An Open-Label Study to Evaluate the Long-Term Safety and Efficacy of Evinacumab in Patients With Homozygous Familial Hypercholesterolemia
Phase: PHASE3
Conditions: Homozygous Familial Hypercholesterolemia
Sponsor: Regeneron Pharmaceuticals

Clinical Study Protocol 
R1500-CL-1719 Amendment 7 
REGENERON CONFIDENTIAL 
Page 1 of 99 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
AN OPEN-LABEL STUDY TO EVALUATE THE LONG-TERM SAFETY 
AND EFFICACY OF EVINACUMAB IN PATIENTS WITH 
HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA 
Compound: 
Evinacumab (REGN1500) 
Clinical Phase: 
3 
Protocol Number: 
R1500-CL-1719 
Protocol Version: 
R1500-CL-1719 Amendment 7 
Amendment 7 Date of Issue: 
See appended electronic signature page 
Amendment 6 FR Admin Date of Issue: 
23 Dec 2021 
Amendment 6 Date of Issue: 
29 May 2020 
Amendment 5B FR Admin Date of Issue: 
19 Dec 2019 
Amendment 5B FR Date of Issue: 
01 Nov 2019 
Amendment 4B Date of Issue: 
11 Oct 2019 
Amendment 2B Date of Issue:  
20 Jul 2018 
Original Date of Issue: 
12 Sep 2017 
Medical/Study Director: 
 
 
 
t 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
Confidential: This submission contains confidential and proprietary commercial information 
and/or trade secrets which are subject to protection under laws and regulations worldwide 
including, but not limited to TRIPS Article 39 and regional, national or state laws whether by 
VV-RIM-00180158-4.0 Approved - 17 Oct 2022 GMT-5:00
NCT03409744
IND Number:  116398 
Eudract Number:  2017-003170-13 

Clinical Study Protocol 
 
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REGENERON CONFIDENTIAL 
 
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legislation or in equity.  For the purposes of compliance with all applicable freedom of 
information laws, and regulations, and their equivalents anywhere in the world including but 
not limited to the US Freedom of Information Act 5 U.S.C. §552, Regeneron expects that, prior 
to disclosure to third parties of any information and/or data related to, or contained within, this 
submission, it will be given every opportunity under applicable laws to protect its commercial 
interests and/or its trade secrets including the opportunity to object to such disclosure and/or 
provide redaction proposals. 
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Clinical Study Protocol 
 
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REGENERON CONFIDENTIAL 
 
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AMENDMENT HISTORY 
Overall Rationale for Amendment 7 
The overall rationale of the amendment is to allow patients who upon their study completion, may 
continue to receive treatment outside of the clinical trial (such as through a Compassionate Use 
Program [CUP], Early Access Program [EAP], or Investigator-Sponsored Study/Trial [ISS/IST]) 
and thereby may forgo the 24-week follow-up period of the study.  The follow-up period was 
intended to be an off-drug follow-up.  No off-drug follow-up period is required for these patients.  
In this situation, the patient’s end-of-treatment visit (EOT) will be their last study visit. 
The following table shows the changes made to the protocol with the rationale and the sections 
changed. 
Change 
Rationale 
Sections Changed 
To allow patients who upon 
their study completion, may 
continue to receive 
treatment outside of the 
clinical trial (such as 
through a CUP, EAP or 
ISS/IST) and thereby may 
forgo the 24-week follow-
up period of the study.  The 
follow-up period was 
intended to be an off-drug 
follow-up.  No off-drug 
follow-up period is required 
for these patients. In this 
situation, the patient’s EOT 
will be their last study visit. 
The 24-week follow-up period 
was intended to be an off-drug 
follow-up. If clinical trial 
patients will transition to 
receive treatment outside of 
the clinical trial such as 
through a CUP, EAP or 
ISS/IST, they will not be 
required to complete the 24-
week follow-up period.   
Clinical Study Protocol Synopsis, Study Design 
Clinical Study Protocol Synopsis, Study Design: 
Follow-up Period 
Section 5.1 Study Description and Duration 
Figure 1: 
Study Flow DiagramTable 3:
 
Schedule of Events – Open-Label 
Treatment Period and Follow-Up 
Section 8.1.3 Footnotes for the Schedule of 
Events Table 3, footnote #14 , and footnote #15  
Section 8.1.4 Early Termination Visit 
Minor editorial and 
administrative changes 
To improve consistency and 
clarity and correct 
typographical errors 
Throughout protocol 
 
Amendment 6 FR Admin 
The following table shows the changes made to the protocol with the rationale and the sections 
changed. 
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Change 
Rationale 
Sections Changed  
To allow continued 
access to evinacumab 
treatment under the 
protocol in France 
following regulatory 
approval 
To allow participants in France 
to continue dosing under the 
protocol and avoid a lapse in 
treatment 
Clinical Study Protocol 
Synopsis, Study Design 
Section 5.1 Study Design and 
Duration 
Editorial change 
The confidential statement was 
updated by Legal 
Protocol Title Page 
Amendment 6 
The following table shows the changes made to the protocol with the rationale and the sections 
changed. 
Change 
Rationale 
Sections Changed  
Added statements to 
address the impact of the 
COVID-19 pandemic on 
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 3.2.3 Risk/Benefit 
Assessment. 
Section 8 Study Schedule of 
Events and Procedures 
Added carotid ultrasound 
imaging to assess for 
carotid intima-media  
thickness. This is only 
applicable to adolescent 
patients at sites with the 
capability to perform the 
assessment and for whom 
the sites can obtain 
images on at least 2 visits 
separated by 6 months or 
a year. 
This change was made in 
accordance with a request from 
the EMA Pediatric Committee 
to assess the effect of 
evinacumab on the progression 
of atherosclerosis in pediatric 
patients. 
Section 2.3 Exploratory 
Objective 
Section 4.5 Ultrasound Imaging 
Table 1 Schedule of Events - 
Run-in and Screening 
Table 2 Schedule of Events-
Screening for Patients with No 
Run-in 
Table 3 Schedule of Events – 
Open-Label Treatment Period 
and Follow-up 
Section 8.1.1 Footnotes to 
Schedule of Events Table 1 
(#11) 
Section 8.1.2 Footnotes for 
Schedule of Events Table 2 
(#10) 
Section 8.1.3 Footnotes for 
Schedule of Events Table 3 
(#18) 
Section 8.2.6 Ultrasound 
Imaging 
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Change 
Rationale 
Sections Changed  
Added a provision for 
patients to receive study 
drug at home or at an 
alternative location if the 
patient is unable to visit 
the site. 
To ensure that patients are able 
to continue evinacumab 
treatment despite travel 
restrictions or challenges as a 
result of the COVID-19 
pandemic.  
Synopsis – Study Design 
Section 5.1 Study Description 
and Duration 
Changed exclusion for 
LDL-C at screening from 
<40 mg/dL to <70 mg/dL. 
This was changed in response 
to a health authority request in 
a country-specific amendment 
but has been applied to this 
protocol to align the eligibility 
criteria across all sites across all 
regions. 
Section 3.2.1 Rationale for 
Study Design 
Section 6.2.2 Exclusion Criteria 
for Evinacumab-Naïve Patients 
(#16)  
Removed the requirement 
that all males with female 
partners of child-bearing 
potential are required to 
consistently use a 
condom, even if the male 
study participant has been 
vasectomized, which was 
added as an urgent safety 
measure (USM) in 
response to results from 
an embryofetal 
development toxicology 
study in rabbits. 
Contraception 
requirements for sexually 
active males includes 
both consistent use of a 
condom or vasectomy. 
The USM was added to version 
4 of the protocol in response to 
non-clinical results from an 
ongoing toxicology study in 
rabbits showing incomplete 
ossification of the 15th vertebra 
in some fetuses fathered by 
males receiving evinacumab. In 
the final report, this finding was 
considered non-adverse 
because the underlying 
cartilage for the vertebra was 
present, indicating that the 
unossified caudal vertebra 
likely represented delayed 
ossification and not a 
malformation. An unossified 
caudal vertebra at birth is a 
common variation that has no 
adverse impact on survival. 
Section 6.2.2 Exclusion Criteria 
for Evinacumab-Naïve Patients 
(#15) 
Section 6.2.3 Exclusion Criteria 
for Patients from a Previous 
Evinacumab Study (#8) 
Table 1 Schedule of Events - 
Run-in and Screening 
Table 2 Schedule of Events-
Screening for Patients with No 
Run-in 
Table 3 Schedule of Events – 
Open-Label Treatment Period 
and Follow-up 
  
Updated introduction and 
benefit-risk and added 
moderate-to-severe 
infusion reactions to list 
of AESIs. 
Updates were made to reflect 
recent clinical data and to align 
with safety updates in IB 
Edition 9. 
Section 1 Introduction 
Section 3.2.3 Risk/Benefit 
Assessment 
Section 9.4.3 Other Events that 
Require Accelerated Reporting 
Retired protocol version 
A (applicable to adult 
subjects only) and 
updated the protocol 
All regions now allow the 
inclusion of adolescent patients.  
   
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Change 
Rationale 
Sections Changed  
amendment nomenclature 
to reflect a single, global 
protocol applicable to 
adult and adolescent 
subjects.  
Editorial revisions 
To make minor edits 
Throughout 
Amendment 5B FR Admin 
This is a non-substantial amendment to correct typographical errors referencing footnotes in 
Table 3 of the Schedule of Events.  
Change 
Sections Changed  
The reference to footnote 12 was removed 
for some visits where PK sampling was 
limited to adolescents (footnote 17). 
Table 3 Schedule of Events – Open-Label Treatment 
Period and Follow-Up. 
 
 
 
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Amendment 5B FR 
The primary purpose for this amendment is to increase the number of patients from 100 to 120 
and to add objectives to assess efficacy and safety in adolescent patients with HoFH.  As a result, 
there are also changes to the statistical analyses. 
Change 
Section Changed 
Study objectives were added to specifically 
assess efficacy and safety of evinacumab in 
adolescent patients with HoFH. As such, the 
number of patients was increased from 100 to 
approximately 120 to allow additional 
evinacumab-naïve adolescents to enter the study 
and gain experience with evinacumab in a 
subpopulation of adolescent patients. As a result, 
the analyses were also revised. 
Synopsis ̶ Objectives 
Synopsis – Population 
Synopsis –Statistical Plan 
Section 2.1 Primary Objectives 
Section 2.2 Secondary Objectives 
Section 5.2 Planned Interim Analysis 
Section 6.1 Number of Patients Planned 
Section 10.2 Justification of Sample Size 
Section 10.4 Statistical Methods 
Section 10.4.1 Patient Disposition 
Section 10.4.2 Demography and Baseline 
Characteristics 
Section 10.4.3 Efficacy Analyses 
Section 10.4.4.1 Adverse Events 
Added topline data from a phase 3, double-blind, 
placebo-controlled study in patients with HoFH 
(R1500-CL-1629). 
Section 1 Introduction 
Section 3.2.3 Risk/Benefit Assessment 
Added a provision for re-screening of patients 
Section 6.5 Re-screening of Patients 
(section added) 
Increased the window from ±5 days to ±7 days 
for evinacumab administration every 4 weeks to 
ease patient burden and provide flexibility in this 
long-term safety study without impacting the 
consistency of drug exposure to evinacumab 
Section 5.1 Study Description and 
Duration 
Section 7.1 Investigational and Reference 
Treatments 
Table 3 Schedule of Events - Open-Label 
Treatment Period and Follow-Up 
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Change 
Section Changed 
Flexibility was added in terms of timing of study 
drug administration in relation to apheresis, 
because Regeneron has collected data showing 
apheresis has a minor effect on drug 
concentrations, which most likely does not 
impact efficacy. 
The PK sampling frequency was reduced for 
most patients because of the amount of PK data 
collected to date in adult patients with HoFH. 
New PK sampling time points were added for the 
additional evinacumab-naïve adolescents who 
will enter this study as well as any patients who 
might undergo plasma exchange. 
Synopsis – Study Design 
Section 5.1 Study Description and 
Duration 
Table 3 Schedule of Events - Open-Label 
Treatment Period and Follow-Up 
Section 8.1.3 Footnotes for Schedule of 
Events Table 3 (#3, #12, #16, #17) 
Removed plasma exchange from the list of 
prohibited procedures to allow assessment of the 
impact of plasma exchange on the PK of 
evinacumab. 
Synopsis – Study Design 
Section 5.1 Study Description and 
Duration 
Section 7.7 Concomitant Medications and 
Procedures 
Section 7.7.1 Permitted Medications and 
Procedures 
Section 7.7.2 Prohibited Medications and 
Procedures 
Section 8.1.3 Footnotes for Schedule of 
Events Table 3 (#3, #12) 
Although bilateral tubal ligation is considered a 
method of highly effective contraception, it does 
not eliminate the need for routine pregnancy 
testing in the study. This was incorrectly 
described in the protocol and corrected in this 
amendment. 
Section 6.2.2 Exclusion Criteria for 
Evinacumab-Naïve Patients 
Section 6.2.3 Exclusion Criteria for 
Patients from a Previous Evinacumab 
Study 
Editorial revisions 
Throughout the protocol 
 
 
 
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Amendment 4B 
After completion of the 2A and 2B versions of the protocol, a country-specific version was 
required, which became R1500-CL-1719 2B FR. Subsequently, the R1500-CL-1719 2B FR was 
amended to become R1500-CL-1719 3B FR. Consequently, to avoid confusion and maintain the 
sequence, the numbering of the present amendment becomes R1500-CL-1719 4B. 
The protocol was amended in response to recent non-clinical findings in the rabbit. The table 
below summarizes the changes and the affected sections:  
Change 
Sections Changed  
In an embryofetal development 
toxicology study in rabbits, incomplete 
ossification of the 15th vertebra was 
observed in some fetuses resulting from 
the mating of male rabbits exposed to 
evinacumab with female rabbits not 
exposed to evinacumab. In male rabbits, 
there were measurable levels of 
evinacumab in seminal fluid and, as a 
safety measure, the current clinical study 
is amended to require consistent use of a 
condom for all sexually active males.  
Section 3.2.3 Risk/Benefit Assessment 
Section 6.2.2 Exclusion Criteria for Evinacumab-
Naïve Patients (#15) 
Section 6.2.3 Exclusion Criteria for Patients from a 
Previous Evinacumab Study (#8) 
Table 1 Schedule of Events – Run-In and 
Screening 
Table 2 Schedule of Events – Screening for 
Patients with No Run-In 
Table 3 Schedule of Events – Open-Label 
Treatment Period and Follow-Up 
Updated Medical/Study Director 
Title page 
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Amendment 2B 
The primary purpose of this amendment is to revise the patient population to allow patients with 
HoFH who have not participated in a previous evinacumab study to enter this study. The 
summary of protocol changes provided below outlines changes from the original protocol dated 
12 Sep 2017 because Amendment 1B of this protocol was not finalized. The following table 
outlines the changes made to the protocol: 
Change 
Section Changed 
Revised the eligibility requirements to allow 
patients who have not participated in a previous 
evinacumab study (ie, patients who are 
evinacumab-treatment naïve) to participate in this 
study. The reason for this change is to obtain 
additional long-term safety and tolerability data 
with evinacumab in patients with HoFH.  As 
such, the sample size was increased to allow up 
to 100 patients to enroll in the study. 
Additionally, the following study design changes 
were made and are only applicable to those 
patients who did not participate in a previous 
evinacumab clinical study: 
− Added inclusion criterion for diagnosis 
of functional HoFH 
− Added a requirement for genotyping 
− Added an exclusion criterion for LDL-C 
<40 mg/dL at the screening visit 
− Added other exclusion criteria related to 
laboratory findings, physical 
examination, past medical history, and 
comorbid diseases consistent with those 
patients who enter this study from a 
previous evinacumab study 
− Added an optional run-in period that can 
be used to stabilize background lipid 
modifying therapies (LMTs) 
− Added new Schedule of Events tables for 
the run-in and screening periods 
 
Synopsis – Study Design 
Synopsis - Study Duration 
Synopsis – Population 
Synopsis –Statistical Plan 
Section 1 Introduction 
Section 3.1 Hypothesis 
Section 3.2.1 Rationale for Study Design 
Section 3.2.2 Rationale for Dose Selection 
Section 5.1 Study Description and 
Duration 
Figure 1 Study Flow Diagram 
Section 6.1 Number of Patients Planned 
Section 6.2 Study Population 
Section 6.2.1 Inclusion Criteria (added #2 
and modified inclusion #2 of original 
protocol and it is now #3) 
Section 6.2.2 Exclusion Criteria for 
Evinacumab-Naïve Patients (new) 
Section 6.2.3 Exclusion Criteria for 
Patients from a Previous Evinacumab 
Study (#1, #2, #3, and #7 and section title) 
Section 7.7 Concomitant Medications and 
Procedures 
Table 1 Schedule of Events – Run-In and 
Screening (new) 
Table 2 Schedule of Events – Screening 
for Patients with No Run-In (new) 
Table 3 Schedule of Events – Open-Label 
Treatment Period and Follow-Up 
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Change 
Section Changed 
Section 8.1.1 Footnotes for Schedule of 
Events Table 1 (all new) 
Section 8.1.2 Footnotes for Schedule of 
Events Table 2 (new) 
Section 8.1.3 Footnotes for Schedule of 
Events Table 3 (new) 
Section 8.2.1 Procedures Performed Only 
at the Screening/Baseline Visit 
Section 8.2.2.5 Laboratory Testing 
Section 8.2.9.2 DNA Sample for HoFH 
Genotyping (new) 
Section 8.2.9.3 Genomics Sub-Study 
(Optional) (new) 
Section 10.2 Justification of Sample Size 
Section 10.4 Statistical Methods 
Section 10.4.2 Demography and Baseline 
Characteristics 
Section 10.4.3 Efficacy Analyses 
Section 10.4.4 Safety Analyses 
Section 10.4.4.1 Adverse Events 
Patients allowed to participate in this study could 
include those who have completed a study 
evaluating the safety and efficacy of alirocumab 
in patients with HoFH, but did not participate in a 
prior evinacumab study. Upon entering the study, 
these patients may discontinue alirocumab, 
continue to receive alirocumab provided by the 
Sponsor, or change to any commercially available 
PCSK9 inhibitor. This allows patients, the 
investigator or the patients’ health care providers 
to decide on the best background treatment 
regimen for the patient prior to entering this 
study. 
Synopsis – Treatment(s) 
Section 6.2 Study Population 
Section 7.2 Background Treatment(s) 
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Change 
Section Changed 
Added a Risk/Benefit Section that provides an 
assessment of LDL-C lowering and the potential 
cardiovascular benefit in patients with LDL-C 
≥40 mg/dL and a summary of the safety 
information with evinacumab. A risk/benefit 
assessment is also provided for the use of 
evinacumab with PCSK9 inhibitors (alirocumab 
or evolocumab) as part of the patient’s 
background LMT. 
Section 3.2.3 Risk/Benefit Assessment 
(new) 
Section 22 References 
Changed the requirement to maintain a stable 
background LMT regimen for at least 48 weeks 
to at least 24 weeks, ie, patients are permitted to 
change the lipoprotein apheresis schedule/setting 
or lomitapide therapy after week 24 of the study. 
This means that patients transitioning into this 
study from a previous evinacumab study will 
receive evinacumab for at least 48 weeks on a 
stable background LMT regimen, which enables 
an evaluation of the durability of evinacumab’s 
LDL-C lowering effect.  
Synopsis – Treatment(s) 
Section 6.2 Study Population 
Section 7.2 Background Treatment(s) 
Section 7.7.1 Permitted Medications and 
Procedures 
Section 7.7.2 Prohibited Medications and 
Procedures 
The statement was added that adolescent patients 
will be enrolled only in participating countries 
where regulatory approval has been obtained to 
include adolescents, and that only patients ≥18 
years of age will be enrolled in countries that 
have not received regulatory approval to enroll 
adolescent patients.   
Synopsis – Population 
Section 6.2 Study Population 
Section 6.2.1 Inclusion Criteria (#1) 
Section 6.2.3 Exclusion Criteria for 
Patients from a Previous Evinacumab 
Study (#6 and #8) 
Added exclusion criteria for patients <12 years 
old and Tanner stage <2. 
Section 6.2.2 Exclusion Criteria for 
Evinacumab-Naïve Patients (#20 and #21) 
Section 6.2.3 Exclusion Criteria for 
Patients from a Previous Evinacumab 
Study (#9 and #10) 
Section 4.1 Demographic and Baseline 
Characteristics 
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Change 
Section Changed 
Added sampling for PK (evinacumab and 
ANGPTL3) at weeks 4, 8, 12, 16, 20 and visits A, 
B, C, D, E only for patients undergoing 
lipoprotein apheresis in order to assess potential 
effects of apheresis on evinacumab PK and 
ANGPTL3 levels 
Table 3 Schedule of Events – Open-Label 
Treatment Period and Follow-Up 
Section 8.1.3 Footnotes for Schedule of 
Events Table 3 (now #16) 
Removed anti-drug antibody (ADA) sampling at 
week 4. 
Table 3 Schedule of Events – Open-Label 
Treatment Period and Follow-up 
Added blood chemistry assessment at the 12 
weeks post last dose visit, and the 20 weeks post 
last dose visit 
Table 3 Schedule of Events – Open-Label 
Treatment Period and Follow-up 
Added hemoglobin A1c (HbA1c) assessment at 
the 12 weeks post last dose visit 
Table 3 Schedule of Events – Open-Label 
Treatment Period and Follow-up 
Replaced the serum pregnancy test at baseline 
(day 1) with a urine pregnancy test as the serum 
pregnancy test is now performed at screening and 
added a urine pregnancy test at run-in.. 
Table 1 Schedule of Events – Run-In and 
Screening 
Table 3 Schedule of Events – Open-Label 
Treatment Period and Follow-Up 
Section 8.2.2.6 Pregnancy Testing 
Added a footnote that for an adolescent patient 
not of childbearing potential at Screening, the site 
confirms whether the patient is of childbearing 
potential at every visit. If an adolescent patient 
becomes of childbearing potential during the 
course of the study, exclusion criterion #14 
applies and pregnancy testing will be 
administered every 4 weeks. 
Section 8.1.1 Footnotes for Schedule of 
Events Table 1 (#7) 
Section 8.1.2 Footnotes for Schedule of 
Events Table 2 (#7) 
Section 8.1.3 Footnotes for Schedule of 
Events Table 3 (#9) 
Section 6.3 Premature Withdrawal from 
the Study 
Added a clause to discourage alcohol 
consumption 48 hours and smoking and intense 
physical exercise 24 hours prior to blood 
sampling for all patients as these may alter 
laboratory results. 
Section 8.2.3 Efficacy Procedures 
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Change 
Section Changed 
Updated the anti-drug antibody (ADA) language 
to state that positive ADA response with a titer 
>240 in the last sample analyzed will be followed 
for 3 to 6 months if needed, to determine or 
follow-up on the off-treatment persistence of 
ADA. 
Section 8.2.5 Anti-Drug Antibody 
Measurements and Samples 
Wording updated to more accurately reflect 
planned ADA analysis 
Section 10.4.6 Analysis of Anti-Drug 
Antibody Data 
Added pharmacokinetic (PK) sampling at week4 
Table 3 Open-Label Treatment Period and 
Follow-Up 
Minor editorial revisions. 
Title page 
Section 1 Introduction 
Section 4.1 Demographic and Baseline 
Characteristics 
Section 4.4 Anti-Drug Antibody Variables 
Section 7.1 Investigational and Reference 
Treatments 
Section 7.5 Method of Treatment 
Assignment 
Section 8.2.3.1 Lipid Panel 
Section 9.4.3 Other Events that Require 
Accelerated Reporting to Sponsor 
Section 10.4.1 Patient Disposition 
Section 14.1 Good Clinical Practice 
Statement 
Section 17.1 Certification of Accuracy of 
Data 
 
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 CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
An Open-Label Study to Evaluate the Long-Term Safety and Efficacy of 
Evinacumab in Patients with Homozygous Familial Hypercholesterolemia 
Site Locations 
 
Principal Investigator 
Multi-center 
Multi-national 
Objectives 
The primary objectives of the study are: 
• 
To evaluate the long-term safety and tolerability of evinacumab 
15 mg/kg intravenous (IV) administered every 4 weeks (Q4W) in 
patients with homozygous familial hypercholesterolemia (HoFH). 
• 
To evaluate the long-term safety and tolerability of evinacumab 
15 mg/kg IV administered Q4W in adolescent patients with HoFH. 
The secondary objectives of the study are: 
• 
To evaluate the effect of evinacumab 15 mg/kg IV on lipid 
parameters (ie, low-density lipoprotein cholesterol [LDL-C], 
apolipoprotein B [Apo B], non-high-density lipoprotein cholesterol 
[HDL-C], total cholesterol [TC], and triglycerides [TG]) in patients 
with HoFH 
• 
To evaluate the effect of evinacumab 15 mg/kg IV on lipid 
parameters (ie, LDL-C, Apo B, non-HDL-C, TC, and TG) in 
adolescent patients with HoFH 
• 
To evaluate the potential development of anti-evinacumab 
antibodies 
Study Design 
This is an open-label study designed to evaluate the long-term safety and 
efficacy of evinacumab in patients with HoFH.  Eligible patients for this 
study are male and female patients with HoFH, receiving stable lipid 
modifying therapy (LMT), as applicable. Lipid modifying therapy may 
include a maximally tolerated statin, ezetimibe, proprotein convertase 
subtilisin/kexin type 9 (PCSK9) inhibitor antibody and lipoprotein 
apheresis. Patients with HoFH who have participated in a previous 
evinacumab study (eg, R1500-CL-1331 and R1500-CL-1629) and 
evinacumab-naïve patients with HoFH are eligible.  
This study consists of 4 periods: a run-in period, a screening period, an 
open-label treatment period, and a follow-up period. Patients who upon their 
study completion, may continue to receive treatment outside of the clinical 
trial (such as through a compassionate use program [CUP], early access 
program [EAP], or investigator sponsored study [ISS/IST]) and thereby may 
forgo the 24-week follow-up period of the study.  The follow-up period was 
intended to be an off-drug follow-up.  No off-drug follow-up period is 
required for these patients. In this situation, the patient’s end-of-treatment 
visit (EOT) will be their last study visit. 
Run-in Period 
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Patients whose HoFH diagnosis cannot be confirmed by the clinical criteria 
listed or from previous genotyping results, may enter the run-in period to 
determine their mutation status. 
Patients whose background lipid modifying therapy (LMT) (as applicable) 
has not been stable prior to baseline (day 1) for at least 4 weeks (6 weeks for 
fibrates, 8 weeks for PCSK9 inhibitor antibodies, 12 weeks for lomitapide, 
24 weeks for mipomersen) or whose apheresis settings and/or schedule (as 
applicable) have not been stable for at least 8 weeks prior to baseline (day1) 
will enter an up to 10-week run-in period. 
Screening Period: 
All evinacumab-naïve patients who are on a stable background LMT will 
enter a 2-week screening period. 
Patients who participated previously in an evinacumab study and do not 
enter this study within 7 days of completing the end of study (EOS) visit of 
the previous study, must undergo screening.  
Open-Label Treatment Period:  
Patients who completed the EOS visit in the previous evinacumab study 
within 7 days of the baseline/day 1 visit for this open-label study do not have 
to undergo the screening visit and may enroll directly into this study if they 
fulfill all of the inclusion criteria and none of the exclusion criteria.  The 
EOS visit from the previous study can serve as the baseline/day 1 visit for 
this open-label study and overlapping assessments do not need to be repeated 
in this study. Baseline assessments and procedures that do not overlap with 
assessments at the EOS visit of the previous study should be performed after 
all EOS assessments and procedures have been completed in the previous 
evinacumab study. 
Starting on day 1 (baseline), all patients will receive evinacumab 15 mg/kg 
IV administered Q4W (±5 days) at the study site. Patients will remain in the 
clinic for monitoring for 60 minutes after the end of each IV infusion. For 
patients unable to go to the site, evinacumab may be administered at an 
alternative location, which could include the patient’s home by a trained 
nurse or other health professional, as allowed by local laws. 
All patients who were supplied with alirocumab 150 mg subcutaneous (SC) 
by the sponsor in a previous study may continue to be provided with 
alirocumab 150 mg SC every 2 weeks (Q2W) in this study. Those entering 
this study after completing a study evaluating the safety and efficacy of 
alirocumab in patients with HoFH, but did not participate in a prior 
evinacumab study, may or may not remain on alirocumab as part of their 
background LMT. Based on the patient’s preference and the judgment of the 
investigator and the patient’s health care provider, each patient may:   
• 
continue treatment with alirocumab supplied by sponsor as part of 
their background LMT 
• 
discontinue alirocumab prior to enrolling into this study 
• 
change to a commercially available PCSK9 inhibitor antibody 
prior to enrolling into this study 
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Clinical laboratory samples must be collected and study assessments must 
be performed before study drug is administered.  Patients who are 
undergoing lipoprotein apheresis or plasma exchange must have their 
clinical laboratory samples drawn and study assessments performed before 
undergoing the procedure. Every effort should be made for the patient to 
receive study drug immediately after completion of the apheresis procedure, 
but patients can receive study drug 1 day before the apheresis procedure. 
Patients on plasma exchange should receive the study drug immediately after 
completing the procedure.  
Patients receiving background LMT, which has been proven to reduce the 
risk of atherosclerotic cardiovascular disease (ASCVD) (eg, statins, 
ezetimibe, PCSK9 inhibitor antibodies), should make their best effort to 
maintain a stable regimen for at least 24 weeks and for the duration of the 
study.  
Patients receiving other LMT (eg, apheresis, lomitapide) may have that LMT 
adjusted after week 24, based on their LDL-C, cardiovascular (CV) risk 
factors, and judgment of the investigator.   
Patients should be on a stable heart healthy diet and exercise regimen 
throughout the duration of the study, starting at the baseline visit and 
continuing through the end of the open-label treatment period. 
Evinacumab treatment will continue until one of the following occurs: 
• 
Clinical development of evinacumab for the indication described 
in this study protocol is discontinued 
• 
Clinical development of evinacumab is terminated 
• 
Risk/benefit of evinacumab in this patient population is deemed 
unfavorable 
• 
Evinacumab is approved by the regulatory authority governing the 
location of the study site* 
• 
For local discontinuation of study: a decision has been made not 
to seek approval of an indication for treatment of patients with 
HoFH in the regulatory region in which the study is being 
conducted (or, to discontinue efforts to obtain such an approval) 
*Note, if in a region evinacumab is not commercially available or available 
through an early access or compassionate use program, treatment may 
continue in that region. 
Patients who prematurely discontinue from study drug should return to the 
clinic (within 5 days if possible), for end of treatment visit assessments.  A 
final end of study (EOS) visit should take place with assessments as 
specified in the EOS visit at 24 weeks after the last dose of study drug.   
Follow-up Period: 
Patients will be followed for 24 weeks after receiving the last dose of study 
drug.  During this time, pregnancy status of all women of childbearing 
potential, including those who discontinue prematurely from the study, will 
be monitored every 4 weeks for 24 weeks post the last dose of study drug 
either during clinic visits or by phone visit.  Patients who upon their study 
completion, may continue to receive treatment outside of the clinical trial 
(such as through a CUP, EAP, or ISS/IST) and thereby may forgo the 24-
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week follow-up period of the study.  The follow-up period was intended to 
be an off-drug follow-up. No off-drug follow-up period is required for these 
patients. In this situation, the patient’s EOT will be their last study visit. 
Study Duration 
Study duration will vary for each patient in this open-label study designed 
to evaluate the long-term safety and efficacy of evinacumab in patients with 
HoFH.  It will range from months up to approximately 4 years.  
End of Study Definition 
The end of study is defined as the last visit of the last patient. 
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Population 
 
 
Sample Size: 
Approximately 120 patients will be enrolled.  
 
Target Population: 
The study population will consist of male and female patients ≥12 years of 
age with HoFH, receiving stable LMT, as applicable. Lipid modifying 
therapies may include a maximally tolerated statin, ezetimibe, PCSK9 
inhibitor and lipoprotein apheresis. Adolescent patients will be enrolled only 
in participating countries where regulatory approval has been obtained to 
include adolescents.  Countries that have not received regulatory approval to 
enroll adolescent patients will enroll only patients ≥18 years of age.  
Treatment(s) 
 
 
Study Drug 
 
Dose/Route/Schedule: 
Starting on day 1 (baseline), patients will receive evinacumab 15 mg/kg IV 
administered Q4W. 
 
Background Treatment 
 
Dose/Route/Schedule: 
All patients who were supplied with alirocumab 150 mg SC by the sponsor 
in a previous study may continue to be provided with alirocumab 150 mg 
SC Q2W in this study. Those entering this study after completing a study 
evaluating the safety and efficacy of alirocumab in patients with HoFH, but 
did not participate in a prior evinacumab study, may or may not remain on 
alirocumab as part of their background LMT. Based on the patient’s 
preference and the judgment of the investigator and the patient’s health care 
provider, each patient may: 
• 
continue treatment with alirocumab supplied by the sponsor as 
part of their background LMT 
• 
discontinue alirocumab prior to enrolling into this study 
• 
change to a commercially available PCSK9 inhibitor antibody 
prior to enrolling into this study 
Patients receiving background LMT that has been proven to reduce the risk 
of ASCVD (eg, statins, ezetimibe, PCSK9 inhibitor antibodies) should make 
their best effort to maintain a stable regimen after week 24 and for the 
duration of the study.  
Patients receiving other LMT (eg, apheresis, lomitapide), may have that 
LMT adjusted after week 24, based on their LDL-C, CV risk factors, and 
judgment of the investigator.  
Endpoint(s) 
 
 
Primary: 
The primary endpoint is the incidence and severity of treatment-emergent 
adverse events (TEAEs) and other safety variables during the open-label 
treatment period in patients treated with evinacumab 15 mg/kg IV Q4W. 
 
Secondary: 
The secondary efficacy endpoints are: 
• 
The percent and absolute change in LDL-C over time 
• 
The percent and absolute change in Apo B over time 
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• 
The percent and absolute change in non-HDL-C over time 
• 
The percent and absolute change in TC over time 
• 
The percent and absolute change in TGs over time 
Procedures and Assessments 
Overall safety will be assessed by monitoring/evaluation of TEAEs, physical 
examinations, electrocardiograms, and clinical safety laboratory tests at 
pre-specified time points.  The potential emergence of anti-evinacumab 
antibodies will also be evaluated.   
Efficacy will be assessed by clinical laboratory evaluation of lipid levels at 
pre-specified time points throughout the study.   
Statistical Plan 
No formal statistical testing will be performed for this open-label study.  The 
safety analysis set (SAF) includes all patients who received at least 1 dose 
or part of a dose of open-label study treatment in this study.  The SAF will 
be the main analysis set for exposure/compliance, clinical safety and 
efficacy.   
All safety analyses summaries will be descriptive in nature and no formal 
inferential testing will be performed.  
The percent and absolute change in lipid data (eg, LDL-C, Apo B, TG) will 
be descriptively summarized by visit.  Missing data will not be imputed.   
For both safety and efficacy analyses, the baseline for each patient is defined 
as follows:   
• 
For patients who participated in a previous evinacumab study, 
R1500-CL-1629, baseline is defined as the last obtained value before 
the first dose of double-blind study drug in R1500-CL-1629 
• 
For patients who participated in the previous evinacumab study 
R1500-CL-1331 or did not participate in any previous evinacumab 
study, baseline is defined as the last obtained value before the first 
dose of study drug in R1500-CL-1719. (Note: Baseline for patients 
who participated in R1500-CL-1331 is defined as the baseline from 
the R1500-CL-1719 study due to the long time between the last 
study treatment in R1500-CL-1331 and the first study treatment in 
R1500-CL-1719.) 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANGPTL3 
Angiopoietin-like 3 
Apo A-1 
Apolipoprotein A-1 
Apo B 
Apolipoprotein B (protein encoded in humans by the APOB gene) 
Apo CIII 
Apolipoprotein CIII 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CAD 
Coronary artery disease 
CEC 
Clinical Events Committee 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CUP 
Compassionate Use Program 
CV 
Cardiovascular 
CVD 
Cardiovascular disease 
NOD 
New onset diabetes 
EAP 
Early access program 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EOS 
End of study 
EOT 
End of treatment 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
HDL 
High-density lipoprotein 
HDL-C 
High-density lipoprotein cholesterol 
Hs-CRP 
high sensitivity C-reactive protein 
FH 
Familial hypercholesterolemia 
FSH 
Follicle-stimulating hormone 
HoFH 
Homozygous familial hypercholesterolemia 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
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IDMC 
Independent Data Monitoring Committee 
IRB 
Institutional Review Board 
ISS 
Investigator-Sponsored Study 
IST 
Investigator-Sponsored Trial 
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 
LOF 
Loss-of-function 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
Non-HDL-C 
Non-high-density lipoprotein cholesterol 
OLTP 
Open-label treatment period 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
POC 
Proof-of-concept 
PT 
Preferred term 
Q2W 
Every 2 weeks 
Q4W 
Every 4 weeks 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Software 
SC 
Subcutaneous 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TC 
Total cholesterol 
TG 
Triglycerides 
TSH 
Thyroid-stimulating hormone 
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ULN 
Upper limit of normal 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................3 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................15 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................21 
1. 
INTRODUCTION ......................................................................................................30 
2. 
STUDY OBJECTIVES ..............................................................................................33 
2.1. 
Primary Objectives .....................................................................................................33 
2.2. 
Secondary Objectives .................................................................................................33 
2.3. 
Exploratory Objective .................................................................................................33 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................33 
3.1. 
Hypothesis ..................................................................................................................33 
3.2. 
Rationale .....................................................................................................................33 
3.2.1. 
Rationale for Study Design .........................................................................................33 
3.2.2. 
Rationale for Dose Selection ......................................................................................35 
3.2.3. 
Risk/Benefit Assessment ............................................................................................35 
4. 
STUDY VARIABLES................................................................................................38 
4.1. 
Demographic and Baseline Characteristics ................................................................38 
4.2. 
Primary and Secondary Endpoints..............................................................................38 
4.3. 
Pharmacokinetic Variables .........................................................................................38 
4.4. 
Anti-Drug Antibody Variables ...................................................................................38 
4.5. 
Ultrasound Imaging ....................................................................................................39 
5. 
STUDY DESIGN .......................................................................................................40 
5.1. 
Study Description and Duration .................................................................................40 
5.1.1. 
End of Study Definition ..............................................................................................44 
5.2. 
Planned Interim Analysis ............................................................................................44 
5.3. 
Study Committees .......................................................................................................44 
5.3.1. 
Independent Data Monitoring Committee ..................................................................44 
5.3.2. 
Clinical Events Committee .........................................................................................45 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............45 
6.1. 
Number of Patients Planned .......................................................................................45 
6.2. 
Study Population .........................................................................................................45 
6.2.1. 
Inclusion Criteria ........................................................................................................46 
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6.2.2. 
Exclusion Criteria for Evinacumab-Naïve Patients ....................................................46 
6.2.3. 
Exclusion Criteria for Patients from a Previous Evinacumab Study ..........................49 
6.3. 
Premature Withdrawal from the Study .......................................................................50 
6.4. 
Replacement of Patients .............................................................................................51 
6.5. 
Re-screening of Patients .............................................................................................51 
7. 
STUDY TREATMENTS............................................................................................51 
7.1. 
Investigational and Reference Treatments ..................................................................51 
7.2. 
Background Treatment(s) ...........................................................................................51 
7.3. 
Dose Modification and Study Treatment Discontinuation Rules ...............................52 
7.3.1. 
Dose Modification ......................................................................................................52 
7.3.2. 
Study Drug Discontinuation .......................................................................................52 
7.3.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................52 
7.3.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................52 
7.4. 
Management of Acute Reactions ................................................................................53 
7.4.1. 
Acute Intravenous Infusion Reactions ........................................................................53 
7.4.1.1. 
Interruption of the Intravenous Infusion .....................................................................53 
7.4.1.2. 
Termination of the Intravenous Infusion ....................................................................53 
7.4.2. 
Acute Injection Reactions ...........................................................................................54 
7.4.2.1. 
Systemic Injection Reactions ......................................................................................54 
7.4.2.2. 
Local Injection Site Reactions ....................................................................................54 
7.5. 
Method of Treatment Assignment ..............................................................................54 
7.5.1. 
Blinding ......................................................................................................................54 
7.6. 
Treatment Logistics and Accountability .....................................................................54 
7.6.1. 
Packaging, Labeling, and Storage ..............................................................................54 
7.6.2. 
Supply and Disposition of Treatments .......................................................................54 
7.6.3. 
Treatment Accountability ...........................................................................................55 
7.6.4. 
Treatment Compliance ................................................................................................55 
7.7. 
Concomitant Medications and Procedures .................................................................55 
7.7.1. 
Permitted Medications and Procedures ......................................................................55 
7.7.2. 
Prohibited Medications and Procedures .....................................................................56 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................56 
8.1. 
Study assessments and procedures are presented by study period and visit in 
Table 1, Table 2 and Table 3. .....................................................................................57 
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8.1.1. 
Footnotes for Schedule of Events Table 1 ..................................................................64 
8.1.2. 
Footnotes for the Schedule of Events Table 2 ............................................................64 
8.1.3. 
Footnotes for Schedule of Events Table 3 ..................................................................65 
8.1.4. 
Early Termination Visit ..............................................................................................67 
8.1.5. 
Unscheduled Visits .....................................................................................................67 
8.2. 
Study Procedures ........................................................................................................67 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................67 
8.2.2. 
Safety Procedures .......................................................................................................68 
8.2.2.1. 
Vital Signs ..................................................................................................................68 
8.2.2.2. 
Physical Examination .................................................................................................68 
8.2.2.3. 
Electrocardiogram .......................................................................................................68 
8.2.2.4. 
Tanner Stages ..............................................................................................................68 
8.2.2.5. 
Laboratory Testing ......................................................................................................68 
8.2.2.6. 
Pregnancy Testing ......................................................................................................70 
8.2.3. 
Efficacy Procedures ....................................................................................................70 
8.2.3.1. 
Lipid Panel ..................................................................................................................71 
8.2.3.2. 
Specialty Lipid Panel ..................................................................................................71 
8.2.4. 
Drug Concentration and Measurements .....................................................................71 
8.2.5. 
Anti-Drug Antibody Measurements and Samples ......................................................71 
8.2.6. 
Ultrasound Imaging ....................................................................................................71 
8.2.7. 
Pharmacodynamic Procedures ....................................................................................71 
8.2.8. 
Future Biomedical Research .......................................................................................72 
8.2.9. 
Other Assessments ......................................................................................................72 
8.2.9.1. 
Review of Diet ............................................................................................................72 
8.2.9.2. 
DNA Sample for HoFH Genotyping ..........................................................................72 
8.2.9.3. 
Genomics Sub-Study (Optional) .................................................................................72 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................73 
9.1. 
Obligations of Investigator .........................................................................................73 
9.2. 
Obligations of Sponsor ...............................................................................................73 
9.3. 
Definitions ..................................................................................................................73 
9.3.1. 
Adverse Event .............................................................................................................73 
9.3.2. 
Serious Adverse Event ................................................................................................73 
9.3.3. 
Adverse Events of Special Interest .............................................................................74 
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9.3.4. 
Infusion Reactions ......................................................................................................74 
9.4. 
Recording and Reporting Adverse Events ..................................................................74 
9.4.1. 
Adverse Events ...........................................................................................................74 
9.4.2. 
Serious Adverse Events ..............................................................................................75 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor ...................................75 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................77 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results .............................77 
9.4.6. 
Follow-up ....................................................................................................................77 
9.5. 
Evaluation of Severity and Causality .........................................................................77 
9.5.1. 
Evaluation of Severity ................................................................................................77 
9.5.2. 
Evaluation of Causality ...............................................................................................78 
9.6. 
Safety Monitoring .......................................................................................................81 
9.7. 
Investigator Alert Notification ....................................................................................81 
10. 
STATISTICAL PLAN................................................................................................82 
10.1. 
Statistical Hypothesis ..................................................................................................82 
10.2. 
Justification of Sample Size........................................................................................82 
10.3. 
Analysis Sets ...............................................................................................................82 
10.3.1. 
Safety Analysis Set .....................................................................................................82 
10.3.2. 
Efficacy Analysis Sets ................................................................................................82 
10.3.3. 
Pharmacokinetic Analysis Sets ...................................................................................82 
10.3.4. 
Anti-Drug Antibody Analysis Sets .............................................................................82 
10.4. 
Statistical Methods ......................................................................................................83 
10.4.1. 
Patient Disposition ......................................................................................................83 
10.4.2. 
Demography and Baseline Characteristics .................................................................84 
10.4.3. 
Efficacy Analyses .......................................................................................................84 
10.4.4. 
Safety Analyses ..........................................................................................................84 
10.4.4.1. 
Adverse Events ...........................................................................................................84 
10.4.4.2. 
Other Safety ................................................................................................................85 
10.4.4.3. 
Treatment Exposure ....................................................................................................86 
10.4.4.4. 
Treatment Compliance ................................................................................................86 
10.4.5. 
Pharmacokinetics ........................................................................................................86 
10.4.5.1. 
Analysis of Drug Concentration Data .........................................................................86 
10.4.6. 
Analysis of Anti-Drug Antibody Data ........................................................................86 
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10.5. 
Additional Statistical Data Handling Conventions .....................................................87 
10.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .........87 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS .....................................87 
11.1. 
Data Management .......................................................................................................87 
11.2. 
Electronic Systems ......................................................................................................87 
12. 
STUDY MONITORING ............................................................................................87 
12.1. 
Monitoring of Study Sites ...........................................................................................87 
12.2. 
Source Document Requirements ................................................................................88 
12.3. 
Case Report Form Requirements ................................................................................88 
13. 
AUDITS AND INSPECTIONS .................................................................................88 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................89 
14.1. 
Good Clinical Practice Statement ...............................................................................89 
14.2. 
Patient Confidentiality and Data Protection ...............................................................90 
14.3. 
Institutional Review Board/Ethics Committee ...........................................................91 
15. 
PROTOCOL AMENDMENTS ..................................................................................91 
16. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................91 
16.1. 
Premature Termination of the Study ...........................................................................91 
16.2. 
Close-out of a Site ......................................................................................................91 
17. 
STUDY DOCUMENTATION ...................................................................................92 
17.1. 
Certification of Accuracy of Data ...............................................................................92 
17.2. 
Retention of Records ..................................................................................................92 
18. 
DATA QUALITY ASSURANCE ..............................................................................92 
19. 
CONFIDENTIALITY ................................................................................................93 
20. 
FINANCING AND INSURANCE .............................................................................93 
21. 
PUBLICATION POLICY ..........................................................................................93 
22. 
REFERENCES ...........................................................................................................94 
23. 
INVESTIGATOR’S AGREEMENT ..........................................................................97 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................99 
 
LIST OF TABLES 
Table 1: 
Schedule of Events – Run-In and Screening ..............................................................57 
Table 2: 
Schedule of Events – Screening for Patients with No Run-In ....................................58 
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Table 3: 
Schedule of Events – Open-Label Treatment Period and Follow-Up ........................60 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................44 
 
LIST OF APPENDICES 
APPENDIX 1. SUMMARY OF THERAPEUTIC LIFESTYLE CHANGES DIET 
FOR HIGH CHOLESTEROL ....................................................................................98 
 
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1. 
INTRODUCTION 
Familial hypercholesterolemia (FH) is an inherited disorder of lipid metabolism that predisposes 
a person to premature severe cardiovascular disease (CVD) (Kolansky 2008). Familial 
hypercholesterolemia can be either an autosomal dominant or an autosomal recessive disease that 
results from mutations in the low-density lipoprotein receptor (LDLR), or in 3 associated genes: 
proprotein convertase subtilisin/kexin type 9 (PCSK9); apolipoprotein B (APOB); and 
low-density lipoprotein (LDL) receptor adaptor protein 1 (LDLRAP1) with a similar phenotype 
and varying severity.  
Homozygous familial hypercholesterolemia (HoFH) is a rare, serious condition that is frequently 
caused by loss-of-function mutations in both alleles of the LDL receptor gene, resulting in the 
decreased clearance of LDL particles from plasma.  Patients with HoFH have severe 
hypercholesterolemia (500-1000 mg/dL), resulting in lifelong exposure to high levels of plasma 
LDL and increased risk of developing atherosclerosis.  Accelerated atherosclerosis results in 
premature CVD and an increased risk of a cardiovascular event.  Although double-blind 
cardiovascular outcome data in this rare population do not exist, observational studies suggest 
that lowering low-density lipoprotein cholesterol (LDL-C) with statin therapy may reduce the 
risk of coronary heart disease by 50% to 80% in patients with familial hypercholesterolemia 
(Harada-Shiba 2010) (Huijgen 2010) (Vermissen 2008) (Neil 2008). The goal of drug therapy in 
adult patients with FH is to achieve LDL-C reduction ≥50% (Goldberg 2011); however, 
management of elevated LDL-C in patients with HoFH is challenging with the current existing 
treatment options.  Because patients with HoFH have impaired or deficient LDL-receptor 
function, they tend to be refractory to statins because the mechanism of action generally lowers 
LDL-C levels through up-regulation of the hepatic LDL receptor.  
Statins can reduce LDL-C by more than 50% in other hypercholesterolemic patients, in HoFH 
patients; however, statins may provide a decrease of <15 to 30% (Crestor 2003) (Lipitor 1996) 
(Zocor 1991). When ezetimibe is added to a statin, LDL-C may be reduced by 21 to 27% 
(Zetia 2002), but many patients with HoFH treated with a high dose statin and ezetimibe remain 
far from their target LDL-C.  Despite the near total loss of functional LDL receptors in HoFH 
patients, statins are still used as first line therapy in order to maximize residual receptor activity 
(Raal 2000) (Marais 2008) (Raal 1997). 
Mipomersen and lomitapide have been approved in some countries for use in patients with 
HoFH, and provide an additional ~25% and 40% reduction in LDL-C, respectively, when used 
along with other lipid-modifying therapies (LMT).  However, these new therapies are not 
commercially available in all countries, and are associated with increases in hepatic fat content 
and liver function tests, and frequent injection site reactions (mipomersen) or gastrointestinal 
side effects (lomitapide) that can impact tolerability (Raal 2010, Cuchel 2013). 
While PCSK9 inhibitor antibody therapy may provide modest efficacy in the treatment of many 
patients with HoFH patients with hypercholesterolemia, it appears to be minimally effective in 
patients with impaired LDL-receptor activity, particularly those patients with null mutations in 
both LDLR alleles (Raal 2014). 
In the recent TESLA study comparing evolocumab on top of statins (with or without ezetimibe) 
in patients with HoFH, the mean percent reduction in LDL-C at week 12 was 23.1% (Raal 2014).  
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Evolocumab therapy did not reduce LDL-C in patients with LDL receptor-negative mutations in 
both alleles (Raal 2014) (Repatha 2015). 
High-dose statins, ezetimibe, PCSK9 inhibitor antibodies, mipomersen, and lomitapide may be 
effective in some patients with HoFH, but many patients still require lipid apheresis.  Lipid 
apheresis can be effective, but entails weekly or bi-weekly treatments, lasting several hours, is 
both costly and associated with a risk of infections (Vella 2001) (Kajinami 1999), and is not 
routinely available (Thompson 2010). Despite treatment with lipid-modifying therapies such as 
pharmacological agents, as well as mechanical removal by lipid apheresis, many patients with 
HoFH remain far from their LDL-C treatment goal.  Therefore, the need for more intensive 
treatment in HoFH, especially those patients with double null mutations, remains. 
Angiopoietin-like 3 (ANGPTL3) has recently emerged as a potential target for the treatment of 
elevated levels of triglycerides (TG), and for the treatment of elevated levels of LDL-C, both 
factors in the development of CVD. Angiopoietin-like 3 (ANGPTL3) acts as a natural inhibitor 
of lipoprotein lipase (LPL), an endothelial-bound enzyme involved in the hydrolysis of the TG 
content of very-low-density lipoproteins (VLDL) and chylomicron lipoproteins. Patients who are 
homozygous for loss-of-function (LOF) mutations in ANGPTL3 have lower levels of LDL-C 
(mean difference of 48% versus control family members). The mechanism by which ANGPTL3 
LOF mutations result in lowered LDL-C levels is not fully understood, but appears to be 
independent of the effects on TGs. It is noteworthy that patients with 1 or 2 ANGPTL3 LOF 
alleles also have reported reductions in serum high-density lipoprotein cholesterol (HDL-C) 
levels. The mechanism for this may be linked to the inhibitory effect of ANGPTL3 on 
endothelial lipase (EL), which is involved in the hydrolysis of HDL phospholipids. Importantly, 
no health deficits have been reported in the (relatively small number of) patients who are 
homozygous for ANGPTL3 LOF mutations. These data suggest that inhibiting ANGPTL3 may 
be a meaningful and well-tolerated strategy for lowering serum LDL C and TGs.  
Evinacumab (REGN1500) is a fully human monoclonal antibody (mAb), created with 
Regeneron’s VelocImmune technology platform, which specifically binds to ANGPTL3. 
Evinacumab (REGN1500) is a fully human monoclonal antibody, created with Regeneron's 
VelocImmune® technology platform, which specifically binds to ANGPTL3 and prevents its 
inhibition of lipoprotein lipase, thereby increasing hydrolysis of TG. Experiments performed in 
animals demonstrate that the administration of evinacumab results in a reduction of serum LDL 
C and serum TGs.  In an open-label, single-arm, proof-of-concept (POC) study in patients with 
genetically-defined HoFH (Study R1500-CL-1331), treatment with evinacumab in 9 patients 
resulted in a mean percent reduction of LDL-C from baseline of 49.2% at week 4 (the primary 
endpoint).  A peak mean reduction of 52.1% was observed at week 6.  Three patients enrolled in 
Study R1500 CL 1331 are homozygous for null mutations in the LDL-R.  Evinacumab provided 
37.3% (range: 26-44%) reductions in LDL-C at week 4 in these 3 null/null HoFH patients.  
Evinacumab in this POC study has been well tolerated.   
The LDL-C lowering effect observed with evinacumab in R1500-CL-1331 was confirmed in 
R1500-CL-1629, the pivotal study evaluating evinacumab in patients with HoFH, and the parent 
study from which most patients continued into this current study, R1500-CL-1719. R1500-CL-
1629 was a randomized, double-blind, placebo-controlled study which enrolled adult and 
adolescent patients with HoFH. The 24-week double-blind treatment period has completed, and 
the results are briefly described here. On average, patients entered the trial with a mean baseline 
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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 placebo (47% 
reduction for evinacumab compared to a 2% increase for placebo, p<0.0001). This reduction 
corresponds 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 significantly 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 were no AEs leading to death or 
discontinuation of study treatment. Two patients (4.5%), both in the evinacumab treatment 
group, experienced 1 serious TEAE (SAE) each (urosepsis and suicide attempt); neither of the 
events were considered related to therapy or led to discontinuation of study treatment and both 
were reported to be recovered/resolved. Treatment with evinacumab was not associated with any 
safety concerns related to hepatic TEAEs or laboratory parameters, muscle events or CK 
elevations, pancreatitis, neurocognitive events, neurologic events, cataracts, new onset diabetes 
(NOD), diabetic complications, or immune complex diseases. A review of safety labs, vital 
signs, and ECG did not reveal any significant differences between evinacumab treatment and 
placebo. 
This study was designed to evaluate the long-term safety and tolerability of evinacumab in 
participants with HoFH who are either evinacumab naïve, or have participated in other 
evinacumab studies (ie, R1500-CL-1331, R1500-CL-1629). All participants received 
evinacumab at a dose of 15 mg/kg IV every 4 weeks (Q4W).  
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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objectives 
The primary objectives of the study are: 
• To evaluate the long-term safety and tolerability of evinacumab 15 mg/kg 
intravenously (IV) administered every 4 weeks (Q4W) in patients with HoFH.   
• To evaluate the long-term safety and tolerability of evinacumab 15 mg/kg IV 
administered Q4W in adolescent patients with HoFH 
2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To evaluate the effect of evinacumab 15 mg/kg IV on lipid parameters (ie, LDL-C, 
Apo B, non-HDL-C, total cholesterol [TC], and TG) in patients with HoFH 
• To evaluate the effect of evinacumab 15 mg/kg IV on lipid parameters (ie, LDL-C, 
Apo B, non-HDL-C, TC, and TG) in adolescent patients with HoFH 
• To evaluate the potential development of anti-evinacumab antibodies 
2.3. 
Exploratory Objective 
An exploratory objective of this study is to explore vascular changes using imaging techniques. 
3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypothesis 
Blockade of ANGPTL3 with evinacumab will reduce or maintain consistent long-term reduction 
in LDL-C and demonstrate an acceptable safety profile in patients with HoFH.   
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
This study is being conducted in patients with HoFH, which may include patients who have 
participated in a previous evinacumab study (eg, R1500-CL-1331, R1500-CL-1629) and also 
evinacumab-naïve patients with HoFH.  The study is intended to provide long-term safety, 
efficacy and pharmacokinetics (PK) information on evinacumab treatment of adult and 
adolescent patients with HoFH.  The study population will include individuals ≥12 years of age.  
Because this disease is characterized by severe hypercholesterolemia from birth and, 
subsequently, the onset of premature CVD during childhood, the HoFH population includes 
children and adolescents. Allowing individuals ≥12 years of age to enroll in this study will 
ensure the study population is reflective of the patient population manifesting disease in 
adolescence and adulthood. 
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Considering the severity of this disease, evinacumab will be added on top of the patient’s 
background LMT, including statins, ezetimibe, and PCSK9 inhibitors.  Patients receiving 
background LMT that has been proven to reduce the risk of ASCVD (eg, statins, ezetimibe, 
PCSK9 inhibitor antibodies) should make their best effort to maintain a stable regimen for the 
entire duration of the study. This guidance is provided so that patients will be able to receive 
maximal benefit from the treatment. Patients receiving other LMT (eg, apheresis, lomitapide) 
may have that LMT adjusted after week 24, based on their LDL-C, CV risk factors, and the 
judgment of the investigator. 
This study employs a single-arm, open-label design, which is appropriate since the primary 
objective of this study is long-term safety and tolerability.  A run-in period is included to ensure 
all patients entering this study are on a stable background LMT regimen. This is important 
because a stable background LMT regimen will ensure a stable LDL-C at the onset of the study, 
which is necessary to adequately assess the secondary objective of efficacy, particularly for the 
evinacumab-naïve patients entering this study. 
The study population will include patients with HoFH, diagnosed by either clinical criteria or 
genotyping.  Patients entering this study from another evinacumab trial will not have to fulfill an 
LDL-C entry criterion. No criterion is applied to this population because most of the patients had 
to fulfill an LDL-C entry criterion of ≥70 mg/dL prior to entering the previous evinacumab study 
in which they participated. These patients are transitioning into this study with the goal of 
maintaining their LMT regimen (including evinacumab) and thus maintaining their LDL-C.  This 
stability allows for the evaluation of the long-term safety and efficacy of evinacumab in patients 
with HoFH. 
Patients who are evinacumab-naïve will have to fulfill an LDL-C criterion of ≥70 mg/dL at 
screening.  This threshold is the target LDL-C recommended in the different treatment guidelines 
for patients at very high risk for ASCVD, which includes patients with HoFH (Grundy, 2018) 
(Catapano, 2016). 
Another consideration for the LDL-C entry criterion in this study is that for this severe patient 
population that falls at the very extreme end of the spectrum of patients with 
hypercholesterolemia, LDL-C levels should be managed so that they are as low as possible. As 
mentioned above, patients with HoFH have severe hypercholesterolemia (≥500 mg/dL). Plasma 
levels of LDL-C are elevated from birth, with reports of elevations greater than 4-fold in infants 
with HoFH. The resulting lifelong exposure to high levels of plasma LDL-C leads to a 
significantly increased risk of developing atherosclerosis. This accelerated atherosclerosis results 
in premature CVD and an increased risk for cardiovascular events. To manage these long-term 
sequelae of extremely elevated levels of LDL-C, patients with HoFH need to achieve the lowest 
possible LDL-C for as long as possible (Gidding 2015). 
Although double-blind cardiovascular outcome data in this rare population do not exist, 
observational studies suggest that lowering LDL-C with statin therapy may reduce the risk of 
coronary heart disease by 50% to 80% in patients with FH (Harada-Shiba 2010) (Huijgen 2010) 
(Vermissen 2008) (Neil 2008).  Additionally, recent outcomes data with ezetimibe, evolocumab, 
and alirocumab for the primary or secondary prevention of CVD in high risk patients with 
hypercholesterolemia have further demonstrated that, similar to statins, other lipid lowering 
agents can also significantly reduce the risk of CHD.  The LDL-C levels achieved in these recent 
outcomes studies ranged from a median of 30 mg/dL in the evolocumab outcomes study 
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(FOURIER) (Sabatine 2017) to approximately 50 mg/dL in the studies with ezetimibe 
(IMPROVE-IT) (Cannon 2015) and alirocumab (ODYSSEY OUTCOMES) (Steg 2018). 
Importantly, these LDL-C levels were associated with a 7 to 15% reduction in cardiovascular 
events (Cannon 2015, Sabatine 2017, Steg 2018). When these data are positioned within the 
context of this study, it provides additional evidence for the LDL-C entry criteria outlined. 
3.2.2. 
Rationale for Dose Selection 
The evinacumab 15 mg/kg IV Q4W dose regimen to be studied in this study is the dose regimen 
evaluated in the pivotal phase 3, double-blind, placebo-controlled study in patients with HoFH 
(R1500-CL-1629). It was selected based on safety in the phase 1 and phase 2 studies and the 
substantial LDL-C reduction observed with that dose in HoFH patients in study R1500-CL-1331. 
The 15 mg/kg IV Q4W dose regimen will continue to be evaluated in this study to obtain 
long-term safety, additional efficacy, and PK information, with the intended dose for registration 
in patients with HoFH. 
The higher dose regimen of 20 mg/kg IV Q4W demonstrated favorable tolerability when given 
as an 8-week treatment in otherwise healthy subjects (R1500-CL-1321).  Long-term 
administration of evinacumab at the 15 mg/kg IV Q4W regimen is expected to also demonstrate 
favorable tolerability because the evinacumab exposure within each dosing interval is expected 
to be lower than 20 mg/kg IV and the accumulation of serum concentration with a monthly 
dosing frequency is predicted to be minimal.  From an efficacy perspective, the 15 mg/kg IV 
dose resulted in evinacumab concentrations above 100 mg/L for approximately 4 weeks, an 
exposure threshold associated with target saturation and maximal effect on TG reduction 
(R1500-CL-1321 and R1500-HV-1214).  Based on these PK/pharmacodynamics (PD) data, 
combined with the efficacy data from the POC study in HoFH (R1500-CL-1331), 15 mg/kg IV is 
expected to maintain target saturation and thereby, provide maximal benefit during the monthly 
dosing interval.   
Pharmacokinetics information is not available from patients aged 12 to 17 years.  Evinacumab 
systemic elimination features a combination of linear clearance and non-linear, target-driven 
clearance.  The linear clearance for monoclonal antibodies is often similar between adults and 
adolescents after adjusting for body-weight.  The comparison of nonlinear clearance between 
adolescents and adults is not known.  However, at 15 mg/kg IV, the contribution of 
target-mediated clearance is likely to be low since target saturation appeared to be present.  
Therefore, evinacumab clearance in adolescents is likely to be similar to adults and the same 
dose as the adult dose is expected to yield evinacumab exposure in the range associated with 
observed efficacy and tolerability in adults.  In the event that PK information from adolescent 
patients becomes available while this study is ongoing, and data suggest meaningful differences 
in PK/PD between adolescents and adults, an amendment to the protocol will be considered to 
modify the dose of study drug for adolescent patients.   
3.2.3. 
Risk/Benefit Assessment 
As mentioned above, patients with HoFH have a lifetime burden of extremely high LDL-C 
levels. These life-long exposures to profound hypercholesterolemia is directly responsible for 
vascular endothelial damage and accelerated atherosclerosis, greatly increasing the risk for 
premature coronary artery disease (CAD), peripheral artery disease, and valvular disease, 
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especially aortic stenosis. The deposition of cholesterol in vascular and extravascular 
compartments, such as tendons and skin, results in xanthomas and the deposition of lipid in the 
cornea of the eyes causes corneal arcus and an increase in intraocular pressure. If left untreated, 
most patients with HoFH develop atherosclerosis before the age of 20 years, and generally do not 
survive past the third decade of life (Ito 2015, Cuchel 2014). 
The goal of therapy in these patients is to slow the progression of atherosclerosis with the aim of 
reducing CV events and mortality. Patients with HoFH should be provided aggressive 
interventions to achieve these goals. Despite the approval of newer treatments, including 
evolocumab, lomitapide, and mipomersen, the need for more intensive therapies remains. 
Evinacumab could be a new addition to the armamentarium of LMT that could contribute to 
lowering the LDL-C in patients with HoFH.  
The ACC/AHA and the EAS guidelines for FH both recommend an initial goal of at least a 
50% reduction in LDL-C in patients with FH to reduce the risk of CVD (Gidding 2015, 
Cuchel 2014). The EAS Consensus Panel recommends that lipid-lowering therapies should be 
started as early as possible in patients with HoFH. This is based on evidence that initiation of 
treatment early can delay the onset of clinically evident ASCVD. If the 50% reduction in LDL-C 
is achieved, the ACC/AHA and EAS additionally recommends further LDL-C lowering to 
achieve LDL-C levels of <100 mg/dL (<2.5 mmol/L) in the absence of CAD or other major risk 
factors or <70 mg/dL (<1.8 mmol/L) in the presence of ASCVD or other major risk factor 
(Gidding 2015, Cuchel 2014).  A limitation to both sets of recommendations is that they are 
based on clinical trials of patients without FH because of the lack of true long-term outcome 
studies in patients with FH. Indeed, due to the long-term sequelae of extremely elevated levels of 
LDL-C described above, at a minimum patients with HoFH need to achieve the goals described 
in the guidelines, but would benefit from more aggressive treatments to achieve the lowest 
LDL-C possible for as long as possible (Gidding 2015). 
Historically, these LDL-C targets have been challenging to achieve with the available treatment 
options, in part because the mutations observed in this patient population renders major classes 
of lipid lowering treatments as either ineffective or less efficacious.  However, with additional, 
newer classes of pharmacotherapy, achieving these goals and even lowering LDL-C beyond 
these goals is slowly becoming a reality.  Moreover, results of several recent outcomes trials 
suggest that achieving lower LDL-C levels than the current recommended target levels may 
provide additional CV benefit. The LDL-C levels achieved in the outcomes studies with 
ezetimibe, evolocumab, and alirocumab ranged from a median of 30 mg/dL in the evolocumab 
outcomes study (FOURIER) (Sabatine 2017) to approximately 50 mg/dL in the studies with 
ezetimibe (IMPROVE-IT) (Cannon 2015) and alirocumab (ODYSSEY OUTCOMES) 
(Steg 2018). These LDL-C levels were associated with a 7-15% reduction in cardiovascular 
events (Cannon 2015, Sabatine 2017, Steg 2018). Additionally, the LDL-C levels in all 3 studies 
were also associated with an acceptable safety profile.   
Considering the growing evidence for aggressively treating LDL-C, even in the setting of what 
some might consider patients with HoFH that might be at their “goal” LDL-C (ie, 70 mg/dL), the 
benefits of adding evinacumab and potentially lowering the LDL-C even further become 
apparent. For patients entering this study from another evinacumab trial there is no LDL-C entry 
criterion as these patients would have been treated with evinacumab for at least 24 weeks prior to 
entering this study and would have achieved their maximal lipid lowering effect.   
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Preliminary data from the proof-of-concept study in patients with HoFH demonstrate the efficacy 
of evinacumab in this patient population, even in the most difficult-to-treat patients with null/null 
mutations in the LDLR gene. Recent data from study R1500-CL-1629 in adult and adolescent 
patients with HoFH demonstrated that adding evinacumab to other lipid-lowering therapies 
decreased LDL-C by a mean of 49% from baseline to week 24. This efficacy data was 
accompanied by an acceptable safety profile. 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). The accumulated safety information from the 
completed and ongoing clinical studies had identified the risk of systemic hypersensitivity 
reactions (including anaphylaxis and infusion reactions). The important potential risks (based on 
preclinical evaluation or risks associated with monoclonal antibodies in general) include 
embryofetal toxicity and immunogenicity. These risks will be managed through careful patient 
selection, routine monitoring, and complete disclosure of safety information. 
Patients entering this study should be on a stable background LMT, which may or may not 
include a statin, ezetimibe, and a PCSK9 inhibitor.  There are 2 PCSK9 inhibitors that are 
commercially available in many countries; evolocumab is approved for use in patients with 
HoFH in most countries, and alirocumab is currently being evaluated in a phase 3 double-blind 
placebo-controlled study in patients with HoFH (study R727-CL-1628, ODYSSEY HoFH). 
Patients entering this study may be taking either evolocumab or alirocumab. Patients who 
complete study R727-CL-1628 (ODYSSEY HoFH) with alirocumab are permitted to participate 
in this study and may continue to receive alirocumab as part of their background LMT.  
Evinacumab and PCSK9 inhibitors, including alirocumab have different mechanisms of action 
and concomitant administration of both agents is not expected to perturb the action of the other. 
Rather, their distinct mechanisms of action are anticipated to complement each other to lower 
LDL-C since they work at different sites of action. Additionally, the safety profile of each agent 
is considered acceptable and the concurrent use of the 2 agents together is not expected to 
augment or exacerbate potential AEs. From the perspective of PK drug-drug interactions, 
co-administration of evinacumab with a PCSK9 inhibitor and the other possible background 
LMT (statin, ezetimibe, etc) is not expected to result in drug-drug interactions with each other or 
other drugs. Therefore, the concurrent use of evinacumab with PCSK9 inhibitors, including 
alirocumab is considered to have an acceptable benefit/risk profile. 
The safety of the use of evinacumab alone or concomitantly with alirocumab will be carefully 
monitored in this study. Safety monitoring will include ongoing reviews by an Independent Data 
Monitoring Committee (IDMC) and by the sponsor’s safety monitoring team and clinical study 
team. If significant safety trends or findings are identified by either the IDMC or the sponsor, 
they will be escalated and appropriately evaluated to understand the best course of action. 
Taken together, the benefit/risk profile for the treatment with evinacumab in patients with HoFH 
is considered to be favorable and additional reduction in LDL-C may translate into significant 
clinical benefit. 
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, 
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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. 
4. 
STUDY VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height), disease 
characteristics including medical and surgical history, medication history, and apheresis schedule 
(if applicable), alcohol and smoking habits for each patient.  In addition, baseline characteristics 
will include Tanner staging for adolescent patients. 
4.2. 
Primary and Secondary Endpoints 
The primary endpoint is the incidence and severity of treatment-emergent adverse events 
(TEAEs) and other safety variables during the open-label treatment period in patients treated 
with evinacumab 15 mg/kg IV Q4W.   
The definition of the baseline value for computation of the change from baseline can be found in 
Section 10.4.3.  
The secondary efficacy endpoints are: 
• The percent and absolute change in LDL-C over time 
• The percent and absolute change in Apo B over time 
• The percent and absolute change in non-HDL-C over time 
• The percent and absolute change in TC over time 
• The percent and absolute change in TGs over time 
4.3. 
Pharmacokinetic Variables 
The PK variable is Ctrough collected at specified time points.   
4.4. 
Anti-Drug Antibody Variables 
Anti-drug antibody (ADA) variables include status (positive or negative) and titer as follows:  
• Treatment emergent ADA response, defined as any post-dose positive ADA assay 
response when the baseline results are negative or missing.  
• Treatment boosted ADA response, defined as any post-dose positive ADA assay 
response that is 9-fold or greater over baseline titer levels when baseline is positive in 
the ADA assay  
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The definition of persistent and transient ADA will be defined a priori in the SAP. 
• Titer values 
• Titer category, by patient’s maximal titer value 
− Low (titer <1,000) 
− Moderate (1,000≤ titer ≤10,000) 
− High (titer >10,000)  
• Neutralizing ADA for samples that are positive in the ADA assay 
4.5. 
Ultrasound Imaging 
Carotid intima-media thickness (cIMT in mm) for adolescent patients will be determined at sites 
with this capability. An assessment should be made at run-in/screening or as soon as possible 
thereafter, then at week 24 and 1 year followed at yearly intervals.  
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5. 
STUDY DESIGN 
5.1. 
Study Description and Duration 
This is an open-label study designed to evaluate the long-term safety and efficacy of evinacumab 
in patients with HoFH.   
Eligible patients for this study are male and female patients with HoFH, receiving LMT, as 
applicable.  Lipid modifying therapies may include maximally tolerated statin, ezetimibe, 
PCSK9 inhibitor antibody, or other lipid lowering therapies, including lipoprotein apheresis. 
Patients may include those who have participated in a previous evinacumab study (eg, 
R1500-CL-1331 and R1500-CL-1629) and evinacumab-naïve patients with HoFH. 
This study consists of a run-in period (for patients who may require HoFH genotyping, patients 
whose background medical LMT has not been stable prior to screening, or those whose apheresis 
settings and/or schedule have not been stable for at least 8 weeks prior to screening), a screening 
period, an open-label treatment period and a follow-up period.  Patients who upon their study 
completion, may continue to receive treatment outside of the clinical trial (such as through a 
compassionate use program [CUP], early access program [EAP], or investigator sponsored study 
[ISS/IST]) and thereby may forgo the 24-week follow-up period of the study.  The follow-up 
period was intended to be an off-drug follow-up.  No off-drug follow-up period is required for 
these patients.  In this situation, the patient’s end-of-treatment visit (EOT) will be their last study 
visit. 
Run-in Period: 
Apheresis therapy - Patients who are undergoing apheresis therapy must have initiated 
lipoprotein apheresis at least 3 months prior to screening and must receive stable weekly 
apheresis (every 7 ±1 days), or other stable regimen (±2 days) and/or stable settings for at least 
8 weeks prior to screening.  Patients whose schedule and/or apheresis settings have not been 
stable for at least 8 weeks before the baseline (day 1) visit, will enter an up to 10-week run-in 
period before screening. After the run-in period, patients whose lipoprotein apheresis schedule 
remains stable will be eligible to enter the 2-week screening period. 
Lipid modifying therapy - Patients who are on background LMT that has not been stable for at 
least 4 weeks (6 weeks for fibrates, 8 weeks for PCSK9 inhibitor antibody, 12 weeks on 
maximum tolerated dose of lomitapide) before the baseline (day 1) visit will enter a run-in period 
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 may enter the run-in period to determine their mutation status. 
Screening Period: 
Patients who are required to enter a 2-week screening period: 
• Evinacumab treatment-naïve patients.  
• Patients from a previous evinacumab study who do not enter this study within 7 days 
of completing the end of study (EOS) visit of the previous study. 
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Open-Label Treatment Period: 
Patients who completed the EOS visit in the previous evinacumab study within 7 days of the 
baseline/day 1 visit for this open label study do not have to undergo the screening visit and may 
enroll directly into this study if they fulfill all of the inclusion criteria and none of the exclusion 
criteria.   
The EOS visit from the previous study can serve as the baseline/day 1 visit for this open-label 
study and overlapping assessments do not need to be repeated in this study. Baseline assessments 
and procedures that do not overlap with assessments at the EOS visit of the previous study 
should be performed after all EOS assessments and procedures have been completed in the 
previous evinacumab study. 
Starting on day 1 (baseline), patients will receive evinacumab 15 mg/kg IV administered Q4W 
(±7 days) at the study site. Patients will remain in the clinic for monitoring for 60 minutes after 
the end of each IV infusion.  For patients unable to go to the site, evinacumab may be 
administered at an alternative location, which could include the patient’s home by a trained nurse 
or other health professional, as allowed by local laws. 
All patients who were supplied with alirocumab 150 mg subcutaneous (SC) by the sponsor in a 
previous study may continue to be provided with alirocumab 150 mg SC every 2 weeks (Q2W) 
in this study. Those entering this study, after completing a study evaluating the safety and 
efficacy of alirocumab in patients with HoFH, but did not participate in a prior evinacumab 
study, may or may not remain on alirocumab as part of their background LMT.  
Based on the patient’s preference and the judgment of the investigator and the patient’s health 
care provider, each patient may: 
• continue treatment with alirocumab supplied by the sponsor as part of their 
background LMT 
• discontinue alirocumab prior to enrolling 
• change to a commercially available PCSK9 inhibitor antibody prior to enrolling into 
this study 
Clinical laboratory samples must be collected and study assessments must be performed before 
study drug is administered.   
Patients who are undergoing apheresis or plasma exchange must have their clinical laboratory 
samples drawn and study assessments performed before undergoing the procedure. Every effort 
should be made for the patient to receive study drug immediately after completion of the 
apheresis procedure, but patients can receive study drug 1 day before the apheresis procedure. 
Patients undergoing plasma exchange should receive the study drug immediately after 
completing the procedure. Given the impact of lipoprotein apheresis, PCSK9 inhibitors, and 
mipomersen on lipid parameters, it is important to match the time of the baseline activities with 
the timing of the week 24 activities. This would mean that the timing between the baseline 
sample collection relative to the most recently completed LDL apheresis procedure, 
administration of a PCSK9 inhibitor or mipomersen should match the timing of the week 24 
sample collection relative to the most recently completed apheresis procedure, administration of 
a PCSK9 inhibitor or mipomersen. 
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Patients receiving background LMT that has been proven to reduce the risk of ASCVD 
(eg, statins, ezetimibe, PCSK9 inhibitor antibodies) should make their best effort to maintain a 
stable regimen after week 24 and for the duration of the study.  
Patients receiving other LMT (eg, apheresis, lomitapide) may have that LMT adjusted after 
week 24, based on their LDL-C levels, CV risk factors, and judgment of the investigator.   
Patients should be on a stable heart healthy diet and exercise regimen throughout the duration of 
the study, starting at the baseline visit and continuing through the end of the open-label treatment 
period. 
Treatment will continue until 1 of the following occurs: 
• Clinical development of evinacumab for the indication described in this study 
protocol is discontinued 
• Clinical development of evinacumab is terminated 
• Risk/benefit of evinacumab in this patient population is deemed unfavorable 
• Evinacumab is approved by the regulatory authority governing the location of the 
study site* 
• For local discontinuation of study:  a decision has been made not to seek approval of 
an indication for treatment of patients with HoFH in the regulatory region in which 
the study is being conducted (or, to discontinue efforts to obtain such an approval) 
*Note, if in a region evinacumab is not commercially available or available through an early 
access or compassionate use program, treatment may continue in that region. 
Overall safety will be assessed by monitoring/evaluation of treatment emergent adverse events 
(TEAEs), physical examinations, electrocardiograms (ECG), and clinical safety laboratory tests 
at pre-specified time points.  The potential emergence of anti-evinacumab antibodies will also be 
evaluated.  Patients who experience an ongoing serious adverse event (SAE) at the study end 
date should be followed until resolution, stabilization, or collection of outcome and related data.   
Efficacy will be assessed by clinical laboratory evaluation of lipid levels at pre-specified time 
points throughout the study.   
Patients who prematurely discontinue from study drug should return to the clinic (within 5 days 
if possible), for end of treatment visit assessments.  A final EOS visit should take place with 
assessments as specified in the EOS visit at 24 weeks after the last dose of study drug.   
Follow-up Period: 
Patients will be followed for 24 weeks after receiving the last dose of study drug.  During this time, 
pregnancy status of all women of childbearing potential (WOCBP), including those who 
discontinue prematurely from the study will be monitored every 4 weeks for 24 weeks post the last 
dose of study drug either during clinic visits or by phone visit.  Patients who upon their study 
completion, may continue to receive treatment outside of the clinical trial (such as through a CUP, 
EAP, or ISS/IST) and thereby may forgo the 24-week follow-up period of the study.  The follow-
up period was intended to be an off-drug follow-up. No off-drug follow-up period is required for 
these patients.  In this situation, the patient’s EOT will be their last study visit. 
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A study flow diagram is in Figure 1  
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Figure 1: 
Study Flow Diagram 
 
Run-in1 
Screening2 
Treatment (Q4W)3,4 
24-week Follow-up5 
 
 
 
 
 
 
 
 
 
 
(Day -85 to -15) 
(Day -14 to -1) 
Baseline2 (Day 1) 
 
End of Treatment 
End of Study
 
 
 
 
 
 
1. Patients who may require HoFH genotyping and patients whose background LMT/apheresis settings and/or schedule has not 
been stable prior to baseline (day 1) will enter an up to 10-week run-in period. 
2 All patients who are on a stable background LMT will enter a 2-week screening period except for those from a previous 
evinacumab study who completed an end of study visit within 7 days prior to the baseline/day 1 visit for this open-label study. 
3. Patients who completed an end of study visit in a previous evinacumab study within 7 days of the baseline/day 1 visit for this 
open-label study do not have to undergo the screening visit and may enroll directly into this study. The EOS visit from the 
previous study can serve as the baseline/day 1 visit for this open-label study and overlapping assessments do not need to be 
repeated in this study.  Only those assessments and procedures not done in the previous study must be conducted at the 
baseline visit. These specific assessments to be administered to all patients are identified in the Schedule of Events, Table 3. 
4. Starting on day 1 (baseline), patients will receive evinacumab 15 mg/kg IV administered Q4W.  
5. Patients will be followed for 24 weeks after receiving the last dose of study drug.  Patients who enter a CUP, EAP, or 
ISS/IST may forgo the 24-week follow-up period after the last dose.  For these patients, the EOT visit will be their 
last visit. 
5.1.1. 
End of Study Definition 
The end of study is defined as last visit of the last patient.   
5.2. 
Planned Interim Analysis 
In order to provide information from this study, data may be analyzed on an ongoing basis. The 
results will not be used to change the conduct of the ongoing study in any aspect.   
Additionally, an interim analysis is planned for the subpopulation of adolescent patients. This 
planned interim analysis will be conducted as soon as all adolescent patients have been enrolled 
and all their data through week 24 have been collected and validated. For adolescent patients, the 
analysis will consist of the final analysis of the primary (safety) and secondary (lipids) endpoints 
collected during the initial 24 weeks of study treatment exposure. The safety and lipids analyses 
will be performed on all data collected and validated at the time of this adolescent subpopulation 
interim analysis.  
5.3. 
Study Committees 
5.3.1. 
Independent Data Monitoring Committee 
An IDMC composed of members who are independent from the sponsor and the study 
investigators, will monitor patient safety by conducting formal reviews of accumulated safety 
data; 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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5.3.2. 
Clinical Events Committee 
The Clinical Events Committee (CEC) is composed of experts in the field of CVD, independent 
of the sponsor and the investigators.  This committee will be responsible for defining, validating, 
and classifying (in a blinded fashion) pre-specified cardiovascular (CV) events and all deaths.   
Patients with suspected or confirmed CV events that occur from study entry until the end of the 
study will have a corresponding adjudication package prepared and submitted to the CEC.  The 
events should also be reported as SAEs, as appropriate.  Adjudicated CV events include all CV 
AEs positively adjudicated.  The adjudication categories include:   
• Coronary heart disease death 
• Nonfatal myocardial infarction  
• Fatal and nonfatal ischemic stroke 
• Unstable angina requiring hospitalization 
• Congestive heart failure requiring hospitalization 
In addition, other deaths (besides coronary heart disease deaths) will be classified by the CEC. 
All coronary revascularizations (percutaneous coronary intervention, coronary artery bypass 
graft surgery) will be submitted to the CEC and analyzed.   
A charter and an adjudication operational manual will specify additional details regarding the 
procedures, criteria, and classification used for adjudication of these events. 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
6.1. 
Number of Patients Planned 
This is an open-label study that will enroll patients with HoFH, including both those who may 
have participated in a previous evinacumab study (R1500-CL-1331 or R1500-CL-1629) and also 
evinacumab-naïve patients with HoFH. Approximately 120 patients will be enrolled. 
6.2. 
Study Population 
The study population will consist of male and female patients ≥12 years of age with HoFH 
receiving stable LMT, as applicable. Lipid modifying therapies may include maximally tolerated 
daily statin, ezetimibe, PCSK9 inhibitor antibody or other lipid lowering therapies, including 
lipoprotein apheresis.  This includes patients with HoFH who participated in other evinacumab 
studies (eg, R1500-CL-1331, R1500-CL-1629) or evinacumab-naïve patients. Adolescent 
patients will be enrolled only in participating countries where regulatory approval has been 
obtained to include adolescents.  Countries that have not received regulatory approval to enroll 
adolescent patients will enroll only patients ≥18 years of age. 
HoFH is defined by having at least one of the following (either genetic or clinical criteria):   
Genetic Criteria:   
1. Documented functional mutation or mutations in both LDLR alleles 
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• Note: patients who have null receptor mutations on both LDLR alleles, ie, double 
null, are eligible 
OR 
2. Documented homozygous or compound heterozygous mutations in Apo B or PCSK9 
• Note: patients who are double heterozygous, ie, mutations on different genes (eg, 
LDLR/PCSK9) and patients with homozygous LDLRAP1 mutations are eligible 
Clinical Criteria:   
Untreated TC >500 mg/dL (12.93 mmol/L) and TGs <300 mg/dL (3.39 mmol/L)  
AND  
both parents with documented TC >250 mg/dL (6.47 mmol/L) OR cutaneous or tendinous 
xanthoma before the age of 10 years 
6.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Male and female patients ≥12 years of age with HoFH.  Patients aged ≥12 years old will 
be enrolled only in countries where permitted by the Regulatory Agency and Institutional 
Review Board (IRB) or Ethics Committee (EC). 
2. Diagnosis of functional HoFH by at least 1 of the following genetic or clinical 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. Presence of homozygous or compound heterozygous mutations in Apo B or PCSK9 
Note: patients who are double heterozygous, ie, mutations on different genes (eg, 
LDLR/PCSK9) and patients with homozygous LDLRAP1 mutations are eligible 
c. Untreated TC >500 mg/dL (12.93 mmol/L) and TG <300 mg/dL (3.39 mmol/L)  
AND 
both parents with documented TC >250 mg/dL (6.47 mmol) 
OR cutaneous or tendinous xanthoma before the age of 10 years 
3. For patients who have participated in a previous evinacumab or alirocumab study: 
completion of the study in which they participated. 
4. Willing and able to comply with clinic visits and study-related procedures. 
5. Provide signed informed consent. 
6.2.2. 
Exclusion Criteria for Evinacumab-Naïve Patients 
A patient who meets any of the following criteria will be excluded from the study: 
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1. Concomitant medications and procedures that have not been stable prior to the baseline 
visit (see Section 7.7.2 for medications and procedures and their associated required 
duration of therapy). 
2. Any new condition or worsening of an existing condition, which in the opinion of the 
investigator would make the patient unsuitable for enrollment, or could interfere with the 
patient participating in or completing the study. 
3. History of a MI, unstable angina leading to hospitalization, coronary artery bypass graft 
surgery, percutaneous coronary intervention, uncontrolled cardiac arrhythmia, carotid 
surgery or stenting, stroke, transient ischemic attack, valve replacement surgery, carotid 
revascularization, endovascular procedure or surgical intervention for peripheral vascular 
disease within 3 months prior to the baseline visit. 
4. Presence of any clinically significant uncontrolled endocrine disease known to influence 
serum lipids or lipoproteins. 
Note: patients on thyroid replacement therapy can be included if the dosage of 
replacement therapy has been stable for at least 12 weeks prior to screening and the 
thyroid stimulating hormone (TSH) level is within the normal range of the central 
laboratory at the screening visit. 
5. Newly diagnosed (within 3 months prior to screening visit diabetes mellitus or poorly 
controlled (HbA1c >9%) diabetes. 
6. Use of systemic corticosteroids, unless used as replacement therapy for pituitary/adrenal 
disease with a stable regimen for at least 6 weeks prior to screening visit. 
Note: topical, intra-articular, nasal, inhaled and ophthalmic steroid therapies are not 
considered as ‘systemic’ and are allowed. 
7. Use of estrogen or testosterone therapy unless the regimen has been stable 6 weeks prior 
to the screening visit and no plans to change the regimen during the study. 
8. Systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg at the 
screening visit. 
9. History of cancer within the past 5 years, except for adequately treated basal cell skin 
cancer, squamous cell skin cancer, or in situ cervical cancer. 
10. History of New York Heart Association (NYHA) Class IV heart failure within 12 months 
before screening. 
11. Laboratory findings during the screening period (applies to patients undergoing 
Screening): 
• 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) 
• Positive serum beta-human chorionic gonadotropin or urine pregnancy test in 
WOCBP 
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• TSH >1.5 x ULN of the central laboratory (1 repeat lab is allowed) for patients not on 
thyroid replacement therapy  
• Positive test for hepatitis B surface antigen and/or hepatitis C antibody (associated 
with a positive HCV RNA polymerase chain reaction)  
• eGFR <30 mL/min/1.73 m2 (calculated by central lab)  
• Postmenopausal status will be confirmed by measurement of follicle-stimulating 
hormone (FSH) 
12. Member of the clinical site study team and/or his/her immediate family.   
13. Pregnant or breastfeeding women. 
14. Women of childbearing potential* who are unwilling to practice highly effective 
contraception prior to the initial dose/start of the first treatment, during the study, and for 
at least 24 weeks after the last dose of study drug. Highly effective contraceptive 
measures include:  
a. stable use of combined (estrogen and progestogen containing) hormonal 
contraception (oral, intravaginal, transdermal) or progestogen-only hormonal 
contraception (oral, injectable, implantable) associated with inhibition of ovulation 
initiated 2 or more menstrual cycles prior to screening 
b. intrauterine device (IUD); intrauterine hormone-releasing system (IUS) 
c. bilateral tubal ligation 
d. vasectomized partner 
e. and/or sexual abstinence†, ‡ 
*Postmenopausal women must be amenorrheic for at least 12 months in order not to be 
considered of childbearing potential.  Pregnancy testing and contraception are not required for 
women with documented hysterectomy, and/or oophorectomy. 
Oocyte donation is prohibited during the study and for 24 weeks after the last administration of 
study drug. 
† Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatments. 
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 amenorrhoea method (LAM) are not acceptable 
methods of contraception. Female condom and male condom should not be used together.  
15. Men who are sexually active with WOCBP and are unwilling to use the following forms 
of medically acceptable birth control during the study drug treatment period and for 
24 weeks after the last injection of study drug: vasectomy with medical assessment of 
surgical success OR consistent use of a condom. Sperm donation is prohibited during the 
study and for up to 24 weeks after the last injection of study drug. 
16. LDL-C level <70 mg/dL at the screening visit. 
17. Use of any active investigational drugs (except alirocumab) within 1 month or 5 
half-lives prior to the screening visit, whichever is longer. 
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18. Age <12 years at the screening visit. 
19. Tanner stage <2 at the screening visit. 
6.2.3. 
Exclusion Criteria for Patients from a Previous Evinacumab Study 
A patient who meets any of the following criteria will be excluded from the study: 
1. Significant protocol deviation in the previous study based on the investigator’s judgment, 
such as non-compliance by the patient. 
2. Concomitant medications and procedures that have not been stable prior to the baseline 
visit (see Section 7.7.2 for medications and procedures and their associated required 
duration of therapy). 
3. Adverse event leading to permanent discontinuation from previous study. 
4. Any new condition or worsening of an existing condition, which in the opinion of the 
investigator would make the patient unsuitable for enrollment, or could interfere with the 
patient participating in or completing the study. 
5. Member of the clinical site study team and/or his/her immediate family.   
6. Pregnant or breastfeeding women. 
7. Women of childbearing potential* who are unwilling to practice highly effective 
contraception prior to the initial dose/start of the first treatment, during the study, and for 
at least 24 weeks after the last dose of study drug. Highly effective contraceptive 
measures include:  
a. stable use of combined (estrogen and progestogen containing) hormonal 
contraception (oral, intravaginal, transdermal) or progestogen-only hormonal 
contraception (oral, injectable, implantable) associated with inhibition of ovulation 
initiated 2 or more menstrual cycles prior to screening 
b. intrauterine device (IUD); intrauterine hormone-releasing system (IUS) 
c. bilateral tubal ligation 
d. vasectomized partner 
e. and/or sexual abstinence†, ‡ 
*Postmenopausal women must be amenorrheic for at least 12 months in order not to be 
considered of childbearing potential.  Pregnancy testing and contraception are not required for 
women with documented hysterectomy, and/or oophorectomy. 
Oocyte donation is prohibited during the study and for 24 weeks after the last administration of 
study drug. 
† Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatments. 
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 amenorrhoea method (LAM) are not acceptable 
methods of contraception. Female condom and male condom should not be used together.  
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8. Men who are sexually active with WOCBP and are unwilling to use the following forms 
of medically acceptable birth control during the study drug treatment period and for 24 
weeks after the last injection of study drug: vasectomy with medical assessment of 
surgical success OR consistent use of a condom. Sperm donation is prohibited during the 
study and for up to 24 weeks after the last injection of study drug. 
9. Age <12 years at the screening visit. 
10. Tanner stage <2 at the screening visit. 
6.3. 
Premature Withdrawal from the Study 
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and/or sponsor have the right to withdraw a patient from the study if it is no 
longer in the interest of the patient to continue in the study, or if the patient’s continuation in the 
study places the scientific outcome of the study at risk (eg, if a patient does not or cannot follow 
study procedures).  An excessive rate of withdrawals would render the study uninterpretable; 
therefore, unnecessary withdrawal of patients should be avoided. 
Patients who are withdrawn prematurely from the study will be asked to complete study 
assessments, as described in Section 8.1.4.  
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 7.3.2. 
Early Termination from the Study 
Patients who prematurely discontinue from study drug or the study should return to the clinic 
(within 5 days if possible), for end of treatment visit assessments.  The assessments completed 
should include pregnancy testing for WOCBP.  They should then return for all regularly 
scheduled study visits and complete all assessments except dosing of study drug.  
If a patient is discontinuing the study and will not be able to return for all regularly scheduled 
study visits, at a minimum, they should return for end of study assessments at least 24 weeks 
after their last dose of study drug.  All sexually active males and WOCBP should be reminded to 
continue to maintain highly effective contraceptive measures for 24 weeks after the last dose of 
study drug.  At the end of treatment/early termination visit, all WOCBP will be provided with 
urine pregnancy tests with instructions to test for pregnancy 4 weeks after this visit and Q4W 
thereafter.  Patients will also be notified of Q4W follow-up phone calls to confirm continued 
contraception use and pregnancy reporting and to obtain the results of the urine pregnancy test.  
The investigator should make the best effort to contact any patient (eg, contacting the patient’s 
family or private physician, review available registries or health care database) who fails to 
return to the site, and to determine health status.  Attempts to contact such patients must be 
documented in the patient’s records (eg, times and dates of attempted telephone contact, receipt 
for sending a registered letter).  The site will be provided a retention manual outlining the best 
practices for patient retention.   
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6.4. 
Replacement of Patients 
Patients prematurely discontinued from the study drug will not be replaced.   
6.5. 
Re-screening of Patients 
Patients who do not meet eligibility criteria during the initial screening may re-screen only once. 
Patients who are re-screened after the screening window ends must re-consent for study 
participation and repeat all screening procedures. 
Patients who do not meet all eligibility criteria during the initial screening, and are still within 
the screening window, may retest once for the assessments that did not meet eligibility criteria. 
7. 
STUDY TREATMENTS 
7.1. 
Investigational and Reference Treatments 
Eligible patients will receive open-label evinacumab at a dose of 15 mg/kg IV Q4W starting on 
day 1. Patients will be monitored for at least 60 minutes after the end of each IV infusion, and 
vital signs will be obtained pre-dose and 30 minutes and 60 minutes after the end of the IV 
infusion.  
The IV dose should be prepared using the patient’s most recent weight. Further instructions on 
dose preparation are provided in the pharmacy manual.  
Dosing should fall within a window of ±7 days; if >14 days has passed, skip the dose and return 
to the original schedule. 
Instructions on management of infusion reactions and injection site reactions are provided in 
Section 7.4.  
7.2. 
Background Treatment(s) 
Patients who are undergoing apheresis therapy must have initiated LDL apheresis at least 
3 months prior to screening and must receive stable weekly apheresis (every 7 ±1 days), or other 
stable regimen (±2 days) and/or stable settings for at least 8 weeks prior to screening. Patients 
whose schedule and/or apheresis settings have not been stable for at least 8 weeks before the 
screening visit will enter an up to 10-week run-in period. 
Patients who are on background LMT that has not been stable for at least 4 weeks (6 weeks for 
fibrates, 8 weeks for PCSK9 inhibitor antibodies) before the screening visit will enter a run-in 
period to stabilize their LMT before entering the screening period. 
Patients receiving background LMT that has been proven to reduce the risk of ASCVD 
(eg, statins, ezetimibe, PCSK9 inhibitor antibodies), should make their best effort to maintain a 
stable regimen after week 24 and for the duration of the study.  
Patients receiving other LMT (eg, apheresis, lomitapide) may have that LMT adjusted after 
week 24, based on their LDL-C, CV risk factors, and judgment of the investigator. 
All patients who were supplied with alirocumab 150 mg SC by the sponsor in a previous study 
may continue to be provided with alirocumab 150 mg SC Q2W in this study. Those entering this 
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study after completing a study evaluating the safety and efficacy of alirocumab in patients with 
HoFH, but did not participate in a prior evinacumab study, may or may not remain on 
alirocumab as part of their background LMT. Based on the patient’s preference and the judgment 
of the investigator and the patient’s health care provider, each patient may: 
• continue treatment with alirocumab supplied by the sponsor as part of their 
background LMT 
• discontinue alirocumab prior to enrolling into this study 
• change to a commercially available PCSK9 inhibitor antibody prior to enrolling into 
this study 
Sterile alirocumab drug product will be supplied at a concentration of 150 mg/mL.   
7.3. 
Dose Modification and Study Treatment Discontinuation Rules 
7.3.1. 
Dose Modification 
Dose modification for an individual patient is not allowed. 
7.3.2. 
Study Drug Discontinuation 
Patients who permanently discontinue from study drug and who do not withdraw from the study 
will be asked to return to the clinic for all remaining study visits per the visit schedule. 
Patients who permanently discontinue from study drug and who opt to withdraw from the study 
will be asked to complete study assessments, per Section 8.1.4. 
7.3.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
Study drug dosing will be permanently stopped in the event of: 
• Evidence of pregnancy 
• Acute systemic infusion reactions with AEs including, but not limited to, anaphylaxis, 
laryngeal/pharyngeal edema, severe bronchospasm, chest pain, seizure, or severe 
hypotension 
• Serious or severe allergic reactions considered related to study drug 
• Patient withdraws consent 
The investigator may permanently discontinue study drug dosing at any time, even without 
consultation with the medical monitor if the urgency of the situation requires immediate action 
and if this is determined to be in the patient’s best interest.  However, the medical monitor 
should be contacted as soon as possible in any case of permanent study drug discontinuation.   
7.3.2.2. 
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.  However, the medical monitor 
should be contacted as soon as possible in any case of temporary study drug discontinuation.  
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Resumption of study drug requires consultation and agreement between the investigator and the 
medical monitor.   
7.4. 
Management of Acute Reactions  
7.4.1. 
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 9.4.1) 
and graded using the grading scales as instructed in Section 9.5.1. 
7.4.1.1. 
Interruption of the Intravenous Infusion 
The infusion should be interrupted if any of the following AEs are observed: 
• Cough 
• Rigors/chills 
• Rash, pruritus (itching) 
• Urticaria (hives, welts, wheals) 
• Diaphoresis (sweating) 
• Hypotension 
• Dyspnea (shortness of breath) 
• Vomiting 
• Flushing 
The reaction(s) should be treated symptomatically, and the infusion may be restarted at 50% of 
the original rate.   
If investigators feel there is a medical need for treatment or discontinuation of the infusion other 
than described above, they should use clinical judgment to provide the appropriate response 
according to typical clinical practice. 
7.4.1.2. 
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 
• chest pain 
• seizure 
• severe hypotension 
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• 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 blood pressure or associated symptoms of end-organ dysfunction 
(eg, hypotonia [collapse], syncope, incontinence) 
7.4.2. 
Acute Injection Reactions 
7.4.2.1. 
Systemic Injection Reactions 
Acute systemic reactions following administration of study drug should be treated using clinical 
judgment, based on standard clinical practice, in order to determine the appropriate response.   
7.4.2.2. 
Local Injection Site Reactions 
Local injection site reactions must be reported as AEs and graded according to the Food and 
Drug Administration (FDA) September 2007 Guidance for Industry, Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials.   
7.5. 
Method of Treatment Assignment 
This is an open-label study.  Starting on day 1, all patients will receive open-label evinacumab 
15 mg/kg IV Q4W.  
7.5.1. 
Blinding 
Study treatment will not be blinded in this open-label study.   
7.6. 
Treatment Logistics and Accountability 
7.6.1. 
Packaging, Labeling, and Storage 
Open-label study drug will display the product lot number on the label. 
Study drug will be stored at the site at a temperature of 2ºC to 8ºC; storage instructions will be 
provided in the pharmacy manual.  
7.6.2. 
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 
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and documentation by the site monitor, all opened and unopened study drug will be returned to 
the sponsor or designee.   
7.6.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug.  These records 
should contain the dates, quantity, and study medication: 
• dispensed to each patient, 
• returned from each patient (if applicable), and 
• disposed of at the site or returned to the sponsor or designee 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
7.6.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the 
sponsor and regulatory agency inspectors. 
7.7. 
Concomitant Medications and Procedures 
Any treatment administered, including apheresis and plasma exchange, from the time of 
informed consent to the end of the treatment period/final study visit will be considered 
concomitant medication. This includes medications that were started before the study and are 
ongoing during the study.  
7.7.1. 
Permitted Medications and Procedures 
The use of all medications and nutritional supplements known to alter serum lipids, including 
(but not limited to) statins, ezetimibe, fibrates, niacin, bile acid resins, red yeast rice, lomitapide, 
mipomersen, and PCSK9 inhibitor antibodies is permitted as long as that therapy has been 
initiated prior to the baseline visit (day 1) and has been stable for at least 4 weeks (6 weeks for 
fibrates, 8 weeks for PCSK9 inhibitor antibody therapy, 12 weeks for lomitapide, 6 months for 
mipomersen).   
Patients from previous evinacumab studies who are receiving background LMT or who are 
undergoing apheresis should continue the same stable LMT and a stable apheresis schedule 
(as applicable) as at the time of the EOS visit of the previous study without any adjustments. 
The use of lomitapide is permitted as long as the therapy has been stable on the maximum 
tolerated dose for 12 weeks prior to the baseline visit (day 1). If lomitapide therapy was 
discontinued prior to baseline (day 1), there should be at least an 8-week washout period prior to 
the baseline visit. 
Lipoprotein apheresis is permitted as long as the patient's schedule and setting have been stable 
for at least 8 weeks prior to the baseline visit.  All patients on lipoprotein apheresis should make 
every effort to adhere to their stable weekly regimen (every 7 ±1 days), or other stable regimen 
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(±2 days) and/or stable settings. If lipoprotein apheresis was discontinued prior to baseline 
(day 1), there should be at least a 6-week washout period prior to the baseline visit. 
Plasma exchange is also allowed. The patient should be on a stable schedule, and study drug 
administration should occur after the procedure. 
Patients’ apheresis schedule and lomitapide therapy (if applicable) may be adjusted after 
week 24, based on their LDL-C, CV risk factors, and judgment of the investigator.   
Patients receiving background LMT that has been proven to reduce the risk of ASCVD 
(eg, statins, ezetimibe, PCSK9s inhibitor antibodies) should make their best effort to maintain a 
stable regimen after study week 24 and for the duration of the study. 
7.7.2. 
Prohibited Medications and Procedures 
The following concomitant medications and procedures are prohibited for the duration of the 
study (unless already stable on the medication or procedure prior to the baseline visit):  
• Background mipomersen treatment that has not been stable for 24 weeks (6 months) 
before baseline (day 1) 
• Nutraceuticals and all medications known to alter serum lipids, at a dose/amount that 
has not been stable for at least 4 weeks prior to baseline (day 1) 
• Thyroid replacement therapy, unless the dosage of replacement therapy has been 
stable for at least 12 weeks prior to baseline (day 1) 
• Background maximally tolerated dose of lomitapide that has not been stable for 
12 weeks before baseline (day 1); washout period less than 8 weeks prior to baseline 
(day 1) in cases when lomitapide therapy was discontinued prior to enrollment; any 
changes in lomitapide therapy during participation in this study prior to week 24. 
• Background PCSK9 inhibitor antibody therapy that has not been stable for at least 
8 weeks prior to baseline (day 1) 
• Lipoprotein apheresis that has not been stable for at least 8 weeks prior to the baseline 
visit; apheresis schedule that is not an every 7 day (±1 day), or other stable schedule 
(±2 days); any changes to apheresis schedule or settings prior to week 24; washout 
period less than 6 weeks prior to baseline (day 1) in cases when apheresis was 
discontinued prior to enrollment. 
• Any changes to the background LMT during participation in this study prior to at 
least week 24 
Note: Patients from previous evinacumab studies who are receiving background LMT or who are 
undergoing apheresis should continue the same stable LMT and a stable apheresis schedule (as 
applicable) as at the time of EOS visit of the previous study without any adjustments. 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
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 
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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. 
8.1. 
Study assessments and procedures are presented by study period and 
visit in Table 1, Table 2 and Table 3.  
Table 1: 
Schedule of Events – Run-In and Screening 
Study Procedure 
Run-in9 
Screening1 
Visit  
-1 
1A 
Day 
-85 to -15 
-14 to -1 
Visit Window (Day) 
 
 
Week 
-12 to -2 
-2 to -1 
Screening: 
 
 
Informed Consent 
X 
 
Inclusion/Exclusion 
 
X 
Medical/Surgical History 
X 
X 
Alcohol/Smoking Habits 
 
X 
Medication History 
X 
X 
Demographics 
 
X 
Treatment: 
 
 
Concomitant Medications and Procedures 
(including LMT and apheresis)2 
X 
X 
Efficacy: 
 
 
Lipid Panel3 
 
X 
Specialty Lipid Panel3 
 
X 
Safety: 
 
 
Adverse Events 
X 
X 
Physical Examination 
 
X 
Measured Height 
 
X 
Body Weight 
 
X 
Vital Signs 
X 
X 
Electrocardiogram4 
 
X 
Tanner Stage5 
 
X 
Contraception Use Reminder 
 
X 
Laboratory Testing: 
 
 
Hematology 
 
X 
Blood Chemistry 
 
X 
Sex Hormones5,6 
 
X 
Serum Pregnancy Test7 
 
X 
Urine Pregnancy Test7 
X 
 
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Study Procedure 
Run-in9 
Screening1 
Visit  
-1 
1A 
Day 
-85 to -15 
-14 to -1 
Visit Window (Day) 
 
 
Week 
-12 to -2 
-2 to -1 
Urinalysis 
 
X 
hs-CRP 
 
X 
FSH7 
X 
 
TSH8 
 
X 
Hepatitis B Surface Antigen8 
 
X 
Hepatitis C Antibody8 
 
X 
Research Samples 
 
X 
DNA Sample for HoFH Genotyping10 
X 
Other: 
 
 
Review of Diet 
X 
X 
Reminder of LMT Compliance 
X 
X 
Carotid Ultrasound Imaging11 
X 
Table 2: 
Schedule of Events – Screening for Patients with No Run-In 
Study Procedure 
Screening1 
Visit  
1A 
Day 
-14 to -1 
Visit Window (Day) 
 
Week 
-2 to -1 
Screening: 
 
Informed Consent 
X 
Inclusion/Exclusion 
X 
Medical/Surgical History 
X 
Alcohol/Smoking Habits 
X 
Medication History 
X 
Demographics 
X 
Treatment: 
 
Concomitant Medications and Procedures (including LMT and 
apheresis)2 
X 
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Study Procedure 
Screening1 
Visit  
1A 
Day 
-14 to -1 
Visit Window (Day) 
 
Week 
-2 to -1 
Efficacy: 
 
Lipid Panel3 
X 
Specialty Lipid Panel3 
X 
Safety: 
 
Adverse Events 
X 
Physical Examination 
X 
Measured Height 
X 
Body Weight 
X 
Vital Signs 
X 
Electrocardiogram4 
X 
Tanner Stage5 
X 
Contraception Use Reminder 
X 
Laboratory Testing: 
 
Hematology 
X 
Blood Chemistry 
X 
Sex Hormones5,6 
X 
Serum Pregnancy Test7 
X 
Urine Pregnancy Test7 
 
Urinalysis 
X 
hs-CRP 
X 
FSH7 
X 
TSH8 
X 
Hepatitis B Surface Antigen8 
X 
Hepatitis C Antibody8 
X 
Research Samples 
X 
DNA sample for HoFH Genotyping9 
X 
Other: 
 
Review of Diet 
X 
Reminder of LMT Compliance 
X 
Carotid Ultrasound Imaging10 
X 
 
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Table 3: 
Schedule of Events – Open-Label Treatment Period and Follow-Up 
Study Procedure 
Baseline1 
Open-Label Treatment Period 
Q4-Week Visit Sequence13 
Visit  
1 
2 
3 
4 
5 
6 
7 
A 
B 
Day 
1 
29 
57 
85 
113 
141 
169 
±7 days 
±7 days 
Visit Window (Day) 
 
±7 
±7 
±7 
±7 
±7 
±7 
Week 
0 
4 
8 
12 
16 
20 
24 
Baseline: 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
 
 
 
Administer IV Open-Label Study Drug3,4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications and Procedures 
(including LMT and apheresis)3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy: 
 
 
 
 
 
 
 
 
 
Lipid Panel3,5 
X 
 
X 
X 
X 
 
X 
 
X 
Specialty Lipid Panel3,5 
X 
 
X 
 
X 
 
X 
 
X 
Safety: 
 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
 
 
 
 
 
 
 
 
Measured Height6 
X 
 
 
 
 
 
X 
 
 
Body Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram7 
X 
 
 
 
 
 
X 
 
 
Tanner Stage6 
 
 
 
 
 
 
X 
 
 
Contraception Use Reminder 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Study Procedure 
Baseline1 
Open-Label Treatment Period 
Q4-Week Visit Sequence13 
Visit  
1 
2 
3 
4 
5 
6 
7 
A 
B 
Day 
1 
29 
57 
85 
113 
141 
169 
±7 days 
±7 days 
Visit Window (Day) 
 
±7 
±7 
±7 
±7 
±7 
±7 
Week 
0 
4 
8 
12 
16 
20 
24 
Laboratory Testing2: 
 
 
 
 
 
 
 
 
 
Hematology 
X 
 
X 
 
X 
 
X 
 
X 
Blood Chemistry 
X 
 
X 
 
X 
 
X 
 
X 
Sex Hormones6,8 
 
 
 
 
 
 
X 
 
 
Serum Pregnancy Test9 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
X 
 
X 
 
X 
 
X 
hs-CRP 
X 
 
X 
 
X 
 
X 
 
X 
HbA1C 
X 
 
 
X 
 
 
X 
 
 
Research Samples 
X 
 
X 
 
 
 
X 
 
X 
ADA Samples10 
X 
 
- 
 
 
 
X 
 
 
Pharmacokinetics (PK) of Evinacumab 11 
X12 
X17 
X17 
X12 
X17 
X17 
X12 
X17 
 
Optional DNA sample16 
 
 
 
 
 
 
 
 
 
Other: 
 
 
 
 
 
 
 
 
 
Review of Diet 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Reminder of LMT Compliance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Carotid Ultrasound Imaging18 
 
 
 
 
 
 
X 
 
 
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Table 3: 
Schedule of Events – Open-Label Treatment Period and Follow-Up (Contd) 
Study Procedure 
Q4-Week Visit 
Sequence10 
End of 
Treatment  
(4 weeks post 
last dose)/ 
Early 
Termination 
Visit14 
 
24-Week 
Follow-up Period 
Visit  
C 
D 
E 
F 
PV 
8 weeks 
post last 
dose15 
12 weeks 
post last 
dose 
PV 
16 weeks 
post last 
dose15 
20 weeks 
post last 
dose 
24 weeks 
post last dose/ 
End of Study Visit 
Visit Window 
(Day) 
±7 
±7 
±7 
±7 
F/U 
±5 
F/U 
±5 
F/U 
±5 
F/U 
±5 
F/U 
±5 
Treatment: 
 
 
 
 
 
 
 
 
 
 
Administer IV Open-
Label Study Drug3 
X 
X 
X 
X 
 
 
 
 
 
 
Concomitant 
Medications and 
Procedures including 
LMT and apheresis)3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy: 
 
 
 
 
 
 
 
 
 
 
Lipid Panel3,5 
X 
X 
 
X 
X 
 
X 
 
 
X 
Specialty Lipid 
Panel3,5 
 
X 
 
X 
X 
 
X 
 
 
X 
Safety: 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X 
Physical Examination 
 
 
 
 
 
 
 
 
 
X 
Measured Height6 
 
 
 
X 
X 
 
 
 
 
X 
Body Weight 
X 
X 
X 
X 
X 
 
 
 
 
X 
Vital Signs4 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Electrocardiogram7 
 
 
 
X 
X 
 
 
 
 
X 
Tanner Stage6,8 
 
 
 
X 
X 
 
 
 
 
X 
Contraception Use 
Reminder 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Study Procedure 
Q4-Week Visit 
Sequence10 
End of 
Treatment  
(4 weeks post 
last dose)/ 
Early 
Termination 
Visit14 
 
24-Week 
Follow-up Period 
Visit  
C 
D 
E 
F 
PV 
8 weeks 
post last 
dose15 
12 weeks 
post last 
dose 
PV 
16 weeks 
post last 
dose15 
20 weeks 
post last 
dose 
24 weeks 
post last dose/ 
End of Study Visit 
Visit Window 
(Day) 
±7 
±7 
±7 
±7 
F/U 
±5 
F/U 
±5 
F/U 
±5 
F/U 
±5 
F/U 
±5 
Laboratory Testing2: 
 
 
 
 
 
 
 
 
 
 
Hematology 
 
X 
 
X 
X 
 
X 
 
X 
X 
Blood Chemistry 
 
X 
 
X 
X 
 
X 
 
X 
X 
Sex Hormones6,8 
 
 
 
X 
X 
 
 
 
 
X 
Serum Pregnancy 
Test9 
 
 
 
 
X 
 
 
 
 
X 
Urine Pregnancy Test9 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Urinalysis 
 
X 
 
X 
X 
 
 
 
 
X 
hs-CRP 
 
X 
 
X 
X 
 
 
 
 
X 
HbA1C 
X 
 
 
X 
X 
 
X 
 
 
X 
Research Samples 
 
 
 
X 
X 
 
 
 
 
X 
ADA Samples10 
 
 
 
X 
X 
 
 
 
 
X 
Pharmacokinetics 
(PK) of Evinacumab11 
X12 
 
 
X12 
X12 
 
 
 
 
X12 
Optional DNA 
Sample16 
X 
 
 
 
 
 
 
 
 
 
Other: 
 
 
 
 
 
 
 
 
 
 
Review of Diet 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Reminder of LMT 
Compliance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Carotid ultrasound 
imaging18 
 
 
 
X 
 
 
 
 
 
X 
 
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8.1.1. 
Footnotes for Schedule of Events Table 1 
1. All evinacumab-naïve patients will enter the screening period. Patients who participated 
in a previous evinacumab study and who completed an end of study visit in the previous 
evinacumab study within 7 days prior to the baseline/day 1 visit for this open label study 
do not have to enter the screening period and may enroll directly in this study. Patients 
from previous evinacumab studies who do not enter this study within 7 days of 
completing the EOS visit of the previous study, must undergo screening. 
2. For patients undergoing apheresis:  Study assessments should be performed and blood 
samples should be collected immediately before the lipoprotein apheresis procedure. 
3. Fasting sample will be collected for the lipid panel: TC, calculated LDL-C, HDL-C, TG, 
and non-HDL-C, and the specialty lipid panel: Apo B, ratio of Apo B/Apo A-1, Lp(a), 
and ApoCIII. 
4. Electrocardiograms should be performed before blood samples are collected at visits 
requiring blood draws. 
5. Assessment of Tanner Stage, sex hormones, and post-baseline height only applicable to 
patients < 18 years old. 
6. Sex hormones include luteinizing hormone, FSH, estradiol, and total testosterone. 
7. WOCBP only, confirm required contraception use and reminder of pregnancy reporting. 
For adolescent patients not of childbearing potential at Screening, confirm whether the 
patient is of childbearing potential at every visit. If an adolescent patient becomes of 
childbearing potential during the course of the study, exclusion criterion #14 applies and 
administer pregnancy tests administered every 4 weeks. 
8. For evinacumab treatment naïve patients only. 
9. Only for patients who require HoFH genotyping, stabilization of their lipoprotein 
apheresis schedule or stabilization on their background medical LMT. 
10. DNA sample for HoFH genotyping should be taken only for patients who have not been 
enrolled in a previous evinacumab or alirocumab clinical study. 
11. Carotid ultrasound imaging for adolescent patients 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 or as soon as possible thereafter. 
The assessments should be separated by at least 1 day. 
8.1.2. 
Footnotes for the Schedule of Events Table 2 
1. All evinacumab-naïve patients will enter the screening period. Patients who participated 
in a previous evinacumab study and who completed an end of study visit in the previous 
evinacumab study within 7 days prior to the baseline/day 1 visit may enroll directly and 
do not have to enter a run-in or screening period. Patients from previous evinacumab 
studies who do not enter this study within 7 days of completing the EOS visit of the 
previous study, must undergo screening. 
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2. For patients undergoing apheresis:  Study assessments should be performed and blood 
samples should be collected immediately before the lipoprotein apheresis procedure. 
3. Fasting sample will be collected for the lipid panel: TC, calculated LDL-C, HDL-C, TG, 
and non-HDL-C, and the specialty lipid panel: Apo B, ratio of Apo B/Apo A-1, Lp(a), 
and ApoCIII. 
4. Electrocardiograms should be performed before blood samples are collected at visits 
requiring blood draws. 
5. Assessment of Tanner Stage, sex hormones, and post-baseline height only applicable to 
patients < 18 years old. 
6. Sex hormones include luteinizing hormone, FSH, estradiol, and total testosterone 
7. WOCBP only, confirm required contraception use and reminder of pregnancy reporting. 
For adolescent patients not of childbearing potential at Screening, confirm whether the 
patient is of childbearing potential at every visit. If an adolescent patient becomes of 
childbearing potential during the course of the study, exclusion criterion #14 applies and 
administer pregnancy tests administered every 4 weeks. 
8. For evinacumab-naïve patients only. 
9. DNA sample for HoFH genotyping should be taken only for patients who have not been 
enrolled in a previous evinacumab or alirocumab clinical study. 
10. Carotid ultrasound imaging for adolescent patients 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 or as soon as possible thereafter. 
The assessments should be separated by at least 1 day. 
8.1.3. 
Footnotes for Schedule of Events Table 3 
1. For patients directly transitioning from a previous evinacumab study: all assessments and 
procedures should be performed after end of study assessments and procedures have been 
completed in the previous study, if applicable.  Only assessments not performed at the 
previous end of study visit need to be performed at the baseline visit.   
2. All laboratory samples should be collected before administration of study drug. 
3. Study assessments should be performed and blood samples should be collected before 
study drug administration.  For patients undergoing apheresis or plasma exchange:  Study 
assessments should be performed and blood samples should be collected before the 
procedure. Every effort should be made for the patient to receive study drug immediately 
after completion of the apheresis procedure, but patients can receive study drug 1 day 
before the apheresis procedure. Patients undergoing plasma exchange should receive 
study drug after the procedure. The timing between the baseline sample collection 
relative to the most recently completed LDL apheresis procedure, administration of a 
PCSK9 inhibitor or mipomersen should match the timing of the week 24 sample 
collection relative to the most recently completed LDL apheresis procedure, 
administration of a PCSK9 inhibitor or mipomersen. Depending on the duration between 
the apheresis procedure and sample collection, the visit window may not apply. 
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4. Vital signs (temperature, sitting blood pressure, pulse, and respiration rate) should be 
measured before study drug administration on days when study drug is administered.  On 
dosing days, patients should remain in the clinic for 60 minutes after the end of the IV 
infusion for monitoring.  Pulse and blood pressure should be measured 30 and 60 minutes 
after the end of the IV infusion.  
5. Fasting sample will be collected for the lipid panel: TC, calculated LDL-C, HDL-C, TG, 
and non-HDL-C, and the specialty lipid panel: Apo B, ratio of Apo B/Apo A-1, Lp(a), 
and ApoCIII. 
6. Assessment of Tanner Stage, sex hormones, and post-baseline height only applicable to 
patients < 18 years old. 
7. Electrocardiograms should be performed before blood samples are collected at visits 
requiring blood draws. 
8. Sex hormones include luteinizing hormone, FSH, estradiol, and total testosterone. 
9. All patients will be reminded of protocol-specified contraception use and pregnancy 
reporting. For adolescent patients not of childbearing potential at Screening, confirm 
whether the patient is of childbearing potential at every visit. If an adolescent patient 
becomes of childbearing potential during the course of the study, exclusion criterion #14 
applies and administer pregnancy tests administered every 4 weeks.  
10. The ADA sample should be drawn before study drug administration or immediately prior 
to the apheresis procedure, if applicable. 
11. Including assay of total ANGPTL3. 
12. PK sample collected in all patients. For patients undergoing apheresis, a PK sample 
should be collected immediately before the apheresis procedure. For patients undergoing 
plasma exchange, a PK sample should be collected immediately before and after the 
procedure. For patients who are not undergoing apheresis, the PK sample should be 
drawn before the dose of study drug. 
13. After the week 24 visit, visits are in a strict sequence of A through F and should occur 
every 4 weeks.  After visit F, the sequence repeats (visits A through F) until the end of 
treatment visit.  
14. The end of treatment visit should occur 4 weeks post the last dose.  Patients who 
prematurely discontinue from study drug should return to the clinic within 5 days if 
possible for end of treatment visit assessments.  At this visit, WOCBP will be provided 
with urine pregnancy tests with instructions to test for pregnancy at home every 4 weeks 
after this visit and Q4W when phone visits are scheduled (weeks 8 and 16 post last dose).  
Urine pregnancy testing will be done during clinic visits at week 12, week 20, and 
week 24.  Patients who upon their study completion, may continue to receive treatment 
outside of the clinical trial (such as through a CUP, EAP, or ISS/IST) and thereby may 
forgo the 24-week follow-up period of the study.  The follow-up period was intended to 
be an off-drug follow-up.  No off-drug follow-up period is required for these patients.  In 
this situation, the patient’s EOT will be their last study visit. 
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15. 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.  Women 
of childbearing potential will report the results of their home pregnancy test.  Patients 
who upon their study completion, may continue to receive treatment outside of the 
clinical trial (such as through a CUP, EAP, or ISS/IST) and thereby may forgo the 24-
week follow-up period of the study.  No off-drug follow-up period is required for these 
patients.  In this situation, the patient’s EOT will be their last study visit. 
16. Should be collected at the baseline visit or at any study visit for patients who have not 
previously been enrolled in an evinacumab or alirocumab clinical study. 
17. PK sample (including ANGPTL3) only for evinacumab-naïve adolescent patients. 
18. Carotid ultrasound imaging for adolescents will be performed only at sites with this 
capability and will be performed at 24 weeks and 1 year and at yearly intervals thereafter. 
8.1.4. 
Early Termination Visit 
Patients who are withdrawn from the study will be asked to return to the clinic for 2 visits: an 
end of treatment/early termination visit and an end of study visit.  The end of treatment/early 
termination visit should take place within 5 days of treatment discontinuation, if possible.  A 
final end of study (EOS) visit should take place with assessments as specified in the EOS visit at 
24 weeks after the last dose of study drug described in Table 3.  
Sexually active patients who discontinue the study prematurely should be reminded to maintain 
highly effective contraceptive measures for 24 weeks after the last dose of study drug.  At the 
end of treatment/early termination visit, WOCBP will be provided urine pregnancy tests with 
instructions to test for pregnancy Q4W until the EOS visit.  All patients should also be notified 
of Q4W follow-up phone calls to confirm contraception use, remind them of pregnancy 
reporting, and to obtain the results of the urine pregnancy test.  Patients who upon their study 
completion, may continue to receive treatment outside of the clinical trial (such as through a 
CUP, EAP, or ISS/IST) and thereby may forgo the 24-week follow-up period of the study.  No 
off-drug follow-up period is required for these patients.  In this situation, the patient’s EOT will 
be their last study visit. 
8.1.5. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule.  Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for 
any other reason, as warranted. 
8.2. 
Study Procedures 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed for the sole purpose of determining study eligibility 
or characterizing the baseline population: TSH, FSH, hepatitis B surface antigen, hepatitis C 
antibody. 
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8.2.2. 
Safety Procedures 
8.2.2.1. 
Vital Signs 
Vital signs, including temperature, sitting blood pressure and pulse and respiration rate, will be 
collected predose at time points according to Table 1, Table 2, and Table 3. Post-dose blood 
pressure and pulse rate will be collected 30 minutes and 60 minutes after the end of the IV 
infusion. Blood pressure should be measured in the same arm throughout the study after the 
patient has been resting quietly for at least 5 minutes. Pulse rate will be measured at the time of 
the measurement of blood pressure.  
8.2.2.2. 
Physical Examination 
A thorough and complete physical examination including height and weight 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. 
8.2.2.3. 
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. Heart rate will be recorded from the ventricular rate, and the PR, QRS, RR and QT 
(QTcF) intervals will be recorded. The ECG strips or reports will be retained with the source. 
8.2.2.4. 
Tanner Stages 
The Tanner stages will be assessed throughout the study for all patients ≥12 years old and 
<18 years old at specified time points shown in Table 1, Table 2, and Table 3.  If possible, for 
each adolescent patient, the Tanner stages assessment should be performed by the same 
investigator/designee trained to assess pubertal development. 
8.2.2.5. 
Laboratory Testing 
All laboratory samples will be collected at visits according to Table 1, Table 2, and Table 3, 
before the dose of study drug is administered and/or before apheresis is performed, if applicable.   
Detailed instructions for blood sample collection are in the laboratory manual provided to study 
sites and specific tests are listed below. 
Blood Chemistry 
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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 
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Urinalysis 
Color 
Glucose 
RBC 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBC 
Yeast 
Other Laboratory Tests 
Other laboratory tests will be performed at time points shown in Table 1, Table 2, and Table 3 
and are as follows:  high sensitivity C-reactive protein (hs-CRP), TSH, FSH, hemoglobin A1c 
(HbA1c), sex hormones (luteinizing hormone, FSH, estradiol, and total testosterone), and 
pregnancy test (serum and urine). 
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 9.4.5. 
8.2.2.6. 
Pregnancy Testing 
Women of childbearing potential will have urine pregnancy testing approximately every 4 weeks 
throughout the study from screening through the end of study visit, and a serum pregnancy test at 
the screening visit, end of treatment/early termination visit, and end of study visit.  During some 
follow-up visits, and in case of early termination, pregnancy testing will occur at home via a 
urine pregnancy test.  Patients will report results of the home urine pregnancy test to clinical site 
study personnel during follow-up visit or phone visits.  
8.2.3. 
Efficacy Procedures 
All laboratory samples will be collected before the dose of study drug is administered.   
Alcohol consumption within 48 hours and smoking or intense physical exercise within 24 hours, 
prior to blood sampling are discouraged. 
Total cholesterol, calculated LDL-C, TG, and non-HDL-C will be directly measured by the 
central laboratory.  Low-density lipoprotein cholesterol will be calculated using the Friedewald 
formula.  If TG values exceed 400 mg/dL (4.52 mmol/L), LDL-C will be measured via the beta 
quantification method (rather than via the Friedewald formula).  If the LDL-C value is less than 
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25 mg/dL (0.65 mmol/L), LDL-C will be measured via the beta quantification method (rather 
than the Friedewald formula). Non-HDL-C will be calculated by subtracting HDL-C from TC.  
High-density lipoprotein cholesterol (HDL-C) will be measured for assessing non-HDL-C but is 
not an efficacy variable for this study.   
Detailed procedures of sample preparation, storage, and shipment are provided in the laboratory 
manual.   
8.2.3.1. 
Lipid Panel 
Fasting (at least 8 hours) blood samples will be collected at specified time points shown in 
Table 1, Table 2, and Table 3, for assessment of the lipid profile, comprising calculated LDL-C, 
non-HDL-C, HDL, 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. 
8.2.3.2. 
Specialty Lipid Panel 
Fasting (at least 8 hours) blood samples will be collected at specified time points shown in 
Table 1, Table 2, and Table 3 for assessment of the specialty lipid profile, comprising Apo B, 
ratio of Apo B/Apo A-1, and lipoprotein a (Lp[a]) as well as for Apo CIII.  Apolipoprotein A-1 
will be measured for assessing ratio of Apo B/Apo A-1 but is not an efficacy variable for this 
study.  The specialty lipid panels will be assessed in the same sample that is collected for the 
lipid panel.   
8.2.4. 
Drug Concentration and Measurements 
Samples for drug concentration will be collected at visits listed in Table 3.  Any unused samples 
may be used for exploratory biomarker research or other investigations. 
8.2.5. 
Anti-Drug Antibody Measurements and Samples 
Samples for ADA assessment will be collected at time points listed in Table 3.  Any unused 
samples collected for ADA assessments may be used for exploratory biomarker research or other 
investigations.   
Patients who exhibit a positive ADA assay response with a titer >240 in their last sample 
analyzed will not participate in any other studies or under any treatment with evinacumab and 
will be followed 3 to 6 months after EOS visit until the titers have returned to <240 or to within 
2 dilution steps from the pre-treatment baseline titer.   
8.2.6. 
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). 
8.2.7. 
Pharmacodynamic Procedures 
Total ANGPTL3 concentrations in serum will be measured using the PK samples collected at 
time points listed in Table 3. 
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8.2.8. 
Future Biomedical Research 
Research samples (serum/plasma) will be collected at time points listed in Table 3. 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 research of HoFH and other diseases. 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. 
8.2.9. 
Other Assessments 
8.2.9.1. 
Review of Diet 
Patients will be asked to follow a heart-healthy diet throughout the duration of the study, starting 
at the baseline visit and continuing through the end of the open-label treatment period (OLTP), 
until the last study visit.  Patients will be queried on compliance with their diet at time points 
listed in Table 1, Table 2, and Table 3.   
Details are provided in Appendix 1.   
8.2.9.2. 
DNA Sample for HoFH Genotyping 
A required blood sample for DNA isolation will be collected to identify or confirm a known 
mutation in PCSK9, LDLR, APOB, and/or LDLRAP1 gene. Genotyping will be done for 
patients who have not been enrolled previously in an evinacumab or alirocumab trial. 
8.2.9.3. 
Genomics Sub-Study (Optional) 
The genomic sample will be taken for patients who have not been enrolled previously in an 
evinacumab or alirocumab study. Patients who agree to participate in the genomics sub-study 
will be required to sign a separate genomics sub-study informed consent form (ICF) 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 double-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 hypercholesterolemia 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 and related 
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. Results from the genomic 
sub-study will not be reported in the CSR. 
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9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
9.1. 
Obligations of Investigator 
The investigator must promptly report to the IRB/EC all unanticipated problems involving risks 
to patients/subjects, according to local regulations.  This may include death from any cause and 
all SAEs related to the use of the study drug. It is recommended that all SAEs be reported to the 
IRB/EC, according to local regulations. 
9.2. 
Obligations of Sponsor 
During the course of the study, the sponsor will report in an expedited manner all SAEs that are 
both unexpected and at least reasonably related to the study drug (suspected unexpected serious 
adverse reaction [SUSAR]), to the health authorities, IRBs/ECs as appropriate, and to the 
investigators.   
Any AE not listed as an expected event in the Reference Safety Information section of the 
Investigator’s Brochure will be considered as unexpected. Any worsening of or new onset of 
symptoms related to HoFH, which occur during the screening/washout period prior to study drug 
administration will be considered expected. 
In addition, the sponsor will report all other SAEs to the health authorities, according to local 
regulations. 
At the completion of the study, the sponsor will report all safety observations made during the 
conduct of the trial in the clinical study report to health authorities and IRBs/ECs as appropriate. 
9.3. 
Definitions 
9.3.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug, which may or 
may not have a causal relationship with the study drug.  Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease, which is 
temporally associated with the use of a study drug, whether or not considered related to the study 
drug. 
An AE also includes any worsening (ie, any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug. 
9.3.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death – includes all deaths, even those that appear to be completely 
unrelated to study drug (eg, a car accident in which a patient is a passenger). 
• Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event.  This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
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• Requires in-patient hospitalization or prolongation of existing hospitalization.  
In-patient hospitalization is defined as admission to a hospital or an emergency room 
for longer than 24 hours.  Prolongation of existing hospitalization is defined as a 
hospital stay that is longer than was originally anticipated for the event, or is 
prolonged due to the development of a new AE as determined by the investigator or 
treating physician. 
• Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions).   
• Is a congenital anomaly/birth defect. 
• Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent one of the other serious outcomes listed above 
(eg, intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development 
of drug dependency or drug abuse). 
Criteria for reporting SAEs must be followed for these events.  See Section 9.4 for more 
information on recording and reporting SAEs. 
9.3.3. 
Adverse Events of Special Interest 
An adverse event of special interest (AESI; serious or non-serious) is one of scientific and 
medical concern specific to the sponsor’s product or program, for which ongoing monitoring and 
rapid communication by the investigator to the sponsor can be appropriate.  Such an event might 
warrant further investigation in order to characterize and understand it.  Depending on the nature 
of the event, rapid communication by the trial sponsor to other parties (eg, regulators) might also 
be warranted (Section 9.4.3). 
9.3.4. 
Infusion Reactions 
Infusion reactions are defined as any relevant AE that occurs during the infusion or within 
2 hours after the infusion is completed. All infusion reactions must be reported as AEs (defined 
in Section 9.4.1) and graded using the grading scales as instructed in Section 9.5.1. 
9.4. 
Recording and Reporting Adverse Events 
9.4.1. 
Adverse Events 
The investigator (or designee) will record all AEs that occur from the time the informed consent 
is signed until the end of study.  Refer to the study reference manual for the procedures to be 
followed. 
Information on follow-up for AEs is provided in Section 9.4.6.  Laboratory, vital signs, or ECG 
abnormalities are to be recorded as AEs as outlined in Section 9.4.5. 
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9.4.2. 
Serious Adverse Events 
All SAEs, regardless of assessment of causal relationship to study drug, must be reported to the 
sponsor (or designee) within 24 hours.  Refer to the study reference manual for the procedure to 
be followed. 
Information not available at the time of the initial report must be documented in a follow-up 
report.  Substantiating data such as relevant hospital or medical records and diagnostic test 
reports may also be requested. 
In the event the investigator is informed of an SAE after the patient completes the study, the 
following will apply: 
• SAE with an onset within 30 days of the end of study or within 168 days (24 weeks) 
of last study drug administration if the patient early terminated from the study - the 
SAE will be reported to the sponsor.  The investigator should make every effort to 
obtain follow-up information on the outcome until the event is considered chronic 
and/or stable. 
• SAE with an onset day greater than 30 days from the end of study/early termination 
visit - only fatal SAEs and those deemed by the investigator to be drug-related SAEs 
will be reported to the sponsor.  The investigator should make every effort to obtain 
follow-up information on the outcome of a drug-related SAE until the event is 
considered chronic and/or stable. 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of 
learning of the event: 
Symptomatic Overdose of Study Drug: 
Accidental or intentional overdose of at least 
2 times the intended dose of study drug within the intended therapeutic window, if associated 
with an AE, 
Pregnancy: 
Although pregnancy is not considered an AE, it is the responsibility of the 
investigator to report to the sponsor (or designee), within 24 hours of identification, any 
pregnancy occurring in a female patient or female partner of a male patient, during the study or 
within 24 weeks of the last dose of study drug. Any complication of pregnancy affecting a 
female study patient or female partner of a male study patient, and/or fetus and/or newborn that 
meets the SAE criteria must be reported as an SAE. Outcome for all pregnancies should be 
reported to the sponsor.  
Adverse Events of Special Interest: All AESI, serious and nonserious, must be reported within 
24 hours of identification using the same reporting process as for SAE reporting, per 
Section 9.4.2.   
Adverse events of special interest for evinacumab include the following:   
• Anaphylactic reactions 
• Moderate or severe infusion reactions 
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• Increase in ALT or AST: ≥3 x ULN (if baseline <ULN), or ≥2 times the baseline 
value (if baseline ≥ ULN) 
• Allergic events and/or local injection site reactions that require medical treatment or 
that require consultation with another physician for further evaluation 
• Pregnancy 
• Symptomatic overdose with investigational medicinal product 
• Neurocognitive events 
• New onset of diabetes* 
• Pancreatitis 
Adverse events of special interest for alirocumab include the following:   
• Increase in ALT: ALT ≥3 x ULN (if baseline ALT <ULN), or ALT ≥2 times the 
baseline value (if baseline ALT ≥ ULN) 
• Allergic events and/or local injection site reactions that require consultation with 
another physician for further evaluation 
• Pregnancy 
• Symptomatic overdose with investigational medicinal product 
• Neurologic events that require additional examinations/procedures and/or referral to a 
specialist 
• Neurocognitive events 
• Cataracts 
• New onset of diabetes* 
*New onset of diabetes is defined as any of the following:   
− Type 1 or type 2 diabetes TEAE (grouping of MedDRA terms will be specified in 
the statistical analysis plan [SAP]) 
− 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) 
Refer to the study manual for the procedures to be followed. 
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9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study 
All AEs that lead to a patient’s withdrawal from the study must be reported to the sponsor’s 
Medical/Study Director within 30 days. 
Refer to the study reference manual for the procedures to be followed. 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results 
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE include: 
• the test result is associated with accompanying symptoms, and/or 
• the test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
• the test result leads to a change in dosing (outside of protocol-stipulated dose 
adjustments), discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy 
Contact the Medical/Study Director in the event the investigator feels that an abnormal test 
finding should be reported as an AE, although it does not meet any of the above criteria. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an 
AE.  Any abnormal test result that is determined to be an error does not require reporting as an 
AE. 
Evaluation of severity of laboratory abnormalities will be assessed according to the scale 
outlined in Section 9.5.1. 
9.4.6. 
Follow-up 
Adverse event information will be collected until the patient’s last study visit. 
Serious adverse event information will be collected until the event is considered chronic and/or 
stable. 
9.5. 
Evaluation of Severity and Causality 
9.5.1. 
Evaluation of Severity 
The severity of AEs will be graded according to the following scale: 
Mild:  Does not interfere in a significant manner with the patient 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. 
Injection Site Reactions 
The severity of injection site reactions will be graded according to the following scale (semi 
colon indicates “or” within description of grade: 
Mild:  Pain that does not interfere with activity; mild discomfort to touch; <5 cm of erythema or 
induration that does not interfere with activity. 
Moderate:  Pain that requires repeated use of non-narcotic pain reliever >24 hours or interferes 
with activity; discomfort with movement; 5.1 cm to 10 cm erythema or induration or induration 
that interferes with activity. 
Severe:  Pain that requires any use of narcotic pain reliever or that prevents daily activity; 
significant discomfort at rest; >10 cm erythema or induration; prevents daily activity; requires 
ER visit or hospitalization; necrosis or exfoliative dermatitis. 
9.5.2. 
Evaluation of Causality 
Relationship of Adverse Events to Study Drug: 
The relationship of AEs to study drug will be assessed by the investigator, and will be a clinical 
decision based on all available information.  The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by the study drug? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by the 
study drug 
Related: 
There is a reasonable possibility that the event may have been caused by the study 
drug 
The investigator should justify the causality assessment of each SAE. 
A list of factors to consider when assessing the relationship of AEs to study drug is provided 
below.  Please note that this list is not exhaustive. 
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Is there a reasonable possibility that the event may have been caused by the study drug? 
No: 
• due to external causes such as environmental factors or other treatment(s) being 
administered 
• due to the patient’s disease state or clinical condition 
• do not follow a reasonable temporal sequence following the time of administration of 
the dose of study drug 
• do not reappear or worsen when dosing with study drug is resumed 
• are not a suspected response to the study drug based upon preclinical data or prior 
clinical data 
Yes: 
• could not be explained by environmental factors or other treatment(s) being 
administered 
• could not be explained by the patient’s disease state or clinical condition 
• follow a reasonable temporal sequence following the time of administration of the 
dose of study drug  
• resolve or improve after discontinuation of study drug  
• reappear or worsen when dosing with study drug  
• are known or suspected to be a response to the study drug based upon preclinical data 
or prior clinical data 
Relationship of Adverse Events to Study Conduct:  
The relationship of AEs to study conduct will be assessed by the investigator, and will be a 
clinical decision based on all available information.  The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by study conduct? 
The possible answers are: 
Not Related: 
There is no reasonable possibility that the event may have been caused by 
study conduct 
Related: There is a reasonable possibility that the event may have been caused by study 
conduct 
The investigator should justify the causality assessment of each SAE. 
A list of factors to consider when assessing the relationship of AEs to study drug is provided 
below.  Please note that this list is not exhaustive. 
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Is there a reasonable possibility that the event may have been caused by the study conduct? 
No: 
• due to external causes such as environmental factors or other treatment(s) being 
administered 
• due to the patient’s disease state or clinical condition 
• do not follow a reasonable temporal sequence following the course of the study 
• do not reappear or worsen when dosing with study participation is resumed 
Yes: 
• could not be explained by environmental factors or other treatment(s) being 
administered 
• could not be explained by the patient’s disease state or clinical condition 
• follow a reasonable temporal sequence following the course of the study 
• resolve or improve after discontinuation from study participation 
• reappear or worsen when study participation is resumed 
Relationship of Adverse Events to Injection Procedure, Study Procedure, or Background 
Treatment:   
The relationship of AEs to injection procedure, study procedure, or background treatment will be 
assessed by the investigator, and will be a clinical decision based on all available information.  
The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by the injection procedure, 
study procedure, or background treatment? 
The possible answers are: 
Not Related: 
There is no reasonable possibility that the event may have been caused by 
the injection procedure, study procedure, or background treatment.   
Related: There is a reasonable possibility that the event may have been caused by the 
injection procedure, study procedure, or background treatment.   
The sponsor will request information to justify the causality assessment of SAEs, as needed. 
A list of factors to consider in assessing the relationship of AEs to injection procedure, study 
procedure, or background treatment is provided below.  Please note that this list is not 
exhaustive. 
Is there a reasonable possibility that the event may have been caused by the injection procedure, 
study procedure, or background treatment? 
No: 
• due to the patient’s disease state or clinical condition 
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• do not follow a reasonable temporal sequence following the injection procedure, 
study procedure, or background treatment 
• do not reappear or worsen when the injection procedure, study procedure, or 
background treatment is resumed 
• are not a suspected response to the injection procedure, study procedure, or 
background treatment based upon preclinical data or prior clinical data 
Yes: 
• could not be explained by environmental factors or other treatment(s) being 
administered 
• could not be explained by the patient’s disease state or clinical condition 
• follow a reasonable temporal sequence following the injection procedure, study 
procedure, or background treatment 
• resolve or improve after discontinuation of study drug or injection procedure, study 
procedure, or background treatment 
• reappear or worsen when the injection procedure, study procedure, or background 
treatment is resumed 
• are known or suspected to be a response to the injection procedure, study procedure, 
or background treatment based upon preclinical data or prior clinical data 
9.6. 
Safety Monitoring 
The investigator will monitor the safety of study patient at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP).  Any questions or 
concerns should be discussed with the sponsor in a timely fashion.  The sponsor will monitor the 
safety data from across all study sites.  The Medical/Study Director will have primary 
responsibility for the emerging safety profile of the compound, but will be supported by other 
departments (eg, Pharmacovigilance and Risk Management; Biostatistics and Data 
Management).  Safety monitoring will be performed on an ongoing basis (eg, individual review 
of SAEs) and on a periodic cumulative aggregate basis. 
9.7. 
Investigator Alert Notification 
Regeneron (or designee) will inform all investigators participating in this clinical trial, as well as 
in any other clinical trial using the same investigational drug, of any SAE that meets the relevant 
requirements for expedited reporting (an AE that is serious, unexpected based on the reference 
safety information in the Investigator’s Brochure, and has a reasonable suspected causal 
relationship to the study drug). 
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10. 
STATISTICAL PLAN 
This section provides the basis for the SAP for this study.  The SAP may be revised during the 
study to accommodate amendments to the clinical study protocol and to make changes to adapt 
to unexpected issues in study execution and data that may affect the planned analyses.  The final 
SAP will be issued before the database is locked. 
Analysis variables are listed in Section 4. 
10.1. 
Statistical Hypothesis 
No formal statistical testing will be performed for this open-label study.   
10.2. 
Justification of Sample Size 
Since this study is an open-label single treatment arm study for patients with HoFH, no 
calculation for sample size was performed.  Approximately 120 patients will be enrolled.   
To gain experience with evinacumab in the subpopulation of adolescent patients, this study will 
plan to enroll approximately 14 patients in the age range of 12 years to <18 years old. Due to the 
rare patient population planned for evaluation, the sample size of 14 patients was chosen for 
practical reasons, centered on the feasibility to identify and enroll these patients into the trial and 
regulatory precedent. 
10.3. 
Analysis Sets 
10.3.1. 
Safety Analysis Set 
The safety analysis set (SAF) includes all patients who received at least 1 dose or part of a dose 
of open-label study treatment in this study.  The SAF will be the main analysis set for 
exposure/compliance, clinical safety and efficacy.   
10.3.2. 
Efficacy Analysis Sets 
The SAF will be the main analysis set for efficacy. 
10.3.3. 
Pharmacokinetic Analysis Sets 
The PK population includes all treated patients who received any study drug and who had at 
least 1 non-missing result following the first dose of study drug.  
10.3.4. 
Anti-Drug Antibody Analysis Sets 
The ADA population includes all treated patients who received any study drug and who had at 
least 1 non-missing result following the first dose of study drug.  
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10.4. 
Statistical Methods 
In general, data will be presented in 3 patient groups, depending on the status of previous 
evinacumab treatment exposure: 
• Continue evinacumab: patients who received evinacumab in a previous study (eg, 
R1500-CL-1331 or R1500-CL-1629); 
• New evinacumab: patients without previous exposure to evinacumab (ie, 
evinacumab-naïve); 
• Total: all patients, regardless of previous (or not) evinacumab exposure. 
These 3 evinacumab exposure groups will be provided for all patients in the respective patient 
analysis sets. Assuming there are enough patients in the subpopulation of adolescent patients to 
perform the evaluation, the 3 evinacumab treatment exposure groups will be provided again for 
the subpopulation of adolescent patients [yes/no]. Adolescent patients [yes] are defined as 
ranging in age from 12 years to < 18 years old. Adult patients, defined as ≥ 18 years of age, will 
also be provided. 
For continuous variables, descriptive statistics will include the following information:  the 
number of patients reflected in the calculation (n), mean, median, standard deviation (SD), Q1, 
Q3, minimum, and maximum.   
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
10.4.1. 
Patient Disposition 
The following will be provided by the status of previous evinacumab treatment exposure, and 
again for the subpopulation of adolescent patients [yes/no]: 
• The total number of screened patients:  defined as originally having met the inclusion 
criteria and signed the ICF 
• 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 in each analysis set (Section 10.3) 
• The total number of patients who completed the OLTP (ie, as collected on the end of 
study CRF) 
• The total number of patients who did not complete the OLTP 
• The total number of patients who discontinued open-label study treatment by main 
reason for permanent treatment discontinuation 
• The total number of patients who completed the study 
• A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation 
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10.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by the status of 
previous evinacumab treatment exposure for all patients in the SAF, and again for the 
subpopulation of adolescent patients [yes/no].  
10.4.3. 
Efficacy Analyses  
The percent and absolute change in lipid data (eg, LDL-C, Apo B, TG) will be descriptively 
summarized for each visit by the status of previous evinacumab treatment exposure for all 
patients in the SAF, and again for the subpopulation of adolescent patients [yes/no] for patients 
in the SAF. A within-patient t-test (lipids with a normal distribution) or Wilcoxon signed-rank 
test (non-parametric test for lipids with a non-normal distribution such as TG) will be provided 
for secondary efficacy endpoints to descriptively compare each patient’s week 24 assessment to 
their baseline assessment. Missing data will not be imputed. 
The baseline value used for determining percent and absolute change for each patient is defined as 
follows:   
• For patients who participated in the previous evinacumab study R1500-CL-1629, 
baseline is defined as the last obtained value before the first dose of double-blind 
study drug in R1500-CL-1629. 
• For patients who participated in the previous evinacumab study R1500-CL-1331 or 
did not participate in any previous evinacumab study, baseline is defined as the last 
obtained value before the first dose of study drug in R1500-CL-1719. (Note: Baseline 
for patients who participated in R1500-CL-1331 is defined as the baseline from the 
R1500-CL-1719 study due to the long time between the last study treatment in 
R1500-CL-1331 and the first study treatment in R1500-CL-1719.) 
10.4.4. 
Safety Analyses 
The summary of safety results will be presented in the SAF as described in Section 10.4.  No 
formal inferential testing will be performed.  Summaries will be descriptive in nature.   
All safety analyses will be performed using the same baseline definitions described above in 
Section 10.4.3. 
10.4.4.1. Adverse Events 
Definitions 
For safety variables, the following observation periods are defined: 
• The pretreatment period is defined as the time from signing the ICF to before the first 
dose of study drug 
• The open-label TEAE period is defined from the day of the first open-label study 
treatment administration to the day of the last open-label study treatment 
administration + 168 days 
• The post-treatment period is defined as the time from the day after the end of the 
respective TEAE periods to the last study visit 
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Open-label TEAEs are defined as those events that developed, worsened, or became serious 
during the open-label TEAE period.   
Analysis 
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®).  Coding will be to lowest level terms.  The 
verbatim text, the preferred term (PT), and the primary system organ class (SOC) will be listed. 
Adverse event incidence tables will present data by SOC sorted alphabetically and PT sorted by 
decreasing frequency, and summarize the number (n) and percentage (%) of patients 
experiencing an AE.  Multiple occurrences of the same event in the same patient will be counted 
only once in the tables.  Data conventions for missing or partial AE dates will be addressed in the 
SAP.  The denominator for computation of percentages is the respective SAF by the status of 
previous evinacumab treatment exposure, and again for the subpopulation of adolescent patients 
[yes/no].   
Summaries of all TEAEs will at least include: 
• All TEAEs (and patient listing) 
• All treatment-emergent SAEs, including patient deaths (and patient listing) 
• Treatment-emergent AESIs (eg, hypersensitivity and anaphylaxis, defined by a 
pre-specified grouping) (Section 9.4.3) 
• TEAEs by severity (according to the grading scale outlined in Section 9.5.1), 
presented by SOC and PT, 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) 
10.4.4.2. Other Safety 
Definitions 
The following definitions will be applied to laboratory parameters and vital signs: 
• The potentially clinically significant value (PCSV) criteria are defined as abnormal 
values considered medically important by the sponsor according to predefined 
criteria/thresholds based on literature review and defined by the sponsor for clinical 
laboratory tests and vital signs.  Potentially clinically significant value criteria will be 
provided in the SAP.   
• PCSV criteria will determine which patients had at least 1 PCSV during the 
respective open-label TEAE period, taking into account all evaluations performed 
during this period, including unscheduled or repeated evaluations.  The number of all 
such patients will be the numerator for the PCSV percentage.   
• Open-label treatment period (OLTP):  The treatment period used for quantitative 
analysis of laboratory and vital signs data in the open-label study period is defined 
from the day after the first dose of open-label study treatment to the day of the last 
dose of open-label study treatment + 28 days.   
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Analysis 
Summary statistics of raw data and change from baseline in all continuous laboratory variables 
(excluding variables in lipid panel) and all vital signs parameters will be presented for each 
protocol-scheduled visit assessed during the OLTP period.   
For selected parameters, mean changes from baseline with the corresponding standard error may 
be plotted over time (at same time points).   
Number and percentage of patients with a potentially clinically significant value (PCSV) at any 
time point during the open-label TEAE 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, regardless of baseline level.   
Listings will be provided with flags indicating the out of laboratory range values.   
10.4.4.3. Treatment Exposure 
The duration of study drug exposure for the open-label treatment period will be calculated as:   
• Patient duration of study drug exposure in weeks: (last study drug administration date 
+ 28 – first study drug administration date +1) / 7, regardless of unplanned 
intermittent discontinuations 
• The total number of study drug infusions by patient 
10.4.4.4. Treatment Compliance 
Compliance during the OLTP will be assessed by infusion frequency, specifically:   
• Defined for each patient as the average number of days between 2 infusions: (last 
dose date – first dose date) / (number of infusions in OLTP -1), for patients receiving 
at least 2 infusions 
10.4.5. 
Pharmacokinetics 
10.4.5.1. Analysis of Drug Concentration Data 
Descriptive statistics of evinacumab serum concentration at each sampling time will be provided.  
No formal statistical analysis will be performed.  
10.4.6. 
Analysis of Anti-Drug Antibody Data 
Listings of ADA positivity and titers presented by patient and time point will be provided. 
Prevalence of treatment-emergent and treatment-boosted ADA will be assessed as absolute 
occurrence (N) and percent of patients (%). 
The influence of ADAs on drug concentrations will be evaluated.  Assessment of impact of ADA 
on safety and efficacy may be provided. 
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10.5. 
Additional Statistical Data Handling Conventions 
Additional analysis and data conventions will be provided in the SAP, including the definitions 
for the analysis windows around each planned visit.   
10.6. 
Statistical Considerations Surrounding the Premature Termination 
of a Study 
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized.  Investigator and sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 16.1.  
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
11.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study 
(including data validation [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) tool: 
Medidata Rave.   
11.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
• IVRS/IWRS system – study drug supply 
• EDC system – data capture 
• Statistical Analysis System (SAS) – statistical review and analysis 
• Pharmacovigilance safety database 
12. 
STUDY MONITORING 
12.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, contract research organization monitor) will visit each 
site prior to enrollment of the first patient, and periodically during the study.   
The investigator must allow study-related monitoring. 
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
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that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH 
GCP, and all applicable regulatory requirements 
12.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). 
The investigator must keep all source documents on file with the CRF.  Case report forms and 
source documents must be available at all times for inspection by authorized representatives of 
the sponsor and regulatory authorities. 
12.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic CRFs within 
the EDC system by trained site personnel.  All required CRFs must be completed for each patient 
enrolled in the study.  After review of the clinical data for each patient, the investigator must 
provide an electronic signature.  A copy of each patient CRF casebook is to be retained by the 
investigator as part of the study record and must be available at all times for inspection by 
authorized representatives of the sponsor and regulatory authorities. 
13. 
AUDITS AND INSPECTIONS 
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities.  Should this occur, the investigator is responsible for: 
Informing the sponsor of a planned inspection by the authorities as soon as notification is 
received, and authorizing the sponsor’s participation in the inspection. 
Providing access to all necessary facilities, study data, and documents for the inspection or audit 
Communicating any information arising from inspection by the regulatory authorities to the 
sponsor immediately. 
Taking all appropriate measures requested by the sponsor to resolve the problems found during 
the audit or inspection. 
Documents subject to audit or inspection include but are not limited to all source documents, 
CRFs, medical records, correspondence, ICFs, IRB/EC files, documentation of certification and 
quality control of supporting laboratories, and records relevant to the study maintained in any 
supporting pharmacy facilities.  Conditions of study material storage are also subject to 
inspection.  In addition, representatives of the sponsor may observe the conduct of any aspect of 
the clinical study or its supporting activities both within and outside of the investigator's 
institution. 
In all instances, the confidentiality of the data must be respected. 
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14. 
ETHICAL AND REGULATORY CONSIDERATIONS 
14.1. 
Good Clinical Practice Statement  
It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable 
regulatory requirements.   
The principles of informed consent are described in ICH guidelines for GCP. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC.  A copy of the IRB/EC -approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
Informed Consent for Adult Patients 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient prior to his/her participation in the study and after the 
aims, methods, objectives, and potential hazards of the study have been explained to the patient 
in language that he/she can understand.  The ICF should be signed and dated by the patient and 
by the investigator or authorized designee who reviewed the ICF with the patient.   
• Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
• Patients who can understand but who can neither write nor read will have the ICF 
read to them in presence of an impartial witness, who will sign and date the ICF to 
confirm that informed consent was given. 
The original ICF must be retained by the investigator as part of the patient’s study record, and a 
copy of the signed ICF must be given to the patient. 
If new safety information results in significant changes in the risk/benefit assessment, the ICF 
must be reviewed and updated appropriately.  All study patients must be informed of the new 
information and provide their written consent if they wish to continue in the study.  The original 
signed revised ICF must be maintained in the patient’s study record and a copy must be given to 
the patient.  
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Informed Consent for Pediatric Patients 
To be used as applicable, see Section 6.2. 
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, the ICF 
must be reviewed and updated appropriately.  All study patients and their parent(s) or legal 
guardian(s) must be informed of the new information and provide their written consent if they 
wish the patient to continue in the study.  The original signed revised ICF must be maintained in 
the patient’s study record and a copy must be given to the patient’s parent(s) or legal guardian(s). 
14.2. 
Patient Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained.  Patients should be identified by 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. 
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14.3. 
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 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. 
15. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an 
IRB/EC-approved amendment.   
16. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
16.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely.  Reasons may include efficacy, 
safety, or futility, among others.  Should the sponsor decide to terminate the study, the 
investigator(s) will be notified in writing. 
16.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
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. 
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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 patient’s interests. 
17. 
STUDY DOCUMENTATION 
17.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the CRF must be signed 
electronically by the investigator.  This signed declaration accompanies each set of patient final 
CRF that will be provided to the sponsor. 
17.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of CRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
regulatory authorities.  The investigator must 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.  
18. 
DATA QUALITY ASSURANCE 
In accordance with ICH E6, the sponsor is responsible for quality assurance to ensure that the 
study is conducted and the data generated, recorded, and reported in compliance with the 
protocol, GCP, and any applicable regulatory requirement(s).  The planned quality assurance and 
quality control procedures for the study are summarized.  
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Data Management 
The sponsor is responsible for the data management of this study including quality checking of 
the data (Section 11.1). 
Study Monitoring 
The investigator must allow study-related monitoring, IRB/EC review, audits, and inspections 
from relevant health regulatory authorities, and provide direct access to source data documents 
(Section 12.1, Section 12.2, Section 13).   
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, 
ICH GCP, and all applicable regulatory requirements (Section 12.1).   
All subject/patient data collected during the study will be recorded on paper or electronic CRF 
unless the data are transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for affirming that data entries in the CRF are accurate and correct by 
electronically signing a declaration that accompanies each set of patient/subject final CRF 
(Section 12.3 and Section 17.1).  
Study Documentation 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF (Section 12.2).  
The investigator will retain all records and documents, including signed ICFs, pertaining to the 
conduct of this study for at least 15 years after study completion, unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor (Section 17.2).  
19. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
20. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
21. 
PUBLICATION POLICY 
The publication policy is provided as a separate agreement. 
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22. 
REFERENCES 
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Spectrum of LDLR Activity. Arterioscler Thromb Vasc Biol. 2019 Nov;39(11):2248-60. 
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Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015 Jun 18;372(25):2387-97. 
Catapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS Guidelines for the Management of 
Dyslipidaemias.  Eur Heart J. 2016 Oct 14;37(39):2999-3058. doi: 10.1093/eurheartj/ehw272. 
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Chora JR, Medeiros AM, Alves AC, Bourbon M. Analysis of publicly available LDLR, APOB, 
and PCSK9 variants associated with familial hypercholesterolemia: application of ACMG 
guidelines and implications for familial hypercholesterolemia diagnosis. Genet Med 
2018;20:591-98. 
Crestor. rosuvastatin U.S Prescribing Information. Revised 06/2015; 2003 
Cuchel M, Bruckert E, Ginsberg HN, et al. Homozygous familial hypercholesterolaemia: new 
insights and guidance for clinicians to improve detection and clinical management. A position 
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Atherosclerosis Society. Eur Heart J 2014. 
Cuchel M, Meagher EA, du Toit Theron H, et al. Efficacy and safety of a microsomal 
triglyceride transfer protein inhibitor in patients with homozygous familial 
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Dewey FE, Gusarova V, Dunbar RL, O'Dushlaine C, Schurmann C, Gottesman O, et al. Genetic 
and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease. N Engl J Med. 2017 
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Doyon A, Kracht D, Bayazit AK, Deveci M, Duzova A, Krmar RT, et al. Carotid artery intima-
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Gidding SS, Champagne MA, de Ferranti SD, et al. The Agenda for Familial 
Hypercholesterolemia: A Scientific Statement From the American Heart Association. 
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28.  
Goldberg AC, Hopkins PN, Toth PP et al., Familial hypercholesterolemia: screening, diagnosis 
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Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 
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 
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Harada-Shiba M, Sugisawa T, Makino H, et al. Impact of Statin Treatment on the Clinical Fate 
of Heterozygous Familial Hypercholesteremia. J Atheroscler Thromb. 2010;17:667-674.  
Huijgen R, Kindt I, Verhoeven SBJ, et al. Two Years after Molecular Diagnosis of Familial 
Hypercholesterolemia: Majority on Cholesterol-lowering Treatment but a Minority Reaches 
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Ito MK, Watts GF. Challenges in the Diagnosis and Treatment of Homozygous Familial 
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in patients with homozygous familial hypercholesterolemia. Am J Cardiol. 2008. 
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statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry 
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homozygous familial hypercholesterolaemia. Atherosclerosis 1997; 135: 249–56. 
Raal FJ, Pappu AS, Illingworth DR. Inhibition of cholesterol synthesis by atorvastatin in 
homozygous familial hypercholesterolaemia. Atherosclerosis. 2000; 421–428. 
Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for 
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Raal FJ, Honarpour N, Blom D, et al. Inhibition of PCSK9 with evolocumab in homozygous 
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Raal FJ, Honarpour N, Blom D, et al. Inhibition of PCSK9 with evolocumab in homozygous 
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refractory hyperlipidemia. Mayo Clin Proc 2001;76(10):1039-46. 
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23. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: An Open-Label Study to Evaluate the Long-Term Safety and 
Efficacy of Evinacumab in Patients with Homozygous Familial Hypercholesterolemia, and agree 
to abide by all provisions set forth therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, 
state, or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor or a 
partnership in which the sponsor is involved.  I will immediately disclose it in writing to the 
sponsor if any person who is involved in the study is debarred, or if any proceeding for 
debarment is pending, or, to the best of my knowledge, threatened. 
This document contains confidential information of the sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the IRB/EC.  I agree to ensure that 
this information will not be used for any purpose other than the evaluation or conduct of the 
clinical investigation without the prior written consent of the sponsor. 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
 
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APPENDIX 1. SUMMARY OF THERAPEUTIC LIFESTYLE CHANGES 
DIET FOR HIGH CHOLESTEROL 
 
Total Fat 
25% - 35% total calories* 
Saturated fat* 
<7% total calories 
Polyunsaturated fat 
up to 10% total calories 
Monounsaturated fat 
up to 20% total calories 
Carbohydrates† 
50% - 60% total calories* 
Protein 
~15% total calories 
Cholesterol 
<200 mg/dL (5.172 mmol/L) 
Plant Sterols 
2g 
Soluble Fiber such as psyllium 
10g - 25g 
* ATP III allows an increase of total fat to 35 percent of total calories and a reduction in carbohydrate 
to 50 percent for persons with the metabolic syndrome. Any increase in fat intake should be in the 
form of either polyunsaturated or monounsaturated fat. Trans-fatty acids are another LDL-raising fat 
that should be kept at a low intake. 
† Carbohydrate should derive predominantly from foods rich in complex carbohydrates including 
grains—especially whole grains—fruits, and vegetables. 
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SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Medical/Study Director, Regulatory Representative, Clinical Study Team Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the conduct of the study. 
Study Title: 
An Open-Label Study to Evaluate the Long-Term Safety and Efficacy of 
Evinacumab in Patients with Homozygous Familial Hypercholesterolemia 
 
Protocol Number: 
R1500-CL-1719 
Protocol Version: 
R1500-CL-1719 Amendment 7  
 
See appended electronic signature page 
Sponsor’s Responsible Medical/Study Director 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Liaison 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Team Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
 
 
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