Communicating any information arising from inspection by the regulatory authorities 
to the sponsor immediately 
 Taking all appropriate measures requested by the sponsor to resolve the problems 
found during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, 
CRFs, medical records, correspondence, ICFs, IRB/EC files, documentation of certification and 
quality control of supporting laboratories, and records relevant to the study maintained in any 
supporting pharmacy facilities. Conditions of study material storage are also subject to 
inspection. In addition, representatives of the sponsor may observe the conduct of any aspect of 
the clinical study or its supporting activities both within and outside of the investigator's 
institution. 
In all instances, the confidentiality of the data must be respected. 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS 
14.1. 
Good Clinical Practice Statement 
It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki (refer to current version), and that are consistent with the ICH guidelines 
for GCP and applicable regulatory requirements. 
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14.2. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP. 
Adults.: 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC. A copy of the IRB/EC-approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient prior to his/her participation in the study and after the 
aims, methods, objectives, and potential hazards of the study have been explained to the patient 
in language that he/she can understand. The ICF should be signed and dated by the patient and 
by the investigator or authorized designee who reviewed the ICF with the patient. 
 Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
 Patients who can understand but who can neither write nor read will have the ICF 
read to them in presence of an impartial witness. The patient will give oral consent 
and the impartial witness 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. 
Pediatric Patients: 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient and his/her parent(s) or legal guardian(s) prior to the 
patient’s participation in the study and after the aims, methods, objectives, and potential hazards 
of the study have been explained to the fullest possible extent in language that the patient and the 
parent(s) or legal guardian(s) can understand. The ICF should be signed and dated by the 
patient’s parent(s) or legal guardian(s) and the same investigator or designee who explained the 
ICF. 
Local law must be observed in deciding whether 1 or both parents/guardians consent is required. 
If only 1 parent or guardian signs the consent form, the investigator must document the reason 
the other parent or guardian did not sign. The patient may also be required to sign and date the 
ICF, as determined by the IRB/EC and in accordance with the local regulations and 
requirements. 
 Patients who can write but cannot read will have the assent form read to them before 
writing their name on the form. 
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 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’s parent(s) or legal guardian(s). 
If new safety information results in significant changes in the risk/benefit assessment, the ICF 
must be reviewed and updated appropriately. All study patients and their parent(s) or legal 
guardian(s) must be informed of the new information and provide their written consent if they 
wish the patient 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’s parent(s) or legal guardian(s). 
14.3. 
Patient Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained. Patients should be identified by their patient identification number, 
only, on CRFs or other documents submitted to the sponsor. Documents that will not be 
submitted to the sponsor (eg, signed ICF) must be kept in strict confidence. 
The patient's and investigator's personal data, which may be included in the sponsor database, 
will be treated in compliance with all applicable laws and regulations. The sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third 
party. 
14.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve: 
 The protocol, ICF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
 Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patients, in 
which case the IRB/EC should be informed as soon as possible  
 Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
In addition, the IRB/EC should be informed of any event likely to affect the safety of patients or 
the continued conduct of the clinical study. 
A copy of the IRB/EC approval letter with a current list of the IRB/EC members and their 
functions must be received by the sponsor prior to shipment of drug supplies to the investigator. 
The approval letter should include the study number and title, the documents reviewed, and the 
date of the review. 
Records of the IRB/EC review and approval of all study documents (including approval of 
ongoing studies) must be kept on file by the investigator. 
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15. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an 
IRB/EC-approved amendment. Regulatory approvals will also be sought where applicable under 
local regulations. 
16. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
16.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely. Reasons may include efficacy, 
safety, or futility, among others. Should the sponsor decide to terminate the study, the 
investigator(s) will be notified in writing. 
16.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
Investigator’s Decision 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at 
least 30 days’ notice. The final decision should be made through mutual agreement with the 
sponsor. Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing. 
Reasons may include the following, among others:  
 The investigator has received all items and information necessary to perform the 
study, but has not enrolled any patient within a reasonable period of time 
 The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines  
 The total number of patients required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB/EC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection 
of the patients’ interests. 
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17. 
STUDY DOCUMENTATION 
17.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the CRF must be signed 
electronically by the investigator. This signed declaration accompanies each set of patient final 
eCRFs 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. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
19. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
20. 
PUBLICATION POLICY 
The publication policy is provided as a separate agreement. 
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21. 
REFERENCES 
Cannon CP, Blazing MA, Giugliano RP, etc; IMPROVE-IT Investigators. Ezetimibe Added to 
Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015 Jun 18;372(25):2387-97. 
Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, Emberson J, etc. 
Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 
170,000 participants in 26 randomised trials. Lancet. 2010 Nov 13;376(9753):1670-81. 
Cuchel M, Meagher EA, du Toit Theron H, et al. Efficacy and safety of a microsomal 
triglyceride 
transfer 
protein 
inhibitor 
in 
patients 
with 
homozygous 
familial 
hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet 2013; 381: 40–46. 
Cuchel M, Bruckert E, Ginsberg HN, et al. Homozygous familial hypercholesterolaemia: new 
insights and guidance for clinicians to improve detection and clinical management. A position 
paper from the Consensus Panel on Familial Hypercholesterolaemia of the European 
Atherosclerosis Society. European heart journal. 2014 Aug 21;35(32):2146-2157. 
Crestor. rosuvastatin U.S. Prescribing Information Revised 06/2015; 2003. 
France, M. Homozygous familial hypercholesterolemia: update on management. Pediatr Int 
Child Health 2016;36(4):243-47. 
Goldberg AC, Hopkins PN, Toth PP et al., Familial hypercholesterolemia: screening, diagnosis 
and management of pediatric and adult patients: clinical guidance from the National Lipid 
Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011; 5(3):133-40. 
Goldstein JL, H.H., M.S.B. Familial Hypercholesterolemia. 8th ed, The Metabolic and Molecular 
Bases of Inherited Disease. New York: McGraw-Hill Information Services Company; 2001. p. 
2863-2913. 
Herrmann C. International experiences with the hospital anxiety and depression scale – a review 
of validation data and clinical results. J Psychosom Res 1997;42(1):17-41 
Kajinami K, Mabuchi H. Therapeutic effects of LDL apheresis in the prevention of 
atherosclerosis. Current opinion in lipidology. 1999 Oct;10(5):401-406. 
Kolansky DM, Cuchel M, Clark BJ, et al. Longitudinal evaluation and assessment of 
cardiovascular disease in patients with homozygous familial hypercholesterolemia. Am J 
Cardiol. 2008. 
Lipitor. atorvastatin U.S. Prescribing Information Revised 06/2015; 1996 
Macchiaiolo M, Gagliardi MG, et al. Homozygous familial hypercholesterolemia. Lancet 
2012 Apr 7;379(9823):1330 
Marais AD, Raal FJ, Stein EA, et al. A dose-titration and comparative study of rosuvastatin and 
atorvastatin in patients with homozygous familial hypercholesterolaemia. Atherosclerosis 2008; 
197: 400–06. 
Moorjani S, Roy M, Torres A, et al. Mutations of low-density-lipoprotein-receptor gene, 
variation in plasma cholesterol, and expression of coronary heart disease in homozygous familial 
hypercholesterolaemia. Lancet. 1993 May 22;341(8856):1303-1306. 
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Raal FJ, Pilcher GJ, Illingworth DR, et al. Expanded-dose simvastatin is effective in 
homozygous familial hypercholesterolaemia. Atherosclerosis 1997; 135: 249–56. 
Raal FJ, Pappu AS, Illingworth DR. Inhibition of cholesterol synthesis by atorvastatin in 
homozygous familial hypercholesterolaemia. Atherosclerosis. 2000; 421–428. 
Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for 
lowering of LDL cholesterol concentrations in patients with homozygous familial 
hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet 2010; 375: 
998–1006. 
Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolocumab in homozygous 
familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled 
trial. Lancet. 2015 Jan 24;385(9965):341-350. 
Rader DJ, Cohen J, Hobbs HH. Monogenic hypercholesterolemia: new insights in pathogenesis 
and treatment. J. Clin. Invest. 2003; 111:1795–1803. 
Repatha. evolocumab U.S. Prescribing Information. 2015. 
Sabatine MS, Giugliano RP, Keech AC, etc; FOURIER Steering Committee and Investigators. 
Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 
2017 May 4;376(18):1713-1722. 
Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the definition and 
management of anaphylaxis: summary report--Second National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network symposium. Allergy Clin Immunol. 
2006 Feb;117(2):391-7. 
Schettler V, Neumann CL, Hulpke-Wette M, et al. Current view: indications for extracorporeal 
lipid apheresis treatment. Clin Res Cardiol Suppl. 2012; 7:15-19. 
Steg PG (2017, March). Evaluation of Cardiovascular Outcomes After an Acute Coronary 
Syndrome During Treatment With Alirocumab - ODYSSEY OUTCOMES. Presented at the 
American College of Cardiology Annual Scientific Session (ACC 2018), Orlando, FL, March 10, 
2018. 
Thompson GR, Catapano A, Saheb S, et al. Severe hypercholesterolaemia: therapeutic goals and 
eligibility criteria for LDL apheresis in Europe. Curr Opin Lipidol. 2010 Dec;21(6):492-8. doi: 
10.1097/MOL.0b013e3283402f53. Review. 
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refractory hyperlipidemia. Mayo Clin Proc 2001;76(10):1039-46. 
Youngblom E, Pariani M, Knowles JW. Familial Hypercholesterolemia. In: Pagon RA, Adam 
MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, 
Smith RJH, Stephens K, editors, GeneReviews(R). Seattle (WA); 1993. 
Zetia. ezetimibe U.S. Prescribing Information. Revised 01/2012; 2002. 
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1983;67:361-370. 
Zocor. simvastatin U.S. Prescribing Information. Revised 02/2015; 1991 
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22. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: “A randomized, double-blind, placebo-controlled, 
parallel-group study to evaluate the efficacy and safety of evinacumab in patients with 
homozygous familial hypercholesterolemia”, and agree to abide by all provisions set forth 
therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, 
state, or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor or a 
partnership in which the sponsor is involved. I will immediately disclose it in writing to the 
sponsor if any person who is involved in the study is debarred, or if any proceeding for 
debarment is pending, or, to the best of my knowledge, threatened. 
This document contains confidential information of the sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the IRB/EC. I agree to ensure that 
this information will not be used for any purpose other than the evaluation or conduct of the 
clinical investigation without the prior written consent of the sponsor. 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
 
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APPENDIX 1. FACTORS TO CONSIDER IN ASSESSING THE 
RELATIONSHIP OF ADVERSE EVENTS TO STUDY 
DRUG AND STUDY CONDUCT OR STUDY PROCEDURE 
OR BACKGROUND TREATMENT, ETC. 
Is there a reasonable possibility that the event may have been caused by the study drug or study 
conduct or study procedure or background treatment, etc.? 
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 study procedure or background treatment, etc. 
 do not reappear or worsen when dosing with study drug or study procedure or 
background treatment, etc is resumed 
 are not a suspected response to the study drug or 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 
 follow a reasonable temporal sequence following the time of administration of the 
dose of study drug or study procedure or background treatment, etc. 
 resolve or improve after discontinuation of study drug or study procedure or 
background treatment, etc. 
 reappear or worsen when dosing with study drug or study procedure or background 
treatment, etc is resumed 
 are known or suspected to be a response to the study drug or study procedure or 
background treatment, etc, based upon preclinical data or prior clinical data 
NOTE:  This list is not exhaustive. 
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APPENDIX 2. SUMMARY OF TLC DIET FOR HIGH CHOLESTEROL 
Total Fat  
25% - 35% total calories*  
Saturated fat*  
<7% total calories  
Polyunsaturated fat  
up to 10% total calories  
Monounsaturated fat  
up to 20% total calories  
Carbohydrates†  
50% - 60% total calories*  
Protein  
~15% total calories  
Cholesterol  
<200 mg/dL (5.172 mmol/l) 
Plant Sterols  
2g  
Soluble Fiber such as psyllium  
10g - 25g  
* ATP III allows an increase of total fat to 35 percent of total calories and a reduction in carbohydrate 
to 50 percent for persons with the metabolic syndrome. Any increase in fat intake should be in the 
form of either polyunsaturated or monounsaturated fat. Trans-fatty acids are another LDL-raising fat 
that should be kept at a low intake. 
† Carbohydrate should derive predominantly from foods rich in complex carbohydrates including 
grains—especially whole grains—fruits, and vegetables. 
 
 
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SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Scientific/Medical Monitor, Regulatory Representative, Clinical Study Team Lead, and 
Biostatistician) 
To the best of my knowledge, this protocol accurately describes the conduct of the study. 
 
Study Title: 
A randomized, double-blind, placebo-controlled, parallel-group study to evaluate 
the efficacy and safety of evinacumab in patients with homozygous familial 
hypercholesterolemia 
Protocol Number: 
R1500-CL-1629 
Protocol Version: 
R1500-CL-1629 Amendment 4B 
 
See appended electronic signature page 
Sponsor’s Responsible Scientific/Medical Monitor 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Representative 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Team Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
 
 
 
 
                                        VV-RIM-00089244-1.0 Approved - 11 Oct 2019 GMT-5:00

Signature Page for VV-RIM-00089244 v1.0
Signature Page for VV-RIM-00089244 v1.0 Approved
ESig Approval
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ESig Approval
11-Oct-2019 17:48:06 GMT+0000
ESig Approval
11-Oct-2019 18:23:26 GMT+0000
ESig Approval
nt
11-Oct-2019 19:11:50 GMT+0000
                                        VV-RIM-00089244-1.0 Approved - 11 Oct 2019 GMT-5:00