Conditions: Homozygous Familial Hypercholesterolemia
Keywords: HoFH
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 65
Healthy volunteers: no

Brief summary:
The primary objective of the study is to demonstrate the reduction of low-density lipoprotein cholesterol (LDL-C) by evinacumab 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 IV on other lipid parameters, evaluate the effect of evinacumab on LDL-C goal attainment, assess the effect of evinacumab on eligibility for apheresis (using German and US apheresis criteria), evaluate the safety and tolerability of evinacumab in patients with HoFH, assess the pharmacokinetics (PK) of evinacumab in patients with HoFH and evaluate the potential development of anti-evinacumab antibodies.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: evinacumab intervention 2: Placebo
Intervention descriptions: intervention 1: IV administration of evinacumab intervention 2: IV administration of placebo

Protocol document:
Prot_000.pdf: 
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 
 
 
 
 
 
 
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NCT03399786


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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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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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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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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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CONFIDENTIAL 
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 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 
 
 
 
 
 
 
VV-RIM-00089244-1.0 Approved - 11 Oct 2019 GMT-5:00
NCT03399786


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Regeneron Pharmaceuticals, Inc. 
 
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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 
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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. 
Vella A, Pineda AA, O’Brien T. Low-density lipoprotein apheresis for the treatment of 
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. 
Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 
1983;67:361-370. 
Zocor. simvastatin U.S. Prescribing Information. Revised 02/2015; 1991 
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CONFIDENTIAL 
 
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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CONFIDENTIAL 
 
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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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 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 
 
 
 
 
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Signature Page for VV-RIM-00089244 v1.0
Signature Page for VV-RIM-00089244 v1.0 Approved
ESig Approval
11-Oct-2019 15:59:06 GMT+0000
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

SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 
STATISTICAL ANALYSIS PLAN 
VERSION: 1.0
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 
Protocol Number: 
R1500-CL-1629 Version 3B 
Clinical Phase:  
Phase 3 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician:  
Clinical Trial Manager: 
Study Medical Director: 
Version/Date:  
1.0 / July 12, 2019 
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NCT03399786


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R1500-CL-1629 Amendment 3B 
Statistical Analysis Plan 
 
Date: July 12, 2019 
 
 
CONFIDENTIAL  
Page 2 of 75 
The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
 
 
See appended electronic signature page 
Study Biostatistician  
 
 
 
See appended electronic signature page 
Study Clinical Pharmacologist 
 
 
 
See appended electronic signature page 
Study Bioanalytical Sciences 
 
 
 
See appended electronic signature page 
Head of Cardiovascular & Metabolism Therapeutics 
 
 
 
See appended electronic signature page 
Project Biostatistician
 
 
 
See appended electronic signature page 
Head of BDM or designee 
 
 
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Statistical Analysis Plan 
 
Date: July 12, 2019 
 
 
CONFIDENTIAL  
Page 3 of 75 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................7 
1. 
OVERVIEW .................................................................................................................9 
1.1. 
Background/Rationale ..................................................................................................9 
1.2. 
Study Objectives .........................................................................................................10 
1.2.1. 
Primary Objectives .....................................................................................................10 
1.2.2. 
Secondary Objectives .................................................................................................10 
1.2.3. 
Other Objectives .........................................................................................................10 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol ................................10 
1.2.5. 
Revision History for Statistical Analysis Plan Amendments .....................................11 
2. 
INVESTIGATION PLAN ..........................................................................................11 
2.1. 
Study Design and Randomization ..............................................................................11 
2.2. 
Sample Size and Power Considerations .....................................................................11 
2.3. 
Study Plan ...................................................................................................................12 
3. 
ANALYSIS POPULATIONS ....................................................................................13 
3.1. 
Efficacy Analysis Sets ................................................................................................13 
3.1.1. 
Intent-to-Treat (ITT) ...................................................................................................13 
3.1.2. 
Modified Intent-to-Treat (mITT) ................................................................................13 
3.2. 
Double-Blind Safety Analysis Set ..............................................................................14 
3.3. 
Open-Label Safety Analysis Set .................................................................................14 
3.4. 
Pharmacokinetic (PK) Analysis Set............................................................................14 
3.5. 
The Anti-evinacumab Antibody Analysis Set ............................................................14 
3.6. 
Quality-of-life Analysis Set ........................................................................................14 
4. 
ANALYSIS VARIABLES .........................................................................................15 
4.1. 
Demographic and Baseline Characteristics ................................................................15 
4.2. 
Medical History ..........................................................................................................16 
4.3. 
Prior and Concomitant Medications ...........................................................................18 
4.4. 
Prohibited Medications and Procedures During Study ...............................................19 
4.5. 
Patient Disposition ......................................................................................................19 
4.6. 
Study Treatment Exposure and Compliance Variables ..............................................20 
4.7. 
Efficacy Variable ........................................................................................................22 
4.7.1. 
Primary Efficacy Variable (s) .....................................................................................22 
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4.7.2. 
Key Secondary Efficacy Variable(s) ..........................................................................22 
4.7.3. 
Other Secondary Efficacy Variables ..........................................................................23 
4.8. 
Safety Variables ..........................................................................................................23 
4.8.1. 
Adverse Events Variables ...........................................................................................24 
4.8.1.1. 
Adverse Events and Serious Adverse Events .............................................................25 
4.8.1.2. 
Adverse Events of Special Interest .............................................................................25 
4.8.1.3. 
Events Causing Death .................................................................................................26 
4.8.2. 
Laboratory Safety Variables .......................................................................................26 
4.8.3. 
Vital Signs ..................................................................................................................27 
4.8.4. 
12-Lead Electrocardiography (ECG) ..........................................................................27 
4.8.5. 
Physical Examination Variables .................................................................................27 
4.9. 
Other Variables ...........................................................................................................27 
4.10. 
Pharmacokinetic Variables .........................................................................................27 
4.11. 
Anti-Drug (evinacumab) Antibody Variables (ADA) ................................................28 
4.12. 
Quality-of-Life Variables ...........................................................................................28 
5. 
STATISTICAL METHODS .......................................................................................29 
5.1. 
Demographics and Baseline Characteristics ...............................................................29 
5.2. 
Medical History ..........................................................................................................29 
5.3. 
Prior and Concomitant Medications ...........................................................................30 
5.4. 
Prohibited Medications ...............................................................................................30 
5.5. 
Patient Disposition ......................................................................................................30 
5.6. 
Extent of Study Treatment Exposure and Compliance ...............................................31 
5.6.1. 
Exposure to Investigational Product ...........................................................................31 
5.6.2. 
Study Treatment Compliance .....................................................................................31 
5.7. 
Analyses of Efficacy Variables ..................................................................................31 
5.7.1. 
Analysis of Primary Efficacy Variable .......................................................................32 
5.7.1.1. 
Sensitivity of the Primary Efficacy Analysis..............................................................32 
5.7.1.2. 
Sub-group Analyses ....................................................................................................34 
5.7.2. 
Analysis of Secondary Efficacy Variables .................................................................35 
5.7.2.1. 
Continuous Endpoints Anticipated to have a Normal Distribution ............................36 
5.7.2.2. 
Continuous Endpoints Anticipated to have a Non-normal Distribution .....................36 
5.7.2.3. 
Binary Endpoint Variables .........................................................................................36 
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Statistical Analysis Plan 
 
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5.7.2.4. 
Sensitivity Analysis of Key Secondary Endpoint Variables ......................................37 
5.7.2.5. 
Summary of Results by Time Point ............................................................................37 
5.8. 
Analysis of Safety Data ..............................................................................................38 
5.8.1. 
Adverse Events ...........................................................................................................39 
5.8.2. 
Analysis of Adverse Events of Special Interest ..........................................................42 
5.8.3. 
Clinical Laboratory Measurements.............................................................................42 
5.8.4. 
Analysis of Vital Signs ...............................................................................................43 
5.8.5. 
Analysis of 12-Lead ECG ...........................................................................................43 
5.8.6. 
Physical Exams ...........................................................................................................43 
5.9. 
Analysis of Other Variables ........................................................................................44 
5.10. 
Analysis of Pharmacokinetic Variables ......................................................................44 
5.11. 
Analysis of Anti-evinacumab Antibody Variables .....................................................44 
5.12. 
Analysis of Quality-of-life Variables .........................................................................45 
6. 
DATA CONVENTIONS ............................................................................................46 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................46 
6.2. 
Data Handling Convention for Efficacy Variables .....................................................46 
6.3. 
Data Handling Convention for Missing Data .............................................................46 
6.4. 
Visit Windows ............................................................................................................47 
6.5. 
Unscheduled Assessments ..........................................................................................48 
6.6. 
Pooling of Centers for Statistical Analyses ................................................................48 
6.7. 
Statistical Technical Issues .........................................................................................48 
7. 
TIMING OF STATISTICAL ANALYSES ................................................................48 
8. 
SOFTWARE ...............................................................................................................49 
9. 
REFERENCES ...........................................................................................................50 
10. 
APPENDIX.................................................................................................................51 
10.1. 
Summary of Statistical Analyses ................................................................................51 
10.2. 
Windows for Analysis Time Points ............................................................................51 
10.3. 
List of AESIs with Data Sources and Definitions of SMQ/CMQ ..............................54 
10.4. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................59 
10.5. 
EQ-5D Utility Score Algorithm..................................................................................62 
10.6. 
Hospital Anxiety and Depression Scale .....................................................................63 
10.7. 
Detailed Description of the Multiple Imputation Procedure ......................................64 
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Statistical Analysis Plan 
 
Date: July 12, 2019 
 
 
CONFIDENTIAL  
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10.8. 
Detailed Description of Pattern Mixture Model .........................................................65 
10.9. 
Schedule of Time and Events .....................................................................................67 
 
LIST OF TABLES 
Table 1: 
Global Analysis Windows ..........................................................................................52 
Table 2: 
Efficacy Analysis Windows – Statistical Testing .......................................................54 
Table 3: 
Summary of AESIs and the Methods of Data Collections and Derivations ...............54 
Table 4: 
CMQ “Neurocognitive disorders – FDA’s recommendation” ...................................58 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................12 
 
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Statistical Analysis Plan 
 
Date: July 12, 2019 
 
 
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LIST OF ABBREVIATIONS AND DEFINITION 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 
Apo CIII 
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) 
CV 
Cardiovascular 
CVD 
Cardiovascular disease 
DBTP 
Double-blind treatment period 
ECG 
Electrocardiogram 
EOT 
End of treatment 
FH 
Familial hypercholesterolemia 
FSH 
Follicle stimulating hormone 
HbA1c 
Hemoglobin A1c 
HDL 
High-density lipoprotein 
HDL-C 
High-density lipoprotein cholesterol 
HoFH 
Homozygous familial hypercholesterolemia 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
ITT 
Intent-to-treat 
IV 
Intravenously 
IVRS 
Interactive voice response system 
LDH 
Lactate dehydrogenase 
LDL-C 
Low-density lipoprotein cholesterol 
LDLR 
Low-density lipoprotein receptor 
LMT 
Lipid modifying therapy 
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Statistical Analysis Plan 
 
Date: July 12, 2019 
 
 
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Lp(a) 
Lipoprotein a 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 
MMRM 
Mixed-effect model with repeated measures 
OLTP 
Open-label treatment period 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PMM 
Pattern Mixture Model 
PT 
Preferred term 
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 
SD 
Standard deviation 
SE 
Standard error 
SMT 
Safety Monitoring Team 
SOC 
System organ class 
TC 
Total cholesterol 
TEAE 
Treatment-emergent adverse event 
TG 
Triglyceride 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
WBC 
White blood cell 
 
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Statistical Analysis Plan 
 
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1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study results 
by pre-specifying prior to the database lock the statistical approaches for the analysis of study 
data. The SAP is intended to be a comprehensive and detailed description of the strategy and 
statistical methods to be used in the analysis of data collected in the R1500-CL-1629 study. The 
content of this SAP is inclusive of both the first and second step analyses as described in the 
protocol. 
This plan may be revised during the study to accommodate protocol amendments and adapt to 
unexpected issues in study execution that may affect planned analyses. These revisions will be 
based on blinded data review, and a final plan will be issued prior to the first step database lock 
(i.e. before treatment assignments become known). For the purposes of this document, 
REGN1500 will be referred to as “evinacumab”. 
1.1. 
Background/Rationale 
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). 
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 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. 
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). 
Evinacumab (REGN1500) is a fully human mAb, created with Regeneron’s VelocImmune 
technology platform, which specifically binds to ANGPTL3. Additional background information 
on the study drug and development program can be found in the Investigator’s Brochure. 
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1.2. 
Study Objectives 
1.2.1. 
Primary Objectives 
The primary objective of the study is to demonstrate the reduction of LDL-C by evinacumab 
15 mg/kg intravenously (IV) in comparison to placebo after 24 weeks in patients with HoFH. 
1.2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
 To evaluate the effect of evinacumab 15 mg/kg IV on other lipid parameters 
(i.e., apolipoprotein [Apo B], non-high-density lipoprotein cholesterol [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 patients meeting eligibility criteria for 
apheresis (using German and US apheresis criteria) 
 To evaluate the safety and tolerability of evinacumab 15 mg/kg IV in patients with 
HoFH 
 To determine concentrations of evinacumab in patients with HoFH 
 To evaluate the potential development of anti-evinacumab antibodies 
1.2.3. 
Other Objectives 
 Genotyping will be performed for all patients to identify mutations causing HoFH and 
to explore potential differences in efficacy and safety based on type of LDLR 
function variant. 
 To assess the effect of evinacumab on quality of life using the EQ-5D and HADS 
QOL questionnaires. 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol 
The summary of modifications is listed in the following table. 
Item 
Protocol Section 
Description 
1 
10.3.2.1 Double-Blind 
Safety Analysis Set 
SAP Section 3.2: 
The second item for determining the as-treated treatment group will be 
changed from  
“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.” 
to 
For patients receiving study drug from more than 1 treatment group during 
the trial, the treatment group allocation for as-treated analysis will be 
evinacumab.  
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1.2.5. 
Revision History for Statistical Analysis Plan Amendments 
This is the first version of Statistical Analysis Plan (SAP). 
2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
This is a randomized, double-blind, placebo-controlled, parallel-group study to evaluate the 
efficacy and safety of evinacumab in patients with homozygous familial hypercholesterolemia 
(HoFH). 
Patients who meet all the inclusion criteria and none of the exclusion criteria will be randomized 
in a 2:1 ratio to receive evinacumab 15 mg/kg IV every 4 weeks (Q4W) or matching placebo IV 
Q4W for the 24-week double-blind treatment period (DBTP). The 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 open-label treatment period (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 
may 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 treatment.  
The 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 treatment period) has 
been collected and validated; this first analysis will consist of the final analysis of the 
double-blind primary and secondary efficacy endpoints. The safety analysis will be performed on 
all safety data collected and validated at the time of the first step analysis database lock. Since 
the double-blind primary efficacy measure data collection 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 performed with the data from the open-label treatment period and 
will consist of the final analysis for the safety and efficacy measures beyond week 24-time point. 
The results of the first analysis will not be used to change the conduct of the ongoing study in 
any aspect. 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. 
2.2. 
Sample Size and Power Considerations 
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 based on a two sample t-test 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% using nQuery 7.0. This 
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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. 
2.3. 
Study Plan 
This study consists of the following periods: up to an 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 (See Figure 1.) 
The Study event table is presented in Appendix 10.9 . 
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 treatment 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. 
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3. 
ANALYSIS POPULATIONS 
In accordance with guidance from the International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (ICH, 1998), below are the patient populations defined 
for statistical analysis. Two efficacy populations are planned for this study, specifically the 
Intent-to-Treat (ITT) population and the Modified Intent-to-Treat population (mITT).  The 
primary efficacy analysis population is the ITT population.  Additional patient populations are 
defined for safety, anti-drug (evinacumab) anti-body (ADA), pharmacokinetic (PK), 
quality-of-life, and open-label analyses. For the purposes of the definitions below, a patient is 
considered randomized to study treatment when they have been screened and received a 
double-blind treatment kit number allocated and recorded in the IVRS/IWRS database, 
regardless of whether the treatment kit was used or not.  
As with all trials, odd cases (usually rare) occur for patient eligibility in the analysis populations.  
The following are three cases with the planned resolution of each type of case should they occur. 
 Patients administered study treatment without randomization or before randomization 
will not be considered as “randomized” and therefore will not be included in any 
analysis population. The safety experience from these patients will be reported 
separately. 
 For patients found to be randomized more than once in this trial, safety data from the 
first randomization will be included in the safety population, with safety data 
associated with the later randomization reported separately.  Inclusion of efficacy data 
from the patient randomized more than once in the two efficacy populations will be 
decided on a case-by-case basis prior to the unblinding of treatment assignments and 
documented in the study report. 
 Patients successfully randomized and administered study treatment, but later found to 
violate inclusion/exclusion criteria, will be included in all analyses with appropriate 
documentation for the protocol deviation.  
3.1. 
Efficacy Analysis Sets 
3.1.1. 
Intent-to-Treat (ITT) 
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 (i.e., as randomized patient group). 
3.1.2. 
Modified Intent-to-Treat (mITT) 
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: 
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 Availability of at least 1 measurement value for calculated LDL-C before first dose of 
study drug (i.e., baseline). 
 Availability of at least 1 calculated LDL-C value during the efficacy treatment period 
and within one of the efficacy 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. 
3.2. 
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 evinacumab. 
3.3. 
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.  
3.4. 
Pharmacokinetic (PK) Analysis Set 
The PK analysis set is defined as all randomized patients who received any study drug and have 
at least 1 non-missing post-baseline measurement of evinacumab concentration.  Treatment 
assignments for the DBTP are based on the treatment received (placebo or evinacumab). 
3.5. 
The Anti-evinacumab Antibody Analysis Set 
The anti-evinacumab antibody (ADA) analysis set is defined as all randomized patients who 
received any study treatment, and have at least 1 evaluable ADA result collected after the first 
dose of study treatment. Treatment assignments for the DBTP are based on the treatment 
received (placebo or evinacumab). 
3.6. 
Quality-of-life Analysis Set  
The analyses for quality of life in the respective treatment period (DBTP and OLTP) will be 
performed on all randomized patients who received any study treatment with a baseline and at 
least 1 post-baseline evaluation. Further for each scale: 
 For EQ-5D, patients will be included when at least 1 post-baseline utility score is 
available. 
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 For HADS, patients will be included for each sub-scale (anxiety and depression) 
when at least 1 post-baseline sub-scale is available, and included for the total score 
when at least one post-baseline total score is available. 
Treatment assignments for the DBTP are based on the treatment received (placebo or 
evinacumab). 
4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
For each patient, demographic and baseline characteristics will be obtained from the last 
available value up to the date of the first study treatment administration (i.e. baseline definition).  
For R727-CL-1628 patients who were immediately randomized into R1500-CL-1629, 
demographic and baseline characteristic measurements will be collected from the last assessment 
obtained in R727-CL-1628. For patients randomized and not treated in R1500-CL-1629, the 
baseline value is defined as the last available measurement prior to the date of randomization.  
All baseline safety and efficacy parameters (apart from those listed below) will be presented 
along with the summary statistics in the safety and efficacy sections. 
The following variables will be summarized:  
Demographic Characteristics 
 Sex (Male, Female) 
 Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other Pacific Islander, Not Reported, Other) 
 Age in years (quantitative and qualitative variable: ≥12 to <18, ≥18 to <45, ≥45 to 
<65, ≥65 to <75, and ≥75 years; and <65, and ≥65 years) 
 Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not reported, Unknown) 
Baseline Characteristics 
 Baseline Weight (kg) 
 Baseline Height (cm) 
 Baseline Body mass index (BMI) in kg/m² (quantitative and qualitative variable 
defined as <30, ≥30) 
 Smoking Status (never, former, and current smoker) 
 Current alcohol consumption (yes/no) 
 Randomization strata as reported in the IVRS  
 Randomization strata as reported from the e-CRF 
 Current apheresis treatment (yes/no) 
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 If apheresis occurring: schedule from the e-CRF (i.e. QW, Q2W, Q3W) 
Baseline Disease Characteristics 
 Lipid parameters - quantitative variables for all efficacy parameters  
 HbA1c both quantitative variable and qualitative variable defined as: <5.7%, ≥5.7% 
to <6.5%, ≥6.5% 
 hs-CRP 
 LDL-C: <70, ≥ 70 to <100, ≥100 to <130, ≥130 to <160, ≥160 to <190, ≥190 mg/dL 
(<1.81, ≥1.81, <2.59, ≥2.59 to <3.37, ≥3.37 to <4.14, ≥4.14 to <4.91, ≥4.91 mmol/L) 
 Fasting TG: <150, ≥150 to <200, ≥200 mg/dL, and category ≥150 mg/dL for mixed 
dyslipidaemia (<1.7, ≥1.7 to <2.3, ≥2.3 mmol/L, and category ≥ 1.7 mmol/L), 
 Lp(a): <30, ≥30 to <50, ≥50 mg/dL, and category ≥30 mg/dL (<75, ≥75 to <125, and 
≥125 nmol/L, and category ≥ 75 nmol/L) 
 Mutation type (e.g. homozygous [defective/defective or negative/negative mutations], 
compound heterozygous [defective/defective, defective/negative or negative/negative 
mutations], and double heterozygous [defective/defective, defective/negative or 
negative/negative]) 
4.2. 
Medical History 
As applicable, patient medical history, pre-listed or not in the e-CRF will be dictionary coded by 
primary system organ class and preferred term using the Medical Dictionary for Regulatory 
Activities (MedDRA), specifically the MedDRA version in effect at the time of the first database 
lock. The medical history of interest collected on dedicated and pre-listed e-CRFs is: 
cardiovascular history and risk factors, patient medical allergic history, and family medical 
allergic history. Primary and secondary CVD prevention, CV risk factors categorized by high 
and very high risk, hyperlipoproteinemia disease history (including LMT therapies), and 
apheresis history (as applicable) are also defined below from pre-defined risk factors collected 
on e-CRF. 
Medical history of interest is defined as the occurrence of these diseases: 
1. Coronary heart disease (CHD)  
2. CHD risk equivalents  
3. Cardiovascular (CV) risk factors other than hypercholesterolemia (hypertension, type 2 
diabetes, type 1 diabetes, family history of premature CHD).  
4. Family history of type 2 diabetes 
5. Patient’s allergies (described using all pre-printed terms collected in the medical allergic 
history e-CRF page). 
CHD and CHD risk equivalents will be derived from the respective e-CRF as follows: 
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1. Coronary heart disease (CHD) (regardless if it is ongoing or not) is defined as the 
occurrence of at least one of the following events: 
 Acute myocardial infarction 
 Silent myocardial infarction 
 Angina (chronic stable or unstable) 
 Coronary revascularization procedure (e.g. PCI, CABG) 
2. CHD risk equivalent (regardless if it is ongoing or not) is defined as the occurrence of at 
least one of the following events: 
 Peripheral arterial disease (PAD)  
 Ischemic stroke 
 Chronic kidney disease (CKD) 
 Known history of diabetes mellitus (type 1 or 2) AND 2 or more additional risk 
factors among: 
 History of ankle-brachial index ≤ 0.90 
 History of hypertension 
 History of microalbuminuria or macroalbuminuria  
 History of proliferative diabetic retinopathy  
 Known family history of premature CHD  
Secondary CVD prevention is defined as patients with any of the following history of CVD 
(other patients will be classified as primary CVD prevention): 
 History of CHD (as defined above) 
 History of ischemic stroke 
 History of PAD with severity criteria defined as one of the following events: 
 PAD and ankle brachial index ≤ 0.90 
 Peripheral revascularization procedure (angioplasty, stenting) for PAD 
 Thrombolysis for PAD 
 Peripheral revascularization surgery (arterial bypass) for PAD 
CV Risk Factors are defined for this study as high risk and very high risk below. 
 Very high CV risk patients are defined as patients with CHD or CHD risk 
equivalents. 
 High CV risk patients are defined as all other patients. 
Hyperlipoproteinemia disease history will be assessed through diagnosis of HoFH, time from 
diagnosis to study randomization (years), method of diagnosis of HoFH (genotyping, clinical 
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diagnosis), lipid modifying therapies history reported in the “History of 
Hypercholesterolemia/Statin Use” e-CRF page.  
Apheresis history information will include the procedure frequency, and treatment technique. 
4.3. 
Prior and Concomitant Medications 
All medications (including statin, non-statin LMT, and CV) taken from the time of informed 
consent to the final study visit, including medications that were started before the study and are 
ongoing during the study, will be reported in Concomitant Medications CRF.  
All medications will be dictionary coded using the World Health Organization-Drug Dictionary 
(WHO-DD) to both an anatomic category and a therapeutic category, with the version in effect at 
the time of the first database lock.  Drug names will be matched to respective Anatomical-
Therapeutic-Chemical (ATC) classification, although a drug can be matched to more than one 
ATC classification (i.e. patients can be counted in several categories for the same medication).   
Prior medications, concomitant medications, and post-treatment medications are defined below 
and will be applied in the respective treatment periods (DBTP and OLTP). 
 Prior medications are defined as medications for which the stop date is before the date 
of the first DBTP study treatment administration. 
 Concomitant medications are defined as medications that are administered to the 
patients during the respective study treatment periods. Specifically: 
 Start date of the concomitant medication is on or after the first study treatment 
administration in respective study treatment periods (≥ DBTP Day 1 or ≥ OLTP 
Week 24); or 
 Start date of the concomitant medication is before the first study treatment 
administration in respective study treatment periods and is “Ongoing” during the 
treatment emergent period; or  
 Start date of the concomitant medication is before the first study treatment 
administration in respective study treatment periods, and the end date is on or 
after the first study treatment administration in respective study treatment periods 
(≥ DBTP Day 1 or ≥ OLTP Week 24). 
The concomitant medication treatment emergent periods are defined as:  
 For concomitant medications in the DBTP, the treatment emergent period is defined 
from the first day of double-blind study treatment administration to the last day of 
double-blind study treatment +168 days (for patients who do not continue into the 
OLTP) or to the day before the first open-label study treatment administration (for 
patients who enter the OLTP). 
 For concomitant medications in the OLTP, the treatment emergent period is defined 
from the first day of open-label study treatment administration to the last day of 
open-label study treatment +168 days. 
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Note: In the case the start date is before first study treatment administration and both 
ongoing status and stop date are missing, the medication will be assumed to be 
concomitant. 
 Post-treatment medications are defined as medications for which the start date is after 
last date of study treatment administration +169 days (≥ last study treatment +169 
days). For patients entering the OL study R1500-CL-1719, post-treatment 
medications period will be truncated at the day before study treatment administration 
in R1500-CL-1719. 
4.4. 
Prohibited Medications and Procedures During Study 
The definitions of prohibited medications and procedures are described in the section 7.8.1 of the 
protocol. They will be reviewed and identified by the study clinician and reported in protocol 
deviations.   
4.5. 
Patient Disposition 
Patient disposition will include the description of patient status at major milestone decisions in 
the study, as well as the patient analysis populations.   
For patient study status, patient double-blind treatment period milestone categories are defined 
below.  As applicable, percentages will be calculated using the number of randomized patients in 
the denominator, with two exceptions.  Specifically, the two exceptions will be for the screened 
and non-randomized categories, which will not have associated percentages shown.  
 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. 
 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 as collected on the end of 
double-blind treatment e-CRF. 
 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 prematurely discontinued study treatment during 
the double-blind period, and the reasons for discontinuation collected on the End of 
Double-blind Treatment e-CRF 
 The total number of patients who do not proceed into OLTP and complete the last 
study follow-up visit (i.e. Follow-up week 20). 
Patient OLTP milestone categories are defined below.  As applicable, percentages will be 
calculated using a denominator of the number of patients administer open-label study treatment.  
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 The total number of patients receiving open-label study treatment. 
 The total number of patients ongoing in OLTP (applicable for the first step analysis) 
 The total number of patients who completed the OLTP as collected on the end of 
open-label treatment e-CRF. 
 The total number of patients who completed the OLTP, defined as at least 44 weeks 
of study treatment exposure and week 48 visit performed. 
 The total number of patients who prematurely discontinued study treatment during 
the OLTP, and the reasons for discontinuation collected on the End of Open-label 
Treatment e-CRF. 
 The total number of patients from OLTP who complete the last study follow-up visit 
(i.e. Follow-up week 20). 
 The total number of patients choosing to proceed into R1500-CL-1719. 
The following patient populations for analyses are defined below: 
 Randomized population 
 Efficacy populations: ITT and mITT populations 
 Double-blind safety analysis set  
 Open-label safety analysis set 
 Anti-evinacumab antibody (ADA) analysis set 
 Pharmacokinetic (PK) analysis set 
 Quality-of-life analysis set 
The following patient listings will provide the details from the patient disposition table. 
 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. 
4.6. 
Study Treatment Exposure and Compliance Variables 
Study treatment exposure variables for infusions administered during the DBTP are listed below 
with associated definitions: 
 Patient duration of double-blind study treatment exposure in weeks defined as: (last 
double-blind study treatment administration date +28 – first double-blind study 
treatment administration date+1)/7. Unplanned intermittent discontinuations in study 
treatment will be addressed on a case-by-case basis, since this is expected to be a rare 
occurrence.  
 The total number of double-blind study treatment infusions by patient.  
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 The following categories will be used for treatment exposure intervals: ≥1 day and <4 
weeks, ≥4 weeks and <8 weeks, ≥8 weeks and <12 weeks, ≥12 weeks and <16 weeks, 
≥16 weeks and <20 weeks, ≥20 weeks.  
Study treatment exposure variables for infusions administered during the OLTP are listed below 
with associated definitions: 
 Patient duration of open-label study treatment exposure in weeks defined as: (last 
open-label evinacumab treatment administration date +28 – first open-label 
evinacumab treatment administration date)/7. Unplanned intermittent 
discontinuations in study treatment will be addressed on a case-by-case basis, since 
this is expected to be a rare occurrence.  
 The total number of open-label evinacumab treatment infusions by patient.  
 The following categories will be used for treatment exposure intervals: ≥1 day and 
<4 weeks, ≥4 weeks and <8 weeks, ≥8 weeks and <12 weeks, ≥12 weeks and 
<16 weeks, ≥16 weeks and <20 weeks, ≥20 weeks.  
Study treatment exposure variables combining DBTP and OLTP are listed below for all patients 
who received evinacumab in the DBTP: 
 Cumulative patient duration of evinacumab exposure in weeks defined as: 
double-blind treatment exposure plus open-label treatment exposure, regardless of 
unplanned intermittent discontinuations. 
 Cumulative total number of evinacumab treatment infusions by patient defined as: 
total number of double-blind infusions plus total number of open-label infusions.  
 The following categories will be used for cumulative patient treatment exposure 
intervals: ≥1 day and <4 weeks, ≥4 weeks and <8 weeks, ≥8 weeks and <12 weeks, 
≥12 weeks and <16 weeks, ≥16 weeks and <20 weeks, ≥20 weeks and <24 weeks, 
≥24 weeks and <28 weeks, ≥28 weeks and <32 weeks, ≥32 weeks and <36 weeks, 
≥36 weeks and <40 weeks, ≥40 weeks and <44 weeks, ≥44 weeks.  
With respect to patient treatment administration compliance, the study treatment is administered 
during the investigative site visits and therefore study compliance will be accessed by infusion 
frequency for respective treatment periods, specifically: 
 DBTP: 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 DBTP 
-1), for patients receiving at least 2 infusions. 
 OLTP: for each patient as the average number of days between 2 infusions: (last 
open-label dose date – first open-label dose date) / (number of infusions in OLTP -1), 
for patients receiving at least 2 infusions. 
All important and minor protocol deviations potentially impacting efficacy analyses, 
randomization and drug-dispensing irregularities, as well as other deviations, will be collected 
and reviewed on an ongoing basis throughout the study as described in the Protocol Deviation 
Plan (PDP).  Both monitoring collected and programmatically derived deviations are listed and 
defined in the PDP. 
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4.7. 
Efficacy Variable 
Efficacy will be assessed through the following lipid parameters: calculated LDL-C (using the 
Friedewald formula), total-C, TG, non-HDL-C (calculated by subtracting HDL-C from Total-C), 
Apo B, Apo CIII, and Lp(a). All lipid parameters will be collected over the course of the study 
and sent to a central laboratory for evaluation, including scheduled and unscheduled blood 
draws.  
All lipid values obtained during the study (scheduled or unscheduled), regardless of fasting status 
(fasting or not fasting), can be used to provide a value for the primary and secondary efficacy 
endpoints, with the following exceptions:  
1. Only fasting TG measurements will be included in the analysis. TG measurements with 
missing fasting status will be excluded from the analyses.  
2. On the day of apheresis, any lipid values collected after apheresis for the respective visit 
will be excluded from the efficacy analyses.  
All measurements will be assigned to efficacy analysis windows defined in Appendix 10.2  of 
this SAP, with the intent to provide an assessment for week 4 to week 24 time points. For all 
time points post-baseline, the value used for the analyses at a given time point (e.g. at week 24) 
is the value obtained within the corresponding efficacy analysis window. The baseline value is 
defined as the last available measurement prior to the date of the first double-blind study 
treatment administration (applicable to measurement derivations during both DBTP and OLTP). 
For patients randomized and not treated, the baseline value is defined as the last available value 
prior to the date of randomization. 
4.7.1. 
Primary Efficacy Variable (s) 
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 efficacy 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. 
4.7.2. 
Key Secondary Efficacy Variable(s) 
The key secondary efficacy variables include: 
 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) 
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 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 change in calculated LDL-C from baseline to week 24 (ITT estimand) 
 The proportion of patients who meet US apheresis eligibility criteria (see US 
[National Lipid Association] Lipid Apheresis Criteria (Goldberg 2011)) at week 24 
(ITT estimand)  
 A patient is considered as meeting US apheresis eligibility criteria if LDL-C 
≥ 300 mg/dL (7.77 mmol/L). 
 The proportion of patients with LDL-C <100 mg/dL [2.59 mmol/L] at week 24 
(ITT estimand) 
 The proportion of patients who meet EU apheresis eligibility criteria (see German 
Apheresis Working Group (Schettler 2012)) at week 24 (ITT estimand)  
 A patient with primary CVD prevention is considered as meeting German 
apheresis eligibility criteria if LDL-C > 160 mg/dL (4.2 mmol/L). 
 A patient with secondary CVD prevention is considered as meeting German 
apheresis eligibility criteria if LDL-C > 120 mg/dL (3.1 mmol/L). 
4.7.3. 
Other Secondary Efficacy Variables 
 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) 
4.8. 
Safety Variables 
Patient safety will be assessed through the collection of reported adverse events (AEs), clinical 
laboratory data, vital signs, and ECG. Unless otherwise noted, the baseline value is defined as 
the last available value before the first dose of double-blind study treatment. 
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4.8.1. 
Adverse Events Variables 
The period of safety observation starts from the time when the patient gives informed consent 
and continues into the following periods: 
 The PRE-TREATMENT period is defined from the day the ICF is signed to the day 
before the first dose of double-blind study treatment administration. 
 The double-blind treatment-emergent adverse event (TEAE) period is defined from 
the day of the first dose of double-blind study treatment administration to the day of 
the last dose of double-blind study treatment administration + 168 days (24 weeks) 
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 double-blind TEAE period will include: 
 The TREATMENT period is defined from the day of first double-blind study 
treatment administration up to the day of last double-blind study treatment 
administration + 35 days. For patients entering into the OLTP, the treatment 
period will be truncated at the day before the first dose of open-label study 
treatment administration. 
 The RESIDUAL TREATMENT period is defined from the day of last double-
blind study treatment administration + 36 days up to the day of last double-blind 
study treatment administration + 168 days (24 weeks), or up to the day before first 
dose of open label study treatment administration, whichever is earlier. 
 The open-label treatment-emergent adverse event (TEAE) 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 (24 weeks). For patients entering the 
open-label study R1500-CL-1719, the TEAE period will be truncated at the day 
before first study treatment administration in R1500-CL-1719. 
The open-label TEAE period will include: 
 The TREATMENT period is defined from the day of first open-label study 
treatment administration up to the day of last open-label study treatment 
administration + 35 days. 
 The RESIDUAL TREATMENT period is defined from the day of last open-label 
study treatment administration + 36 days up to the day of last open-label study 
treatment administration + 168 days (24 weeks). 
 The POST-TREATMENT period is defined from the day after the end of the 
respective TEAE periods to the last study visit. For patients entering the open-label 
study R1500-CL-1719, the post-treatment period will be truncated at the day before 
first study treatment administration in R1500-CL-1719. 
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4.8.1.1. 
Adverse Events and Serious Adverse Events 
Adverse events (including serious adverse events (SAE), AEs causing permanent treatment 
discontinuation, deaths, and AEs of special interest) are recorded from the time of signed 
informed consent until the end of study. All AEs diagnosed by the Investigator will be reported 
and described. 
All AEs will be dictionary coded by “lowest level term (LLT)”, “preferred term (PT)”, “high 
level term (HLT)”, “high level group term (HLGT)” and associated primary “system organ class 
(SOC)” using the version of MedDRA in effect at the time of the first database lock. 
Adverse Event Observation Period  
 Pre-treatment AEs are AEs that developed or worsened or became serious during the 
pre-treatment period. 
 Double-Blind and open-label TEAEs are AEs that developed or worsened or became 
serious during the respective TEAE periods.  
 Post-treatment AEs are AEs that developed or worsened or became serious during the 
post-treatment period. 
4.8.1.2. 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) are AEs (serious or non-serious) required to be 
monitored, documented, and managed in a pre-specified manner. AESIs will be recorded on the 
adverse event e-CRF using dedicated tick boxes, and/or identified using standard MedDRA 
queries (SMQ), company MedDRA queries (CMQ), and/or applicable laboratory assessments. 
Appendix 10.3 contains the definitions used to identify AESIs: 
The AESIs include: 
 Anaphylactic reactions (e-CRF) 
 General allergic events (SMQ) 
 Infusion reactions (e-CRF) 
 Hepatic Disorder (SMQ, lab data) 
 Pregnancy (e-CRF) 
 Symptomatic overdose with investigational medicinal product (e-CRF) 
 Neurocognitive events (CMQ) 
 Neurologic events (e-CRF) 
 New onset of diabetes (NOD) (lab data, HLT, concomitant medications) for patients 
without diabetes mellitus at baseline 
 Diabetic complication (CMQ, concomitant medications) for patients with diabetes 
mellitus at baseline 
 Pancreatitis (e-CRF) 
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 Cataracts (MedDRA HLT) 
 Immune complex diseases (SMQ) 
 Muscle events/CK elevation (MedDRA SOC, SMQ, lab data) 
4.8.1.3. 
Events Causing Death 
The observation periods for patient deaths are per the observation periods defined above.  
 Death on-treatment:  deaths occurring during the respective TEAE period 
(double-blind or open-label), 
 Death post-treatment:  deaths occurring during the post-treatment period. 
4.8.2. 
Laboratory Safety Variables 
Clinical laboratory tests will consist of blood analyses (including hematology, clinical chemistry 
and other) and urinalysis. Clinical laboratory values will be converted and analyzed in both 
international units and US conventional units, with associated normal ranges provided by the 
central laboratory. Both actual test values and “change from baseline” values (defined as the 
post-baseline value minus the baseline value) will be used in the result summaries.  Potentially 
clinically significant values (PCSV) ranges will be applied to the laboratory test values as 
applicable (see Appendix 10.4 for PCSV definitions). For those laboratory tests that do not have 
PCSV ranges, central laboratory normal ranges will be applied to identify out-of-range values.  
All laboratory test samples will be collected before study treatment administration during the 
protocol scheduled visits. 
Unless otherwise specified below, blood samples for clinical laboratories will be collected at the 
protocol scheduled visits, and visits will be assigned to the Global Analysis Windows 
(See Appendix 10.9). The laboratory parameters (excluding those considered as efficacy 
parameters) will be classified as follows: 
Hematology: 
 Red blood cells and platelets:  hemoglobin, hematocrit, erythrocytes count, red blood 
cells, platelets count, reticulocyte count, red blood indices 
 White blood cells: white blood cells, neutrophils, lymphocytes, monocytes, basophils, 
eosinophils 
Clinical chemistry: 
 Metabolism:  glucose, total protein, albumin, creatine phosphokinase 
 Electrolytes:  sodium, potassium, chloride, calcium, bicarbonate 
 Renal function:  creatinine, blood urea nitrogen (BUN), uric acid 
 Liver function:  ALT, aspartate aminotransferases (AST), alkaline phosphatase 
(ALP), total bilirubin, LDH 
Other Laboratory Tests 
High sensitivity C-reactive protein (hs-CRP), HbA1c. 
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Urinalysis 
Urinalysis will include the following parameters: color, clarity, pH, specific gravity, ketones, 
protein, glucose, blood, bilirubin, leukocyte esterase, nitrite, WBC, RBC, hyaline and other casts, 
bacteria, epithelial cells, crystals, and yeast. 
4.8.3. 
Vital Signs 
Vital signs parameters will include weight (kg), heart rate (bpm), respiration (rpm), temperature 
(C or F), systolic and diastolic blood pressure (mmHg) after resting at least five minutes. Both 
actual test values and “change from baseline” values (defined as the post-baseline value minus 
the baseline value) will be provided for protocol specified visits and visits will be assigned to the 
Global Analysis Windows (See Appendix 10.2 ). Potentially clinically significant values (PCSV) 
ranges will be applied to the vital sign parameter values as applicable (see Appendix 10.4 for 
PCSV definitions).  
4.8.4. 
12-Lead Electrocardiography (ECG) 
Electrocardiograms will be recorded in the supine position after the patient has rested for at least 
10 min. Electrocardiogram assessments will be described as normal or abnormal, and visits will 
be assigned to the Global Analysis Windows (See Appendix 10.2). 
4.8.5. 
Physical Examination Variables 
Physical examination will be conducted at the protocol scheduled visits (See Appendix 10.9 for 
schedule of event). The result is an outcome of clinically significant (Yes/No, not examined) and 
visits will be assigned to the Global Analysis Windows (See Appendix 10.2). 
4.9. 
Other Variables 
Other assessment endpoints are listed and defined below. Protocol schedule visits will be 
assigned to the Global Analysis Windows (See Appendix 10.2).   
 The change in hemoglobin A1c (HbA1c [%]) from baseline over time 
 The percent change in hs-CRP from baseline over time  
 The percent change in HDL-C from baseline over time  
 The percent change in Apo A1 from baseline over time 
 The percent change in Apo B/Apo A1 ratio from baseline over time 
 
4.10. 
Pharmacokinetic Variables 
Pharmacokinetic (PK) variables include total evinacumab concentrations, Total ANGPTL3 
concentrations, alirocumab concentrations, total PCSK9 concentrations, and statins 
concentrations (rosuvastatin, atorvastatin, simvastatin) at each time point. 
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4.11. 
Anti-Drug (evinacumab) Antibody Variables (ADA) 
Anti-drug antibody variables will include ADA status (positive or negative), titer and 
neutralizing antibody (NAb) status for analyzed samples collected at each time point. 
4.12. 
Quality-of-Life Variables 
EQ-5D 
EQ-5D is a standardized and generic instrument for measuring the health status and health 
related quality of life for clinical and economic assessment (Dolan 1997). The EQ-5D instrument 
includes 5 items corresponding to the following dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each item can take one of three responses: (1.) “no 
problem”, (2.) “some problems”, and (3.) “severe problems”. Overall health state is defined as a 
5-digit number and will be converted into a standard utility score ranging between - 0.594 
(representing severe problems) and 1 (representing no problem): the single index utility score, 
using a regression model (Dolan 1997) (Appendix 10.5). If response to one or more dimensions 
is missing, the utility score will be missing.   
Quality of life endpoints include response to each EQ-5D items at week 0 and week 24.  The 
change in utility score from baseline will also be evaluated at each post-baseline week. Protocol 
schedule visits will be assigned to the Global Analysis Windows (See Appendix 10.2).   
Hospital Anxiety and Depression Scale (HADS) 
HADS is a validated, widely used questionnaire designed to identify anxiety disorders and 
depression in patients at non-psychiatric medical institutions. Repeated administration also 
provides information about changes in a patient’s emotional state (Bjelland 2002, 
Herrmann 1997, Zigmond 1983).  The HADS questionnaire consists of 14 items that assess 
symptoms experienced in the previous week, with 7 items that are related to anxiety and 7 that 
are related to depression (See Appendix 10.6 for the details). Patients provided responses to each 
item based on a 4-point Likert scale. Each item on the questionnaire is scored from 0 (the best) to 
3 (the worst); thus, a person can score between 0 and 21 for each subscale (anxiety and 
depression). A high score is indicative of a poor state. Scores of 8 or more on the HADS-Anxiety 
or the HADS-Depression subscale are considered to be indicative of anxiety or depression, 
respectively (Bjelland 2002). 
The HADS total score is the sum of the two sub-scores, anxiety and depression. In the case a 
sub-score is missing, the HADS total score is considered missing. Similarly, in the case 
questionnaire items are missing, the applicable sub-score is considered also missing. 
Both the HADS total score and the total score change from baseline will be provided. Change in 
HADS total score from baseline over time will be derived. Protocol schedule visits will be 
assigned to the Global Analysis Windows (See Appendix 10.2).   
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5. 
STATISTICAL METHODS 
5.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group 
and overall for the study, as well as by treatment group and overall for the study within each of 
the stratification factors (IVRS/IWRS defined yes/no of apheresis treatment status and 
geographical region [Japan, Rest of World]).   
Continuous data will be summarized using the number of patients with data, mean, SD, median, 
minimum and maximum for each treatment group and for each of the strata. First quartile (Q1) 
and third quartile (Q3) will be also provided for baseline lipid parameters, HbA1c, and hs-CRP. 
Categorical and ordinal data will be summarized using the number and percentage of patients in 
each treatment group. 
Treatment group comparisons for demographic characteristics and disease characteristics will be 
provided for descriptive purposes (i.e., confirmation of the randomization process to equally 
distribute relevant patient background profiles among the two treatment groups) using the Fisher 
exact test for categorical data and the asymptotic one-way ANOVA test for Wilcoxon scores 
(Kruskal-Wallis test) for continuous data. As applicable, other safety baseline data not listed in 
Section 4.1 will be presented collectively in the descriptive statistics summary tables containing 
respective post-baseline data. 
For the open-label safety population, demographic and baseline characteristics will be 
summarized by all patients and by treatment group of the DBTP (i.e., evinacumab, placebo). 
Parameters listed in Section 4.1 will be summarized as described for the DBTP, except for 
treatment group comparison testing. 
5.2. 
Medical History  
Medical history will be descriptively summarized by treatment group and overall for the study in 
ITT population. 
All reported patient’s medical history will be presented by primary SOC and HLT.  The tables 
will be presented by SOC sorted alphabetically and decreasing patient frequency of HLT based 
on the overall incidence in the study.  In addition, all medical history of specific interest, primary 
and secondary CVD prevention including corresponding criteria, as described in Section 4.2, will 
be summarized by patient incidence and percentage. 
The number (%) of patients will be summarized by CVD prevention status (i.e. primary and 
secondary CVD prevention status).  
In addition, smoking status will be summarized in patients with primary CVD prevention status. 
For patient disease characteristics, as described in Section 4.2, continuous data will be 
summarized using the number of patients with data, mean, SD, median, Q1, Q3, minimum and 
maximum for the study and for each of the strata. Categorical and ordinal data will be 
summarized using the number and percentage of patients in the study and for each stratum.   
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5.3. 
Prior and Concomitant Medications  
All prior medications, dictionary coded by WHO-DD, will be descriptively summarized by 
treatment group and overall for the study, for patients in the double-blind safety population. 
Summaries will present patient counts (and percentages) for all prior medications, by decreasing 
frequency of the overall incidence of ATC followed by therapeutic class.  In case of equal 
frequency across anatomic or therapeutic categories, alphabetical order will be used. Patients will 
be counted once in each ATC category (anatomic or therapeutic) linked to the medication, but 
may be counted several times for the same medication. Prior LMT (statins and non-statin) and 
CV medication use will also be summarized.  
All concomitant medications during the DBTP, dictionary coded by WHO-DD, will be 
descriptively summarized by treatment group, for patients in the double-blind safety population. 
Summaries will present patient counts (and percentages) for the concomitant medication groups 
described in Section 4.3 for all concomitant medications (including statin, LMT, CV), by 
decreasing frequency of the evinacumab group incidence of ATC followed by therapeutic class.  
In case of equal frequency across anatomic or therapeutic categories, alphabetical order will be 
used. Patients will be counted once in each ATC category (anatomic or therapeutic) linked to the 
medication, hence may be counted several times for the same medication.  Additionally, 
concomitant medications pre-specified from e-CRF as statin, LMT, and CV will be summarized 
by patient counts (and percentages) for the standardized medication names. Post-treatment 
medications will be summarized as described above for all medications. 
For the OLTP, concomitant and post-treatment medications will be dictionary coded by 
WHO-DD and will be descriptively summarized as described for the DBTP. Medications will be 
summarized for all patients and by treatment group of the DBTP (i.e., evinacumab, placebo) for 
patient in the open-label safety population. Summaries will present patient counts (and 
percentages). 
5.4. 
Prohibited Medications  
Listing of prohibited medications will be provided for the patients in the safety analysis set for 
the DBTP and OLTP. 
5.5. 
Patient Disposition 
Patient disposition includes the description of patient status at major milestone decisions in the 
study, as well as the patient analysis populations. 
Patient study status for the DBTP will be summarized by treatment group and overall for the 
study (screened patients, screen failures, and non-randomized but treated patients only).  
Summaries will provide the frequency (and percentage as applicable) of patients that met the 
criteria for the variables described in Section 4.5.  Exception listings will be generated for any 
patient treated but not randomized, randomized but not treated, and treated differently than 
randomized. 
DBTP patient analysis populations will be summarized by treatment group, depicting frequencies 
(and percentages) of patients that met the criteria for each population described in Section 3.  
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For the OLTP, the patient study status and patient analysis populations will be summarized by all 
patients and by treatment group of the DBTP (i.e., evinacumab, placebo) on the open-label safety 
population for the variables described in Section 4.5.  
For both the DBTP and OLTP, the incidence of premature study treatment discontinuation 
(irrespective of the reason) and premature treatment discontinuation due to AEs will be presented 
graphically by treatment group in the respective safety analysis set using the Kaplan-Meier 
method. 
5.6. 
Extent of Study Treatment Exposure and Compliance 
The extent of study treatment exposure for the DBTP described in Section 4.6 will be assessed 
and summarized by treatment group, for patients in the safety analysis set. The extent of study 
treatment exposure for the OLTP described in Section 4.6 will be assessed and summarized for 
all patients and by treatment group of the DBTP (i.e., evinacumab, placebo) for patients in the 
open-label safety analysis set. 
5.6.1. 
Exposure to Investigational Product 
Study treatment exposure in the DBTP and OLTP will be descriptively summarized for treatment 
duration and total number of infusions as described in Section 4.6. Treatment duration and total 
number of infusions will be summarized using the number of patients with data, mean, SD, Q1, 
Q3, median, minimum and maximum.  
Additionally, evinacumab dosing exposure will be summarized cumulatively across the study, 
combining DBTP and OLTP for patients who received evinacumab in the DBTP. 
5.6.2. 
Study Treatment Compliance 
Both monitored and derived protocol deviations will be summarized for important deviations 
(counts of deviations), patients (incurring a deviation by count and percentage), and by type of 
important deviation (patient count and percentage). A patient listing of all important and minor 
protocol deviations will be provided. 
Descriptive statistics of the infusion frequency will be summarized. Further, study treatment 
infusion interruptions and incomplete infusions with reason will be summarized by patient count 
(percentage) and a patient listing will be provided for those patients with incomplete infusions. 
Cases of study treatment overdose will be reported in the AE e-CRF page and will be described 
in the adverse event analysis. 
5.7. 
Analyses of Efficacy Variables 
For statistics where international and conventional units do not impact the results (e.g. means and 
least square (LS) means for percent changes from baseline, statistical testing for both percent and 
absolute changes from baseline, rates of patients below a threshold), derivations will be 
calculated and statistical models will be run using conventional units. For other statistics (e.g. 
descriptive statistics at baseline and over time, absolute changes from baseline), derivations will 
be presented in both international and conventional units. 
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Statistical analyses for the primary efficacy endpoints, key secondary endpoints, and other 
secondary efficacy endpoints will be conducted in the DBTP as described below, and will be 
completed during the step 1 efficacy analyses (Section 7). Remaining descriptive efficacy 
analyses will be completed during step 2. The definition for baseline is applicable to derived 
variables (e.g., percent change from baseline) in both DBTP and OLTP. 
5.7.1. 
Analysis of Primary Efficacy Variable 
For the double-blind primary comparison of the evinacumab group to the placebo group, the 
percent change from baseline in calculated LDL-C at week 24 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 efficacy 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 (evinacumab versus placebo), randomization strata 
(apheresis [Yes/No] and region [Japan, Rest of World]), time point (weeks 2, 4, 8, 12, 16, 20, 
and 24), treatment-by-time point interaction, and strata-by-time point interaction, as well as the 
continuous fixed covariates of baseline calculated LDL-C value and baseline value-by-time point 
interaction.  
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 (LS) means estimates at week 24 for both treatment 
groups with their corresponding standard errors.  
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 hypothesis that will be tested is 
“H0: µ0 =µ1” versus “H1: µ0≠µ1”.  Therefore, the evinacumab group will be compared to the 
placebo group using an appropriate contrast statement tested at the 2-sided 0.05 level, with 
corresponding least square estimate of mean difference, SE and 95% confidence interval. 
Within treatment group least-square means and standard errors will be adjusted using weights 
equal to the observed proportion of patients in strata variable levels across the study population 
(i.e. “population weight”), rather than equal weights.  Population weights are considered more 
appropriate than equal coefficients due to potential imbalances observed in the study population 
between levels of the randomization stratification factors.  
Prior to performing the primary efficacy analysis, statistical analysis method assumptions will be 
checked for baseline homogeneity of calculated LDL-C levels between treatment groups, 
normality of the percent change calculated LDL-C distribution for each treatment group, and 
homogeneity of variances between treatment groups using residual plot.  
5.7.1.1. 
Sensitivity of the Primary Efficacy Analysis 
Robustness of the primary analysis statistical methods will be assessed through sensitivity 
analyses, including a different methodology for missing data (e.g., pattern mixture model to 
assess the potential violation of the missing at random assumption) and on-treatment analysis for 
more clinically relevant treatment comparisons of the percent change in calculated LDL-C from 
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baseline to week 24 (i.e., mITT patient population using calculated LDL-C values collected 
during the efficacy treatment period [on-treatment estimand]). 
Sensitivity to Stratification at Randomization 
To assess the robustness of the primary analysis to stratification mistakes made at the time of 
randomization (i.e. the stratum recorded in IVRS/IWRS differs from the actual stratum recorded 
in the e-CRF), the MMRM model will be re-run replacing the IVRS/IWRS strata with the e-CRF 
actual strata. 
Sensitivity to On-treatment Calculated LDL-C Values 
To assess the robustness of more clinically relevant between group comparisons for the analysis 
of the primary efficacy endpoint, the same statistical analysis method approach as described 
above in Sec 5.7.1 will be applied in the mITT population. The intent-to-treat estimand will be 
replaced by the on-treatment estimand, which is defined as all LDL-C values collected during the 
efficacy treatment period (Sec 3.1.2). 
Sensitivity to Non-Good Clinical Practice (GCP) Compliant Sites 
To assess the impact of non-GCP compliance sites on the primary efficacy endpoint, the primary 
efficacy analysis will be performed excluding non-GCP compliant sites.  Sites known to be 
non-GCP compliant at the time of database lock will be identified for this analysis before 
database lock.  Any additional sites determined to be non-GCP compliant post-database lock will 
be separately identified. 
Sensitivity to the Handling of Missing Data 
Sensitivity analyses will be conducted to assess the robustness of primary efficacy analysis with 
regards to the handling of missing data (Little RJ 2012).  
Visual examination 
 In order to explore the missing data pattern, post-baseline calculated LDL-C 
observations (in the ITT population) will be described according to the following 
groups:  
1. Calculated LDL-C available at week 24 (i.e. primary efficacy endpoint available), 
2. Calculated LDL-C available at week 20 but missing at week 24, 
3. Calculated LDL-C available at week 16 but missing from week 20, 
4. Calculated LDL-C available at week 12 but missing from week 16, 
5. Calculated LDL-C available at week 8 but missing from week 12, 
6. Calculated LDL-C available at week 4 but missing from week 8, 
7. Calculated LDL-C available at week 2 but missing from week 4, 
8. Calculated LDL-C missing from week 2.  
A graph of mean percent change from baseline calculated LDL-C levels ± SE at baseline, 
and at weeks 2, 4, 8, 12, 16, 20, and 24 will be provided by missing data pattern, for each 
treatment group. 
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 In the ITT population, demographic and baseline lipids will be described within the 
missing data pattern number 1 above versus the remaining missing data patterns 
above. P-values from Fisher exact test for categorical data and from asymptotic 
one-way ANOVA test for Wilcoxon scores (Kruskal-Wallis test) for continuous data, 
will be also provided, for descriptive purposes.  
Pattern mixture model (PMM) 
The MMRM model relies on the “missing-at-random” (MAR) assumption.  Because the 
possibility for a not-missing-at-random (NMAR) missingness mechanism can never be excluded, 
sensitivity analysis to explore the impact of non-ignorable missingness on the primary efficacy 
analysis will be conducted using the PMM approach as described below (see Appendix 10.8 for 
more details). 
In the PMM approach, different imputation strategies will be applied to calculated LDL-C values 
missing during the double-blind on-treatment period (i.e. within the time period from the first 
double-blind study treatment administration up to the day of last double-blind administration 
+35 days) versus calculated LDL C values missing due to treatment discontinuation after the 
on-treatment period (i.e. after the day of last double-blind administration +35 days) based on the 
following assumptions: 
 Patients within 35 days of their last double-blind study treatment administration 
would continue to show benefit from treatment similar to that observed at the 
scheduled time point.  Therefore, LDL-C values missing during the on-treatment 
period (e.g., samples obtained out-side the specified window, no blood sample 
available although visit was performed, etc.) should be considered “Missing at 
Random” and imputed based on other observed measurements in the on-treatment 
period. 
 Patients who stopped taking their study treatment no longer benefited from it after 
discontinuation, and thus tended to have LDL-C values returning to baseline.  
Therefore, LDL-C values missing after the on-treatment period should be imputed 
based on patient’s own baseline value. 
Missing data from the randomized population will be imputed 100 times to generate 100 
complete data sets, using the SAS MI procedure (using Markov Chain Monte Carlo).  The 100 
completed datasets of observed and imputed LDL-C data will be used for the sensitivity analysis 
of the primary efficacy analysis method. 
For the percent change from baseline calculated LDL-C endpoint, the 100 complete datasets of 
observed and imputed LDL-C data at week 24 will be analyzed using an ANCOVA model with 
treatment group and randomization strata as fixed effect, and the baseline LDL-C value as 
continuous covariate.  The SAS MIANALYZE procedure will be used to generate valid 
statistical inferences by combining results from the 100 analyses using Rubin’s formulae. 
5.7.1.2. 
Sub-group Analyses 
To assess the homogeneity of the treatment effect across various subgroups, 
treatment-by-subgroup factor, time point-by-subgroup factor and treatment-by time point-by 
subgroup factor interaction terms and a subgroup factor term will be added in the primary 
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MMRM model. LS mean difference versus placebo at week 24 will be provided, as well as the 
corresponding SE and 95% CI, within each subgroup. The significance level of the treatment-by-
subgroup factor interaction term at week 24 will be also provided for each factor for descriptive 
purpose. Forest plots will be provided. In order to handle imbalances between randomization 
stratification factors levels, population weights will be used as for the primary analysis model.  
The following subgroups of interest will be evaluated, assuming there are enough patients in 
each subgroup level to perform the evaluation.  For the subgroup factors that are also 
randomization stratification factors, the IVRS strata will be used. 
 The baseline apheresis status (Yes, No) per IVRS, 
 Geographical region (Japan, Rest of World) per IVRS, 
 Gender (Female, Male),  
 Age (<65, ≥65), 
 Race 
 Ethnicity 
 Baseline LDL-C (<130, ≥130 mg/dL), 
 HoFH genotyping (homozygous, compound heterozygous, and double heterozygous) 
 Receptor-negative mutation in both LDLR alleles (i.e. receptor-negative defined as a 
mutation resulting in termination codons, splice site mutations, frame shifts and large 
insertion/deletions) (Yes, No) 
Subgroup analysis for Japanese patients 
With respect to the subgroup analysis for Japan, 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 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 5.7.1). 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 ratio of the Japanese LS mean point estimate over 
the global study point estimate is ≥ 0.5. 
5.7.2. 
Analysis of Secondary Efficacy Variables 
Statistical analyses for the key secondary efficacy endpoints (defined in Section 4.7.2) and other 
secondary efficacy endpoints (described in Section 4.7.3) will be performed in the ITT 
population using the ITT estimand. 
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For descriptive summaries, percent change, and when appropriate, absolute change from baseline 
in LDL-C, Apo B, total-C, TG, non-HDL-C, Lp(a), and Apo CIII will be provided at each time 
point for each treatment group.  All measurements, scheduled or unscheduled, will be assigned to 
efficacy analysis windows defined in Appendix 10.2 in order to provide an assessment for these 
time points.  For TGs, measurements on not-fasting patients will be excluded.  The time profile 
of each parameter will be plotted by treatment group with the corresponding standard errors.  
Similar tables (with either percent change from baseline or absolute change from baseline for the 
ratio) and plots will be provided for other efficacy parameters:  Apo A-1 and ratio Apo B/Apo 
A-1.  
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 LDL-C), continuous measurements expected to have a non-normal distribution 
(example: TG), and binary measurements (example: proportion of patients with at least 30% 
reduction in LDL-C). 
5.7.2.1. 
Continuous Endpoints Anticipated to have a Normal Distribution 
Continuous secondary variables defined in Section 4.7.2 and 4.7.3 anticipated to have a normal 
distribution (i.e. lipids other than TG and Lp(a)) will be analyzed using the same MMRM model 
as described for the primary endpoint.  Specifically, the model will contain the fixed categorical 
effects of treatment group, randomization strata (as per IVRS/IWRS), planned time points up to 
week 24, strata-by-time point, and treatment-by-time point interaction, as well as, the continuous 
fixed covariates of corresponding baseline value and baseline value-by-time point interaction. 
5.7.2.2. 
Continuous Endpoints Anticipated to have a Non-normal Distribution 
Continuous secondary efficacy variables defined  in Section 4.7.2 and  4.7.3 anticipated to have a 
non-normal distribution (i.e. TG and Lp(a)) will be analyzed using the multiple imputation 
approach for handling of missing values as described  in Appendix 10.7, with data 
log-transformed before imputation process and then back transformed to create the imputed data 
sets using the TRANSFORM statement of SAS MI procedure. 
The percent change from baseline at time point of interest will be derived from observed and 
imputed lipid values at this time point. Multiple imputation will be followed by robust regression 
model (Mehrotra 2012) to compare treatment group differences, with the endpoint of interest as 
the response variable using M-estimation (using SAS ROBUSTREG procedure) with treatment 
group, randomization strata (as per IVRS/IWRS) and corresponding baseline value(s).  
Combined means estimates for both treatment groups, as well as the differences of these 
estimates, with their corresponding SEs, 95% CIs and p-value will be provided through the SAS 
MIANALYZE procedure. 
5.7.2.3. 
Binary Endpoint Variables 
Binary secondary efficacy endpoints defined in Section 4.7.2 and  4.7.3 will be analyzed using 
the multiple imputation approach for handling of missing values as described in Appendix 10.7. 
The binary endpoint at time point of interest will be derived from observed and imputed lipid 
values at this time point. Multiple imputation will be followed by stratified logistic regression, 
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(with strata defined as randomized in the IVRS/IWRS) using the strata option of the SAS logistic 
procedure. The logistic regression procedure will be used to compare treatment group 
differences, with the model containing treatment group and corresponding baseline value(s) as 
covariate, stratified by randomization strata defined as per IVRS/IWRS. Combined estimates of 
odds ratio versus placebo, 95% CI, and p-value will be obtained through the SAS MIANALYZE 
procedure. 
In the data dependent case such logistic regression is not applicable (e.g. 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. 
Treatment effects would be compared using the stratified exact conditional logistic regression 
method, specifically using the strata option of the SAS logistic procedure (with strata defined as 
randomized in the IVRS/IWRS). In case the model would not converge with stratification 
variables, an unstratified exact logistic regression will be performed. The LOCF imputation 
method will consist of using the last value obtained up to the week 24 efficacy analysis window 
to impute the missing week 24 value. 
In case of computing issues with exact logistic regression, the baseline level(s) will be entered in 
the model as a categorical variable(s) using quartiles. Exact odds ratio versus placebo, 95% CI, 
and p-value will be provided. 
5.7.2.4. 
Sensitivity Analysis of Key Secondary Endpoint Variables 
In order to assess the robustness of more clinically relevant between group comparisons for the 
analysis of the key secondary efficacy endpoint, the same statistical analysis method approach as 
described above in Sec 5.7.2 will be applied in the mITT population. The intent-to-treat estimand 
will be replaced by the on-treatment estimand, which is defined as all key secondary efficacy 
endpoints values collected during the efficacy treatment period (Sec 3.1.2). 
5.7.2.5. 
Summary of Results by Time Point 
Central laboratory values (in conventional (US) and international units), percent change from 
baseline, and/or when appropriate absolute change from baseline (in conventional and 
international units) will be summarized at protocol scheduled visits by treatment group for 
calculated LDL-C, Total-C, fasting TG, non-HDL-C, Apo B, Apo CIII, Lp(a), Apo-A1, and ratio 
Apo-B/Apo-A1. Summaries will include both the ITT and mITT populations. Further details are 
described below:  
 For lipids other than TG and Lp(a): LS mean and SE for each treatment group, 
obtained from the same MMRM models as used for endpoints above and including 
planned time points (see Section 5.7.2.1) and with raw values, changes from baseline, 
and percent change from baseline as response variable in the model as appropriate.  
 For lipids other than TG and Lp(a):  Observed data raw values, change from baseline 
(as applicable), and percent change from baseline response variables will be 
summarized by patient counts, mean and SD for each treatment group at all planned 
time points. 
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 For TG and Lp(a): mean and SE for each treatment group obtained from multiple 
imputation approach followed by the robust regression models as used for endpoints 
above and including planned time points (see Section 5.7.2.2) and with raw values or 
percent changes from baseline as response variable in the model as appropriate. 
 For TG and Lp(a): Observed data raw values and percent change from baseline 
response variables will be summarized by patient counts, mean and SD for each 
treatment group at all planned time points.  
During the OLTP, efficacy variables will be explored through descriptive statistics at each 
protocol 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 double-blind treatment period 
(i.e., evinacumab, placebo).  Formal statistical testing is not planned.  Descriptive statistics will 
include the observed values of the same parameters as described for each variable in the DBTP, 
for patients in the open-label safety analysis set.  
For patients receiving evinacumab in the DBTP, a combined summary including both the DBTP 
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.  Descriptive statistics will include the 
observed values of the same parameters as described for each variable in the DBTP, for patients 
in the double-blind safety analysis set.  
Adjustment for Multiple Comparison 
In order to handle multiple key secondary endpoints during the DBTP for the comparison of the 
evinacumab group and the placebo group, the overall type-I error will be controlled by the use of 
a hierarchical inferential approach.  Statistical significance of the primary parameter at the 0.05 
alpha level is required before drawing inferential conclusions about first key secondary 
parameter.  Inferential conclusions about successive key secondary parameters require statistical 
significance of the prior one. The hierarchy testing sequence is the order of endpoints as 
presented in Sections 4.7.1 and 4.7.2. 
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 purpose only. 
No adjustment will be made for the first step and second-step statistical analyses (Section 7), 
since the primary and key secondary endpoints testing will have been concluded at the time of 
the first step analysis. 
5.8. 
Analysis of Safety Data 
The summary of safety results will be presented separately for the DBTP and OLTP, unless 
otherwise noted. Safety summaries for the DBTP will be presented by treatment groups 
(evinacumab, placebo) containing patients from the double-blind safety analysis set. Safety 
summaries for the OLTP will be presented by all patients and by treatment group in DBTP (i.e., 
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evinacumab, placebo), for patients in the open-label safety analysis set. No formal inferential 
testing will be performed for either period. Summaries will be descriptive in nature.  
General common rules 
All safety analyses will be performed, unless otherwise specified, using the following common 
rules: 
 Safety data in patients who do not belong to the safety analysis set (i.e., exposed but 
not randomized) will be listed separately. 
 PCSV values 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 version 
dated January 2009 [Appendix 10.4]). Considering that the threshold defined in the 
PCSV list for monocytes and basophils can be below the ULN, the following PCSV 
criterion will be used for the PCSV analysis of monocytes and basophils:  
 PCSV criterion for monocytes: >0.7 Giga/L or >ULN (if ULN ≥0.7 Giga/L). 
 PCSV criterion for basophils: >0.1 Giga/L or >ULN (if ULN ≥0.1 Giga/L). 
 PCSV criteria will determine which patients had at least 1 PCSV during the 
respective TEAE periods, taking into account all evaluations including unscheduled 
or repeated evaluations. 
 The treatment-emergent PCSV denominator by treatment group for a given parameter 
will be based on the number of patients assessed for that given parameter at least once 
during the respective TEAE periods. 
 All measurements, scheduled or unscheduled, fasting or not fasting, will be assigned 
to Global Analysis Windows defined in Appendix 10.2 /Table 1 in order to provide 
an assessment for the screening visit through follow-up visit time points. 
 For quantitative safety parameters including central laboratory measurements and 
vital sign scores, descriptive statistics will be used to summarize observed values and 
change from baseline values by visit.  
 Analyses performed according to diabetes status will be done considering diabetic 
patients as patients with either type 1 or type 2 diabetes in the medical history e-CRF 
page (regardless of the ongoing status). 
5.8.1. 
Adverse Events  
In general, the primary focus of AE reporting will be on TEAEs summarized in respective TEAE 
periods, specifically the DBTP and OLTP.  Post-treatment AEs will be summarized separately.  
If an AE onset date (occurrence, worsening, or becoming serious) is incomplete, an imputation 
algorithm will be used to classify the AE as pre-treatment, treatment-emergent, or 
post-treatment.  The algorithm for imputing date of onset will be conservative and will classify 
an AE as treatment-emergent unless there is definitive information to determine pre-treatment or 
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post-treatment status.  Details on classification of AEs with missing or partial onset dates are 
provided in Section 6.3. 
Adverse event incidence tables will present the number (n) and percentage (%) of patients 
experiencing an AE by SOC and PT.  In addition, incidence tables by SOC, HLGT, HLT, and PT 
will be provided for all TEAEs, serious TEAEs, and TEAEs leading to permanent treatment 
discontinuation. Multiple occurrences of the same event in the same patient will be counted only 
once in the tables within a treatment phase (TEAE or post-treatment AE). For tables presenting 
severity of events, the worst severity will be chosen for patients with multiple instances of the 
same event. The denominator for computation of percentages is the respective safety analysis set 
within each treatment group. 
AE incidence tables will present data by SOC sorted alphabetically and PT sorted by decreasing 
frequency of the evinacumab treated group, and summarize the number (n) and percentage (%) 
of patients experiencing an AE. 
Analysis of all treatment-emergent adverse events 
The following TEAE summaries will be generated: 
 Overview of TEAEs, summarizing number (%) of patients with any 
 TEAE; 
 Serious TEAE; 
 TEAE leading to death; 
 TEAE leading to permanent treatment discontinuation. 
 All TEAEs by primary SOC, HLGT, HLT, and PT 
 All TEAEs by primary SOC and PT 
 Number (%) of patients experiencing common TEAE(s) presented by primary SOC 
and PT (PT incidence ≥ 5 % in any treatment group) 
 All TEAEs relationship (related/not related) to evinacumab 
 All TEAEs by maximum severity (i.e., mild, moderate or severe) 
 A common TEAE related to any clinically significant signal will be further 
characterized as appropriate. The characterization of the clinically significant signal 
can include Kaplan-Meier curves for time from first dose to first occurrence of 
selected TEAE, time to resolution, and event duration. Patients without any event will 
be censored at the end of the respective TEAE period. 
 
Analysis of all treatment emergent serious adverse event(s) 
 All Serious TEAEs by primary SOC, HLGT, HLT, and PT 
 All Serious TEAEs by primary SOC and PT 
 Patient listings of serious TEAEs will be provided in the report appendix. 
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 All Serious TEAEs relationship (related/not related) to evinacumab 
 A serious TEAE related to any clinically significant signal will be further 
characterized as appropriate. The characterization of the clinically significant signal 
can include Kaplan-Meier curves for time from first dose to first occurrence of 
selected TEAE, time to resolution, and event duration. Patients without any event will 
be censored at the end of the respective TEAE period. 
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
 All TEAEs leading to permanent treatment discontinuation, by primary SOC, HLGT, 
HLT, and PT 
 All TEAEs leading to permanent treatment discontinuation, by primary SOC and PT 
 Patient listings of TEAEs leading to permanent treatment discontinuation will be 
provided in the report appendix.  
 A TEAE leading to permanent treatment discontinuation and related to any clinically 
significant signal will be further characterized as appropriate. The characterization of 
the clinically significant signal can include Kaplan-Meier curves for time from first 
dose to first occurrence of selected TEAE, time to resolution, and event duration. 
Patients without any event will be censored at the end of the respective TEAE period. 
Post-treatment adverse events  
 All post-treatment AEs by primary SOC and PT 
 All post-treatment SAEs by primary SOC and PT 
Analysis of Cardiovascular events 
 TEAEs suspected of being CV events by primary SOC and PT 
 TEAEs suspected of being CV events categorized by adjudicated outcome of positive, 
negative, or in-process (as applicable) 
 Number of patients with adjudication positive by outcome categories, specifically 
CHD death, non-fatal MI, fatal and non-fatal ischemic stroke, unstable angina 
requiring hospitalization, congestive heart failure requiring hospitalization, ischemia 
driven coronary revascularization procedure   
 Patient listing of positively adjudicated TEAE CV events 
Analysis of all treatment-emergent adverse event(s) by status of negative mutation in both 
LDLR alleles (Yes, No) – receptor-negative/negative vs not receptor-negative/negative  
 All TEAEs by primary SOC and PT 
 All Serious TEAEs by primary SOC and PT 
 All TEAEs leading to permanent treatment discontinuation, by primary SOC and PT 
 All TEAEs leading to death by primary SOC and PT 
Patient Deaths 
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The following summaries of deaths will be generated. 
 Number (%) of patients who died by study period (TEAE and post-treatment) and 
reason for death;  
 TEAEs leading to death (death as an outcome on the AE CRF page, as reported by 
the Investigator) by SOC and PT. 
5.8.2. 
Analysis of Adverse Events of Special Interest  
 Treatment-emergent adverse events of special interest (AESI), as listed in 
Section 4.8.1.2, will be presented by SOC and PT.  AESI are defined by SMQ, CMQ, 
and dedicated e-CRF as described in Appendix 10.3 .   
The following variables will also be tabulated for infusion reactions TEAEs: 
 Intensity of the event (mild, moderate, severe or very severe); 
 Number of events divided by the number of study treatment administrations received 
in respective treatment periods; 
 Time from first study treatment administration (DBTP or OLTP depending on the 
analysis) to first infusion reaction; 
5.8.3. 
Clinical Laboratory Measurements  
For respective treatment period (DBTP and OLTP), clinical laboratory parameter actual values 
(quantitative) and change from baseline values will be descriptively summarized at baseline and 
each post-baseline visit (collected up to the day of last dose of study treatment +28 days) by at 
least patient number, mean, median, Q1, Q3, SD, minimum and maximum. Clinical laboratory 
parameters mean changes from baseline, with the corresponding SE, can be plotted at each visit 
in the case results warrant further investigation.  These parameters will be presented by the 
biological functions defined in Section 4.8.2.  For glucose, only fasting samples will be included 
in the summaries. 
Individual patient laboratory parameter measurements will be additionally evaluated by PCSV 
criteria (See Appendix 10.4), specifically identifying patients with at least one post-baseline 
measurement that meets the PCSV criteria within the respective TEAE periods. These laboratory 
parameters will be presented by the biological functions defined in Section 4.8.2. 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 (according to PCSV criterion/criteria)/missing 
 Abnormal according to PCSV criterion or criteria 
Patient listings of laboratory measurements that meet PCSV criteria will be provided for the 
report appendix.  For those laboratory parameters that don’t have an associated PCSV criteria, 
similar summary tables can be provided based on measurements outside the central laboratory 
normal ranges, if applicable. 
Drug-induced liver injury 
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For respective treatment period (DBTP and OLTP), an evaluation of drug-induced serious 
hepatotoxicity (eDISH) with the graph of distribution of peak values of ALT versus peak values 
of total bilirubin will also be presented using post-baseline values during respective TEAE 
periods. Note that the ALT and total bilirubin values are presented on a logarithmic scale. The 
graph will be divided into 4 quadrants with a vertical line corresponding to 3 x ULN for ALT 
and a horizontal line corresponding to 2 x ULN for total bilirubin. 
Patient listing of possible Hy’s law cases identified by treatment group (i.e., patients with any 
elevated ALT>3 x ULN, and associated with an increase in bilirubin >2 x ULN, concomitantly 
or not) with ALT, AST, ALP, total bilirubin, and if available direct and indirect bilirubin will be 
provided. 
5.8.4. 
Analysis of Vital Signs 
For respective treatment period (DBTP and OLTP), the vital sign actual values and change from 
baseline values obtained while sitting will be descriptively summarized at baseline and each 
post-baseline visit (collected up to the day of last dose of study treatment +28 days) by at least 
patient number, mean, median, Q1, Q3, SD, minimum and maximum. Vital sign mean changes 
from baseline, with the corresponding SE, can be plotted at each visit in the case results warrant 
further investigation. 
Individual patient vital sign measurements (regardless of sitting position) will be additionally 
evaluated by PCSV criteria, specifically identifying patients with at least one post-baseline 
measurement that meets the PCSV criteria within the TEAE period.  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 (according to PCSV criterion/criteria)/missing 
 Abnormal according to PCSV criterion or criteria 
Patient listings of vital sign measurements that meet PCSV criteria will be provided for the 
report appendix.   
5.8.5. 
Analysis of 12-Lead ECG 
For respective treatment period (DBTP and OLTP), ECG parameters will be described through 
an overall interpretation of ECG status (e.g. normal, abnormal [clinically significant (Yes/No)]). 
The count and percentage of patients with at least 1 abnormal post-baseline ECG during the 
respective TEAE period will be summarized according to the following baseline status 
categories: 
 Normal/missing; 
 Abnormal 
5.8.6. 
Physical Exams 
A list of patients with any clinically significant abnormality results will be generated. 
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5.9. 
Analysis of Other Variables 
The summary of results for other variables will be presented separately for the DBTP and OLTP, 
unless otherwise noted. Summaries for the DBTP will be presented by treatment groups 
(evinacumab, placebo) containing patients from the double-blind safety analysis set. Summaries 
for the OLTP will be presented by all patients and by treatment group in DBTP (i.e., 
evinacumab, placebo), for patients in the open-label safety analysis set. No formal inferential 
testing will be performed for either period. Summaries will be descriptive in nature.  
All measurements, scheduled or unscheduled, fasting or not fasting, will be assigned to Global 
Analysis Windows (Appendix 10.2) in order to provide an assessment for all post-baseline visit.   
Hs-CRP, HbA1c, HDL-C, Apo A1, and Apo B/Apo A1 ratio parameters will be summarized for 
the number of patients with data, mean, SD, median, minimum, maximum, Q1 and Q3 by 
analysis visit during the treatment period. The medians (with Q1-Q3) will be plotted for hs-CRP, 
and means (+/- SE) for HbA1c, HDL-C, Apo A1, and Apo B/Apo A1 ratio. Applying the PCSV 
criteria at any time during the TEAE period, the number of patients (and percentages) meeting 
the criteria will be summarized.  
Correlations between HoFH genotype status and lipid parameters will be explored (e.g., plot of 
mean percent change from baseline ±SE in lipids over time by genotype). 
5.10. 
Analysis of Pharmacokinetic Variables 
Descriptive statistics of concentrations of total evinacumab, total ANGPTL3, total alirocumab 
and total PCSK9 will be presented. Mean concentrations of each analyte will be tabulated by 
visit and treatment group, with concentrations below the LLOQ set to zero. 
Plots of the mean concentrations (linear and log scales) will be presented by nominal sampling 
time. Plots of the individual concentrations (linear and log scales) will be presented by actual 
sampling time. In the linear-scaled plots, concentrations below the LLOQ will be set to zero; in 
the log-scaled plots, concentrations below the LLOQ will be imputed as LLOQ/2. 
Descriptive statistics will be provided for concentrations of statins at each sampling time. The 
ratio of concentration at week 24 over baseline will be presented for individual patient, when 
available.  
Descriptive comparison of concentrations of evinacumab and total ANGPTL3 between 
Caucasian patients and Japanese patients may be performed, if sufficient data are collected. 
When appropriate, relationship between concentrations of evinacumab and LDL-C or other 
biomarkers may be evaluated descriptively.  
5.11. 
Analysis of Anti-evinacumab Antibody Variables 
The ADA variables described in Section 4.11 will be summarized using descriptive statistics by 
dose/cohort group in the ADA analysis set. Listings of ADA positivity and titers presented by 
patient, time point, and study treatment received will be provided. Prevalence of 
treatment-emergent ADA will be assessed as absolute occurrence (N) and percent of patients 
(%), grouped by study treatment received. 
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The influence of ADA on drug concentrations will be evaluated. Assessment of impact of ADA 
on safety and efficacy may be provided.  
Anti-drug antibody status (negative or positive) and titer over the study duration may be 
classified as follows:  
 Pre-existing immunoreactivity, defined as a positive ADA assay response at baseline, 
with all post-dose ADA results negative, or a positive assay response at baseline, with 
all post-dose ADA assay responses less than 9-fold over baseline titer levels. 
 Treatment emergent - defined as any post-dose ADA positive response when baseline 
results are negative or missing. Treatment emergent ADA responses will be further 
classified into persistent, indeterminate and transient. 
 Persistent - A positive result in the ADA assay detected in at least 2 consecutive 
post baseline samples separated by at least a 16-week post baseline period [based 
on nominal sampling time], with no ADA-negative results in-between, regardless 
of any missing samples 
 Indeterminate - A positive result in the ADA assay at the last collection time point 
analyzed only, regardless of any missing samples 
 Transient - Not persistent or indeterminate regardless of any missing samples 
 Treatment boosted - defined as any post-dose ADA response that is at least 9-fold 
over baseline titer levels when baseline results are positive 
A second ad-hoc analysis set may also be generated that employs definitions as outlined 
in the Shankar et. al publication. Two sets of results will be presented in the Clinical 
Pharmacology report for the study, one using our definitions as provided in the SAP 
(Primary results) and one using the Shankar et. al definitions (Secondary or ad-hoc 
results). The primary results will be reported in the CSR. 
 Titer category for subjects, by maximum ADA titer value: 
 Low (titer <1,000) 
 Moderate (1,000≤ titer ≤10,000) 
 High (titer >10,000) 
 NAb status (positive or negative) 
 Subgroup analysis of ADA data may be performed for Japanese patients when 
appropriate. 
5.12. 
Analysis of Quality-of-life Variables 
The summary of results for quality-of-life variables will be presented separately for the DBTP 
and OLTP, unless otherwise noted. Summaries for the DBTP will be presented by treatment 
groups (evinacumab, placebo) containing patients from the quality-of-life analysis set. 
Summaries for the OLTP will be presented by all patients and by treatment group in DBTP (i.e., 
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evinacumab, placebo), for patients in the quality-of-life analysis set. No formal inferential testing 
will be performed for either period. Summaries will be descriptive in nature.  
The baseline value is defined as the last available measurement prior to the date of the first 
double-blind study treatment administration (applicable to measurement derivations during both 
DBTP and OLTP). 
EQ-5D 
Individual EQ-5D items 
Responses for each one of the 5 EQ-5D items will be summarized by patient frequency and 
percentage at baseline and each post-baseline visit. Responses are defined by 4 levels, 
specifically reporting level 1 (no problems), level 2 (some problems) and level 3 (extreme 
problems), and level 4 (not answered).    
EQ-5D utility score 
The observed value and the change from baseline of the utility score will be summarized using 
mean, median, Q1, Q3, SD, minimum and maximum for each post-baseline visit. Cumulative 
distribution functions for the change in utility score from baseline will be displayed at 
post-baseline visits.  
HADS 
The analysis of data from HADS instrument will be performed on the HADS quality-of-life 
analysis set.  
The total score is the sum of the two sub-scores of anxiety and depression. Descriptive statistics 
(mean, median, Q1, Q3, SD, minimum and maximum) of the observed total scores and the 
change from baseline observed total scores will be summarized by visit.   
6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis.  
6.1. 
Definition of Baseline for Efficacy/Safety Variables 
Unless otherwise specified, the baseline assessment is programmatically as the last available 
measurement prior to the date of the first double-blind study treatment administration. For 
patients randomized and not treated, the baseline value is defined as the last available value prior 
to the date of randomization. 
6.2. 
Data Handling Convention for Efficacy Variables  
Rules for handling missing data for primary and secondary efficacy variables are described in 
Section 5.7.1 and Section 5.7.2. 
6.3. 
Data Handling Convention for Missing Data 
Missing data will not be imputed in listings.  This section includes the methods for missing data 
imputation for some summary analyses, if necessary. 
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Date and Time of First/Last Study Treatment 
Since the study drug is administered at the site, the date and time of study drug administration 
are filled in e-CRF. No missing data is expected. Date of first/last administration is the first/last 
start date of study drug filled in e-CRF. 
Adverse Event 
If the intensity of a TEAE is missing, it will be classified as “severe” in the frequency tables by 
intensity of TEAEs. If the assessment of relationship of a TEAE to the investigational product is 
missing, it will be classified as related to the investigational product. 
When the partial AE date/time information does not indicate that the AE started prior to study 
treatment or after the TEAE period, the AE will be classified as treatment-emergent. 
Medication/Procedure 
No imputation of medication/procedure start/end dates or times will be performed.  If a 
medication date or time is missing or partially missing and it cannot be determined whether it 
was taken prior or concomitantly or stopped prior to the first study treatment administration, it 
will be considered as concomitant medication/procedure. 
Potentially Clinically Significant Value (PCSV) 
If a patient has a missing baseline value, this patient will be grouped in the category 
“normal/missing at baseline.” 
For PCSVs with 2 conditions, one based on a change from baseline value and the other on a 
threshold value or a normal range, with the first condition being missing, the PCSV will be based 
only on the second condition. 
For a PCSV defined on a threshold and/or a normal range, this PCSV will be derived using this 
threshold if the normal range is missing; e.g., for eosinophils the PCSV is >0.5 giga/L or >ULN 
if ULN ≥0.5 giga/L.  When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSVs. 
6.4. 
Visit Windows 
Visit windows will be programmatically imposed on those efficacy and safety measures 
repeatedly collected over the course of the study. These visit windows are derived from the 
number of days in study, specifically assigning day ranges to represent the study assessment 
schedule provided in the protocol.  Data analyzed by time point (including efficacy, laboratory 
safety data, vital signs, ECG, quality of life, drug concentration and ADA) will be summarized 
using the analysis windows given in Appendix 10.2 (i.e. efficacy analysis windows for efficacy 
and global analysis windows for safety). These analysis windows will be applicable for all 
analyses, and they are defined to provide more homogeneous data for time point-specific 
analyses. If multiple valid values of a variable exist within an analysis window, the nearest from 
the targeted study day will be selected for analysis, unless otherwise specified. If the difference 
is a tie, the value after the targeted study day will be used. If multiple valid values of a variable 
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exist within a same day, then the first value of the day will be selected when time is available, 
else the scheduled visit will be selected. 
6.5. 
Unscheduled Assessments 
For efficacy, safety laboratory data, vital signs, ECG, ED-5D, and HADS, unscheduled visit 
measurements may be used to provide a measurement for a time point, including baseline, if 
appropriate according to their definitions. The measurements may also be used to determine 
abnormal values, AESIs, and PCSVs. 
6.6. 
Pooling of Centers for Statistical Analyses 
The randomization scheme was not stratified by center because the primary efficacy variable is 
centrally assessed and expected not to be influenced by the center when other factors such as diet 
are already controlled. Therefore, the center will not be added as factor in the primary analysis 
model. 
6.7. 
Statistical Technical Issues 
Not Applicable. 
7. 
TIMING OF STATISTICAL ANALYSES 
Efficacy and safety analyses for this study will be performed in two steps, specifically for patient 
data collected up to the time the last patient completes efficacy assessments at week 24 (step 1 
consisting of the DBTP) and at the end of the study (step 2 for the OLTP). No formal interim 
analysis for efficacy is planned since analyses of primary and key secondary efficacy endpoints 
will be final at the time of first step analysis. Therefore, no multiplicity adjustment for multiple 
analyses is needed (see Section 5.7.2.5 ). The timing for patient data to be reported is defined 
below for each step: 
 First step: efficacy analyses up to week 24 and interim safety analysis  
 This analysis will be conducted on all randomized patients when all patients will 
have all their lipid data up to week 24 efficacy analysis window collected and 
validated. 
 The efficacy analyses will be performed up to week 24 visit. Analyses of 
endpoints up to week 24 visit will correspond to the final analyses for these 
endpoints. Analysis of lipid parameters beyond week 24 visit will be descriptive.  
 The safety analyses will be performed on all safety data (double-blind and 
open-label) collected up to the common cut-off date. For this analysis, the 
common cut-off date is defined as date of the last week 24 visit. 
 Second-step: final analysis 
 This analysis will be conducted at the end of the study and will consist of the final 
analysis of efficacy data at time points beyond the week 24 visit and final safety 
analysis.  
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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. The results of the first 
analysis will not be used to change the conduct of the ongoing study in any aspect.  
Analyses methods and conventions described in the other sections of this SAP will be applied for 
all analyses as applicable. The following additional rules will apply for analyses performed at 
first step analysis: 
 Any lipid assessments within efficacy analysis windows up to the week 24 visit will 
be taken into account (may include few unscheduled lipid data soon after the cut-off 
date).  
 Patients without end of treatment visit performed at the time of the cut-off date will 
be considered as ongoing and exposed up to the cut-off date. Therefore: 
 Patients who did not complete the respective treatment period nor prematurely 
discontinued the study treatment at cut-off date will be analyzed as “ongoing” in 
the disposition summary. 
 Their TEAE period and treatment period will end at the cut-off date. 
 Their treatment duration will be derived by considering date of cut-off as last 
administration date.  
 Analyses of number of administrations, and mean administration frequency will be 
performed up to the last administration reported in the e-CRF up to the cut-off date.  
 AEs occurring, worsening or becoming serious after the cut-off date will not be 
included in the analyses. However, any available outcome before database lock, 
regardless of timing in relation to the cut-off date, of an adverse event starting prior to 
the cut-off date will be taken into account. Medications, treatment 
discontinuations/completions and deaths occurring after the cut-off date will not be 
included in the analyses.  
 Post-treatment period, and post-study period are not applicable for ongoing patients. 
Analyses of post-treatment AEs, post-study deaths and post-treatment medications 
will be performed for patients who either completed or prematurely discontinued the 
treatment before or at the cut-off date. 
 Analysis of status at last study contact and proportion of patients with insufficient 
follow-up will be provided for patients who either completed or prematurely 
discontinued the treatment before or at the cut-off date. 
8. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or higher. 
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9. 
REFERENCES 
1. ICH. (1996, July 30). ICH Harmonized tripartite guideline: Structure and content of 
clinical study reports (E3). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
2. ICH. (1997, July 17). ICH Harmonized tripartite guideline: General considerations for 
clinical trials (E8). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
3. ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for 
clinical trials (E9). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
4. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd, Criqui M, et al. 
Markers of inflammation and cardiovascular disease: application to clinical and public 
health practice: A statement for healthcare professionals from the Centers for Disease 
Control and Prevention and the American Heart Association. Circulation. 2003 Jan 
28;107(3):499-511. 
5. Zigmond AS, Snaith RP: The Hospital Anxiety and Depression Scale. Acta Psychiatrica 
Scandinavica 1983, 67:361-70. 
6. Bjelland I, Dahl AA, Haug TT et al. Review: The validity of the hospital anxiety and 
depression scale, an updated literature review. J Psychosom Res 2002;52:69-77. 
7. Herrmann C.  International Experiences with the Hospital Anxiety and Depression Scale 
– A Review of Validation Data and Clinical Results; Journal of Psychosomatic Research, 
Vol. 42, No. 1, pp 17-41, 1997 
8. Dolan P. Modeling valuations for EuroQol health states. Med Care. 1997 Nov; 
35(11):1095-108. 
9. Little RJ, D'Agostino R, Cohen ML, Dickersin K, Emerson SS, Farrar JT, et al. The 
prevention and treatment of missing data in clinical trials. N Engl J Med. 2012 Oct 
4;367(14):1355-60. doi: 10.1056/NEJMsr1203730. 
10. Mehrotra DV, Li X, Liu J, Lu K. Analysis of longitudinal clinical trials with missing data 
using multiple imputation in conjunction with robust regression. Biometrics. 2012 
Dec;68(4):1250-9. doi: 10.1111/j.1541-0420.2012.01780.x. 
11. 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 
12. Shankar G, Arkin S, Cocea L, et al. Assessment and Reporting of the Clinical 
Immunogenicity of Therapeutic Proteins and Peptides—Harmonized Terminology and 
Tactical Recommendations. AAPS J. 2014;16(4): 658-673. doi: 10.1208/s12248-014-
9599-2 
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10. 
APPENDIX 
10.1. 
Summary of Statistical Analyses 
Primary Efficacy Analysis: 
Endpoint 
Analysis 
Populations 
Estimand 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Primary Endpoint 
Percent 
change 
from 
baseline in 
calculated 
LDL-C at 
week 24 
ITT 
ITT estimand: 
The calculated 
LDL-C at 
week 24 will 
be the LDL-C 
value obtained 
within the 
week 24 
efficacy 
analysis 
window, 
regardless of 
adherence to 
treatment and 
subsequent 
therapies. 
MMRM 
Yes 
Yes 
 
1. mITT 
2. PMM (randomized 
population) 
3. MMRM using strata 
based on observed 
data 
10.2. 
Windows for Analysis Time Points 
Below are the definitions for the visit windows programmatically imposed on measures 
repeatedly collected over the course of the study.  These visit windows reflect the study schedule 
of assessments as described in the protocol.  
The visit windows are constructed using ranges applied to the number of days in study (study 
days) when the measure is collected. Below are the relevant definitions for the analysis visit 
windows:  
1. Study day is defined as the number of days since the first study treatment administration 
+1. The first study treatment occurs on  
2. Study Day 1. 
3. Open-label study day is defined as the number of days since the first open-label study 
treatment administration+1 
4. Since the protocol specifies that measurements be collected before study treatment is 
administered on a given day, it is appropriate that baseline include Day 1. 
5. For randomized but not treated patients, Day 1 is the day of randomization.   
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Table 1: 
Global Analysis Windows 
Visit label 
Targeted Study 
Day 
Targeted Open-Label Study 
Day 
Analysis Window in Study Day 
Screening 
< Day 1 
N/A 
Measurement obtained prior to first 
study treatment, and not defined as 
baseline visit 
Baseline  
1 
N/A 
Measurement obtained closest to first 
study treatment, while remaining prior to 
first study treatment 
Week 2 
15 
N/A 
2 to 21 
Week 4 
29 
N/A 
22 to 42 
Week 8 
57 
N/A 
43 to 70 
Week 12 
85 
N/A 
71 to 98 
Week 16 
113 
N/A 
99 to 126 
Week 20 
141 
N/A 
127 to 154 
Week 24 
169 
Day 1 
155 to 182 for patients not entering 
OLTP or 155 to first OL treatment day 
for patients entering OLTP  
Week 28 
197 
29 
first OL treatment day+1 to 210 
Week 32 
225 
57 
211 to 238 
Week 36 
253 
85 
239 to 266 
Week 40 
281 
113 
267 to 294 
Week 44 
309 
141 
295 to 322 
Week 48 
337 
169 
323 to 350 
FU – W4   
For patients 
prematurely 
discontinued trt: last 
study trt to 28 days 
after last study trt 
For patients completed 
OLTP: 365 
 For patients prematurely 
discontinued trt: last study trt to 28 
days after last study trt 
For patients completed OLTP: 197 
For patients prematurely discontinued 
trt: Last study trt day +1 to 56 days after 
last study trt 
For patients completed OLTP:351 to 
392 
 FU – W12 
 For patients 
prematurely 
discontinued trt: last 
study trt to 84 days 
after last study trt 
For patients completed 
OLTP: 421 
 For patients prematurely 
discontinued trt: last study trt to 84 
days after last study trt 
For patients completed OLTP: 253 
For patients prematurely discontinued 
trt: 57 days after last study trt to 112 
days after last study trt 
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Visit label 
Targeted Study 
Day 
Targeted Open-Label Study 
Day 
Analysis Window in Study Day 
FU – W20 
For patients 
prematurely 
discontinued trt: last 
study trt to 140 days 
after last study trt 
For patients completed 
OLTP: 477 
 For patients prematurely 
discontinued trt: last study trt to 140 
days after last study trt 
For patients completed OLTP: 309 
For patients prematurely discontinued 
trt: 113 days after last study trt to 168 
days after last study trt 
For patients completed OLTP:449 to 
504 
FU > W20 
N/A 
N/A 
For patients prematurely discontinued 
trt: >168 days after last study trt  
For patients completed OLTP:>504 
Study days are calculated from the day of first double-blind IMP administration, the day of first double-blind IMP administration 
being Day 1. For randomized but not treated patients, Day 1 is the day of randomization.  
 
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Table 2: 
Efficacy Analysis Windows – Statistical Testing 
Visit Label 
Targeted study day 
Analysis window in study days 
Screening 
< Day 1 
Measurement obtained prior to first study treatment, and 
not defined as baseline visit 
Baseline  
1 
Measurement obtained closest to first study treatment, 
while remaining prior to first study treatment 
Week 2 
15 
2 to 21 
Week 4 
29 
22 to 42 
Week 8 
57 
43 to 70 
Week 12 
85 
71 to 98 
Week 16 
113 
99 to 126 
Week 20 
141 
127 to 154 
Week 24 
169 
155 to 182 for patients not entering OLTP or 155 to first 
OL treatment day for patients entering OLTP 
10.3. 
List of AESIs with Data Sources and Definitions of SMQ/CMQ  
Table 3: 
Summary of AESIs and the Methods of Data Collections and Derivations 
AESI 
Using an e-CRF specific tick 
box on AE page 
Using Standard MedDRA Query 
(SMQ)/company MedDRA Query 
(CMQ) or lab data 
Anaphylactic reactions   
 
Yes 
No 
General allergic events  
No 
SMQ “hypersensitivity” (broad and 
narrow) excluding the following 
preferred terms linked to local injection 
site reactions (“infusion site 
dermatitis”, “infusion site 
hypersensitivity”, “infusion site rash”, 
“infusion site urticaria”, “injection site 
dermatitis”, “injection site 
hypersensitivity”, “injection site rash”, 
“injection site urticaria”, “injection site 
vasculitis”) plus “idiopathic 
angioedema” 
Infusion reactions  
Yes 
No 
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Date: July 12, 2019 
 
 
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Hepatic Disorders 
 
No 
 SMQ Drug-related hepatic disorder 
 Potentially clinically significant 
value (PCSV) in Appendix 10.4 
Hy’s law eDISH plot, 
 
Pregnancy 
Yes 
No 
Symptomatic overdose with 
investigational medicinal product 
Yes 
No 
Neurocognitive events 
No 
 CMQ for neurocognitive events as 
defined based on Regulatory 
Agency request for another lipid 
lowering program (See Table 4 in 
Appendix 10.3 for the list of terms) 
Neurologic events  
Yes 
No 
                                        VV-RIM-00083002-1.0 Approved - 16 Jul 2019 GMT-5:00


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Protocol: R1500-CL-1629 Amendment 3B 
Statistical Analysis Plan 
 
Date: July 12, 2019 
 
 
CONFIDENTIAL  
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New onset of diabetes (NOD) for 
patients without diabetes mellitus at 
baseline 
No 
No medical history of diabetes as 
specified in Cardiovascular History 
and Cardiovascular Risk Factors and 
Medical History CRF pages AND one 
of the following: 
Lab criteria: 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. 
OR 
Lab criteria: 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. 
OR 
HLT Diabetes mellitus (including 
subtypes) 
OR 
Initiation of any new concomitant 
medication for hyperglycemia during 
the treatment period 
Diabetic complication for patients 
No 
For patients with medical history of 
diabetes as specified in Cardiovascular 
History and Cardiovascular Risk 
                                        VV-RIM-00083002-1.0 Approved - 16 Jul 2019 GMT-5:00


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Protocol: R1500-CL-1629 Amendment 3B 
Statistical Analysis Plan 
 
Date: July 12, 2019 
 
 
CONFIDENTIAL  
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with diabetes mellitus at baseline 
Factors and Medical History CRF 
pages, each of the following criteria 
will be considered, respectively: 
 
Diabetes mellitus or diabetic 
complication TEAEs using 
HLGT Diabetic complications, 
HLT Diabetes mellitus (incl 
subtypes), and PTs Blood 
glucose increases, 
Glycosylated haemoglobin 
increased, Hyperglycaemia, 
Hyperglycaemic 
unconsciousness, and 
Hyperglycaemic seizure 
 
Changes in diabetic 
medication dosage 
(specifically increases in 
dosage) or initiation of 
additional diabetic medication 
 
Pancreatitis 
Yes 
No 
Cataracts 
No 
HLT Cataract conditions 
Immune complex diseases 
No 
SMQ (Narrow) Systemic lupus 
erythematous  
SMQ (Narrow) Vasculitis 
SMQ (Narrow) Guillain-Barre 
syndrome 
Muscle events/CK elevation 
No 
 
Lab data analyses (e.g. PCSV) 
 
All preferred terms under system 
organ class (SOC): 
Musculoskeletal and connective 
tissue disorders  
 
Rhabdomyolysis/myopathy 
(Narrow SMQ) 
 
 
                                        VV-RIM-00083002-1.0 Approved - 16 Jul 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R1500-CL-1629 Amendment 3B 
Statistical Analysis Plan 
 
Date: July 12, 2019 
 
 
CONFIDENTIAL  
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Table 4: 
CMQ “Neurocognitive disorders – FDA’s recommendation” 
MedDRA level 
MedDRA Term Label 
PTCD 
Amnesia 
PTCD 
Amnestic disorder 
PTCD 
Anterograde Amnesia 
PTCD 
Behavioural and Psychiatric Symptoms of Dementia 
PTCD 
Change in sustained attention 
LLTCD 
Cognitive Deterioration 
PTCD 
Cognitive Disorder 
LLTCD 
Confusion 
LLTCD 
Confusion Aggravated 
PTCD 
Confusional State 
PTCD 
Delirium 
PTCD 
Dementia 
PTCD 
Dementia Alzheimer's type 
LLTCD 
Dementia Nos 
LLTCD 
Dementia Nos Aggravated 
LLTCD 
Dementia of the Alzheimer's type NOS 
PTCD 
Dementia with Lewy Bodies 
PTCD 
Disorientation 
PTCD 
Disturbance in attention 
PTCD 
Executive dysfunction 
PTCD 
Frontotemporal Dementia 
LLTCD 
Global Amnesia 
PTCD 
Illogical Thinking 
PTCD 
Impaired reasoning 
PTCD 
Incoherent 
PTCD 
Judgement impaired 
PTCD 
Memory Impairment 
PTCD 
Mental Impairment 
LLTCD 
Mental Impairment Nos 
LLTCD 
Mental State Abnormal Aggravated 
PTCD 
Mental Status Changes 
PTCD 
Mini Mental Status Examination Abnormal 
PTCD 
Presenile Dementia 
PTCD 
Retrograde Amnesia 
PTCD 
Senile Dementia 
LLTCD 
Senile Dementia Nos 
LLTCD 
Short-term Memory Loss 
PTCD 
Thinking Abnormal 
LLTCD 
Thinking Slowed 
PTCD 
Transient Global Amnesia 
PTCD 
Vascular Dementia 
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Statistical Analysis Plan 
 
Date: July 12, 2019 
 
 
CONFIDENTIAL  
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10.4. 
Criteria for Potentially Clinically Significant Values (PCSV) 
Parameter 
PCSV 
Clinical chemistry 
ALT 
By distribution analysis: 
 
>2 ULN and baseline ≤ 2 ULN 
>3 ULN and baseline ≤ 3 ULN 
>5 ULN and baseline ≤ 5 ULN 
>10 ULN and baseline ≤ 10 ULN 
>20 ULN and baseline ≤ 20 ULN 
 
AST 
By distribution analysis: 
 
>2 ULN and baseline ≤ 2 ULN 
>3 ULN and baseline ≤ 3 ULN 
>5 ULN and baseline ≤ 5 ULN 
>10 ULN and baseline ≤ 10 ULN 
>20 ULN and baseline ≤ 20 ULN  
Alkaline Phosphatase 
> 1.5 ULN and baseline ≤ 1.5 ULN 
Total Bilirubin 
> 1.5 ULN and baseline ≤ 1.5 ULN 
> 2 ULN and baseline ≤ 2 ULN 
Conjugated bilirubin 
> 35% total bilirubin (when total bilirubin >1.5 ULN) 
ALT and Total Bilirubin 
ALT > 3 ULN and Total Bilirubin > 2 ULN and baseline ALT≤3 ULN or Total 
bilirubin ≤ 2 ULN 
CPK 
> 3 ULN and ≤ 5 ULN and baseline ≤ 3ULN 
>5 ULN and ≤  10 ULN and baseline ≤ 5 ULN 
>10 ULN and baseline ≤ 10 ULN 
Creatinine 
 150 mol/L (adults) 
 30% from baseline 
 100% from baseline 
CLcr (mL/min) 
(Estimated creatinine 
clearance based on the 
Cokcroft-Gault equation) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
eGFR (mL/min/1.73m2) 
(Estimate of GFR based on 
an MDRD equation)  
 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
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Parameter 
PCSV 
Uric Acid 
   Hyperuricemia: 
   Hypouricemia: 
 
>408 µmol/L 
<120 µmol/L 
Blood Urea Nitrogen 
≥17 mmol/L 
Chloride 
<80 mmol/L 
>115 mmol/L 
Sodium 
129 mmol/L 
 160 mmol/L 
Potassium 
< 3  mmol/L 
 5.5 mmol/L 
Glucose 
   Hypoglycaemia 
   Hyperglycaemia 
 
 3.9 mmol/L and < LLN 
  7 mmol/L (fasted);  11.1 mmol/L (unfasted) 
HbA1c 
>8% 
Albumin 
≤25 g/L 
Hs-CRP 
> 2 ULN or 
 >10 mg/L, if ULN not provided 
Hematology 
WBC 
< 3.0 Giga/L (3000/ mm3) (Non-Black) 
< 2.0 Giga/L (2000/ mm3) (Black) 
≥16.0 Giga/L (16000/ mm3) 
 
Lymphocytes 
>4.0 Giga/L 
Neutrophils 
< 1.5 Giga/L (1500/ mm3) (Non-Black) 
< 1.0 Giga/L (1000/ mm3) (Black) 
Monocytes 
>0.7 Giga/L 
Eosinophils 
> 0.5 Giga/L (500/ mm3) 
or > ULN if ULN  0.5 Giga/L 
Hemoglobin 
≤115 g/L (Male); ≤95 g/L (Female) 
≥185 g/L (Male); ≥165 g/L (Female) 
Decrease from Baseline ≥15 g/L 
Decrease from Baseline ≥20 g/L 
 
Hematocrit 
≤0.37 v/v (Male) ; ≤0.32 v/v (Female) 
≥0.55 v/v (Male) ; ≥0.5 v/v (Female) 
RBC 
≥6 Tera/L 
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Parameter 
PCSV 
Platelets 
< 100 Giga/L (100 000/mm3) 
≥700 Giga/L (700000/mm3) 
Urinalysis 
pH 
≤4.6 
≥8 
Vital signs 
HR 
 50 bpm and decrease from baseline  20 bpm 
 120 bpm and increase from baseline  20 bpm 
SBP 
 95 mmHg and decrease from baseline  20 mmHg 
 160 mmHg and increase from baseline  20 mmHg 
DBP 
Young and elderly patients 
 45 mmHg and decrease from baseline  10 mmHg 
 110 mmHg and increase from baseline  10 mmHg 
Orthostatic Hypotension 
SBP St – Su  - 20 mmHg 
DBP St – Su  - 10 mmHg 
Weight 
5% increase versus baseline 
5% decrease versus baseline 
ECG parameters 
HR 
 50 bpm and decrease from baseline  20 bpm 
 120 bpm and increase from baseline  20 bpm 
PR 
≥220 ms and increase from baseline ≥20 ms 
QRS 
 120 ms 
QTc 
Borderline 
Prolonged* 
Additional 
Absolute values (ms) 
Borderline  
      431-450 ms (Male) 
      451-470 ms (Female) 
Prolonged* 
       > 450 ms (Male)        
       > 470 ms (Female) 
       QTc   ≥500 ms            
 
Increase versus baseline (Males and Females) 
Borderline 
 30-60 ms 
Prolonged * 
 > 60 ms 
 
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Statistical Analysis Plan 
 
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10.5. 
EQ-5D Utility Score Algorithm 
 
EQ-5D Utility Score Algorithm 
Algorithm: UK based 
/*=========================================================================*/
; 
/*  Aim                      : Derive the EQ5-D index (utility)            
*/; 
/*  Source for the algorithm : scoring EQ-5D health states (Rosalind Rabin 
*/; 
/*            (cf. G:\_HE\PRO questionnaire\EQ5D\scoring\YorkTariffx.doc)  
*/; 
/*  Note                     : UK based population (Dolan, 1997)           
*/; 
/*=========================================================================*/
; 
Answer to questions in numeric format, from 1 (no problem) to 3 (severe problem); Q1 
(mobility), Q2 (self-care), Q3 (usual activities), Q4 (pain/discomfort), Q5 (anxiety/depression) 
Result of the algorithm: Utility (EQ-5D utility score). 
If at least one of the answer to questions is missing then the utility score is missing. 
Start with Utility =1 and apply the following sequential algorithm. 
 
**********Mobility********* 
if Q1=2 then Utility = Utility - 0.069 
if Q1=3 then Utility = Utility - 0.314 
 
********Self-care********** 
if Q2=2 then Utility = Utility - 0.104 
if Q2=3 then Utility = Utility - 0.214 
 
******Usual activities***** 
if Q3=2 then Utility = Utility - 0.036 
if Q3=3 then Utility = Utility - 0.094 
 
*****Pain/discomfort****** 
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Protocol: R1500-CL-1629 Amendment 3B 
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Date: July 12, 2019 
 
 
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if Q4=2 then Utility = Utility - 0.123 
if Q4=3 then Utility = Utility - 0.386 
 
*****Anxiety/depression***** 
if Q5=2 then Utility = Utility - 0.071 
if Q5=3 then Utility = Utility - 0.236 
 
if (Q1 ≠ 1 or Q2 ≠ 1 or Q3 ≠ 1 or Q4 ≠ 1 or Q5 ≠ 1) then Utility = Utility - 0.081 
if (Q1=3 or Q2=3 or Q3=3 or Q4=3 or Q5=3) then Utility = Utility - 0.269 
End of the sequential algorithm 
10.6. 
Hospital Anxiety and Depression Scale 
 
Note: Questions with response scoring under column header D are depression related questions. Otherwise, those are 
depression related questions.    
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Statistical Analysis Plan 
 
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10.7. 
Detailed Description of the Multiple Imputation Procedure 
The following is a detailed description of the multiple imputation procedure which will be used 
for analysis of the secondary efficacy endpoints. 
In general, the missing pattern is anticipated to be not monotone, a two-step approach will be 
used: 
 Step 1:  the MCMC method will be used in conjunction with the 
IMPUTE=MONOTONE option to create an imputed data set with a monotone 
missing pattern. Set the SEED=1629 option in SAS MI procedure.  
 Step 2:  Using the monotone data set from step 1, missing data will be imputed using 
the regression method. Set the SEED=9261 option in SAS MI procedure. 
The imputation model for step 1 will include the treatment group and the values of the analyzed 
parameter at baseline and planned time-points up to week 24. 
The imputation model for step 2 will include the same variables as in step 1 with the following 
additional variables: 
 the randomization strata (apheresis treatment status strata); 
 age, BMI, and gender (age and BMI included as continuous variables). 
Non-continuous variables included in the imputer’s model (i.e., treatment group, randomization 
strata and gender) are not expected to be missing. 
In addition, for continuous efficacy variables anticipated to have a non-normal distribution 
(i.e. TG and Lp(a)), data will be log-transformed before imputation process and then 
back-transformed to create the imputed data sets using the TRANSFORM statement of SAS MI 
procedure. 
For variables other than those continuous efficacy variables anticipated to have a non-normal 
distribution (i.e. TG and Lp(a)), for each simulation leading to negative imputed value, another 
value will be redrawn using MINIMUM option of SAS MI procedure. 
The number of imputations (100) will be informally verified by replicating sets of 100 
imputations and checking whether the combined results are stable. If not stable, the number of 
imputations will be increased and informally checked as above, and thus continued until stable 
estimates are obtained. 
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10.8. 
Detailed Description of Pattern Mixture Model 
As a sensitivity analysis of the primary efficacy endpoint (i.e. percent change from baseline to 
Week 24 in LDL-C), a pattern-mixture model approach will be used, with a different imputation 
strategy applied for missing LDL-C values during the on-treatment period (i.e. within the time 
period from the first double-blind study treatment administration up to the day of the last double-
blind study treatment administration +35 days or to the day before the first open-label study 
treatment administration, whichever comes first) and missing  LDL-C values after treatment 
discontinuation (i.e. after the day of last study treatment administration +35 days) based on the 
following assumptions: 
 Patients within 35 days of their last study treatment administration would continue to 
show benefit from treatment similar to that observed at the scheduled time point. 
Therefore, LDLC values missing during the on-treatment period will be considered 
“Missing at Random” and imputed using a model estimated using all samples 
collected on treatment. 
 Patients who stopped taking their study treatment no longer benefited from it in the 
future, and thus tended to have LDL-C values returning to baseline. Thus LDL-C 
values missing after treatment discontinuation will be imputed based on patient’s own 
baseline value. 
The assumptions for this approach are based on the following considerations: 
 Missing values during the on-treatment period are mostly consecutive to: 
 Visits performed outside of the pre-specified time-window  
 No blood sample available although visit was done 
 LDL-C not measurable due to technical reasons 
In addition, these missing data are often intermittent, i.e. followed by LDL-C values 
collected at subsequent visits. It is therefore considered reasonable to assume that these 
missing data were “At Random”. 
Missing LDL-C values will be imputed 100 times to generate 100 complete data sets. The 
percent change from baseline to Week 24 will be derived from observed and imputed LDL-C at 
this time point. The completed data sets will be analyzed using an analysis of covariance 
(ANCOVA) model with treatment group and randomization strata as fixed effects, and the 
baseline LDL-C value as continuous covariate. The results from the 100 analyses will be 
combined using Rubin’s formulae. If necessary, the number of imputations (100) will be 
increased until stable estimates are obtained. 
Imputation of missing data during the on-treatment period 
Missing LDL-C values during the on-treatment period will be imputed from other on-treatment 
measurements assuming Missing At Random, using SAS® MI procedure. 
Only LDL-C values collected during the on-treatment period will be included in the imputation 
model. This way, missing LDL-C values during the on-treatment period will be imputed based 
solely on observed on-treatment LDL-C values. 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R1500-CL-1629 Amendment 3B 
Statistical Analysis Plan 
 
Date: July 12, 2019 
 
 
CONFIDENTIAL  
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The imputation model will include the treatment arm, baseline LDL-C value, and all LDL-C 
values at pre-specified visits. Since the pattern of missing data will necessarily be non-monotone, 
a Monte-Carlo Markov Chain (MCMC) method will be used. A minimum value of 0 will be 
specified in order to avoid negative imputed LDL-C values. 
A sample SAS code is provided below: 
proc mi data=DATAIN out=DATAOUT nimpute=100 minimum=. 0 0 0 0 0 0 0 0 seed=1629; 
  mcmc impute=monotone; 
  var ARM LDL_BASE LDL_W2 LDL_W4 LDL_W8 LDL_W12 LDL_W16 LDL_W20 
LDL_W24; 
run; 
As stated above, the input dataset DATAIN will include only LDL-C values collected during the 
on-treatment period. Any LDL-C values collected during the post-treatment period will be 
excluded from the input dataset. In practice, the MI procedure will generate imputed values for 
all missing values (whether on-treatment or post-treatment), but only imputed values during the-
on-treatment period will be kept in the final datasets that will be analyzed using ANCOVA. 
Imputed values during the post-treatment period will be discarded and replaced by imputed 
values described in the next paragraph. 
Imputation of missing data after treatment discontinuation 
Missing LDL-C values during the post-treatment period will be imputed assuming LDL-C values 
would on average return to baseline values. 
For each patient, missing post-treatment LDL-C values will be imputed 100 times, using a 
random draw from a normal distribution (SEED=9261), with mean equal to patient’s own 
baseline value and variance equal to the conditional variance at the specific time-point, given the 
baseline value. 
Let Y0 and Y1 denote the LDL-C at baseline and at the specific time-point respectively. Since Y0 
and Y1 are assumed to have a bivariate normal distribution, the conditional variance of Y1 given 
Y0 is: 
)
1(
)
(
2
2
1
0
0
1




y
Y
Y
Var
 
Where 
2
1
 denotes the variance of Y1 and ρ the coefficient of correlation between Y0 and Y1. 
The conditional variance will be estimated from observed data within the same treatment arm at 
the specific time-point. 
During the random generation process, a minimum value of 0 will also be applied in order to 
avoid negative imputed LDL-C values.  
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Statistical Analysis Plan 
 
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10.9. 
Schedule of Time and Events 
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 
 
 
 
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 
Footnotes for Schedule of Events – Run-in Period 
1. Study assessments will be performed and blood samples will be collected before the dose 
of study drug in all patients. For patients undergoing apheresis:  Study assessments will 
be performed and blood samples will be collected immediately before the lipid-apheresis 
procedure; study drug will be administered after the apheresis procedure. 
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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, i.e., 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) 
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CONFIDENTIAL  
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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 
 
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 
Footnotes for Schedule of Events – Screening for Patients with No Run-in 
1. Study assessments will be performed and blood samples will be collected before the dose 
of study drug in all patients. For patients undergoing apheresis:  Study assessments will 
be performed and blood samples will 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 
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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 
 
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Protocol: R1500-CL-1629 Amendment 3B 
Statistical Analysis Plan 
 
Date: July 12, 2019 
 
 
CONFIDENTIAL  
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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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
                                        VV-RIM-00083002-1.0 Approved - 16 Jul 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R1500-CL-1629 Amendment 3B 
Statistical Analysis Plan 
 
Date: July 12, 2019 
 
 
CONFIDENTIAL  
Page 72 of 75 
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 
Laboratory Testing8: 
Hematology 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
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 
 
                                        VV-RIM-00083002-1.0 Approved - 16 Jul 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R1500-CL-1629 Amendment 3B 
Statistical Analysis Plan 
 
Date: July 12, 2019 
 
 
CONFIDENTIAL  
Page 73 of 75 
Footnotes for Schedule of Events – Baseline, Double-Blind Treatment Period, and Open-
Label Treatment Period 
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 duplicated during the R1500-CL-1629 baseline 
visit; only assessments footnoted will need to be performed. 
2. Study assessments will be performed and blood samples will be collected before the dose 
of study drug in all patients. For patients undergoing apheresis:  Study assessments will 
be performed and blood samples will 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. 
13. Should be collected at the baseline visit, or at any study visit 
14. All end of treatment (EOT) assessments will be performed and blood samples will be 
collected before the dose of open-label study drug in all patients. For patients undergoing 
                                        VV-RIM-00083002-1.0 Approved - 16 Jul 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R1500-CL-1629 Amendment 3B 
Statistical Analysis Plan 
 
Date: July 12, 2019 
 
 
CONFIDENTIAL  
Page 74 of 75 
apheresis:  Study assessments will be performed and blood samples will 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. 
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 
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 
                                        VV-RIM-00083002-1.0 Approved - 16 Jul 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R1500-CL-1629 Amendment 3B 
Statistical Analysis Plan 
 
Date: July 12, 2019 
 
 
CONFIDENTIAL  
Page 75 of 75 
Footnotes for Schedule of Events –Follow-up Period 
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. 
 
                                        VV-RIM-00083002-1.0 Approved - 16 Jul 2019 GMT-5:00


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                                        VV-RIM-00083002-1.0 Approved - 16 Jul 2019 GMT-5:00