Conditions: Hypertriglyceridemia
Keywords: Severe Hypertriglyceridemia (HTG) Recurrent Acute Pancreatitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 21
Healthy volunteers: no

Brief summary:
The primary objective of the study is to determine the proportion of patients with elevated triglycerides (TG), without familial chylomicronemia syndrome (FCS) due to loss of function (LoF) mutations in lipoprotein lipase (LPL), and a history of hypertriglyceridemia (HTG)-associated acute pancreatitis (AP) who experience a recurrent episode of AP after treatment with evinacumab versus placebo.

The secondary objectives of the study are:

* To determine the change in the standard lipid profile after therapy with evinacumab versus placebo
* To determine the changes in specialty lipoprotein parameters (ApoC3, ApoB48, ApoB100, and nuclear magnetic resonance \[NMR\] lipid profile) after therapy with evinacumab versus placebo
* To measure the number of AP episodes per patient
* To assess the safety and tolerability of evinacumab
* To assess the potential immunogenicity of evinacumab
* To assess the concentrations of total evinacumab and total angiopoietin-like 3 (ANGPTL3)

Detailed description:

Arms:
arm 1: Randomized 1:1 arm 2: Randomized 1:1

Interventions: intervention 1: evinacumab intervention 2: Placebo
Intervention descriptions: intervention 1: Intravenous infusion every 4 weeks (Q4W) intervention 2: Intravenous infusion Q4W

Protocol document:
Prot_000.pdf: 
EudraCT Number: 2021-000437-13 
IND Number: 116398 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of 
Evinacumab in Patients with Severe Hypertriglyceridemia for the Prevention of Recurrent Acute 
Pancreatitis  
Compound: 
REGN1500 (evinacumab) 
Clinical Phase: 
2b 
Protocol Number: 
R1500-HTG-20118 
Protocol Version: 
R1500-HTG-20118 Amendment 2  
Amendment 2 Date of Issue: 
See appended electronic signature page 
Amendment 1 Date of Issue: 
21 Apr 2021 
Original Date of Issue: 
22 March 2021 
Medical/Study Director: 
 
 
 
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 
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. 
VV-RIM-00178604-1.0 Approved - 16 Dec 2021 GMT-5:00
NCT Number: NCT04863014


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Regeneron Pharmaceuticals, Inc. 
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AMENDMENT HISTORY 
Amendment 2 
Overall rationale for Amendment 2 
The purpose of this protocol amendment is to implement revisions to protocol inclusion criteria 
to enhance enrollment. 
The following table outlines the changes made to the protocol and the affected sections: 
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Description of Change 
Brief Rationale 
Section # and Name 
Revised the definition of the study 
population 
Broadened the inclusion criteria for 
the trial.  In addition to enrolling 
patients with TG value >880 mg/dL 
at the screening visit, also allowing 
patients with a TG value at screening 
>500 mg/dL if they have a prior 
fasting measurement >1000 mg/dL 
or if they have had 2 or more 
episodes of pancreatitis in the past 24 
months. 
Clinical Study Synopsis, Target 
Population, Statistical Plan 
Section 3.2.1 Rationale for Study 
Design 
Section 2.1 Primary Objective 
Section 6.1 Study Description and 
Duration 
Figure 1 Study Flow Diagram 
Section 7.2.1 Inclusion Criteria, #3 
Broadened the entry criteria with 
regard to fasting TG values at study 
entry and consequently removed 
Visit 2 during the Screening Period; 
Extended the time period for patients 
having a documented history of HTG 
from 15 to 24 months of screening 
See rationale above.  Since requiring 
only a single TG screening value, 
eliminating visit 2 which had the 
purpose of checking a second 
screening value.  This decreases the 
burden on participants and sites, 
while still enrolling patients who 
have demonstrated high fasting TG 
values. 
Clinical Study Protocol Synopsis, 
Objectives, Study Design, Study 
Duration 
Section 2.1 Primary Objective 
Section 3.1 Hypotheses 
Section 3.2.1 Rationale for Study 
Design 
Section 6.1 Study Description and 
Duration 
Section 7.2.1 Inclusion Criteria, 
Criterion #2 
Table 1 Schedule of Events for 
DBTP 
Section 11.4.3.1 Primary Efficacy 
Analysis 
Broadened the entry criteria with 
regard to BMI at study entry 
Feedback from investigators and 
experts in this area have stated that a 
BMI range of 18-40 is too restrictive. 
Therefore the upper limit was 
increased to 45. 
Section 7.2.1 Inclusion Criteria, 
Criterion #5 
Added exclusion criterion for 
patients with a history of 
hypersensitivity to study drug or 
excipients, and for patients having 
received COVID-19 vaccination 
within 1 week of start of study 
medication. 
The exclusion for hypersensitivity 
was an omission in the last version of 
the protocol that is now being 
updated.  The exclusion for COVID-
19 was added as the study drug has 
not been tested together with 
vaccines for COVID-19.  
Section 7.2.2 Exclusion Criteria, new 
criteria #20, and #21 
Section 8.9.1 Prohibited Medications 
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Reduced the off-drug follow-up 
period from 48 weeks to 20 weeks 
and the total study duration from 100 
weeks to 72 weeks 
Feedback from investigators, experts, 
and potential patients has been that a 
48-week off-drug follow-up period is 
excessive and discourages 
participation.  Other studies have 
demonstrated that evinacumab serum 
concentrations are minimal (ie, 
<1 ug/mL and <1% of Cmax) by 24 
weeks after the last drug 
administration 
Clinical Study Protocol Synopsis, 
Study Design, Study Duration 
Section 3.2.1 Rationale for Study 
Design 
Section 6.1 Study Description and 
Duration 
Figure 1 Study Flow Diagram 
Section 8.3.2 Study Drug 
Discontinuation 
Table 1 Schedule of Events for the 
DBTP 
Table 2 Schedule of Events for the 
Off-Drug Follow-up Period  
Revised definition of study follow-up 
period 
Patient disposition summaries were 
adjusted to align with the 20-week 
follow-up period. Simplified the 
definition of screened patients. 
Simplified the descriptions of TEAE 
summaries that will be provided. 
Section 11.4.1 Patient Disposition 
Section 11.4.5.1 Adverse Events 
Distinguished separate timepoints for 
collection of lipids and special lipids 
This was an oversight in the last 
version of the protocol.  Special 
Lipids (ApoC3, ApoB48, ApoB100, 
and ApoB Total) collections were 
reduced as was the original intention. 
Table 1 Schedule of Events for the 
DBTP 
Table 2 Schedule of Events for the 
Off-Drug Follow-up Period 
Section 9.1.1.1 Footnotes for Table 1 
Schedule of Events (DBTP), #6 
Section 9.1.1.2 Footnotes for Table 2 
Schedule of Events (Off Drug 
Follow-up Period), #1 
Section 9.2.2.2 Fasting Blood 
Samples for Assessment of Lipid 
Profile (For Efficacy and PD 
Variables) 
Specified that immunogenicity 
sample collection should occur prior 
to infusion 
This corrects an error in the prior 
version.  Immunogenicity only needs 
to be sampled prior to infusion. 
Section 9.1.1.2 Footnotes for Table 2 
Schedule of Events (Off Drug 
Follow-up Period), #6 
Removed eligibility criteria 
redundant text 
To minimize repetition of identical 
text to avoid discrepancies and 
enhance readability 
Clinical Study Protocol Synopsis, 
Study Design 
Added APOE genotypes to the list of 
genes encoding proteins in the LPL 
pathway 
APOE genotypes will be explored 
when patients are sequenced to 
assess their response to evinacumab 
Section 1 Introduction 
Revised screening language to allow 
the potential for patients who failed 
screening to be rescreened following 
a discussion with the medical 
monitor 
To enhance enrollment 
Section 6.1 Study Description and 
Duration 
Editorial change related to genotypic 
or other biomarker differences 
Revised for clarity 
Section 2.3 Exploratory Objectives 
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Amendment 1 
The following table outlines the changes made to the protocol and the affected sections: 
Description of Change 
Brief Rationale  
Section # and Name  
The schedule of events were updated 
to add “weight” at each dosing visit 
and during in-person visits in the off-
drug follow up period. 
Correspondingly, weight was added 
as an assessment in the Safety 
Procedures section. 
Body weight measurement is needed 
for treatment dosing which is weight-
based, and for safety assessment. 
Weight was inadvertently omitted in 
the original protocol. 
Table 1. Schedule of Events for the 
DBTP 
Table 2. Schedule of Events for the 
Off-Drug Follow-Up Period 
Section 9.2.3.1 Vital Signs and Body 
Weight  
 
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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 
APAC 
Acute Pancreatitis Adjudication Committee 
APO 
Apolipoprotein 
AP 
Acute pancreatitis 
AST 
Aspartate aminotransferase 
β-HCG 
Human chorionic gonadotrophin 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CABG 
Coronary artery bypass grafting 
CI 
Confidence interval 
COA 
Clinical outcome assessment 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
CT 
Computer tomography 
DBTP 
Double-blind treatment period 
DNA 
Deoxyribonucleic acid 
EC 
Ethics committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
FBR 
Future biomedical research 
FCS 
Familial chylomicronemia syndrome 
FH 
Familial hypercholesterolemia 
FSH 
Follicle-stimulating hormone 
FT4 
Free thyroxine 
GCP 
Good Clinical Practice 
HbA1c 
Glycosylated hemoglobin 
HDL 
High-density lipoprotein 
HDL-C 
High-density lipoprotein cholesterol 
HoFH 
Homozygous familial hypercholesterolemia 
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HTG 
Hypertriglyceridemia 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent ethics committee 
IRB 
Institutional review board 
ITT 
Intent to treat 
IV 
Intravenous 
IVRS 
Interactive voice response system 
IWRS 
Interactive web response system 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LDL-C 
Low-density lipoprotein cholesterol 
LLN 
Lower limit of normal 
LoF 
Loss of function 
LPL 
Lipoprotein lipase 
mAb 
Monoclonal antibody 
MDRD 
Modification of diet in renal disease  
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 
mITT 
Modified ITT 
MMRM 
Mixed-effect model for repeated measures 
MRI 
Magnetic resonance imaging 
NAb 
Neutralizing antibodies 
NMR 
Nuclear magnetic resonance 
NYHA 
New York Heart Association 
PCI 
Percutaneous coronary intervention 
PCR 
Polymerase chain reaction 
PK 
Pharmacokinetic 
PopPK 
Population pharmacokinetics 
PP 
Posterior probability 
PT 
Preferred term 
Q4W 
Every 4 weeks 
RBC 
Red blood cell 
RBQM 
Risk-based quality monitoring 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
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SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Software 
SDR 
Source data review 
SDV 
Source data verification 
SE 
Standard error 
sHTG 
Severe hypertriglyceridemia 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TC 
Total cholesterol 
TEAE 
Treatment-emergent adverse event 
TG 
Triglycerides 
TIA 
Transient ischemic attack 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
VLDL 
Very-low-density lipoproteins 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................6 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................15 
1. 
INTRODUCTION ......................................................................................................19 
2. 
STUDY OBJECTIVES ..............................................................................................21 
2.1. 
Primary Objective .......................................................................................................21 
2.2. 
Secondary Objectives .................................................................................................21 
2.3. 
Exploratory Objectives ...............................................................................................21 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................22 
3.1. 
Hypotheses ..................................................................................................................22 
3.2. 
Rationale .....................................................................................................................22 
3.2.1. 
Rationale for Study Design .........................................................................................22 
3.2.2. 
Rationale for Dose Selection ......................................................................................24 
3.3. 
Risk-Benefit ................................................................................................................24 
3.3.1. 
Risks-Benefits for Evinacumab ..................................................................................24 
4. 
ENDPOINTS ..............................................................................................................26 
4.1. 
Primary Efficacy Endpoint .........................................................................................26 
4.2. 
Secondary Efficacy Endpoints ....................................................................................26 
4.2.1. 
Key Secondary Efficacy Endpoints ............................................................................26 
4.2.2. 
Other Secondary Efficacy Endpoints ..........................................................................26 
4.3. 
Exploratory Efficacy Endpoints .................................................................................27 
4.4. 
Safety Endpoints .........................................................................................................27 
4.5. 
Other Endpoints ..........................................................................................................27 
5. 
STUDY VARIABLES................................................................................................28 
5.1. 
Demographic and Baseline Characteristics ................................................................28 
5.2. 
Efficacy Variables ......................................................................................................28 
5.2.1. 
Acute Pancreatitis Episodes ........................................................................................28 
5.2.2. 
Laboratory Variables for the Assessment of Efficacy ................................................28 
5.2.3. 
Clinical Outcome Assessments ...................................................................................29 
5.3. 
Safety Variables ..........................................................................................................29 
5.4. 
Pharmacokinetic Variables .........................................................................................29 
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5.5. 
Immunogenicity Variables ..........................................................................................29 
5.6. 
Pharmacodynamic and Other Biomarker Variables ...................................................29 
6. 
STUDY DESIGN .......................................................................................................30 
6.1. 
Study Description and Duration .................................................................................30 
6.1.1. 
End of Study Definition ..............................................................................................32 
6.2. 
Planned Interim Analysis ............................................................................................32 
6.3. 
Study Committees .......................................................................................................33 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............34 
7.1. 
Number of Patients Planned .......................................................................................34 
7.2. 
Study Population .........................................................................................................34 
7.2.1. 
Inclusion Criteria ........................................................................................................34 
7.2.2. 
Exclusion Criteria .......................................................................................................34 
7.3. 
Premature Withdrawal from the Study .......................................................................38 
7.4. 
Replacement of Patients .............................................................................................38 
8. 
STUDY TREATMENTS............................................................................................39 
8.1. 
Investigational and Reference Treatments ..................................................................39 
8.2. 
Background Treatment(s) ...........................................................................................39 
8.3. 
Dose Modification and Study Treatment Discontinuation Rules ...............................39 
8.3.1. 
Dose Modification ......................................................................................................39 
8.3.2. 
Study Drug Discontinuation .......................................................................................39 
8.3.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................39 
8.3.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................40 
8.4. 
Management of Acute Reactions ................................................................................40 
8.4.1. 
Acute Intravenous Infusion Reactions ........................................................................40 
8.4.1.1. 
Interruption of the Intravenous Infusion .....................................................................40 
8.4.1.2. 
Termination of the Intravenous Infusion ....................................................................41 
8.5. 
Method of Treatment Assignment ..............................................................................41 
8.6. 
Blinding ......................................................................................................................41 
8.7. 
Emergency Unblinding ...............................................................................................42 
8.8. 
Treatment Logistics and Accountability .....................................................................42 
8.8.1. 
Packaging, Labeling, and Storage ..............................................................................42 
8.8.2. 
Supply and Disposition of Treatments .......................................................................43 
8.8.3. 
Treatment Accountability ...........................................................................................43 
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8.8.4. 
Treatment Compliance ................................................................................................43 
8.9. 
Concomitant Medications ...........................................................................................43 
8.9.1. 
Prohibited Medications ...............................................................................................43 
8.9.2. 
Permitted Medications ................................................................................................44 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................45 
9.1. 
Schedule of Events .....................................................................................................45 
9.1.1. 
Footnotes for the Schedule of Events Tables .............................................................49 
9.1.1.1. 
Footnotes for Table 1 Schedule of Events (DBTP) ....................................................49 
9.1.1.2. 
Footnotes for Table 2 Schedule of Events (Off Drug Follow-up Period) ..................50 
9.1.2. 
Early Termination Visit ..............................................................................................50 
9.1.3. 
Unscheduled Visits .....................................................................................................50 
9.2. 
Study Procedures ........................................................................................................50 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................50 
9.2.2. 
Efficacy Procedures ....................................................................................................51 
9.2.2.1. 
Acute Pancreatitis Episodes ........................................................................................51 
9.2.2.2. 
Fasting Blood Samples for Assessment of Lipid Profile (For Efficacy and 
PD Variables) ..............................................................................................................51 
9.2.2.3. 
NMR Lipid Profile ......................................................................................................52 
9.2.2.4. 
Clinical Outcome Assessments ...................................................................................52 
9.2.3. 
Safety Procedures .......................................................................................................52 
9.2.3.1. 
Vital Signs and Body Weight .....................................................................................52 
9.2.3.2. 
Physical Examination .................................................................................................52 
9.2.3.3. 
Electrocardiogram .......................................................................................................52 
9.2.3.4. 
Laboratory Testing ......................................................................................................53 
9.2.4. 
Drug Concentration and Measurements .....................................................................54 
9.2.5. 
Immunogenicity Measurements and Samples ............................................................54 
9.2.6. 
Pharmacodynamic and Exploratory Biomarker Procedures .......................................54 
9.2.7. 
DNA Sample for FCS Genotyping .............................................................................54 
9.2.8. 
Future Biomedical Research (Optional) .....................................................................55 
9.2.9. 
Pharmacogenomic Analysis (Optional) ......................................................................55 
10. 
SAFETY EVALUATION AND REPORTING .........................................................56 
10.1. 
Recording and Reporting Adverse Events ..................................................................56 
10.1.1. 
General Guidelines .....................................................................................................56 
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10.1.2. 
Reporting Procedure ...................................................................................................57 
10.1.3. 
Events that Require Expedited Reporting to Sponsor ................................................57 
10.2. 
Definitions ..................................................................................................................58 
10.2.1. 
Adverse Event .............................................................................................................58 
10.2.2. 
Serious Adverse Event ................................................................................................58 
10.2.3. 
Adverse Events of Special Interest .............................................................................58 
10.2.4. 
Infusion Reactions ......................................................................................................59 
10.2.5. 
Severity .......................................................................................................................59 
10.2.6. 
Causality .....................................................................................................................59 
10.3. 
Safety Monitoring .......................................................................................................60 
10.4. 
Notifying Health Authorities, Institutional Review Board/Ethics Committee, 
and Investigators .........................................................................................................61 
11. 
STATISTICAL PLAN................................................................................................62 
11.1. 
Statistical Hypothesis ..................................................................................................62 
11.2. 
Justification of Sample Size........................................................................................62 
11.3. 
Analysis Sets ...............................................................................................................62 
11.3.1. 
Efficacy Analysis Sets ................................................................................................62 
11.3.1.1. 
Intent-to-Treat .............................................................................................................62 
11.3.1.2. 
Modified Intent-to-Treat .............................................................................................62 
11.3.2. 
Safety Analysis Set .....................................................................................................63 
11.3.3. 
Pharmacokinetic Analysis Set ....................................................................................63 
11.3.4. 
Immunogenicity Analysis Set .....................................................................................63 
11.4. 
Statistical Methods ......................................................................................................63 
11.4.1. 
Patient Disposition ......................................................................................................63 
11.4.2. 
Demography and Baseline Characteristics .................................................................64 
11.4.3. 
Efficacy Analyses .......................................................................................................64 
11.4.3.1. 
Primary Efficacy Analysis ..........................................................................................64 
11.4.3.2. 
Secondary Efficacy Analysis ......................................................................................65 
11.4.4. 
Control of Multiplicity ................................................................................................67 
11.4.5. 
Safety Analysis ...........................................................................................................67 
11.4.5.1. 
Adverse Events ...........................................................................................................68 
11.4.5.2. 
Other Safety ................................................................................................................69 
11.4.5.3. 
Treatment Exposure ....................................................................................................69 
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11.4.5.4. 
Treatment Compliance ................................................................................................70 
11.4.6. 
Pharmacokinetics ........................................................................................................70 
11.4.6.1. 
Analysis of Drug Concentration Data .........................................................................70 
11.4.7. 
Analysis of Immunogenicity Data ..............................................................................70 
11.5. 
Timing of Statistical Analyses ....................................................................................71 
11.5.1. 
Interim Analysis ..........................................................................................................71 
11.5.2. 
First Step: Main Efficacy and Safety Analysis ...........................................................71 
11.5.3. 
Final Analysis .............................................................................................................72 
11.6. 
Additional Statistical Data Handling Conventions .....................................................72 
11.7. 
Statistical Considerations Surrounding the Premature Termination of a Study .........72 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................73 
12.1. 
Data Management and Electronic Systems ................................................................73 
12.1.1. 
Data Management .......................................................................................................73 
12.1.2. 
Electronic Systems ......................................................................................................73 
12.2. 
Study Monitoring ........................................................................................................73 
12.2.1. 
Monitoring of Study Sites ...........................................................................................73 
12.2.2. 
Source Document Requirements ................................................................................74 
12.2.3. 
Case Report Form Requirements ................................................................................74 
12.3. 
Audits and Inspections ................................................................................................74 
12.4. 
Study Documentation .................................................................................................75 
12.4.1. 
Certification of Accuracy of Data ...............................................................................75 
12.4.2. 
Retention of Records ..................................................................................................75 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................76 
13.1. 
Good Clinical Practice Statement ...............................................................................76 
13.2. 
Informed Consent .......................................................................................................76 
13.3. 
Patients Confidentiality and Data Protection ..............................................................76 
13.4. 
Institutional Review Board/Ethics Committee ...........................................................77 
13.5. 
Clinical Study Data Transparency ..............................................................................77 
14. 
PROTOCOL AMENDMENTS ..................................................................................78 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................79 
15.1. 
Premature Termination of the Study ...........................................................................79 
15.2. 
Close-out of a Site ......................................................................................................79 
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16. 
CONFIDENTIALITY ................................................................................................79 
17. 
FINANCING AND INSURANCE .............................................................................79 
18. 
PUBLICATION POLICY ..........................................................................................79 
19. 
REFERENCES ...........................................................................................................80 
20. 
INVESTIGATOR’S AGREEMENT ..........................................................................81 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................82 
 
LIST OF TABLES 
Table 1: 
Schedule of Events for the DBTP ...............................................................................46 
Table 2: 
Schedule of Events for the Off-Drug Follow-up Period .............................................48 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................30 
 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy 
and 
Safety 
of 
Evinacumab 
in 
Patients 
with 
Severe 
Hypertriglyceridemia for the Prevention of Recurrent Acute Pancreatitis 
Site Locations 
 
Principal Investigator 
Multiple centers in North America and the European Union (EU) 
A coordinating principal investigator will be identified prior to the start of 
the study  
Objectives 
The primary objective of the study is to determine the proportion of patients 
with elevated triglycerides (TG), without Familial Chylomicronemia 
Syndrome (FCS) due to loss of function (LoF) mutations in lipoprotein 
lipase (LPL), and a history of hypertriglyceridemia (HTG)-associated acute 
pancreatitis (AP) who experience a recurrent episode of AP after treatment 
with evinacumab versus placebo. 
The secondary objectives of the study are: 
• 
To determine the change in the standard lipid profile after therapy 
with evinacumab versus placebo  
• 
To determine the changes in specialty lipoprotein parameters 
(ApoC3, 
ApoB48, 
ApoB100, 
and 
nuclear 
magnetic 
resonance [NMR] lipid profile) after therapy with evinacumab 
versus placebo 
• 
To measure the number of AP episodes per patient 
• 
To assess the safety and tolerability of evinacumab 
• 
To assess the potential immunogenicity of evinacumab  
• 
To assess the concentrations of total evinacumab and 
total angiopoietin-like 3 (ANGPTL3) 
Study Design 
This 
is 
a 
phase 
2b, 
multicenter, 
international, 
randomized, 
placebo-controlled study intended to demonstrate that evinacumab can 
prevent recurrent AP episodes in patients with severe hypertriglyceridemia 
(sHTG) and a recent history of HTG-associated AP. Approximately 
120 adult patients will be randomized 1:1 to receive evinacumab or 
matching placebo.  
The study consists of 3 periods: a screening period, a double-blind treatment 
period (DBTP), and a safety follow-up period. The screening period of up 
to 28 days will determine participant eligibility and will include an 
evaluation of prior episodes of HTG-associated AP, genotyping to exclude 
patients with familial chylomicronemia syndrome (FCS) due to loss of 
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function mutations in lipoprotein lipase (LPL), and a measurement of fasting 
TG levels.  
Patients who fulfill all the eligibility criteria will be randomized and receive 
their first dose of assigned study drug on day 1, with subsequent doses 
administered approximately every 4 weeks (Q4W) during the 52-week 
DBTP. This will be followed by a 20-week off-drug follow-up period.  
Efficacy will be assessed by measuring the number of patients with at least 
1 independently adjudicated positive event of AP over 52 weeks of 
treatment with evinacumab versus placebo. The study will have an 
independent committee to adjudicate these episodes in accordance with 
clinical standards for diagnosis of AP. Efficacy will also be assessed by 
clinical laboratory evaluation of lipid levels at pre-specified time points 
throughout the study. 
Safety will be assessed throughout the study by comparing the frequency 
and severity of adverse events (AEs) between the evinacumab and placebo 
groups, 
as 
well 
as 
evaluating 
abnormal 
laboratory 
findings, 
electrocardiogram (ECG) findings, and anti-drug antibody (ADA) and 
neutralizing antibodies (NAb) assessments. 
Study Duration 
The duration of the treatment period for individual patients is 52 weeks, after 
which patients will continue in a 20-week follow-up period for a total study 
duration of 72 weeks, excluding the screening period.  
End of Study Definition 
The end of study is defined as the date the last patient completes the last 
study visit, withdraws from the study, or is lost to follow-up (ie, the patient 
can no longer be contacted by the investigator).  
Population 
 
 
Sample Size: 
Approximately 120 patients  
 
Target Population: 
Adult patients 18 to 80 years of age without FCS due to LPL loss of function 
mutations with elevated baseline fasting TGs and AP criteria as follows:  
• 
Fasting serum TG values >880 mg/dL (10 mmol/L) 
determined during the screening period and a documented 
history of 1 HTG-associated AP episode within 24 months of 
screening, or  
• 
Fasting serum TG values >500 mg/dL (5.6 mmol/L) 
determined during the screening period in patients with a 
history of 2 or more HTG-associated AP episodes within 24 
months of screening, or  
• 
Fasting serum TG values >500 mg/dL (5.6 mmol/L) 
determined during the screening period and a documented 
fasted TG values >1000 mg/dL (11.3 mmol/L) and a history of 
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1 or more HTG-associated AP episodes(s) within 24 months 
of screening. 
Treatment 
 
 
Study Drug 
 
Dose/Route/Schedule: 
Evinacumab  
20 mg/kg administered intravenously (IV) over a 1-hour infusion Q4W, ±4 
days  
 
Placebo 
 
Route/Schedule: 
Matching placebo  
Intravenous infusion Q4W (±4 days)  
Endpoints 
 
 
Primary Efficacy: 
The primary endpoint is for efficacy: the proportion of patients with at least 
1 positively adjudicated AP episode during the 52 weeks of the DBTP.  
 
Secondary Efficacy: 
 
 
 
 
 
 
 
 
 
 
Safety Endpoints: 
 
 
 
Other Endpoints: 
 
Key Secondary Efficacy: 
• 
Percent change in ApoC3 from baseline to week 52 
• 
Percent change in fasting TGs from baseline to week 52  
Other Secondary Efficacy: 
• 
Percent change in other fasting standard lipid profile parameters 
(total cholesterol [TC], non-high-density lipoprotein cholesterol 
[non-HDL-C]) from baseline to week 52 
• 
Percent change in other fasting specialty lipoprotein parameters 
(ApoB48, ApoB100 levels, and NMR-determined particle size and 
number) from baseline to week 52 
• 
Number of independently adjudicated episodes of AP per patient 
during 52 weeks of the DBTP  
• 
Incidence and severity of treatment-emergent adverse event 
(TEAEs), serious adverse events (SAEs), laboratory abnormalities, 
and other safety variables in patients treated with evinacumab 
throughout the study 
• 
Incidence of treatment-emergent ADA and NAb  
• 
The percent change in fasting HDL-C and LDL-C from baseline to 
week 52  
• 
Concentrations of total evinacumab and total ANGPTL3 over time 
Procedures and Assessments 
Efficacy will be assessed by measurement of adjudicated events of AP, and 
measurement of lipids, specialty lipids, and lipoproteins. 
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Safety will be monitored via AE reporting, physical examinations, routine 
vital signs, clinical laboratory tests (blood chemistry and hematology), and 
standard 12-lead ECG. 
Serum samples for the determination of total evinacumab and total 
ANGPTL3 concentrations, and ADA and NAb will be collected. 
Serum and plasma samples will be collected for analysis of additional 
biomarkers. 
Statistical Plan 
The primary efficacy comparison will evaluate the evinacumab 20 mg/kg 
IV treatment group versus placebo, using the primary efficacy endpoint of 
the proportion of patients with at least 1 positively adjudicated AP event 
during the 52 weeks of DBTP (intent-to-treat [ITT] estimand-binary). The 
primary efficacy endpoint will be analyzed in the ITT population using the 
method of logistic regression, and the model will include at least treatment 
group, and number of historical AP episodes within the previous 24 months. 
The evinacumab group will be compared to the placebo group with odds 
ratio and 95% confidence interval (CI) provided for each treatment group. 
The statistical testing of the treatment group comparison for the primary 
measure will be evaluated at a 2-sided significance level of 0.049.  
For early termination (ET) patients who did not complete the week 52 
efficacy assessment, the missing primary endpoint will follow a data 
imputation strategy. 
For the key secondary efficacy endpoints and other secondary efficacy 
endpoints collected in the DBTP, descriptive summaries and analyses will 
be performed in the ITT population, using values obtained regardless of 
adherence to study treatment and subsequent therapies (ITT estimands). 
Safety results will be summarized descriptively by the treatment group. 
 
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1. 
INTRODUCTION  
Severely elevated levels of serum triglycerides (TGs) are associated with an increased risk for 
acute pancreatitis (AP). Episodes of AP secondary to severe hypertriglyceridemia (sHTG; 
TG >880 mg/dL [10 mmol/L]) frequently require hospitalization, and while most events can be 
treated with conservative therapy such as intravenous fluids and pain management, approximately 
20% of patients suffer severe attacks associated with prolonged hospitalization and significant 
morbidity and mortality. Further, a prior episode of sHTG-associated AP markedly increases the 
risk for recurrent AP. While current lipid guidelines recommend lifestyle interventions and 
medications to lower TG levels to prevent AP (Berglund, 2012)((Jacobson, 2015), patients with 
sHTG often require robust (>50%) reductions in TG to lower the risk of AP. Indeed, a substantial 
proportion of patients have persistent hypertriglyceridemia (HTG), despite the use of multiple 
medications to lower TG levels. Current available therapies for lowering TG levels (eg, statins, 
fibrates, niacin, omega-3 fatty acids) typically provide 20% to 50% reductions in TG levels, which 
is often insufficient to lower TGs to a target level of <500 mg/dL (5.6 mmol/L) ((Brisson, 2010).  
Patients with TGs >880 mg/dL (>10 mmol/L) typically have chylomicronemia that may be either 
multifactorial (polygenic and environmental) in origin, or much more rarely, due to the presence 
of highly penetrant gene mutations in lipoprotein lipase (LPL) ((Brown, 2012) (Minicocci, 2012) 
or genes encoding proteins in the LPL pathway (APOA5, APOC2, APOE, GPIHBP1, and LMF1), 
as observed in Familial Chylomicronemia Syndrome (FCS). Lipoprotein lipase is an 
endothelial-bound enzyme involved in the hydrolysis of the TG content of very-low-density 
lipoproteins (VLDL) and chylomicron lipoproteins. Mutations in the LPL gene lead to varying 
levels of loss of LPL functional activity and elevated levels of plasma TGs, especially in 
chylomicrons (Surendran, 2012). However, there is a high degree of genetic polymorphism and 
combinatorial effects of genes, diseases (such as type 2 diabetes), and environment. There is an 
unmet medical need for additional treatment options for patients with sHTG and a history of AP 
to further lower TG levels and the risk of recurrent attacks of AP, regardless of their genetic 
background. 
Angiopoietin-like 3 (ANGPTL3) acts as a natural inhibitor of LPL and has emerged as a target for 
the treatment of elevated levels of TG and low-density lipoprotein cholesterol (LDL-C). Loss of 
function of ANGPTL3 in humans has been associated with reductions in TG and LDL-C 
(Minicocci, 2013). 
Evinacumab (REGN1500) is a human IgG4 monoclonal antibody (mAb) specific for ANGPTL3. 
It 
is 
currently 
approved 
as 
an 
adjunctive 
treatment 
for 
homozygous 
familial 
hypercholesterolemia (HoFH, EvkeezaTM) and is being evaluated for treatment of dyslipidemia 
including HTG. Evinacumab has been studied in approximately 580 individuals with elevations in 
LDL-C and TG and has been generally well tolerated up to single doses of 20 mg/kg 
intravenously (IV) and in multiple subcutaneous (SC) doses up to 450 mg administered 
weekly (QW), and 20 mg/kg IV administered every 4 weeks (Q4W) for approximately 8 weeks 
(ie 2 doses).  
A phase 2, randomized, placebo-controlled study (R1500-HTG-1522) was conducted to evaluate 
the safety and TG-lowering effects of evinacumab in patients with various causes of sHTG, and at 
risk for AP, including homozygous/heterozygous loss of function (LoF) gene mutations in LPL, 
mutations in other genes in the LPL pathway, and other polygenic/environmental causes of 
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severely elevated TGs. The 12-week, double-blind treatment period (DBTP) enrolled 52 patients 
who were randomized to receive either evinacumab 15 mg/kg or matching placebo administered 
IV Q4W, followed by a 12-week, single-blind treatment period (SBTP) in which all patients 
(N=47) received evinacumab Q4W. 
The primary endpoint was predefined as the mean within-patient change in TGs, and the study did 
not meet the threshold of a clinically important reduction (>40%). This applied to the overall study 
population and also for genotypic strata based on the presence of LPL pathway LoF mutations. 
Several factors may have contributed to a lack of efficacy. There was large variability in TGs, 
which was compounded by the absence of a diet-stabilization period and efficacy determined by a 
single post-treatment TG measurement. In addition, there was variability in drug exposure, where 
patients with the lowest trough levels of evinacumab had little to no treatment response. In this 
context, when examining median percent changes to minimize the impact of outliers, the 
evinacumab-treated patients overall showed a clinically important reduction (>40%) in 
fasting TGs at each post-baseline visit, culminating in a median reduction of approximately 57% 
at week 12 during the DBTP. The treatment effect was even more pronounced when excluding 
patients with FCS, where non-FCS patients had a median reduction in TGs of approximately 80%. 
When including patients that switched to evinacumab during the SBTP, the median percent 
reduction in TGs after 12 weeks of evinacumab exposure was approximately 70% for non-FCS 
patients. 
In the DBTP, 5 patients (3 in the evinacumab group; 2 in the placebo group) experienced an 
episode of AP (all serious adverse events or SAEs); all resolved within 7 days. For the evinacumab-
treated patients, 1 participant had FCS and did not have a TG response to therapy; 1 patient had an 
episode of AP within 48 hours after receiving his first dose of evinacumab; 1 patient had 
persistently low trough concentrations of evinacumab. Treatment-emergent adverse events 
(TEAEs) that occurred more frequently in the evinacumab group compared to the placebo group 
included Abdominal pain (14.3% versus 12.5%), Headache (11.4% versus 6.3%), and Constipation 
(8.6% versus 0). In the SBTP, 12 (25.5%) patients had SAEs of Acute pancreatitis; none was 
considered related to the study drug. The majority of episodes occurred during the off-drug period 
(>4 weeks after the last dose of evinacumab) and episodes of AP were not independently 
adjudicated, with some patients diagnosed with AP despite the absence of pathologic findings on 
pancreatic imaging and/or elevated lipase/amylase levels. 
The current study is a phase 2b randomized, placebo-controlled study intended to demonstrate that 
evinacumab can prevent recurrent episodes of HTG-associated AP in patients with sHTG, but 
without FCS due to mutations in LPL. The secondary aims are to evaluate the effects of 
evinacumab on safety and changes in biomarkers of TG-rich lipoprotein metabolism, including 
serum TG, ApoC3, ApoB48, and ApoB100 in this patient population. 
Additional background information on the study drug and development program can be found in 
the Investigator’s Brochure. 
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2. 
STUDY OBJECTIVES  
2.1. 
Primary Objective 
The primary objective of the study is to determine the proportion of patients with elevated TGs, 
without FCS due to LoF mutations in LPL, and a history of HTG-associated AP* who experience 
a recurrent episode of AP after treatment with evinacumab versus placebo. 
*Includes adult patients with 1) elevated baseline fasting TGs >880 mg/dL and history of 
1 HTG-associated AP within 24 months of screening or 2) elevated baseline fasting TG 
values >500 mg/dL in patients with a history of 2 or more HTG-associated AP within 24 months 
or 3) elevated baseline fasting TG values >500 mg/dL with a prior documented fasted TG values 
>1000 mg/dL and a history of 1 or more HTG-associated AP within 24 months.  All participants 
are without FCS due to LPL loss of function mutations.   
2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To determine the change in the standard lipid profile after therapy with evinacumab 
versus placebo  
• To determine the changes in specialty lipoprotein parameters (ApoC3, ApoB48, 
ApoB100, and nuclear magnetic resonance [NMR] lipid profile) after therapy with 
evinacumab versus placebo 
• To measure the number of AP episodes per patient 
• To assess the safety and tolerability of evinacumab 
• To assess the potential immunogenicity of evinacumab  
• To assess the concentrations of total evinacumab and total ANGPTL3  
2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
• To evaluate responder categories of fasting TG levels 
• To measure length of stay for patients hospitalized for AP 
• To assess the effect of evinacumab versus placebo on the frequency and severity of 
abdominal pain  
• To study evinacumab’s mechanism of action in modulating lipoprotein metabolism in 
HTG, and related diseases 
• To explore genotypic or other biomarker differences that may influence efficacy and 
safety of evinacumab for further understanding of HTG, or other conditions 
associated with ANGPTL3 antagonism (for patients who consent to participate in a 
genomics sub-study) 
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3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypotheses 
Primary: 
Evinacumab reduces recurrent episodes of AP in patients with sHTG but without FCS due to LoF 
mutations in LPL, and a history of HTG-associated AP. 
Key Secondary: 
In patients with sHTG and a history of HTG-associated AP, evinacumab reduces serum TGs and 
serum ApoC3. 
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
This is a phase 2b, multicenter, double-blind, randomized, placebo-controlled study to evaluate 
the efficacy and safety of repeated doses of IV evinacumab for the treatment of patients with a 
recent history of HTG-associated AP with sHTG. The primary aim of the study is to evaluate the 
efficacy of evinacumab in reducing attacks of recurrent AP in patients with sHTG. 
Markedly elevated blood levels of TGs are associated with the development of AP. Current 
therapies for lowering TG levels (eg, weight reduction, lifestyle changes, statins, fibrates, fish oils, 
niacin) have limited efficacy and none of these therapies have had appropriate studies to evaluate 
a role in reducing the risk of recurrent AP.   
Studies have demonstrated that patients with genetic LoF mutations that decrease the activity of 
LPL have severe elevations in TGs. Given that ANGPTL3 acts as a natural inhibitor of LPL, 
blockade of ANGPTL3 and preventing LPL inhibition is a rational target for the treatment of 
elevated levels of TGs. This effect was clearly shown in study R1500-HTG-1522, a phase 2 study 
of evinacumab in patients with HTG. In that study, patients with TG levels ≥500 mg/dL and 
without LoF mutations in LPL experienced an approximately 80% median reduction in blood 
levels of TGs in the DBTP. The study was not designed to determine an impact on risk of recurrent 
AP. 
An unmet need exists for additional, more effective methods of treating markedly elevated 
TG levels. Significant reductions in TGs may benefit patients with severe elevations in TGs at risk 
for pancreatitis. This is particularly true for secondary prevention of AP because these patients 
have a markedly higher risk of HTG-associated AP compared to the primary prevention 
population. 
Patient Population 
The study population consists of patients with severe HTG with a history of AP within 24 months 
of screening. Patients must fulfill 1 of the following TG and AP criteria:  1) elevated baseline 
fasting TG values >880 mg/dL and history of 1 HTG-associated AP within 24 months of screening 
or 2) elevated baseline fasting TG values >500 mg/dL in patients with a history of 2 or more 
HTG-associated AP within 24 months or 3) elevated baseline fasting TG values >500 mg/dL with 
a prior documented fasted TG value >1000 mg/dL and a history of 1 or more HTG-associated AP 
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within 24 months.  All participants are without FCS due to LPL loss of function mutations.  These 
patients have a very high unmet need for TG lowering. While there are medications such as statins, 
fibrates, niacin, and fish oils that can reduce TG, these treatments are often unable to achieve the 
large reductions (>50%) in TGs required to prevent hypertriglyceridemic AP for these patients. 
Based on real-world patient medical records of approximately 6.7 million patients, it is estimated 
that there are approximately 6,300 adult patients in the US that match the study population (data 
on file).  
A similar patient population was studied in study R1500-HTG-1522, where patients were analyzed 
in 3 cohorts based on the presence of LoF mutations in genes in the LPL pathway, as determined 
by the Regeneron Genetics Center: 
• Cohort 1: Homozygous or compound heterozygous mutations  
• Cohort 2: Heterozygous mutations 
• Cohort 3: No mutations in LPL pathway genes 
During the DBTP, cohorts 2 and 3 both demonstrated an approximately 80% reduction in 
TG levels. Cohort 1 (ie, patients with FCS) did not show a clinically significant reduction in 
TG levels compared to placebo. For the current study, patients with FCS due to LoF mutations in 
LPL will be excluded. Study R1500-HTG-1522 was neither designed nor powered to draw a 
conclusion on the effect of evinacumab on the risk of recurrent AP, though there were numerically 
fewer AP events in patients while receiving evinacumab compared to the period when not 
receiving evinacumab.  
Endpoints 
The primary endpoint will be the first occurrence of an episode of AP. The study will have an 
independent committee to adjudicate these episodes guided by clinical standards for diagnosis of 
AP: acute onset of persistent, severe, epigastric pain; elevations in serum lipase or amylase 
significantly above the upper limit of normal (ULN); characteristic findings of AP on imaging 
(contrast-enhanced computed tomography [CT], magnetic resonance imaging [MRI], or 
transabdominal ultrasonography). 
Study Duration 
This study will have a 52-week DBTP consisting of therapy with evinacumab or placebo, followed 
by an off-drug follow-up period of 20 weeks duration. 
Combination of Drugs 
Patients will not be required to have any specific background lipid-lowering therapy. However, 
patients will be required to have a stable lipid-lowering treatment regimen prior to screening and 
will be required to maintain their TG-lowering background therapy throughout the study. 
It is expected that the TG-lowering effect size and variance will be similar between cohorts 2 and 3 
of study R1500-HTG-1522 and the current study. Additional biomarkers of TG-rich lipoprotein 
metabolism, such as levels of ApoC3, will also be measured and are expected to show clinically 
significant declines, similar to the R1500-HTG-1522 study. 
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3.2.2. 
Rationale for Dose Selection  
An IV dose of 20 mg/kg was selected to test the efficacy and safety of evinacumab under Q4W 
administration in this study. In study R1500-HTG-1522, a 15 mg/kg IV Q4W regimen achieved 
mean steady-state concentrations of 162 mg/L in patients with severe sHTG at risk for AP. This 
was approximately 30% lower than steady-state concentrations under the same evinacumab dosing 
regimen in phase 2 and phase 3 studies of patients with familial hypercholesterolemia (FH), and 
suggested greater target-mediated clearance in the sHTG population versus the FH population.   
Empirical analysis of concentration of total evinacumab in serum versus response in patients in 
study R1500-HTG-1522 (in cohorts where TG levels showed statistically significant reductions 
from baseline) suggested that patients with exposures in the highest quartiles of concentration of 
total evinacumab saw the greatest reductions from baseline in TG response, while those in the 
lowest concentration quartile saw comparatively smaller reductions, on average. This suggests that 
in patients with severely high baseline TG levels in the current study, a regimen that induces higher 
exposures would be expected to benefit more patients, thereby justifying the need for a larger dose 
than the one given in the previous study (15 mg/kg IV Q4W). 
To simulate exposures in support of this goal, a population pharmacokinetics (PopPK) model for 
evinacumab was updated to describe the pharmacokinetics (PK) in the sHTG population. 
Simulations of a 20 mg/kg IV Q4W regimen using the updated PopPK model yielded mean steady-
state trough concentrations of 264 mg/L after 6 administered doses, exceeding the mean 
concentration (250 mg/L) associated with maximal TG lowering in study R1500-HTG-1522. 
These anticipated trough concentrations are comparable to steady state trough concentrations 
achieved in prior phase 2 and 3 studies of evinacumab in HoFH; in all prior studies, evinacumab 
had an acceptable safety profile and was well tolerated at these concentrations.  
3.3. 
Risk-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, the 
sponsor plans to obtain approvals from health authorities/Ethics Committees (ECs) to enable 
initiation of study sites for this study, as allowed by local laws and regulations. 
3.3.1. 
Risks-Benefits for Evinacumab 
Evinacumab has been evaluated in 6 completed clinical studies and 3 ongoing clinical studies and 
has been generally well tolerated. In placebo-controlled studies, infusion reactions have been 
reported more frequently in patients treated with evinacumab than in patients treated with placebo. 
In most cases, such reactions were nonserious and did not lead to interruption of the evinacumab 
infusion. A serious case of moderate Anaphylaxis in a patient treated with evinacumab 
15 mg/kg IV Q4W, which led to discontinuation of evinacumab treatment, has been reported. As 
such, systemic hypersensitivity reactions, including anaphylaxis and infusion reactions, are 
considered an important identified risk associated with evinacumab administered IV.  
Other potential risks with evinacumab (based on preclinical evaluation or risks associated with 
mAbs in general) include immunogenicity and embryofetal toxicity. Anti-drug antibody (ADA) 
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samples collected during evinacumab clinical studies are analyzed to determine any effects on 
efficacy or safety. To date, no subject or patient treated with evinacumab tested positive for ADA. 
Embryofetal toxicity is a potential risk with evinacumab based on animal studies, and therefore, 
pregnant or breastfeeding women should not be treated with evinacumab. 
Elevated blood levels of TGs have been associated with the development of AP. Current therapies 
for lowering TGs (weight reduction, lifestyle changes, fibrates, omega-3 fatty acids) have limited 
efficacy and/or tolerability issues and have not been shown to reduce the risk of recurrent AP. 
Thus, a significant unmet need exists for additional and improved methods for treating elevated 
TG levels. A therapeutic targeted to ANGPTL3 and disinhibiting LPL could provide beneficial 
changes in TG-rich lipoprotein metabolism and would benefit patients with severe elevations in 
TGs who are at risk for recurrent pancreatitis. 
A detailed risk-benefit statement with respect to the overall development program is provided in 
Section 7 of the Investigator’s Brochure. 
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4. 
ENDPOINTS  
4.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of patients with at least 1 positively adjudicated 
AP episode during the 52 weeks of the DBTP (intent-to-treat [ITT] estimand - binary).  
The ITT estimand – binary used for the primary efficacy analysis is defined as the treatment policy 
strategy, specifically the occurrence of intercurrent events (ie adherence to study treatment and 
subsequent therapies) is irrelevant; the value for the primary efficacy endpoint is used regardless 
of whether or not intercurrent events occur (Section 11.4.3.1). 
Note: AP is defined in Section 5.2.1. 
4.2. 
Secondary Efficacy Endpoints 
4.2.1. 
Key Secondary Efficacy Endpoints 
The key secondary efficacy endpoints are: 
• Percent change in ApoC3 from baseline to week 52 (ITT estimand - normal)  
• Percent change in fasting TGs from baseline to week 52 (ITT estimand – non-normal) 
The fasting TG and ApoC3 assessment at week 52 will be the respective measurement obtained 
within the week-52 analysis window. Scheduled and unscheduled measurements may be used to 
provide a value for the key secondary efficacy endpoints. The analysis window used to allocate a 
time point to a measurement will be defined in the statistical analysis plan (SAP). The baseline 
value is defined as the last available value before the first dose of double-blind study treatment.  
The ITT estimand used for the key secondary efficacy analyses is the treatment policy strategy, 
specifically the occurrence of the intercurrent events (ie adherence to study treatment and 
subsequent therapies) is irrelevant; the value for the key secondary endpoints is used regardless of 
whether or not the intercurrent events occur (Section 11.4.3.2).  
4.2.2. 
Other Secondary Efficacy Endpoints 
Other secondary efficacy endpoints are: 
• Percent change in other fasting standard lipid profile parameters (total cholesterol or 
TC, non-HDL-C) from baseline to week 52 (ITT estimand - normal)  
• Percent change in other fasting specialty lipoprotein parameters (ApoB48, ApoB100 
levels and NMR-determined particle size and number) from baseline to week 52 
(ITT estimand - normal)  
• Number of independently adjudicated episodes of AP per patient during 52 weeks of 
the DBTP (ITT estimand - normal)  
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4.3. 
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints are: 
• Proportion of patient responders during 52 weeks of therapy with evinacumab versus 
placebo, with response defined as reaching common clinical TG thresholds of 
≤880 mg/dL, ≤500 mg/dL, ≤150 mg/dL  
• Length of stay for AP hospitalizations during 52 weeks of therapy with evinacumab 
versus placebo  
• Proportion of abdominal pain-free intervals during 52 weeks of therapy with 
evinacumab versus placebo, measured via a single-item questionnaire 
• Mean change in abdominal pain scores on the Hypertriglyceridemia and Acute 
Pancreatitis: Pain Questionnaire (HAP-Pain) during 52 weeks of therapy with 
evinacumab versus placebo 
4.4. 
Safety Endpoints 
Other secondary endpoints include safety endpoints: 
• Incidence and severity of TEAEs, SAEs, laboratory abnormalities, and other safety 
variables in patients treated with evinacumab throughout the study 
• Incidence of treatment-emergent ADA and neutralizing antibodies (NAb)  
4.5. 
Other Endpoints 
• The percent change in fasting HDL-C and LDL-C from baseline to week 52  
• Concentrations of total evinacumab and total ANGPTL3 over time  
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5. 
STUDY VARIABLES  
5.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height, BMI, 
etc), disease characteristics, medical history including detailed cardiovascular and pancreatitis 
history, and medication history. 
5.2. 
Efficacy Variables 
5.2.1. 
Acute Pancreatitis Episodes 
The primary efficacy variable is the occurrence of an episode of AP as determined by an 
independent acute pancreatitis adjudication committee (APAC). Suspected AP events will be 
reviewed by 2 independent physicians (phase 1). In the event of disagreement between these 
2 initial reviewers, the case will be reviewed by at least 3 physicians meeting as a committee 
(phase 2). The final adjudicated result will be either the initial independently agreed-upon result 
from phase 1, or the majority decision from phase 2. Every effort will be made to maintain the 
same group of physician reviewers for adjudication. 
Acute pancreatitis adjudication committee members will be blinded to TG values to avoid 
treatment unblinding. 
The diagnosis of AP is based on meeting either clinical or imaging criteria, or both:  
1) Clinical symptoms and signs 
a. Acute onset abdominal pain, or nausea or vomiting  
AND 
b. Biochemical evidence of pancreatic inflammation 
i. Serum amylase or lipase >3x ULN for individuals without a medical history 
of chronic pancreatitis; OR 
ii. Serum amylase or lipase >2x ULN for individuals with a medical history of 
chronic pancreatitis 
2) Pancreatic inflammation assessed by imaging 
a. Characteristic findings of AP on imaging (contrast-enhanced CT, MRI, or 
transabdominal ultrasonography. These findings include but are not limited to: 
pancreatic enlargement, necrosis, edema, peripancreatic stranding, and 
peripancreatic fluid collections.  
Additional details will be provided in the APAC charter. 
5.2.2. 
Laboratory Variables for the Assessment of Efficacy 
Efficacy in this study includes the following lipid parameters: 
• Fasting TG levels 
• Non-HDL-C levels  
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• TC levels 
• ApoC3, ApoB48, ApoB100, NMR-determined particle size and number (biomarkers 
of TG-rich lipoprotein metabolism)  
These laboratory variables are relevant to the characterization and disease mechanisms of patients 
with HTG. 
5.2.3. 
Clinical Outcome Assessments 
The following clinical outcome assessment (COA) will be completed by the patient: 
• A single-item assessment on presence of abdominal pain 
• The HAP-Pain Questionnaire 
5.3. 
Safety Variables 
The safety variables in this study include: 
• TEAEs 
• Vital signs  
• Physical examination 
• Electrocardiogram (ECG) 
• Routine safety laboratory tests (hematology, chemistry, urinalysis, and pregnancy 
testing [for women of childbearing potential or WOCBP]) 
• Concomitant medications and treatments 
5.4. 
Pharmacokinetic Variables 
The pharmacokinetic variables consist of the concentrations of total evinacumab and 
total ANGPTL3 in serum at each time point (both pre-dose and end-of-infusion samples). These 
sampling time points are specified in Table 1. 
5.5. 
Immunogenicity Variables 
The immunogenicity variables are ADA status, titer, NAb status, and time point/visit. Samples in 
this study will be collected at the clinic visits specified in Table 1 and Table 2.  
5.6. 
Pharmacodynamic and Other Biomarker Variables 
The pharmacodynamic (PD) variables in this study are high-density lipoprotein cholesterol 
(HDL-C) and LDL-C.  
ApoC3, ApoB48, ApoB100, and NMR-determined particle size and number are biomarkers of 
TG-rich lipoprotein metabolism and are also efficacy variables in this study. 
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6. 
STUDY DESIGN  
6.1. 
Study Description and Duration 
This is a phase 2b, multicenter, international, randomized, placebo-controlled study intended to 
demonstrate that evinacumab can prevent recurrent AP in patients with HTG and a recent history 
of HTG-associated AP.  
Approximately 120 adult patients will be randomized 1:1 to receive evinacumab or matching 
placebo. A study schematic is provided in Figure 1. 
The study consists of 3 periods: a screening period, a DBTP, and a safety follow-up period. The 
screening period of up to 28 days will determine participant eligibility and will include an 
evaluation of prior episodes of HTG-associated AP, genotyping to exclude patients with FCS due 
to LoF mutations in LPL, and a measurement of fasting TG level. Patients must have baseline 
fasting TGs >880 mg/dL and a history of HTG-associated AP within 24 months of screening or 
they must have baseline fasting TGs >500 mg/dL if they have had 2 or more episodes of 
HTG-associated AP within 24 months of screening or if they have had baseline fasting TG values 
>500 mg/dL and documented fasting TG values >1000 mg/dL with a history of HTG-associated 
AP within 24 months of screening to be enrolled in the study. 
Patients who fulfill all the eligibility criteria will be randomized and receive their first dose of 
assigned study drug on day 1, with subsequent doses administered approximately Q4W during the 
52-week DBTP. This will be followed by an off-drug follow-up period of 20 weeks.  
Every effort will be made to keep patients in the study and to collect the week 52 visit data, even 
if study drug administration has been discontinued for the patient. 
Efficacy will be assessed by measuring the number of patients with at least 1 independently 
adjudicated positive event of AP over 52 weeks of treatment with evinacumab versus placebo. The 
study will have an independent committee to adjudicate these episodes in accordance with clinical 
standards for diagnosis of AP (see Section 5.2.1). Efficacy will also be assessed by clinical 
laboratory evaluation of lipid levels at pre-specified time points throughout the study. 
Safety will be assessed throughout the study by comparing the frequency and severity of adverse 
events (AEs) between the evinacumab and placebo groups, as well as evaluating abnormal 
laboratory findings, ECG findings, and ADA and NAb assessments. 
Figure 1: 
Study Flow Diagram   
 
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Screening (Day -28 to -1) 
The screening period may last up to 28 days and consists of 1 visit. During the screening period, 
all patients will undergo the informed consent process and standard screening procedures. 
Laboratory assessments used to determine eligibility may be repeated once during the screening 
period. The fasting TG measurement can be repeated once for values >500 mg/dL but <880 mg/dL.  
A mandatory sample for DNA isolation will be obtained for patients who do not have 
documentation of prior genetic testing in order to confirm the absence of FCS due to homozygous 
or compound heterozygous LoF mutations in LPL. For these patients, the results of the screening 
FCS genotyping confirming no homozygous or compound heterozygous LoF mutations in LPL 
must be available before the patient can be enrolled in the study.   
Patients who have screen-failed are not eligible for rescreening, unless rescreening is discussed 
and agreed with the medical monitor.  
After confirmation of eligibility, patients will proceed to visit 2 for randomization.  
Double-Blind Treatment Period (Day 1 to Day 365) 
Principal investigators, study site personnel, study patients, and the Regeneron study team will all 
be blinded to treatment during the DBTP. 
Randomized patients will receive either evinacumab administered IV at a dose of 20 mg/kg IV or 
matching placebo Q4W (±4 days) during the DBTP. On dosing days, all assessments and lab 
samples (including urine or serum pregnancy tests for WOCBP) should be performed before the 
dose of study drug is administered. All samples should be collected following at least an 8-hour 
fast. Medications are permitted to be taken with water as medically indicated. Electrocardiograms 
should be performed before blood is drawn. Additionally, vital signs should be measured, and AEs 
monitored pre-dose, at the end of study drug infusion, and at 30 minutes and 60 minutes post-end 
of infusion. Patients will be closely monitored for a minimum of 60 minutes after IV administration 
of evinacumab or matching placebo.   
Efficacy and safety procedures, including a standard lipid panel, dietary and alcohol use review, 
and the completion of a pain questionnaire will be performed as outlined in the Schedule of Events 
(Table 1).  
Serum samples for the determination of total evinacumab and total ANGPTL3 should be collected 
prior to AND at the end of infusion of study drug (within 30 minutes from the end of infusion).  
Serum and plasma samples will be collected for analysis of additional biomarkers, including 
specialty lipid measurements, and will also be collected for measurement of ADA and NAb. 
Off-Drug Treatment Follow-up Period (Day 366 to Day 700 [End of Study]) 
Patients will be monitored for 20 weeks after the last dose of study drug with 2 in-clinic visits. 
Efficacy and safety procedures will be performed as outlined in the Schedule of Events. 
Throughout the Study 
Patients will adhere to their diet, and submit to a dietary review and an alcohol intake review at 
each visit. Patients will be reminded to maintain a stable diet and refrain from drinking more than 
1 serving per day of an alcoholic beverage.  
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Patients will also be reminded at visits and during phone calls to adhere to a highly effective birth 
control method. Pregnancy status of female patients of childbearing potential will be monitored 
throughout the study and for 20 weeks post the last dose of study drug. 
COVID-19 
Recognizing that the “Coronavirus Disease 2019” (COVID-19) pandemic will have an impact on 
the conduct of clinical trials, the sponsor does not intend to screen any patients in this study until 
the impact of the COVID-19 pandemic is deemed manageable and no longer interfering with the 
conduct of trials at individual sites, and patients can safely participate in this study. Until then, the 
sponsor plans to obtain approvals from health authorities/ECs to enable initiation of study sites for 
this study, as allowed by local laws and regulations. 
In light of the public health emergency related to COVID-19, the continuity of clinical study 
conduct 
and 
oversight 
may 
require 
implementation 
of 
temporary 
or 
alternative 
mechanisms. Examples of such mechanisms may include, but are not limited to, any of the 
following:  phone contact, virtual visits, telemedicine visits, online meetings, non-invasive remote 
monitoring devices, use of local clinic or laboratory locations, and home visits by skilled 
staff. Additionally, no waivers to deviate from protocol enrollment criteria due to COVID-19 will 
be granted. All temporary mechanisms utilized, and deviations from planned study procedures, are 
to be documented as being related to COVID-19 and will remain in effect only for the duration of 
the public health emergency. 
6.1.1. 
End of Study Definition 
The end of study is defined as the date the last study participant completes the last study visit, 
withdraws from the study, or is lost to follow-up (ie, the participant can no longer be contacted by 
the investigator).   
6.2. 
Planned Interim Analysis  
An interim analysis is planned when approximately 50% (N=60) of patients have completed the 
DBTP. This will consist of the final data contributing to the analysis of the applicable variables up 
to the week-52 visit for these patients. The efficacy analyses will be performed up to the week-52 
visit for these patients and will be descriptive in nature. The safety analysis will be performed for 
these patients on all safety data collected and validated at the time of the interim analysis. A small 
alpha adjustment of 0.001 has been made to account for this treatment-unblinded interim, since 
the sponsor does not plan to stop the study early for evinacumab treatment benefit. Therefore, the 
significance level for the final efficacy analysis will be 0.049.  
The purpose of this interim analysis is administrative, specifically to aid in planning of future 
studies. The interim statistical analysis will be performed external to Regeneron with the intent to 
reduce data bias in the patients ongoing in the DBTP at the time of the interim. Interim analysis 
summary results will be provided to Regeneron senior management only. The interim analysis 
process, the measures used to protect the blind and the integrity of the study, the communication 
plan, and the confidentiality agreement will be described in a separate document. 
A description of the statistical methods to be employed is in Section 11.5.1, and blinding 
implications are discussed in Section 8.6. 
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6.3. 
Study Committees  
The Independent Data Monitoring Committee (IDMC) for the evinacumab program will be 
utilized. In addition, a separate independent committee (APAC) consisting of clinical specialists 
will be formed for adjudicating cases of AP to ensure a clinically accepted and consistent diagnosis 
for this primary endpoint. Every effort will be made to maintain the same group of physician 
reviewers for adjudication. 
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7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
7.1. 
Number of Patients Planned 
Approximately 120 patients (randomized 1:1, evinacumab: placebo).  
7.2. 
Study Population  
7.2.1. 
Inclusion Criteria  
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Adults 18 to 80 years of age without FCS due to LPL loss of function mutations 
2. Documented history of 1 HTG-associated AP episode within 24 months of screening (can 
be determined by study investigator; does not need to be confirmed by independent 
adjudication committee) and.  
3. Fasting serum TG value >880 mg/dL (10 mmol/L) determined during the screening period. 
Triglyceride measurement can be repeated once for values >500 mg/dL (5.6 mmol/L) but 
<880 mg/dL (10 mmol/L)  
OR 
Fasting serum TG value >500 mg/dL (5.6 mmol/L) determined during the screening period 
in patients with a history of 2 or more HTG-associated AP episodes within 24 months of 
screening 
OR 
Fasting serum TG value >500 mg/dL (5.6 mmol/L) determined during the screening period 
and a documented fasted serum TG value >1000 mg/dL (11.3 mmol/L) and a history of 1 
or more HTG-associated AP episode(s) within 24 months of screening. 
4. Stable dose of lipid-lowering therapy (≥8 weeks) and willingness to maintain a stable 
regimen throughout the study  
5. Body mass index ≥18.0 and ≤45.0 kg/m2 
6. Compliance with a stable diet and exercise regimen at screening and willingness to 
continue the diet through the end of the study 
7. Willing and able to comply with clinic visits and study-related procedures 
8. Provide informed consent signed by study patient or legally acceptable representative 
9. Able to understand and complete study-related questionnaires 
7.2.2. 
Exclusion Criteria  
A patient who meets any of the following criteria will be excluded from the study: 
1. Hospitalization for AP within 4 weeks of screening 
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2. Known genetic FCS defined as homozygous or compound heterozygous LoF mutations in 
LPL, as documented by prior genotype result or determined from FCS genotyping at 
screening (see Section 9.2.7).  
3. Symptomatic gallstone disease within 6 months prior to screening. Incidental and/or 
asymptomatic gallstones are permitted. Patients with symptomatic gallstone disease in the 
past 6 months who have undergone cholecystectomy >3 months prior to screening are 
permitted. 
4. Use of any medication or nutraceutical known to alter serum lipids which has not been part 
of a stable therapeutic regimen for at least 8 weeks, and there are no plans to change the 
regimen during the study 
5. Presence of any clinically significant, uncontrolled endocrine disease known to influence 
serum lipids, including but not limited to: 
a. Newly diagnosed (within 3 months) diabetes by medical history, including screening 
value glycosylated hemoglobin (HbA1c) >6.5% without a prior history of diabetes 
b. Diabetes with HbA1c >10.0% 
c. Thyroid disease with thyroid-stimulating hormone (TSH) <lower limit of normal 
(LLN) or >1.5x ULN 
d. Thyroid replacement therapy that has not been stable for at least 12 weeks 
 
Note: For laboratory values, 1 repeat measurement is allowed. Other laboratory values that 
meet the inclusion/exclusion criteria do not need to be repeated. 
6. Use of estrogen or testosterone therapy unless the regimen has been stable in the past 
6 weeks and there are no plans to change the regimen during the study 
7. Any clinically significant abnormality identified at the time of screening that, in the 
judgment of the investigator or any sub-investigator, would preclude safe completion of 
the study or constrain endpoints assessment; eg, major systemic diseases, patients with 
short life expectancy, or considered by the investigator or any sub-investigator as 
inappropriate for this study for any reason, including but not limited to: 
a. Deemed unable to meet specific protocol requirements, such as scheduled visits 
b. Deemed unable to tolerate injections, as per the patient or the investigator 
c. Part of a vulnerable population such as the institutionalized 
d. Presence of any other conditions (eg, geographic or social), either actual or anticipated, 
that the investigator feels would restrict or limit the patient’s participation for the 
duration of the study 
8. Laboratory findings (for the reason that patients with these findings, who have a higher 
likelihood of liver, muscle, or kidney adverse events regardless of treatment assignment, 
are expected to be rare, they may not be evenly distributed across treatment groups and 
thus may confound the analysis of safety): 
a. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 according to 
4-variable Modification of Diet in Renal Disease study equation (MDRD, calculated 
by central laboratory) 
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Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3x ULN at 
screening  
b. Creatine phosphokinase (CPK) >3x ULN at screening  
 
Note: For all laboratory values, 1 repeat measurement is allowed. 
9. Systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg at the 
screening visit or time of randomization (1 repeat allowed). The uneven distribution of 
these patients across treatment groups could confound the analysis of safety. 
10. History of heart failure (New York Heart Association [NYHA] Class III-IV) within 
12 months before screening. The uneven distribution of these patients across treatment 
groups could confound the analysis of safety. 
11. Within 3 months of screening, a history of myocardial infarction (MI), unstable angina 
leading to hospitalization, coronary artery bypass grafting (CABG) surgery, percutaneous 
coronary interventions (PCI), uncontrolled cardiac arrhythmia, carotid surgery or stenting, 
stroke, transient ischemic attack (TIA), carotid revascularization, endovascular procedure, 
or surgical intervention for peripheral vascular disease. The uneven distribution of these 
patients across treatment groups could confound the analysis of safety. 
12. Significant concomitant illness including, but not limited to: cardiac, renal, neurological, 
endocrinological, hepatic, metabolic, or lymphatic disease, that would adversely affect the 
patient’s participation in the study 
13. 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 
14. Participation in a clinical research study evaluating an investigational drug within 30 days 
or at least 5 half-lives of the investigational drug, before screening, whichever is longer 
15. History or evidence of drug or alcohol abuse within 24 months before screening. 
Additionally, patients who do not agree to limit alcohol intake to no more than 1 drink per 
day will be excluded.  
16. Documented* positive polymerase chain reaction (PCR) or equivalent test based on 
regional recommendations for COVID-19 or suspected SARS-CoV-2 infection, and:  
a. Has not recovered from COVID-19 (ie, all COVID-19-related symptoms and major 
clinical findings which can potentially affect the safety of the patient have not been 
resolved), and  
b. Did not have 2 negative results from nucleic acid amplification (PCR) test or equivalent 
test based on regional recommendations for COVID-19 (at least 48 hours apart) to 
confirm that the patient is negative for SARS-CoV-2 or, if COVID-19 PCR (or 
equivalent) testing is not feasible, at least 3 months have transpired since the initial 
diagnosis 
* Note: Screening for COVID-19 will not be performed as part of eligibility assessments 
for this study. 
17. Members of the clinical site study team and/or his/her immediate family, unless prior 
approval granted by the sponsor. 
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18. Pregnant or breastfeeding women. 
19. 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. 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 (provided that the male vasectomized partner is the sole sexual 
partner of the WOCBP study participant and that the vasectomized partner has obtained 
medical assessment of surgical success for the procedure); and/or 
e. Sexual abstinence†, ‡ 
 
*WOCBP are defined as women who are fertile following menarche until becoming 
postmenopausal, unless permanently sterile. Permanent sterilization methods include 
hysterectomy, 
bilateral 
salpingectomy, 
and 
bilateral 
oophorectomy. 
 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy. However, in the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient to determine the occurrence 
of a postmenopausal state. The above definitions are according to the Clinical Trial 
Facilitation Group (CTFG) guidance. Pregnancy testing and contraception are not 
required 
for 
women 
with 
documented 
hysterectomy 
or 
tubal 
ligation. 
 
†Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
drugs. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient. 
 
‡Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are 
not acceptable methods of contraception. Female condom and male condom should not 
be used together. 
20. Patients with a history of serious hypersensitivity reactions to evinacumab or to any of the 
excipients. 
21. Has received a COVID-19 vaccination (initial series or booster) within 1-week of planned 
start of study medication or for which the planned COVID-19 vaccinations would not be 
completed 1-week prior to start of the study. 
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7.3. 
Premature Withdrawal from the Study  
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and/or sponsor have the right to withdraw a patient from the study if it is no longer 
in the interest of the patient to continue in the study, or if the patient’s continuation in the study 
places the scientific outcome of the study at risk (eg, if a patient does not or cannot follow study 
procedures). An excessive rate of withdrawals would render the study uninterpretable; therefore, 
unnecessary withdrawal of patients should be avoided. 
Patients who are withdrawn prematurely from the study will be asked to complete the early 
termination visit, as described in Section 9.1.2. 
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 8.3.2. 
7.4. 
Replacement of Patients 
Patients prematurely discontinued from study drug will not be replaced. 
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8. 
STUDY TREATMENTS  
8.1. 
Investigational and Reference Treatments 
Evinacumab or placebo will be supplied for IV administration. The 2 study treatment groups are: 
• Evinacumab 20 mg/kg administered IV over a 1-hour infusion Q4W (±4 days)  
• Matching placebo administered IV Q4W (±4 days)  
Instructions on management of infusion reactions are provided in Section 8.4.  
Instructions on dose preparation are provided in the pharmacy manual. 
8.2. 
Background Treatment(s) 
Prior to screening, all patients should be on a stable, lipid-lowering therapeutic regimen, which 
may include a statin, fibrate, niacin, or fish oils. Participants will be expected to continue their 
therapeutic regimen throughout the DBTP. There is no mandatory background therapy required 
for participation. 
8.3. 
Dose Modification and Study Treatment Discontinuation Rules 
8.3.1. 
Dose Modification 
Dose modification for an individual patient is not allowed. 
8.3.2. 
Study Drug Discontinuation 
Patients who permanently discontinue from study drug should be encouraged to remain in the 
study. Those who agree and do not withdraw from the study will be asked to return to the clinic 
for all remaining study visits and assessments per the visit schedule, especially the week 52 visit, 
including the off-drug follow-up visits (Table 1 and Table 2). 
Patients who permanently discontinue from study drug and who opt to withdraw from the study 
(ie, are unable or unwilling to attend the study visits as described above ) will be asked to complete 
study assessments at an early termination (ET) visit, per Section 9.1.2. These patients will then 
enter the off-drug treatment follow-up period, and should be followed for at least 20 weeks from 
the last dose of study drug or up to recovery or stabilization of any AE to be followed-up as 
specified in this protocol, whichever comes last. The off-drug follow-up period will include 2 in-
clinic visits with assessments as specified under visit 16 and visit 17 (Table 2). 
8.3.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
Study drug dosing will be permanently stopped in the event of: 
• Evidence of pregnancy 
• Severe, acute infusion reactions related to study treatment including, but not limited 
to, anaphylaxis 
• Specific types of liver dysfunction (eg, Hy’s law is met ([Guidance for Industry Drug 
Induced Liver Injury: Premarketing Clinical Evaluation FDA 2009]) 
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Liver impairment as evidenced by 1 or more of the following criteria and no other 
reason can be found to explain the following lab abnormalities, such as viral hepatitis 
A, B, or C; pre-existing or acute liver disease; or another drug capable of causing the 
observed injury: 
− ALT or AST >8× ULN, or 
− ALT or AST >5× ULN for more than 2 weeks, or 
− ALT or AST >3× ULN and total bilirubin >2× ULN (or international normalized 
ratio [INR] >1.5)  
− ALT or AST >3x ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
• Patient withdraws consent 
8.3.2.2. 
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 Regeneron medical 
monitor should be contacted as soon as possible. Resumption of study drug dosing requires 
consultation and agreement between the investigator and the Regeneron medical monitor. 
If a patient requires a prohibited medication at any time during the study, the principal investigator 
should contact the Regeneron medical monitor (except for illness requiring prompt treatment). 
Based on the discussions, study drug may be continued or temporarily or permanently 
discontinued. 
8.4. 
Management of Acute Reactions  
8.4.1. 
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 10.2.4) and 
graded using the grading scales as instructed in Section 10.2.5. 
8.4.1.1. 
Interruption of the Intravenous Infusion 
The infusion should be interrupted if any of the following AEs are observed: 
• Sustained/severe cough 
• Rigors/chills 
• Rash, pruritus (itching) 
• Urticaria (hives, welts, wheals) 
• Diaphoresis (sweating) 
• Hypotension 
• Dyspnea (shortness of breath) 
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• 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. 
8.4.1.2. 
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 
• 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) 
8.5. 
Method of Treatment Assignment  
Approximately 120 patients will be randomized in a 1:1 ratio to receive either evinacumab or 
placebo according to a central randomization scheme provided by an interactive voice response 
system (IVRS)/interactive web response system (IWRS) to the designated study pharmacist (or 
qualified designee).   
8.6. 
Blinding 
Study patients, the principal investigators, and study site personnel will remain blinded to all 
randomization assignments throughout the study. The Regeneron medical/study director, study 
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monitor, and any other Regeneron and contract research organization (CRO) personnel who are in 
regular contact with the study site will remain blinded to all patient randomization assignments. 
Lipid results from blood samples collected after the randomization visit will not be communicated 
to the sites, and the sponsor’s operational team will not have access to these laboratory results until 
after the final database is locked for this study. 
One interim analysis is planned. The team performing the interim analysis will be external to 
Regeneron with the intent to reduce data bias in the patients ongoing at the time of the interim. No 
study personnel involved in the day-to-day conduct of the study will have access to any unblinded 
data before the final database is locked for this study.  
8.7. 
Emergency Unblinding  
Unblinding of treatment assignment for a patient may be necessary due to a medical emergency or 
any other significant medical event (eg, pregnancy) and when a treatment decision is contingent 
on knowing the patient’s treatment assignment. Study drug will be discontinued for patients whose 
treatment has been unblinded (Section 8.3.2).  
• If unblinding is required: 
− Only the investigator will make the decision to unblind the treatment assignment. 
− Only the affected patients will be unblinded. 
− The designated study pharmacist(s)/designee at the study site will provide the 
treatment assignment to the investigator. If there is no study pharmacist, the 
investigator for the site will unblind/unmask the patient. Unblinding is performed 
using the IVRS/IWRS which will notify Regeneron.   
− The investigator will notify Regeneron and/or designee as soon as possible after 
unblinding the patient. 
Treatment assignment is not to be provided to site personnel other than the unblinded study 
pharmacist (when applicable), at any time during the conduct of the study, except in the case of a 
true emergency and when a treatment decision is contingent on knowing the patient’s treatment 
assignment. In the event that there is no study pharmacist, the individual at the site fulfilling that 
role will be the only unblinded member of the site personnel. 
8.8. 
Treatment Logistics and Accountability 
8.8.1. 
Packaging, Labeling, and Storage 
A medication numbering system will be used to label blinded investigational study drug. Lists 
linking medication numbers with product lot numbers will be maintained by the groups (or 
companies) responsible for study drug packaging. In order to maintain the blind, these lists will 
not be accessible to individuals involved in study conduct. 
Study drug will be stored at the site at a temperature of 2ºC to 8ºC; storage instructions will be 
provided in the pharmacy manual. 
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8.8.2. 
Supply and Disposition of Treatments  
Study drug will be shipped at a temperature of 2ºC to 8ºC to the investigator or designee at regular 
intervals or as needed during the study. At specified time points during the study (eg, interim site 
monitoring visits), at the site close-out visit, and following drug reconciliation and documentation 
by the site monitor, all opened and unopened study drug will be destroyed/returned to the sponsor 
or designee. 
8.8.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug. These records 
should contain the dates, quantity, and study medication 
• Dispensed to each patient 
• Returned from each patient (if applicable), and 
• Disposed of at the site or returned to the sponsor or designee. 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
8.8.4. 
Treatment Compliance 
All doses of study drug will be administered in the clinic. All drug compliance records must be 
kept current and made available for inspection by the sponsor and regulatory agency inspectors. 
8.9. 
Concomitant Medications  
Any treatment administered from the time of informed consent to the final study visit will be 
considered concomitant medication. This includes medications that were started before the study 
and are ongoing during the study. Vaccination for COVID-19 should also be considered a 
concomitant medication.  
8.9.1. 
Prohibited Medications  
The following concomitant medications and procedures are prohibited during the study: 
• Glybera® 
• Lipid apheresis or plasma exchange 
• Lomitapide 
• Mipomersen and other antisense lipid therapies 
• Systemic corticosteroids, with the following exceptions: 
− Used as replacement therapy for pituitary/adrenal disease with a stable regimen 
for at least 6 weeks prior to the screening visit 
− Used for ≤5 days during the treatment period for an acute illness as medically 
indicated 
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• Live or attenuated vaccination with replicating potential 
8.9.2. 
Permitted Medications  
The use of medications and nutritional supplements known to lower TG, including statins, fibrates, 
niacin, and omega-3s are permitted as long as therapy has been stable for at least 8 weeks prior to 
the screening visit. Patients must continue taking their background medical TG-modifying therapy 
for the duration of the study starting at screening and through the end of treatment visit. 
Patients on thyroid replacement therapy can be included if the dosage of thyroxine has been stable 
for at least 12 weeks prior to the screening visit. 
Topical, intra-articular, nasal, inhaled, and ophthalmic steroid therapies are not considered as 
‘systemic’ and are allowed. 
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9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
9.1. 
Schedule of Events 
In light of the public health emergency related to COVID-19, the continuity of clinical study 
conduct and oversight may require implementation of temporary or alternative mechanisms. 
Examples of such mechanisms may include, but are not limited to, any of the following: phone 
contact, virtual visits, telemedicine visits, online meetings, non-invasive remote monitoring 
devices, use of local clinic or laboratory locations, and home visits by skilled staff. Additionally, 
no waivers to deviate from protocol enrollment criteria due to COVID-19 will be granted. All 
temporary mechanisms utilized, and deviations from planned study procedures in response to 
COVID-19, are to be documented as being related to COVID-19 and will remain in effect only for 
the duration of the public health emergency. 
Study assessments and procedures for the DBTP are presented by visit in Table 1, and in Table 2 
for the off-drug follow-up period. 
 
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Table 1: 
Schedule of Events for the DBTP 
 
Screening 
Period 
Double-Blind Treatment Period (DBTP) 
Visit # (V) 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
Week 
 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
Day 
-28 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
Window (day) 
 
 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
Study Procedure 
Screening/Baseline: 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
Medical History1   
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
Height, Weight, BMI2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
Amylase and Lipase 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
FT4, TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (for women only)3  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment: 
Administer Study Drug4   
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Meds and 
Treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy: 
Lipid Profile5,6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Special Lipids6 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Presence of Abdominal 
Pain (1-Item Question) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAP-Pain 
Questionnaire  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety: 
Weight 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
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Screening 
Period 
Double-Blind Treatment Period (DBTP) 
Visit # (V) 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
Week 
 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
Day 
-28 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
Window (day) 
 
 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
Study Procedure 
Electrocardiogram8  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory: 5 
Hematology 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Chemistry 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Pregnancy Test9,10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetics and Immunogenicity Sampling:   
Drug Conc. Sample11 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
ADA and NAb sample12  
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Biomarkers: 
Biomarker 
Serum/Plasma13  
 
X 
 
 
  
 
 
X 
 
 
 
 
 
 
Lipoprotein Analysis by 
NMR 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Optional Pharmacogenomics: 
DNA Sample 
(Optional)14   
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Other: 
Mandatory DNA 
Sample for FCS 
Genotyping for Subset 
of Patients15  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dietary Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Alcohol Intake Review  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Table 2: 
Schedule of Events for the Off-Drug Follow-up Period 
 
End of DBTP 
Off Drug Follow-Up  
Visit # (V) 
V15 
V16 
End of Study V17 
Week 
52 
62 
72 
Day 
365 
435 
505 
Window (day) 
±4 
±7 
±7 
 
Efficacy: 
Lipid Profile1  
X 
X 
X 
Special Lipids1 
X 
 
X 
Presence of Abdominal Pain (1-Item Question) 
X 
X 
X 
HAP-Pain Questionnaire 
X 
X 
X 
Safety: 
Concomitant Meds and Treatment 
X 
X 
X 
Weight 
X 
X 
X 
Vital Signs 
X 
X 
X 
Physical Examination 
 
 
X 
Electrocardiogram2  
 
 
X 
Adverse Events 
X 
X 
X 
Laboratory :3  
Hematology 
X 
 
X 
Blood Chemistry 
X 
X 
X 
Pregnancy Test4,5  
X 
 
X 
Pharmacokinetics and Immunogenicity Sampling:6  
Drug Conc. Sample 
X 
 
X 
ADA and NAb Sample 
X 
 
X 
Biomarkers: 
Biomarker Serum/Plasma  
X 
 
X  
Lipoprotein Analysis by NMR 
X 
 
 
Other: 
Dietary Review 
X 
X 
X 
Alcohol Intake Review 
X 
X 
X 
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9.1.1. 
Footnotes for the Schedule of Events Tables 
9.1.1.1. 
Footnotes for Table 1 Schedule of Events (DBTP) 
1. Medical history should include detailed cardiovascular and pancreatitis history. 
2. Height will be measured in meters (m). Body weight will be assessed using calibrated 
scales. Patients should void (empty bladder) prior to weight assessment. Patients should 
be wearing undergarments only and no shoes during weight assessments. Body weight 
will be recorded to the nearest 0.1 kg. Body mass index (BMI) is calculated as weight 
(kg)/height(m)2. 
3. Postmenopausal status will be confirmed by measurement of FSH. 
4. At dosing visits, all assessments (including urine or serum pregnancy tests for WOCBP) 
should be performed before the dose of study drug is administered. 
5. All blood samples should be collected before the administration of study drug. All 
samples should be collected following at least an 8-hour fast. Medications are permitted 
to be taken with water as medically indicated. 
6. Lipids and lipoproteins (Lipid Profile): TC, TG, HDL-C, LDL-C will be measured.  
Special lipids:  ApoC3, ApoB48, ApoB100, ApoB Total. 
7. On dosing days, vital signs should also be measured, and AEs monitored pre-dose, at the 
end of study drug infusion, and at 30 minutes and 60 minutes post-end of infusion. Patients 
will be closely monitored for a minimum of 60 minutes after IV administration of study 
drug. 
8. Electrocardiograms should be performed before blood is drawn. 
9. Pregnancy test for WOCBP: A serum test will be done at the screening visit and a urine 
test will be done at all other visits indicated. Any positive urine test should be confirmed 
with a serum pregnancy test. 
10. All patients will be reminded of protocol-specified contraception use and pregnancy 
reporting. 
11. Blood samples for drug concentration and total ANGPTL3 should be obtained prior to 
AND at the end of infusion of study drug (within 30 minutes from the end of infusion). 
12. Blood samples for ADA and NAb samples should be collected prior to the administration 
of study drug.  
13. Residual biomarker samples as well as unused drug concentration and immunogenicity 
samples from the study may be utilized for future biomedical research (FBR) as 
permitted by patient consent and local regulatory policies. Samples may be stored for up 
to 15 years or as permitted by local regulatory policies, whichever is shorter, for FBR. 
14. Patients who agree to participate in the genomics sub-study will be required to consent to 
this optional sub-study before collection of the samples. Whole blood samples for 
DNA extraction should be collected on day 1/baseline (pre-dose), but can be collected at 
a later study visit. 
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15. Mandatory DNA sample for FCS genotyping is only for patients who have no 
documentation of prior genotype testing that confirms the absence of FCS due to 
LoF mutations in LPL. 
9.1.1.2. 
Footnotes for Table 2 Schedule of Events (Off Drug Follow-up Period) 
1. Lipids and lipoproteins (Lipid Profile): TC, TG, HDL-C, LDL-C will be measured.  
Special lipids:  ApoC3, ApoB48, ApoB100, ApoB Total. 
2. Electrocardiograms should be performed before blood is drawn. 
3. All samples should be collected following at least an 8-hour fast. Medications are 
permitted to be taken with water as medically indicated. 
4. Pregnancy test for WOCBP: A urine test will be done at all other visits indicated. Any 
positive urine test should be confirmed with a serum pregnancy test. 
5. All patients will be reminded of protocol-specified contraception use and pregnancy 
reporting. 
6. Drug concentration should occur prior to and at the end of infusion of study drug, if 
applicable.  Immunogenicity collection should occur prior to infusion of study drug, if 
applicable. 
9.1.2. 
Early Termination Visit 
Patients who are withdrawn from the study before the end of the DBTP (visit 16, week 52) will be 
asked to return to the clinic for an ET visit consisting of the end of DBTP assessments described 
under visit 16 (Table 2). After the ET visit, patients will enter the off-drug treatment follow-up 
period. 
9.1.3. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule. Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for any 
other reason, as warranted. 
9.2. 
Study Procedures 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed for the sole purpose of determining study eligibility 
or characterizing the baseline population: 
• Obtain informed consent (including optional sub-studies) 
• Review inclusion/exclusion criteria 
• Record demographics 
• Record medical history. Medical history should include detailed cardiovascular and 
pancreatitis history. 
• Record prior medications (within 12 weeks prior to screening) 
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• Perform physical examination 
• Measure height and weight for BMI calculation 
• Blood sample for serum amylase and lipase  
• Blood sample to assess FSH to verify postmenopausal status, if applicable 
• Blood sample to assess free thyroxine (FT4) and TSH to evaluate thyroid function 
and diagnose thyroid diseases  
• Mandatory DNA sample for FCS genotyping for patients who have no documentation 
of prior genotype testing that confirms the absence of FCS due to LoF mutations in 
LPL 
9.2.2. 
Efficacy Procedures  
9.2.2.1. 
Acute Pancreatitis Episodes 
The primary efficacy measurement in this study is the occurrence of AP in any study patient at any 
time during the DBTP as reported by the investigator and adjudicated by the APAC (see diagnostic 
criteria in Section 5.2.1).  
Patients will receive an emergency card to take with them to the hospital in the event of AP. The 
card will inform the hospital staff that the patient is a participant in a clinical trial and include 
contact information for the investigator. 
9.2.2.2. 
Fasting Blood Samples for Assessment of Lipid Profile (For Efficacy and PD 
Variables) 
All laboratory samples will be collected before the dose of study drug is administered. 
Blood samples for lipid panels should be collected in the morning, in fasting condition 
(ie, overnight, at least an 8-hours fast, only water) for all clinic visits. Medications are permitted 
to be taken with water as medically indicated. Alcohol consumption within 48 hours, and smoking 
or intense physical exercise within 24 hours, preceding blood sampling are discouraged. 
Note: If the patient is not in the fasting condition, the blood sample should not be collected, and a 
new appointment can be scheduled the day after (or as close as possible to this date) with a 
reminder to be fasted. Patients who are not fasted should 1) be reminded that they should fast, and 
2) should be seen by study staff the next day or as close as possible in a fasted state. 
Fasting blood samples will be collected at specified time points listed in Table 1 for assessment of 
the standard lipid profile, including plasma TG, LDL-C by direct measurement, HDL-C, 
non-HDL-C, and TC. As TG values may exceed 400 mg/dL (4.52 mmol/L), LDL-C will be 
measured via the beta quantification method (rather than via the Friedewald formula). 
The specialty lipid panel (ApoC3, ApoB48, ApoB100, ApoB Total) will be assessed with a 
separate sample that is collected at applicable visits.  The standard lipid panel and specialty lipid 
panel will be directly measured by the central laboratory.  
Detailed procedures of sample preparation, storage, and shipment are provided in the laboratory 
manual. 
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9.2.2.3. 
NMR Lipid Profile 
Lipoprotein particle concentrations will be measured by NMR. 
9.2.2.4. 
Clinical Outcome Assessments 
9.2.2.4.1. Presence of Abdominal Pain 
The Presence of Abdominal Pain questionnaire is a single-item, dichotomous questionnaire which 
will be used to determine if abdominal pain was present in the 7 days before the visit. The item 
asks the following question: “Did you have abdominal pain related to your disease during the past 
week?” If the patient answers ‘yes’ to this question, they will be asked to complete the HAP-Pain 
questionnaire. 
9.2.2.4.2. HAP-Pain 
The abdominal pain patient-reported outcome to be used in this study is the HAP-Pain 
questionnaire, which contains 4 items that measure aspects of pain due to AP. The HAP-Pain has 
a 7-day recall period. Each question is rated on an 11-point scale with 0 indicating ‘no pain’ and 
10 indicating ‘worst possible pain.’ Patients will complete the HAP-Pain questionnaire at each 
visit if they answer ‘yes’ on the Presence of Abdominal Pain questionnaire.  
9.2.3. 
Safety Procedures  
9.2.3.1. 
Vital Signs and Body Weight 
Vital signs, including temperature, sitting blood pressure, pulse, and respiration, will be measured 
pre-dose and at other time points at visits according to Table 1 and Table 2. Body weight (kg) and 
height will be measured at screening for BMI determination. Weight (to be recorded to the nearest 
0.1 kg) will also be measured during the DBTP (Table 1) and off-drug follow-up period (Table 2).  
Patients will be closely monitored for a minimum of 60 minutes after IV administration of study 
drug.  
9.2.3.2. 
Physical Examination 
A thorough and complete physical examination will be performed at time points according to 
Table 1. Care should be taken to examine and assess any abnormalities that may be present, as 
indicated by the patient’s medical history. 
9.2.3.3. 
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 and Table 2. 
A 12-lead ECG should be performed in the supine position after resting for at least 10 minutes. 
For each ECG recording throughout the study, the electrodes should be positioned in the same 
place as much as possible. The ECG will be interpreted locally by the investigator. Heart rate will 
be recorded from the ventricular rate, and the PR, QRS, RR, QTcB, and QTcF intervals will be 
recorded. Any clinically significant abnormality should be documented as an AE/SAE as 
applicable. Each ECG tracing will be analyzed in comparison with the screening record trace. The 
ECG strips or reports will be retained with the source.   
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9.2.3.4. 
Laboratory Testing 
Hematology, chemistry, and serum pregnancy testing samples will be analyzed by a central 
laboratory. Urine pregnancy testing samples will be analyzed locally (patients will use a pregnancy 
test provided by the site for phone visits in the follow-up). Detailed instructions for blood sample 
collection are in the laboratory manual provided to study sites. 
Samples for laboratory testing will be collected at visits according to Table 1 and Table 2. Tests 
will include: 
Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin 
Potassium 
Creatinine 
Uric acid 
Chloride 
Blood urea nitrogen (BUN) 
Creatine phosphokinase (CPK) 
Carbon dioxide 
Aspartate aminotransferase (AST) 
Phosphorus 
Calcium 
Alanine aminotransferase (ALT) 
Magnesium 
Glucose 
Alkaline phosphatase 
 
Albumin 
Lactate dehydrogenase (LDH) 
 
 
Note: Blood chemistry should be performed after the patients have fasted for at least approximately 8 hours at the 
visits defined in the Schedule of Events.   
Hematology 
Hemoglobin 
Differential:  
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
Other Laboratory Tests 
• Pregnancy testing (WOCBP only): serum human chorionic gonadotrophin (β-HCG) 
pregnancy testing at screening, and urine pregnancy testing at all subsequent scheduled 
visits  
• Pregnancy testing and contraception are not required for women with documented 
hysterectomy or tubal ligation. 
• Postmenopausal women must be amenorrheic for at least 12 months in order not to be 
considered of childbearing potential. Follicle-stimulating hormone will be measured 
for verifying postmenopausal status, as applicable. 
• Blood sample for FT4 and TSH 
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Abnormal Laboratory Values and Laboratory Adverse Events 
All laboratory values must be reviewed by the investigator or authorized designee. 
Significantly abnormal test results that occur after start of treatment must be repeated to confirm 
the nature and degree of the abnormality. When necessary, appropriate ancillary investigations 
should be initiated. If the abnormality fails to resolve or cannot be explained by events or 
conditions unrelated to the study medication or its administration, the medical/study director must 
be consulted.   
The clinical significance of an abnormal test value, within the context of the disease under study, 
must be determined by the investigator. 
Criteria for reporting laboratory values as an AE are provided in Section 10.1.1. 
9.2.4. 
Drug Concentration and Measurements 
Samples for concentrations of total evinacumab and total ANGPTL3 in serum will be collected at 
visits listed in Table 1 and Table 2.  
Any unused samples may be used for exploratory biomarker research. 
9.2.5. 
Immunogenicity Measurements and Samples 
Samples for ADA and NAb assessments will be collected at visits listed in Table 1 and Table 2. 
They will be collected pre-dose on days when study drug is administered. Any unused samples 
may be used for exploratory biomarker research. 
9.2.6. 
Pharmacodynamic and Exploratory Biomarker Procedures 
In this study, research assessments will be performed to explore how evinacumab may modify 
TG-rich lipoprotein metabolism underlying the risk of recurrent AP in patients with HTG and a 
recent history of HTG-associated AP. In particular, the role of inhibition of ANGPTL3 and the 
effect of evinacumab on PD markers or biomarkers will be explored.   
Biomarker samples will be collected at time points according to Table 1 and Table 2. 
Pharmacodynamic marker/biomarker measurements will be performed to determine effects on 
biomarkers of HTG or relevant physiological and pathogenic processes. The biomarkers studied 
are believed to be relevant to the pathophysiology of indication, target engagement, mechanism of 
action of evinacumab, and possible toxicities. 
9.2.7. 
DNA Sample for FCS Genotyping 
For patients without documentation of prior genetic testing that confirms the absence of FCS due 
to LoF mutations in LPL, a required blood sample for DNA isolation will be collected to identify 
or confirm known mutations in LPL, APOC2, APOA5, LMF1, and GPIHBP1, the genes 
implicated in FCS, and results will be reported back to the investigator. 
Patients who have FCS due to LoF mutations in LPL as determined by the screening genotyping 
will be considered screen failures. The presence of mutations in other genes implicated in FCS 
(APOC2, APOA5, LMF1, GPIHBP1) will be determined for informational purposes and will not 
exclude patients from participating. This includes double heterozygote patients, with an LoF 
mutation in LPL and an LoF mutation in another FCS-related gene. 
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9.2.8. 
Future Biomedical Research (Optional) 
Patients who agree to participate in the FBR sub-study will be required to consent to this optional 
sub-study before samples are banked for FBR. Residual 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 (or for a shorter time period if required per regional laws and regulations). 
The samples may be utilized for FBR that may or may not be directly related to the study, including 
being used as reference samples and assay development or validation. The results of these 
FBR analyses will not be presented in the clinical study report (CSR). 
9.2.9. 
Pharmacogenomic Analysis (Optional)  
Patients who agree to participate in the genomics sub-study will be required to consent to this 
optional sub-study before collection of the samples. Whole blood samples for DNA extraction 
should be collected on day 1/baseline (pre-dose) but can be collected at a later study visit. The 
DNA sample will be collected for pharmacogenomics analyses to understand the genetic 
determinants of efficacy and safety associated with the treatments in this study and the molecular 
basis of HTG and related diseases. Samples will be single-coded as defined by the International 
Council for Harmonisation (ICH) guideline E15. Samples will be stored for up to 15 years after 
the final date of the database lock (or for a shorter time period if required per regional laws and 
regulations). If there are specific site or country requirements involving the pharmacogenomic 
analyses which the sponsor is unable to comply with, samples will not be collected at those sites.   
The purpose of the pharmacogenomic analyses is to identify genomic associations with clinical or 
biomarker response to evinacumab, other HTG clinical outcome measures, and possible AEs. In 
addition, associations between genomic variants and prognosis or progression of HTG, as well as 
related disorders of lipid metabolism, 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, target pathway, or HTG 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, and 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 
analyses will not be reported in the CSR. 
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10. 
SAFETY EVALUATION AND REPORTING 
10.1. 
 Recording and Reporting Adverse Events  
10.1.1. 
General Guidelines 
The investigator must promptly record all clinical events occurring during the study data 
collection, from the time of signing the informed consent form (ICF) to the end of study (see 
Section 11.4.5.1). Medical conditions that existed or were diagnosed prior to the signing of the 
informed consent will be recorded as part of medical history. Abnormal laboratory values and vital 
signs observed at the time of informed consent should also be recorded as medical history. Any 
subsequent worsening (ie, any clinically significant change in frequency and/or intensity) of a 
pre-existing condition that is temporally associated with the use of the study drug should also be 
recorded as an AE. 
At each visit, the investigator will determine whether any AEs have occurred by evaluating the 
patient. Adverse events may be directly observed, or reported spontaneously by the patient or by 
questioning the patient at each study visit. Patients should be questioned in a general way, without 
asking about the occurrence of any specific symptoms. The investigator must assess all AEs to 
determine seriousness, severity, and causality, in accordance with the definitions in Section 10.2. 
The investigator’s assessment must be clearly documented in the site’s source documentation with 
the investigator’s signature. The investigator should follow up on SAEs (and adverse events of 
special interest or AESIs) until they have resolved or are considered clinically stable; AEs should 
be followed until they are resolved or last study visit, whichever comes first. 
Always report the diagnosis as the AE or SAE term. When a diagnosis is unavailable, report the 
primary sign or symptom as the AE or SAE term with additional details included in the narrative 
until the diagnosis becomes available. If the signs and symptoms are distinct and do not suggest a 
common diagnosis, report them as individual entries of AE or SAE.   
Laboratory results, vital signs, and other diagnostic results or findings should be appraised by the 
investigator to determine their clinical significance. Isolated abnormal laboratory results, vital sign 
findings, or other diagnostic findings (ie, not part of a reported diagnosis) should be reported as 
AEs if they are symptomatic, lead to study drug discontinuation or dose reduction, require 
corrective treatment, or constitute an AE in the investigator’s clinical judgment. 
For events that are serious due to hospitalization, the reason for hospitalization must be reported 
as the SAE (diagnosis or symptom requiring hospitalization). A procedure is not an AE or SAE, 
but the reason for the procedure may be an AE or SAE. Pre-planned (prior to signing the ICF) 
procedures, treatments requiring hospitalization for pre-existing conditions that do not worsen in 
severity, and admission for palliative or social care should not be reported as SAEs (see 
Section 10.2 for Definitions).   
For deaths, the underlying or immediate cause of death should always be reported as an SAE.   
Any SAE that may occur subsequent to the reporting period (end of the on-treatment period) that 
the investigator assesses as related to study drug should also be reported. 
All AEs, SAEs, AESIs, and pregnancy reports are to be reported according to the procedures in 
Section 10.1.3.   
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10.1.2. 
Reporting Procedure  
All events (serious and non-serious) must be reported with the investigator’s assessment of the 
event’s seriousness, severity, and causality to the (when applicable: blinded) study drug. For SAEs 
and AESIs, a detailed narrative summarizing the course of the event, including its evaluation, 
treatment, and outcome should be provided on the AE case report form (CRF). Specific or 
estimated dates of event onset, treatment, and resolution should be included, when available. 
Medical history, concomitant medications, and laboratory data that are relevant to the event should 
also be summarized in the narrative. For fatal events, the narrative should state whether an autopsy 
was or will be performed and include the results if available. Information not available at the time 
of the initial report must be documented in a follow-up report. Source documents (including 
hospital or medical records, diagnostic reports, etc) will be summarized in the narrative on the 
AE CRF and retained at the study center and available upon request.   
Urgent safety queries must be followed up and addressed promptly. Follow-up information and 
response to non-urgent safety queries should be combined for reporting to provide the most 
complete data possible within each follow-up.  
10.1.3. 
Events that Require Expedited Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of learning 
of the event: 
• SAEs. 
• Selected AESI (see definition in Section 10.2.3); serious and nonserious: Adverse 
events of special interest for this study include the following:   
− Anaphylactic reactions 
− Moderate/severe infusion reactions 
− Allergic reactions that require medical treatment or consultation with another 
physician for further evaluation 
− Increase in ALT or AST: ≥3x ULN (if baseline <ULN), or ≥2x baseline value (if 
baseline ≥ULN) 
• 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 during the study or within 24 weeks of the 
last dose of study drug. Any complication of pregnancy affecting a female 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. 
• Symptomatic overdose with study drug: Accidental or intentional overdose of at least 
2 times the intended dose of study drug within the intended therapeutic window, if 
associated with an AE. 
 
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10.2. 
Definitions 
10.2.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug which may or 
may not have a causal relationship with the study drug. Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease which is temporally 
associated with the use of a study drug, whether or not considered related to the study drug (ICH 
E2A Guideline. Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting, Oct 1994). 
10.2.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death – includes all deaths, even those that appear to be completely 
unrelated to study drug (eg, a car accident in which a patient is a passenger). 
• Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event. This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
• Requires in-patient hospitalization or prolongation of existing hospitalization. 
In-patient hospitalization is defined as a hospital admission (any duration) or an 
emergency room visit for longer than 24 hours. Prolongation of existing 
hospitalization is defined as a hospital stay that is longer than was originally 
anticipated for the event, or is prolonged due to the development of a new AE as 
determined by the investigator or treating physician. 
• Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions).   
• Is a congenital anomaly/birth defect 
• Is an important medical event. Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent one of the other serious outcomes listed above 
(eg, intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development 
of drug dependency or drug abuse). 
Criteria for reporting SAEs must be followed for these events.  
10.2.3. 
Adverse Events of Special Interest 
An AESI, serious or non-serious, is one of scientific and medical interest specific to the sponsor’s 
product or program, for which ongoing monitoring and rapid communication by the investigator 
to the sponsor can be appropriate. Such an event might warrant further investigation in order to 
characterize and understand it.   
Adverse events of special interest for this study are listed in Section 10.1.3.  
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10.2.4. 
Infusion Reactions 
Infusion reactions are defined as any relevant AE that occurs during the infusion or within 1 hour 
after the infusion is completed.  
10.2.5. 
Severity 
The severity of AEs will be graded according to the following scale: 
Mild:  Does not interfere in a significant manner with the patient’s normal functioning level. It 
may be an annoyance. Prescription drugs are not ordinarily needed for relief of symptoms, but may 
be given because of personality of the patient. 
Moderate:  Produces some impairment of functioning but is not hazardous to health. It is 
uncomfortable or an embarrassment. Treatment for symptom may be needed. 
Severe:  Produces significant impairment of functioning or incapacitation and is a definite hazard 
to the patient’s health. Treatment for symptom may be given and/or patient hospitalized. 
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
Infusion Reactions 
The severity of infusion reactions will be graded according to the following scale (semi-colon 
indicates “or” within description of the grade): 
Mild:  Mild transient reaction; infusion interruption not indicated; intervention not indicated. 
Moderate:  Therapy or infusion interruption indicated but responds promptly to symptomatic 
treatment (eg, antihistamines, NSAIDs, narcotics, IV fluids); prophylactic medications indicated 
for ≤24 hours. 
Severe:  Prolonged (eg, not rapidly responsive to symptomatic medication and/or brief interruption 
of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for 
clinical sequelae; life-threatening consequences; urgent intervention indicated; death. 
10.2.6. 
Causality 
The investigator must provide causality assessment as to whether or not there is a reasonable 
possibility that the drug caused the adverse event, based on evidence or facts, his/her clinical 
judgment, and the following definitions. The causality assessment must be made based on the 
available information and can be updated as new information becomes available. 
The following factors should be considered when assessing causality: 
• Temporal relationship: time to onset versus time drug was administered 
• Nature of the reactions: immediate versus long term 
• Clinical and pathological features of the events  
• Existing information about the drug and same class of drugs  
• Concomitant medications  
• Underlying and concurrent illnesses  
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• Response to dechallenge (drug discontinuation) or dose reduction  
• Response to rechallenge (re-introduction of the drug) or dose increase, when 
applicable  
• Patient’s medical and social history  
Causality to the study drug (including study drug administration): 
• Related: 
− The AE follows a reasonable temporal sequence from study drug administration, 
and cannot be reasonably explained by the nature of the reaction, patient’s clinical 
state (eg, disease under study, concurrent diseases, concomitant medications), or 
other external factors. 
or 
− The AE follows a reasonable temporal sequence from study drug administration, 
and is a known reaction to the drug under study or its class of drugs, or is 
predicted by known pharmacology. 
• Not Related: 
− The AE does not follow a reasonable sequence from study drug administration, or 
can be reasonably explained by the nature of the reaction, patient’s clinical state 
(eg, disease under study, concurrent diseases, and concomitant medications) or 
other external factors. 
Causality to the study conduct (protocol-specified procedure): 
• Related: 
− The AE follows a reasonable temporal sequence from a protocol-specified 
procedure, and cannot be reasonably explained by the nature of the reaction, 
patient’s clinical state (eg, disease under study, concurrent diseases, concomitant 
medications), or other external factors. 
• Not Related: 
− The AE does not follow a reasonable sequence from a protocol-specified 
procedure, or can be reasonably explained by the nature of the reaction, patient’s 
clinical state (eg, disease under study, concurrent diseases, and concomitant 
medications) or other external factors. 
10.3. 
Safety Monitoring 
The investigator will monitor the safety of study patient at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP). Any questions or 
concerns should be discussed with the sponsor in a timely fashion. The sponsor will monitor the 
safety data from across all study sites. The medical/study director will have primary responsibility 
for the emerging safety profile of the compound, but will be supported by other departments 
(eg, GPS; 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. 
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10.4. 
Notifying Health Authorities, Institutional Review Board/Ethics 
Committee, and Investigators 
During the study, the sponsor and/or the CRO will inform health authorities, institutional review 
boards/independent ethics committees (IRB/EC), and the participating investigators of any 
SUSARs (suspected unexpected serious adverse reactions) occurring in other study centers or 
other studies of the active study drug (evinacumab), as appropriate per local reporting 
requirements. In addition, the sponsor and/or CRO will comply with any additional local safety 
reporting requirements. All notifications to investigators will contain only blinded information.  
Upon receipt of the sponsor’s notification of a SUSAR that occurred with the study drug, the 
investigator will inform the IRB/EC unless delegated to the sponsor. 
Event expectedness for study drug (evinacumab) is assessed against the Reference Safety 
Information section of the Investigator’s Brochure that is effective for expedited safety reporting.   
At the completion of the study, the sponsor will report all safety observations made during the 
conduct of the trial in the CSR to health authorities and IRB/EC as appropriate. 
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11. 
STATISTICAL PLAN 
This section provides the basis for the SAP for the study. The SAP may be revised during the study 
to accommodate amendments to the clinical study protocol and to make changes to adapt to 
unexpected issues in study execution and data that may affect the planned analyses. The final SAP 
will be issued before the database is locked at the time of the interim analysis (ie, when 
approximately 50% of patients have completed the DBTP). 
Analysis endpoints are listed in Section 4.   
11.1. 
Statistical Hypothesis  
Let p1 and p2 be the proportion of ITT patients with at least 1 positively adjudicated AP episode 
during the 52 weeks of the DBTP under placebo and evinacumab, respectively. The following null 
hypothesis and alternative will be tested: 
H0 : p1 = p2 
versus 
H1 : p1 ≠ p2 
Stratification factors are not planned for this study. 
11.2. 
Justification of Sample Size 
For the primary efficacy hypothesis during the DBTP, a total sample size of 120 patients 
(60 patients in each treatment group) will have 90% power to detect a treatment group difference 
in positively adjudicated AP event rates of 24% (placebo event rate: 30%; evinacumab event 
rate: 6%), with 0.049 two-sided significance level (data on file). This sample size has been 
adjusted for a 5% non-evaluable patient rate for the primary efficacy endpoint.   
11.3. 
Analysis Sets  
11.3.1. 
Efficacy Analysis Sets 
11.3.1.1. Intent-to-Treat 
The ITT population is defined as all randomized patients who received 1 dose or part of a dose of 
study drug. Patients in the ITT population will be analyzed according to the treatment group 
allocated by randomization (ie, as-randomized treatment group). 
11.3.1.2. Modified Intent-to-Treat 
The modified ITT (mITT) population is defined as the all-randomized population who took at least 
1 dose or part of a dose of study drug and includes patients for whom the primary endpoint is 
evaluated during the efficacy treatment period. The efficacy treatment period is defined as the time 
from the first double-blind study drug administration up to 35 days after the last double-blind study 
drug administration. Patients in the mITT population will be analyzed according to the treatment 
group allocated by randomization. 
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11.3.2. 
Safety Analysis Set 
The 
safety 
analysis 
set 
(SAF) 
considered 
for 
safety 
analyses 
and 
treatment 
compliance/administration will be the randomized population who received at least 1 dose or part 
of a dose of double-blind study drug. Patients will be analyzed according to the treatment received 
(placebo or evinacumab). In addition:   
• Randomized patients for whom it is unclear whether they took the study drug will be 
included in the safety population as randomized. 
• For patients receiving study drug from more than 1 treatment group during the trial, 
the treatment group allocation for as-treated analysis will be the one in which the 
patient was treated with the highest number of infusions 
11.3.3. 
Pharmacokinetic Analysis Set 
The PK analysis set will be all randomized patients who received any study drug and for each 
patient who has at least 1 non-missing post-baseline measurement of evinacumab concentration. 
Treatment assignments are based on the treatment received (placebo or evinacumab). 
11.3.4. 
Immunogenicity Analysis Set 
The ADA analysis set will be the all-randomized patients who received any study drug and for 
each patient who has at least 1 evaluable ADA result collected after the first dose of study 
treatment. Treatment assignments are based on the treatment received (placebo or evinacumab). 
The NAb analysis set includes all patients who received any study drug and who are negative in 
the ADA assay or with at least 1 non-missing result in the NAb assay (patients who are 
ADA-negative are set to negative in the NAb analysis set). 
11.4. 
Statistical Methods  
For continuous variables, descriptive statistics will include the following information: the number 
of patients reflected in the calculation (n), mean, standard deviation, Q1, median, Q3, minimum, 
and maximum.  
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
11.4.1. 
Patient Disposition 
The following data will be summarized: 
• The total number of screened patients who have signed the ICF  
• The total number of randomized patients, defined as all screened patients with a 
double-blind treatment kit number allocated and recorded in the IVRS database, 
regardless of whether the treatment kit was used 
For any patient randomized more than once, safety data from the first randomization 
will be included in the SAF, with safety data associated with the later randomization 
reported separately. Since this is expected to be a rare event, inclusion of efficacy 
data from the patient randomized more than once in the efficacy population will be 
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decided on a case-by-case basis prior to the unblinding of treatment assignments and 
will be documented in the clinical study report. 
• The total number of patients randomized but not receiving study treatment 
• The total number of patients randomized and receiving study treatment 
• The total number of patients who completed the DBTP, defined as at least 48 weeks 
of study treatment exposure and visit week 52 performed 
• The total number of patients who prematurely discontinued study treatment during 
the DBTP, and the reasons for discontinuation 
• The total number of patients who did not complete the study follow-up period, 
defined as the last visit performed less than 20 weeks after the last study treatment 
infusion. Patients who died during the study are excluded. 
• The total number of patients in each analysis set 
• A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized 
• A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation 
11.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group 
and by all patients combined, for patients in the ITT population. Continuous variables will be 
descriptively summarized with mean, median, SD, minimum, and maximum. Categorical variables 
will be descriptively summarized with frequency and percentage. 
11.4.3. 
Efficacy Analyses 
11.4.3.1. Primary Efficacy Analysis 
Intent-to-Treat Estimand – Binary 
The ITT estimand – binary used for the primary efficacy analysis is defined as the treatment 
policy strategy, specifically: 
A. The patient population is defined as the ITT population (Section 11.3.1.1). 
B. The primary efficacy endpoint is defined in Section 4.1. 
C. The intercurrent events of interest are the administration of study treatment and the 
administration of subsequent therapies. The interruption of study treatment and the change 
in subsequent therapies are ignored, and the value for the primary efficacy endpoint is used 
regardless of adherence to study treatment and subsequent therapies. 
D. The analysis method of logistic regression will yield the population-level summary of odds 
ratio and 95% confidence interval (CI) for each study treatment group, and p value for 
treatment comparisons. 
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Statistical Analysis 
The primary efficacy comparison will evaluate the evinacumab 20 mg/kg IV treatment group 
versus placebo using the primary efficacy endpoint of the proportion of patients with at least 1 
positively adjudicated AP during the 52 weeks of DBTP (ITT estimand - binary). The primary 
efficacy endpoint will be analyzed in the ITT population using the method of logistic regression, 
and the model will include at least treatment group, and number of historical AP episodes within 
the previous 24 months. The evinacumab group will be compared to the placebo group, with odds 
ratio and 95% CI provided for each treatment group. The statistical testing of the treatment group 
comparison for the primary measure will be evaluated at a 2-sided significance level of 0.049.  
Every effort will be made for patients to return to the clinic for the week-52 assessment of the 
efficacy endpoints (regardless of study drug administration) to minimize missing data that was 
required to be collected in this protocol. 
For ET patients who did not complete the week-52 efficacy assessment, the missing primary 
endpoint will be imputed according to the following rules: 
• Early termination patients who had a primary endpoint event during the 52-week 
DBTP will be analyzed as “event occurred.” (Observed, thus no imputation) 
• Direct imputation of missing primary endpoint at the week-52 visit: 
− Patient deaths prior to week 52 that are adjudicated to be AP-related will be 
included as “event occurred.” 
− Remaining ET patients (including non-AP deaths) across both treatment groups 
will be imputed to the average placebo score (estimated placebo event rate).  
• Imputed scores along with observed patient data will be utilized in the logistic 
regression analysis. 
Robustness of the primary analysis statistical methods will be assessed through sensitivity analyses 
detailed in the SAP, including a tipping point analysis, observed-case analysis (ie ITT population 
in the absence of imputed primary endpoint data), and an on-treatment analysis (ie mITT patient 
population using the primary endpoint collected during the efficacy treatment period [on-treatment 
estimand]). 
11.4.3.2. Secondary Efficacy Analysis 
Intent-to-Treat Estimand 
The intent-to-treat estimand used for the key secondary efficacy analyses is the treatment policy 
strategy, specifically: 
A. The patient population is defined as the ITT population (Section 11.3.1.1). 
B. The key secondary efficacy endpoints are defined in Section 4.2.1. 
C. The intercurrent events of interest are the administration of study treatment and the 
administration of subsequent therapies. The interruption of study treatment and the change 
in subsequent therapies are ignored, and the value for the key secondary efficacy endpoint 
is used regardless of adherence to study treatment and subsequent therapies. 
D. For the percent change in fasting TGs, the analysis method of robust regression for a 
non-normal distribution will yield the population-level summary for each treatment group 
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of mean with associated standard error (SE), and the mean difference between the treatment 
groups will be provided with the SE, 95% CI, and p value. 
For the percent change in ApoC3, the analysis method of mixed-effect model with repeated 
measures (MMRM) approach for a normal distribution will yield the population-level 
summary for each treatment group of mean with associated SE, and the mean difference 
between the treatment groups will be provided with the SE, 95% CI and p value. 
Statistical Analysis 
For the key secondary efficacy endpoints (defined in Section 4.2.1) and other secondary efficacy 
endpoints (described in Section 4.2.2) collected in the DBTP, descriptive summaries and analyses 
will be performed in the ITT population, using values obtained regardless of adherence to study 
treatment and subsequent therapies (ITT estimands). 
For descriptive summaries, percent change, and when appropriate change from baseline, in TC, 
TG, calculated non-HDL-C, ApoC3, ApoB48, and ApoB100, will be provided at each time point. 
All measurements, scheduled or unscheduled, will be assigned to analysis windows defined in the 
SAP in order to provide an assessment for these time points. Laboratory assessments other than 
the ones provided by the central laboratory will be excluded. For TG, measurements on non-fasting 
patients will be excluded. The time profile of each parameter will be plotted by treatment group 
with the corresponding SEs. 
Multiple types of measurements are planned to be analyzed during differing time points in the trial, 
specifically continuous measurements expected to have a normal distribution (example: percent 
change in TC), continuous measurements expected to have a non-normal distribution (example: 
TG), and binary measurements.   
I. Continuous endpoints anticipated to have a normal distribution  
Continuous secondary variables anticipated to have a normal distribution (ie, lipids other than TG) 
will be analyzed in the ITT population at week 52 using an MMRM approach. Specifically, the 
model will contain fixed categorical effects of treatment group, planned time points up to the time 
point of interest, and treatment-by-time point interaction, as well as the continuous fixed covariates 
of corresponding baseline value and baseline value-by-time point interaction. This model will be 
run using Statistical Analysis Software (SAS) mixed procedure with an unstructured correlation 
matrix to model the within-patient errors. 
II. Continuous endpoints anticipated to have a non-normal distribution 
Continuous secondary efficacy endpoints anticipated to have a non-normal distribution (ie, TG), 
will be analyzed in the ITT population at week 52 using a robust regression model (ie, 
ROBUSTREG SAS procedure with M-estimation option) with treatment group as main effect and 
corresponding baseline value(s) as a covariate. Missing values will be addressed using a multiple 
imputation approach, which will be described in the SAP. The variables in the multiple imputation 
model will at least include the same variables as used in the robust regression model. The treatment 
group combined means will be provided with respective SE estimates. The combined mean 
difference between the treatment groups will be provided with the SE, 95% CI, and p value. 
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III. Binary endpoints 
Binary secondary efficacy endpoints will be analyzed using logistic regression with treatment 
group as main effect and corresponding baseline value(s) as a covariate. Missing values will be 
addressed using a multiple imputation approach, which will be described in the SAP. The variables 
in the multiple imputation model will at least include the same variables as used in the logistic 
regression model. Treatment effects will be compared, and the combined odds ratio estimate 
between the treatment groups with their corresponding 95% CI and p value will be provided. 
11.4.4. 
Control of Multiplicity 
Interim Analysis 
An interim analysis is planned when approximately 50% (N=60) of patients have completed the 
DBTP. This will consist of the final data contributing to the analysis of the applicable variables up 
to the week-52 visit for these patients. A small alpha adjustment of 0.001 has been made to account 
for this treatment-unblinded interim, since the sponsor does not plan to stop the study early for 
evinacumab treatment benefit – efficacy analyses will be descriptive in nature. The purpose of this 
interim analysis is administrative, specifically to aid in the planning of future studies. Therefore, 
the significance level for the final efficacy analysis at the first-step analysis will be 0.049.  
First-Step Analysis 
The first step analysis will be conducted when all patients have been randomized and all data 
through week 52 (DBTP) has been collected and validated. In order to address multiple key 
secondary efficacy endpoints (eg, percent change ApoC3 from baseline to week 52, and percent 
change fasting TG from baseline to week 52) at the first-step analysis, the overall type-I error will 
be controlled by the use of a hierarchical inferential approach. Statistical significance of the 
primary parameter is required before drawing inferential conclusions about the first key secondary 
parameter at the 0.049 alpha level. Inferential conclusions about successive key secondary 
parameters require statistical significance of the prior parameter within the hierarchy. The 
hierarchy testing sequence is the order of endpoints as presented in Section 4.2.1 Key Secondary 
Efficacy Endpoints. This fixed hierarchical approach will ensure a strong control of the overall 
type-I error rate at the 0.049 level.  
No further adjustments will be made for other secondary endpoints, for which p values will be 
provided for descriptive purposes only. 
No adjustment will be made for the final (Section 11.5.3) statistical analyses, since the primary 
and key secondary efficacy endpoints will have been concluded at the time of the first step analysis. 
11.4.5. 
Safety Analysis 
Summaries of safety results will be presented by treatment group for patients in the SAF. No 
formal inferential testing will be performed. Summaries will be descriptive in nature. 
All safety analyses will be performed using the following common rule: 
• The baseline value is defined as the last available value before the first dose of 
double-blind study treatment. 
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11.4.5.1. Adverse Events 
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®). The verbatim text, the preferred term (PT), and 
the system organ class (SOC) will be provided in patient listings. 
Definitions 
For safety variables, the following observation periods are defined: 
• The pre-treatment period is defined from the day the ICF is signed to the day before 
the first dose of double-blind study treatment. 
• The TEAE observation period is defined from the day of the first dose of double-blind 
study treatment to the day of the last dose of double-blind study treatment + 168 days 
(24 weeks) (residual effect of treatment for IV dose regimen is expected until 24 weeks 
after the last dose of study drug).  
The post-treatment observation period is defined as the time from the day after the end of the 
TEAE period to the last study visit. 
Treatment-emergent adverse events are defined as those adverse events that developed, worsened, 
or became serious during the TEAE period.  
Analysis 
Adverse event incidence tables will present data by SOC sorted alphabetically and PT sorted by 
decreasing frequency, and summarize the number (n) and percentage (%) of patients experiencing 
an AE. Multiple occurrences of the same event in the same patient will be counted only once in 
the tables. Data conventions for missing or partial AE dates will be addressed in the SAP. The 
denominator for computation of percentages is the SAF population within each treatment group. 
Summaries of TEAE incidences will include: 
• All TEAEs  
• All treatment-emergent SAEs, including patient deaths  
• All treatment-emergent AESIs   
• TEAEs by severity (according to the grading scale outlined in Section 10.2.5), 
depicting the worse TEAE severity for those patients with multiple occurrences of the 
same event  
• All TEAEs leading to permanent treatment discontinuation  
An AE patient listing will be provided for all patient deaths occurring during the TEAE period and 
the post-treatment period. 
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11.4.5.2. Other Safety 
Definitions 
The following definitions will be applied to laboratory parameters and vital signs: 
• The potentially clinically significant value (PCSV) criteria are defined as abnormal 
values considered medically important by the sponsor according to predefined 
criteria/thresholds based on literature review and defined by the sponsor for clinical 
laboratory tests and vital signs. Potentially clinically significant value criteria will be 
provided in the SAP. 
• PCSV criteria will determine which patients had at least 1 PCSV during the 
TEAE period, taking into account all evaluations performed including unscheduled or 
repeated evaluations. The number of all such patients will be the numerator for the 
PCSV percentage. 
• The treatment period used for the quantitative analysis of laboratory and vital sign data 
is defined from the day after the first dose of double blind study treatment to the day of 
the last dose of double-blind study treatment + 28 days. 
Analysis 
Summary statistics of all laboratory variables (including lipid HDL-C) and all vital sign parameters 
(raw data and changes from baseline) will be calculated for each protocol-scheduled visit assessed 
during the respective treatment periods. For selected parameters, mean changes from baseline with 
the corresponding SE may be plotted over time in each treatment group. 
The incidence of PCSVs at any time during the respective TEAE periods will be summarized 
regardless of the baseline level, and again according to the following baseline categories: 
• Normal/missing 
• Abnormal according to PCSV criterion or criteria 
For laboratory parameters for which a PCSV criterion is not defined, similar table(s) using the 
normal range will be provided, regardless of baseline level. 
Listings will be provided with flags indicating the laboratory values meeting PCSV criteria. 
11.4.5.3. Treatment Exposure 
The duration of study treatment exposure will be calculated as: 
• Patient duration of study treatment exposure in weeks: (last double-blind study 
treatment administration date + 28 – first double-blind study treatment administration 
date +1 day)/7, regardless of unplanned intermittent discontinuations. 
• The total number of study treatment infusions by patient. 
The duration of study treatment exposure, measured in weeks, will be summarized by at least 
mean, median, SD, and minimum/maximum. The categorical data for number of study treatment 
infusions will be summarized by patient counts and percentages. 
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11.4.5.4. Treatment Compliance 
Since study treatment infusions will be performed at the investigative clinic, compliance will be 
assessed by infusion frequency, specifically: 
• Defined for each patient as the average number of days between 2 infusions: (last 
double-blind dose date – first double-blind dose date) / (number of infusions in 
double-blind -1), for patients receiving at least 2 infusions. 
Infusion frequency for the double-blind period will be summarized by at least mean, median, SD, 
and minimum/maximum. 
11.4.6. 
Pharmacokinetics 
11.4.6.1. Analysis of Drug Concentration Data 
Summaries of total evinacumab concentrations and total ANGPTL3 concentrations will be 
presented by nominal time point. Plots of individual concentration will be presented by actual time 
(linear and log scales). Plots of mean or median concentrations will be presented by nominal time 
(linear and log scales). 
11.4.7. 
Analysis of Immunogenicity Data 
Immunogenicity will be characterized by the ADA and NAb response observed:  
• Pre-existing immunoreactivity, defined as a positive ADA assay response at baseline, 
with all post-dose ADA results negative, or a positive assay response at baseline, with 
all post-dose ADA assay responses less than 9-fold over baseline titer levels 
• Treatment-emergent ADA response, defined as any post-dose positive ADA assay 
response when the baseline results are negative 
• Treatment-emergent ADA response may be further characterized as persistent, 
transient, or indeterminate  
− Persistent Response – Treatment-emergent ADA positive response with 2 or more 
consecutive ADA positive sampling time points, separated by at least a 16-week 
period (based on nominal sampling time), with no ADA negative samples in 
between, regardless of any missing samples   
− Indeterminate Response –Treatment-emergent ADA positive response with only 
the last collected sample positive in the ADA assay, regardless of any missing 
samples 
− Transient Response –Treatment-emergent ADA positive response that is not 
considered persistent or indeterminate, regardless of any missing samples 
• Treatment-boosted ADA response, defined as any post-dose positive ADA assay 
response that is 9-fold over baseline titer levels when baseline is positive in the 
ADA assay  
• Maximum ADA Titer values 
− Low (titer <1,000) 
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− Moderate (1,000≤ titer ≤10,000) 
− High (titer >10,000)  
• NAb status for samples that are positive in the ADA assay  
Listings of pre-existing, treatment-boosted, and treatment-emergent ADA responses, ADA titers, 
and NAb positivity presented by patient, time point, and treatment group will be provided. 
Incidence of treatment-emergent ADA and NAb will be assessed as absolute occurrence (N) and 
percent of patients (%), grouped by study treatment and ADA titer level. 
Plots of drug concentrations will be examined and the influence of ADAs and NAbs on individual 
PK profiles evaluated. Assessment of impact of ADA and NAbs on safety and efficacy may be 
provided. 
11.5. 
Timing of Statistical Analyses 
Three analyses are planned for this study.  
11.5.1. 
Interim Analysis 
An interim analysis is planned when approximately 50% (N=60) of the patients have completed 
the DBTP. This will consist of the final data contributing to the analysis of the applicable variables 
up to the week-52 visit for these patients. The efficacy analyses will be performed up to the 
week 52 visit for these patients and will be descriptive in nature. The safety analysis will be 
performed for these patients on all safety data collected and validated at the time of the interim 
analysis. A small alpha adjustment of 0.001 has been made to account for this treatment-unblinded 
interim, since the sponsor does not plan to stop the study early for evinacumab treatment benefit. 
Therefore, the significance level for the final efficacy analyses at the first step analysis will be 
0.049. 
The purpose of this interim analysis is administrative, specifically to aid in the planning of future 
studies. The interim statistical analysis will be performed external to Regeneron with the intent to 
reduce data bias in the patients ongoing in the DBTP at the time of the interim. Interim analysis 
summary results will be provided to Regeneron senior management only. The results of this 
interim analysis will not be used to change the conduct of the ongoing study in any aspect. The 
interim analysis process, the measures used to protect the blind and the integrity of the study, the 
communication plan, and the confidentiality agreement will be described in a separate document.  
11.5.2. 
First Step: Main Efficacy and Safety Analysis 
The first step analysis will be conducted as soon as all patients have been randomized and all data 
through week 52 (double-blind period) has been collected and validated. This first analysis will 
consist of the final analysis of the primary and secondary efficacy endpoints. The safety analysis 
will be performed on all safety data collected and validated at the time of the first analysis. 
The results of the first step analysis will not be used to change the conduct of the ongoing study in 
any aspect. Since data collection for the primary efficacy measure and key secondary efficacy 
measures will have been concluded at the time of this first step analysis, no further adjustment will 
be made to the study alpha level for the step 1 efficacy analysis (0.049).  
Individuals involved in the first step analysis of the study will not be involved in the conduct of 
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the study afterwards; individual patient identification will not be released to anyone who is directly 
involved in the conduct of the study. The first step analysis process, the measures used to protect 
the blind and the integrity of the study, the communication plan, and the confidentiality agreement 
will be described in a separate document. 
11.5.3. 
Final Analysis 
The final analysis will be conducted at the end of study (all patients have completed protocol 
assessments) and will consist of the final analysis for safety and follow-up visits. 
11.6. 
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. 
11.7. 
Statistical Considerations Surrounding the Premature Termination 
of a Study 
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized. Investigator and sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 15.1. 
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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
In accordance with ICH E6, the sponsor is responsible for quality assurance to ensure that the 
study is conducted and the data generated, recorded, and reported in compliance with the protocol, 
GCP, and any applicable regulatory requirement(s). The planned quality assurance and quality 
control procedures for the study are described in this section.   
12.1. 
Data Management and Electronic Systems 
12.1.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation [quality-checking], cleaning, correcting, releasing) will be maintained and stored 
at Regeneron (sponsor). 
A medical coding plan will specify the processes and the dictionary used for coding. All data 
coding (eg, AEs, baseline findings, medication, medical history) 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. 
12.1.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
• IVRS/IWRS system – randomization, study drug supply 
• EDC system – data capture – Medidata Rave 
• SAS – statistical review and analysis 
• Pharmacovigilance safety database 
12.2. 
Study Monitoring 
12.2.1. 
Monitoring of Study Sites 
Regeneron uses a study-specific risk-based approach to study monitoring and oversight, aligned 
with risk-based quality principles, outlined in ICH E6 (R2) Guideline for Good Clinical Practice. 
Risk-based quality monitoring (RBQM) methodology focuses on employing a fit-for-purpose 
monitoring strategy, supported either directly by Regeneron as sponsor, or via our CRO partners. 
Risk-based quality monitoring strategies include: reduced source data verification (SDV), targeted 
source data review (SDR), the use of off-site/remote and triggered on-site monitoring visits, and 
centralized monitoring to identify site-level risks and study-level trends. The investigator must 
allow study-related monitoring activities to occur. 
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 
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accordance with the current, approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements. 
12.2.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). The site is responsible to ensure quality within their records and systems and is 
accountable for ensuring that all source data and CRF data are timely, accurate, and complete. 
The investigator must keep all source documents on file with the CRF (throughout this protocol, 
CRF refers to either a paper CRF or an electronic CRF [eCRF]). Case report forms and source 
documents must be available at all times for inspection by authorized representatives of the 
sponsor and regulatory authorities. 
12.2.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on eCRFs within the 
EDC system by trained site personnel. All required CRFs must be completed for each and every 
patient enrolled in the study. The investigator must ensure the accuracy, completeness, and 
timeliness of the data reported to the sponsor in the CRFs. After review of the clinical data for 
each patient, the investigator must provide an electronic signature. A copy of each patient CRF 
casebook is to be retained by the investigator as part of the study record and must be available at 
all times for inspection by authorized representatives of the sponsor and regulatory authorities. 
All changes, including date and person performing corrections, will be available via the audit trail, 
which is part of the EDC system. For corrections made via data queries, a reason for any alteration 
must be provided. 
12.3. 
Audits and Inspections  
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities. Should this occur, the investigator is responsible for: 
• Informing the sponsor of a planned inspection by the authorities as soon as 
notification is received, and authorizing the sponsor’s participation in the inspection 
• Providing access to all necessary facilities, study data, and documents for the 
inspection or audit 
• Communicating any information arising from inspection by the regulatory authorities 
to the sponsor immediately 
• Taking all appropriate measures requested by the sponsor to resolve the problems 
found during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, CRFs, 
medical records, correspondence, ICFs, IRB/EC files, documentation of certification and quality 
control of supporting laboratories, and records relevant to the study maintained in any supporting 
pharmacy facilities. Conditions of study material storage are also subject to inspection. In addition, 
representatives of the sponsor may observe the conduct of any aspect of the clinical study or its 
supporting activities both within and outside of the investigator’s institution. 
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In all instances, the confidentiality of the data must be respected. 
12.4. 
Study Documentation 
12.4.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the eCRF must be signed 
electronically by the investigator.  This signed declaration accompanies each set of patient final 
eCRFs that will be provided to the sponsor. 
12.4.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of CRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
regulatory authorities. The investigator must obtain written approval from the sponsor before 
discarding or destroying any essential study documents during the retention period following study 
completion or discontinuation. Records must be destroyed in a manner that ensures confidentiality. 
If the investigator’s personal situation is such that archiving can no longer be ensured, the 
investigator must inform the sponsor (written notification) and the relevant records will be 
transferred to a mutually agreed-upon destination.  
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13. 
ETHICAL AND REGULATORY CONSIDERATIONS  
13.1. 
Good Clinical Practice Statement  
It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory 
requirements. 
13.2. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC. A copy of the IRB/EC-approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient prior to his/her participation in the study and after the 
aims, methods, objectives, and potential hazards of the study have been explained to the patient in 
language that he/she can understand. The ICF should be signed and dated by the patient and by the 
investigator or authorized designee who reviewed the ICF with the patient.   
• Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
• Patients who can understand but who can neither write nor read will have the ICF 
read to them in the 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, or if there 
are significant changes to the study procedures, 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. 
13.3. 
Patients Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained. Patients should be identified by a patient identification number only, 
on CRFs or other documents submitted to the sponsor. Documents that will not be submitted to 
the sponsor (eg, signed ICF) must be kept in strict confidence. 
The patient’s and investigator's personal data, which may be included in the sponsor database, will 
be treated in compliance with all applicable laws and regulations. The sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third party. 
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13.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve: 
• The protocol, ICF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
• Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patient, in 
which case the IRB/EC should be informed as soon as possible  
• Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
In addition, the IRB/EC should be informed of any event likely to affect the safety of patients or 
the continued conduct of the clinical study. 
A copy of the IRB/EC approval letter with a current list of the IRB/EC members and their functions 
must be received by the sponsor prior to shipment of drug supplies to the investigator. The approval 
letter should include the study number and title, the documents reviewed, and the date of the 
review. 
Records of the IRB/EC review and approval of all study documents (including approval of ongoing 
studies) must be kept on file by the investigator. 
13.5. 
Clinical Study Data Transparency 
Final study results will be published on a public clinical trial website according to applicable local 
guidelines and regulations. Treatment codes will be disseminated to each investigation site 
thereafter. 
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14. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an 
IRB/EC-approved amendment. Where required per local legislation, regulatory authority approval 
will also be sought.  
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15. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
15.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely. Reasons may include efficacy, safety, 
or futility, among others. Should the sponsor decide to terminate the study, the investigator(s) will 
be notified in writing. 
15.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
Investigator’s Decision 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at least 
30 days’ notice. The final decision should be made through mutual agreement with the sponsor. 
Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing. Reasons 
may include the following, among others:  
• The investigator has received all items and information necessary to perform the 
study, but has not enrolled any patient within a reasonable period of time. 
• The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines.  
• The total number of patients required for the study is enrolled earlier than expected. 
In all cases, the appropriate IRB/EC and health authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection of 
the patients’ interests. 
16. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
17. 
FINANCING AND INSURANCE  
Financing and insurance information is provided as a separate agreement. 
18. 
PUBLICATION POLICY  
Publication rights and procedures will be outlined in a separate clinical study agreement. 
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19. 
REFERENCES  
Berglund L, Brunzell JD, Goldberg AC, Goldberg IJ, Sacks F, Murad MH, et al. Evaluation and 
treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. J Clin 
Endocrinol Metab 2012; 97(9):2969-2989. 
Brisson D, Méthot J, Tremblay K, Tremblay M, Perron P,Gaudet D. Comparison of the efficacy 
of fibrates on hypertriglyceridemic phenotypes with different genetic and clinical characteristics. 
Pharmacogenet Genomics 2010; 20(12):742-747. 
Brown WV, Brunzell JD, Eckel RH,Stone NJ. Severe hypertriglyceridemia. J Clin Lipidol 2012; 
6(5):397-408. 
Jacobson TA, Maki KC, Orringer CE, Jones PH, Kris-Etherton P, Sikand G, et al. National Lipid 
Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 2. J Clin 
Lipidol 2015; 9(6 Suppl):S1-122.e121. 
Minicocci I, Montali A, Robciuc MR, Quagliarini F, Censi V, Labbadia G, et al. Mutations in the 
ANGPTL3 gene and familial combined hypolipidemia: a clinical and biochemical 
characterization. J Clin Endocrinol Metab 2012; 97(7):E1266-1275. 
Minicocci I, Santini S, Cantisani V, Stitziel N, Kathiresan S, Arroyo JA, et al. Clinical 
characteristics and plasma lipids in subjects with familial combined hypolipidemia: a pooled 
analysis. J Lipid Res 2013; 54(12):3481-3490. 
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: summary report--Second 
National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
symposium. J Allergy Clin Immunol 2006; 117(2):391-397. 
Surendran RP, Visser ME, Heemelaar S, Wang J, Peter J, Defesche JC, et al. Mutations in LPL, 
APOC2, APOA5, GPIHBP1 and LMF1 in patients with severe hypertriglyceridaemia. J Intern 
Med 2012; 272(2):185-196. 
 
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20. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: “A Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate 
the 
Efficacy 
and 
Safety 
of 
Evinacumab 
in 
Patients 
with 
Severe 
Hypertriglyceridemia for the Prevention of Recurrent Acute Pancreatitis” 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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Clinical Study Protocol 
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Page 82 
CONFIDENTIAL 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Medical/Study Director, Regulatory Representative, Clinical Study Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the planned conduct of the study. 
Study Title: 
 A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy 
and Safety of Evinacumab in Patients with Severe Hypertriglyceridemia for the Prevention of 
Recurrent Acute Pancreatitis 
Protocol Number: 
R1500-HTG-20118 
Protocol Version: 
R1500-HTG-20118 Amendment 2 
 
See appended electronic signature page 
Sponsor’s Responsible Medical/Study Director 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Liaison 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
 
 
                                        VV-RIM-00178604-1.0 Approved - 16 Dec 2021 GMT-5:00


Signature Page for VV-RIM-00178604 v1.0
Signature Page for VV-RIM-00178604 v1.0 Approved
Approval/eSignature
14-Dec-2021 20:48:52 GMT+0000
Approval/eSignature
14-Dec-2021 20:54:17 GMT+0000
Approval/eSignature
16-Dec-2021 09:33:57 GMT+0000
                                        VV-RIM-00178604-1.0 Approved - 16 Dec 2021 GMT-5:00

SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 
ABBREVIATED  
STATISTICAL ANALYSIS PLAN 
VERSION: FINAL 
A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of Evinacumab in Patients with Severe 
Hypertriglyceridemia for the Prevention of Recurrent Acute Pancreatitis 
Compound: 
Evinacumab 
Protocol Number: 
R1500-HTG-20118 Amendment 2 
Clinical Phase:  
Phase 2b 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician:  
 
Clinical Trial Manager: 
 
Study Director/Medical Director: 
 
Version/Date:  
V1.0 / March 15, 2023 
VV-RIM-00294814-1.0 Approved - 21 Mar 2023 GMT-5:00
NCT Number: NCT04863014


 
Clinical Development and Regulatory Affairs 
 
 
Biostatistics and Data Management 
 
CONFIDENTIAL  
Page 2 of 49 
 
The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
 
 
See appended electronic signature page 
  
 
 
 
See appended electronic signature page 
 
 
 
See appended electronic signature page 
 
 
 
See appended electronic signature page 
 
 
 
See appended electronic signature page 
 
 
 
See appended electronic signature page 
 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................7 
1. 
OVERVIEW ...............................................................................................................10 
1.1. 
Background/Rationale ................................................................................................10 
1.2. 
Study Objectives .........................................................................................................11 
1.2.1. 
Primary Objectives .....................................................................................................11 
1.2.2. 
Secondary Objectives .................................................................................................11 
1.2.3. 
Exploratory Objectives ...............................................................................................11 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol ................................12 
1.2.5. 
Revision History for Statistical Analysis Plan Amendments .....................................12 
2. 
INVESTIGATION PLAN ..........................................................................................13 
2.1. 
Study Design ...............................................................................................................13 
2.2. 
Sample Size and Power Considerations .....................................................................13 
2.3. 
Study Plan ...................................................................................................................13 
3. 
ANALYSIS POPULATIONS ....................................................................................15 
3.1. 
Efficacy Analysis Set ..................................................................................................15 
3.1.1. 
Intent-to-Treat .............................................................................................................15 
3.1.2. 
Modified Intent-to-Treat .............................................................................................15 
3.2. 
Safety Analysis Set .....................................................................................................15 
3.3. 
Pharmacokinetic (PK) Analysis Set............................................................................15 
3.4. 
The Immunogenicity Analysis Sets ............................................................................16 
4. 
ANALYSIS VARIABLES .........................................................................................17 
4.1. 
Demographic and Baseline Characteristics ................................................................17 
4.2. 
Medical History ..........................................................................................................17 
4.3. 
Prior and Concomitant Medications ...........................................................................18 
4.4. 
Prohibited Medications and Procedures During Study ...............................................18 
4.5. 
Patient Disposition ......................................................................................................19 
4.6. 
Study Treatment Exposure Variables .........................................................................20 
4.7. 
Primary and Secondary Efficacy Endpoints ...............................................................20 
4.7.1. 
Primary Efficacy Endpoint .........................................................................................20 
4.7.2. 
Secondary Efficacy Endpoints ....................................................................................21 
4.7.2.1. 
Key Secondary Efficacy Endpoints ............................................................................21 
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4.7.2.2. 
Other Secondary Efficacy Endpoints ..........................................................................21 
4.7.3. 
Exploratory Efficacy Endpoints .................................................................................22 
4.8. 
Safety Variables ..........................................................................................................22 
4.8.1. 
Adverse Events Variables ...........................................................................................22 
4.8.1.1. 
Adverse Events and Serious Adverse Events .............................................................23 
4.8.1.2. 
Adverse Events of Special Interest .............................................................................23 
4.8.1.3. 
Other AEs Require Reporting to the Sponsor.............................................................23 
4.8.1.4. 
Events Causing Death .................................................................................................24 
4.8.2. 
Laboratory Safety Variables .......................................................................................24 
4.8.3. 
Vital Signs Variables ..................................................................................................24 
4.8.4. 
12-Lead Electrocardiography (ECG) Variables .........................................................25 
4.8.5. 
Physical Examination Variables .................................................................................25 
4.9. 
Pharmacokinetic Variables .........................................................................................25 
4.10. 
Immunogenicity Variables ..........................................................................................25 
4.11. 
Pharmacodynamic and Other Biomarker Variables ...................................................25 
5. 
STATISTICAL METHODS .......................................................................................26 
5.1. 
Demographics and Baseline Characteristics ...............................................................26 
5.2. 
Medical History ..........................................................................................................26 
5.3. 
Prior and Concomitant Medications ...........................................................................26 
5.4. 
Prohibited Medications ...............................................................................................27 
5.5. 
Patient Disposition ......................................................................................................27 
5.6. 
Extent of Study Treatment Exposure and Protocol Deviations ..................................27 
5.6.1. 
Exposure to Investigational Product ...........................................................................27 
5.6.2. 
Protocol Deviations ....................................................................................................27 
5.7. 
Analyses of Efficacy Variables ..................................................................................28 
5.8. 
Analysis of Safety Data ..............................................................................................28 
5.8.1. 
Adverse Events ...........................................................................................................29 
5.8.2. 
Analysis of Adverse Events of Special Interest ..........................................................30 
5.8.3. 
Clinical Laboratory Measurements.............................................................................31 
5.8.4. 
Analysis of Vital Signs ...............................................................................................31 
5.8.5. 
Analysis of 12-Lead ECG ...........................................................................................32 
5.8.6. 
Physical Exams ...........................................................................................................32 
5.9. 
Analysis of Pharmacokinetic Variables ......................................................................32 
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5.10. 
Analysis of Immunogenicity Variables ......................................................................33 
5.10.1. 
Analysis of Anti-evinacumab Antibody (ADA) Variables ........................................33 
5.10.2. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................34 
6. 
DATA CONVENTIONS ............................................................................................35 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................35 
6.2. 
Data Handling Convention for Efficacy Variables .....................................................35 
6.3. 
Data Handling Convention for Missing Data .............................................................35 
6.4. 
Visit Windows ............................................................................................................36 
6.5. 
Unscheduled Assessments ..........................................................................................36 
6.6. 
Pooling of Centers for Statistical Analyses ................................................................36 
6.7. 
Statistical Technical Issues .........................................................................................36 
7. 
TIMING OF STATISTICAL ANALYSES ................................................................36 
8. 
SOFTWARE ...............................................................................................................36 
9. 
REFERENCES ...........................................................................................................37 
10. 
APPENDIX.................................................................................................................39 
10.1. 
Summary of Statistical Analyses ................................................................................39 
10.2. 
Windows for Analysis Time Points ............................................................................39 
10.3. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................40 
10.4. 
Schedule of Time and Events .....................................................................................44 
10.4.1. 
Footnotes for the Schedule of Events Tables .............................................................48 
10.4.1.1. 
Footnotes for Table 1 Schedule of Events (DBTP) ....................................................48 
10.4.1.2. 
Footnotes for Table 2 Schedule of Events (Off Drug Follow-up Period) ..................49 
10.4.2. 
Early Termination Visit ..............................................................................................49 
10.4.3. 
Unscheduled Visits .....................................................................................................49 
 
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LIST OF TABLES 
Table 1: 
Global Analysis Windows ..........................................................................................40 
Table 2:  
Schedule of Events for the DBTP ...............................................................................45 
Table 3: 
Schedule of Events for the Off-Drug Follow-up Period .............................................47 
 
LIST OF FIGURES 
Figure 1:  Study Flow Diagram ...................................................................................................14 
 
 
 
 
 
 
 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANGPTL3 
Angiopoietin-like 3 
APAC 
Acute Pancreatitis Adjudication Committee 
APO 
Apolipoprotein 
AP 
Acute pancreatitis 
AST 
Aspartate aminotransferase 
β-HCG 
Human chorionic gonadotrophin 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CABG 
Coronary artery bypass grafting 
CI 
Confidence interval 
COA 
Clinical outcome assessment 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
CT 
Computer tomography 
DBTP 
Double-blind treatment period 
DNA 
Deoxyribonucleic acid 
EC 
Ethics committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
FBR 
Future biomedical research 
FCS 
Familial chylomicronemia syndrome 
FH 
Familial hypercholesterolemia 
FSH 
Follicle-stimulating hormone 
FT4 
Free thyroxine 
GCP 
Good Clinical Practice 
HbA1c 
Glycosylated hemoglobin 
HDL 
High-density lipoprotein 
HDL-C 
High-density lipoprotein cholesterol  
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HoFH 
Homozygous familial hypercholesterolemia 
HTG 
Hypertriglyceridemia 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent ethics committee 
IRB 
Institutional review board 
ITT 
Intent to treat 
IV 
Intravenous 
IVRS 
Interactive voice response system 
IWRS 
Interactive web response system 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LDL-C 
Low-density lipoprotein cholesterol 
LLN 
Lower limit of normal 
LoF 
Loss of function 
LPL 
Lipoprotein lipase 
mAb 
Monoclonal antibody 
MDRD 
Modification of diet in renal disease  
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 
mITT 
Modified ITT 
MMRM 
Mixed-effect model for repeated measures 
MRI 
Magnetic resonance imaging 
NAb 
Neutralizing antibodies 
NMR 
Nuclear magnetic resonance 
NYHA 
New York Heart Association 
PCI 
Percutaneous coronary intervention 
PCR 
Polymerase chain reaction 
PK 
Pharmacokinetic 
PopPK 
Population pharmacokinetics 
PP 
Posterior probability 
PT 
Preferred term 
Q4W 
Every 4 weeks 
RBC 
Red blood cell 
RBQM 
Risk-based quality monitoring 
SAE 
Serious adverse event 
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SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Software 
SDR 
Source data review 
SDV 
Source data verification 
SE 
Standard error 
sHTG 
Severe hypertriglyceridemia 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TC 
Total cholesterol 
TEAE 
Treatment-emergent adverse event 
TG 
Triglycerides 
TIA 
Transient ischemic attack 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
VLDL 
Very-low-density lipoproteins 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
 
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1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study results 
by pre-specifying prior to the database lock the statistical approaches for the analysis of study 
data. The SAP is intended to be a comprehensive and detailed description of the strategy and 
statistical methods to be used in the analysis of data collected in the R1500-HTG-20118 study. 
For the purposes of this document, REGN1500 will be referred to as “evinacumab”. 
Due to poor recruitment progress and unlikely to meet planned enrolment, a decision was made 
on August 25, 2022 to administratively discontinue the 20118 study. An abbreviated CSR will be 
produced after the final database lock. This abbreviated SAP describes the analyses which will 
be performed for the abbreviated CSR. 
1.1. 
Background/Rationale 
Severely elevated levels of serum triglycerides (TGs) are associated with an increased risk for 
acute pancreatitis (AP). Episodes of AP secondary to severe hypertriglyceridemia (sHTG; 
TG >880 mg/dL [10 mmol/L]) frequently require hospitalization, and while most events can be 
treated with conservative therapy such as intravenous fluids and pain management, 
approximately 20% of patients suffer severe attacks associated with prolonged hospitalization 
and significant morbidity and mortality. Further, a prior episode of sHTG-associated AP 
markedly increases the risk for recurrent AP. While current lipid guidelines recommend lifestyle 
interventions and medications to lower TG levels to prevent AP, patients with sHTG often 
require robust (>50%) reductions in TG to lower the risk of AP. Indeed, a substantial proportion 
of patients have persistent hypertriglyceridemia (HTG), despite the use of multiple medications 
to lower TG levels. Current available therapies for lowering TG levels (eg, statins, fibrates, 
niacin, omega-3 fatty acids) typically provide 20% to 50% reductions in TG levels, which is 
often insufficient to lower TGs to a target level of <500 mg/dL (5.6 mmol/L).  
Patients with TGs >880 mg/dL (>10 mmol/L) typically have chylomicronemia that may be either 
multifactorial (polygenic and environmental) in origin, or much more rarely, due to the presence 
of highly penetrant gene mutations in lipoprotein lipase (LPL) or genes encoding proteins in the 
LPL pathway (APOA5, APOC2, APOE, GPIHBP1, and LMF1), as observed in Familial 
Chylomicronemia Syndrome (FCS). Lipoprotein lipase is an endothelial-bound enzyme involved 
in the hydrolysis of the TG content of very-low-density lipoproteins (VLDL) and chylomicron 
lipoproteins. Mutations in the LPL gene lead to varying levels of loss of LPL functional activity 
and elevated levels of plasma TGs, especially in chylomicrons. However, there is a high degree 
of genetic polymorphism and combinatorial effects of genes, diseases (such as type 2 diabetes), 
and environment. There is an unmet medical need for additional treatment options for patients 
with sHTG and a history of AP to further lower TG levels and the risk of recurrent attacks of AP, 
regardless of their genetic background. 
Angiopoietin-like 3 (ANGPTL3) acts as a natural inhibitor of LPL and has emerged as a target 
for the treatment of elevated levels of TG and low-density lipoprotein cholesterol (LDL-C). Loss 
of function of ANGPTL3 in humans has been associated with reductions in TG and LDL-C. 
Evinacumab (REGN1500) is a human IgG4 monoclonal antibody (mAb) specific for ANGPTL3. 
It is currently approved as an adjunctive treatment for homozygous familial 
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hypercholesterolemia (HoFH, EvkeezaTM) and is being evaluated for treatment of dyslipidemia 
including HTG. Evinacumab has been studied in approximately 580 individuals with elevations 
in LDL-C and TG and has been generally well tolerated up to single doses of 20 mg/kg 
intravenously (IV) and in multiple subcutaneous (SC) doses up to 450 mg administered 
weekly (QW), and 20 mg/kg IV administered every 4 weeks (Q4W) for approximately 8 weeks 
(ie 2 doses).  
The current study is a phase 2b randomized, placebo-controlled study intended to demonstrate 
that evinacumab can prevent recurrent episodes of HTG-associated AP in patients with sHTG, 
but without FCS due to mutations in LPL. The secondary aims are to evaluate the effects of 
evinacumab on safety and changes in biomarkers of TG-rich lipoprotein metabolism, including 
serum TG, ApoC3, ApoB48, and ApoB100 in this patient population. 
Additional background information on the study drug and development program can be found in 
the Investigator’s Brochure. 
1.2. 
Study Objectives 
1.2.1. 
Primary Objectives 
The primary objective of the study is to determine the proportion of patients with elevated TGs, 
without FCS due to LoF mutations in LPL, and a history of HTG-associated AP* who 
experience a recurrent episode of AP after treatment with evinacumab versus placebo. 
*Includes adult patients with 1) elevated baseline fasting TGs >880 mg/dL and history of 
1 HTG-associated AP within 24 months of screening or 2) elevated baseline fasting TG 
values >500 mg/dL in patients with a history of 2 or more HTG-associated AP within 24 months 
or 3) elevated baseline fasting TG values >500 mg/dL with a prior documented fasted TG values 
>1000 mg/dL and a history of 1 or more HTG-associated AP within 24 months.  All participants 
are without FCS due to LPL loss of function mutations.   
1.2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To determine the change in the standard lipid profile after therapy with evinacumab 
versus placebo  
• To determine the changes in specialty lipoprotein parameters (ApoC3, ApoB48, 
ApoB100, and nuclear magnetic resonance [NMR] lipid profile) after therapy with 
evinacumab versus placebo 
• To measure the number of AP episodes per patient 
• To assess the safety and tolerability of evinacumab 
• To assess the potential immunogenicity of evinacumab  
• To assess the concentrations of total evinacumab and total ANGPTL3  
1.2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
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• To evaluate responder categories of fasting TG levels 
• To measure length of stay for patients hospitalized for AP 
• To assess the effect of evinacumab versus placebo on the frequency and severity of 
abdominal pain  
• To study evinacumab’s mechanism of action in modulating lipoprotein metabolism in 
HTG, and related diseases 
• To explore genotypic or other biomarker differences that may influence efficacy and 
safety of evinacumab for further understanding of HTG, or other conditions 
associated with ANGPTL3 antagonism (for patients who consent to participate in a 
genomics sub-study) 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol 
Considering the few patients enrolled in the study due to the early termination of the protocol, 
the following analyses will not be performed: 
• The efficacy analyses and test for the statistical hypothesis described in the statistical 
sections in the final protocol 
• The analyses for the mITT population  
• The analyses of the other secondary endpoints of the NMR-determined particle size and 
number (biomarkers of TG-rich lipoprotein metabolism) 
• The analyses of the exploratory efficacy endpoints 
• The NAb analyses for the immunogenicity variables 
1.2.5. 
Revision History for Statistical Analysis Plan Amendments 
This is the first version of the Statistical Analysis Plan (SAP). 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design 
This is a phase 2b, multicenter, international, randomized, placebo-controlled study intended to 
demonstrate that evinacumab can prevent recurrent AP in patients with HTG and a recent history 
of HTG-associated AP.  
Eligible patients for this study are patients with documented history of 1 HTG-associated AP 
episode within 24 months of screening, and fasting serum TG value >880 mg/dL (10 mmol/L) or 
fasting serum TG value >500 mg/dL (5.6 mmol/L) in patients with a history of 2 or more HTG-
associated AP episodes within 24 months of screening determined during the screening period. 
2.2. 
Sample Size and Power Considerations 
For the primary efficacy hypothesis during the DBTP, a total sample size of 120 patients 
(60 patients in each treatment group) will have 90% power to detect a treatment group difference 
in positively adjudicated AP event rates of 24% (placebo event rate: 30%; evinacumab event 
rate: 6%), with 0.049 two-sided significance level (data on file). This sample size has been 
adjusted for a 5% non-evaluable patient rate for the primary efficacy endpoint.   
2.3. 
Study Plan 
The study consists of 3 periods: a screening period, a DBTP, and a safety follow-up period. The 
screening period of up to 28 days will determine participant eligibility and will include an 
evaluation of prior episodes of HTG-associated AP, genotyping to exclude patients with FCS due 
to LoF mutations in LPL, and a measurement of fasting TG level. Patients must have baseline 
fasting TGs >880 mg/dL and a history of HTG-associated AP within 24 months of screening or 
they must have baseline fasting TGs >500 mg/dL if they have had 2 or more episodes of 
HTG-associated AP within 24 months of screening or if they have had baseline fasting TG 
values >500 mg/dL and documented fasting TG values >1000 mg/dL with a history of HTG-
associated AP within 24 months of screening to be enrolled in the study. 
Patients who fulfill all the eligibility criteria will be randomized and receive their first dose of 
assigned study drug on day 1, with subsequent doses administered approximately Q4W during 
the 52-week DBTP. This will be followed by an off-drug follow-up period of 20 weeks. Every 
effort will be made to keep patients in the study and to collect the week 52 visit data, even if 
study drug administration has been discontinued for the patient. 
Approximately 120 adult patients will be randomized 1:1 to receive evinacumab or matching 
placebo. A study schematic is provided in Figure 1. 
Efficacy will be assessed by measuring the number of patients with at least 1 independently 
adjudicated positive event of AP over 52 weeks of treatment with evinacumab versus placebo. 
The study will have an independent committee to adjudicate these episodes in accordance with 
clinical standards for diagnosis of AP (see Section 4.7.1). Efficacy will also be assessed by 
clinical laboratory evaluation of lipid levels at pre-specified time points throughout the study. 
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Safety will be assessed throughout the study by comparing the frequency and severity of adverse 
events (AEs) between the evinacumab and placebo groups, as well as evaluating abnormal 
laboratory findings, ECG findings, and ADA and NAb assessments. 
Figure 1:  
Study Flow Diagram 
 
 
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3. 
ANALYSIS POPULATIONS 
In accordance with guidance from the International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (ICH, 1998), below are the patient populations defined 
for statistical analysis. The Intent-to-Treat Analysis Set will be the main analysis set for efficacy. 
The Safety Analysis Set will be the main analysis set for exposure/compliance, clinical safety. 
Additional analysis sets are defined for pharmacokinetic (PK), anti-drug (evinacumab) antibody 
(ADA).  
3.1. 
Efficacy Analysis Set 
3.1.1. 
Intent-to-Treat 
The ITT population is defined as all randomized patients who received 1 dose or part of a dose of 
study drug. Patients in the ITT population will be analyzed according to the treatment group 
allocated by randomization (ie, as-randomized treatment group). 
3.1.2. 
Modified Intent-to-Treat 
The modified ITT (mITT) population is defined as the all-randomized population who took at 
least 1 dose or part of a dose of study drug and includes patients for whom the primary endpoint 
is evaluated during the efficacy treatment period. The efficacy treatment period is defined as the 
time from the first double-blind study drug administration up to 35 days after the last double-
blind study drug administration. Patients in the mITT population will be analyzed according to 
the treatment group allocated by randomization. 
3.2. 
Safety Analysis Set 
The safety analysis set (SAF) considered for safety analyses and treatment 
compliance/administration will be the randomized population who received at least 1 dose or 
part of a dose of double-blind study drug. Patients will be analyzed according to the treatment 
received (placebo or evinacumab). In addition:   
• Randomized patients for whom it is unclear whether they took the study drug will be 
included in the safety population as randomized. 
• For patients receiving study drug from more than 1 treatment group during the trial, 
the treatment group allocation for as-treated analysis will be the one in which the 
patient was treated with the highest number of infusions 
3.3. 
Pharmacokinetic (PK) Analysis Set 
The PK analysis set will be all randomized patients who received any study drug and for each 
patient who has at least 1 non-missing post-baseline measurement of evinacumab concentration. 
Treatment assignments are based on the treatment received. 
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The Target Analysis Set: The total target analysis set includes all treated subjects who received 
any study drug and who had at least 1 non-missing post-dose total ANGPTL3 measurement 
following the first dose of study drug.   
3.4. 
The Immunogenicity Analysis Sets 
The ADA analysis set includes all treated patients who received any amount of study drug 
(active or placebo [safety analysis set]) and had at least one non-missing ADA result following 
the first dose of the study drug or placebo. The ADA analysis set is based on the actual treatment 
received (as treated) rather than as randomized.  
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
For each patient, demographic and baseline characteristics will be obtained according to the 
definition of baseline specified in Section 6.1. 
All baseline safety and efficacy parameters (apart from those listed below) will be presented 
along with the summary statistics in the safety and efficacy sections. 
The following variables will be summarized:  
Demographic Characteristics 
• Sex (Male, Female) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Not Reported) 
• Age in years (quantitative and qualitative variable: <45, ≥45 to <65, ≥65 to <75, and 
≥75 years; and <65, and ≥65 years) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not reported) 
Baseline Characteristics 
• Baseline Weight (kg) 
• Baseline Height (cm) 
• Baseline Body mass index (BMI) in kg/m² (quantitative and qualitative variable 
defined as <30, ≥30) 
• Alcohol consumption status (never, former, and current) 
Baseline Disease Characteristics 
• Lipid parameters - quantitative variables for all efficacy parameters  
• Fasting TG qualitative variable defined as: <500, >=500 to <880, >=880 to <1000, 
>=1000 mg/dL (<12.93, >=12.93 to 22.76, >=22.76 to <25.86, >=25.86 mmol/L) 
• HbA1c both quantitative variable and qualitative variable defined as: <5.7%, ≥5.7% 
to <6.5%, ≥6.5% 
4.2. 
Medical History 
As applicable, patient medical history, pre-listed or not in the e-CRF will be dictionary coded by 
primary system organ class and preferred term using the Medical Dictionary for Regulatory 
Activities (MedDRA), specifically the MedDRA version in effect at the time of the first database 
lock.  
The medical history of interest collected on dedicated and pre-listed e-CRFs is: acute pancreatitis 
history, cardiovascular history. 
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4.3. 
Prior and Concomitant Medications 
All medications taken from the time of informed consent to the final study visit, including 
medications that were started before the study and are ongoing during the study, will be reported 
in Concomitant Medications CRF.  
All medications will be dictionary coded using the World Health Organization-Drug Dictionary 
(WHO-DD) to both an anatomic category and a therapeutic category, with the version in effect at 
the time of the first database lock.  Drug names will be matched to respective Anatomical-
Therapeutic-Chemical (ATC) classification, although a drug can be matched to more than one 
ATC classification (i.e. patients can be counted in several categories for the same medication).   
Prior medications, concomitant medications, and post-treatment medications are defined below. 
• Prior medications are defined as medications for which the stop date is before the date 
of the first study treatment administration. 
• Concomitant medications are defined as medications that are administered to the 
patients during the study treatment period. Specifically: 
➢ Start date of the concomitant medication is on or after the first study treatment 
administration in study treatment period; or 
➢ Start date of the concomitant medication is before the first study treatment 
administration in study treatment period and is “Ongoing” during the treatment 
emergent period; or  
➢ Start date of the concomitant medication is before the first study treatment 
administration in study treatment period, and the end date is on or after the first 
study treatment administration in study treatment period. 
The concomitant medication treatment emergent period is defined as:  
• For concomitant medications in the study treatment period, the treatment emergent 
period is defined from the first day of study treatment administration to the last day of 
study treatment +168 days. 
Note: In the case the start date is before first study treatment administration and both 
ongoing status and stop date are missing, the medication will be assumed to be 
concomitant. 
• Post-treatment medications are defined as medications for which the start date is after 
last date of study treatment administration +169 days (≥ last study treatment +169 
days). 
4.4. 
Prohibited Medications and Procedures During Study 
The definitions of prohibited medications and procedures are described in the Section 7.7.2 of 
the protocol. They will be reviewed and identified by the study clinician and reported in protocol 
deviations.   
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4.5. 
Patient Disposition 
Patient disposition will include the description of patient status at major milestone decisions in 
the study, as well as the patient analysis populations.   
For patient study status, patient milestone categories are defined below. As applicable, 
percentages will be calculated using a denominator of the number of patients treated with study 
treatment, with two exceptions.  Specifically, the two exceptions will be for the screened and 
screen failure categories, which will not have associated percentages shown. 
• The total number of screened patients: defined as originally having met the inclusion 
criteria and signed the ICF 
• The total number of patients failed screening 
• The total number of patients randomized 
• The total number of patients randomized but not receiving study treatment. 
• The total number of patients randomized and receiving study treatment. 
• The total number of patients who completed the study treatment period as collected 
on the End of Treatment e-CRF. 
• The total number of patients who prematurely discontinued study treatment during 
the study treatment period, and the reasons for discontinuation collected on the End of 
Treatment e-CRF. 
• The total number of patients ongoing in study treatment period (applicable for the 
interim analyses) 
• The total number of patients who complete the study as collected on the End of Study 
e-CRF 
The following patient populations for analyses are listed below: 
• Intent-to-Treat (ITT) Analysis Set 
• Modified ITT (mITT) Analysis Set 
• Safety (SAF) Analysis Set 
• Pharmacokinetic (PK) Analysis Set  
• Immunogenicity (ADA and NAb) Analysis Sets 
The following patient listings will provide the details from the patient disposition table. 
• A listing of patients treated but not randomized, patients randomized but not treated. 
• A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation. 
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4.6. 
Study Treatment Exposure Variables 
Study treatment exposure variables for infusions administered during the study are listed below 
with associated definitions: 
• Patient duration of study treatment exposure in weeks defined as: (last study 
treatment administration date in the study +28 – first study treatment administration 
date in the study +1)/7. Unplanned intermittent discontinuations in study treatment 
will be addressed on a case-by-case basis, since this is expected to be a rare 
occurrence. 
• Patient duration of study treatment exposure in patient-years is calculated as the 
patient duration in weeks multiplied by 7/365. 
• The following categories will be used for treatment exposure intervals: ≥1 day and <4 
weeks, ≥4 weeks and <8 weeks, ≥8 weeks and <12 weeks, ≥12 weeks and <16 weeks, 
≥16 weeks and <20 weeks, ≥20 weeks and <24 weeks, ≥24 weeks and <28 weeks, 
≥28 weeks and <32 weeks, ≥32 weeks and <36 weeks, ≥36 weeks and <40 weeks, 
≥40 weeks and <44 weeks, ≥44 weeks and <48 weeks, ≥48 weeks and <52 weeks, 
≥52 weeks and <56 weeks, etc. 
• The total number of study treatment infusions by patient.  
All important and minor protocol deviations potentially impacting safety and efficacy analyses, 
and drug-dispensing irregularities, as well as other deviations, will be collected and reviewed on 
an ongoing basis throughout the study as described in the Protocol Deviation Plan (PDP).  Both 
monitoring-collected and programmatically derived deviations are listed and defined in the PDP. 
4.7. 
Primary and Secondary Efficacy Endpoints 
4.7.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of patients with at least 1 positively adjudicated 
AP episode during the 52 weeks of the DBTP. 
The primary efficacy variable is the occurrence of an episode of AP as determined by an 
independent acute pancreatitis adjudication committee (APAC). Suspected AP events will be 
reviewed by 2 independent physicians (phase 1). In the event of disagreement between these 
2 initial reviewers, the case will be reviewed by at least 3 physicians meeting as a committee 
(phase 2). The final adjudicated result will be either the initial independently agreed-upon result 
from phase 1, or the majority decision from phase 2. Every effort will be made to maintain the 
same group of physician reviewers for adjudication. 
Acute pancreatitis adjudication committee members will be blinded to TG values to avoid 
treatment unblinding. 
The diagnosis of AP is based on meeting either clinical or imaging criteria, or both:  
1) Clinical symptoms and signs 
a. Acute onset abdominal pain, or nausea or vomiting  
AND 
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b. Biochemical evidence of pancreatic inflammation 
i. Serum amylase or lipase >3x ULN for individuals without a medical 
history of chronic pancreatitis; OR 
ii. Serum amylase or lipase >2x ULN for individuals with a medical history 
of chronic pancreatitis 
2) Pancreatic inflammation assessed by imaging 
a. Characteristic findings of AP on imaging (contrast-enhanced CT, MRI, or 
transabdominal ultrasonography. These findings include but are not limited to: 
pancreatic enlargement, necrosis, edema, peripancreatic stranding, and 
peripancreatic fluid collections.  
Additional details are provided in the APAC charter. 
4.7.2. 
Secondary Efficacy Endpoints 
4.7.2.1. 
Key Secondary Efficacy Endpoints 
The key secondary efficacy endpoints are: 
• Percent change in ApoC3 from baseline to week 52  
• Percent change in fasting TGs from baseline to week 52  
The fasting TG and ApoC3 assessment at week 52 will be the respective measurement obtained 
within the week-52 analysis window. Scheduled and unscheduled measurements may be used to 
provide a value for the secondary efficacy endpoints. The analysis window used to allocate a 
time point to a measurement will be defined in Appendix 10.2. The lipid value at each post-
baseline time point will be the lipid value obtained within the global analysis window, regardless 
of adherence to treatment and subsequent therapies. The definition of the baseline value for 
computation of the change from baseline can be found in Section 6.1.   
The secondary efficacy lipid endpoints of the percent change in the lipid parameters from 
baseline over time is defined as:  100x (lipid value - lipid value at baseline)/lipid value at 
baseline. 
All lipid values (scheduled or unscheduled, fasting or not fasting) may be used to provide a value 
for the secondary efficacy endpoint, if appropriate, with the following exceptions:  
• Only fasting TG measurements will be included in the analysis. TG measurements 
with missing fasting status will be excluded from the analyses.  
4.7.2.2. 
Other Secondary Efficacy Endpoints 
The other secondary efficacy endpoints are: 
• The percent change in non-HDL-C from baseline to week 52 
• The percent change in TC from baseline to week 52 
• The percent change in ApoB48 from baseline to week 52 
• The percent change in ApoB100 from baseline to week 52 
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• The percent change in NMR-determined particle size and number (biomarkers of TG-
rich lipoprotein metabolism) from baseline to week 52 
• Number of independently adjudicated episodes of AP per patient during 52 weeks of 
the DBTP 
4.7.3. 
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints are: 
• Proportion of patient responders during 52 weeks of therapy with evinacumab versus 
placebo, with response defined as reaching common clinical TG thresholds of 
≤880 mg/dL, ≤500 mg/dL, ≤150 mg/dL  
• Length of stay for AP hospitalizations during 52 weeks of therapy with evinacumab 
versus placebo  
• Proportion of abdominal pain-free intervals during 52 weeks of therapy with 
evinacumab versus placebo, measured via a single-item questionnaire 
• Mean change in abdominal pain scores on the Hypertriglyceridemia and Acute 
Pancreatitis: Pain Questionnaire (HAP-Pain) during 52 weeks of therapy with 
evinacumab versus placebo 
4.8. 
Safety Variables 
The safety variables in this study include: 
• TEAEs 
• Routine safety laboratory tests (hematology, chemistry, urinalysis, and pregnancy 
testing [for women of childbearing potential or WOCBP]) 
• Vital signs  
• Electrocardiogram (ECG) 
• Physical examination 
4.8.1. 
Adverse Events Variables 
The period of safety observation starts from the time when the patient gives informed consent 
and continues into the following periods: 
• The pre-treatment period is defined from the day the ICF is signed to the day before 
the first dose of study treatment administration. 
• The treatment-emergent adverse event (TEAE) period is defined from the day of the 
first study treatment administration to the day of the last study treatment 
administration + 168 days (24 weeks).  
• The post-treatment period is defined from the day after the end of the TEAE period to 
the last study visit.  
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4.8.1.1. 
Adverse Events and Serious Adverse Events 
Adverse events (including serious adverse events (SAE), AEs causing permanent treatment 
discontinuation, deaths, and AEs of special interest) are recorded from the time of signed 
informed consent until the end of study. All AEs diagnosed by the Investigator will be reported 
and described. 
All AEs will be dictionary coded by “lowest level term (LLT)”, “preferred term (PT)”, “high 
level term (HLT)”, “high level group term (HLGT)” and associated primary “system organ class 
(SOC)” using the version of MedDRA in effect at the time of the first database lock. 
Adverse Event Observation Period  
• Pre-treatment AEs are AEs that developed or worsened or became serious during the 
pre-treatment period. 
• TEAEs are AEs that developed or worsened or became serious during the TEAE 
period.  
• Post-treatment AEs are AEs that developed or worsened or became serious during the 
post-treatment period. 
4.8.1.2. 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) are AEs (serious or non-serious) required to be 
monitored, documented, and managed in a pre-specified manner. AESIs will be recorded on the 
adverse event e-CRF using dedicated tick boxes. 
The AESIs include the following: 
• Anaphylactic reactions 
• Moderate/severe infusion reactions 
• Allergic reactions that require medical treatment or consultation with another 
physician for further evaluation 
• Increase in ALT or AST: ≥3x ULN (if baseline <ULN), or ≥2x baseline value (if 
baseline ≥ULN) 
4.8.1.3. 
Other AEs Require Reporting to the Sponsor  
The other AEs which require reporting to the sponsor (or designee) within 24 hours of learning 
of the event are: 
• 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 during the study or within 24 weeks of 
the last dose of study drug. Any complication of pregnancy affecting a female 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. 
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• Symptomatic overdose with 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. 
4.8.1.4. 
Events Causing Death 
The observation periods for patient deaths are per the observation periods defined above.  
• Death on-treatment:  deaths occurring during the TEAE period, 
• Death post-treatment:  deaths occurring during the post-treatment period. 
4.8.2. 
Laboratory Safety Variables 
Clinical laboratory tests will consist of blood analyses (including hematology, clinical chemistry 
and other). Clinical laboratory values will be converted and analyzed in both international units 
and US conventional units, with associated normal ranges provided by the central laboratory. 
Both actual test values and “change from baseline” values (defined as the post-baseline value 
minus the baseline value) will be used in the result summaries.  Potentially clinically significant 
values (PCSV) ranges will be applied to the laboratory test values as applicable 
(see Appendix 10.3 for PCSV definitions). For those laboratory tests that do not have PCSV 
ranges, central laboratory normal ranges will be applied to identify out-of-range values.  All 
laboratory test samples will be collected before study treatment administration during the 
protocol scheduled visits. 
Unless otherwise specified below, blood samples for clinical laboratories will be collected at the 
protocol scheduled visits, and visits will be assigned to the Global Analysis Windows 
(See Appendix 10.2). The laboratory parameters (excluding those considered as efficacy 
parameters) will be classified as follows: 
Hematology: 
• Red blood cells and platelets:  hemoglobin, hematocrit, erythrocytes count, platelets 
count, red blood indices 
• White blood cells: white blood cells, neutrophils, lymphocytes, monocytes, basophils, 
eosinophils 
Clinical chemistry: 
• Metabolism:  glucose, total protein, albumin, creatine phosphokinase, HbA1c 
• Electrolytes:  sodium, potassium, chloride, calcium, bicarbonate 
• Renal function:  creatinine, blood urea nitrogen (BUN), uric acid 
• Liver function:  ALT, aspartate aminotransferases (AST), alkaline phosphatase 
(ALP), total bilirubin, LDH 
4.8.3. 
Vital Signs Variables 
Vital signs variables will include height (cm), weight (kg), heart rate (bpm), respiration (rpm), 
temperature (C or F), systolic and diastolic blood pressure (mmHg) after resting at least five 
minutes. Both actual test values and “change from baseline” values (defined as the post-baseline 
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value minus the baseline value) will be provided for protocol specified visits and visits will be 
assigned to the Global Analysis Windows (See Appendix 10.2 ). Potentially clinically significant 
values (PCSV) ranges will be applied to the vital sign parameter values as applicable 
(see Appendix 10.3 for PCSV definitions).  
4.8.4. 
12-Lead Electrocardiography (ECG) Variables 
Electrocardiograms will be performed before blood samples are collected at visits requiring 
blood draws. A standard 12-lead ECG will be performed at specified time points according to 
Appendix 10.4. The ventricular rate, PR, QRS, RR, QT, QTcF, and QTcB intervals will be 
recorded. Electrocardiogram assessments will be described as normal or abnormal, and visits will 
be assigned to the Global Analysis Windows (See Appendix 10.2). 
4.8.5. 
Physical Examination Variables 
Physical examination will be conducted at the protocol scheduled visits (See Appendix 10.4 for 
schedule of events). The visits will be assigned to the Global Analysis Windows 
(See Appendix 10.2). 
4.9. 
Pharmacokinetic Variables 
Pharmacokinetic (PK) variables include total evinacumab concentrations and total ANGPTL3 
concentrations collected at each specified time point (both pre-dose and end-of-infusion samples) 
specified in Appendix 10.4. 
4.10. 
Immunogenicity Variables   
Anti-drug antibody variables will include ADA status, titer and time-point/visit. Serum samples 
for ADA will be collected at the clinic visits specified in Appendix 10.4. Considering the few 
patients enrolled in the study due to the early termination of the protocol, samples positive in the 
ADA assay will be characterized for ADA titers, but NAb analyses will not be performed.  
4.11. 
Pharmacodynamic and Other Biomarker Variables 
The pharmacodynamic (PD) variables in this study are high-density lipoprotein cholesterol 
(HDL-C) and LDL-C.  
ApoC3, ApoB48, ApoB100, and NMR-determined particle size and number are biomarkers of 
TG-rich lipoprotein metabolism and are also efficacy variables in this study. 
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5. 
STATISTICAL METHODS 
In general, demographic, baseline characteristics, and medical history will be summarized and 
presented in treatment groups and overall for the study in the safety analysis set. The exposure, 
prior and concomitant medications, and the safety data will be summarized and presented in 
treatment groups for the safety analysis set. The efficacy data will be summarized and presented 
in treatment groups for the ITT analysis set. 
Continuous data will be summarized descriptively using the number of patients with data, 
mean, SD, median, minimum and maximum for each treatment group for the study. First quartile 
(Q1) and third quartile (Q3) will be also provided for baseline lipid parameters, HbA1c.  
Categorical and ordinal data will be summarized using the number and percentage of patients for 
each treatment group for the study. 
5.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group 
and overall for the study in the safety analysis set.   
Parameters listed in Section 4.1 will be summarized as described. As applicable, other safety 
baseline data not listed in Section 4.1 will be presented collectively in the descriptive statistics 
summary tables containing respective post-baseline data. 
5.2. 
Medical History  
Medical history will be descriptively summarized by treatment group and overall for the study in 
the safety analysis set. 
All reported patient’s medical history will be presented by primary SOC and HLT.  The tables 
will be presented by SOC sorted alphabetically and decreasing patient frequency of HLT based 
on the overall incidence in the study.   
In addition, acute pancreatitis history and cardiovascular history will be summarized by 
treatment group. Continuous data will be summarized using the number of patients with data, 
mean, SD, median, Q1, Q3, minimum and maximum for the study and for each of the treatment 
groups. Categorical and ordinal data will be summarized using the number and percentage of 
patients in the study and for each of the treatment groups.  
5.3. 
Prior and Concomitant Medications  
All prior medications, dictionary coded by WHO-DD, will be descriptively summarized by 
treatment group for the study in the safety analysis set. Summaries will present patient counts 
and percentages for all prior medications, by decreasing frequency of the overall incidence of 
ATC followed by therapeutic class.  In case of equal frequency across anatomical or therapeutic 
categories, alphabetical order will be used. Patients will be counted once in each ATC category 
(anatomical or therapeutic) linked to the medication, but may be counted several times for the 
same medication.  
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All concomitant medications during the study, dictionary coded by WHO-DD, will be 
descriptively summarized by treatment group for the study. Summaries will present patient 
counts and percentages for all concomitant medications, by decreasing frequency of the 
evinacumab group incidence of ATC followed by therapeutic class.  In case of equal frequency 
across anatomical or therapeutic categories, alphabetical order will be used. Patients will be 
counted once in each ATC category (anatomic or therapeutic) linked to the medication, hence 
may be counted several times for the same medication.  Additionally, concomitant lipid lowering 
treatment (LLT) use will also be summarized by patient counts and percentages.  
5.4. 
Prohibited Medications  
Listing of prohibited medications will be provided for the patients in the safety analysis set for 
the study. 
5.5. 
Patient Disposition 
Patient disposition includes the description of patient status at major milestone decisions in the 
study. 
Patient study status for the study will be summarized by treatment group for the study (screened 
patients, screen failures, and non-enrolled but treated patients only).  Summaries will provide the 
frequency (and percentage as applicable) of patients that met the criteria for the variables 
described in Section 4.5.  Exception listings will be generated for any patient treated but not 
enrolled, enrolled but not treated. 
All patient analysis populations will be summarized by treatment group for the study, depicting 
frequencies (and percentages) of patients that met the criteria for each population described in 
Section 3.  
The summary of patient disposition will be provided for all patients in the study. 
5.6. 
Extent of Study Treatment Exposure and Protocol Deviations 
The extent of study treatment exposure and compliance for the study described in Section 4.6 
will be assessed and summarized by treatment group for the study, for patients in the safety 
analysis set. 
5.6.1. 
Exposure to Investigational Product 
Study treatment exposure in the study will be descriptively summarized for treatment duration 
and total number of infusions as described in Section 4.6. Treatment duration (including patient-
years) and total number of infusions will be summarized using the number of patients with data, 
mean, SD, Q1, Q3, median, minimum and maximum. Categorized 4-week intervals of treatment 
duration will be summarized descriptively by counts and percentages. 
5.6.2. 
Protocol Deviations 
Both monitored and derived protocol deviations will be summarized for important deviations 
(counts of deviations), patients (incurring a deviation by count and percentage), and by type of 
important deviation (patient count and percentage). A patient listing of all important and minor 
protocol deviations will be provided. 
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5.7. 
Analyses of Efficacy Variables 
For statistics where international and conventional units do not impact the results (e.g. percent 
changes from baseline, rates of patients below a threshold), derivations will be calculated and 
summaries will be run using conventional units. For other statistics (e.g. values at baseline and 
over time, absolute changes from baseline), derivations will be presented in both international 
and conventional units. 
Considering the few patients enrolled in the study due to the early termination of the protocol, 
the efficacy analyses and test for the statistical hypothesis described in the statistical section in 
the final protocol will not be performed. Instead, descriptive statistics over time will be provided 
for the efficacy endpoints by treatment group for the Intent-to-Treat population. No formal 
inferential testing will be performed. The analyses for the mITT population, the analyses of the 
other secondary endpoints of the NMR-determined particle size and number (biomarkers of TG-
rich lipoprotein metabolism, and the analyses of the exploratory endpoints will not be performed. 
5.8. 
Analysis of Safety Data 
Safety summaries for the study will be presented by treatment group for the study in the safety 
analysis set. No formal inferential testing will be performed. Summaries will be descriptive in 
nature.  
All safety analyses will be performed using the baseline definitions described in Section 6.1. 
General common rules 
All safety analyses will be performed, unless otherwise specified, using the following common 
rules: 
• Safety data in patients who do not belong to the safety analysis set (e.g., exposed but 
not enrolled) will be listed separately. 
• The potentially clinically significant value (PCSV) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests and vital signs (PCSV version dated January 2009 [Appendix 10.3 ]).  
Considering that the threshold defined in the PCSV list for monocytes and basophils 
can be below the ULN, the following PCSV criterion will be used for the PCSV 
analysis of monocytes and basophils:  
➢ PCSV criterion for monocytes: >0.7 Giga/L or >ULN (if ULN ≥0.7 Giga/L). 
➢ PCSV criterion for basophils: >0.1 Giga/L or >ULN (if ULN ≥0.1 Giga/L). 
• PCSV criteria will determine which patients had at least 1 PCSV during the TEAE 
period, taking into account all evaluations including unscheduled or repeated 
evaluations. 
• The treatment-emergent PCSV denominator by treatment group for a given parameter 
will be based on the number of patients assessed for that given parameter at least once 
during the TEAE period. 
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• All measurements, scheduled or unscheduled, fasting or not fasting, will be assigned 
to Global Analysis Windows defined in Appendix 10.2 /Table 1 in order to provide 
an assessment for the screening visit through follow-up visit time points. 
• For quantitative safety parameters including central laboratory measurements and 
vital sign scores, descriptive statistics will be used to summarize observed values and 
change from baseline values by visit.  
5.8.1. 
Adverse Events  
In general, the primary focus of AE reporting will be on TEAEs summarized in TEAE period.  
Post-treatment AEs will be summarized separately.  
If an AE onset date (occurrence, worsening, or becoming serious) is incomplete, an imputation 
algorithm will be used to classify the AE as pre-treatment, treatment-emergent, or 
post-treatment.  The algorithm for imputing date of onset will be conservative and will classify 
an AE as treatment-emergent unless there is definitive information to determine pre-treatment or 
post-treatment status.  Details on classification of AEs with missing or partial onset dates are 
provided in Section 6.3. 
Adverse event incidence tables will present the number (n) and percentage (%) of patients 
experiencing an AE by SOC and PT.  In addition, incidence tables by SOC, HLGT, HLT, and PT 
will be provided for all TEAEs, serious TEAEs, and TEAEs leading to permanent treatment 
discontinuation. Multiple occurrences of the same event in the same patient will be counted only 
once in the tables within a treatment phase (TEAE or post-treatment AE). For tables presenting 
by severity of events, the worst severity will be chosen for patients with multiple instances of the 
same event. The denominator for computation of percentages is the safety analysis set within 
each treatment group. 
AE incidence tables will present data by SOC sorted alphabetically and PT sorted by decreasing 
frequency of the overall patient, and summarize the number (n) and percentage (%) of patients 
experiencing an AE. 
Analysis of all treatment-emergent adverse events 
The following TEAE summaries will be generated: 
• Overview of TEAEs, summarizing number (%) of patients with any 
➢ TEAE; 
➢ Serious TEAE; 
➢ TEAE leading to death; 
➢ TEAE leading to permanent treatment discontinuation. 
• All TEAEs by primary SOC, HLGT, HLT, and PT 
• All TEAEs by primary SOC and PT 
• Number (%) of patients experiencing common TEAE(s) presented by primary SOC 
and PT (PT incidence ≥ 5 % in any treatment group) 
• All TEAEs relationship (related/not related) to evinacumab 
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• All TEAEs by maximum severity (i.e., mild, moderate or severe) 
Analysis of all treatment emergent serious adverse event(s) 
• All Serious TEAEs by primary SOC, HLGT, HLT, and PT 
• All Serious TEAEs by primary SOC and PT 
• Patient listings of serious TEAEs will be provided in the report appendix. 
• All Serious TEAEs relationship (related/not related) to study treatment 
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
• All TEAEs leading to permanent treatment discontinuation, by primary SOC, HLGT, 
HLT, and PT 
• All TEAEs leading to permanent treatment discontinuation, by primary SOC and PT 
• Patient listings of TEAEs leading to permanent treatment discontinuation will be 
provided in the report appendix.  
Post-treatment adverse events  
• All post-treatment AEs by primary SOC and PT 
• All post-treatment SAEs by primary SOC and PT 
Analysis of Acute Pancreatitis Events 
• TEAEs suspected of being AP events by primary SOC and PT 
• TEAEs suspected of being AP events adjudicated as positive by primary SOC and PT 
• TEAEs suspected of being AP events categorized by adjudicated outcome of positive, 
negative, or in-process (applicable for the interim analyses) 
• Patient listing of positively adjudicated TEAE AP events 
Patient Deaths 
The following summaries of deaths will be generated. 
• Number (%) of patients who died by study period (TEAE and post-treatment) and 
reason for death;  
• TEAEs leading to death (death as an outcome on the AE CRF page, as reported by 
the Investigator) by SOC and PT 
5.8.2. 
Analysis of Adverse Events of Special Interest  
Treatment-emergent adverse events of special interest (AESI), as listed in Section 4.8.1.2, will be 
presented by SOC and PT as applicable.  AESI are defined by dedicated e-CRF.   
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5.8.3. 
Clinical Laboratory Measurements  
Clinical laboratory parameter actual values (quantitative) and change from baseline values will 
be descriptively summarized at baseline and each post-baseline visit for the study treatment 
period, by at least patient number, mean, median, Q1, Q3, SD, minimum and maximum.  
Clinical laboratory parameters mean changes from baseline, with the corresponding SE, can be 
plotted at each visit in the case results warrant further investigation.  These parameters will be 
presented by the biological functions defined in Section 4.8.2.  For glucose, only fasting samples 
will be included in the summaries. 
Individual patient laboratory parameter measurements will be additionally evaluated by PCSV 
criteria (See Appendix 10.3), specifically identifying patients with at least one post-baseline 
measurement that meets the PCSV criteria within the TEAE period. These laboratory parameters 
will be presented by the biological functions defined in Section 4.8.2. The incidence of PCSVs at 
any time during the TEAE period will be summarized regardless of the baseline level, and again 
according to the following baseline categories: 
• Normal (according to PCSV criterion/criteria)/missing 
• Abnormal according to PCSV criterion or criteria 
Patient listings of laboratory measurements that meet PCSV criteria will be provided for the 
report appendix.   
For those laboratory parameters that don’t have an associated PCSV criteria, similar summary 
tables can be provided based on measurements outside the central laboratory normal ranges, if 
applicable. 
Drug-induced liver injury 
For the treatment period, an evaluation of drug-induced serious hepatotoxicity (eDISH) with the 
graph of distribution of peak values of ALT versus peak values of total bilirubin will also be 
presented using post-baseline values during TEAE period. Note that the ALT and total bilirubin 
values are presented on a logarithmic scale. The graph will be divided into 4 quadrants with a 
vertical line corresponding to 3 x ULN for ALT and a horizontal line corresponding to 2 x ULN 
for total bilirubin. 
Patient listing of possible Hy’s law cases identified by treatment group (i.e., patients with any 
elevated ALT>3 x ULN, and associated with an increase in bilirubin >2 x ULN, concomitantly 
or not) with ALT, AST, ALP, total bilirubin, and if available direct and indirect bilirubin will be 
provided. 
The summary of clinical laboratory parameter measurements will be provided by treatment 
group for the study in the safety analysis set. 
5.8.4. 
Analysis of Vital Signs 
The vital sign actual values and change from baseline values obtained while sitting will be 
descriptively summarized at baseline and each post-baseline visit for the study treatment period, 
by at least patient number, mean, median, Q1, Q3, SD, minimum and maximum. Vital signs 
mean changes from baseline, with the corresponding SE, can be plotted at each visit in the case 
results warrant further investigation. 
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Individual patient vital sign measurements (regardless of sitting position) will be additionally 
evaluated by PCSV criteria, specifically identifying patients with at least one post-baseline 
measurement that meets the PCSV criteria within the TEAE period.  The incidence of PCSVs at 
any time during the TEAE period will be summarized regardless of the baseline level, and again 
according to the following baseline categories: 
• Normal (according to PCSV criterion/criteria)/missing 
• Abnormal according to PCSV criterion or criteria 
Patient listings of vital sign measurements that meet PCSV criteria will be provided for the 
report appendix.   
The summary of vital signs will be provided by treatment group for the study in the safety 
analysis set. 
5.8.5. 
Analysis of 12-Lead ECG 
For the treatment period, ECG parameters will be described through an overall interpretation of 
ECG status (e.g. normal, abnormal [clinically significant (Yes/No)]). The count and percentage 
of patients with at least 1 abnormal post-baseline ECG during the TEAE period will be 
summarized according to the following baseline status categories: 
• Normal/missing; 
• Abnormal 
Individual patient ECG measurements will be additionally evaluated by PCSV criteria, 
specifically identifying patients with at least one post-baseline measurement that meets the 
PCSV criteria within the TEAE period.  The incidence of PCSVs at any time during the 
respective TEAE periods will be summarized regardless of the baseline level, and again 
according to the following baseline categories: 
• Normal (according to PCSV criterion/criteria)/missing 
• Abnormal according to PCSV criterion or criteria 
Patient listings of ECG measurements that meet PCSV criteria will be provided for the report 
appendix.   
The summary of ECG data will be provided by treatment group for the study in the safety 
analysis set. 
5.8.6. 
Physical Exams 
A list of patients with data collected on the Physical Exams eCRF page will be generated. 
5.9. 
Analysis of Pharmacokinetic Variables 
Descriptive statistics of concentrations of total evinacumab and total ANGPTL3 in serum at each 
sampling time will be presented.  
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Mean concentrations in serum of evinacumab and ANGPTL3 will be plotted by nominal 
sampling time. Individual concentrations in serum of evinacumab and ANGPTL3 will be 
presented by actual sampling time. 
Descriptive subgroup analyses may be performed as appropriate. 
When appropriate, relationship between concentrations of evinacumab and ApoC3, fasting TGs, 
or other biomarkers may be evaluated descriptively.   
5.10. 
Analysis of Immunogenicity Variables 
The summary of immunogenicity variables will be provided for all patients in the study in the 
safety analysis set. 
5.10.1. 
Analysis of Anti-evinacumab Antibody (ADA) Variables 
The ADA variables described in Section 4.10  will be summarized using descriptive statistics. 
Immunogenicity will be characterized by ADA status, ADA category and maximum titer 
observed in patients in the ADA analysis sets. For samples confirmed as drug specific ADA 
positive, but found negative at the lowest titer dilution, the lowest dilution in the titer assay is 
imputed.  
The ADA status of each patient may be classified as one of the following:   
• Positive  
• Pre-existing - If the baseline sample is positive and all post baseline ADA titers are 
reported as less than 9-fold the baseline titer value  
• Negative - If all samples are found to be negative in the ADA assay.  
The ADA category of each positive patient is classified as:  
• Treatment-boosted - A positive result at baseline in the ADA assay with at least one 
post baseline titer result ≥ 9-fold the baseline titer value.  
• Treatment-emergent - A negative result or missing result at baseline with at least one 
positive post baseline result in the ADA assay. Patients that are treatment-emergent 
will be further categorized as follows:  
Treatment-emergent is further sub-categorized as:  
• Persistent - A positive result in the ADA assay detected in at least 2 consecutive post 
baseline samples separated by at least a 16-week post baseline period [based on 
nominal sampling time], with no ADA-negative results in-between, regardless of any 
missing samples  
• Indeterminate - A positive result in the ADA assay at the last collection time point 
only, regardless of any missing samples  
• Transient - Not persistent or indeterminate, regardless of any missing samples  
The maximum titer category of each patient is classified as:  
• Low (titer <1,000)  
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• Moderate (1,000 ≤ titer ≤ 10,000)  
• High (titer >10,000)  
The following will be summarized by treatment group and ADA titer level:  
• Number (n) and percent (%) of ADA-negative patients  
• Number (n) and percent (%) of pre-existing patients 
• Number (n) and percent (%) of treatment-emergent ADA positive patients 
➢ Number (n) and percent (%) of persistent treatment-emergent ADA positive 
patients  
➢ Number (n) and percent (%) of indeterminate treatment-emergent ADA positive 
patients  
➢ Number (n) and percent (%) of transient treatment-emergent ADA positive 
patients  
• Number (n) and percent (%) of treatment-boosted ADA positive patients 
Listing of all ADA titer levels will be provided for patients with pre-existing, treatment-emergent 
and treatment-boosted ADA response.  
Considering the few patients enrolled in the study due to the early termination of the protocol, 
samples positive in the ADA assay will be further characterized for ADA titers, but NAb 
analyses will not be performed. 
5.10.2. 
Association of Immunogenicity with Exposure, Safety and Efficacy 
Associations between ADA response and titer categories and systemic exposure to evinacumab 
may be explored. Plots of evinacumab concentration may be provided for analyzing the potential 
impact of titer (high, moderate or low), treatment-emergent, persistent ADA and NAb responses 
on drug exposure. 
Associations between the ADA response and safety events may be explored.  
Associations between the ADA variables and key efficacy endpoints may be explored for the 
evinacumab treated group. Plots of efficacy variables may be analyzed for potential impact of 
treatment-emergent ADA on efficacy.   
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis.  
6.1. 
Definition of Baseline for Efficacy/Safety Variables 
Unless otherwise specified, the baseline assessment is programmatically defined as the latest 
available measurement taken before first administration of study treatment. For patients 
randomized but not-treated, the baseline will be the last available measurement before 
randomization.  
6.2. 
Data Handling Convention for Efficacy Variables  
Missing data of efficacy variables will not be imputed for the efficacy data summary analyses. 
6.3. 
Data Handling Convention for Missing Data 
Missing data will not be imputed in listings.  This section includes the methods for missing data 
imputation for some summary analyses, if necessary. 
Date of First/Last Study Treatment 
Since the study drug is administered at the site, the date of study drug administration is filled in 
e-CRF. No missing data is expected. Date of first/last administration is the first/last start date of 
study drug filled in e-CRF. 
Adverse Event 
If the intensity of a TEAE is missing, it will be classified as “severe” in the frequency tables by 
intensity of TEAEs. If the assessment of relationship of a TEAE to the investigational product is 
missing, it will be classified as related to the investigational product. 
When the partial AE date information does not indicate that the AE started prior to study 
treatment or after the TEAE period, the AE will be classified as treatment-emergent. 
Medication/Procedure 
No imputation of medication/procedure start/end dates will be performed.  If a medication date is 
missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly or stopped prior to the first study treatment administration, it will be considered as 
concomitant medication/procedure. 
Potentially Clinically Significant Value (PCSV) 
If a patient has a missing baseline value, this patient will be grouped in the category 
“normal/missing at baseline.” 
For PCSVs with 2 conditions, one based on a change from baseline value and the other on a 
threshold value or a normal range, with the first condition being missing, the PCSV will be based 
only on the second condition. 
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For a PCSV defined on a threshold and/or a normal range, this PCSV will be derived using this 
threshold if the normal range is missing; e.g., for eosinophils the PCSV is >0.5 giga/L or >ULN 
if ULN ≥0.5 giga/L.  When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSVs. 
6.4. 
Visit Windows 
Visit windows will be programmatically imposed on those efficacy and safety measures 
repeatedly collected over the course of the study. These visit windows are derived from the 
number of days in study, specifically assigning day ranges to represent the study assessment 
schedule provided in the protocol.  Data analyzed by time point (including efficacy, laboratory 
safety data, vital signs, ECG, quality of life, drug concentration and ADA) will be summarized 
using the analysis windows given in Appendix 10.2. These analysis windows will be applicable 
for all analyses, and they are defined to provide more homogeneous data for time point-specific 
analyses. If multiple valid values of a variable exist within an analysis window, the nearest from 
the targeted study day will be selected for analysis, unless otherwise specified. If the difference 
is a tie, the value after the targeted study day will be used. If multiple valid values of a variable 
exist within a same day, then the first value of the day will be selected when time is available, 
else the scheduled visit will be selected. 
6.5. 
Unscheduled Assessments 
For efficacy, safety laboratory data, vital signs, ECG, unscheduled visit measurements may be 
used to provide a measurement for a time point, including baseline, if appropriate according to 
their definitions. The measurements may also be used to determine abnormal values, AESIs, and 
PCSVs. 
6.6. 
Pooling of Centers for Statistical Analyses 
Not applicable. 
6.7. 
Statistical Technical Issues 
Not applicable. 
7. 
TIMING OF STATISTICAL ANALYSES 
Due to poor recruitment progress and unlikely to meet planned enrolment, a decision was made 
on August 25, 2022 to stop the 20118 study. An abbreviated CSR will be produced after the final 
database lock.  
8. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or higher. 
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9. 
REFERENCES 
1. Berglund L, Brunzell JD, Goldberg AC, Goldberg IJ, Sacks F, Murad MH, et al. 
Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice 
guideline. J Clin Endocrinol Metab 2012; 97(9):2969-2989. 
2. Brisson D, Méthot J, Tremblay K, Tremblay M, Perron P,Gaudet D. Comparison of the 
efficacy of fibrates on hypertriglyceridemic phenotypes with different genetic and clinical 
characteristics. Pharmacogenet Genomics 2010; 20(12):742-747. 
3. Brown WV, Brunzell JD, Eckel RH,Stone NJ. Severe hypertriglyceridemia. J Clin 
Lipidol 2012; 6(5):397-408. 
4. ICH. (1996, July 30). ICH Harmonized tripartite guideline: Structure and content of 
clinical study reports (E3). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
5. ICH. (1997, July 17). ICH Harmonized tripartite guideline: General considerations for 
clinical trials (E8). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
6. ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for 
clinical trials (E9). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
7. Jacobson TA, Maki KC, Orringer CE, Jones PH, Kris-Etherton P, Sikand G, et al. 
National Lipid Association Recommendations for Patient-Centered Management of 
Dyslipidemia: Part 2. J Clin Lipidol 2015; 9(6 Suppl):S1-122.e121. 
8. Little RJ, D'Agostino R, Cohen ML, Dickersin K, Emerson SS, Farrar JT, et al. The 
prevention and treatment of missing data in clinical trials. N Engl J Med. 2012 Oct 
4;367(14):1355-60. doi: 10.1056/NEJMsr1203730. 
9. Mehrotra DV, Li X, Liu J, Lu K. Analysis of longitudinal clinical trials with missing data 
using multiple imputation in conjunction with robust regression. Biometrics. 2012 
Dec;68(4):1250-9. doi: 10.1111/j.1541-0420.2012.01780.x. 
10. Minicocci I, Montali A, Robciuc MR, Quagliarini F, Censi V, Labbadia G, et al. 
Mutations in the ANGPTL3 gene and familial combined hypolipidemia: a clinical and 
biochemical characterization. J Clin Endocrinol Metab 2012; 97(7):E1266-1275. 
11. Minicocci I, Santini S, Cantisani V, Stitziel N, Kathiresan S, Arroyo JA, et al. Clinical 
characteristics and plasma lipids in subjects with familial combined hypolipidemia: a 
pooled analysis. J Lipid Res 2013; 54(12):3481-3490. 
12. Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock SA, Branum A, 
et al. Second symposium on the definition and management of anaphylaxis: summary 
report--Second National Institute of Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network symposium. J Allergy Clin Immunol 2006; 117(2):391-397. 
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13. Surendran RP, Visser ME, Heemelaar S, Wang J, Peter J, Defesche JC, et al. Mutations 
in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients with severe 
hypertriglyceridaemia. J Intern Med 2012; 272(2):185-196. 
 
 
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10. 
APPENDIX 
10.1. 
Summary of Statistical Analyses 
All efficacy and safety data will be summarized descriptively. 
10.2. 
Windows for Analysis Time Points 
Below are the definitions for the visit windows programmatically imposed on measures 
repeatedly collected over the course of the study.  These visit windows reflect the study schedule 
of assessments as described in the protocol.  
The visit windows are constructed using ranges applied to the number of days in study (study 
days) when the measure is collected. Below are the relevant definitions for the analysis visit 
windows:  
1. Study day is defined as the number of days since the first study treatment administration 
+1. The first study treatment occurs on Day 1. 
2. Since the protocol specifies that measurements be collected before study treatment is 
administered on a given day, it is appropriate that baseline include Day 1. 
3. For randomized but not treated patients, Day 1 is the day of randomization.   
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Table 1: 
Global Analysis Windows 
Visit label 
Targeted Study 
Day 
Analysis Window in Study Day 
Screening 
< Day 1 
Measurement obtained prior to first study treatment, and not defined as 
baseline visit 
Day 1  
1 
Measurement obtained closest to first study treatment, while remaining prior 
to first study treatment 
Week 4 
29 
15 to 42 
Week 4K, where 
K=2,3,…13 
28K+1 
15+28*(K-1) to 42+28*(K-1) 
FU – W10   
435 
379 - 470 
FU – W20 
505 
> 470 
Study days are calculated from the day of first study treatment administration, the day of first study treatment administration 
being Day 1.   
10.3. 
Criteria for Potentially Clinically Significant Values (PCSV) 
Parameter 
PCSV 
Clinical chemistry 
ALT 
By distribution analysis: 
 
>2 ULN and baseline ≤ 2 ULN 
>3 ULN and baseline ≤ 3 ULN 
>5 ULN and baseline ≤ 5 ULN 
>10 ULN and baseline ≤ 10 ULN 
>20 ULN and baseline ≤ 20 ULN 
 
AST 
By distribution analysis: 
 
>2 ULN and baseline ≤ 2 ULN 
>3 ULN and baseline ≤ 3 ULN 
>5 ULN and baseline ≤ 5 ULN 
>10 ULN and baseline ≤ 10 ULN 
>20 ULN and baseline ≤ 20 ULN  
Alkaline Phosphatase 
> 1.5 ULN and baseline ≤ 1.5 ULN 
Total Bilirubin 
> 1.5 ULN and baseline ≤ 1.5 ULN 
> 2 ULN and baseline ≤ 2 ULN 
Conjugated bilirubin 
> 35% total bilirubin (when total bilirubin >1.5 ULN) 
ALT and Total Bilirubin 
ALT > 3 ULN and Total Bilirubin > 2 ULN and baseline ALT≤3 ULN or Total 
bilirubin ≤ 2 ULN 
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Parameter 
PCSV 
CPK 
> 3 ULN and ≤ 5 ULN and baseline ≤ 3ULN 
>5 ULN and ≤  10 ULN and baseline ≤ 5 ULN 
>10 ULN and baseline ≤ 10 ULN 
Creatinine 
 150 mol/L (adults) 
 30% from baseline 
 100% from baseline 
CLcr (mL/min) 
(Estimated creatinine 
clearance based on the 
Cokcroft-Gault equation) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
eGFR (mL/min/1.73m2) 
(Estimate of GFR based on 
an MDRD equation)  
 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
Uric Acid 
   Hyperuricemia: 
   Hypouricemia: 
 
>408 µmol/L 
<120 µmol/L 
Blood Urea Nitrogen 
≥17 mmol/L 
Chloride 
<80 mmol/L 
>115 mmol/L 
Sodium 
129 mmol/L 
 160 mmol/L 
Potassium 
< 3  mmol/L 
 5.5 mmol/L 
Glucose 
   Hypoglycaemia 
   Hyperglycaemia 
 
 3.9 mmol/L and < LLN 
  7 mmol/L (fasted);  11.1 mmol/L (unfasted) 
HbA1c 
>8% 
Albumin 
≤25 g/L 
Hs-CRP 
> 2 ULN or 
 >10 mg/L, if ULN not provided 
Hematology 
WBC 
< 3.0 Giga/L (3000/ mm3) (Non-Black) 
< 2.0 Giga/L (2000/ mm3) (Black) 
≥16.0 Giga/L (16000/ mm3) 
 
Lymphocytes 
>4.0 Giga/L 
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Parameter 
PCSV 
Neutrophils 
< 1.5 Giga/L (1500/ mm3) (Non-Black) 
< 1.0 Giga/L (1000/ mm3) (Black) 
Monocytes 
>0.7 Giga/L 
Eosinophils 
> 0.5 Giga/L (500/ mm3) 
or > ULN if ULN  0.5 Giga/L 
Hemoglobin 
≤115 g/L (Male); ≤95 g/L (Female) 
≥185 g/L (Male); ≥165 g/L (Female) 
Decrease from Baseline ≥15 g/L 
Decrease from Baseline ≥20 g/L 
 
Hematocrit 
≤0.37 v/v (Male) ; ≤0.32 v/v (Female) 
≥0.55 v/v (Male) ; ≥0.5 v/v (Female) 
RBC 
≥6 Tera/L 
Platelets 
< 100 Giga/L (100 000/mm3) 
≥700 Giga/L (700000/mm3) 
Urinalysis 
pH 
≤4.6 
≥8 
Vital signs 
HR 
 50 bpm and decrease from baseline  20 bpm 
 120 bpm and increase from baseline  20 bpm 
SBP 
 95 mmHg and decrease from baseline  20 mmHg 
 160 mmHg and increase from baseline  20 mmHg 
DBP 
Young and elderly patients 
 45 mmHg and decrease from baseline  10 mmHg 
 110 mmHg and increase from baseline  10 mmHg 
Orthostatic Hypotension 
SBP St – Su  - 20 mmHg 
DBP St – Su  - 10 mmHg 
Weight 
5% increase versus baseline 
5% decrease versus baseline 
ECG parameters 
HR 
 50 bpm and decrease from baseline  20 bpm 
 120 bpm and increase from baseline  20 bpm 
PR 
≥220 ms and increase from baseline ≥20 ms 
QRS 
 120 ms 
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CONFIDENTIAL  
Page 43 of 49 
Parameter 
PCSV 
QTc 
Borderline 
Prolonged* 
Additional 
Absolute values (ms) 
Borderline  
      431-450 ms (Male) 
      451-470 ms (Female) 
Prolonged* 
       > 450 ms (Male)        
       > 470 ms (Female) 
       QTc   ≥500 ms            
 
Increase versus baseline (Males and Females) 
Borderline 
 30-60 ms 
Prolonged * 
 > 60 ms 
 
 
                                        VV-RIM-00294814-1.0 Approved - 21 Mar 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R1500-HTG-20118 Amendment 2 
Statistical Analysis Plan 
Date: March 15, 2023 
 
CONFIDENTIAL  
Page 44 of 49 
10.4. 
Schedule of Time and Events  
                                        VV-RIM-00294814-1.0 Approved - 21 Mar 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R1500-HTG-20118 Amendment 2 
Statistical Analysis Plan 
Date: March 15, 2023 
 
 
CONFIDENTIAL  
Page 45 of 49 
Table 2:  
Schedule of Events for the DBTP 
 
Screening 
Period 
Double-Blind Treatment Period (DBTP) 
Visit # (V) 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
Week 
 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
Day 
-28 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
Window (day) 
 
 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
Study Procedure 
Screening/Baseline: 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
Medical History1   
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
Height, Weight, BMI2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
Amylase and Lipase 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
FT4, TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (for women only)3  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment: 
Administer Study Drug4   
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Meds and 
Treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy: 
Lipid Profile5,6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Special Lipids6 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Presence of Abdominal 
Pain (1-Item Question) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAP-Pain 
Questionnaire  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety: 
Weight 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
                                        VV-RIM-00294814-1.0 Approved - 21 Mar 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R1500-HTG-20118 Amendment 2 
Statistical Analysis Plan 
Date: March 15, 2023 
 
 
CONFIDENTIAL  
Page 46 of 49 
 
Screening 
Period 
Double-Blind Treatment Period (DBTP) 
Visit # (V) 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
Week 
 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
Day 
-28 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
Window (day) 
 
 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
Study Procedure 
Physical Examination 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram8  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory: 5 
Hematology 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Chemistry 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Pregnancy Test9,10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetics and Immunogenicity Sampling:   
Drug Conc. Sample11 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
ADA and NAb sample12  
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Biomarkers: 
Biomarker 
Serum/Plasma13  
 
X 
 
 
  
 
 
X 
 
 
 
 
 
 
Lipoprotein Analysis by 
NMR 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Optional Pharmacogenomics: 
DNA Sample 
(Optional)14   
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Other: 
Mandatory DNA 
Sample for FCS 
Genotyping for Subset 
of Patients15  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dietary Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Alcohol Intake Review  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
                                        VV-RIM-00294814-1.0 Approved - 21 Mar 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R1500-HTG-20118 Amendment 2 
Statistical Analysis Plan 
Date: March 15, 2023 
 
 
CONFIDENTIAL  
Page 47 of 49 
Table 3: 
Schedule of Events for the Off-Drug Follow-up Period 
 
End of DBTP 
Off Drug Follow-Up  
Visit # (V) 
V15 
V16 
End of Study V17 
Week 
52 
62 
72 
Day 
365 
435 
505 
Window (day) 
±4 
±7 
±7 
 
Efficacy: 
Lipid Profile1  
X 
X 
X 
Special Lipids1 
X 
 
X 
Presence of Abdominal Pain (1-Item Question) 
X 
X 
X 
HAP-Pain Questionnaire 
X 
X 
X 
Safety: 
Concomitant Meds and Treatment 
X 
X 
X 
Weight 
X 
X 
X 
Vital Signs 
X 
X 
X 
Physical Examination 
 
 
X 
Electrocardiogram2  
 
 
X 
Adverse Events 
X 
X 
X 
Laboratory :3  
Hematology 
X 
 
X 
Blood Chemistry 
X 
X 
X 
Pregnancy Test4,5  
X 
 
X 
Pharmacokinetics and Immunogenicity Sampling:6  
Drug Conc. Sample 
X 
 
X 
ADA and NAb Sample 
X 
 
X 
Biomarkers: 
Biomarker Serum/Plasma  
X 
 
X  
Lipoprotein Analysis by NMR 
X 
 
 
Other: 
Dietary Review 
X 
X 
X 
Alcohol Intake Review 
X 
X 
X 
                                        VV-RIM-00294814-1.0 Approved - 21 Mar 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R1500-HTG-20118 Amendment 2 
Statistical Analysis Plan 
Date: March 15, 2023 
 
 
CONFIDENTIAL  
Page 48 of 49 
10.4.1. 
Footnotes for the Schedule of Events Tables 
10.4.1.1. Footnotes for Table 1 Schedule of Events (DBTP) 
1. Medical history should include detailed cardiovascular and pancreatitis history. 
2. Height will be measured in meters (m). Body weight will be assessed using calibrated 
scales. Patients should void (empty bladder) prior to weight assessment. Patients should 
be wearing undergarments only and no shoes during weight assessments. Body weight 
will be recorded to the nearest 0.1 kg. Body mass index (BMI) is calculated as weight 
(kg)/height(m)2. 
3. Postmenopausal status will be confirmed by measurement of FSH. 
4. At dosing visits, all assessments (including urine or serum pregnancy tests for WOCBP) 
should be performed before the dose of study drug is administered. 
5. All blood samples should be collected before the administration of study drug. All 
samples should be collected following at least an 8-hour fast. Medications are permitted 
to be taken with water as medically indicated. 
6. Lipids and lipoproteins (Lipid Profile): TC, TG, HDL-C, LDL-C will be measured.  
Special lipids:  ApoC3, ApoB48, ApoB100, ApoB Total. 
7. On dosing days, vital signs should also be measured, and AEs monitored pre-dose, at the 
end of study drug infusion, and at 30 minutes and 60 minutes post-end of infusion. 
Patients will be closely monitored for a minimum of 60 minutes after IV administration 
of study drug. 
8. Electrocardiograms should be performed before blood is drawn. 
9. Pregnancy test for WOCBP: A serum test will be done at the screening visit and a urine 
test will be done at all other visits indicated. Any positive urine test should be confirmed 
with a serum pregnancy test. 
10. All patients will be reminded of protocol-specified contraception use and pregnancy 
reporting. 
11. Blood samples for drug concentration and total ANGPTL3 should be obtained prior to 
AND at the end of infusion of study drug (within 30 minutes from the end of infusion). 
12. Blood samples for ADA and NAb samples should be collected prior to the administration 
of study drug.  
13. Residual biomarker samples as well as unused drug concentration and immunogenicity 
samples from the study may be utilized for future biomedical research (FBR) as 
permitted by patient consent and local regulatory policies. Samples may be stored for up 
to 15 years or as permitted by local regulatory policies, whichever is shorter, for FBR. 
14. Patients who agree to participate in the genomics sub-study will be required to consent to 
this optional sub-study before collection of the samples. Whole blood samples for 
DNA extraction should be collected on day 1/baseline (pre-dose), but can be collected at 
a later study visit. 
                                        VV-RIM-00294814-1.0 Approved - 21 Mar 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R1500-HTG-20118 Amendment 2 
Statistical Analysis Plan 
Date: March 15, 2023 
 
 
CONFIDENTIAL  
Page 49 of 49 
15. Mandatory DNA sample for FCS genotyping is only for patients who have no 
documentation of prior genotype testing that confirms the absence of FCS due to 
LoF mutations in LPL. 
10.4.1.2. Footnotes for Table 2 Schedule of Events (Off Drug Follow-up Period) 
1. Lipids and lipoproteins (Lipid Profile): TC, TG, HDL-C, LDL-C will be measured.  
Special lipids:  ApoC3, ApoB48, ApoB100, ApoB Total. 
2. Electrocardiograms should be performed before blood is drawn. 
3. All samples should be collected following at least an 8-hour fast. Medications are 
permitted to be taken with water as medically indicated. 
4. Pregnancy test for WOCBP: A urine test will be done at all other visits indicated. Any 
positive urine test should be confirmed with a serum pregnancy test. 
5. All patients will be reminded of protocol-specified contraception use and pregnancy 
reporting. 
6. Drug concentration should occur prior to and at the end of infusion of study drug, if 
applicable.  Immunogenicity collection should occur prior to infusion of study drug, if 
applicable. 
10.4.2. 
Early Termination Visit 
Patients who are withdrawn from the study before the end of the DBTP (visit 16, week 52) will 
be asked to return to the clinic for an ET visit consisting of the end of DBTP assessments 
described under visit 16 (Table 5). After the ET visit, patients will enter the off-drug treatment 
follow-up period. 
10.4.3. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule. Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for 
any other reason, as warranted. 
 
 
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