Clinical trial NCT04233918
Conditions: Homozygous Familial Hypercholesterolemia
Keywords: HoFH
Sponsor: Regeneron Pharmaceuticals
Start date: 2020-06-29; Completion date: 2023-05-30
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective for Part A of the study is to assess the pharmacokinetics (PK) of evinacumab in pediatric patients with homozygous familial hypercholesterolemia (HoFH).

The primary objective for Part B of the study is to demonstrate a reduction of low-density lipoprotein cholesterol (LDL-C) by evinacumab in pediatric (5 to 11 years of age) patients with HoFH.

The secondary objective for Part A of the study is to evaluate the safety and tolerability of evinacumab administered intravenous (IV) in pediatric patients with HoFH.

The secondary objectives for Part B of the study are:

* To evaluate the effect of evinacumab on other lipid parameters (ie, apolipoprotein B (Apo B), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), lipoprotein a \[Lp(a)\]) in pediatric patients with HoFH
* To evaluate the safety and tolerability of evinacumab administered IV in pediatric patients with HoFH
* To assess the PK of evinacumab in pediatric patients with HoFH
* To assess the immunogenicity of evinacumab in pediatric patients with HoFH over time
* To evaluate patient efficacy by mutation status

Detailed description:
Part A is Phase 1b Part B is Phase 3

Arms: arm 1: Part A: Single intravenous (IV) dose Part B: IV dose every 4 weeks (Q4W) until week 20 Part C: IV dose Q4W
Interventions: intervention 1: Evinacumab
Intervention descriptions: intervention 1: Part A: Single IV dose Part B \& C: IV dose Q4W

Protocol documents:
Prot_002.pdf: 
EudraCT Number: 2019-001931-30 
IND Number: 116,398 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A THREE-PART, SINGLE-ARM, OPEN-LABEL STUDY TO EVALUATE 
THE EFFICACY, SAFETY, AND PHARMACOKINETICS OF 
EVINACUMAB IN PEDIATRIC PATIENTS WITH HOMOZYGOUS 
FAMILIAL HYPERCHOLESTEROLEMIA 
Compound: 
REGN1500 (Evinacumab) 
Clinical Phase: 
1b/3 
Protocol Number: 
R1500-CL-17100 
Protocol Version: 
R1500-CL-17100 Amendment 2 
Amendment 2 Date of Issue: 
See appended electronic signature page
Amendment 1 Date of Issue: 
07 May 2020 
Original Date of Issue 
11 Dec 2019 
Medical /Study Director: 
 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
 
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NCT04233918


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Page 2 of 96 
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Page 3 of 96 
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AMENDMENT HISTORY 
Overall Rationale for Amendment 2 
The overall rationale of the amendment is to allow patients who enter into the compassionate use 
program (CUP) or early access program (EAP) to forgo the follow-up period of the study.  The 
follow-up period was intended to be an off-drug follow-up period.  For patients entering EAP, 
there may be no off-drug follow-up period.  In addition, due to difficulties in recruitment, the 
overall study participant target population is being reduced from 24 to 20, and the part B target is 
being reduced from 18 to 14.   
The following table shows the changes made to the protocol and the affected sections: 
Change 
Rationale 
Sections Changed 
Decreased the target sample 
size in part B from 18 to 14 
Despite rigorous efforts, 
recruitment of additional 
pediatric Homozygous 
Familial Hypercholesterolemia 
(HoFH) patients has been 
challenging.  Therefore, the 
sample size has been reduced 
from 18 to 14. 
Clinical Study Protocol Synopsis, Study Design, 
Part B 
Clinical Study Protocol Synopsis, Population, 
Sample Size, Statistical Plan 
Section 1 Introduction 
Section 6.1 Study Description and Duration 
Section 7.1 Number of Patients Planned 
Section 11.2 Justification of Sample Size 
Allowed patients who enter 
the CUP or EAP to forgo 
the 24-week follow-up 
period in this study after the 
last dose 
The 24-week follow-up period 
was intended to be an off-drug 
period.  With many physicians 
and Principal Investigators 
(PIs) applying for or 
expressing interest in CUP or 
EAP for evinacumab, the 
sponsor is amending the 
protocol to allow patients to 
forgo the off-drug follow-up 
period if they are acquiring 
early access to evinacumab.  
This is to avoid the patients 
having a 24-week period off 
drug with uncontrolled Low-
density lipoprotein cholesterol 
(LDL-C) levels. 
Clinical Study Protocol Synopsis, Study Design, 
Part C 
Synopsis, Study Duration 
Section 6.1 Study Description and Duration 
Figure 3 Study Flow Diagram - Extension 
Section 9.1 Schedule of Events, Part C 
Section 9.1.1.3 Footnotes for the Schedule of 
Events Table – Part C, footnote #14, and new 
footnote #17 
Section 9.1.2 Early Termination Visit 
Section 10.1.2 Data Collection Period 
Editorial 
changes/typographical 
errors 
Revised for accuracy, 
consistency, and clarity 
Throughout the protocol 
Amendment 1 
The following table shows the changes made to the protocol and the affected sections: 
Change 
Rationale 
Sections Changed  
The study design has 
been revised. The 
treatment period of Part 
The primary objective of 
Part B is to demonstrate 
efficacy, and the primary 
Synopsis – Site Location(s), Study Design, 
Study Duration, and Population - Sample 
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Change 
Rationale 
Sections Changed  
B has been reduced from 
48 weeks to 24 weeks. 
The treatment period of 
Part C has been reduced 
from up to 3 years to 48 
weeks.  
efficacy endpoint is percent 
change from baseline in 
calculated LDL-C at 
week 24. As such, the 
treatment period of Part B 
now matches the timing of 
the efficacy endpoint.  
Part C has been reduced to 
allow the study to complete 
in a timely manner, but still 
provide sufficient exposure 
to assess long-term safety 
and tolerability(inclusive of 
the 24-week follow-up 
period). 
Size, Treatment(s) – Background, 
Endpoints - Secondary 
Section 2.3 Exploratory Objectives 
Section 3.2.1 Rationale for Study Design 
Section 6.1 Study Description and Duration 
Section 6.1.1 Description of Dose Selection 
Section 7.1 Number of Patients Planned 
Section 7.2.2 Exclusion Criteria #4 
Section 8.3 Background Treatments 
Section 8.4.2 Study Drug Discontinuation 
Section 8.9.1 Prohibited Medications 
Section 8.9.2 Permitted Medications 
Table 1 Schedule of Events – Part A, PK 
and PD Portion 
Table 2 Schedule of Events – Part B, 24-
week Efficacy and Safety Portion 
Table 3 Schedule of Events – Part C 
Section 11.4.3.2 Secondary Efficacy 
Analysis for Part B 
Section 11.5.3 Third Step: Final Safety 
Analysis 
Removed the use of 
acceptable methods of 
contraception (double 
barrier), updated the 
contraception 
requirements to only 
include highly effective 
contraception, and added 
the duration that highly 
effective contraception 
should be used in case a 
patient becomes sexually 
active during the study 
and initiates 
contraception use. 
Highly effective 
contraception should be 
used for 24 weeks after the 
last dose of evinacumab 
because that is generally the 
duration evinacumab 
concentrations remain 
above the lower limit of 
quantitation 
Section 7.2.2 Exclusion Criteria, #15 and 
#16 
Added absolute change in 
LDL-C at week 24 as an 
endpoint. 
This was an omission from 
the original protocol 
Section 4.1.2 Secondary Endpoints 
Added an exclusion 
criterion for patients who 
are accommodated in an 
institution by official or 
court order. 
Requested by an Ethics 
Committee 
Section 7.2.2 Exclusion Criteria, #17 
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Change 
Rationale 
Sections Changed  
Added neurocognitive 
events, new onset of 
diabetes, pancreatitis, and 
moderate or severe 
infusion reactions to list 
of AESIs 
Additions made in response 
to FDA comments. 
Section 10.1.4 Events that Require 
Expedited reporting to Sponsor 
Clarifications and 
corrections: 
Clarified rationale for 
dose selection 
Provided more detailed 
safety data for risk 
benefit assessment 
Clarified inclusion 
criterion for informed 
consent and assent 
Clarified exclusion 
criterion for 
hypersensitivity to mAbs 
Infusion of evinacumab 
over 65 minutes instead 
of 1 hour 
Clarified weight measure 
to be used to calculate 
dose of evinacumab. 
Removed serum 
pregnancy tests 
throughout. Only urine 
pregnancy tests will be 
done. 
Updated visits and timing 
of some laboratory 
assessments, Tanner 
stage, and PK, 
Updated footnotes for 
schedule of events tables.  
Removed assessments at 
visit 1 of Part C, and 
added imaging at Visit 7 
of Part C. 
Clarified early 
termination visit. 
Removed “long term 
extension” and OLTP. 
Changes made to clarify 
protocol, make corrections, 
and correct inconsistencies 
Section 3.2.2 Rationale for Dose Selection 
Section 3.3 Risk Benefit 
Section 4.1.3 Exploratory Endpoints 
Section 5.6 Ultrasound Imaging 
Section 7.2.1 Inclusion Criteria #7 
Section 7.2.2 Exclusion Criteria, #12, #13  
Section 8.1 Investigational and Reference 
Treatments 
Table 1 Schedule of Events – Part A, PK 
and PD portion 
Table 2 Schedule of Events – Part B, 24-
week Efficacy and Safety Portion 
Table 3 Schedule of Events – Part C 
Section 9.1.1.1 Footnotes for Schedule of 
Events Table 1 #8 and #17 
Section 9.1.1.2 Footnotes for Schedule of 
Events Table 2 #16 and #17 
Section 9.1.1.3 Footnotes for Schedule of 
Events Table 3 #13, #15, #16 
Section 9.1.2 Early Termination Visit 
Section 10.2.6 Causality 
Section 11.3.1 Efficacy Analysis Set for 
Part B 
Section 11.3.2 Safety Analysis Set 
Section 11.4.1 Patient disposition 
Section 11.4.3.3 Other Efficacy Analyses 
for Part B 
Section 11.4.5 Safety Analysis 
Section 11.4.5.1 Adverse Events 
Section 11.4.5.2 Other Safety 
Section 11.4.5.3 Treatment Exposure 
Section 11.4.5.4 Treatment Compliance 
Section 11.4.7 Analysis of Immunogenicity 
Data 
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Change 
Rationale 
Sections Changed  
Instead, referred to Part C 
and treatment period. 
Added statements to 
address the impact of the 
COVID-19 pandemic on 
the conduct of the study,  
To explain the plan for 
ensuring continuity of 
clinical study activities and 
study oversight activities 
during the COVID-19 
public health emergency. 
Section 3.3 Risk-Benefit 
Section 9 Study Schedule of Events and 
Procedures 
 
 
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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  
Apolipoprotein 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
cIMT 
Carotid intima-media thickness 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
CUP 
Compassionate use program  
CVD 
Cardiovascular disease 
EAP 
Early access program 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FH 
Familial Hypercholesterolemia 
GCP 
Good Clinical Practice 
HDL 
High-density lipoprotein 
HoFH 
Homozygous Familial Hypercholesterolemia 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent data monitoring committee 
IRB 
Institutional Review Board 
IV 
Intravenous 
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 
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LOF 
Loss of function 
mAb 
Monoclonal antibody 
NAb 
Neutralizing antibody 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PK 
Pharmacokinetic 
QW 
Weekly 
Q2W 
Every 2 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 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
WBC 
White blood cell 
 
 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................7 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................15 
1. 
INTRODUCTION ......................................................................................................20 
2. 
STUDY OBJECTIVES ..............................................................................................23 
2.1. 
Primary Objective .......................................................................................................23 
2.2. 
Secondary Objective(s) ...............................................................................................23 
2.3. 
Exploratory Objective(s) ............................................................................................23 
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 
3.3. 
Risk-Benefit ................................................................................................................26 
4. 
ENDPOINTS ..............................................................................................................29 
4.1. 
Primary and Secondary Endpoints..............................................................................29 
4.1.1. 
Primary Endpoint ........................................................................................................29 
4.1.2. 
Secondary Endpoints ..................................................................................................29 
4.1.3. 
Exploratory Endpoints ................................................................................................30 
5. 
STUDY VARIABLES................................................................................................31 
5.1. 
Demographic and Baseline Characteristics ................................................................31 
5.2. 
Efficacy Variables ......................................................................................................31 
5.3. 
Safety Variables ..........................................................................................................31 
5.4. 
Pharmacokinetic Variables .........................................................................................31 
5.5. 
Immunogenicity Variables ..........................................................................................31 
5.6. 
Ultrasound Imaging ....................................................................................................31 
6. 
STUDY DESIGN .......................................................................................................32 
6.1. 
Study Description and Duration .................................................................................32 
6.1.1. 
Description of Dose Selection ....................................................................................37 
6.1.2. 
End of Study Definition ..............................................................................................37 
6.2. 
Planned Interim Analysis ............................................................................................37 
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6.3. 
Study Committees .......................................................................................................37 
6.3.1. 
Independent Data Monitoring Committee ..................................................................37 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............38 
7.1. 
Number of Patients Planned .......................................................................................38 
7.1.1. 
Rescreening of Patients ...............................................................................................38 
7.2. 
Study Population .........................................................................................................38 
7.2.1. 
Inclusion Criteria ........................................................................................................38 
7.2.2. 
Exclusion Criteria .......................................................................................................39 
7.3. 
Premature Withdrawal from the Study .......................................................................41 
7.4. 
Replacement of Patients .............................................................................................42 
8. 
STUDY TREATMENTS............................................................................................43 
8.1. 
Investigational and Reference Treatments ..................................................................43 
8.2. 
Run-in Treatment(s) ....................................................................................................43 
8.3. 
Background Treatment(s) ...........................................................................................43 
8.4. 
Dose Modification and Study Treatment Discontinuation Rules ...............................44 
8.4.1. 
Dose Modification ......................................................................................................44 
8.4.2. 
Study Drug Discontinuation .......................................................................................44 
8.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................44 
8.4.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................44 
8.5. 
Management of Acute Reactions ................................................................................44 
8.5.1. 
Acute Intravenous Infusion Reactions ........................................................................44 
8.5.1.1. 
Interruption of the Intravenous Infusion .....................................................................44 
8.5.1.2. 
Termination of the Intravenous Infusion ....................................................................45 
8.6. 
Method of Treatment Assignment ..............................................................................46 
8.7. 
Blinding ......................................................................................................................46 
8.8. 
Treatment Logistics and Accountability .....................................................................46 
8.8.1. 
Packaging, Labeling, and Storage ..............................................................................46 
8.8.2. 
Supply and Disposition of Treatments .......................................................................46 
8.8.3. 
Treatment Accountability ...........................................................................................46 
8.8.4. 
Treatment Compliance ................................................................................................46 
8.9. 
Concomitant Medications ...........................................................................................47 
8.9.1. 
Prohibited Medications ...............................................................................................47 
8.9.2. 
Permitted Medications ................................................................................................47 
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9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................48 
9.1. 
Schedule of Events .....................................................................................................48 
9.1.1. 
Footnotes for the Schedule of Events Table ...............................................................58 
9.1.1.1. 
Table 1 Schedule of Events – Part A, PK and PD Portion .........................................58 
9.1.1.2. 
Table 2 Schedule of Events – Part B, 48-Week Efficacy and Safety Portion ............59 
9.1.1.3. 
Table 3 Schedule of Events – Part C ..........................................................................60 
9.1.2. 
Early Termination Visit ..............................................................................................61 
9.1.3. 
Unscheduled Visits .....................................................................................................62 
9.2. 
Study Procedures ........................................................................................................62 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................62 
9.2.2. 
Efficacy Procedures ....................................................................................................62 
9.2.2.1. 
Lipid Panel ..................................................................................................................62 
9.2.2.2. 
Specialty Lipid Panel ..................................................................................................62 
9.2.3. 
Safety Procedures .......................................................................................................62 
9.2.3.1. 
Vital Signs ..................................................................................................................62 
9.2.3.2. 
Physical Examination .................................................................................................63 
9.2.3.3. 
Tanner Stages ..............................................................................................................63 
9.2.3.4. 
Electrocardiogram .......................................................................................................63 
9.2.3.5. 
Laboratory Testing ......................................................................................................63 
9.2.4. 
Drug Concentration and Measurements .....................................................................65 
9.2.5. 
Immunogenicity Measurements and Samples ............................................................65 
9.2.6. 
Ultrasound Imaging ....................................................................................................65 
9.2.7. 
Other Assessments ......................................................................................................65 
9.2.7.1. 
Review of Diet and Compliance with LMT ...............................................................65 
9.2.7.2. 
DNA Sample for HoFH Genotyping ..........................................................................65 
9.2.7.3. 
Future Biomedical Research (Optional) .....................................................................65 
9.2.7.4. 
Pharmacogenomic Analysis (Optional) ......................................................................66 
10. 
SAFETY EVALUATION AND REPORTING .........................................................67 
10.1. 
Recording and Reporting Adverse Events ..................................................................67 
10.1.1. 
General Guidelines .....................................................................................................67 
10.1.2. 
Data Collection Period ................................................................................................68 
10.1.3. 
Reporting Procedure ...................................................................................................68 
10.1.4. 
Events that Require Expedited Reporting to Sponsor ................................................68 
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10.2. 
Definitions ..................................................................................................................69 
10.2.1. 
Adverse Event .............................................................................................................69 
10.2.2. 
Serious Adverse Event ................................................................................................69 
10.2.3. 
Adverse Events of Special Interest .............................................................................70 
10.2.4. 
Infusion Reactions ......................................................................................................70 
10.2.5. 
Severity .......................................................................................................................70 
10.2.6. 
Causality .....................................................................................................................71 
10.3. 
Safety Monitoring .......................................................................................................72 
10.4. 
Notifying Health Authorities, Institutional Review Board /Ethics Committee, 
and Investigators .........................................................................................................72 
11. 
STATISTICAL PLAN................................................................................................74 
11.1. 
Statistical Hypothesis ..................................................................................................74 
11.2. 
Justification of Sample Size........................................................................................74 
11.3. 
Analysis Sets ...............................................................................................................74 
11.3.1. 
Efficacy Analysis Set for Part B .................................................................................74 
11.3.2. 
Safety Analysis Set .....................................................................................................74 
11.3.3. 
Pharmacokinetic Analysis Sets ...................................................................................75 
11.3.4. 
Immunogenicity Analysis Sets ...................................................................................75 
11.4. 
Statistical Methods ......................................................................................................75 
11.4.1. 
Patient Disposition ......................................................................................................75 
11.4.2. 
Demography and Baseline Characteristics .................................................................76 
11.4.3. 
Efficacy Analyses .......................................................................................................76 
11.4.3.1. 
Primary Efficacy Analysis for Part B .........................................................................76 
11.4.3.2. 
Secondary Efficacy Analysis for Part B .....................................................................77 
11.4.3.3. 
Other Efficacy Analyses for Part B ............................................................................77 
11.4.4. 
Control of Multiplicity ................................................................................................77 
11.4.5. 
Safety Analysis ...........................................................................................................78 
11.4.5.1. 
Adverse Events ...........................................................................................................78 
11.4.5.2. 
Other Safety ................................................................................................................79 
11.4.5.3. 
Treatment Exposure ....................................................................................................80 
11.4.5.4. 
Treatment Compliance ................................................................................................80 
11.4.6. 
Pharmacokinetics ........................................................................................................81 
11.4.6.1. 
Analysis of Drug Concentration Data .........................................................................81 
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11.4.7. 
Analysis of Immunogenicity Data ..............................................................................81 
11.5. 
Timing of Analyses .....................................................................................................82 
11.5.1. 
First Step: PK and Safety Analysis for Part A ............................................................82 
11.5.2. 
Second Step: Efficacy and Safety Analysis for Part B ...............................................82 
11.5.3. 
Third Step: Final Safety Analysis ...............................................................................83 
11.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .........83 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................84 
12.1. 
Data Management and Electronic Systems ................................................................84 
12.1.1. 
Data Management .......................................................................................................84 
12.1.2. 
Electronic Systems ......................................................................................................84 
12.2. 
Study Monitoring ........................................................................................................84 
12.2.1. 
Monitoring of Study Sites ...........................................................................................84 
12.2.2. 
Source Document Requirements ................................................................................85 
12.2.3. 
Case Report Form Requirements ................................................................................85 
12.3. 
Audits and Inspections ................................................................................................85 
12.4. 
Study Documentation .................................................................................................86 
12.4.1. 
Certification of Accuracy of Data ...............................................................................86 
12.4.2. 
Retention of Records ..................................................................................................86 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................87 
13.1. 
Good Clinical Practice Statement ...............................................................................87 
13.2. 
Informed Consent .......................................................................................................87 
13.3. 
Patients Confidentiality and Data Protection ..............................................................88 
13.4. 
Institutional Review Board/Ethics Committee ...........................................................88 
13.5. 
Clinical Study Data Transparency ..............................................................................88 
14. 
PROTOCOL AMENDMENTS ..................................................................................89 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................90 
15.1. 
Premature Termination of the Study ...........................................................................90 
15.2. 
Close-out of a Site ......................................................................................................90 
16. 
CONFIDENTIALITY ................................................................................................90 
17. 
FINANCING AND INSURANCE .............................................................................90 
18. 
PUBLICATION POLICY ..........................................................................................90 
19. 
REFERENCES ...........................................................................................................91 
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20. 
INVESTIGATOR’S AGREEMENT ..........................................................................93 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................94 
 
LIST OF TABLES 
Table 1: 
Schedule of Events – Part A, PK and PD Portion ......................................................49 
Table 2: 
Schedule of Events – Part B, 24-Week Efficacy and Safety Portion .........................52 
Table 3: 
Schedule of Events – Part C .......................................................................................56 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram Part A .......................................................................................32 
Figure 2: 
Study Flow Diagram Part B ........................................................................................34 
Figure 3: 
Study Flow Diagram – Extension ...............................................................................36 
 
LIST OF APPENDICES 
APPENDIX 1. DETAILED DESCRIPTION OF PATTERN MIXTURE MODEL ..................95 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Three-Part, Single-Arm, Open-Label Study to Evaluate the Efficacy, 
Safety, and Pharmacokinetics of Evinacumab in Pediatric Patients with 
Homozygous Familial Hypercholesterolemia 
Site Location(s) 
 
Principal Investigator 
The study will be conducted globally (eg, Europe, North America, Asia) at 
approximately 24 sites.  
To be determined 
Objective(s) 
Primary 
The primary objective for Part A of the study is to assess the 
pharmacokinetics (PK) of evinacumab in pediatric patients with 
homozygous familial hypercholesterolemia (HoFH). 
The primary objective for Part B of the study is to demonstrate a reduction 
of low-density lipoprotein (LDL) cholesterol (LDL-C) by evinacumab in 
pediatric (5 to 11 years of age) patients with HoFH. 
Secondary 
The secondary objective for Part A of the study is to evaluate the safety and 
tolerability of evinacumab administered IV in pediatric patients with HoFH 
The secondary objectives for Part B of the study are: 
• 
To evaluate the effect of evinacumab on other lipid parameters 
(ie, Apo B, non-HDL-C, TC, lipoprotein a [Lp(a)]) in pediatric 
patients with HoFH 
• 
To evaluate the safety and tolerability of evinacumab 
administered IV in pediatric patients with HoFH 
• 
To assess the PK of evinacumab in pediatric patients with HoFH 
• 
To assess the immunogenicity of evinacumab in pediatric 
patients with HoFH over time 
• 
To evaluate patient efficacy by mutation status 
Study Design 
Part A is a phase 1B single-dose, open-label study to determine the safety, 
PK and pharmacodynamics (PD) of evinacumab 15 mg/kg intravenous (IV) 
in approximately 6 patients ages 5 to 11 years with HoFH. To ensure a 
distribution of body weight within Part A of the study, every effort will be 
made to enroll 3 patients <25 kg and 3 patients ≥25 kg. Additionally, to 
ensure a distribution of ages, every effort will be made to enroll 2 patients 
<10 years of age. All patients who successfully complete Part A may 
continue receiving evinacumab in an extension of the study, Part C. Initially, 
patients from Part A who enter the Part C will receive evinacumab 15 mg/kg 
IV Q4W. When PK data from all patients in Part A have been sufficiently 
analyzed, the dose for Part B will be determined using the cumulative data 
to date with evinacumab and data from Part A. If data from 6 patients is 
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insufficient, up to 4 more patients may be enrolled to confirm the dose in 
Part B. The dose for Part B will also be the final dose in Part C. The dose 
for Part B (and final dose in Part C) will likely remain at 15 mg/kg IV every 
4 weeks (Q4W). However, there is a small possibility that the exposure 
analysis or the observed PD effect indicate a small increase in the dose is 
needed for the pediatric population to match the exposure and PD effect 
observed in adult patients. As such, the dose in Part B (and final dose in Part 
C) could be between 15-20 mg/kg IV Q4W. A maximum dose of 20 mg/kg 
is selected as the top dose because it is the highest dose evaluated in the prior 
evinacumab studies. 
Part A consists of up to 4 periods: run-in, screening, single-dose, open-label 
treatment, and 16-week observation. Upon completion of Part A, patients 
will have the opportunity to continue into Part C.  
Part B is a phase 3 single-arm, open-label study to assess the efficacy and 
safety of evinacumab in pediatric patients (age 5 to 11 years) with HoFH.  
Part B will begin once dose-selection for Part B has been completed.  Part 
B will enroll approximately 14 pediatric patients. Patients enrolled in Part B 
will not include patients from Part A. Upon completion of Part B, patients 
will have the opportunity to continue into the extension, Part C. 
Part B consists of up to 4 periods: run-in, screening, 24-week open-label 
treatment, and follow-up (for patients who do not enter the extension, Part 
C). 
Part C is an extension of the study for patients from both Part A and Part B 
and consists of 2 periods, a 48-week treatment period and a 24-week follow-
up period after the last dose of study drug. All patients from Part A who 
enter Part C will initially receive open-label evinacumab 15 mg/kg IV Q4W. 
The final dose in Part C will be the same as the dose in Part B; therefore, the 
dose in Part C could be adjusted to align with the dose in Part B. Patients 
who are receiving background LMT or who are undergoing apheresis should 
make every effort to maintain a stable LMT and a stable apheresis schedule 
(as applicable) throughout the duration of the study to the end of the study. 
The frequency of apheresis may be reduced during this part of the study 
based on the investigator’s judgement. The Sponsor of this study, consistent 
with our corporate policy governing access to investigational drugs in 
confirmatory clinical studies, is committed to provide evinacumab to 
patients after their participation in this trial has concluded, if permitted per 
local laws.  Agreement to continue treatment beyond this study is a treatment 
decision that must be made by the investigator, and the patient or their 
parent/guardian. After completion of the study, investigators interested in 
continuing treatment with evinacumab in patients considered to have a 
positive response can discuss post-trial treatment options with the Sponsor, 
including participation in a CUP or EAP. 
Study Duration 
For a patient in Part A, the duration of the study is up to approximately 34 
weeks, which includes up to an 8-week run-in period, a 2-week screening 
period, a 16-week open-label treatment and observation period, an 8-week 
follow-up period (for those patients who decide not to enter Part C). For 
patients who enter Part C, there will be no follow-up period for Part A and 
the combined duration of Part A and Part C could be up to 98 weeks, 
including a 24-week follow-up period after the last dose of study drug in 
Part C.  Although, patients who enter a CUP or EAP may forgo the 24-week 
follow-up period after the last dose. 
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For a patient in Part B, the duration of the study is up to 54 weeks, which 
includes, up to an 8-week run-in period, a 2-week screening period, a 
24-week open-label treatment period, and a 20-week follow-up period (for 
those patients who decide not to enter Part C).  For patients who enter Part C, 
there will be no follow-up period for Part B and the combined duration of 
Part B and Part C could be up to 106 weeks, including a 24-week follow-up 
period after the last dose of study drug in Part C.  Although, patients who 
enter a CUP or EAP may forgo the 24-week follow-up period after the last 
dose. 
End of Study Definition 
The end of study is defined as the date of the last visit of the last patient. 
Population 
 
 
Sample Size: 
For Part A, approximately 6 patients are planned. If data from 6 patients is 
insufficient, up to 4 more patients may be enrolled to confirm the dose in 
Part B. 
An additional 14 pediatric patients are planned for Part B and will not 
include patients from Part A. Patients from both Part A and Part B may enter 
Part C of the study. 
 
Target Population: 
Males and females age 5 through 11 years diagnosed with HoFH receiving 
any combination of lipid-lowering therapies. 
Treatment(s) 
 
 
Study Drug 
 
Dose/Route/Schedule: 
Evinacumab (REGN1500). 
For Part A, a single administration of evinacumab 15 mg/kg IV, given over 
a 65 minute infusion 
For Part B, evinacumab with a dose determined by Part A, will be 
administered IV over a 65 minute infusion Q4W starting at day 1. The last 
dose will be at week 20. 
All patients from Part A who enter Part C will initially receive evinacumab 
15 mg/kg IV Q4W. The final dose for Part C will be based on data from Part 
A and all available data from other evinacumab studies.  Therefore, the dose 
for Part C for patients from Part A may be adjusted once the dose selection 
for Part B is completed. 
 
Background Treatment 
Patients should be on a maximally tolerated lipid-modifying therapy (LMT) 
regimen.  
Patients in Part B who are receiving background LMT or who are 
undergoing lipid apheresis should maintain stable LMT and a stable 
apheresis schedule (as applicable)  from screening to the end of treatment  
visit (week 24) in Part B. 
Endpoint(s) 
 
 
Primary: 
The primary endpoint for Part A is the PK parameters for evinacumab, 
including Cmax, AUC, and linear t½ following a single administration of 
evinacumab. 
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The primary endpoint for Part B is the percent change in calculated LDL-C 
from baseline to week 24 (intent-to-treat [ITT] estimand) in Part B. 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. 
 
Secondary: 
The secondary endpoint for Part A is: 
• 
Incidence of treatment-emergent adverse events (TEAE) and 
other safety variables over time 
The secondary endpoints in Part B 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 total cholesterol (TC) from baseline to 
week 24 (ITT estimand) 
• 
The proportion of patients with ≥50% reduction in calculated 
LDL-C at week 24 (ITT estimand) 
• 
The percent change in calculated LDL-C from baseline to 
week 24 in patients who have negative/negative and null/null 
mutations (ITT estimand) 
• 
The percent change in lipoprotein a [Lp(a)] from baseline to 
week 24 (ITT estimand) 
• 
The absolute change in LDL-C at week 24 (ITT estimand) 
• 
Incidence of treatment-emergent adverse events (TEAE) and 
other safety variables over time 
• 
Concentrations of total evinacumab over time 
• 
Incidence and titer of treatment-emergent anti-drug 
antibodies over time 
Procedures and Assessments 
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 and evaluation of 
TEAEs, 
physical 
examinations, 
pulse 
rate, 
blood 
pressure, 
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 
Since this is an open-label, single treatment arm study, formal statistical 
testing is not planned, therefore, a calculation for patient sample size is not 
applicable. Six patients are planned to be enrolled for Part A and 14 pediatric 
patients are planned to be enrolled for Part B. 
Primary Efficacy Analysis for Part B. The percent change from baseline 
in calculated LDL-C at week 24 will be analyzed in the ITT population using 
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a pattern mixture model (PMM) approach as described below (see 
Appendix 1 for more details). 
In the PMM approach, different imputation strategies will be applied to 
calculated LDL-C values missing during the on-treatment period (ie, within 
the time period from the first study treatment administration up to the day 
of last study treatment administration +35 days in Part B) versus calculated 
LDL-C values missing due to treatment discontinuation after the 
on-treatment period (ie, after the day of last study treatment administration 
+35 days in Part B) based on the following assumptions: 
• 
Patients within 35 days of their last study treatment 
administration in Part B would continue to show benefit from 
treatment similar to that observed at the scheduled time point.  
Therefore, calculated LDL-C values missing during the 
on-treatment period (eg, samples obtained outside 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 in Part B no 
longer benefited from it after discontinuation, and thus tended to 
have calculated LDL-C values returning to baseline.  Therefore, 
calculated LDL-C values missing after the on-treatment period 
should be imputed based on patient’s own baseline value. 
Missing data from the ITT 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 
calculated LDL-C data will be used for the primary analysis. 
For the percent change from baseline calculated LDL-C endpoint, the 100 
complete datasets of observed and imputed calculated LDL-C data at week 
24 will be analyzed using the SAS MEANS procedure.  The SAS 
MIANALYZE procedure will be used to generate valid statistical inferences 
by combining results from the 100 analyses using Rubin’s formulae. 
Combined estimate for mean at Week 24 will be provided with the standard 
error (SE) and 95% confidence interval (CI). Formal statistical testing is not 
planned. 
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1. 
INTRODUCTION 
Familial hypercholesterolemia (FH), a primary hyperlipidemia driven by genetic mutation(s) 
primarily in the low-density lipoprotein (LDL) receptor (LDLR), is the most common 
monogenic hypercholesterolemia condition in children. The most rare and severe form of FH is 
homozygous familial hypercholesterolemia (HoFH). It is an inherited autosomal dominant 
disorder primarily resulting from mutations in the LDLR or, less frequently, from mutations in 3 
associated genes: proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein B 
(APOB), and LDL receptor adaptor protein 1 (LDLRAP1). Depending on the genes affected and 
the mutations that are present, patients are categorized as either true homozygotes, compound 
heterozygotes, or double heterozygotes. True homozygotes have the same mutation on both 
alleles. Compound heterozygotes have different mutations on the 2 alleles. Double heterozygotes 
have mutations in 2 different genes. The resulting phenotype includes deficient or defective LDL 
receptors on the surface of hepatocytes causing impaired clearance of circulating low-density 
lipoprotein cholesterol (LDL-C). This leads to severe hypercholesterolemia, often 3 to 6 times 
normal (≥500 mg/dL), starting in infancy, which results in an exceedingly high risk of 
developing premature atherosclerosis, as well as valvular and supravalvular stenosis. 
The etiology of the hypercholesterolemia observed in patients with HoFH is the same for both 
adult and pediatric patients. It is a consequence of the above mentioned abnormal lipoprotein 
metabolism due to mutations in the key genes listed above, and the markedly diminished hepatic 
LDL-C clearance from plasma (Goldstein, 2001)(Kolansky, 2008)(Macchiaiolo, 2012) 
(Rader, 2003). These high plasma levels lead to vascular damage starting from birth and 
morphological and functional vascular changes by 8 years of age or earlier. Children as young as 
7 years of age can present with coronary atherosclerosis even without any clinically apparent 
coronary artery disease. This accelerated atherosclerosis results in premature cardiovascular 
disease (CVD) and an increased risk of CV events at a young age. Evidence of accelerated 
atherosclerosis include children with increased carotid intima-media thickness (cIMT) and cIMT 
progression at a rate approximately double that of unaffected siblings. An observational study of 
HoFH patients showed that the mean age for first major CV event was 20 years 
(Goldstein, 2001)(Kolansky, 2008)(Macchiaiolo, 2012)(Rader, 2003). Indeed, if left untreated, 
children and adolescents with HoFH, have an extremely high risk for premature CVD and 
reduced life expectancy. For example, in a longitudinal study of 39 pediatric patients with HoFH 
followed for up to 8 years, 88% of patients >16 years of age and 9% <16 years of age developed 
CVD. Further, during follow-up, 7 patients developed progression of coronary and/or aortic 
valvular disease and 4 required surgical intervention (Kolansky, 2008), demonstrating the need 
for early aggressive lipid-lowering therapy in pediatric subjects with HoFH. 
The frequency of HoFH in the general population is historically reported as 1/1,000,000. This 
estimate is based on a heterozygous familial hypercholesterolemia (HeFH) prevalence of 1/500 
and the application of the Hardy-Weinberg equilibrium (1/1,000,000 = 1/500 mother * 1/500 
father * 1/4 risk for child). However, based on more recent data, HoFH has an estimated 
prevalence of 1/300,000, which would be the same in children. Populations with a founder effect 
have higher prevalence rates. 
Diagnosis of HoFH can be made based on clinical criteria or genetic criteria (Section 7.2.1 ). An 
LDL-C level ≥13 mmol/L (≥500 mg/dL) is consistent with phenotypic HoFH. However, the 
LDL-C criteria could be lower depending on the presence of positive family history and age of 
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screening. Additional phenotypic characteristics include premature coronary heart disease, aortic 
valve disease, and tendon xanthomas in the hands and Achilles tendons. Clinically identified 
patients could undergo genetic testing to confirm diagnosis. 
Patients with HoFH can be further classified based on the phenotype of the LDLR mutation(s), 
ranging from defective mutations (where the LDLR retains some LDL-binding functionality) to 
null or negative mutations where no functioning LDLR is expressed. Patients who have LDLR 
activity <15% are considered null and patients whose LDLR activity is impaired but >15% are 
LDLR defective (Banerjee, 2019). Another method that could be used to categorize these 
mutations is to define a negative mutation status as having mutations in stop codons, frame 
shifts, splice site changes, small and large insertions/deletions, and copy number variations 
(CNVs) predicted to result in the loss of function of the LDLR. The most extreme cases are those 
patients who are LDL-receptor negative or null in both alleles. These patients tend to have LDL-
C levels at the highest end of the range and experience very little efficacy from existing therapies 
such as statins and PCSK9 inhibitors. As such, significantly accelerated atherosclerosis and 
worse clinical outcomes are observed in these patients compared to those who are LDLR 
defective (Kolansky, 2008) (Moorjani, 1993). Patients who are LDLR null or negative develop 
xanthomas sooner than patients who are LDLR receptor defective, and untreated patients who 
are LDLR null or negative rarely live past the second decade of life (Kolansky, 2008) 
(Moorjani, 1993). 
Current approved therapies for patients with HoFH include statins, lomitapide, ezetimibe, 
evolocumab, and lipoprotein apheresis. All but lomitapide are approved for use in pediatric 
patients ≥12 years of age. Some of the statins are approved in younger patients (rosuvastatin 
approved in ages ≥6 years; atorvastatin and simvastatin approved for ages ≥10 years). Because 
the etiology of the disease is the same for both adult and pediatric patients, the overarching goal 
of therapy is also the same, to lower LDL-C. The current American College of 
Cardiology/American Heart Association (ACC/AHA) guidelines and the European 
Atherosclerosis Society (EAS) recommend at least a 50% reduction in LDL-C in all patients with 
FH to reduce the risk of CVD (Gidding, 2015)(Grundy, 2019)(Wiegman, 2015). The EAS 
further recommends a target LDL-C <130 mg/dl (3.5 mmol/L) in patients >10 years 
(Wiegman, 2015). Lipid-lowering therapy should be started as early as possible (Cuchel, 2014) 
(France, 2016) (Wiegman, 2015). 
Angiopoietin-like protein 3 (ANGPTL3) has recently emerged as a target for treatment of 
elevated levels of LDL-C.  Individuals who are homozygous for loss of function (LOF) 
mutations in ANGPTL3 have lower levels of LDL-C (mean difference of >50% versus control 
subjects (Minicocci, 2012)). The mechanism by which ANGPTL3 LOF mutations result in 
lowering LDL-C is not fully understood but appears to be independent of the LDLR. These data 
suggest that inhibiting ANGPTL3 may be a meaningful and well-tolerated strategy for lowering 
serum LDL-C in patients with HoFH, especially those considered to have LDLR negative 
mutations in both alleles. 
Evinacumab (REGN1500) is a fully human monoclonal antibody (mAb), created with 
Regeneron’s VelocImmune® technology platform, which specifically binds to and inhibits 
ANGPTL3. In an open-label, single-arm, proof-of-concept study in patients with HoFH 
(R1500-CL-1331), evinacumab demonstrated a mean percent reduction from baseline of 49.2% 
(n=9) at week 4, 2 weeks after a single dose of 15 mg/kg IV, with a duration of effect of at least 
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10 weeks (n=7). A peak mean reduction of 52.1% was observed at week 6. Three patients in the 
study had null/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%. 
The LDL-C lowering effect observed with evinacumab in the R1500-CL-1331 study was 
confirmed in study R1500-CL-1629, a large randomized, double-blind, placebo-controlled study 
consisting of adult and adolescent patients with HoFH. On average, patients entered the trial with 
a mean baseline LDL-C of 255 mg/dL, despite treatment with other lipid-lowering therapies, 
including maximally-tolerated statins, PCSK9 inhibitors, ezetimibe, LDL apheresis and 
lomitapide. The trial met its primary endpoint, showing that adding evinacumab to other 
lipid-lowering therapies decreased LDL-C by a mean of 49% from baseline to week 24, 
compared to lipid-lowering therapies alone (47% reduction for evinacumab compared to a 2% 
increase for placebo, p<0.0001). This reduction translates to a mean absolute change in LDL-C 
of 132 mg/dL from baseline, compared to placebo (135 mg/dL reduction for evinacumab 
compared to a 3 mg/dL reduction for placebo, p<0.0001). The decreases in LDL-C were 
observed from the first lipid assessment at week 2 and were maintained throughout the 24-week 
double-blind treatment period. Importantly, similar levels of LDL-C lowering were observed in 
the most difficult-to-treat null/null or negative/negative patients. The dramatic reduction in 
LDL-C led to the achievement of LDL-C levels <100 mg/dL in 47% of the patients treated with 
evinacumab compared to 23% treated with  placebo (nominal p=0.0203). Evinacumab also 
reduced apolipoprotein B (Apo B), non-high-density lipoprotein (HDL) cholesterol 
(non-HDL-C) and total cholesterol (TC) compared to placebo. 
The positive efficacy data in the R1500-CL-1629 study were accompanied by an acceptable 
safety profile.  Evinacumab was generally well-tolerated. During the double-blind treatment 
period, 66% of evinacumab patients and 81% of placebo patients experienced an adverse event 
(AE). AEs that occurred in at least 5% of patients and more commonly with evinacumab were 
influenza-like illness (11% evinacumab, 0% placebo) and rhinorrhea (7% evinacumab, 0% 
placebo). During the double-blind treatment period there was no difference in the incidence of 
nausea, abdominal pain or diarrhea between treatment groups, and there were no deaths, major 
adverse cardiovascular events or findings related to hepatic disorders. 
The primary purpose of this current study is to demonstrate the efficacy, safety and tolerability of 
evinacumab in pediatric patients, aged 5 through 11 years, with HoFH. The study will consist of 
3 parts: Part A (phase 1b), Part B (phase 3), and Part C (phase 3). Part A is a single-dose, 
open-label study to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of 
evinacumab 15 mg/kg intravenous (IV) in approximately 6 patients ages 5 to 11 years with 
HoFH.  Part B is a 24-week, single-arm, open-label study to assess the efficacy and safety of 
evinacumab in approximately 14 pediatric patients with HoFH. Part B will begin when PK data 
from all patients in Part A have been sufficiently analyzed to determine the dose for Part B. Part 
C is an extension of the study available to patients who complete Part A or Part B to continue to 
receive evinacumab. 
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 for Part A of the study is: 
• To assess the PK of evinacumab in pediatric patients with HoFH 
The primary objective for Part B of the study is: 
• To demonstrate a reduction of LDL-C by evinacumab in pediatric (5 to 11 years of 
age) patients with HoFH 
2.2. 
Secondary Objective(s) 
The secondary objective for Part A of the study is: 
• To evaluate the safety and tolerability of evinacumab administered IV in pediatric 
patients with HoFH 
The secondary objectives for Part B of the study are: 
• To evaluate the effect of evinacumab on other lipid parameters (ie, Apo B, non-
HDL-C, TC, lipoprotein a [Lp(a)]) in pediatric patients with HoFH 
• To evaluate the safety and tolerability of evinacumab administered IV in pediatric 
patients with HoFH 
• To assess the PK of evinacumab in pediatric patients with HoFH 
• To assess the immunogenicity of evinacumab in pediatric patients with HoFH over 
time 
• To evaluate patient efficacy by mutation status. 
2.3. 
Exploratory Objective(s) 
The exploratory objectives of the study are: 
• To evaluate the efficacy of evinacumab in the extension of the study (Part C) in 
patients with HoFH 
• To explore vascular changes using imaging techniques 
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3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypothesis 
Blockade of ANGPTL3 with evinacumab will reduce LDL-C in pediatric patients with HoFH. 
3.2. 
Rationale 
3.2.1. 
Rationale for Study Design 
This study is intended to demonstrate the efficacy and safety of evinacumab in the treatment of 
pediatric patients with HoFH.  Diagnosis of HoFH will be based on either genotyping or clinical 
criteria. The genetic definition will include all individuals considered to be 
• Homozygotes: presence of the same mutation(s) in both alleles for LDLR, Apo B, 
PCSK9 or LDLRAP1 (autosomal recessive hypercholesterolemia),  
• Compound heterozygotes: presence of different mutations in the same allele 
• Double heterozygotes: presence of mutations in different genes 
The study will be conducted in 3 parts: 
Part A is a single-dose, open-label study to assess the safety, PK, and PD of evinacumab. The 
purpose of this part of the study is to confirm the dose for Part B and  Part C. To address this 
objective, patients will only receive a single dose of evinacumab, followed by semi-dense PK 
sampling to adequately assess the PK profile in these patients. To ensure a distribution of body 
weight within Part A of the study, every effort will be made to enroll 3 patients <25 kg and 3 
patients ≥25 kg. Additionally, to ensure a distribution of ages, every effort will be made to enroll 
2 patients <10 years of age. 
Part B is a 24-week multiple-dose, single-arm, open-label study to assess the efficacy and safety 
of evinacumab. The purpose of this part of the study is to evaluate the LDL-C lowering effects of 
evinacumab in pediatric patients with HoFH 
Part C is an extension of the study for patients completing Part A and Part B. The purpose of this 
part of the study is to evaluate the long-term safety of evinacumab in pediatric patients with 
HoFH. Initially, patients from Part A who enter Part C will receive evinacumab 15 mg/kg Q4W. 
When all patients complete the PK/PD portion (Part A), the dose for Part B will be determined 
using the cumulative data to date with evinacumab from prior studies and data from Part A. The 
dose for Part B will also be the final dose in Part C. 
The duration of the study for the study participants will be up to approximately 2 years for 
patients in Part A (98 weeks) and for patients in Part B (106 weeks), assuming all patients 
participate in the extension (Part C). This duration was selected to sufficiently assess long-term 
safety and tolerability, including growth and development. 
The primary endpoint of Part B is the percent change in LDL-C from baseline to week 24. 
LDL-C is an accepted surrogate endpoint for CV risk and has repeatedly been used as the 
primary endpoint for approval of other HoFH treatments. This study is designed as an open-label 
trial with the addition of evinacumab on top of patients’ existing treatment regimens of 
maximally tolerated lipid-modifying therapy (LMT), including lipoprotein apheresis. This study 
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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 therapy from patients’ existing treatment regimen 
may lead to an increase in LDL-C and possibly contribute to the serious CV sequelae seen in this 
severe disease with high CV risk. 
3.2.2. 
Rationale for Dose Selection 
The initial dose selected for this study is 15 mg/kg IV Q4W, but could be adjusted to up to a 
maximum of 20 mg/kg IV Q4W. Evinacumab exhibits marked target-mediated drug disposition 
(TMDD), on which the impact of age and body-weight has not been thoroughly evaluated. Body 
weight, in general, has an effect on the linear clearance of mAbs, where mAbs exhibit decreasing 
exposure with decreasing body weight. This trend is due to the over-correction effect when the 
dose is scaled down linearly with body weight, while clearance is scaled down in a 
less-than-linear manner (Zhang, 2015) (Xu, 2019). For this reason, it is possible a dose higher 
than 15 mg/kg may be needed in pediatric patients so that similar exposures seen in the adult 
population are achieved. In addition, the similarity or difference in the PK/PD relationship in 
LDL-C lowering between children younger than 12 years old and adults has not been evaluated. 
To address these uncertainties, Part A, a single dose PK/PD study will be conducted for pediatric 
patients with HoFH (5 to 11 years of age). Based on current data collected from adult patients 
with HoFH, an effect on lowering LDL-C is expected in most patients following a single IV dose 
of evinacumab. Semi-dense PK samples will be collected to characterize PK of evinacumab in 
the pediatric population. Total ANGPTL3 concentrations, a target engagement marker, and LDL-
C reduction, the efficacy measurement, will be evaluated to characterize the PK/PD relationship. 
These data will be compared to those observed in adults and adolescents and data analysis will 
be facilitated by PK/PD modeling and simulation. 
A single dose of 15 mg/kg IV is selected for Part A. It is the dose tested in adolescents (age ≥12 
to <18 years) and adults (age ≥18 years) with HoFH in the on-going phase 3, double-blind, 
placebo-controlled study, R1500-CL-1629 and the phase 3 open-label, long-term safety study, 
R1500-CL-1719. Based on the current PK/PD profile, exposures in Part A are not expected to be 
higher than those observed in adults and adolescents who received the same dose. A similar 
degree of LDL-C lowering is also anticipated to those observed in the ongoing studies.  The final 
dose selection will be based on PK/PD data analysis from Part A and all other available data in 
the evinacumab program. The goals of the dose selection are to: 1) achieve exposure levels in the 
intended pediatric patients within the range observed in the adult and adolescent patients in phase 
3 studies; 2) achieve a similar magnitude of LDL-C reduction as adult patients with HoFH, or to 
have a magnitude of LDL-C reduction considered adequate for the intended pediatric population; 
3) maintain an adequate duration of efficacy during the proposed dosing interval. 
The dose for Part B (and final dose in Part C) will likely remain at 15 mg/kg IV every 4 weeks 
(Q4W). However, there is a small possibility that the exposure analysis or the observed PD effect 
indicate a small increase in the dose is needed for the pediatric population. As such, the dose in 
Part B (and final dose in Part C) could be between 15 and 20 mg/kg IV Q4W. A maximum dose 
of 20 mg/kg is selected as the top dose because it is the highest dose evaluated in the prior 
evinacumab studies.  Preclinical studies in adult cynomolgus monkeys, adult rat, and juvenile 
rats concluded the no-observed-adverse-effect-level (NOAEL) in those studies was considered to 
be 100 mg/kg/dose via IV or subcutaneous (SC). The dose range of 15 to 20 mg/kg IV Q4W 
proposed in the present study is expected to generate steady-state exposure that falls within the 
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range of systemic exposure measured at the NOAEL levels identified during these nonclinical 
toxicology studies. 
A treatment and observation period up to 16 weeks should be an adequate duration to 
characterize the full PK/PD profile in this pediatric population and to allow comparisons with the 
profile observed in the adult patients and the limited number of adolescent patients in the 
ongoing studies. 
3.3. 
Risk-Benefit 
Patients with HoFH have extremely high LDL-C levels are far from their target level and will 
require significant reductions to get to their treatment goal. Statins are the only pharmacological 
LMT approved for use in pediatric patients below the age of 10. Unfortunately, they are unable 
to lower LDL-C sufficiently, even when used in the highest doses and in combination with other 
therapies. Moreover, the unmet need is greatest in patients with null/null mutations of the LDLR 
who typically have the highest levels of LDL-C and in whom statins have minimum to no 
effects.  In addition to pharmacologic treatment, lipoprotein apheresis is the standard of care for 
pediatric patients with HoFH. However, the availability of lipoprotein apheresis is limited, and 
the procedure is expensive, invasive and burdensome for young children and their caregivers. 
Therefore, there is a high unmet need for additional therapeutic options for pediatric patients 
with HoFH. Evinacumab could be a new addition to the armamentarium of LMT that could 
contribute to lowering the LDL-C of HoFH pediatric patients, including patients with null/null 
mutations. 
In study R1500-CL-1331, evinacumab demonstrated a mean percent reduction from baseline of 
49.2% (n=9) at week 4, 2 weeks after a single dose of 15 mg/kg IV, with a duration of effect of 
at least 10 weeks (n=7). A peak mean reduction of 52.1% was observed at week 6. Three patients 
in the study had null/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%. The LDL-C lowering effect observed with evinacumab in the R1500-CL-1331 
study was confirmed in study R1500-CL-1629, a large randomized, double-blind, placebo-
controlled study consisting of adult and adolescent patients with HoFH. On average, patients 
entered the trial with a mean baseline LDL-C of 255 mg/dL, despite treatment with other 
lipid-lowering therapies, including maximally-tolerated statins, PCSK9 inhibitors, ezetimibe, 
LDL apheresis and lomitapide. The trial met its primary endpoint, showing that adding 
evinacumab to other lipid-lowering therapies decreased LDL-C by a mean of 49% from baseline 
to week 24, compared to lipid-lowering therapies alone (47% reduction for evinacumab 
compared to a 2% increase for placebo, p<0.0001). This reduction translated in this study to a 
mean absolute change in LDL-C of 132 mg/dL from baseline, compared to placebo (135 mg/dL 
reduction for evinacumab compared to a 3 mg/dL reduction for placebo, p<0.0001). The 
decreases in LDL-C were observed from the first lipid assessment at week 2 and were 
maintained throughout the 24-week double-blind treatment period. Importantly, similar levels of 
LDL-C lowering were observed in the most difficult-to-treat null/null or negative/negative 
patients. The dramatic reduction in LDL-C led to the achievement of LDL-C levels <100 mg/dL 
in 47% of the patients treated with evinacumab compared to 23% treated with placebo (nominal 
p=0.0203). Evinacumab also reduced Apo B, non-HDL-C and TC compared to placebo. Based 
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on these data in adults, it is expected that the addition of evinacumab to existing treatments will 
lead to significant LDL-C reductions in the pediatric HoFH population. 
In non-FH populations, numerous epidemiological studies and CV outcomes studies with 
lipid-lowering therapies have continually demonstrated that lowering LDL-C reduces the risk of 
CV events.  In fact, 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 (Baigent, 2010). Moreover, results from recent outcomes trials with ezetimibe 
(IMPROVE-IT (Cannon, 2015)), alirocumab (ODYSSEY OUTCOMES (Schwartz, 2018)) and 
evolocumab (FOURIER (Sabatine, 2017)) reinforce this concept, providing additional evidence 
for the relationship between LDL-C lowering through diverse mechanisms and reductions in CV 
events. Within the context of this study in the HoFH pediatric patient population, additional 
reductions in LDL-C at an early age may get patients closer to their LDL-C target and 
maintaining these levels could translate into significant benefit in reducing CV risk. 
It is also expected that treatment with evinacumab will be well tolerated and have an acceptable 
safety profile. The accumulated safety information from the most recent phase 2 and phase 3 
studies where evinacumab was given IV in patients with HoFH (R1500-CL-1629, 
R1500-CL-1719) or persistent hypercholesterolemia (R1500-CL-1643) shows that the more 
common adverse events across all the studies include Nasopharyngitis, Rhinorrhoea, Upper 
respiratory tract infection, Influenza-like illness, Back pain, Pain in extremity, Dizziness, 
Headache, Nausea, Abdominal pain, and Fatigue. 
A review of all available safety data shows there is one identified risk of Systemic 
hypersensitivity reactions, including Infusion reactions, and rarely Anaphylaxis. In most cases, 
the allergic reactions were mild to moderate in intensity, nonserious and, in the case of infusion 
reactions, did not lead to interruption or discontinuation of the evinacumab infusion. One event 
of Anaphylaxis was observed in the phase 2 dose ranging study in patients with severe 
hypercholesterolemia (R1500-CL-1643). Briefly, the anaphylactic reaction was reported in a 
single patient randomized to the evinacumab 15 mg/kg IV treatment group. This patient with 
relevant medical history of syncope, palpitations, asthma, obesity, and seasonal allergy 
experienced an anaphylactic reaction during the second infusion of evinacumab on study day 28. 
Within 5 minutes of initiating the infusion, the patient felt dizzy with a racing heart, followed by 
chest pressure, arms and legs tingling, shortness of breath, itchiness, and feeling warm and 
lethargic. The patient was noticeably flushed with face and chest redness. The infusion was 
stopped. The patient was treated with diphenhydramine orally due to continued itching. The 
event was considered resolved on the same day. The investigator assessed the event as moderate 
in severity and related to study treatment. Study treatment was permanently discontinued. 
Further details of this event are provided in the Investigator’s Brochure. 
The important potential risks include immunogenicity and embryofetal toxicity. These risks will 
be managed through careful patient selection and monitoring. Additionally, any potential effects 
of evinacumab on a child’s development during childhood and early adolescence will be 
monitored via Tanner staging, sex hormones, and overall growth by tracking weight and height. 
A risk-benefit statement with respect to the overall development program is provided in the 
Investigator’s Brochure. 
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Recognizing that the “Coronavirus Disease 2019” (COVID-19) pandemic will have an impact on 
the conduct of clinical trials, the Sponsor does not intend to screen any patients in this study until 
the impact of the COVID-19 pandemic is deemed manageable and no longer interfering with the 
conduct of trials at individual sites, and patients can safely participate in this study. Until then, 
the Sponsor plans to obtain approvals from Health Authorities/Ethics Committees to enable 
initiation of study sites for this study, as allowed by local laws and regulations. 
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4. 
ENDPOINTS 
4.1. 
Primary and Secondary Endpoints 
4.1.1. 
Primary Endpoint 
The primary endpoint for Part A is: 
• The PK parameters for evinacumab, including Cmax, AUC, and linear t1/2, following a 
single administration of evinacumab 
The primary endpoint for Part B is: 
• The percent change in calculated LDL-C from baseline to week 24 (intent-to-treat 
[ITT] estimand) in Part B. 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 is defined as the last calculated LDL-C value obtained before the first 
dose of study treatment in Part B. 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). 
4.1.2. 
Secondary Endpoints 
The secondary endpoint in Part A is: 
• Incidence of treatment-emergent adverse events (TEAE) and other safety variables 
over time 
The secondary endpoints in Part B 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 ≥50% reduction in calculated LDL-C at week 24 (ITT 
estimand) 
• The percent change in calculated LDL-C from baseline to week 24 in patients who 
have negative/negative and null/null mutations (ITT estimand) 
• The percent change in Lp(a) from baseline to week 24 (ITT estimand) 
• The absolute change in LDL-C at week 24 (ITT estimand) 
• Incidence of TEAEs and other safety variables over time 
• Concentrations of total evinacumab over time 
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• PK parameters including Cmax,ss, AUCtau.ss, Ctrough.ss, 
• Incidence and titer of treatment-emergent anti-drug antibodies (ADA) over time 
4.1.3. 
Exploratory Endpoints 
The exploratory endpoints are: 
• Vascular changes via carotid intima-media thickness at baseline and at 6 month 
intervals, as clinically indicated (for intra-patient comparison) 
 
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5. 
STUDY VARIABLES 
5.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height), disease 
characteristics, medical history, and medication history for each patient. 
5.2. 
Efficacy Variables 
The efficacy variables include LDL-C, Apo B, non-HDL-C, TC, and Lp(a). 
5.3. 
Safety Variables 
The safety variables include AEs, laboratory data, vital signs, Tanner stages, and 
electrocardiograms (ECG). 
5.4. 
Pharmacokinetic Variables 
The PK variables are the concentrations of total evinacumab at each time point.  These sampling 
timepoints are specified in Table 1, Table 2, and Table 3. 
Although not a PK variable, total ANGPTL3 concentration in serum is a measure of target 
engagement by evinacumab and will be determined in the samples obtained to evaluate 
evinacumab concentration. 
5.5. 
Immunogenicity Variables 
The immunogenicity variables are ADA status, titer, and neutralizing antibody (NAb) status and 
time-point/visit.  Neutralizing antibody analysis will be conducted for all phases (Part A, B, and 
C) of the study. Samples positive in the ADA assay will be analyzed in the NAb assay.  Samples 
in this study will be collected at the clinic visits specified in Table 1, Table 2, and Table 3. 
5.6. 
Ultrasound Imaging 
Carotid intima-media thickness (cIMT in mm) will be determined at sites with this capability at 
visits specified in Table 1, Table 2, and Table 3. 
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6. 
STUDY DESIGN 
6.1. 
Study Description and Duration 
This study consists of 3 parts: Part A, Part B, and Part C 
• Part A: phase 1B single arm, single dose PK/PD study 
• Part B: phase 3, single-arm, 24-week, open-label efficacy and safety study 
• Part C: phase 3, 48-week treatment period and 24-week follow-up period 
− Note, for patients who enter a CUP or EAP, they may forgo the 24-week follow-
up period after the last dose.  In this situation, the end of treatment (EOT) visit 
will be their last visit. 
Part A is a phase 1B single-dose, open-label study to determine the safety, PK and PD of 
evinacumab 15 mg/kg IV in approximately 6 patients ages 5 to 11 years with HoFH. To ensure a 
distribution of body weight within Part A of the study, every effort will be made to enroll 3 patients 
<25 kg and 3 patients ≥25 kg. Additionally, to ensure a distribution of ages, every effort will be 
made to enroll 2 patients <10 years of age. All patients who successfully complete Part A may 
continue receiving evinacumab in Part C. Initially, patients from Part A who enter Part C will 
receive evinacumab 15 mg/kg IV Q4W. When PK data from all patients in Part A have been 
sufficiently analyzed, the dose for Part B will be determined using the cumulative data to date with 
evinacumab and data from Part A. If data from 6 patients is insufficient, up to 4 more patients may 
be enrolled to confirm the dose in Part B. The dose for Part B will also be the final dose in Part C. 
The dose for Part B (and final dose in Part C) will likely remain at 15 mg/kg IV Q4W. However, 
there is a small possibility that the exposure analysis or the observed PD effect indicate a small 
increase in the dose is needed for the pediatric population to match the exposure and PD effect 
observed in adult patients. As such, the dose in Part B (and final dose in Part C) could be between 
15 and 20 mg/kg IV Q4W. A maximum dose of 20 mg/kg is selected as the top dose because it is 
the highest dose evaluated in the prior evinacumab studies. 
Part A consists of up to 4 periods: run-in; screening; single-dose open-label treatment and 16-week 
observation, and a follow-up period (for patients who do not enter Part C).  Upon completion of 
Part A, patients will have the opportunity to continue into Part C (Figure 1). 
Figure 1: 
Study Flow Diagram Part A  
 
 
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Run-in 
The run-in period is optional and available if a patient requires stabilization of background LMT 
or requires genotyping to confirm diagnosis of HoFH. 
Lipoprotein apheresis therapy - Patients who are undergoing lipoprotein-apheresis with a 
schedule and/or setting not stable for approximately 8 weeks before the screening visit will enter 
an 8-week run-in period before the screening period. All patients undergoing apheresis should be 
on a weekly (every 7±1 days) or every other week (every 14±2 days) schedule. After the 8-week 
run-in period, patients whose lipoprotein-apheresis schedule remains stable will be eligible to 
enter the 2-week screening period. The use of plasmapheresis is excluded. 
Pharmacological lipid-modifying therapy - Patients who are on background LMT not stable for 
at least 4 weeks before the screening visit will enter a 4-week run-in period to stabilize their 
LMT before entering the screening period. 
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 on a stable background LMT (as applicable) for at least 4 weeks (8 weeks for apheresis) 
before the screening visit, will enter a 2-week screening period. Every effort should be made to 
perform the screening visit immediately before apheresis, if applicable, to ensure an accurate 
assessment of the lipid parameters. 
Open-Label Treatment and Observation 
Patients who meet all inclusion criteria and none of the exclusion criteria will be enrolled to 
receive 1 dose of evinacumab 15 mg/kg IV at the baseline visit. 
Patients who are receiving background LMT should maintain stable LMT throughout the 
duration of the study, from screening to the end of study visit for Part A (week 16). Patients on 
apheresis will need to temporarily discontinue apheresis from the baseline visit through 4 weeks 
after the single dose administration of evinacumab. The duration between the apheresis treatment 
prior to the baseline visit and the baseline visit should be at least either 14 days or 7 days, 
depending on the frequency of the patient’s apheresis treatment regimen. Patients will be allowed 
to resume their apheresis schedule after completing all Week 4 assessments. 
After completion of the 16-week open-label treatment and observation period, all patients who 
have successfully completed Part A may enter Part C, the extension of the study (see below). 
Follow-up Period (if applicable) 
Patients not entering Part C will enter an 8-week follow-up period after receiving the single dose 
of evinacumab. In general, a follow-up period of 24 weeks after the single dose of study drug 
will be required for any patient who prematurely discontinues study treatment.   
Part B is a phase 3 single-arm, open-label study to assess the efficacy and safety of evinacumab 
in pediatric patients (age 5 to11 years) with HoFH.  Part B will begin once dose-selection for 
Part B has been completed.  Part B will enroll approximately 14 pediatric patients. Patients 
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enrolled into Part B will not include patients from Part A. Upon completion of Part B, patients 
will have the opportunity to continue into  Part C. 
Part B consists of up to 4 periods: run-in; screening; 24-week open-label treatment; follow-up 
(for patients who do not enter Part C) (Figure 2).   
Figure 2: 
Study Flow Diagram Part B 
 
 
Run-in 
The run-in period is optional and available if a patient requires stabilization of background LMT 
or requires genotyping to confirm diagnosis of HoFH 
Lipoprotein apheresis therapy - Patients who are undergoing lipoprotein-apheresis therapy with 
a schedule and/or setting not stable for approximately 8 weeks before the screening visit will 
enter an 8-week run-in period before the screening period.  All patients undergoing apheresis 
should be on a weekly (every 7±1 days) or every other week (every 14±2 days) schedule. After 
the 8-week run-in period, patients whose lipoprotein-apheresis schedule remains stable will be 
eligible to enter the 2-week screening period. The use of plasmapheresis is excluded.  
Pharmacological lipid-modifying therapy - Patients who are on background medical LMT not 
stable for at least 4 weeks before the screening visit will enter a 4-week run-in period to stabilize 
their LMT before entering the screening period. 
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. 
Open-Label Treatment 
Patients who meet all inclusion criteria and none of the exclusion criteria will be enrolled to 
receive evinacumab IV Q4W. The dose can be between 15 to 20 mg/kg but will likely remain at 
evinacumab 15 mg/kg. The final dose will be confirmed at a dose selection meeting once 
sufficient data from Part A are available. 
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Administration of evinacumab during the treatment period will take place at the study site, 
starting at the baseline visit (visit 2) through week 20 (visit 10). For patients on apheresis, every 
effort should be made to administer evinacumab within 1 day of completing apheresis. 
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 open-label treatment period visit (week 24). 
After completion of the 24-week treatment period, all patients may enter  Part C (see below). All 
patients who enter Part C will continue to receive open-label evinacumab at the dose 
administered in Part B. 
Follow-up Period (if applicable) 
Patients not entering Part C will enter a 20-week follow-up period after completion of the 
treatment period. A follow-up period of 24 weeks after the last dose of study drug will be 
required for any patient who prematurely discontinues study treatment.   
Part C is an extension for patients from both Part A and Part B. It consists of 2 periods: a 
48-week treatment period and a 24-week follow-up period after the last dose of study drug 
(Figure 3). Patients who participate in Part C should enter directly from Part A or Part B. The 
first visit (visit 1) in Part C can occur on the same day as the EOT visit in Part A (visit 11)/Part B 
(visit 11). Overlapping assessments completed at the EOT visit do not need to be duplicated 
during visit 1 in Part C.  
All patients from Part A who enter Part C will initially receive open-label evinacumab 15 mg/kg 
IV Q4W. The final dose in Part C will be the same as the dose in Part B; therefore, the dose in 
Part C for patients entering from Part A may need to be adjusted to align with the dose in Part B. 
Extension 
Administration of evinacumab during Part C will take place at the study site. For patients on 
apheresis, every effort should be made to administer evinacumab within 1 day of completing 
apheresis. 
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Figure 3: 
Study Flow Diagram – Extension 
 
Patients who are receiving background LMT or who are undergoing apheresis should make 
every effort to maintain a stable LMT and a stable apheresis schedule (as applicable) throughout 
the duration of the study to the end of the study. The frequency of apheresis may be reduced 
during this part of the study based on the investigator’s judgement. 
The Sponsor of this study, consistent with our corporate policy governing access to 
investigational drugs in confirmatory clinical studies, is committed to provide evinacumab to 
patients after their participation in this trial has concluded, if permitted per local laws.  
Agreement to continue treatment beyond this study is a treatment decision that must be made by 
the investigator and the patient and/or their parent/guardian. After completion of the study, 
investigators interested in continuing treatment with evinacumab in patients considered to have a 
positive response can discuss post-trial access options with the Sponsor. 
Follow-up Period 
Patients will enter a 24-week follow-up period after the last dose of evinacumab in Part C.  
However, for patients entering a compassionate use or extended access program, they may forgo 
the follow-up period.  The EOT visit will be their last visit.    
Throughout the Study 
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. All samples for clinical 
laboratory evaluation must be obtained prior to evinacumab administration. For patients 
undergoing apheresis, all samples for clinical laboratory evaluation must be obtained 
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immediately prior to apheresis. This is to ensure the effect of apheresis on lipid parameters is 
minimized as much as possible. 
Overall safety will be assessed by monitoring and evaluation of TEAEs, physical examinations, 
vital signs, including blood pressure, ECG, Tanner stages, 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. 
6.1.1. 
Description of Dose Selection 
Pharmacokinetic, PD, and safety data from Part A of the study will be used to determine the dose 
for Part B and the final dose for Part C. This will occur when PK, PD, and safety data from Part 
A have been sufficiently analyzed and reviewed at a Dose Determination Review meeting. This 
meeting will be led by a designated member of the Regeneron clinical team (generally either the 
medical director/study director or the clinical study lead) and at a minimum will be attended by 
the Regeneron Medical Monitor and the Risk Management Lead or designee; other individuals, 
including the Clinical Pharmacology Lead, may be included. The final dose selected will not 
exceed evinacumab 20 mg/kg. 
6.1.2. 
End of Study Definition 
The end of study is defined as the date of the last visit of the last patient. 
6.2. 
Planned Interim Analysis 
No interim analysis is planned. 
6.3. 
Study Committees 
6.3.1. 
Independent Data Monitoring Committee 
An independent data monitoring committee (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; if requested, the IDMC may have access to any other 
requested data for the purposes of a risk-benefit assessment. 
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. 
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7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
7.1. 
Number of Patients Planned 
For Part A, approximately 6 patients are planned. If data from 6 patients is insufficient, up to 4 
more patients may be enrolled to confirm the dose in Part B. 
For Part B, approximately 14 patients are planned. Patients for Part B will not include patients 
from Part A. Patients from Part A and Part B may enter Part C. 
7.1.1. 
Rescreening of Patients 
Patients who do not meet eligibility criteria during the initial screening may rescreen.  Patients 
who are rescreened 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 those assessments that did not meet eligibility criteria. 
7.2. 
Study Population 
Males and females age 5 through 11 years, diagnosed with HoFH receiving any combination of 
lipid-lowering therapies (additional information on background therapies provided in 
Section 6.1). 
HoFH diagnosis can be confirmed by either the genetic or clinical criteria shown in 
Section 7.2.1. 
7.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Males and females ages 5 to 11 years at the time of the screening visit 
2. Diagnosis of functional HoFH by either genetic or clinical criteria: 
Genetic Criteria 
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. Documented homozygous mutations in LDLRAP1, or homozygous or compound 
heterozygous mutations in APOB or PCSK9 
Note: Patients who are double heterozygous, i.e. mutations on different genes 
[LDLR/PCSK9 or LDLR/APOB] are eligible 
 
Clinical Criteria 
 
c. Untreated TC >500 mg/dL (>13 mmol/L) and triglycerides (TGs) <300 mg/dL (<7.8 
mmol/L)  
 
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AND 
Both parents with documented TC >250 mg/dL OR cutaneous or tendinous xanthoma 
in the study patient before age 10 years 
3. LDL-C >130 mg/dL at the screening visit 
4. Body weight ≥15 kg 
5. Receiving stable maximally tolerated therapy*at the screening visit 
*Maximally tolerated therapy could include a daily statin. 
Note: Patients who are not able to be on a maximum daily statin should be on the 
appropriate dose for the patient or no statin, according to the investigator's judgment. 
Some examples of acceptable reasons for a patient taking a lower statin dose include but 
are not limited to: adverse effects on higher doses, lack of efficacy, regional practices, 
local prescribing information, concomitant medications. The reason(s) will be 
documented in the case report form (CRF). 
6. Willing and able to comply with clinic visits and study-related procedures 
7. Parent(s) or legal guardian(s) must provide the signed informed consent form (ICF). 
Patients ≥5 years of age (or above age determined by the IRB/EC and in accordance with 
the local regulations and requirements) must also provide informed assent forms (IAFs) 
to enroll in the study, and sign and date a separate IAF or ICF signed by the 
parent(s)/legal guardian(s) (as appropriate based on local regulations and requirements) 
7.2.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. Background pharmacologic LMT, nutraceuticals or over-the-counter (OTC) therapies 
known to affect lipids, at a dose/regimen that has not been stable for at least 4 weeks (8 
weeks for PCSK9 inhibitors) before the screening visit and patient is unwilling to enter 
the run-in period 
2. For patients entering Part A, unable to temporarily discontinue apheresis from the 
baseline visit through the week 4 visit  
3. Receiving lipid apheresis, a setting (if applicable) and schedule that has not been stable 
for approximately 8 weeks before the screening visit or an apheresis schedule that is not 
anticipated to be stable over the duration of the treatment period (48 weeks). A stable 
schedule is defined as a weekly (every 7±1 days) or every other week (every 14±2 days) 
schedule 
4. Plasmapheresis within 8 weeks of the screening visit, or plans to undergo plasmapheresis 
during Part A or Part B 
5. Presence of any clinically significant uncontrolled endocrine disease known to influence 
serum lipids or lipoproteins 
6. Newly diagnosed (within 3 months prior to randomization visit [week 0/day 1]) diabetes 
mellitus or poorly controlled (hemoglobin A1c [HbA1c] >9%) diabetes 
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7. Chronic use of systemic corticosteroids, unless used as replacement therapy for 
pituitary/adrenal disease with a stable regimen for at least 6 weeks prior to randomization 
Note: topical, intra-articular, nasal, inhaled and ophthalmic steroid therapies are not 
considered as ‘systemic’ and are allowed 
8. History of a myocardial infarction (MI), percutaneous coronary intervention (PCI), 
uncontrolled cardiac arrhythmia, carotid surgery or stenting, stroke, transient ischemic 
attack (TIA), valve replacement surgery, carotid revascularization, endovascular 
procedure or surgical intervention for peripheral vascular disease within 3 months prior to 
the screening visit 
9. History of cancer within the past 5 years 
10. Use of any active investigational drugs within 1 month or 5 half-lives, whichever is 
longer 
11. 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 
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, that the investigator feels would restrict or limit the patient’s 
participation for the duration of the study 
12. Laboratory findings during screening period (not including randomization labs): 
• Positive urine pregnancy test in females of childbearing potential 
• Triglycerides >300 mg/dL (>4.52 mmol/L) (1 repeat lab is allowed)  
• 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) 
13. Known hypersensitivity to monoclonal antibodies or any excipient in the evinacumab 
solution for infusion 
14. Sexually active males, and sexually active females of childbearing potential at screening 
15. Female patients who have commenced menstruating at any time during the study and are 
either: 
• Found to have a positive urine pregnancy test, or 
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• Sexually active, not using or not willing to use an established highly effective 
contraception method prior to subsequent dosing of study treatment, during the study, 
and for at least 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, 
injectable, implantable 
− Intrauterine device or 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 
− 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. 
16. Male patients who become sexually active at any time during the study and do not use an 
established acceptable contraception method of consistent use of barrier contraception 
with spermicide during the study and for up to 24 weeks after the last infusion of study 
drug. 
17. Individuals who are accommodated in an institution by official or court order. 
7.3. 
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 the early 
termination visit, as described in Section 9.1.2. 
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 8.4.2. 
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7.4. 
Replacement of Patients 
Patients prematurely discontinued from study drug will not be replaced. 
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8. 
STUDY TREATMENTS 
8.1. 
Investigational and Reference Treatments 
In Part A, patients will receive 1 dose of evinacumab 15 mg/kg IV infusion over 65 minutes at 
the baseline visit (day 1). 
In Part B, patients will receive evinacumab at a dose assessed from Part A and will be 
administered IV over a 65-minute infusion Q4W starting at the baseline visit (day 1). The last 
dose of evinacumab will be at week 20. 
In Part C, patients from Part A will initially receive evinacumab at 15 mg/kg IV Q4W. The final 
dose selection in Part C will be based on data from Part A and data in adults from other studies.  
Therefore, the dose for patients from Part A entering Part C may be adjusted once the dose 
selection for Part B is completed. 
The IV dose should be prepared using the patient’s most recent weight. The most recent weight 
is either the current visit’s weight or, if the current visit’s weight is not available when preparing 
the dose, the weight from the previous visit. Further instructions on dose preparation are 
provided in the pharmacy manual. 
Dosing should fall within a window of ±7 days; if >14 days have passed, skip the dose and return 
to the original schedule. 
8.2. 
Run-in Treatment(s) 
Patients who are undergoing apheresis therapy should be on a stable weekly (every 7±1 days) or 
every other week (every 14±2 days) schedule and/or stable settings for approximately 8 weeks 
prior to screening.  Patients with a schedule and/or apheresis settings not stable for 
approximately 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 (4 weeks for 
statins and ezetimibe, 8 weeks for PCSK9 inhibitors) before the screening visit will enter a run-in 
period to stabilize their LMT before entering the screening period. 
8.3. 
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 the treatment period visit (week 24) of Part B. For patients who 
enter Part C of the study, and are receiving lipid apheresis, the frequency of apheresis may be 
reduced based on the investigator’s judgement. 
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, 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. 
 
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8.4. 
Dose Modification and Study Treatment Discontinuation Rules 
8.4.1. 
Dose Modification 
Dose modification for an individual patient is not allowed. 
8.4.2. 
Study Drug Discontinuation 
Patients who permanently discontinue from study drug should be encouraged to remain in the 
study.  Those who agree and do not withdraw from the study will be asked to return to the clinic 
for all remaining study visits per the visit schedule. 
Patients in Part B and Part C who prematurely discontinue study drug  and agree to remain in the 
study should undergo all study visits and procedures with the exception of study drug dosing.  At 
the time of study drug discontinuation, the patient should have, as soon as possible, an 
unscheduled visit with assessments normally planned at the week 24 EOT visit (Part B patients) 
or the week 48 visit (Part C patients) and then resume the original study schedule until the end of 
study (EOS) visit.   
Patients who permanently discontinue from study drug and who opt to withdraw from the study 
will be asked to complete study assessments (EOS/early termination [ET]), per Section 9.1.2. 
8.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
An individual will permanently discontinue study drug dosing in the event of: 
• Evidence of pregnancy 
• Serious or severe allergic reactions considered related to study drug 
• Specific types of liver dysfunction (eg, Hy’s law is met ([Guidance for Industry Drug 
Induced Liver Injury: Premarketing Clinical Evaluation FDA 2009]) 
• Patient withdraws consent 
8.4.2.2. 
Reasons for Temporary Discontinuation of Study Drug 
The investigator may temporarily 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. 
8.5. 
Management of Acute Reactions 
8.5.1. 
Acute Intravenous Infusion Reactions 
Emergency equipment and medication for the treatment of infusion reactions must be available 
for immediate use.  All infusion reactions must be reported as AEs (as defined in Section 10.2.4) 
and graded using the grading scales as instructed in Section 10.2.5. 
8.5.1.1. 
Interruption of the Intravenous Infusion 
The infusion should be interrupted if any of the following AEs are observed: 
• cough 
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• rigors/chills 
• rash, pruritus (itching) 
• urticaria (hives, welts, wheals) 
• diaphoresis (sweating) 
• hypotension 
• dyspnea (shortness of breath) 
• vomiting 
• flushing 
The reaction(s) should be treated symptomatically, and the infusion may be restarted at 50% of 
the original rate per investigator discretion. 
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. 
8.5.1.2. 
Termination of the Intravenous Infusion 
The infusion should be terminated and NOT restarted if any of the following AEs occur: 
• anaphylaxis* 
• laryngeal/pharyngeal edema 
• severe bronchospasm 
• severe chest pain 
• seizure 
• severe hypotension 
• other neurological symptoms (confusion, loss of consciousness, paresthesia, paralysis, 
etc.) 
• any other symptom or sign that, in the opinion of the investigator, warrants 
termination of the IV infusion 
*Consider anaphylaxis if the following is observed (Sampson, 2006): acute onset of an illness 
(minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, generalized 
hives, pruritus or ﬂushing, swollen lips-tongue-uvula) AND AT LEAST ONE OF THE 
FOLLOWING  
• Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia) 
• Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence) 
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8.6. 
Method of Treatment Assignment 
This is an open-label study in which all patients receive evinacumab. 
8.7. 
Blinding 
This study is not blinded as it is a single-arm, open-label study. 
To reduce bias, a central lab will be used. 
8.8. 
Treatment Logistics and Accountability 
8.8.1. 
Packaging, Labeling, and Storage 
Open-label study drug will display the product lot number on the label. A medication numbering 
system will be used in labeling investigational study drug.  Lists linking medication numbers 
with product lot numbers will be maintained by the groups responsible for study drug packaging 
and labeling. 
Study drug will be stored at the site at a temperature of 2ºC to 8ºC; storage instructions will be 
provided in the pharmacy manual. 
8.8.2. 
Supply and Disposition of Treatments 
Study drug will be shipped at a temperature of 2ºC to 8ºC to the investigator or designee at 
regular intervals or as needed during the study.  At specified time points during the study (eg, 
interim site monitoring visits), at the site close-out visit, and following drug reconciliation and 
documentation by the site monitor, all opened and unopened study drug will be destroyed / 
returned to the sponsor or designee. 
8.8.3. 
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. 
8.8.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the 
sponsor and regulatory agency inspectors. 
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8.9. 
Concomitant Medications 
Any treatment administered, including apheresis, from the time of informed consent to 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. 
8.9.1. 
Prohibited Medications  
The following concomitant medications and procedures are prohibited in Part A or Part B: 
• Background LMT (if applicable) that has not been stable for at least 4 weeks (eg, 
statins and ezetimibe) with the exception of PCSK9 inhibitors, which is prohibited 
unless stable for 8 weeks before the screening visit (week -2) (unless participating in 
the run-in period to stabilize) 
• Recent discontinuation of lomitapide that has not been washed out for at least 8 
weeks before the screening visit (week -2) 
• Lipid apheresis schedule that is not an approximately every 7 day (±1 day) or an 
every 14 day (±2 days) regimen or has not been stable for approximately 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) 
• Chronic 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) 
8.9.2. 
Permitted Medications  
The use of all nutritional supplements and approved medications known to alter serum lipids, 
including (but not limited to) statins, PCSK9 inhibitors, ezetimibe, fibrates, niacin, bile acid 
resins, red yeast rice is permitted as long as that therapy has been stable for at least 4 weeks for 
most LMT with the exception of PCSK9 inhibitors, which is 8 weeks prior to the screening visit 
(week -2). Patients in Part B should continue taking their background LMT for the duration of 
the study starting at screening and through visit 10 (week 24). Similarly, patients should maintain 
their apheresis regimen (if applicable) starting at screening and through the end of visit 10 
(week 24). 
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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9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
9.1. 
Schedule of Events 
Study assessments and procedures are presented by study period and visit in Table 1, Table 2, 
and Table 3. 
In light of the public health emergency related to COVID-19, the continuity of clinical study 
conduct and oversight may require implementation of temporary or alternative mechanisms. 
Examples of such mechanisms may include, but are not limited to, any of the following: phone 
contact, virtual visits, telemedicine visits, online meetings, non-invasive remote monitoring 
devices, use of local clinic or laboratory locations, and home visits by skilled staff. Additionally, 
no waivers to deviate from protocol enrollment criteria due to COVID-19 will be granted. All 
temporary mechanisms utilized, and deviations from planned study procedures, are to be 
documented as being related to COVID-19 and will remain in effect only for the duration of the 
public health emergency. 
If patients and their physicians decide to enter a compassionate use or early access program, they 
may forgo the 24-week follow-up period following the last dose of evinacumab.  In this case, the 
EOT visit will be their last visit.  There is no need to complete the EOS assessments as they are 
identical to the EOT assessments other than the testing of high sensitivity C-reactive protein (hs-
CRP). 
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Table 1: 
Schedule of Events – Part A, PK and PD Portion 
 
Run-
in13 
Screening 
Open-Label Treatment and Observation Period 
Follow-
up16 
Study Procedure 
Visit 1 
Visit 1a 
Baseline 
Visit 2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
EOT17 
Visit 11 
EOS 
Visit 12 
Day 
-70 to -
14 
-14 to -1 
1 
8 
15 
22 
29 
43 
57 
71 
85 
113 
169 
Week 
-10 to -2 
-2 to -1 
0 
1 
2 
3 
4 
6 
8 
10 
12 
16 
24 
Visit Window (day) 
 
 
±1 
±1 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
Screening/Baseline: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent and 
Assent 
X14 
X 
 
 
 
 
 
 
 
 
 
 
 
Pharmacogenomics 
consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Future Biomedical 
Research Consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Medication History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer Study Drug 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant Meds and 
Treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid Panel (fasting): 
total C, LDL-C, HDL-C, 
TG, non-HDL-C1 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Specialty Lipid Panel 
(fasting): Apo B, Apo A-
1, ApoCIII, ApoE, 
Lp(a)1 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
Safety: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Electrocardiogram2 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Tanner Stage 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
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Run-
in13 
Screening 
Open-Label Treatment and Observation Period 
Follow-
up16 
Study Procedure 
Visit 1 
Visit 1a 
Baseline 
Visit 2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
EOT17 
Visit 11 
EOS 
Visit 12 
Day 
-70 to -
14 
-14 to -1 
1 
8 
15 
22 
29 
43 
57 
71 
85 
113 
169 
Week 
-10 to -2 
-2 to -1 
0 
1 
2 
3 
4 
6 
8 
10 
12 
16 
24 
Visit Window (day) 
 
 
±1 
±1 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
Height 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing3: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
Blood Chemistry 
 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
HbA1c 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
Sex Hormones4 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Urine Pregnancy Test5 
 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
Urinalysis 
 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
TSH 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Hs-CRP 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
PK/Drug Concentration and ADA Samples: 
PK/Drug conc. 
Sample6,7,8 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
ADA sample9 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
Biomarkers: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Future Biomedical 
Research Serum10 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
Future Biomedical 
Research Plasma10 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
Pharmacogenomics: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for HoFH 
genotyping (mandatory) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Whole Blood for DNA 
(optional)11 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of Diet/ 
compliance with LMT  
X 
X 
X 
X 
x 
X 
X 
X 
X 
X 
X 
X 
X 
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CONFIDENTIAL 
 
Run-
in13 
Screening 
Open-Label Treatment and Observation Period 
Follow-
up16 
Study Procedure 
Visit 1 
Visit 1a 
Baseline 
Visit 2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
EOT17 
Visit 11 
EOS 
Visit 12 
Day 
-70 to -
14 
-14 to -1 
1 
8 
15 
22 
29 
43 
57 
71 
85 
113 
169 
Week 
-10 to -2 
-2 to -1 
0 
1 
2 
3 
4 
6 
8 
10 
12 
16 
24 
Visit Window (day) 
 
 
±1 
±1 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
Carotid Ultrasound 
Imaging12 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
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Table 2: 
Schedule of Events – Part B, 24-Week Efficacy and Safety Portion 
 
Run-
In14 
Screening  
Baseline 
Treatment Period 
Study Procedure 
Visit 1 
Visit 1a 
Visit 2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
EOT16 
Visit 
11 
Day 
-70 to -
14 
-14 to -1 
1 
8 
15 
29 
43 
57 
85 
113 
141 
169 
Week 
-10 to -2 
-2 to -1 
0 
1 
2 
4 
6 
8 
12 
16 
20 
24 
Visit Window (day) 
 
 
±1 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
Screening/Baseline: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
Informed Consent and 
Assent 
X17 
X 
 
 
 
 
 
 
 
 
 
 
Pharmacogenomics 
consent 
 
X 
 
 
 
 
 
 
 
 
 
 
Future Biomedical 
Research Consent 
 
X 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
 
X 
 
 
 
 
 
 
 
 
 
 
Medication History 
 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer Study Drug 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
 
Concomitant Meds and 
Treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid Panel (fasting): total 
C, LDL-C, HDL-C, TG, 
non-HDL-C1 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Specialty Lipid Panel 
(fasting): Apo B, Apo A-
1, ApoCIII, ApoE, Lp(a)1 
 
 
X 
 
 
X 
 
X 
X 
 
 
X 
Safety: 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
 
X 
 
 
 
 
 
 
 
 
 
X 
Electrocardiogram3 
 
X 
 
 
 
 
 
 
 
 
 
X 
Tanner Stage 
 
X 
 
 
 
 
 
 
 
 
 
X 
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Run-
In14 
Screening  
Baseline 
Treatment Period 
Study Procedure 
Visit 1 
Visit 1a 
Visit 2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
EOT16 
Visit 
11 
Day 
-70 to -
14 
-14 to -1 
1 
8 
15 
29 
43 
57 
85 
113 
141 
169 
Week 
-10 to -2 
-2 to -1 
0 
1 
2 
4 
6 
8 
12 
16 
20 
24 
Visit Window (day) 
 
 
±1 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
Height 
 
X 
 
 
 
 
 
 
 
 
 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing4: 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
 
X 
X 
 
 
 
 
X 
X 
X 
 
X 
Blood Chemistry 
 
X 
X 
 
 
 
 
X 
X 
X 
 
X 
HbA1c 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Sex Hormones5 
 
X 
X 
 
 
 
 
 
 
 
 
X 
Urine Pregnancy Test6 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
Urinalysis 
 
X 
X 
 
 
 
 
X 
X 
X 
 
X 
TSH 
 
X 
 
 
 
 
 
 
 
 
 
 
Hs-CRP 
 
 
X 
 
 
 
 
 
 
 
 
X 
PK/Drug Concentration and ADA Samples: 
PK/Drug conc. Sample7,8,9 
 
 
X 
 
 
X 
 
X 
X 
 
 
X 
ADA sample10 
 
 
X 
 
 
 
 
 
 
 
 
X 
Biomarkers: 
 
 
 
 
 
 
 
 
 
 
 
 
Future Biomedical 
Research Serum11 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Future Biomedical 
Research Plasma11 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Pharmacogenomics: 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for HoFH 
genotyping (mandatory) 
 
 
X 
 
 
 
 
 
 
 
 
 
Whole Blood for DNA 
(optional)12 
 
 
X 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
Review of Diet, 
compliance with LMT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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CONFIDENTIAL 
 
Run-
In14 
Screening  
Baseline 
Treatment Period 
Study Procedure 
Visit 1 
Visit 1a 
Visit 2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
EOT16 
Visit 
11 
Day 
-70 to -
14 
-14 to -1 
1 
8 
15 
29 
43 
57 
85 
113 
141 
169 
Week 
-10 to -2 
-2 to -1 
0 
1 
2 
4 
6 
8 
12 
16 
20 
24 
Visit Window (day) 
 
 
±1 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
Carotid Ultrasound 
Imaging13 
X 
 
 
 
 
 
 
 
 
X 
 
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Table 2 (contd): 
Schedule of Events – Part B (cont’d) 
 
Follow-Up Period15 
Study Procedure 
Phone Visit 
12 
Visit 13 
Phone 
Visit 14 
Visit 15 
EOS 
Day 
225 
253 
281 
309 
Week 
32 
36 
40 
44 
Visit Window (day) 
±5 
±5 
±5 
±5 
Treatment: 
 
 
 
Administer Study Drug 
 
 
 
 
Concomitant Meds and Treatment 
X 
X 
X 
X 
Efficacy: 
 
 
 
Lipid Panel (fasting): total C, LDL-
C, HDL-C, TG, non-HDL-C1 
 
X 
 
X 
Specialty Lipid Panel (fasting): Apo 
B, Apo A-1, ApoCIII, ApoE, Lp(a)1 
 
 
 
 
Safety: 
 
 
 
Vital Signs2 
 
X 
 
X 
Physical Examination 
 
 
 
X 
Electrocardiogram3 
 
 
 
X 
Height 
 
 
 
X 
Weight 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
Tanner Stage 
 
 
 
X 
Laboratory Testing4: 
 
 
 
Hematology 
 
X 
 
X 
Blood Chemistry 
 
X 
 
X 
Sex Hormones5 
 
 
 
X 
HbA1c 
 
 
 
X 
Urine Pregnancy Test6 
X 
X 
X 
X 
Urinalysis 
 
X 
 
X 
TSH 
 
 
 
 
Hs-CRP 
 
 
 
 
PK/Drug  
Concentration and ADA Samples: 
 
 
 
 
PK/Drug conc. Sample7,8,9 
 
 
 
X 
ADA sample10 
 
 
 
X 
Biomarkers: 
 
 
 
 
Future Biomedical Research Serum 
 
 
 
X 
Future Biomedical Research Plasma 
 
 
 
X 
Pharmacogenomics: 
 
 
 
 
Whole Blood for DNA (optional)11 
 
 
 
 
Other 
 
 
 
 
Review of Diet, compliance with 
LMT 
X 
X 
X 
X 
Carotid Ultrasound Imaging 
 
 
 
 
 
 
 
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Table 3: 
Schedule of Events – Part C 
 
Treatment Period 
24-Week Follow-up 
Period14 
Study Procedure 
V115 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 V11 
V12 
V13 
EOT17 
PV 
14 
V 
15 
PV 
16 
EOS 
V17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weeks post last dose 
Week 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
+8 
+12 
+16 
+24 
Visit Window (day) 
 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer Study Drug 
X16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Concomitant Meds and 
Treatment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid Panel (fasting): total 
C, LDL-C, HDL-C, TG, 
non-HDL-C1 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Specialty Lipid Panel 
(fasting): Apo B, Apo A-1, 
ApoCIII, ApoE, Lp(a)1 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Safety: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Physical Examination 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Electrocardiogram3 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Tanner Stage4 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Height4 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Weight 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing5: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Blood Chemistry 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
HbA1c 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
Sex Hormones4,6 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Urine Pregnancy Test7 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
Hs-CRP 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
PK/Drug Concentration and ADA Samples: 
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Treatment Period 
24-Week Follow-up 
Period14 
Study Procedure 
V115 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 V11 
V12 
V13 
EOT17 
PV 
14 
V 
15 
PV 
16 
EOS 
V17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weeks post last dose 
Week 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
+8 
+12 
+16 
+24 
Visit Window (day) 
 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
PK/Drug conc. Sample8,9,10 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
ADA sample11 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Biomarkers: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Future Biomedical 
Research Serum12  
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Future Biomedical 
Research Plasma12 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of Diet, 
compliance with LMT 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Carotid Ultrasound 
Imaging13 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
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9.1.1. 
Footnotes for the Schedule of Events Table 
9.1.1.1. 
Table 1 Schedule of Events – Part A, PK and PD Portion 
1. Study assessments are to be performed and blood samples are to be collected before the 
dose of study drug in all patients. 
2. ECG should be performed before blood samples are collected at visits requiring blood 
draws. 
3. All laboratory samples should be collected before administration of study drug. 
4. Sex hormones include luteinizing hormone, FSH, estradiol, and total testosterone. 
5. Pregnancy test with a local urine pregnancy test should be done on sexually active 
females who have experienced menarche and are of childbearing potential. 
6. Including assay of total ANGPTL3. Extra samples may be used to assess the 
concentration of concomitant medications, eg, statins. 
7. The PK sample should be drawn predose and at the end of the IV infusion on days when 
study drug is administered 
8.  If apheresis is administered on a dosing day, it is preferred to administer apheresis before 
the evinacumab infusion. The PK sample should be collected prior to apheresis and at the 
end of the evinacumab infusion. In the event apheresis is administered after evinacumab 
administration, the PK sample should be collected prior to and at the end of evinacumab 
infusion, prior to apheresis. 
9. The ADA sample should be drawn before study drug administration. 
10. Parent or legal guardian must sign a separate informed consent form (ICF) and patient 
must sign a separate informed assent prior to collection of Future Biomedical Research 
samples. Patients are still eligible to enroll in the study if they do not wish to participate 
in the Future Biomedical Research. 
11. Parent or legal guardian must sign a separate informed consent form (ICF) and patient 
must sign a separate informed assent to participate in the optional genomics sub-study 
prior to collection of whole blood DNA samples. Patients are still eligible to enroll in the 
study if they do not wish to participate in the genomics sub-study 
12. Carotid ultrasound imaging will be performed only at sites with this capability. Every 
effort should be made for patients to undergo 2 carotid ultrasound imaging assessments 
before the first dose of study drug. The assessments should be separated by at least 1 day.  
13. For patients who require stabilization of their background LMT (including apheresis) or 
need to undergo genotyping to confirm diagnosis of HoFH. 
14. If the patient requires a run-in the ICF should be signed at that time; otherwise ICF 
should be signed at screening visit. 
15. 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 
16. For patients who do not enter Part C, there will be an 8-week follow-up period (visit 12).   
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17. If continuing to Part C, this visit can occur on the same day as visit 1 of Part C. 
9.1.1.2. 
Table 2 Schedule of Events – Part B, 48-Week Efficacy and Safety Portion 
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 before the apheresis procedure; 
every effort should be made to administer study drug within 1 day of the apheresis 
procedure. 
2. 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 
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. Sex hormones include luteinizing hormone, follicle stimulating hormone, estradiol, and 
total testosterone. 
6. Pregnancy test with a local urine pregnancy test should be done on sexually active 
females of childbearing potential. 
7. Including assay of total ANGPTL3. Extra samples may be used to assess the 
concentration of concomitant medications, eg, statins. 
8. The PK sample should be collected predose and at the end of the IV infusion on days 
when study drug is administered. 
9. For patients who are not undergoing apheresis, the PK sample should be drawn before the 
administration of study drug. For patients undergoing apheresis, a PK sample should be 
collected immediately before the apheresis procedure if it is performed before the 
evinacumab infusion. 
10. For patients who are not undergoing apheresis, the ADA sample should be drawn before 
study drug administration. For patients undergoing apheresis, the ADA sample should be 
drawn before the apheresis procedure if it is performed before the evinacumab infusion. 
11. Parent or legal guardian must sign a separate informed consent form (ICF) and patient 
must sign a separate informed assent prior to collection of Future Biomedical Research 
samples. Patients are still eligible to enroll in the study if they do not wish to participate 
in the Future Biomedical Research. 
12. Parent or legal guardian must sign a separate informed consent form (ICF) and patient 
must sign a separate informed assent to participate in the optional genomics sub-study 
prior to collection of whole blood DNA samples. Patients are still eligible to enroll in the 
study if they do not wish to participate in the genomics sub-study.  One DNA sample for 
the genomics sub-study should be collected on day 1 (visit 2) but can be collected at any 
visit after that. 
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13. Carotid ultrasound imaging will be performed only at sites with this capability. Every 
effort should be made for patients to undergo 2 carotid ultrasound imaging assessments 
before the first dose of study drug. The assessments should be separated by at least 1 day. 
14. For patients who require stabilization of their background LMT (including apheresis) or 
need to undergo genotyping to confirm diagnosis of HoFH. 
15. Only for patients who do not enter Part C.   
16. If continuing to Part C, this visit can occur on the same day as visit 1 of Part C. 
17. If the patient requires a run-in, the ICF should be signed at that time; otherwise, the ICF 
should be signed at the screening visit. 
9.1.1.3. 
Table 3 Schedule of Events – Part C 
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 before the apheresis procedure; 
every effort should be made to administer study drug within 1 day of the apheresis 
procedure. 
2. 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 
3. ECG should be performed before blood samples are collected at visits requiring blood 
draws. 
4. Assessment of Tanner Stage, sex hormones, and post-baseline height only applicable to 
patients < 18 years old. 
5. All laboratory samples should be collected before administration of study drug. 
6. Sex hormones include luteinizing hormone, follicle stimulating hormone, estradiol, and 
total testosterone. 
7. Pregnancy test with a local urine pregnancy test should be done on sexually active 
females of childbearing potential. 
8. Including assay of total ANGPTL3. Extra samples may be used to assess the 
concentration of concomitant medications, eg, statins. 
9. The PK sample should be collected predose and at the end of the IV infusion on days 
when study drug is administered. 
10. For patients who are not undergoing apheresis, the PK sample should be drawn before the 
dose of study drug. For patients undergoing apheresis, a PK sample should be collected 
immediately before the apheresis procedure if it is performed before the evinacumab 
infusion. 
11. For patients who are not undergoing apheresis, the ADA sample should be drawn before 
study drug administration. For patients undergoing apheresis, the ADA sample should be 
drawn immediately before the apheresis procedure if it is performed before the 
evinacumab infusion. 
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12. Parent or legal guardian must sign a separate informed consent form (ICF) and patient 
must sign a separate informed assent prior to collection of Future Biomedical Research 
samples. Patients are still eligible to enroll in the study if they do not wish to participate 
in the Future Biomedical Research 
13. Carotid ultrasound imaging will be performed only at sites with this capability. The 
assessment should be performed approximately every 6 months at every other Visit F. 
14. At weeks 8 and 16 of the follow-up period all patients will be contacted by phone to 
query LMT compliance, to inquire about AEs or changes to concomitant medications, 
confirm required contraception use, and remind patients of pregnancy reporting.  
Sexually active females of childbearing potential will report the results of their home 
pregnancy test.  For patients who decide to enter a compassionate use or early access 
program, the EOT visit will be their last visit and they will forgo the 24-week follow-up 
period. 
15. Overlapping assessments completed at the EOT visit of Part A or Part B do not need to 
be duplicated during visit 1 of Part C. Part C visit 1 should occur on the same day as 
Part A visit 11 or Part B visit 11. All necessary assessments are listed in the applicable 
SOE (Part A or Part B) column for visit 11.   
16. Patient can only receive the dose once all assessments from Part A or Part B Visit 11 are 
completed. 
17. For patients who decide to enter a CUP or EAP, the EOT visit will be their last visit and 
they will forgo the 24-week follow-up period. 
9.1.2. 
Early Termination Visit 
For patients in Part A who are withdrawn from the study early, an ET should occur as soon as 
possible with assessments normally planned at the Part A, EOT visit. 
For patients in Part B who permanently discontinue study drug before week 24, an ET visit 
should occur as soon as possible with assessments normally planned at the Part B, EOT visit 
(week 24). 
For patients in Part C who permanently discontinue study drug before the week 48 visit, an ET 
visit should occur as soon as possible with assessments normally planned at the Part C, EOT visit 
(week 48). 
If the patient agrees to continue in the study, after completing the ET visit, the patient should 
resume the original study schedule (except for study treatment administration) until the EOS. 
Specifically, for patients in Part B, all efforts should be made to perform the week 24 
assessments (regardless of study treatment administration). 
If the patient does not agree to continue in the study after completing the ET visit, patients 
should enter the follow-up period and 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.   
If a patient enters a CUP or EAP, they may forgo the 24-week follow-up period. 
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9.1.3. 
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. 
9.2. 
Study Procedures 
9.2.1. 
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:  Demographics, medical/surgical history, medication 
history, and thyroid-stimulating hormone (TSH). 
9.2.2. 
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 conditions (ie, 
overnight, at least 8 hours fast, only water) for all clinic visits. Intense physical exercise within 
24 hours, preceding blood sampling is discouraged. 
Total-C, HDL-C, Apo B, Apo A-1, TG, and Lp(a) 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 TC. 
Detailed procedures of sample preparation, storage, and shipment are provided in the laboratory 
manual. 
9.2.2.1. 
Lipid Panel 
Fasting (at least 8 hours) blood samples will be collected at specified time points shown in 
Section  9.1 for assessment of the lipid profile, comprising calculated LDL-C, HDL-C, non-HDL 
C, TC, 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. 
9.2.2.2. 
Specialty Lipid Panel 
Fasting (at least 8 hours) blood samples will be collected at specified time points shown in 
Section 9.1 for assessment of the specialty lipid profile, comprising Apo B, Apo A-1, ratio of 
Apo B/Apo A-1, ApoCIII, ApoE, and Lp(a). The specialty lipid panels will be assessed in the 
same sample that is collected for the lipid panel. 
9.2.3. 
Safety Procedures 
9.2.3.1. 
Vital Signs 
Vital signs, including temperature, sitting blood pressure, pulse, and respiration rate, will be 
collected predose at time points according to Table 1, Table 2, and Table 3. 
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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. 
9.2.3.2. 
Physical Examination 
A thorough and complete physical examination will be performed at time points according to 
Table 1, Table 2, and Table 3. 
Care should be taken to examine and assess any abnormalities that may be present, as indicated 
by the patient’s medical history. 
9.2.3.3. 
Tanner Stages 
The Tanner stages will be assessed throughout the study for all patients according to Table 1, 
Table 2, and Table 3. 
If possible, for each patient, the Tanner stages assessment should be performed by the same 
investigator/designee trained to assess pubertal development. 
9.2.3.4. 
Electrocardiogram 
Electrocardiograms should be performed before blood is drawn during visits requiring blood 
draws.  A standard 12-lead ECG will be performed at time points according to Table 1, Table 2, 
and Table 3. 
The ECG strips or reports will be retained with the source. 
9.2.3.5. 
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, and 
Table 3 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 
Uric acid 
Chloride 
Blood urea nitrogen (BUN) 
Creatine phosphokinase (CPK) 
Carbon dioxide 
Aspartate aminotransferase (AST) 
 
Calcium 
Alanine aminotransferase (ALT) 
 
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, and Table 3 
and are as follows:  TSH, hs-CRP, HbA1c, sex hormones (luteinizing hormone, follicle 
stimulating hormone, estradiol, and total testosterone), 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/Study Director 
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 10.1.1. 
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9.2.4. 
Drug Concentration and Measurements 
Samples for assessment of evinacumab and total ANGPTL3 concentrations (marker of target 
engagement) will be collected at time points listed in Table 1, Table 2, and Table 3. They will be 
collected predose and at the end of the IV infusion on days when study drug is administered. 
Any unused samples collected for drug concentration measurements may be used to assess the 
concentration of concomitant medications, eg, statins, and for exploratory biomarker research or 
other investigations. 
9.2.5. 
Immunogenicity Measurements and Samples 
Samples for ADA assessment will be collected at time points listed in Table 1, Table 2, and 
Table 3. 
Samples positive in the ADA assay will be analyzed in the NAb assay. 
In case of a suspected SAE such as hypersensitivity or anaphylactic reaction, additional samples 
may be collected at or near the time of the event. 
Any unused samples collected for ADA assessments may be used for exploratory research or 
bioanalytical investigations. 
9.2.6. 
Ultrasound Imaging 
Carotid ultrasound is a reliable method to measure carotid intima-media thickness (cIMT; in 
mm), which has been shown to be increased in children with HoFH (Kusters, 2014). The 
technique has shown reliable results with an interobserver coefficient of variation of 7.3% 
(Doyon, 2013). 
9.2.7. 
Other Assessments 
9.2.7.1. 
Review of Diet and Compliance with LMT 
Patients should maintain a stable and exercise routine. Patients will be queried on compliance 
with their diet and compliance with LMT during the study, at time points according to 
Section 9.1. 
9.2.7.2. 
DNA Sample for HoFH Genotyping 
A required blood sample for DNA extraction will be collected from all patients to identify or 
confirm known mutations in PCSK9, LDLR, APOB, and LDLRAP1 genes. 
9.2.7.3. 
Future Biomedical Research (Optional) 
Research samples (serum/plasma) will be collected at time points listed in Table 1, Table 2, and 
Table 3. 
Parents or legal guardians of patients who agree to participate in the future biomedical research 
sub-study will be required to consent and patients required to assent to this optional sub-study 
before samples are banked in long-term storage.  The unused biomarker samples for study-
related research, as well as unused PK and ADA samples, will be stored for up to 15 years after 
the final date of the database lock. The unused samples may be utilized for future biomedical 
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research of FH and related diseases, evinacumab (safety and/or efficacy) or ANGPTL3. No 
additional samples will be collected for future biomedical research.  After 15 years, any residual 
samples will be destroyed. The results of these future biomedical research analyses will not be 
presented in the Clinical Study Report. 
9.2.7.4. 
Pharmacogenomic Analysis (Optional) 
Parents or legal guardians of patients who agree to participate in the genomics sub-study will be 
required to sign a separate genomics sub-study informed consent form (ICF) and patients must 
sign a separate informed assent form before collection of the samples. Patients are not required to 
participate in the genomics sub-study in order to enroll in the primary study. Samples for DNA 
extraction should be collected on day 1/baseline (predose) but may be collected at any study 
visit. 
DNA samples for the genomics sub-study will be coded as defined by the International Council 
for Harmonisation (ICH) guideline E15. Sub-study samples will be stored for up to 15 years after 
the final date of the database lock and may be used for research purposes. The purpose of the 
genomic analyses is to identify genomic associations with clinical or biomarker response, other 
clinical outcome measures and possible AEs. In addition, associations between genomic variants 
and prognosis or progression of HoFH as well as related diseases may also be studied. These 
data may be used or combined with data collected from other studies to identify and validate 
genomic markers related to the study drug or HoFH and other diseases. Analyses may include 
sequence determination or single nucleotide polymorphism studies of candidate genes and 
surrounding genomic regions. Other methods, including whole-exome sequencing, whole 
genome sequencing, DNA copy number variation may also be performed. The list of methods 
may be expanded to include novel methodology that may be developed during the course of this 
study or sample storage period. 
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10. 
SAFETY EVALUATION AND REPORTING 
10.1. 
Recording and Reporting Adverse Events 
10.1.1. 
General Guidelines 
The investigator must promptly record all clinical events occurring during the study data 
collection period from the time of signing the ICF or first dose to the end of the treatment period 
(see Section 11.4.5.1).  Medical conditions that existed or were diagnosed prior to the signing of 
the Informed Consent will be recorded as part of medical history.  Abnormal laboratory values 
and vital signs observed at the time of Informed Consent should also be recorded as medical 
history.  Any subsequent 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 
should also be recorded as an AE. 
At each visit, the investigator will determine whether any AEs have occurred by evaluating the 
patient.  Adverse events may be directly observed, reported spontaneously by the patient, or by 
questioning the patient at each study visit.  Patients should be questioned in a general way, 
without asking about the occurrence of any specific symptoms.  The Investigator must assess all 
AEs to determine seriousness, severity, and causality, in accordance with the definitions in 
Section 10.2.  The Investigator’s assessment must be clearly documented in the site’s source 
documentation with the Investigator’s signature.  The Investigator should follow up on SAEs 
(and AESIs) until they have resolved or are considered clinically stable; AEs should be followed 
until they are resolved or last study visit, whichever comes first. 
Always report the diagnosis as the AE or SAE term.  When a diagnosis is unavailable, report the 
primary sign or symptom as the AE or SAE term with additional details included in the narrative 
until the diagnosis becomes available.  If the signs and symptoms are distinct and do not suggest 
a common diagnosis, report them as individual entries of AE or SAE. 
Laboratory results, vital signs, and other diagnostic results or findings should be appraised by the 
Investigator to determine their clinical significance.  Isolated abnormal laboratory results, vital 
sign findings, or other diagnostic findings (ie, not part of a reported diagnosis) should be 
reported as AEs if they are symptomatic, lead to study drug discontinuation, dose reduction, 
require corrective treatment, or constitute an AE in the investigator’s clinical judgment. 
For events that are serious due to hospitalization, the reason for hospitalization must be reported 
as the serious adverse event (diagnosis or symptom requiring hospitalization).  A procedure is 
not an AE or SAE, but the reason for the procedure may be an AE or SAE.  Pre-planned (prior to 
signing the Informed Consent Form) procedures, treatments requiring hospitalization for 
pre-existing conditions that do not worsen in severity, and admission for palliative or social care 
should not be reported as SAEs (see Section 10.2 for Definitions). 
For deaths, the underlying or immediate cause of death should always be reported as an SAE. 
Any SAE that may occur subsequent to the reporting period (end of the on-treatment period) that 
the Investigator assesses as related to study drug should also be reported. 
All AEs, serious adverse events (SAEs), AESIs, and pregnancy reports are to be reported 
according to the procedures in Section 10.1.4. 
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10.1.2. 
Data Collection Period 
The investigator will record all events, serious and non-serious, that occur from the time of 
signing the informed consent and for 24 weeks after the last dose of study drug (ie, the 
follow-up/post treatment period).  The follow-up/post treatment period applies to all patients 
who complete the study or terminate early (excludes those who withdraw consent).  However, 
for those patients entering a CUP or EAP, they may forgo the 24-week follow-up period. 
From the time of signing the informed consent and prior to first dose of study drug, the 
investigator will report the following types of events on the AE CRF: 
• SAEs 
• Events, serious and non-serious, attributed to study conduct, such as a 
protocol-mandated procedure or intervention (eg, events related to an invasive 
procedure such as a biopsy) 
Other events that occur prior to the first dose of study drug should be reported on the medical 
history CRF. 
From first dose of study drug, report all AEs on the AE CRF until EOS visit, which includes the 
follow-up/post treatment period after last dose. 
10.1.3. 
Reporting Procedure  
All events (serious and non-serious) must be reported with investigator’s assessment of the 
event’s seriousness, severity, and causality to the (when applicable: blinded) study drug.  For 
SAEs and AESIs, a detailed narrative summarizing the course of the event, including its 
evaluation, treatment, and outcome should be provided on the AE CRF.  Specific or estimated 
dates of event onset, treatment, and resolution should be included, when available.  Medical 
history, concomitant medications, and laboratory data that are relevant to the event should also 
be summarized in the narrative.  For fatal events, the narrative should state whether an autopsy 
was or will be performed, and include the results if available.  Information not available at the 
time of the initial report must be documented in a follow-up report.  Source documents 
(including hospital or medical records, diagnostic reports, etc.) will be summarized in the 
narrative on the AE CRF, and retained at the study center and available upon request. 
Urgent safety queries must be followed up and addressed promptly.  Follow-up information and 
response to non-urgent safety queries should be combined for reporting to provide the most 
complete data possible within each follow-up. 
10.1.4. 
Events that Require Expedited Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of 
learning of the event: 
• SAEs. 
• Adverse Events of Special Interest (AESI; serious and nonserious):  Adverse events 
of special interest for this study include the following: 
− Anaphylactic reactions 
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− Allergic reactions that require consultation with another physician for further 
evaluation or requiring medical treatment 
− Moderate or severe infusion reactions 
− Increase in ALT or AST: ≥3 x ULN (if baseline <ULN), or ≥2 times the baseline 
value (if baseline ≥ ULN) 
− Symptomatic overdose with investigational medicinal product 
− Neurocognitive events 
− Pancreatitis 
− New onset of diabetes (NOD) in patients without diabetes at baseline. New onset 
of diabetes is defined as either: 
− At least 2 HbA1c measurements ≥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 qualify the patient as NOD by 
default) 
− At least 2 fasting glucose measurements ≥126 mg/dL (7.0 mmol/L). For 
patients with several fasting glucose measurements but with only 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) 
− NOTE: Diabetes at baseline is based on documented medical history, baseline 
fasting glucose ≥126 mg/dL (7.0 mmol/L), or baseline HbA1c ≥6.5% 
• Pregnancy: 
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. 
10.2. 
Definitions 
10.2.1. 
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 (ICH E2A Guideline. Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting, Oct 1994). 
10.2.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
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• 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 a hospital admission (any duration) or an 
emergency room visit for longer than 24 hours.  Prolongation of existing 
hospitalization is defined as a hospital stay that is longer than was originally 
anticipated for the event, or is prolonged due to the development of a new AE as 
determined by the investigator or treating physician. 
• Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect 
• Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent one of the other serious outcomes listed above 
(eg, intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development 
of drug dependency or drug abuse). 
Criteria for reporting SAEs must be followed for these events. 
10.2.3. 
Adverse Events of Special Interest 
An adverse event of special interest (AESI; serious or non-serious) is one of scientific and 
medical interest 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. 
10.2.4. 
Infusion Reactions 
Infusion reactions are defined as any relevant AE that occurs during the infusion or within 2 
hours after the infusion is completed. 
10.2.5. 
Severity 
The severity of AEs will be graded according to the following scale: 
Mild: Does not interfere in a significant manner with the patient normal functioning level.  It 
may be an annoyance.  Prescription drugs are not ordinarily needed for relief of symptoms, but 
may be given because of personality of the patient. 
Moderate: Produces some impairment of functioning but is not hazardous to health.  It is 
uncomfortable or an embarrassment.  Treatment for symptom may be needed. 
Severe: Produces significant impairment of functioning or incapacitation and is a definite hazard 
to the subject’s health.  Treatment for symptom may be given and/or patient hospitalized. 
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If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
Infusion Reactions 
The severity of infusion reactions will be graded according to the following scale (semi-colon 
indicates “or” within description of the grade): 
Mild: Mild transient reaction; infusion interruption not indicated; intervention not indicated. 
Moderate: Therapy or infusion interruption indicated but responds promptly to symptomatic 
treatment (eg, antihistamines, NSAIDs, narcotics, IV fluids); prophylactic medications indicated 
for ≤24 hours. 
Severe: Prolonged (eg, not rapidly responsive to symptomatic medication and/or brief 
interruption of infusion); recurrence of symptoms following initial improvement; hospitalization 
indicated for clinical sequelae; life-threatening consequences; urgent intervention indicated; 
death. 
10.2.6. 
Causality 
The investigator must provide causality assessment as whether or not there is a reasonable 
possibility that the drug caused the adverse event, based on evidence or facts, his/her clinical 
judgment, and the following definitions.  The causality assessment must be made based on the 
available information and can be updated as new information becomes available. 
The following factors should be considered when assessing causality: 
• Temporal relationship: time to onset vs time drug was administered 
• Nature of the reactions: immediate vs. long term 
• Clinical and pathological features of the events 
• Existing information about the drug & same class of drugs 
• Concomitant medications 
• Underlying and concurrent illnesses 
• Response to dechallenge (drug discontinuation) or dose reduction 
• Response to rechallenge (re-introduction of the drug) or dose increase, when 
applicable 
• Patient’s medical and social history 
Causality to the study drug (including study drug administration): 
• Related: 
− The AE follows a reasonable temporal sequence from study drug administration, 
and cannot be reasonably explained by the nature of the reaction, patient’s clinical 
(eg, disease under study, concurrent diseases, concomitant medications), or other 
external factors. 
or 
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− The AE follows a reasonable temporal sequence from study drug administration, 
and is a known reaction to the drug under study or its class of drugs, or is 
predicted by known pharmacology. 
• Not Related: 
− The AE does not follow a reasonable sequence from study drug administration, or 
can be reasonably explained by the nature of the reaction, patient’s clinical state 
(eg, disease under study, concurrent diseases, and concomitant medications) or 
other external factors. 
Causality to the study conduct (protocol specified procedure): 
• Related: 
− The AE follows a reasonable temporal sequence from a protocol specified 
procedure, and cannot be reasonably explained by the nature of the reaction, 
patient’s clinical (eg, disease under study, concurrent diseases, concomitant 
medications), or other external factors. 
• Not Related: 
− The AE does not follow a reasonable sequence from a protocol specified 
procedure, or can be reasonably explained by the nature of the reaction, patient’s 
clinical state (eg, disease under study, concurrent diseases, and concomitant 
medications) or other external factors. 
10.3. 
Safety Monitoring 
The investigator will monitor the safety of study patient at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP).  Any questions or 
concerns should be discussed with the sponsor in a timely fashion.  The sponsor will monitor the 
safety data from across all study sites.  The Medical/Study Director will have primary 
responsibility for the emerging safety profile of the compound, but will be supported by other 
departments (eg, Pharmacovigilance; 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. 
10.4. 
Notifying Health Authorities, Institutional Review Board /Ethics 
Committee, and Investigators 
During the study, the sponsor and/or the CRO will inform health authorities, IECs/IRBs, and the 
participating investigators of any SUSARs (Suspected Unexpected Serious Adverse Reactions) 
occurring in other study centers or other studies of the active study drug (REGN1500), as 
appropriate per local reporting requirements. In addition, the sponsor and/or CRO will comply 
with any additional local safety reporting requirements. 
Upon receipt of the sponsor’s notification of a SUSAR that occurred with the study drug, the 
investigator will inform the Institutional Review Board (IRB)/Ethics Committee (EC) unless 
delegated to the sponsor. 
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Event expectedness for study drug (REGN1500) is assessed against the Reference Safety 
Information section of the current Investigator’s Brochure that is effective for expedited safety 
reporting. 
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 IECs/IRB as 
appropriate. 
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11. 
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 first database lock. 
Endpoints are listed in Section 4.  Analysis variables are listed in Section 5. 
11.1. 
Statistical Hypothesis 
No formal statistical testing will be performed for this open-label study. 
11.2. 
Justification of Sample Size 
Since this is an open-label single treatment arm study, formal statistical testing is not planned, 
Therefore, a calculation for patient sample size is not applicable. 
Six patients are planned to be enrolled for Part A and 14 pediatric patients are planned to be 
enrolled for Part B, considering the recruitment constraints in this rare patient population. 
11.3. 
Analysis Sets 
11.3.1. 
Efficacy Analysis Set for Part B 
Intent-to Treat 
The intent-to-treat (ITT) population is defined as all patients who received at least 1 dose or part 
of a dose of study drug in Part B. 
Modified Intent-to-Treat 
The modified ITT (mITT) population is defined as all patients who received at least 1 dose or 
part of a dose of open-label study drug in Part B and have an evaluable primary efficacy 
endpoint. The endpoint is considered as evaluable when both of the following conditions are 
met: 
1. Availability of at least 1 measurement value for calculated LDL-C before first dose of 
study drug (ie, baseline). 
2 Availability of at least 1 calculated LDL-C value during the efficacy treatment period and 
within one of the analysis windows up to week 24. The efficacy treatment period is 
defined as the time from the first study drug administration up to 35 days after the last 
study drug administration in Part B. 
11.3.2. 
Safety Analysis Set 
Safety Analysis Set: The safety analysis set (SAF) includes all patients who received at least 1 
dose or part of a dose of study drug. 
Part C Safety Analysis Set: The Part C safety analysis set includes all patients who received at 
least 1 dose or part of a dose of study drug in Part C.  
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11.3.3. 
Pharmacokinetic Analysis Sets 
The PK analysis population includes all patients who received any study drug and who had a at 
least 1 non-missing result for concentration of evinacumab following the first dose of study drug. 
The total target analysis population includes all patients who received any study drug and who 
had a at least 1 non-missing result for concentration of total ANGPTL3 following the first dose 
of study drug. 
11.3.4. 
Immunogenicity Analysis Sets 
The ADA analysis set includes all patients who received any study drug and had at least 1 
non-missing ADA result following the first dose of study drug. 
Samples positive in the ADA assay may be analyzed in neutralizing antibody assay. 
The NAb analysis set includes all patients who received any study drug and who are negative in 
the ADA assay or with at least 1 non-missing result in the NAb assay following the first dose of 
the study drug. Patients who are ADA negative are set to negative in the NAb analysis set. 
11.4. 
Statistical Methods 
For continuous variables, descriptive statistics will include the following information: the 
number of patients reflected in the calculation (n), mean, standard deviation, Q1, median, Q3, 
minimum, and maximum. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
Data for patients in Part A and patients in Part B will be summarized and listed separately. 
Similar analyses will be performed for patients in Part A and patients in Part B, respectively, 
unless otherwise specified. 
11.4.1. 
Patient Disposition 
The following will be provided: 
• The total number of screened patients: met the inclusion criteria regarding the target 
indication and signed the ICF 
• The total number of patients in each analysis set (eg, ITT, SAF, provided in 
Section 11.3) 
• The total number of patients who discontinued the study, and the reasons for 
discontinuation 
• The total number of patients who prematurely discontinued study treatment in Part B, 
and the reasons for discontinuation 
• The total number of patients who entered Part C 
• The total number of patients who prematurely discontinued study treatment in Part C 
and the reasons for discontinuation 
• A listing of patients prematurely discontinued from study treatment, along with 
reasons for discontinuation 
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11.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively for patients in the 
SAF for Part A, and for patients in the ITT population for Part B. 
11.4.3. 
Efficacy Analyses 
11.4.3.1. Primary Efficacy Analysis for Part B 
The percent change from baseline in calculated LDL-C at week 24 will be analyzed in the ITT 
population using a pattern mixture model (PMM) approach as described below (see Appendix 1 
for more details). 
In the PMM approach, different imputation strategies will be applied to calculated LDL-C values 
missing during the on-treatment period (ie, within the time period from the first study treatment 
administration up to the day of last study treatment administration +35 days in Part B) versus 
calculated LDL-C values missing due to treatment discontinuation after the on-treatment period 
(ie, after the day of last study treatment administration +35 days in Part B) based on the 
following assumptions: 
• Patients within 35 days of their last study treatment administration in Part B would 
continue to show benefit from treatment similar to that observed at the scheduled time 
point.  Therefore, calculated LDL-C values missing during the on-treatment period 
(eg, 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 in Part B no longer benefited from 
it after discontinuation, and thus tended to have calculated LDL-C values returning to 
baseline.  Therefore, calculated LDL-C values missing after the on-treatment period 
should be imputed based on patient’s own baseline value. 
Missing data from the ITT 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 calculated LDL-C data will be used for the primary analysis. 
For the percent change from baseline calculated LDL-C endpoint, the 100 complete datasets of 
observed and imputed calculated LDL-C data at week 24 will be analyzed using the SAS 
MEANS procedure.  The SAS MIANALYZE procedure will be used to generate valid statistical 
inferences by combining results from the 100 analyses using Rubin’s formulae. Combined 
estimate for mean at Week 24 will be provided with the standard error (SE) and 95% confidence 
interval (CI). Formal statistical testing is not planned. 
Robustness of this statistical method will be assessed through sensitivity analyses detailed in the 
SAP, including an ITT analysis and an on-treatment analysis of the percent change in calculated 
LDL-C from baseline to week 24 using a mixed-effect model with repeated measures (MMRM) 
approach. All post-baseline data available within the week 1 to week 24 analysis windows will 
be used and missing data will be accounted for by the MMRM model. The model will include 
the fixed categorical effect of time point, as well as the continuous fixed covariate of baseline 
LDL-C value. 
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11.4.3.2. Secondary Efficacy Analysis for Part B 
For the secondary efficacy endpoints (defined in Section 4.1.2), 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, non-HDL-C, Apo B, and Lp(a) will be provided at each time point 
during the 24-week open-label treatment period. 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. The time profile of each parameter will be plotted 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 (eg, percent 
change in calculated LDL-C), continuous measurements expected to have a non-normal 
distribution [eg, Lp(a)], and binary measurements (eg, proportion of patients with ≥50% 
reduction in calculated LDL-C). 
I 
Continuous endpoints anticipated to have a normal distribution 
Continuous secondary efficacy endpoints anticipated to have a normal distribution (ie, lipids 
other than Lp(a)) will be analyzed using the same PMM approach as for the primary endpoint. In 
addition, the same sensitivity analyses using MMRM approach as for the primary endpoint will 
be conducted in the ITT population and mITT population. 
II 
Continuous endpoints anticipated to have a non-normal distribution 
Continuous secondary efficacy endpoints anticipated to have a non-normal distribution (ie, 
Lp(a)), will be analyzed using a robust regression model (ie, ROBUSTREG SAS procedure with 
M-estimation option) with baseline value as a covariate. Missing values will be addressed using 
a multiple imputation approach, which will be described in the SAP. The combined means will 
be provided with respective SE estimates and 95% CI. 
III 
Binary Endpoints 
Binary secondary efficacy endpoints will be analyzed with multiple imputation approach for 
handling of missing values, which will be described in the SAP. Combined proportions will be 
provided with corresponding 95% CI. 
11.4.3.3. Other Efficacy Analyses for Part B 
For patients who entered Part C, a combined summary including both the Part B and Part C 
assessments will be considered, referencing the Part B baseline for variable calculations. 
Prolonged time between last dose of study treatment in Part B and first dose of study treatment in 
Part C will need to be taken into consideration when combining longitudinal efficacy data. 
11.4.4. 
Control of Multiplicity 
Not applicable. 
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11.4.5. 
Safety Analysis 
The summary of safety results will be presented for patients in the SAF analysis set. 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 study 
treatment. 
Safety analyses for the Part C treatment period in the Part C safety analysis set of Part A patients 
will be performed separately for the period pre- versus post-switch to adjusted dose if applicable. 
Safety analyses for the combined treatment period of Part B and Part C will be performed in the 
Part C safety analysis set of Part B patients. 
11.4.5.1. 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 primary system organ class (SOC) will be listed. 
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 study treatment. 
• The TEAE observation period (Part A or Part B) is defined from the day of the first 
study treatment administration to the day of the last study treatment administration + 
168 days (24 weeks). For patients entering Part C, the TEAE period was truncated at 
the day before the first study treatment administration in Part C. 
• The Part C TEAE observation period is defined from the day of the first study 
treatment administration in Part C to the day of the last study treatment administration 
in Part C + 168 days (24 weeks). 
• The Part B/Part C combined TEAE observation period is defined from the day of the 
first study treatment administration in Part B to the day of the last study treatment 
administration in Part C or to the last study treatment administration in Part B for 
patients not entering into Part C + 168 days (24 weeks). 
• The post-treatment period is defined as the time from the day after the end of the 
respective TEAE period to the last study visit. 
Treatment-emergent adverse events are defined as those events that developed, worsened, or 
became serious during the respective 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 
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SAP. The denominator for computation of percentages is the respective SAF analysis sets (ie, 
SAF or Part C SAF). 
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 
• TEAEs by severity (according to the grading scale outlined in Section 10.2.5), 
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 period and the post-treatment period. 
11.4.5.2. 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 TEAE 
period, taking into account all evaluations performed during the TEAE period, 
including unscheduled or repeated evaluations. The number of all such patients will 
be the numerator for the PCSV percentage. 
• Treatment period (Part A or Part B): the treatment period used for quantitative 
analysis of laboratory and vital signs data is defined from the day after the first  study 
treatment administration to the day of the last study treatment administration + 28 
days for those patients not proceeding into Part C, or up to the day of the first study 
treatment administration in Part C for those patients proceeding into Part C. 
• Part C treatment period: the treatment period used for quantitative analysis of 
laboratory and vital signs data is defined from the day after the first study treatment 
administration in Part C to the day of the last  study treatment administration in Part C 
+ 28 days. 
• Part B/Part C combined treatment period: the treatment period used for quantitative 
analysis of laboratory and vital signs data is defined from the day after the first study 
treatment administration in Part B to the day of the last study treatment administration 
in Part C or to last study treatment administration in Part B for patients not entering 
into the Part C + 28 days. 
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Analysis 
Summary statistics of all laboratory variables and all vital signs parameters (raw data and 
changes from baseline) will be calculated for each protocol scheduled visit assessed during the 
respective treatment period. For selected parameters, mean changes from baseline with the 
corresponding SE may be plotted over time (at same time points). 
The incidence of PCSVs at any time during the respective treatment period 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. 
Listings will be provided with flags indicating the laboratory values meeting PCSV criteria. 
11.4.5.3. Treatment Exposure 
The Part A or Part B duration of study treatment will be calculated as: 
• Patient duration of study treatment exposure in weeks: (last study treatment 
administration date + 28 – first study treatment administration date +1 day)/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 treatment infusions by patient. 
The Part C duration of study treatment exposure will be calculated as: 
• Patient duration of Part C study treatment exposure in weeks: (last study treatment 
administration date in Part C + 28 – first study treatment administration date in Part C 
+1 day)/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 Part C treatment infusions by patient. 
The combined Part B/Part C duration of study treatment exposure will be calculated as: 
• Combined patient duration of study treatment exposure in weeks: Part B treatment 
duration + Part C treatment duration. 
• Combined total number of treatment infusions by patient defined as: total number of 
Part B study treatment infusions + total number of Part C treatment infusions. 
The durations of study treatment exposure measured in weeks, will be summarized by at least; 
mean, median, SD, and minimum/maximum. The categorical data for number of study treatment 
infusions will be summarized by patient counts and percentages. 
11.4.5.4. Treatment Compliance 
Compliance will be assessed by infusion frequency for the Part A treatment period, the Part B 
treatment period, and the combined Part B/Part C treatment period, specifically: 
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• Defined for each patient as the average number of days between 2 infusions during 
the respective period: (last dose date – first dose date) / (number of infusions -1), for 
patients receiving at least 2 infusions. 
Infusion frequency will be summarized by at least; mean, median, SD, and minimum/maximum. 
11.4.6. 
Pharmacokinetics 
11.4.6.1. Analysis of Drug Concentration Data 
The PK parameters for Part A may include, but are not limited to: 
• Cmax 
• AUClast 
• AUCinf 
• CL 
• Linear t1/2 
• Vss 
• MRT 
The PK parameters for Part B include: 
• Cmax.ss 
• AUCtau.ss 
• Ctrough.ss 
The concentrations of total evinacumab over time and selected PK parameters for Part A will be 
summarized by descriptive statistics for the purpose of estimating exposures.  This descriptive 
statistical assessment will include the geometric means for selected PK parameters, as deemed 
appropriate. 
No formal statistical hypothesis testing will be performed. 
11.4.7. 
Analysis of Immunogenicity Data 
Immunogenicity will be characterized by the ADA response observed: 
• Pre-existing immunoreactivity, defined as a positive ADA assay response at baseline, 
with all post-first dose ADA results negative, or a positive assay response at baseline, 
with all post-first dose ADA assay responses less than 9-fold of baseline titer levels 
• Treatment-emergent ADA response, defined as any post-first dose positive ADA 
assay response when the baseline results are negative 
− For Part B and Part C of the study, treatment-emergent ADA response will be 
further characterized as persistent, transient, or indeterminate: 
− Persistent Response – Treatment-emergent ADA positive response with 2 or more 
consecutive ADA positive sampling time points, separated by at least 16-week 
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period (based on nominal sampling time), with no ADA negative samples in 
between, regardless of any missing samples. 
− Indeterminate Response –Treatment-emergent ADA positive response with only 
the last collected sample positive in the ADA assay. 
− Transient Response –Treatment-emergent ADA positive response that is not 
considered persistent or indeterminate. 
• Treatment boosted ADA response, defined as any post-first dose positive ADA assay 
response that is 9-fold over baseline titer levels when baseline is positive in the ADA 
assay 
• Maximum ADA Titer values 
− Low (titer <1,000) 
− Moderate (1,000≤ titer ≤10,000) 
− High (titer >10,000) 
• Samples positive in the ADA assay will be analyzed for neutralizing antibody, 
− NAb status (negative or positive) in the neutralizing antibody assay 
Listings of pre-existing, treatment-emergent, persistent, and treatment-boosted ADA responses, 
ADA titers and NAb positivity presented by patient and dose group will be provided. Incidence 
of treatment-emergent ADA, persistent, and NAb will be assessed as absolute occurrence (N) 
and percent of patients (%), grouped by dose group and ADA titer level. 
Plots of drug concentrations will be examined and the influence of ADAs and NAbs on 
individual PK profiles may be evaluated.  Assessment of impact of ADA and NAbs on safety 
and efficacy may be provided. 
11.5. 
Timing of Analyses 
11.5.1. 
First Step: PK and Safety Analysis for Part A 
The first step will be an analysis of PK data from all patients in Part A when PK data have been 
collected and validated for these patients. 
11.5.2. 
Second Step: Efficacy and Safety Analysis for Part B 
The second analysis will be conducted as soon as all patient data through week 24 in Part B have 
been collected and validated; this will consist of the final analysis of the primary and secondary 
efficacy endpoints up to week 24 for Part B patients. The safety analysis will be performed on all 
safety data collected and validated at the time of the second analysis for Part B patients. 
The results of the second analysis will not be used to change the conduct of the ongoing study in 
any aspect. This second analysis may be used for the submission dossier to health authorities. 
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11.5.3. 
Third Step: Final Safety Analysis 
The third analysis will be conducted at the end of the study and will consist of the final safety 
analysis. 
11.6. 
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 15.1. 
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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
In accordance with ICH E6, the sponsor is responsible for quality assurance to ensure that the 
study is conducted, and the data generated, recorded, and reported in compliance with the 
protocol, GCP, and any applicable regulatory requirement(s).  The planned quality assurance and 
quality control procedures for the study are described in this section. 
12.1. 
Data Management and Electronic Systems 
12.1.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study 
(including data validation [quality-checking], cleaning, correcting, releasing) will be maintained 
and stored at Regeneron (Sponsor). 
A medical coding plan will specify the processes and the dictionary used for coding.  All data 
coding (eg, AEs, baseline findings, medication, medical history/surgical history) will be done 
using internationally recognized and accepted dictionaries. 
The CRF data for this study will be collected with an electronic data capture (EDC) system: 
Medidata Rave. 
12.1.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
• IVRS/IWRS system – study drug supply 
• EDC system – data capture – Medidata Rave 
• Statistical Analysis System (SAS) – statistical review and analysis 
• Pharmacovigilance safety database 
12.2. 
Study Monitoring 
12.2.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, contract research organization [CRO] monitor) will visit 
each site prior to enrollment of the first patient, and periodically during the study.  This study 
will use the principles of risk-based monitoring (ICH).  This means that the number of visits for 
any given site may vary based on site risk indicators.  The investigator must allow study-related 
monitoring. 
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH 
GCP, and all applicable regulatory requirements. 
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12.2.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents).  The site is responsible to ensure quality within their records and systems and are 
accountable for ensuring that all source data and CRF data are timely, accurate and complete. 
The investigator must keep all source documents on file with the CRF (throughout this protocol, 
CRF refers to either a paper CRF or an electronic CRF).  Case report forms and source 
documents must be available at all times for inspection by authorized representatives of the 
sponsor and regulatory authorities. 
12.2.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic Case Report 
Forms (CRFs) within the EDC system by trained site personnel.  All required CRFs must be 
completed for each and every patient enrolled in the study.  The investigator must ensure the 
accuracy, completeness, and timeliness of the data reported to the sponsor in the CRFs.  After 
review of the clinical data for 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.  
For studies with EDC:  All changes, including date and person performing corrections, will be 
available via the audit trail, which is part of the EDC system.  For corrections made via data 
queries, a reason for any alteration must be provided. 
12.3. 
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. 
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In all instances, the confidentiality of the data must be respected. 
12.4. 
Study Documentation 
12.4.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the eCRF must be signed 
electronically by the investigator.  This signed declaration accompanies each set of patient final 
eCRF that will be provided to the sponsor. 
12.4.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of CRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
regulatory authorities.  The investigator must obtain written approval from the sponsor before 
discarding or destroying any essential study documents during the retention period following 
study completion or discontinuation.  Records must be destroyed in a manner that ensures 
confidentiality. 
If the investigator's personal situation is such that archiving can no longer be ensured, the 
investigator must inform the sponsor (written notification) and the relevant records will be 
transferred to a mutually agreed-upon destination. 
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13. 
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1. 
Good Clinical Practice Statement 
It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable 
regulatory requirements. 
13.2. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for Good Clinical Practice. 
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 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. 
• 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, or if there 
are significant changes to the study procedures, 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). 
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13.3. 
Patients Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained. Patients should be identified by a patient identification number only, 
on CRFs or other documents submitted to the sponsor. Documents that will not be submitted to 
the sponsor (eg, signed ICF) must be kept in strict confidence. 
The patient’s and investigator's personal data, which may be included in the sponsor database, 
will be treated in compliance with all applicable laws and regulations.  The sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third 
party. 
13.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve: 
• The protocol, ICF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
• Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patient, in 
which case the IRB/EC should be informed as soon as possible  
• Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
In addition, the IRB/EC should be informed of any event likely to affect the safety of patients or 
the continued conduct of the clinical study. 
A copy of the IRB/EC approval letter with a current list of the IRB/EC members and their 
functions must be received by the sponsor prior to shipment of drug supplies to the investigator.  
The approval letter should include the study number and title, the documents reviewed, and the 
date of the review. 
Records of the IRB/EC review and approval of all study documents (including approval of 
ongoing studies) must be kept on file by the investigator. 
13.5. 
Clinical Study Data Transparency 
Final study results will be published on a public clinical trial website according to applicable 
local guidelines and regulations. 
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14. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an 
IRB/EC-approved amendment.  Where required per local legislation, regulatory authority 
approval will also be sought. 
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15. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
15.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely.  Reasons may include efficacy, 
safety, or futility, among others.  Should the sponsor decide to terminate the study, the 
investigator(s) will be notified in writing. 
15.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
Investigator’s Decision 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at 
least 30 days’ notice.  The final decision should be made through mutual agreement with the 
sponsor.  Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing.  
Reasons may include the following, among others: 
• The investigator has received all items and information necessary to perform the 
study, but has not enrolled any patient within a reasonable period of time 
• The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines 
• The total number of patients required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB/EC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection 
of the patients’ interests. 
16. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
17. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
18. 
PUBLICATION POLICY 
Publication rights and procedures will be outlined in a separate clinical study agreement. 
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19. 
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AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on 
the Management of Blood Cholesterol: A Report of the American College of 
Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 
2019; 139(25):e1082-e143. 
Guidance for Industry Drug Induced Liver Injury: Premarketing Clinical Evaluation FDA 2009. 
Kolansky DM, Cuchel M, Clark BJ, Paridon S, McCrindle BW, Wiegers SE, et al. Longitudinal 
evaluation and assessment of cardiovascular disease in patients with homozygous familial 
hypercholesterolemia. Am J Cardiol 2008; 102(11):1438-43. 
Kusters DM, Wiegman A, Kastelein JJ, Hutten BA. Carotid intima-media thickness in children 
with familial hypercholesterolemia. Circ Res 2014; 114(2):307-10. 
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Macchiaiolo M, Gagliardi MG, Toscano A, Guccione P, Bartuli A. Homozygous familial 
hypercholesterolaemia. Lancet 2012; 379(9823):1330. 
Minicocci I, Montali A, Robciuc MR, Quagliarini F, Censi V, Labbadia G, et al. Mutations in the 
ANGPTL3 gene and familial combined hypolipidemia: a clinical and biochemical 
characterization. J Clin Endocrinol Metab 2012; 97(7):E1266-75. 
Moorjani S, Roy M, Torres A, Betard C, Gagne C, Lambert M, 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; 341(8856):1303-6. 
Rader DJ, Cohen J, Hobbs HH. Monogenic hypercholesterolemia: new insights in pathogenesis 
and treatment. J Clin Invest 2003; 111(12):1795-803. 
Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. 
Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med 
2017; 376(18):1713-22. 
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock SA, Branum A, 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. Ann Emerg Med 2006; 47(4):373-80. 
Schwartz G, Szareck M, Bhatt D, al. e. The ODYSSEY OUTCOMES Trial: Topline Results 
Alirocumab in Patients After Acute Coronary Syndrome. 2018. 
Wiegman A, Gidding SS, Watts GF, Chapman MJ, Ginsberg HN, Cuchel M, et al. Familial 
hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing 
detection and treatment. Eur Heart J 2015; 36(36):2425-37. 
Xu Y, Adedokun OJ, Chan D, Hu C, Xu Z, Strauss RS, et al. Population Pharmacokinetics and 
Exposure-Response Modeling Analyses of Golimumab in Children With Moderately to Severely 
Active Ulcerative Colitis. J Clin Pharmacol. 2019;59(4):590-604. 
Zhang Y, Wei X, Bajaj G, Barrett JS, Meibohm B, Joshi A, et al. Challenges and considerations 
for development of therapeutic proteins in pediatric patients. J Clin Pharmacol. 2015;55 Suppl 
3:S103-15. 
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CONFIDENTIAL 
20. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: A THREE-PART, SINGLE-ARM, OPEN-LABEL STUDY 
TO EVALUATE THE EFFICACY, SAFETY, AND PHARMACOKINETICS OF 
EVINACUMAB IN PEDIATRIC 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 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
 (Medical/Study Director, Regulatory Representative, Clinical Study Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the conduct of the study. 
Study Title: 
 A Three-Part, Single-Arm, Open-Label Study to Evaluate the Efficacy, Safety, 
and Pharmacokinetics of Evinacumab in Pediatric Patients with Homozygous Familial 
Hypercholesterolemia  
Protocol Number: 
R1500-CL-17100 
Protocol Version: 
R1500-CL-17100 Amendment 2 
 
See appended electronic signature page 
Sponsor’s Responsible Medical/Study Director 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Liaison 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
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Page 95 of 96 
CONFIDENTIAL 
APPENDIX 1. DETAILED DESCRIPTION OF PATTERN MIXTURE 
MODEL 
As the primary analysis of the primary efficacy endpoint (ie, percent change from baseline to 
week 24 in calculated LDL-C for Part B), a pattern-mixture model approach will be used with a 
different imputation strategy applied for missing calculated LDL-C values during the on-
treatment period (ie, within the time period from the first study treatment administration up to the 
day of the last study treatment administration +35 days or to the day before the first long-term 
extension treatment administration, whichever comes first for Part B) and missing LDL-C values 
after treatment discontinuation (ie, after the day of last study treatment administration +35 days 
in Part B) based on the following assumptions: 
• Patients within 35 days of their last study treatment administration in Part B would 
continue to show benefit from treatment similar to that observed at the scheduled time 
point. Therefore, calculated 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 calculated LDL-C values returning to baseline. Thus 
calculated 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, ie, 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 the SAS MEANS procedure. 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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CONFIDENTIAL 
The imputation model will include 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 0 SEED=17100; 
 ovar LDL_BASE LDL_W1 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. 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=34200), 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: 
 
Where  
denotes the variance of Y1 and ρ the coefficient of correlation between Y0 and Y1. 
The conditional variance will be estimated from observed data 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. 
)
1(
)
(
2
2
1
0
0
1


−
=
= y
Y
Y
Var
2
1

                                        VV-RIM-00192921-1.0 Approved - 25 May 2022 GMT-5:00


Signature Page for VV-RIM-00192921 v1.0
Signature Page for VV-RIM-00192921 v1.0 Approved
Approval/eSignature
22 15:06:59 GMT+0000
Approval/eSignature
-2022 09:04:47 GMT+0000
Approval/eSignature
000
Approval/eSignature
-2022 07:49:08 GMT+0000
                                        VV-RIM-00192921-1.0 Approved - 25 May 2022 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: FINAL
A THREE-PART, SINGLE-ARM, OPEN-LABEL STUDY TO EVALUATE 
THE EFFICACY, SAFETY, AND PHARMACOKINETICS OF 
EVINACUMAB IN PEDIATRIC PATIENTS WITH HOMOZYGOUS 
FAMILIAL HYPERCHOLESTEROLEMIA 
Compound: 
REGN1500 (Evinacumab) 
Protocol Number: 
R1500-CL-17100 
Clinical Phase:  
Phase 1b/3 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician:  
 
Clinical Trial Manager: 
 
Study Medical Director: 
 
Version/Date:  
1.0 / February 16, 2021 
VV-RIM-00144336-1.0 Approved - 18 Feb 2021 GMT-5:00
NCT04233918


Clinical Development and Regulatory Affairs 
 
 
Biostatistics and Data Management 
 
CONFIDENTIAL 
Page 2 of 76 
The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
See appended electronic signature page 
Study Biostatistician  
 
 
 
See appended electronic signature page 
Study Clinical Pharmacologist (
) 
 
 
See appended electronic signature page 
Study Bioanalytical Sciences 
 
 
 
See appended electronic signature page 
Study Director 
 
 
 
See appended electronic signature page 
Project Biostatistician
) 
 
 
See appended electronic signature page 
Head of BDM or designee (
 
                                        VV-RIM-00144336-1.0 Approved - 18 Feb 2021 GMT-5:00


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Statistical Analysis Plan 
Date: February 16, 2021 
 
 
CONFIDENTIAL 
Page 3 of 76 
 
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. 
Exploratory 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 .....................................10 
2. 
INVESTIGATION PLAN ..........................................................................................11 
2.1. 
Study Design and Randomization ..............................................................................11 
2.2. 
Sample Size and Power Considerations .....................................................................12 
2.3. 
Study Plan ...................................................................................................................12 
2.4. 
Combining Data Across Study Parts ..........................................................................13 
2.4.1. 
Data Pooling Strategy for Statistical Analyses ...........................................................13 
3. 
ANALYSIS POPULATIONS ....................................................................................14 
3.1. 
Efficacy Analysis Sets for Part B ...............................................................................15 
3.1.1. 
Intent-to-Treat (ITT) ...................................................................................................15 
3.1.2. 
Modified Intent-to-Treat (mITT) ................................................................................15 
3.2. 
Safety Analysis Set .....................................................................................................15 
3.3. 
Part C Safety Analysis Set ..........................................................................................15 
3.4. 
Pooled Safety Analysis Set .........................................................................................15 
3.5. 
Pharmacokinetic (PK) Analysis Set............................................................................15 
3.6. 
The Immunogenicity Analysis Set..............................................................................15 
3.6.1. 
ADA Analysis Set .......................................................................................................15 
3.6.2. 
NAb Analysis Set .......................................................................................................16 
3.7. 
The Target Analysis Set ..............................................................................................16 
3.8. 
The Concentration-Response (C-R) Analysis Set ......................................................16 
4. 
ANALYSIS VARIABLES .........................................................................................16 
4.1. 
Demographic and Baseline Characteristics ................................................................16 
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4.2. 
Medical History ..........................................................................................................17 
4.3. 
Prior and Concomitant Medications ...........................................................................17 
4.4. 
Prohibited Medications and Procedures During Study ...............................................18 
4.5. 
Patient Disposition ......................................................................................................19 
4.6. 
Study Treatment Exposure and Compliance Variables ..............................................21 
4.7. 
Efficacy Variable ........................................................................................................22 
4.7.1. 
Primary Efficacy Variable (s) .....................................................................................23 
4.7.2. 
Secondary Efficacy Variable(s) ..................................................................................23 
4.8. 
Safety Variables ..........................................................................................................24 
4.8.1. 
Adverse Events Variables ...........................................................................................24 
4.8.1.1. 
Adverse Events and Serious Adverse Events .............................................................24 
4.8.1.2. 
Adverse Events of Special Interest .............................................................................25 
4.8.1.3. 
Events Causing Death .................................................................................................25 
4.8.2. 
Laboratory Safety Variables .......................................................................................25 
4.8.3. 
Vital Signs ..................................................................................................................26 
4.8.4. 
12-Lead Electrocardiography (ECG) ..........................................................................27 
4.8.5. 
Tanner stages ..............................................................................................................27 
4.8.6. 
Physical Examination Variables .................................................................................27 
4.9. 
Other Variables ...........................................................................................................27 
4.10. 
Pharmacokinetic Variables .........................................................................................27 
4.11. 
Immunogenicity Variables (ADA and NAb) ..............................................................27 
5. 
STATISTICAL METHODS .......................................................................................27 
5.1. 
Demographics and Baseline Characteristics ...............................................................28 
5.2. 
Medical History ..........................................................................................................28 
5.3. 
Prior and Concomitant Medications ...........................................................................28 
5.4. 
Prohibited Medications ...............................................................................................29 
5.5. 
Patient Disposition ......................................................................................................29 
5.6. 
Extent of Study Treatment Exposure and Compliance ...............................................30 
5.6.1. 
Exposure to Investigational Product ...........................................................................30 
5.6.2. 
Study Treatment Compliance .....................................................................................30 
5.7. 
Analyses of Efficacy Variables ..................................................................................30 
5.7.1. 
Analysis of Primary Efficacy Variable for Part B ......................................................30 
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5.7.1.1. 
Sensitivity of the Primary Efficacy Analysis..............................................................31 
5.7.1.2. 
Sub-group Analyses ....................................................................................................32 
5.7.1.3. 
Multiplicity Considerations ........................................................................................33 
5.7.2. 
Analysis of Secondary Efficacy Variables for Part B ................................................33 
5.7.2.1. 
Continuous Endpoints Anticipated to have a Normal Distribution ............................33 
5.7.2.2. 
Continuous Endpoints Anticipated to have a Non-Normal Distribution ....................33 
5.7.2.3. 
Binary Endpoint Variables .........................................................................................34 
5.7.3. 
Summary of Results by Time Point ............................................................................34 
5.7.4. 
Analysis of Efficacy Variables for Part A and Part C ................................................34 
5.7.5. 
Pooled Analysis of Efficacy Variables .......................................................................35 
5.8. 
Analysis of Safety Data ..............................................................................................35 
5.8.1. 
Adverse Events ...........................................................................................................36 
5.8.2. 
Analysis of Adverse Events of Special Interest ..........................................................38 
5.8.3. 
Clinical Laboratory Measurements.............................................................................38 
5.8.4. 
Analysis of Vital Signs ...............................................................................................40 
5.8.5. 
Analysis of 12-Lead ECG ...........................................................................................40 
5.8.6. 
Tanner Stages ..............................................................................................................41 
5.8.7. 
Physical Exams ...........................................................................................................41 
5.9. 
Analysis of Other Variables ........................................................................................41 
5.10. 
Analysis of Pharmacokinetic Variables ......................................................................41 
5.11. 
Analysis of Immunogenicity Data ..............................................................................42 
5.11.1. 
Analysis of ADA data .................................................................................................42 
5.11.2. 
Analysis of Neutralizing Antibody (NAb) Data .........................................................43 
5.11.3. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................43 
5.11.3.1. 
Immunogenicity and Exposure ...................................................................................43 
5.11.3.2. 
Immunogenicity and Safety and Efficacy ...................................................................43 
6. 
DATA CONVENTIONS ............................................................................................44 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................44 
6.2. 
Data Handling Convention for Efficacy Variables .....................................................44 
6.3. 
Data Handling Convention for Missing Data .............................................................44 
6.4. 
Visit Windows ............................................................................................................45 
6.5. 
Unscheduled Assessments ..........................................................................................46 
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Statistical Analysis Plan 
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6.6. 
Pooling of Centers for Statistical Analyses ................................................................46 
6.7. 
Statistical Technical Issues .........................................................................................46 
7. 
TIMING OF STATISTICAL ANALYSES ................................................................46 
7.1. 
First Step: PK and Safety Analysis for Part A ............................................................46 
7.2. 
Second Step: Efficacy and Safety Analysis for Part B ...............................................46 
7.3. 
Third Step: Final Safety Analysis ...............................................................................46 
7.4. 
Additional Rules .........................................................................................................46 
8. 
SOFTWARE ...............................................................................................................47 
9. 
REFERENCES ...........................................................................................................48 
10. 
APPENDIX.................................................................................................................49 
10.1. 
Summary of Statistical Analyses ................................................................................49 
10.2. 
Windows for Analysis Time Points ............................................................................50 
10.3. 
List of AESIs with Data Sources and Definitions of SMQ/CMQ ..............................55 
10.4. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................58 
10.5. 
Detailed Description of the Multiple Imputation Procedure ......................................61 
10.6. 
Detailed Description of Pattern Mixture Model .........................................................62 
10.7. 
Schedule of Time and Events .....................................................................................64 
 
LIST OF TABLES 
Table 1: 
Global Analysis Windows for Part A .........................................................................50 
Table 2: 
Global Analysis Windows for Part B .........................................................................51 
Table 3: 
Efficacy Analysis Windows for Part B .......................................................................52 
Table 4: 
Global Analysis Windows for Part C .........................................................................52 
Table 5: 
Pooled Analysis Windows for the Integrated Data Pool ............................................53 
Table 6: 
Summary of AESIs and the Methods of Data Collections and Derivations ...............55 
Table 7: 
CMQ “Neurocognitive disorders – FDA’s recommendation” ...................................56 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram Part A .......................................................................................12 
Figure 2: 
Study Flow Diagram Part B ........................................................................................12 
Figure 3: 
Study Flow Diagram – Extension ...............................................................................13 
 
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Statistical Analysis Plan 
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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 
ASCVD 
Atherosclerotic cardiovascular disease 
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 
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Statistical Analysis Plan 
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LDL-C 
Low-density lipoprotein cholesterol 
LDLR 
Low-density lipoprotein receptor 
LMT 
Lipid modifying therapy 
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 
SC 
Subcutaneous 
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 
Date: February 16, 2021 
 
 
CONFIDENTIAL 
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1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study results 
by pre-specifying the statistical approaches for the analysis of study data prior to database lock. 
The SAP is intended to be a comprehensive and detailed description of the strategy and statistical 
methods to be used in the analysis of data collected in R1500-CL-17100 study. The content of 
this SAP is inclusive of all analyses (the first, second, and third 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 data review, and a final plan will be issued prior to the first step database lock. For the 
purpose of this document, REGN1500 will be referred to as “evinacumab”. 
1.1. 
Background/Rationale 
Familial hypercholesterolemia (FH), a primary hyperlipidemia driven by genetic mutation(s) 
primarily in the low-density lipoprotein (LDL) receptor (LDLR), is the most common 
monogenic hypercholesterolemia condition in children. The most rare and severe form of FH is 
homozygous familial hypercholesterolemia (HoFH). It is an inherited autosomal dominant 
disorder primarily resulting from mutations in the LDLR or, less frequently, from mutations in 3 
associated genes: proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein B 
(APOB), and LDL receptor adaptor protein 1 (LDLRAP1). Depending on the genes affected and 
the mutations that are present, patients are categorized as either true homozygotes, compound 
heterozygotes, or double heterozygotes. True homozygotes have the same mutation on both 
alleles. Compound heterozygotes have different mutations on the 2 alleles. Double heterozygotes 
have mutations in 2 different genes. The resulting phenotype includes deficient or defective LDL 
receptors on the surface of hepatocytes causing impaired clearance of circulating low-density 
lipoprotein cholesterol (LDL-C). This leads to severe hypercholesterolemia, often 3 to 6 times 
normal (≥500 mg/dL), starting in infancy, which results in an exceedingly high risk of 
developing premature atherosclerosis, as well as valvular and supravalvular stenosis. 
Evinacumab (also referred to as REGN1500) is a fully human monoclonal antibody that 
specifically binds to and inhibits angiopoietin-like 3 (ANGPTL3). Evinacumab inhibition of 
ANGPTL3 leads to reductions in LDL-C, high-density lipoprotein cholesterol (HDL-C), and 
TGs, mirroring the lipid phenotype observed in humans with ANGPTL3 loss of function (LOF). 
Evinacumab reduces LDL-C independent of the presence of LDL receptor (LDLR) by promoting 
very low-density lipoprotein (VLDL) processing and clearance upstream of LDL formation. 
Evinacumab blockade of ANGPTL3 lowers TGs and HDL-C by rescuing lipoprotein lipase and 
endothelial lipase activities, respectively. 
Treatment with evinacumab in adult and adolescent patients with HoFH resulted in an 
approximately 50% mean reduction in LDL-C in the pivotal phase 3 study, R1500-CL-1629. 
The primary purpose of this current study is to demonstrate the efficacy, safety and tolerability of 
evinacumab in pediatric patients, aged 5 through 11 years, with HoFH. Additional background 
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information on the study drug and development program can be found in the Investigator’s 
Brochure. 
1.2. 
Study Objectives  
1.2.1. 
Primary Objectives 
The primary objective for Part A of the study is: 
• To assess the PK of evinacumab in pediatric patients with HoFH 
The primary objective for Part B of the study is: 
• To demonstrate a reduction of LDL-C by evinacumab in pediatric (5 to 11 years of age) 
patients with HoFH 
1.2.2. 
Secondary Objectives 
The secondary objective for Part A of the study is: 
• To evaluate the safety and tolerability of evinacumab administered IV in pediatric 
patients with HoFH 
The secondary objectives for Part B of the study are: 
• To evaluate the effect of evinacumab on other lipid parameters (i.e., Apo B, non-HDL 
C, total cholesterol (TC), lipoprotein a [Lp(a)]) in pediatric patients with HoFH 
• To evaluate the safety and tolerability of evinacumab administered IV in pediatric 
patients with HoFH 
• To assess the PK of evinacumab in pediatric patients with HoFH  
• To assess the immunogenicity of evinacumab in pediatric patients with HoFH over 
time 
• To evaluate patient efficacy by mutation status. 
1.2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
• To evaluate the efficacy of evinacumab in the extension of the study (Part C) in 
patients with HoFH 
• To explore vascular changes using imaging techniques  
1.2.4. 
Modifications from the Statistical Section in the Final Protocol 
The content of this SAP reflects the content of the statistical section of Protocol R1500-CL-
17100 Amendment 1.  
1.2.5. 
Revision History for Statistical Analysis Plan Amendments 
This is the first version of Statistical Analysis Plan (SAP). 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
This study consists of 3 parts: Part A, Part B, and Part C 
• Part A: phase 1B single arm, single dose PK/PD analysis 
• Part B: phase 3, single-arm, 24-week, open-label efficacy and safety study 
• Part C: phase 3 48-week treatment period and 20-week follow-up period 
Part A is a phase 1B single-dose, open-label study to determine the safety, PK and PD of 
evinacumab 15 mg/kg IV in approximately 6 patients ages 5 to 11 years with HoFH. To ensure a 
distribution of body weight within Part A of the study, every effort will be made to enroll 3 
patients <25 kg and 3 patients ≥25 kg. Additionally, to ensure a distribution of ages, every effort 
will be made to enroll 2 patients <10 years of age. All patients who successfully complete Part A 
may continue receiving evinacumab in  Part C. Initially, patients from Part A who enter Part C 
will receive evinacumab 15 mg/kg IV Q4W. When concentrations of total evinacumab in serum 
from all patients in Part A have been sufficiently analyzed, the dose for Part B will be 
determined using the cumulative data to date with evinacumab and data from Part A. If data from 
6 patients are insufficient, up to 4 more patients may be enrolled to confirm the dose in Part B. 
The dose for Part B will also be the final dose in Part C. The dose for Part B (and final dose in 
Part C) will likely remain at 15 mg/kg IV Q4W. However, due to the nonlinear relationship 
between body weight and exposure, it is possible that increased dose may be required to match 
the exposures observed in adults. As such, the dose in Part B (and final dose in Part C) could be 
between 15 and 20 mg/kg IV Q4W. A maximum dose of 20 mg/kg is selected as the top dose 
because it is the highest dose evaluated in prior evinacumab studies. 
Part B is a phase 3 single-arm, open-label study to assess the efficacy and safety of evinacumab 
in pediatric patients (age 5 to 11 years) with HoFH.  Part B will begin once dose-selection for 
Part B has been completed.  Part B will enroll approximately 18 pediatric patients. Patients 
enrolled into Part B will not include patients from Part A. Upon completion of Part B, patients 
will have the opportunity to continue into  Part C. 
Part C is an extension for patients from both Part A and Part B. 
The analyses will be conducted in 3 steps. The first step will be an analysis of PK data and safety 
data from all patients in Part A when at least 8 weeks of concentrations of total evinacumab in 
serum have been collected and analyzed for these patients. The second analysis will be 
conducted as soon as all patient data through week 24 in Part B have been collected and 
validated; this will consist of the final analysis of the primary and secondary efficacy endpoints 
up to week 24 for Part B patients. The safety analysis will be performed on all safety data 
collected and validated at the time of the second analysis for Part B patients. The results of the 
second analysis will not be used to change the conduct of the ongoing study in any aspect. This 
second analysis may be used for the submission dossier to health authorities. The third analysis 
will be conducted at the end of the study and will consist of the final safety analysis. 
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2.2. 
Sample Size and Power Considerations 
Since this is an open-label single treatment arm study, formal statistical testing is not planned, 
Therefore, a calculation for patient sample size is not applicable. 
Six patients are planned to be enrolled for Part A and 18 pediatric patients are planned to be 
enrolled for Part B, considering the recruitment constraints in this rare patient population. 
2.3. 
Study Plan 
Part A and Part B are the two main study parts. Part C is an extension for patients from both Part 
A and Part B. 
Part A consists of up to 4 periods: run-in; screening; single-dose open-label treatment and 16-
week observation, and a 8-week follow-up period (for patients who do not enter Part C). Upon 
completion of Part A, patients will have the opportunity to continue into  Part C (See Figure 1). 
Figure 1: 
Study Flow Diagram Part A  
 
 
Part B consists of up to 4 periods: run-in; screening; 24-week open-label treatment period; 20-
week follow-up (for patients who do not enter Part C) (See Figure 2) 
Figure 2: 
Study Flow Diagram Part B 
 
 
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Part C consists of 2 periods: a 48-week treatment period and a 20-week follow-up period 
(See Figure 3). Patients who participate in Part C should enter directly from Part A or Part B. 
The first visit (visit 1) in Part C can occur on the same day as the EOT visit in Part A (visit 
11)/Part B (visit 11). Overlapping assessments completed at the EOT visit do not need to be 
duplicated during visit 1 in Part C.  
All patients from Part A who enter Part C will initially receive open-label evinacumab 15 mg/kg 
IV Q4W. The final dose in Part C will be the same as the dose in Part B; therefore, the dose in 
Part C for patients entering from Part A may need to be adjusted to align with the dose in Part B. 
Figure 3: 
Study Flow Diagram – Extension 
 
The Study event table is presented in Appendix 10.7 . 
2.4. 
Combining Data Across Study Parts 
This section describes the integrated data pool and the data pooling strategy for analysis. By 
combining the individual data across study parts into an integrated data pool, there is a better 
chance for detecting a safety signal, for example, in uncommon adverse events (AEs), and a 
more accurate estimation of the rate for common AEs. 
2.4.1. 
Data Pooling Strategy for Statistical Analyses 
All post-baseline visit data from Part B and Part C will be included in the pool. Data in Part A 
will not be integrated into the data pool, since the safety profile for the single treatment 
administration in Part A can be different from the multiple study treatment administrations in 
Parts B and C. Patients enrolled in Part A will only contribute Part C data to the pool. 
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The following safety and efficacy parameters will be included in the pooled datasets: selected 
demographics and baseline characteristics, evinacumab exposure, AEs (including all TEAEs, 
SAEs, TEAE leading to permanent treatment discontinuation, death, AESIs), laboratory data, 
vital signs, ECGs, and lipid parameters (calculated LDL-C, Apo B, non-HDL-C, TC, Lp(a)). 
The integration of evinacumab data includes study treatment period and follow-up data collected 
during Part B and Part C. Patients participating in multiple Parts of the study will have their 
individual data (within a patient) chronologically combined across those parts as follows: 
A. Patients treated in Part A who proceed to be treated in Part C: Common reference point 
for pooled study treatment Day 1 is Part C Study Day 1. Note: Part A data will not be 
included in the pool.  
B. Patients treated in Part B: A Part B patient will have the Part B assessments combined 
with Part C, if applicable, to assess longer term evinacumab exposure. Specifically, Part 
C visits will be chronologically appended to the last Part B visit, so all patients in Part B 
will have a common reference for first study treatment, defined as Part B first study 
treatment (Study Day 1). Operationally, Extension Study Day will be defined for Part C 
visits as Part C visit date – Part B first study treatment date +1. 
Using the redefined Study Day structure above, individual patient data will be pooled. 
Specifically, patients in Bullet A + Bullet B above will be pooled, using the structure of 
redefined Study Day definitions (common reference for first study treatment) also described 
above for evinacumab treatment duration. A pooled analysis visit window label will be defined 
using the evinacumab treatment duration (see Appendix 10.2). Following the overlay of the 
pooled data visit windows to each patient’s data, the data are pooled by visit, as well as 
assessment date, for repeated study assessments (example: laboratory assessments). 
The integrated data will be summarized by the following types of patient groups.  
• Part A Patients: Patients who were enrolled to Part A and received any IV dose of 
evinacumab in Part C.  
• Part B Patients: Patients who were enrolled and treated with at least one IV dose of 
evinacumab in Part B. 
• Total: Combined patients in the above two groups. 
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), and pharmacokinetic (PK).     
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3.1. 
Efficacy Analysis Sets for Part B 
3.1.1. 
Intent-to-Treat (ITT) 
The intent-to-treat (ITT) population is defined as all patients who received at least 1 dose or part 
of a dose of study drug in Part B. 
3.1.2. 
Modified Intent-to-Treat (mITT) 
The modified ITT (mITT) population is defined as all patients who received at least 1 dose or 
part of a dose of open-label study drug in Part B and have an evaluable primary efficacy 
endpoint. The endpoint is considered as evaluable when both of the following conditions are 
met: 
1. Availability of at least 1 measurement value for calculated LDL-C before first dose of 
study drug (i.e., baseline). 
2. Availability of at least 1 calculated LDL-C value during the efficacy treatment period and 
within one of the analysis windows up to week 24. The efficacy treatment period is 
defined as the time from the first study drug administration up to 35 days after the last 
study drug administration in Part B. 
3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all patients in Part A or Part B who received at least 1 
dose or part of a dose of study drug in the respective study treatment period. 
3.3. 
Part C Safety Analysis Set 
The Part C safety analysis set includes all patients who received at least 1 dose or part of a dose 
of study drug in Part C.  
3.4. 
Pooled Safety Analysis Set 
The pooled safety analysis set includes all Patients in Part A who received at least 1 or part of a 
dose of study drug in Part C and all patients in Part B who received at least 1 dose or part of a 
dose of study drug in Part B.  
3.5. 
Pharmacokinetic (PK) Analysis Set 
The PK analysis population includes all patients who received any study drug and who had at 
least 1 non-missing result for concentration of evinacumab following the first dose of study drug. 
3.6. 
The Immunogenicity Analysis Set 
3.6.1. 
ADA Analysis Set 
The ADA analysis set includes all patients who received any study drug and had at least 1 non-
missing ADA result following the first dose of study drug. 
Samples positive in the ADA assay may be further analyzed in neutralizing antibody assay. 
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3.6.2. 
NAb Analysis Set 
The NAb analysis set includes all patients who received any study drug and who are either 
negative in the ADA assay or positive for ADA with at least 1 non-missing result in the NAb 
assay following the first dose of the study drug. Patients and samples that are ADA negative are 
set to negative in the NAb analysis set. 
3.7. 
The Target Analysis Set 
The (total) target analysis set includes all treated subjects who received any study drug and who 
had at least 1 non-missing post-dose total ANGPTL3 measurement following the first dose of 
study drug. 
3.8. 
The Concentration-Response (C-R) Analysis Set 
The concentration-response (C-R) analysis set consists of the PK analysis set and at least one 
non-missing baseline and one non-missing post dose response assessment for LDL-C and/or any 
other relevant lipid parameter. 
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), 
regardless of the study treatment period. 
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: ≥5 to <10, and ≥10 to <12 years) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not reported, Unknown) 
Baseline Characteristics 
• Baseline Weight (kg) (quantitative and categorical variable: <25 kg, and ≥25 kg) 
• Baseline Height (cm) 
• Body mass index (BMI) in kg/m² (quantitative and categorical variable: <P5: 
Underweight, ≥P5 to <P85: Healthy weight, ≥P85 to <P95: Overweight and ≥P95: 
Obesity, using the World Health Organization [WHO] growth reference 5-19 years 
(Cole, 1992;WHO, 2006; Rigby, 2004). 
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• Current apheresis treatment (yes/no) 
• If apheresis occurring, schedule from the e-CRF (i.e. QW, Q2W) 
Baseline Disease Characteristics 
• Lipid parameters (pre-apheresis, if applicable) - quantitative variables for all efficacy 
parameters  
• Mutation type (e.g. homozygous, compound heterozygous, and double heterozygous) 
• Receptor-negative mutation in both LDLR or LDLRAP1 alleles (i.e. receptor-
negative defined as a mutation resulting in termination codons, splice site mutations, 
frame shifts and large insertion/deletions) (Yes, No) 
• LDLR activity (null/null [LDLR activity ≤15%], not null/null [LDLR activity 
> 15%]) 
4.2. 
Medical History 
As applicable, patient medical history 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.  
Hypercholesterolemia disease history will be assessed through diagnosis of HoFH, time from 
diagnosis to first study treatment administration (years), method of diagnosis of HoFH 
(genotyping, clinical diagnosis), lipid modifying therapies history reported in the “History of 
HoFH/LMT” e-CRF page.  
Apheresis history information will include the procedure frequency and treatment technique. 
4.3. 
Prior and Concomitant Medications 
All medications 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 (Part A, Part B, and Part C). 
• Prior medications are defined as medications for which the stop date is before the date 
of the first study treatment administration. 
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• 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 (≥ Day 1 for Part A, or Part 
B, or ≥ Week 0 of Part C for Part C); 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 
(≥ Day 1 for Part A, or Part B, or ≥ Week 0 of Part C for Part C). 
The concomitant medication treatment emergent periods are defined as:  
• For concomitant medications in the Part A or Part B, the treatment emergent period is 
defined from the first day of study treatment administration to the last day of study 
treatment +168 days (for patients who do not continue into the Part C) or to the day 
before the first Part C study treatment administration (for patients who enter the Part 
C). 
• For concomitant medications in the Part C, the treatment emergent period is defined 
from the first day of Part C study treatment administration to the last day of Part C 
study treatment +168 days. 
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).  
4.4. 
Prohibited Medications and Procedures During Study 
The definitions of prohibited medications and procedures are described in the section 8.9.1 of the 
protocol. They will be reviewed and identified by the study clinician and reported in protocol 
deviations.   
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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 milestone categories for Part A are defined below.  As 
applicable, percentages will be calculated using the number of enrolled patients in the 
denominator, with two exceptions.  Specifically, the two exceptions will be for the screened and 
screen failure 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 screen failure (SF) patients. 
• The total number of enrolled patients, defined as all screened patients with a 
treatment kit number allocated and recorded in the IVRS database, regardless of 
whether the treatment kit was used. 
• The total number of patients enrolled but not receiving study treatment. 
• The total number of patients enrolled and receiving study treatment. 
• The total number of patients who completed the Part A observation period. 
• The total number of patients who prematurely discontinued the Part A observation 
period, and the reasons for discontinuation  
• The total number of patients in Part A who do not proceed into Part C and who 
complete the 8-week follow-up visit. 
• The total number of patients in Part A who do not proceed into Part C and who do not 
complete the 8-week follow-up visit. Patients who died during the study are excluded. 
For patient study status, patient milestone categories for Part B are defined below.  As 
applicable, percentages will be calculated using the number of enrolled patients in the 
denominator, with two exceptions.  Specifically, the two exceptions will be for the screened and 
screen failure 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 screen failure (SF) patients: 
• The total number of enrolled patients, defined as all screened patients with a 
treatment kit number allocated and recorded in the IVRS database, regardless of 
whether the treatment kit was used. 
• The total number of patients enrolled but not receiving study treatment. 
• The total number of patients enrolled and receiving study treatment. 
• The total number of patients who completed Part B treatment period as collected on 
the End of Treatment e-CRF. 
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• The total number of patients who completed Part B treatment period, defined as at 
least 20 weeks of study treatment administration and visit week 24 performed. 
• The total number of patients who prematurely discontinued Part B treatment, and the 
reasons for discontinuation collected on the End of Treatment e-CRF 
• The total number of patients in Part B who do not proceed into Part C and complete 
the last study follow-up visit (i.e. Follow-up Week 20). 
• The total number of patients in Part B who do not proceed into Part C and do not 
complete the study follow-up period, defined as the last visit performed less than 
22 weeks after the last study treatment administration. Patients who died during the 
study are excluded.  
Patient milestone categories for Part C are defined below.  As applicable, percentages will be 
calculated using a denominator of the number of patients receiving Part C study treatment.  
• The total number of patients receiving Part C study treatment. 
• The total number of patients ongoing in Part C (applicable for the first step and 
second step analyses) 
• The total number of patients who completed Part C treatment period as collected on 
the End of Treatment e-CRF. 
• The total number of patients who completed Part C treatment period, defined as at 
least 44 weeks of Part C study treatment administration and Part C visit week 48 
performed. 
• The total number of patients who prematurely discontinued study treatment during 
Part C, and the reasons for discontinuation collected on the End of Treatment e-CRF. 
• The total number of patients in Part C who complete the last study follow-up visit 
(i.e. Follow-up week 24). 
• The total number of patients who did not complete the study follow-up period, 
defined as the last visit performed less than 22 weeks after the last study treatment 
administration. Patients who died during the study are excluded. 
The following patient populations for analyses are defined in Section 4.2: 
• Efficacy populations (for Part B only): ITT and mITT populations 
• Safety analysis set  
• Part C safety analysis set 
• Pooled safety analysis set 
• Anti-evinacumab antibody (ADA) analysis set 
• Neutralizing anti-evinacumab antibody (NAb) analysis set 
• Pharmacokinetic (PK) analysis set 
• Target analysis set 
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• Concentration-Response (C-R) analysis set 
The following patient listings will provide the details from the patient disposition table. 
• A listing of patients treated but not enrolled, and patients enrolled but not treated. 
• 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 in Part A are listed below with 
associated definitions: 
• The total number of Part A study treatment infusions by patient. 
• Patient duration of Part A observation treatment period in weeks defined as: (last visit 
date during the Part A observation period - first study treatment administration date in 
Part A)/7. 
Study treatment exposure variables for infusions administered in Part B are listed below with 
associated definitions: 
• Patient duration of Part B study treatment exposure in weeks defined as: (last Part B 
study treatment administration date +28 – first Part B study 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. Values will be 
rounded to one decimal place. 
• The total number of Part B study treatment infusions by patient.  
• The following categories will be used for treatment exposure at 4 week 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.  
Study treatment exposure variables for infusions administered in Part C are listed below with 
associated definitions: 
• Patient duration of Part C study treatment exposure in weeks defined as: (last Part C 
study treatment administration date +28 – first Part C study 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. Values will be 
rounded to one decimal place. 
• The total number of Part C study treatment infusions by patient.  
• The following categories will be used for treatment exposure at 4 week 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 and <48 weeks, ≥48 weeks 
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Study treatment exposure variables on the integrated data pool (Section 2.4) are listed below 
with associated definitions: 
• Cumulative patient duration of study treatment exposure in weeks defined as: Part C 
treatment exposure for Part A patients, and Part B treatment exposure plus Part C 
treatment exposure for Part B patients. 
• Cumulative total number of study treatment infusions by patient defined as: total 
number of Part C infusions for Part A patients, and total number of Part B infusions 
plus total number of Part C infusions for Part B patients.  
• The following categories will be used for cumulative patient treatment exposure at 
4 week 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 and 
<48 weeks, ≥48 weeks and <52 weeks, ≥52 weeks and <56 weeks, ≥56 weeks and 
<60 weeks, ≥60 weeks and <64 weeks, ≥64 weeks and <68 weeks, ≥68 weeks and 
<72 weeks, ≥72 weeks, etc.  
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 Part B treatment period, and Part C treatment period, specifically: 
• The mean infusion/injection frequency for study treatment will be defined for each 
patient as the average number of days between 2 consecutive infusions: (last study 
treatment administration date – first study treatment administration date) / (number of 
infusions -1), for patients receiving at least 2 infusions. 
All important and minor protocol deviations potentially impacting efficacy analyses, 
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.  
4.7. 
Efficacy Variable 
Efficacy will be assessed through the following lipid parameters: calculated LDL-C (using the 
Friedewald formula), total cholesterol (TC), non-HDL-C (calculated by subtracting HDL-C from 
TC), Apo B, 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. On the day of apheresis, any lipid values collected after apheresis for the respective 
visit will be excluded from the efficacy analyses. 
All efficacy 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 1 to week 24 
timepoints for Part B. For all time points post-baseline, the value used for the analyses at a given 
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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 study treatment administration regardless of the study treatment period.  
4.7.1. 
Primary Efficacy Variable (s) 
The primary efficacy endpoint for Part B is: 
• The percent change in calculated LDL-C from baseline to week 24 (intent-to-treat [ITT] 
estimand) in Part B. 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 is defined as the last calculated LDL-C value obtained before the first 
dose of study treatment in Part B. The calculated LDL-C at week 24 will be the LDL-C value 
obtained within the week 24 analysis window.  
The intent-to-treat estimand used for the primary efficacy analysis is the treatment policy 
strategy, specifically the occurrence of the intercurrent events is irrelevant; the value for the 
primary efficacy endpoint is used regardless of whether or not the intercurrent events occur. The 
intent-to-treat estimand for the primary efficacy analysis is defined as: 
A. The patient population is defined as the Intent-to-treat population (Section 3.1.1). 
B. The primary efficacy endpoint is defined above. 
C. The intercurrent events of interest are the administration of study treatment and the 
administration of subsequent therapies. The interruption of study treatment and the 
change in  subsequent therapies are ignored, and the value for the primary efficacy 
endpoint is used regardless of adherence to study treatment and subsequent therapies. 
D. The population-level summary for the primary efficacy endpoint is evinacumab mean 
value, SE and 95% confidence interval. 
4.7.2. 
Secondary Efficacy Variable(s) 
The secondary continuous efficacy endpoints in Part B are provided below, applying the ITT 
estimand described for primary efficacy endpoint (Section 4.7.1 definitions A, C and D). 
• 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 percent change in calculated LDL-C from baseline to week 24 in patients who 
have negative/negative and null/null mutations (ITT estimand) 
• The percent change in Lp(a) from baseline to week 24 (ITT estimand) 
• The absolute change in LDL-C at week 24 (ITT estimand) 
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The secondary binary efficacy endpoint in Part B is provided below, applying the ITT estimand 
described for primary efficacy endpoint (Section 4.7.1 definitions A and C). The definition for 
the population-level summary (definition D) is evinacumab proportion and 95% confidence 
interval. 
• The proportion of patients with ≥50% reduction in calculated LDL-C at 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, tanner stages and ECG. Unless otherwise noted, the baseline value is 
defined as the last available value before the first dose of study treatment, regardless of the study 
treatment period.  
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 study treatment administration. 
• The treatment-emergent adverse event (TEAE) period (Part A or Part B) is defined 
from the day of the first dose of study treatment administration to the day of the last 
dose of study treatment administration in Part A or Part B respectively + 168 days 
(24 weeks). For patients entering Part C, the TEAE period is truncated at the day 
before the first study treatment administration in Part C. 
• The Part C TEAE period is defined from the day of the first study treatment 
administration in Part C to the day of the last study treatment administration in Part C 
+ 168 days (24 weeks).  
• The pooled TEAE period is defined below:  
− Part A Patients: defined as the Part C TEAE period. 
− Part B Patients: defined from the day of the first study treatment administration in 
Part B to the day of the last study treatment administration in Part C + 168 days 
(24 weeks) or to the last study treatment administration in Part B + 168 days 
(24 weeks) for patients not entering into Part C. 
• The POST-TREATMENT period is defined from the day after the end of the 
respective TEAE periods to the last study visit.  
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. 
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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. 
• TEAEs are AEs that developed or worsened or became serious during the respective 
TEAE period.  
• 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), MedDRA terms, 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) 
• Moderate or severe infusion reactions (e-CRF) 
• Hepatic Disorder (SMQ, lab data) 
• Pregnancy (e-CRF) 
• Symptomatic overdose with investigational medicinal product (e-CRF) 
• Neurocognitive events (CMQ) 
• New onset of diabetes (NOD) (lab data, HLT, and concomitant medications) 
• Pancreatitis (e-CRF) 
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, 
• 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 
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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. The laboratory parameters (excluding those considered as efficacy 
parameters) will be classified as follows: 
Hematology: 
• Red blood cells and platelets:  hemoglobin, hematocrit, erythrocytes count, platelets 
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:  Alanine aminotransferase (ALT), aspartate aminotransferases (AST), 
alkaline phosphatase (ALP), total bilirubin, LDH 
Non-Efficacy Lipid Panel 
HDL-C, TG, Apo A-1, Apo CIII, Apo E, and ratio Apo B/Apo A-1. 
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. 
Other 
TSH, sex hormones (luteinizing hormone, follicle stimulating hormone, estradiol, and total 
testosterone). 
4.8.3. 
Vital Signs 
Vital signs parameters will include weight (kg or lb), height (cm or in), BMI (kg/m2), 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 used in the result 
summaries. Potentially clinically significant values (PCSV) ranges will be applied to the vital 
sign parameter values as applicable (see Appendix 10.4 for PCSV definitions).  
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BMI and height percentiles will be calculated (Cole, 1992; WHO, 2006; Rigby, 2004). 
4.8.4. 
12-Lead Electrocardiography (ECG) 
A standard 12-lead ECG will be performed at specified time points according to Appendix 10.7.  
The ventricular rate, PR, QRS, RR, QTcF, QTcB, and QT intervals will be recorded.   
Electrocardiogram assessments will be described as normal or abnormal. 
4.8.5. 
Tanner stages 
Tanner stage assessments will be performed at specified time points according to Appendix 10.7.  
Tanner stages (1, 2, 3, 4, 5) will be recorded. 
4.8.6. 
Physical Examination Variables 
Physical examination will be conducted at the protocol scheduled visits (See Appendix 10.7 for 
schedule of event). The result is an outcome of clinically significant (Yes/No, not examined). 
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 to post-baseline visits. 
• The percent change in hs-CRP from baseline over time.  
• The percent change in HDL-C from baseline over time. 
• The change in carotid intima-media thickness (cIMT in mm) from baseline over time 
4.10. 
Pharmacokinetic Variables 
The PK variables are the concentrations of total evinacumab at each time point.   
Total ANGPTL3 concentration in serum is a measure of target engagement by evinacumab and 
will be determined in the samples obtained to evaluate evinacumab concentration.  
4.11. 
Immunogenicity Variables (ADA and NAb) 
The immunogenicity variables are ADA status, titer, and neutralizing antibody (NAb) status for 
analyzed samples at time-point/visit.  Serum samples for ADA will be collected at the clinic 
visits specified in Appendix 10.2.  
5. 
STATISTICAL METHODS 
In general, patient data collected in Part A will be summarized for all patients (i.e., Part A Total). 
For Part B, data will be summarized again for all patients (i.e., Part B Total). Part C data 
summaries will show three columns, specifically, patients treated in Part A, patients treated in 
Part B, and Total. The baseline value is defined as the last available measurement prior to the 
date of the first study treatment administration regardless of the study treatment period. 
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In addition, pooled analyses will summarize data in three columns, specifically, Part A Patients, 
Part B Patients, and Total. The baseline value for the pooled analyses is defined as the last 
available measurement prior to the date of the first study treatment administration regardless of 
the study treatment period. Note: Although Part A patients only contributed data from Part C for 
the pooled analyses, Part A patient’s baseline is defined as Part A baseline for variable 
derivations. 
5.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be descriptively summarized by total patients 
within each main study part (Part A or Part B). Parameters described in Section 4.1 will be 
summarized for patients in the SAF for Part A, and for patients in the ITT population for Part B. 
Continuous data will be summarized using the number of patients with data, mean, SD, median, 
minimum and maximum. 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. 
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 Part C safety analysis set, demographic and baseline characteristics will be summarized by 
total patients in Part C and by main study part (Part A or Part B) in which patients are originally 
enrolled at the beginning of the study.  
Selected demographic and baseline characteristics will also be summarized for the pooled data in 
the pooled safety analysis set, by patient groups defined in Section 2.4.1. 
5.2. 
Medical History  
Medical history will be descriptively summarized by total patients within each main study part 
(Part A or Part B) and Part C.  Parameters described in Section 4.2 will be summarized for 
patients in the SAF for Part A and C, and for patients in the ITT population for Part B. 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 each main study part.  
For patient disease characteristics, continuous data will be summarized using the number of 
patients with data, mean, SD, median, minimum and maximum. Categorical and ordinal data will 
be summarized using the number and percentage of patients.   
5.3. 
Prior and Concomitant Medications  
All prior medications, dictionary coded by WHO-DD, will be descriptively summarized by total 
patients within each main study part (Part A or Part B) for patients in the safety analysis set. 
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.  
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For patients in the safety analysis set, all concomitant medications during the respective 
treatment period, dictionary coded by WHO-DD, will be descriptively summarized by total 
patients within each main study part (Part A or Part B). Summaries will present patient counts 
(and percentages) for the concomitant medication groups described in  Section 4.3 for all 
concomitant medications, by decreasing frequency of the 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 for LMT will be summarized by patient 
counts (and percentages) for the standardized medication names.  
For Part C treatment period, concomitant medications will be dictionary coded by WHO-DD and 
will be descriptively summarized as described above. For patient in the Part C safety analysis set, 
medications will be summarized for all patients and by main study part (Part A or Part B) in 
which patients are originally enrolled at the beginning of the study. Summaries will present 
patient counts (and percentages). 
Post-treatment medications will be dictionary coded by WHO-DD and will be provided in the 
study datasets. 
5.4. 
Prohibited Medications  
Listing of prohibited medications will be provided for the patients in the safety analysis set 
within main study part (Part A or Part B) and in the Part C safety analysis set during the 
extension (Part C).  
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 main study part (Part A or Part B) will be summarized by total 
patients for the study (screened patients, screen failures, and non-enrolled 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 enrolled, and enrolled but not treated. 
Patient analysis populations will be summarized by total patients within main study part (Part A 
or Part B), depicting frequencies (and percentages) of patients that met the criteria for each 
population described in Section 3.  
For Part C treatment period, the patient study status and patient analysis populations will be 
summarized for all patients and by main study part (Part A or Part B) in which patients are 
originally enrolled at the beginning of the study on the Part C safety population for the variables 
described in Section 4.5.  
The incidence of premature study treatment discontinuation (irrespective of the reason) and 
premature treatment discontinuation due to AEs will be presented graphically by total patients 
within Part B, or Part C in the respective safety analysis set using the Kaplan-Meier method. 
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5.6. 
Extent of Study Treatment Exposure and Compliance 
The extent of study treatment exposure for the main study part (Part A or Part B) described in 
Section 4.6 will be assessed and summarized for all patients in the safety analysis set. 
The extent of study treatment exposure for Part C described in Section 4.6 will be assessed and 
summarized for patients in the Part C safety analysis set, specifically for all patients and again by 
main study part (Part A or Part B) in which patients are originally enrolled at the beginning of 
the study.  
The extent of study treatment exposure on the pooled data described in Section 4.6 will be 
assessed and summarized in the pooled safety analysis set by patient groups. 
5.6.1. 
Exposure to Investigational Product 
Study treatment exposure in the respective treatment period will be descriptively summarized for 
treatment duration, total number of infusions, and observation period duration (Part A) 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, median, minimum and maximum.  
5.6.2. 
Study Treatment Compliance 
Both monitored and derived protocol deviations will be summarized for important deviation 
categories by count (percentage), and again 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 of study treatment 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, 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. 
Statistical analyses for the primary efficacy endpoint and secondary efficacy endpoints will be 
conducted in Part B as described below, and will be completed during the step 2 efficacy 
analyses (Section 7). Remaining descriptive efficacy analyses will be completed during step 3.  
5.7.1. 
Analysis of Primary Efficacy Variable for Part B 
While applying the ITT estimand, the percent change from baseline in calculated LDL-C at week 
24 will be descriptively summarized for all patients in the ITT population using mean, SE, and 
95% CI. Missing data will be imputed using a pattern mixture model (PMM) approach as 
described below (see Appendix 10.6 for more details). 
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In the PMM approach, different imputation strategies will be applied to calculated LDL-C values 
missing during the on-treatment period (i.e., within the time period from the first study treatment 
administration up to the day of last study treatment administration +35 days in Part B) versus 
calculated LDL-C values missing due to treatment discontinuation after the on-treatment period 
(i.e., after the day of last study treatment administration +35 days in Part B) based on the 
following assumptions: 
• Patients within 35 days of their last study treatment administration in Part B would 
continue to show benefit from treatment similar to that observed at the scheduled time 
point.  Therefore, calculated LDL-C values missing during the on-treatment period 
(e.g., samples obtained out-side the specified window for apheresis, 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 in Part B no longer benefited from 
it after discontinuation, and thus tended to have calculated LDL-C values returning to 
baseline.  Therefore, calculated LDL-C values missing after the on-treatment period 
should be imputed based on patient’s own baseline value. 
Missing data from the ITT 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 calculated LDL-C data will be used for the primary analysis. 
For the percent change from baseline calculated LDL-C endpoint, the 100 complete datasets of 
observed and imputed calculated LDL-C data at week 24 will be analyzed using the SAS 
MEANS procedure.  The SAS MIANALYZE procedure will be used to generate valid statistical 
inferences by combining results from the 100 analyses using Rubin’s formulae. Combined 
estimate for mean at Week 24 will be provided with the standard error (SE) and 95% confidence 
interval (CI). Formal statistical testing is not planned. 
5.7.1.1. 
Sensitivity of the Primary Efficacy Analysis 
Robustness of the primary analysis statistical method will be assessed through sensitivity 
analyses, including an ITT analysis and an on-treatment analysis of the percent change in 
calculated LDL-C from baseline to week 24 using a mixed-effect model with repeated measures 
(MMRM) approach.  
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 the primary efficacy analysis 
with regards to the handling of missing data (Little RJ 2012).  
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Mixed-effect Model with Repeated Measures (MMRM) Approach 
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 1 to week 24 analysis windows regardless of adherence to 
treatment and subsequent therapies will be used and missing data are accounted for by the 
MMRM model. The MMRM model assumes “missing-at-random” (MAR). The model will 
include the fixed categorical effect of time point (weeks 1, 2, 4, 8, 12, 16, 20, and 24), as well as 
the continuous fixed covariates of baseline calculated LDL-C value.  
This model will be run using Statistical Analysis Software (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 mean estimate at week 24 with their corresponding 
standard error.  
Sensitivity to On-treatment Calculated LDL-C Values 
To assess the robustness of the more clinically relevant data for the analysis of the primary 
efficacy endpoint, the same statistical analysis method approach as described above for the 
MMRM approach will be applied in the mITT population. The intent-to-treat estimand will be 
replaced by the on-treatment estimand.  
The on-treatment estimand used for the primary efficacy sensitivity analysis is the “while on 
treatment strategy” estimand. The on-treatment estimand for the primary efficacy sensitivity 
analysis is defined as: 
A. The patient population is defined as the Modified Intent-to-treat (mITT) population 
(Section 3.1.2).  
B. Same definition as the treatment policy estimand described for primary efficacy 
analysis. 
C. The intercurrent events of interest are the administration of study treatment and the 
administration of subsequent therapies. The discontinuation of study treatment 
impacts the primary efficacy endpoint values used in the analysis, specifically 
including those values collected during the efficacy treatment period (Section 3.1.2). 
For subsequent therapies, any changes are ignored in the analysis. 
D. The population-level summary for the primary efficacy sensitivity analysis is the least 
square estimate of mean calculated using the mixed effect model with repeated 
measures (MMRM) approach. 
5.7.1.2. 
Sub-group Analyses 
To assess the homogeneity of the treatment effect across various subgroups, the percent change 
in LDL-C from baseline at Week 24 will be summarized by the following subgroups of interest, 
assuming there are enough patients in each subgroup level to perform the evaluation, using the 
same ITT estimand and PMM approach for missing data as for the primary endpoint: 
• Gender (Female, Male) 
• Age (≥5 to <10, ≥10 to <12 years) 
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• Race 
• Ethnicity 
• The baseline apheresis status (Yes, No) 
• Receptor-negative mutation in both LDLR or LDLRAP1 alleles (i.e. receptor-
negative defined as a mutation resulting in termination codons, splice site mutations, 
frame shifts and large insertion/deletions) (Yes, No) 
• LDLR activity (null/null [LDLR activity ≤15%], not null/null [LDLR activity > 
15%]) 
5.7.1.3. 
Multiplicity Considerations  
Not applicable. 
5.7.2. 
Analysis of Secondary Efficacy Variables for Part B 
For the secondary efficacy endpoints (defined in Section 4.7.2), 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, non-HDL-C, Apo B, and Lp(a) will be provided at each time point 
during the 24-week treatment period. 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. Lipid assessments other than the ones provided by the central 
laboratory will be excluded. The time profile of each parameter will be plotted 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 (e.g., percent 
change in calculated LDL-C), continuous measurements expected to have a non-normal 
distribution [e.g., Lp(a)], and binary measurements (e.g., proportion of patients with ≥50% 
reduction in calculated LDL-C). 
5.7.2.1. 
Continuous Endpoints Anticipated to have a Normal Distribution 
Continuous secondary variables defined in Section 4.7.2 anticipated to have a normal distribution 
(i.e. lipids other than Lp(a)) will be analyzed using the same ITT estimand and PMM approach 
for missing data as described for the primary efficacy endpoint.  
5.7.2.2. 
Continuous Endpoints Anticipated to have a Non-Normal Distribution 
Continuous secondary efficacy variables defined  in Section 4.7.2 anticipated to have a non-
normal distribution (i.e. Lp(a)) will be analyzed using the multiple imputation approach for 
handling of missing values as described  in Appendix 10.5, 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. 
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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), with the endpoint of interest as the response variable using M-
estimation (using SAS ROBUSTREG procedure) with corresponding baseline value(s).  
Combined means estimates with their corresponding SEs and 95% CIs 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 will be descriptively summarized 
using the ITT estimand for all patients in the ITT population with the proportion and 95% CI. 
Missing data will be imputed using the same PMM approach as described for the primary 
efficacy endpoint. 
5.7.3. 
Summary of Results by Time Point 
For Part B, 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 total patients for 
calculated LDL-C, Total-C, non-HDL-C, Apo B, and Lp(a). The time profile of each parameter 
will be plotted with the corresponding standard errors. Further details are described below:  
• For lipids other than Lp(a): observed and imputed values, change from baseline (as 
applicable), and percent change from baseline, will be summarized using the same 
ITT estimand and PMM approach for missing data for all patients in the ITT 
population as described for endpoints above by mean and SE at all planned time 
points (see Section 5.7.2.1). 
• For Lp(a): observed and imputed values, and percent change from baseline, will be 
summarized using the same ITT estimand and multiple imputation approach for 
missing data for all patients in the ITT population as described above by mean and SE 
at all planned time points (see Section 5.7.2.1). 
• Observed data raw values, change from baseline (as applicable), and percent change 
from baseline response variables will be descriptively summarized using the ITT 
estimand for all patients in the ITT population by patient counts, mean, SD, median, 
Q1, Q3, minimum, and maximum at all planned time points. 
• Observed data raw values, change from baseline (as applicable), and percent change 
from baseline response variables will be descriptively summarized using the on-
treatment estimand for all patients in the mITT population by patient counts, mean, 
SD, median, Q1, Q3, minimum, and maximum at all planned time points. On-
treatment estimand is defined as all secondary efficacy endpoints values collected 
during the efficacy treatment period (Section 3.1.2).  
5.7.4. 
Analysis of Efficacy Variables for Part A and Part C 
For Part A treatment and observation period, observed 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 descriptively summarized 
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at protocol scheduled visits by total patients in the safety analysis set within Part A for calculated 
LDL-C, Total-C, non-HDL-C, Apo B, and Lp(a). Descriptive statistics include patient counts, 
mean, SD, median, Q1, Q3, minimum, and maximum. 
For Part C treatment period, similar analyses will be performed for all patients in the Part C 
safety analysis set and by main study part (Part A or Part B) in which patients are originally 
enrolled at the beginning of the study. The time profile of each parameter may be plotted with 
the corresponding standard errors.  
5.7.5. 
Pooled Analysis of Efficacy Variables 
Lipids analyses will also be performed on the pooed data in the pooled safety analysis set by 
patient groups. Observed 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 descriptively summarized over time by patient 
groups for calculated LDL-C, Total-C, non-HDL-C, Apo B, and Lp(a). Descriptive statistics 
include patient counts, mean, SD, median, Q1, Q3, minimum, and maximum. 
5.8. 
Analysis of Safety Data 
In general, for main study part (Part A or Part B), the summary of safety results for patients in 
the safety analysis set will be presented by each study part. No formal inferential testing will be 
performed. Summaries will be descriptive in nature. 
For Part C, the summary of safety results for patients in the Part C safety analysis set will be 
presented for all patients and by main study part (Part A or Part B) in which patients are 
originally enrolled at the beginning of the study.  
In addition, the safety analyses will be performed on the pooled data in the pooled safety analysis 
set. The summary of safety results will be presented by patient groups defined in Section 2.4.1. 
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 enrolled) 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). 
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• 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 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 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.  
5.8.1. 
Adverse Events  
In general, the primary focus of AE reporting will be on TEAEs summarized in respective TEAE 
periods, specifically the Part A, Part B, Part C, and pooled treatment periods.  
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 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 TEAE leading to permanent treatment 
discontinuation. Multiple occurrences of the same event in the same patient will be counted only 
once in a table. 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. 
AE 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. 
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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 ≥ 2 patients)  
• 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 
• 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.  
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• 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. 
Patient Deaths 
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 as applicable.  AESI are defined by SMQ, CMQ, lab data, and/or 
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, or severe); 
• Number of events divided by the number of study treatment administrations received 
in respective treatment periods; 
• Time from first study treatment administration to first infusion reaction; 
5.8.3. 
Clinical Laboratory Measurements  
The following definitions will be applied to laboratory parameters: 
• Part A treatment and observation period: the period used for quantitative analysis for 
Part A is defined from the day after the first  study treatment administration to the day 
of last visit during the Part A observation period. 
• Part B treatment period: the treatment period used for quantitative analysis is defined 
from the day after the first  study treatment administration to the day of the last study 
treatment administration + 28 days for those patients not proceeding into Part C, or up 
to the day of the first study treatment administration in Part C for those patients 
proceeding into Part C. 
• Part C treatment period: the treatment period used for quantitative analysis is defined 
from the day after the first study treatment administration in Part C to the day of the 
last  study treatment administration in Part C + 28 days. 
• Pooled treatment period: for Part A patients, the treatment period used for 
quantitative analysis is defined from the day after the first study treatment 
administration in Part C to the day of the last  study treatment administration in Part C 
+ 28 days. For Part B patients, the treatment period used for quantitative analysis is 
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defined from the day after the first study treatment administration in Part B to the day 
of the last study treatment administration in Part C + 28 days or to last study 
treatment administration in Part B + 28 days for patients not entering into the Part C. 
For respective treatment period, clinical laboratory parameter actual values (quantitative) and 
change from baseline values will be descriptively summarized at baseline and each post-baseline 
visit 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 
For respective treatment period, 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 (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. 
Sex hormones  
For respective treatment period, the sex hormones will be described separately by gender. 
• For girls 
− Values and changes from baseline will be descriptively summarized by time point 
for estradiol, FSH and LH.  
− Similar table as for PCSA will be provided using normal range during the 
respective TEAE period. The number (%) of patients with at least one estradiol 
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value <LLN and LH >ULN, estradiol value<LLN and FSH >ULN, estradiol value 
<LLN and LH>ULN and FSH >ULN) during the TEAE period. 
• For boys 
− Values and changes from baseline will be descriptively summarized by time point 
for testosterone, FSH and LH.  
− Similar table as for PCSA will be provided using the normal range. The number 
(%) of patients with at least one testosterone value <LLN and LH >ULN, 
testosterone value<LLN and FSH >ULN, testosterone value<LLN and LH>ULN 
and FSH >ULN) during the respective TEAE period. 
5.8.4. 
Analysis of Vital Signs 
For respective treatment period as defined for clinical laboratory measurements (Section 4.8.2), 
the vital sign actual values and change from baseline values obtained while sitting will be 
descriptively summarized at baseline and each post-baseline visit by at least patient number, 
mean, median, Q1, Q3, SD, minimum and maximum. 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 as defined for clinical laboratory measurements (Section 5.8.3), 
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 
Individual patient ECG measurements 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: 
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• Normal (according to PCSV criterion/criteria)/missing 
• Abnormal according to PCSV criterion or criteria 
• Patient listings of ECG measurements that meet PCSV criteria will be provided for 
the report appendix.   
• administration in Part B for patients not entering into the Part C + 28 days. 
5.8.6. 
Tanner Stages 
For respective treatment period as defined for clinical laboratory measurements (Section 5.8.3), 
tanner stages (outcome categories of 1, 2, 3, 4, 5) will be summarized by patient frequency and 
percentage at baseline and each post-baseline visit. The change from baseline in tanner stage by 
visits will be assessed (No change in Tanner stage, change in Tanner stage ≥1). 
5.8.7. 
Physical Exams 
A list of patients with any clinically significant abnormality results will be generated. 
5.9. 
Analysis of Other Variables 
In general, for main study part (Part A or Part B), the summary of results for other variables for 
patients in the safety analysis set will be presented by each study part. No formal inferential 
testing will be performed. Summaries will be descriptive in nature. 
For Part C, the summary of results for other variables for patients in the Part C safety analysis set 
will be presented for all patients and by main study part (Part A or Part B) in which patients are 
originally enrolled at the beginning of the study.  
In addition, the analyses for other variables will be performed on the pooled data in the pooled 
safety analysis set. The summary of results will be presented by patient groups defined in 
Section 2.4.1. 
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 and cIMT 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. The means (+/-SE) will 
be plotted for HbA1c, HDL-C and cIMT. In addition, HbA1C will be summarized at each visit 
by diabetic status as recorded in the medical history e-CRF page (regardless of the ongoing 
status). Applying the PCSV criteria to HbA1c at any time during the TEAE period, the number 
of patients (and percentages) meeting the criteria will be summarized.  
5.10. 
Analysis of Pharmacokinetic Variables  
PK parameters for Part A may include, but are not limited to: 
• Cmax 
• AUClast 
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• AUCinf 
• CL 
• Vss 
• MRT 
PK parameters for Part B may include, but are not limited to: 
• Cmax.ss 
• Ctrough.ss 
Descriptive statistics of concentrations of total evinacumab and total ANGPTL3 will be 
presented. For the determination of arithmetic means and descriptive statistics, individual 
concentration values below the LLOQ, will be set to zero. If geometric means are determined, 
individual concentrations values below the LLOQ will be imputed as LLOQ/2. 
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. 
When appropriate, relationship between concentrations of evinacumab and LDL-C or other 
biomarkers may be evaluated descriptively. 
5.11. 
Analysis of Immunogenicity Data 
5.11.1. 
Analysis of ADA data 
The ADA variables described in Section 4.11 will be summarized using descriptive statistics.  
Immunogenicity will be characterized by ADA responses and titers observed in patients in the 
ADA analysis set. ADA response categories and titer categories are defined as follows:  
Anti-drug antibody status and titer over the study duration may be classified as follows:  
• ADA Negative, defined as ADA negative response in the assay at all timepoints, 
regardless of any missing samples.  
• Pre-existing immunoreactivity, defined as a positive ADA assay response at baseline, 
with all post-first dose ADA results negative, or a positive assay response at baseline, 
with all post-first dose ADA assay responses less than 9-fold of baseline titer levels 
• Treatment-emergent ADA response, defined as any post-first dose positive ADA assay 
response when the baseline results are negative 
− For Part B and Part C of the study, treatment-emergent ADA response will be 
further characterized as persistent, transient, or indeterminate: 
− 
Persistent Response – Treatment-emergent ADA positive response with 2 or more 
consecutive ADA positive sampling time points, separated by at least 16-week period 
(based on nominal sampling time), with no ADA negative samples in between, 
regardless of any missing samples. 
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− 
Indeterminate Response –Treatment-emergent ADA positive response with only 
the last collected sample positive in the ADA assay. 
− 
Transient Response –Treatment-emergent ADA positive response that is not 
considered persistent or indeterminate. 
• Treatment boosted ADA response, defined as any post-first dose positive ADA assay 
response that is 9-fold over baseline titer levels when baseline is positive in the ADA 
assay 
• Maximum ADA Titer values 
− Low (titer <1,000) 
− Moderate (1,000≤ titer ≤10,000) 
− High (titer >10,000) 
The following analysis will be provided:  
• Number (n) and percent (%) of ADA-negative patients (pre-existing immunoreactivity or 
negative in the ADA assay at all time points) by treatment groups   
• Number (n) and percent (%) of treatment-emergent ADA positive patients by treatment 
groups and ADA titer categories  
• Number (n) and percent (%) of persistent treatment-emergent ADA positive patients  
• Number (n) and percent (%) of indeterminate treatment-emergent ADA positive patients  
• Number (n) and percent (%) of transient treatment-emergent ADA positive patients  
• Number (n) and percent (%) of treatment-boosted ADA positive patients by treatment 
groups and ADA titer categories   
Listing of all ADA titer levels will be provided for patients with pre-existing, treatment-
emergent, treatment-boosted ADA response.  
5.11.2. 
Analysis of Neutralizing Antibody (NAb) Data  
The absolute occurrence (n) and percent of subjects/patients (%) with NAb status in 
the NAb analysis set will be provided by treatment groups.   
5.11.3. 
Association of Immunogenicity with Exposure, Safety and Efficacy  
5.11.3.1. Immunogenicity and Exposure 
Potential association between immunogenicity and systemic exposure to REGN1500 will be 
explored. Plots of REGN1500 concentration may be provided for analyzing the potential impact 
of ADA response status, titer and NAb on the concentration time profiles.  
5.11.3.2. Immunogenicity and Safety and Efficacy 
Potential association between immunogenicity variables and safety may be explored with a 
primary focus on the following safety events during the TEAE period:  
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• Injection site reaction (serious or severe and lasting 24 hours or longer) 
• Hypersensitivity (SMQ: Hypersensitivity [Narrow]) 
• Anaphylaxis (SMQ: Anaphylaxis [Narrow]) 
Potential association  immunogenicity variables and efficacy endpoints may be explored (e.g. 
scatter plot or spaghetti plot).  
The safety and efficacy analyses mentioned above will be conducted using the following 
categories: 
• ADA positive patients, that is patients with treatment-emergent or treatment-boosted 
response. 
• ADA negative patients, that is subjects/patients with pre-existing immunoreactivity or 
negative in the ADA assay at all time points. 
• Patients with persistent treatment-emergent ADA response 
• NAb positive patients, that is ADA positive patients who were positive in the NAb assay 
at any time point analyzed.  
• Maximum post-baseline titer in treatment-emergent or treatment-boosted ADA positive 
patients:  
− Low (titer <1,000) 
− Moderate (1,000 ≤ titer ≤ 10,000) 
− High (titer >10,000) 
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 defined as the last 
available measurement prior to the date of the first study treatment administration, regardless of 
the study treatment period. 
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 5.7.1.3. 
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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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 provided 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, and ECG) will be summarized using the analysis windows given in 
Appendix 10.2 (i.e. efficacy analysis windows for Part B efficacy and global analysis windows 
for others). 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 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. 
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6.5. 
Unscheduled Assessments 
For efficacy, safety laboratory data, vital signs, and ECG, 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 
Not applicable. 
6.7. 
Statistical Technical Issues 
Not applicable.  
7. 
TIMING OF STATISTICAL ANALYSES 
7.1. 
First Step: PK and Safety Analysis for Part A  
The first step will be an analysis of PK data and safety data from all patients in Part A to 
determine the dose for Part B. The analysis will be performed when at least 8 weeks of 
concentrations of total evinacumab in serum have been collected and analyzed for all patients in 
Part A. Subsequent analyses may be conducted using additional accrued PK, LDL-C or safety 
data if needed to confirm the dose selection for Part B and Part C.  
7.2. 
Second Step: Efficacy and Safety Analysis for Part B  
The second analysis will be conducted as soon as all Part B patient data through week 24 have 
been collected and validated; this will consist of the final analysis of the primary and secondary 
efficacy endpoints up to week 24 for Part B patients. The safety analysis will be performed on all 
safety data collected and validated at the time of the second analysis for Part B patients. 
The results of the second analysis will not be used to change the conduct of the ongoing study in 
any aspect. This second analysis may be used for the submission dossier to health authorities. 
7.3. 
Third Step: Final Safety Analysis 
The third analysis will be conducted at the end of the study when all Part B and Part C patients 
have concluded the study, and will consist of the final efficacy and safety analyses. 
7.4. 
Additional Rules 
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 and second step analyses: 
• Any lipid assessments within efficacy analysis windows up to the week 24 visit for 
Part B will be taken into account (may include few unscheduled lipid data soon after 
the cut-off date).  
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• 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.  
• 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 respective data cut-off 
date. 
− Their treatment duration will be derived by considering date of cut-off as last 
administration date.  
− Analyses of number of IP administrations, and mean IP 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-study deaths and post-treatment medications will be 
performed for patients who either completed or prematurely discontinued the 
treatment before or at the data 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 data 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. (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. 
2. Cole TJ, Green PJ. Smoothing reference centile curves: the LMS method and penalized 
likelihood. Stat Med. 1992;11(10):1305-19. 
3. WHO Multicentre Growth Reference Study Group. WHO Child Growth Standards: 
Length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body 
mass index-for-age: Methods and development. Geneva: World Health Organization; 
2006. 
4. Rigby RA, Stasinopoulos DM. Smooth centile curves for skew and kurtotic data 
modelled using the Box-Cox power exponential distribution. Stat Med. 
2004;23(19):3053-76. 
5. 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. 
6. 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. 
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10. 
APPENDIX 
10.1. 
Summary of Statistical Analyses 
Primary Efficacy Analysis – Part B: 
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. 
PMM 
Yes 
Yes 
1. MMRM - 
ITT 
2. MMRM - 
mITT 
 
 
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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 Study Day 1. 
2. Part C study day is defined as the number of days since the first Part C study treatment 
administration+1 
3. 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.   
Table 1: 
Global Analysis Windows for Part A  
Visit label 
Targeted Study Day 
Analysis Window in Study Day 
Baseline 
1 
Measurement obtained closest to first study 
treatment, while remaining prior to first study 
treatment 
Week 1 
8 
2 to 11 
Week 2 
15 
12 to 18 
Week 3 
22 
19 to 25 
Week 4 
29 
26 to 35 
Week 6 
43 
36 to 49 
Week 8 
57 
50 to 63 
Week 10 
71 
64 to 77 
Week 12 
85 
78 to 98 
Week 16 
113 
99 to 140 
FU- W8 
For patients prematurely discontinued Part 
A: EOT visit study day + 56 days  
For patients completed Week 16 visit: 169 
For patients prematurely discontinued Part A: 
EOT visit to 84 days after EOT visit 
For patients completed Week 16 visit: 141 to 
196 
Study days are calculated from the day of first IMP infusion, the day of first IMP infusion being Day 1.  
 
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Table 2: 
Global Analysis Windows for Part B  
Visit label 
Targeted Study Day 
Analysis Window in Study Day 
Baseline 
1 
Measurement obtained closest to first study 
treatment, while remaining prior to first study 
treatment 
Week 1 
8 
2 to 11 
Week 2 
15 
12 to 21 
Week 4 
29 
22 to 35 
Week 6 
43 
36 to 49 
Week 8 
57 
50 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 196 
FU- W8 
For patients prematurely discontinued trt: last 
study trt + 84 days  
For patients completed Part B trt period: 225 
For patients prematurely discontinued trt: 56 to 
97 days after last trt 
For patients completed Part B trt period: 197 to 
238 
FU-W12 
For patients prematurely discontinued trt: last 
study trt + 112 days  
For patients completed Part B trt period: 253 
For patients prematurely discontinued trt: 98 to 
125 days after last trt 
For patients completed Part B trt period: 239 to 
266 
FU-W16 
For patients prematurely discontinued trt: last 
study trt + 140 days  
For patients completed Part B trt period: 281 
For patients prematurely discontinued trt: 126 to 
153 days after last trt 
For patients completed Part B trt period: 267 to 
294 
FU-W20 
For patients prematurely discontinued trt: last 
study trt + 168 days  
For patients completed Part B trt period: 309 
For patients prematurely discontinued trt: 154 to 
181 days after last trt 
For patients completed Part B trt period: 295 to 
322 
Study days are calculated from the day of first IMP infusion, the day of first IMP infusion being Day 1.  
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Table 3: 
Efficacy Analysis Windows for Part B 
Visit Label 
Targeted study day 
Analysis window in study days 
Baseline  
1 
Measurement obtained closest to first study 
treatment, while remaining prior to first study 
treatment 
Week 1 
8 
2 to 11 
Week 2 
15 
12 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 196 
 
Table 4: 
Global Analysis Windows for Part C  
Visit label 
Targeted Study Day 
Analysis Window in Study Day 
Week 0  
1 
1 
Week 4 
29 
15 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 
Week 28 
197 
183 to 210 
Week 32 
225 
211 to 238 
Week 36 
253 
239 to 266 
Week 40 
281 
267 to 294 
Week 44 
309 
295 to 322 
Week 48 
337 
323 to 364 
FU – W8 
For patients prematurely discontinued 
trt: last study trt + 56 days  
For patients completed Part C trt 
period: 365 
For patients prematurely discontinued trt: 28 to 69 
days after last trt 
For patients completed Part C trt period: 337 to 
378 
FU – W12 
For patients prematurely discontinued 
trt: last study trt + 84 days  
For patients completed Part C trt 
period: 393 
For patients prematurely discontinued trt: 70 to 97 
days after last trt 
For patients completed Part C trt period: 379 to 
406 
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Visit label 
Targeted Study Day 
Analysis Window in Study Day 
FU – W16 
For patients prematurely discontinued 
trt: last study trt + 112 days  
For patients completed Part C trt 
period: 421 
For patients prematurely discontinued trt: 98 to 
139 days after last trt 
For patients completed Part C trt period: 407 to 
448 
FU – W24 
For patients prematurely discontinued 
trt: last study trt + 168 days  
For patients completed Part C trt 
period: 477 
For patients prematurely discontinued trt: 140 to 
195 days after last trt 
For patients completed Part C trt period: 449 to 
504 
Study days are calculated from the day of first Part C IMP infusion, the day of first Part C IMP infusion being Day 
1. 
Table 5: 
Pooled Analysis Windows for the Integrated Data Pool  
Patients 
Part A Patients  
Part B Patients 
 
Visit Label 
Targeted 
Study Day 
from  
Part C Day 1 
Targeted 
Study Day 
from  
Part B Day 1 
Analysis Window in Study Day in 
Combine Open-Label Treatment 
Period 
Baseline  
N/A 
1 
Part A patients: measurement obtained 
closest to first Part A study treatment, 
while remaining prior to first Part A 
study treatment. 
Part B patients: measurement obtained 
closest to first Part B study treatment, 
while remaining prior to first Part B 
study treatment.  
Week 4 
29 
29 
15 to 42 
Week 8 
57 
57 
43 to 70 
Week 12 
85 
85 
71 to 98 
Week 16 
113 
113 
99 to 126 
Week 20 
141 
141 
127 to 154 
Week 24 
169 
169 
155 to 182 
Week 28 
197 
197 
183 to 210 
Week 32 
225 
225 
211 to 238 
Week 36 
253 
253 
239 to 266 
Week 40 
281 
281 
267 to 294 
Week 44 
309 
309 
295 to 322 
Week 48 
337 
337 
323 to 350 
Week 52 
N/A 
365 
351 to 378 
Week 56 
N/A 
393 
379 to 406 
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Patients 
Part A Patients  
Part B Patients 
 
Visit Label 
Targeted 
Study Day 
from  
Part C Day 1 
Targeted 
Study Day 
from  
Part B Day 1 
Analysis Window in Study Day in 
Combine Open-Label Treatment 
Period 
Week 60 
N/A 
421 
407 to 434 
Week 64 
N/A 
449 
435 to 462 
Week 68 
N/A 
477 
463 to 490 
Week 72 
N/A 
505 
491 to 518 
FU – W12   
Last study trt + 84 days  
Last study trt + 84 days 
70 to 97 days after last trt 
FU – W16 
Last study trt + 112 days 
Last study trt + 112 days 
98 to 139 days after last trt 
FU – W24 
Last study trt + 168 days 
Last study trt + 168 days 
140 to 195 days after last study trt 
Study days for Part A patients are calculated from the day of first Part C IMP infusion, the day of first Part C IMP 
infusion being Day 1. 
Study days for Part B patients are calculated from the day of first Part B IMP infusion, the day of first Part B IMP 
infusion being Day 1. 
 
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10.3. 
List of AESIs with Data Sources and Definitions of SMQ/CMQ 
Table 6: 
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 
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 
define based on Regulatory Agency 
request for another lipid lowering 
program (See Table 5 in Appendix 10.3 
for the list of terms) 
New onset of diabetes (NOD) 
No 
No medical history of diabetes as 
specified in “Cardiovascular History 
and Cardiovascular Risk Factors” CRF 
page  
AND 
one of the following criteria: 
• 
 
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, 
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AESI 
Using an e-CRF specific tick 
box on AE page 
Using Standard MedDRA Query 
(SMQ)/company MedDRA Query 
(CMQ) or lab data 
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 (incl 
subtypes) 
OR 
• 
Initiation of any new concomitant 
medication for hyperglycemia 
during the treatment period 
Pancreatitis 
Yes 
No 
 
Table 7: 
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 
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MedDRA level 
MedDRA Term Label 
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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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 
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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Protocol: R1500-CL-17100 
Statistical Analysis Plan 
Date: February 16, 2021 
 
 
CONFIDENTIAL 
Page 61 of 76 
10.5. 
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=17100 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=34200 option in SAS MI procedure 
The imputation model for step 1 will include 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: 
• age, BMI, and gender (age and BMI included as continuous variables). 
Non-continuous variables included in the imputer’s model (i.e., 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. 
                                        VV-RIM-00144336-1.0 Approved - 18 Feb 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R1500-CL-17100 
Statistical Analysis Plan 
Date: February 16, 2021 
 
 
CONFIDENTIAL 
Page 62 of 76 
10.6. 
Detailed Description of Pattern Mixture Model 
As the primary analysis of the primary efficacy endpoint (i.e., percent change from baseline to 
week 24 in calculated LDL-C for Part B), a pattern-mixture model approach will be used with a 
different imputation strategy applied for missing calculated LDL-C values during the on-
treatment period (i.e., within the time period from the first study treatment administration up to 
the day of the last study treatment administration +35 days or to the day before the first long-
term extension treatment administration, whichever comes first for Part B) and missing LDL-C 
values after treatment discontinuation (i.e., after the day of last study treatment administration 
+35 days in Part B) based on the following assumptions: 
• Patients within 35 days of their last study treatment administration in Part B would 
continue to show benefit from treatment similar to that observed at the scheduled time 
point. Therefore, calculated 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 calculated LDL-C values returning to baseline. Thus 
calculated 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 the SAS MEANS procedure. 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. 
The imputation model will include 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 
                                        VV-RIM-00144336-1.0 Approved - 18 Feb 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R1500-CL-17100 
Statistical Analysis Plan 
Date: February 16, 2021 
 
 
CONFIDENTIAL 
Page 63 of 76 
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 0 
SEED=17100; 
  var LDL_BASE LDL_W1 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. 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=34200), 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 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. 
  
 
                                        VV-RIM-00144336-1.0 Approved - 18 Feb 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 Protocol: R1500-CL-17100 
Statistical Analysis Plan 
Date: February 16, 2021 
 
 
CONFIDENTIAL 
Page 64 of 76 
10.7. 
Schedule of Time and Events 
Schedule of Events – Part A, PK and PD Portion 
 
Run-in13 
Screening 
Open-Label Treatment and Observation Period 
Follow-
up16 
Study Procedure 
Visit 1 
Visit 1a 
Baseline 
Visit 2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
EOT17 
Visit 11 
EOS 
Visit 12 
Day 
-70 to -
14 
-14 to -1 
1 
8 
15 
22 
29 
43 
57 
71 
85 
113 
169 
Week 
-10 to -2 
-2 to -1 
0 
1 
2 
3 
4 
6 
8 
10 
12 
16 
24 
Visit Window (day) 
 
 
±1 
±1 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
Screening/Baseline: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent and 
Assent 
X14 
X 
 
 
 
 
 
 
 
 
 
 
 
Pharmacogenomics 
consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Future Biomedical 
Research Consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Medication History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer Study Drug 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant Meds and 
Treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid Panel (fasting): 
total C, LDL-C, HDL-C, 
TG, non-HDL-C1 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Specialty Lipid Panel 
(fasting): Apo B, Apo A-
1, ApoCIII, ApoE, Lp(a)1 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
Safety: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
                                        VV-RIM-00144336-1.0 Approved - 18 Feb 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 Protocol: R1500-CL-17100 
Statistical Analysis Plan 
Date: February 16, 2021 
 
 
CONFIDENTIAL 
Page 65 of 76 
 
Run-in13 
Screening 
Open-Label Treatment and Observation Period 
Follow-
up16 
Study Procedure 
Visit 1 
Visit 1a 
Baseline 
Visit 2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
EOT17 
Visit 11 
EOS 
Visit 12 
Day 
-70 to -
14 
-14 to -1 
1 
8 
15 
22 
29 
43 
57 
71 
85 
113 
169 
Week 
-10 to -2 
-2 to -1 
0 
1 
2 
3 
4 
6 
8 
10 
12 
16 
24 
Visit Window (day) 
 
 
±1 
±1 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
Electrocardiogram2 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Tanner Stage 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing3: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
Blood Chemistry 
 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
HbA1c 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
Sex Hormones4 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Urine Pregnancy Test5 
 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
Urinalysis 
 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
TSH 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Hs-CRP 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
PK/Drug Concentration and ADA Samples: 
PK/Drug conc. 
Sample6,7,8 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
ADA sample9 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
Biomarkers: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Future Biomedical 
Research Serum10 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
Future Biomedical 
Research Plasma10 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
Pharmacogenomics: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for HoFH 
genotyping (mandatory) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Whole Blood for DNA 
(optional)11 
 
X 
 
 
 
 
 
 
 
 
 
 
 
                                        VV-RIM-00144336-1.0 Approved - 18 Feb 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 Protocol: R1500-CL-17100 
Statistical Analysis Plan 
Date: February 16, 2021 
 
 
CONFIDENTIAL 
Page 66 of 76 
 
Run-in13 
Screening 
Open-Label Treatment and Observation Period 
Follow-
up16 
Study Procedure 
Visit 1 
Visit 1a 
Baseline 
Visit 2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
EOT17 
Visit 11 
EOS 
Visit 12 
Day 
-70 to -
14 
-14 to -1 
1 
8 
15 
22 
29 
43 
57 
71 
85 
113 
169 
Week 
-10 to -2 
-2 to -1 
0 
1 
2 
3 
4 
6 
8 
10 
12 
16 
24 
Visit Window (day) 
 
 
±1 
±1 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of Diet/ 
compliance with LMT  
X 
X 
X 
X 
x 
X 
X 
X 
X 
X 
X 
X 
X 
Carotid Ultrasound 
Imaging12 
X 
 
 
 
 
 
 
 
 
X 
 
Footnotes for Schedule of Events – Part A, PK and PD Portion 
1. Study assessments are to be performed and blood samples are to be collected before the dose of study drug in all patients. 
1. ECG should be performed before blood samples are collected at visits requiring blood draws. 
2. All laboratory samples should be collected before administration of study drug. 
3. Sex hormones include luteinizing hormone, FSH, estradiol, and total testosterone. 
4. Pregnancy test with a local urine pregnancy test should be done on sexually active females who have experienced menarche 
and are of childbearing potential. 
5. Including assay of total ANGPTL3. Extra samples may be used to assess the concentration of concomitant medications, e.g., 
statins. 
6. The PK sample should be drawn predose and at the end of the IV infusion on days when study drug is administered 
7.  If apheresis is administered on a dosing day, it is preferred to administer apheresis before the evinacumab infusion. The PK 
sample should be collected prior to apheresis and at the end of the evinacumab infusion. In the event apheresis is administered 
after evinacumab administration, the PK sample should be collected prior to and at the end of evinacumab infusion, prior to 
apheresis. 
8. The ADA sample should be drawn before study drug administration. 
                                        VV-RIM-00144336-1.0 Approved - 18 Feb 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 Protocol: R1500-CL-17100 
Statistical Analysis Plan 
Date: February 16, 2021 
 
 
CONFIDENTIAL 
Page 67 of 76 
9. Parent or legal guardian must sign a separate informed consent form (ICF) and patient must sign a separate informed assent 
prior to collection of Future Biomedical Research samples. Patients are still eligible to enroll in the study if they do not wish to 
participate in the Future Biomedical Research. 
10. Parent or legal guardian must sign a separate informed consent form (ICF) and patient must sign a separate informed assent to 
participate in the optional genomics sub-study prior to collection of whole blood DNA samples. Patients are still eligible to 
enroll in the study if they do not wish to participate in the genomics sub-study 
11. Carotid ultrasound imaging will be performed only at sites with this capability. Every effort should be made for patients to 
undergo 2 carotid ultrasound imaging assessments before the first dose of study drug. The assessments should be separated by 
at least 1 day.  
12. For patients who require stabilization of their background LMT (including apheresis) or need to undergo genotyping to 
confirm diagnosis of HoFH. 
13. If the patient requires a run-in the ICF should be signed at that time; otherwise ICF should be signed at screening visit. 
14. 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 
15. For patients who do not enter Part C, there will be an 8-week follow-up period (visit 12). 
16. If continuing to Part C, this visit can occur on the same day as visit 1 of Part C. 
 
                                        VV-RIM-00144336-1.0 Approved - 18 Feb 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 Protocol: R1500-CL-17100 
Statistical Analysis Plan 
Date: February 16, 2021 
 
 
CONFIDENTIAL 
Page 68 of 76 
Schedule of Events – Part B, 24-Week Efficacy and Safety Portion 
 
Run-In14 
Screening  
Baseline 
Treatment Period 
Study Procedure 
Visit 1 
Visit 1a 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
EOT16 
Visit 11 
Day 
-70 to -14 
-14 to -1 
1 
8 
15 
29 
43 
57 
85 
113 
141 
169 
Week 
-10 to -2 
-2 to -1 
0 
1 
2 
4 
6 
8 
12 
16 
20 
24 
Visit Window (day) 
 
 
±1 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
Screening/Baseline: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
Informed Consent and 
Assent 
X17 
X 
 
 
 
 
 
 
 
 
 
 
Pharmacogenomics 
consent 
 
X 
 
 
 
 
 
 
 
 
 
 
Future Biomedical 
Research Consent 
 
X 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
 
X 
 
 
 
 
 
 
 
 
 
 
Medication History 
 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer Study Drug 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
 
Concomitant Meds and 
Treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid Panel (fasting): total 
C, LDL-C, HDL-C, TG, 
non-HDL-C1 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Specialty Lipid Panel 
(fasting): Apo B, Apo A-1, 
ApoCIII, ApoE, Lp(a)1 
 
 
X 
 
 
X 
 
X 
X 
 
 
X 
Safety: 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
 
X 
 
 
 
 
 
 
 
 
 
X 
Electrocardiogram3 
 
X 
 
 
 
 
 
 
 
 
 
X 
Tanner Stage 
 
X 
 
 
 
 
 
 
 
 
 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
                                        VV-RIM-00144336-1.0 Approved - 18 Feb 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 Protocol: R1500-CL-17100 
Statistical Analysis Plan 
Date: February 16, 2021 
 
 
CONFIDENTIAL 
Page 69 of 76 
 
Run-In14 
Screening  
Baseline 
Treatment Period 
Study Procedure 
Visit 1 
Visit 1a 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
EOT16 
Visit 11 
Day 
-70 to -14 
-14 to -1 
1 
8 
15 
29 
43 
57 
85 
113 
141 
169 
Week 
-10 to -2 
-2 to -1 
0 
1 
2 
4 
6 
8 
12 
16 
20 
24 
Visit Window (day) 
 
 
±1 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
Laboratory Testing4: 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
 
X 
X 
 
 
 
 
X 
X 
X 
 
X 
Blood Chemistry 
 
X 
X 
 
 
 
 
X 
X 
X 
 
X 
HbA1c 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Sex Hormones5 
 
X 
X 
 
 
 
 
 
 
 
 
X 
Urine Pregnancy Test6 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
Urinalysis 
 
X 
X 
 
 
 
 
X 
X 
X 
 
X 
TSH 
 
X 
 
 
 
 
 
 
 
 
 
 
Hs-CRP 
 
 
X 
 
 
 
 
 
 
 
 
X 
PK/Drug Concentration and ADA Samples: 
PK/Drug conc. Sample7,8,9 
 
 
X 
 
 
X 
 
X 
X 
 
 
X 
ADA sample10 
 
 
X 
 
 
 
 
 
 
 
 
X 
Biomarkers: 
 
 
 
 
 
 
 
 
 
 
 
 
Future Biomedical 
Research Serum11 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Future Biomedical 
Research Plasma11 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Pharmacogenomics: 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for HoFH 
genotyping (mandatory) 
 
 
X 
 
 
 
 
 
 
 
 
 
Whole Blood for DNA 
(optional)12 
 
 
X 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
Review of Diet, 
compliance with LMT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Carotid Ultrasound 
Imaging13 
X 
 
 
 
 
 
 
 
 
X 
 
 
                                        VV-RIM-00144336-1.0 Approved - 18 Feb 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 Protocol: R1500-CL-17100 
Statistical Analysis Plan 
Date: February 16, 2021 
 
 
CONFIDENTIAL 
Page 70 of 76 
Schedule of Events – Part B (cont’d) 
 
Follow-Up Period15 
Study Procedure 
Phone Visit 12 
Visit 13 
Phone 
Visit 14 
Visit 15 
EOS 
Day 
225 
253 
281 
309 
Week 
32 
36 
40 
44 
Visit Window (day) 
±5 
±5 
±5 
±5 
Treatment: 
 
 
 
Administer Study Drug 
 
 
 
 
Concomitant Meds and Treatment 
X 
X 
X 
X 
Efficacy: 
 
 
 
Lipid Panel (fasting): total C, LDL-C, HDL-C, TG, 
non-HDL-C1 
 
X 
 
X 
Specialty Lipid Panel (fasting): Apo B, Apo A-1, 
ApoCIII, ApoE, Lp(a)1 
 
 
 
 
Safety: 
 
 
 
Vital Signs2 
 
X 
 
X 
Physical Examination 
 
 
 
X 
Electrocardiogram3 
 
 
 
X 
Height 
 
 
 
X 
Weight 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
Tanner Stage 
 
 
 
X 
Laboratory Testing4: 
 
 
 
Hematology 
 
X 
 
X 
Blood Chemistry 
 
X 
 
X 
Sex Hormones5 
 
 
 
X 
HbA1c 
 
 
 
X 
Urine Pregnancy Test6 
X 
X 
X 
X 
Urinalysis 
 
X 
 
X 
TSH 
 
 
 
 
Hs-CRP 
 
 
 
 
PK/Drug  
Concentration and ADA Samples: 
 
 
 
 
PK/Drug conc. Sample7,8,9 
 
 
 
X 
ADA sample10 
 
 
 
X 
                                        VV-RIM-00144336-1.0 Approved - 18 Feb 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 Protocol: R1500-CL-17100 
Statistical Analysis Plan 
Date: February 16, 2021 
 
 
CONFIDENTIAL 
Page 71 of 76 
 
Follow-Up Period15 
Study Procedure 
Phone Visit 12 
Visit 13 
Phone 
Visit 14 
Visit 15 
EOS 
Day 
225 
253 
281 
309 
Week 
32 
36 
40 
44 
Visit Window (day) 
±5 
±5 
±5 
±5 
Biomarkers: 
 
 
 
 
Future Biomedical Research Serum 
 
 
 
X 
Future Biomedical Research Plasma 
 
 
 
X 
Pharmacogenomics: 
 
 
 
 
Whole Blood for DNA (optional)11 
 
 
 
 
Other 
 
 
 
 
Review of Diet, compliance with LMT 
X 
X 
X 
X 
Carotid Ultrasound Imaging 
 
 
 
 
Footnotes for Schedule of Events – Part B, 24-Week Efficacy and Safety Portion 
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 before the 
apheresis procedure; every effort should be made to administer study drug within 1 day of the apheresis procedure. 
2. 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 
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. Sex hormones include luteinizing hormone, follicle stimulating hormone, estradiol, and total testosterone. 
6. Pregnancy test with a local urine pregnancy test should be done on sexually active females of childbearing potential. 
7. Including assay of total ANGPTL3. Extra samples may be used to assess the concentration of concomitant medications, e.g., 
statins. 
8. The PK sample should be collected predose and at the end of the IV infusion on days when study drug is administered. 
9. For patients who are not undergoing apheresis, the PK sample should be drawn before the administration of study drug. For 
patients undergoing apheresis, a PK sample should be collected immediately before the apheresis procedure if it is performed 
before the evinacumab infusion. 
                                        VV-RIM-00144336-1.0 Approved - 18 Feb 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 Protocol: R1500-CL-17100 
Statistical Analysis Plan 
Date: February 16, 2021 
 
 
CONFIDENTIAL 
Page 72 of 76 
10. For patients who are not undergoing apheresis, the ADA sample should be drawn before study drug administration. For 
patients undergoing apheresis, the ADA sample should be drawn before the apheresis procedure if it is performed before the 
evinacumab infusion. 
11. Parent or legal guardian must sign a separate informed consent form (ICF) and patient must sign a separate informed assent 
prior to collection of Future Biomedical Research samples. Patients are still eligible to enroll in the study if they do not wish to 
participate in the Future Biomedical Research. 
12. Parent or legal guardian must sign a separate informed consent form (ICF) and patient must sign a separate informed assent to 
participate in the optional genomics sub-study prior to collection of whole blood DNA samples. Patients are still eligible to 
enroll in the study if they do not wish to participate in the genomics sub-study.  One DNA sample for the genomics sub-study 
should be collected on day 1 (visit 2) but can be collected at any visit after that. 
13. Carotid ultrasound imaging will be performed only at sites with this capability. Every effort should be made for patients to 
undergo 2 carotid ultrasound imaging assessments before the first dose of study drug. The assessments should be separated by 
at least 1 day. 
14. For patients who require stabilization of their background LMT (including apheresis) or need to undergo genotyping to 
confirm diagnosis of HoFH. 
15. Only for patients who do not enter Part C. 
16. If continuing to Part C, this visit can occur on the same day as visit 1 of Part C. 
17. If the patient requires a run-in, the ICF should be signed at that time; otherwise, the ICF should be signed at the screening visit. 
 
                                        VV-RIM-00144336-1.0 Approved - 18 Feb 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 Protocol: R1500-CL-17100 
Statistical Analysis Plan 
Date: February 16, 2021 
 
 
CONFIDENTIAL 
Page 73 of 76 
Schedule of Events – Part C 
 
Treatment Period 
24-Week Follow-up 
Period14 
Study Procedure 
V115 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
EOT 
PV 
14 
V 
15 
PV 
16 
EOS 
V17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weeks post last dose 
Week 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
+8 
+12 
+16 
+24 
Visit Window (day) 
 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer Study Drug 
X16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Concomitant Meds and 
Treatment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid Panel (fasting): total 
C, LDL-C, HDL-C, TG, 
non-HDL-C1 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Specialty Lipid Panel 
(fasting): Apo B, Apo A-1, 
ApoCIII, ApoE, Lp(a)1 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Safety: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Physical Examination 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Electrocardiogram3 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Tanner Stage4 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Height4 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Weight 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing5: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Blood Chemistry 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
HbA1c 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
Sex Hormones4,6 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Urine Pregnancy Test7 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
Hs-CRP 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
                                        VV-RIM-00144336-1.0 Approved - 18 Feb 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 Protocol: R1500-CL-17100 
Statistical Analysis Plan 
Date: February 16, 2021 
 
 
CONFIDENTIAL 
Page 74 of 76 
 
Treatment Period 
24-Week Follow-up 
Period14 
Study Procedure 
V115 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
EOT 
PV 
14 
V 
15 
PV 
16 
EOS 
V17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weeks post last dose 
Week 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
+8 
+12 
+16 
+24 
Visit Window (day) 
 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
PK/Drug Concentration and ADA Samples: 
PK/Drug conc. Sample8,9,10 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
ADA sample11 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Biomarkers: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Future Biomedical 
Research Serum12  
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Future Biomedical 
Research Plasma12 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of Diet, compliance 
with LMT 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Carotid Ultrasound 
Imaging13 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
                                        VV-RIM-00144336-1.0 Approved - 18 Feb 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R1500-CL-17100 
Statistical Analysis Plan 
Date: February 16, 2021 
 
 
CONFIDENTIAL 
Page 75 of 76 
Footnotes for Schedule of Events – Part C 
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 before the apheresis procedure; 
every effort should be made to administer study drug within 1 day of the apheresis 
procedure. 
2. 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 
3. ECG should be performed before blood samples are collected at visits requiring blood 
draws. 
4. Assessment of Tanner Stage, sex hormones, and post-baseline height only applicable to 
patients < 18 years old. 
5. All laboratory samples should be collected before administration of study drug. 
6. Sex hormones include luteinizing hormone, follicle stimulating hormone, estradiol, and 
total testosterone. 
7. Pregnancy test with a local urine pregnancy test should be done on sexually active 
females of childbearing potential. 
8. Including assay of total ANGPTL3. Extra samples may be used to assess the 
concentration of concomitant medications, e.g., statins. 
9. The PK sample should be collected predose and at the end of the IV infusion on days 
when study drug is administered. 
10. For patients who are not undergoing apheresis, the PK sample should be drawn before the 
dose of study drug. For patients undergoing apheresis, a PK sample should be collected 
immediately before the apheresis procedure if it is performed before the evinacumab 
infusion. 
11. For patients who are not undergoing apheresis, the ADA sample should be drawn before 
study drug administration. For patients undergoing apheresis, the ADA sample should be 
drawn immediately before the apheresis procedure if it is performed before the 
evinacumab infusion. 
12. Parent or legal guardian must sign a separate informed consent form (ICF) and patient 
must sign a separate informed assent prior to collection of Future Biomedical Research 
samples. Patients are still eligible to enroll in the study if they do not wish to participate 
in the Future Biomedical Research 
13. Carotid ultrasound imaging will be performed only at sites with this capability. The 
assessment should be performed approximately every 6 months at every other Visit F. 
14. At weeks 8 and 16 of the follow-up period all patients will be contacted by phone to 
query LMT compliance, to inquire about AEs or changes to concomitant medications, 
confirm required contraception use, and remind patients of pregnancy reporting.  
                                        VV-RIM-00144336-1.0 Approved - 18 Feb 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R1500-CL-17100 
Statistical Analysis Plan 
Date: February 16, 2021 
 
 
CONFIDENTIAL 
Page 76 of 76 
Sexually active females of childbearing potential will report the results of their home 
pregnancy test. 
15. Overlapping assessments completed at the EOT visit of Part A or Part B do not need to 
be duplicated during visit 1 of Part C. Part C visit 1 should occur on the same day as 
Part A visit 11 or Part B visit 11. All necessary assessments are listed in the applicable 
SOE (Part A or Part B) column for visit 11. 
16. Patient can only receive the dose once all assessments from Part A or Part B Visit 11 are 
completed. 
 
                                        VV-RIM-00144336-1.0 Approved - 18 Feb 2021 GMT-5:00


Signature Page for VV-RIM-00144336 v1.0
Signature Page for VV-RIM-00144336 v1.0 Approved
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ESig Approval
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ESig Approval
-2021 13:16:43 GMT+0000
ESig Approval
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ESig Approval
-2021 21:27:25 GMT+0000
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                                        VV-RIM-00144336-1.0 Approved - 18 Feb 2021 GMT-5:00