Conditions: Severe Hypertriglyceridemia (sHTG)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 52
Healthy volunteers: no

Brief summary:
The primary objective is to determine the change in Triglyceride (TG) levels following 12 weeks of repeated Intravenous (IV) doses of evinacumab.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: evinacumab intervention 2: Placebo
Intervention descriptions: intervention 1: Administered by Intravenous (IV) intervention 2: Administered by Intravenous (IV)

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol 
R1500-HTG-1522 Amendment 5 
Regeneron Pharmaceuticals, Inc. 
Page 1 of 99 
CONFIDENTIAL 
EudraCT Number: 2016-003307-62 
IND Number: 116398 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A PHASE 2, RANDOMIZED, PLACEBO-CONTROLLED STUDY OF 
SAFETY AND EFFICACY FOLLOWING REPEAT-DOSE 
ADMINISTRATION OF EVINACUMAB (ANTI-ANGPTL3) IN PATIENTS 
WITH SEVERE HYPERTRIGLYCERIDEMIA (SHTG) AT RISK FOR 
ACUTE PANCREATITIS 
Compound: 
evinacumab (REGN1500) 
Clinical Phase: 
2 
Protocol Number:
R1500-HTG-1522 
Protocol Version
R1500-HTG-1522 Amendment 5 
Amendment 5 Date of Issue 
See appended electronic signature page 
Amendment 4 Date of Issue 
18 Jan 2018 
Amendment 3 Date of Issue 
20 Sep 2017 
Amendment 2 Date of Issue 
31 July 2017 
Amendment 1 Date of Issue 
05 June 2017 
Original Date of Issue:
11 January 2017 
Scientific/Medical Monitor:
 
Cardiovascular and Metabolism 
Clinical Development and Regulatory Affairs 
      Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
 
. 
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NCT03452228


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R1500-HTG-1522 Amendment 5 
Regeneron Pharmaceuticals, Inc. 
 
Page 2 of 99 
CONFIDENTIAL 
AMENDMENT 5 
The protocol was amended in response to recent nonclinical findings in the rabbit. The table 
below summarizes the changes and the affected sections:  
Change 
Sections Changed  
In an embryofetal development toxicology study 
in rabbits, incomplete ossification of the 15th 
vertebra was observed in some fetuses resulting 
from the mating of male rabbits exposed to 
evinacumab with female rabbits not exposed to 
evinacumab. In male rabbits, there were 
measurable levels of evinacumab in seminal 
fluid and, as a safety measure, the current 
clinical study is amended to require consistent 
use of a condom for all sexually active males. 
Section 3.2.1 Rationale for Study Design 
Section 6.2.2 Exclusion Criteria, #25 
Table 1 Schedule of Events 
Updated Scientific/Medical Monitor 
Title page 
 
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Regeneron Pharmaceuticals, Inc. 
 
Page 3 of 99 
CONFIDENTIAL 
AMENDMENT 4 
The table below summarizes the changes and affected sections: 
Change 
Sections Changed  
The descriptions of the cohorts have been 
updated to use only genotype information in the 
medical history (or lack of genotype 
information) for cohort assignment. This change 
has been made based upon recent data indicating 
that the baseline measurements of LPL activity 
may not be sufficiently robust to differentiate 
individuals in cohorts 2 and 3. 
Clinical Study Protocol Synopsis: Objectives, Study Design, 
Endpoints, Statistical Plan 
Section 2.1 Primary Objectives 
Section 2.2 Secondary Objectives 
Section 2.3 Exploratory Objectives 
Section 3.1 Hypothesis 
Section 3.2.1 Rationale for Study Design  
Section 4.2.1 Primary Endpoint 
Section 4.2.2 Secondary Endpoints 
Section 4.2.3 Exploratory Endpoints 
Section 5.1 Study Description and Duration 
Section 6.2 Study Population 
Section 8.2.9.1 Genomics Study 
Section 10.2 Justification of Sample Size 
Section 10.4.3.1 Primary Efficacy Analysis 
Appendix 1 Known LPL and APOC2 Null (Total Loss of 
Function) Mutations 
Updated text regarding blinding for drug product 
and placebo 
Section 7.6.1 Blinding 
Section 7.7.1 Packaging, Labeling, and Storage 
Edits/Clarifications/Updates 
Section 6.2.1 Inclusion Criteria, #4 
Section 8.2.4.1 18F-FDG PET 
Section 8.2.6.2 Anti-Drug Antibody Measurements and 
Samples 
Section 10.4.3.1 Primary Efficacy Analysis 
Section 10.4.3.2 Secondary and Exploratory Efficacy Analysis 
Section 21 References 
 
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Regeneron Pharmaceuticals, Inc. 
 
Page 4 of 99 
CONFIDENTIAL 
AMENDMENT 3 
The protocol is amended in response to comments from FDA. The table below summarizes the 
changes and affected sections:   
Change 
Sections Changed  
Updated ADA variables and added a sentence 
for follow-up of patients whose last sample was 
positive in the ADA assay  
Section 4.4 Anti-Drug Antibody Variables 
Section 8.2.6.2 Anti-Drug Antibody Measurements and 
Samples 
Modified a secondary objective/endpoint for 
MRI T2 imaging and added to exploratory 
objectives/endpoints 
Clinical Study Protocol Synopsis: Objectives, Endpoints 
Section 2.2 Secondary Objectives 
Section 2.3 Exploratory Objectives 
Section 4.2.2 Secondary Endpoints 
Section 4.2.3 Exploratory Endpoints 
Allowed more flexibility for a planned interim 
analysis 
Section 5.2 Planned Interim Analysis 
Section 10.5 Interim Analysis 
Allowed other select individuals at the sponsor 
to have access to unblinded data for safety or 
other data review. 
Added text for an unblinded 
pharmacist/qualified designee 
Section 7.6.1 Blinding 
Added more specificity to the daily symptom 
and symptom/dietary impact questionnaires 
Table 1 Schedule of Events 
Moved collection of the baseline (visit 3) ADA 
sample to day 1 (visit 5), and added an ADA 
sample at day 29 (visit 7) 
Table 1 Schedule of Events 
Expanded list of AESIs for evinacumab 
Section 9.4.3 Other Events that Require Accelerated Reporting 
to Sponsor 
Edits/Clarifications 
Clinical Study Protocol Synopsis: Study Design 
Section 3.2.1  Rationale for Study Design 
Section 5.1 Study Description and Duration 
Section 6.2 Study Population 
Section 6.2.2 Exclusion Criteria 
Section 7.1 Investigational and Reference Treatments 
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CONFIDENTIAL 
AMENDMENT 2 
The following table outlines the changes made to the protocol and the affected sections: 
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Regeneron Pharmaceuticals, Inc. 
 
Page 6 of 99 
CONFIDENTIAL 
Change 
Section Changed 
Clarified the age range of the patient population, which 
was specified in an additional inclusion criterion 
Specified that the screening TG measurements at Visit 1 
and Visit 1b should be at least 4 days apart  
Added measurement of C-peptide and aligned 
inflammation parameters in schedule of events table with 
the listings of laboratory tests in other parts of the 
protocol 
Changed “Study Enrollment” to “Cohort Assignment” in 
schedule of events to clarify timing of cohort assignment 
Added line to schedule of events to denote timing of 
randomization at visit 5 
Renumbered relative timing of visits to make Day 1 
correspond to first visit of double blind period 
Extended the screening period to ensure that all required 
assessments can be completed 
Minor alterations of footnotes in schedule of events to 
improve clarity 
Clarified blinding of lipid measurements and analysis sets 
Clarifications/Edits 
Clinical Study Protocol Synopsis: Study Design, 
Treatment, Population, Statistical Plan 
Section 2.3 Exploratory Objectives 
Section 3.2.1 Rationale for Study Design 
Section 4.2.3 Exploratory Endpoints 
Section 5.1 Study Description and Duration 
Figure 1 Study Flow Diagram 
Section 6.2 Study Population 
Section 6.2.1 Inclusion Criteria #1 and #2 
Section 7.1 Investigational and Reference Treatments 
Section 7.2 Run-in Treatment(s) 
Section 7.4.2 Study Drug Discontinuation 
Section 7.6 Method of Treatment Assignment 
Section 7.6.1 Blinding 
Table 1 Schedule of Events 
Section 8.1.1 Footnotes for Schedule of Events Table 
Section 8.1.2 Early Termination Visit 
Section 8.2.4.2 Magnetic Resonance Imaging 
Section 8.2.5.4 Laboratory Testing 
Section 10.3.1 Full Analysis Set 
Section 10.3.2 Safety Analysis Set 
Section 10.3.3 Pharmacokinetics Analysis Set 
Section 10.4.3.1 Primary Efficacy Analysis 
Section 10.4.3.2 Secondary and Exploratory Efficacy 
Analysis 
Section 10.4.5.1 Adverse Events 
Section 10.4.9.1 First Step: Main Efficacy and Safety 
Analysis 
Section 10.4.9.2 Second Step: Final Efficacy and Safety 
Analysis 
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CONFIDENTIAL 
AMENDMENT 1 
The following table outlines the changes made to the protocol and the affected sections: 
Change 
Section Changed 
Sample size increase to “up to 50 patients” to evaluate 
effect of evinacumab on recurrent acute pancreatitis. 
Increase number of sites to approximately 20. 
Changed classification of study from phase 1b to phase 2 
Updated and added exploratory objectives and endpoints 
regarding acute pancreatitis and post heparin LPL activity 
Title Page  
Clinical Study Protocol Synopsis: Title, Site Location, 
Objectives, Endpoints, Study Design, Population 
Section 1 Introduction 
Section 2.2 Secondary Objectives 
Section 2.3 Exploratory Objectives 
Figure 1 Study Flow Diagram 
Section 3.2.1 Rationale for Study Design 
Section 4.2.2 Secondary Endpoints 
Section 4.2.3 Exploratory Endpoints 
Section 5.1 Study Description and Duration 
Section 5.2 Planned Interim Analysis 
Section 6.1 Number of Patients Planned 
Section 6.2 Study Population 
Section 7.6 Method of Treatment Assignment 
Section 10.2 Justification of Sample Size 
Section 10.5 Interim Analysis 
Section 22 Investigator’s Agreement 
Signature of Sponsor’s Responsible Officers 
Added explanation regarding the rationale for the single- 
and double-blind periods 
Section 3.2.1 Rationale for Study Design 
Inclusion criteria modified to include patients with a 
history of pancreatitis in the past 10 years 
Updated inclusion and exclusion criteria regarding 
alcohol consumption, lipid modifying diets & medication 
and history of cardio vascular disease  
Clarified the description of the cohorts 
Updated enrollment procedure for patients according to 
genotypes in the medical history and/or LPL activity 
measurements at visit 2 
Clinical Study Protocol Synopsis: Study Design 
Section 1 Introduction 
Section 3.2.1 Rationale for Study Design 
Section 5.1 Study Description and Duration 
Section 6.2 Study Population 
Section 6.2.1 Inclusion Criteria: #2, #3, and #5 
Section 6.2.2 Exclusion Criteria: #3 and #10  
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Regeneron Pharmaceuticals, Inc. 
 
Page 8 of 99 
CONFIDENTIAL 
Change 
Section Changed 
Updated language regarding study drug concentration and 
anti-drug antibody concentration 
Added footnote that PK samples will also be used for 
analysis of total ANGPTL3 concentration and added 
ANGPTL3 to the drug concentration data 
Updated visits when ADA samples are taken 
Clinical Study Protocol Synopsis: Objectives, Endpoints 
Section 2.2 Secondary Objectives 
Section 3.2.2 Rationale for Dose Selection 
Section 4.2.2 Secondary Endpoints 
Section 4.3 Pharmacokinetic Variables 
Section 4.4 Anti-Drug Antibody Variables 
Table 1 Schedule of Events 
Section 8.1.1 Footnotes for the Schedule of Events Table: 
footnote #21 
Section 10.3.4 Anti-Drug Antibody Analysis Set 
Section 10.4.6 Analysis of Drug Concentration Data 
Section 10.4.7 Analysis of Anti-Drug Antibody Data 
Table 1 Schedule of Events 
Added lomitapide and mipomersen to the list of 
prohibited medications and disallowed concomitant use 
during the study. Specified if PCSK9 inhibitors are used 
as background LMT, the dose should be stable for at least 
8 weeks prior to screening. 
Modified the list of permitted medications and procedures 
Clinical Study Protocol Synopsis: Study Design 
Section 5.1 Study Description and Duration 
Section 6.2.1 Inclusion Criteria: #3 
Section 6.2.2 Exclusion Criteria: #16 
Section 7.8.1 Prohibited Medications  
Section 7.8.2 Permitted Medications and Procedures 
Add end of study definition 
Section 5.1.1 End of Study Definition 
Clarified primary efficacy analysis with respect to 
baseline  
Simplified first step analyses.  Modified description of 
interim analysis to allow for planned early analysis of TG 
efficacy in cohort 1 (FCS) 
Clinical Study Protocol Synopsis: Statistical Plan 
Section 5.2 Planned Interim Analysis 
Section 10.4.3.1 Primary Efficacy Analysis  
Section 10.4.9.1 First Step: Main Efficacy and Safety 
Analysis 
Section 10.5 Interim Analysis 
Updated contraception language to add male 
contraception and clarified text regarding pregnancy 
status and contraception.  
Provide greater detail of study drug discontinuation and 
early termination, particularly with regards to women of 
child-bearing potential 
Added information that sites will provide urine pregnancy 
tests to female patients of childbearing potential to be 
used at home. 
Added pregnancy reporting for female partners of male 
patients  
Clinical Study Protocol Synopsis: Study Design 
Section 5.1 Study Description and Duration  
Section 6.2.2 Exclusion Criteria: #25 
Section 7.4.2 Study Drug Discontinuation 
Table 1 Schedule of Events 
Section 8.1.1 Footnotes for Schedule of Events Table: 
footnote #23 
Section 8.1.2 Early Termination Visit 
Section 8.2.5.4 Laboratory Testing 
Section 9.4.3 Other Events That Require Accelerated 
Reporting to Sponsor 
Table 1 Schedule of Events 
Added an Independent Data Monitoring Committee 
Section 5.3.1 Independent Data Monitoring Committee 
Sponsor will provide site with retention manual  
Updated information regarding follow-up of patients who 
prematurely discontinue the study  
Section 6.3 Premature Withdrawal from the Study 
Section 7.4.2 Study Drug Discontinuation 
Section 8.1.2 Early Termination Visit 
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Regeneron Pharmaceuticals, Inc. 
 
Page 9 of 99 
CONFIDENTIAL 
Change 
Section Changed 
Added Sampson criteria for anaphylaxis 
Section 7.5.1.2 Termination of the Infusion 
Section 21 References 
Provide more detail about blinding 
Section 7.7.1 Packaging, Labeling, and Storage 
Added assessment of “adverse events” at visit 1b in the 
schedule of events 
Added urine pregnancy assessments at phone visits 
Table 1 Schedule of Events 
Updated information on electrocardiograms 
Section 8.2.5.3 Electrocardiogram 
Added adverse events of special interest (anaphylactic 
reaction and allergic reaction) 
Section 9.4.3 Other Events that Require Accelerated 
Reporting to Sponsor 
Remove the requirement that patients be identified by 
their initials on CRFs and other documents submitted to 
the sponsor to preserve patient confidentiality 
Section 14.3 Patient Confidentiality and Data Protection 
Included information regarding amendments, where 
applicable, need to be approved by local regulatory 
agency 
Section 15 Protocol Amendments 
Updated study drug name from REGN1500 to 
evinacumab and provided units for TG in mmol/L 
Made editorial changes for clarity and consistency  
Various sections 
Update to reference 
Section 1 Introduction 
Section 3.2.1 Rationale for Study Description 
Section 21 References 
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Regeneron Pharmaceuticals, Inc. 
 
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CONFIDENTIAL 
TABLE OF CONTENTS 
AMENDMENT 5.............................................................................................................................2 
AMENDMENT 4.............................................................................................................................3 
AMENDMENT 3.............................................................................................................................4 
AMENDMENT 2.............................................................................................................................5 
AMENDMENT 1.............................................................................................................................7 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................16 
1. 
INTRODUCTION ......................................................................................................26 
2. 
STUDY OBJECTIVES ..............................................................................................28 
2.1. 
Primary Objectives .....................................................................................................28 
2.2. 
Secondary Objectives .................................................................................................28 
2.3. 
Exploratory Objectives ...............................................................................................28 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................29 
3.1. 
Hypothesis ..................................................................................................................29 
3.2. 
Rationale .....................................................................................................................29 
3.2.1. 
Rationale for Study Design .........................................................................................29 
3.2.2. 
Rationale for Dose Selection ......................................................................................32 
4. 
STUDY VARIABLES................................................................................................33 
4.1. 
Demographic and Baseline Characteristics ................................................................33 
4.2. 
Primary and Secondary Endpoints..............................................................................33 
4.2.1. 
Primary Endpoint ........................................................................................................33 
4.2.2. 
Secondary Endpoints ..................................................................................................33 
4.2.3. 
Exploratory Endpoints ................................................................................................34 
4.3. 
Pharmacokinetic Variables .........................................................................................35 
4.4. 
Anti-Drug Antibody Variables ...................................................................................35 
5. 
STUDY DESIGN .......................................................................................................35 
5.1. 
Study Description and Duration .................................................................................35 
5.1.1. 
End of Study Definition ..............................................................................................38 
5.2. 
Planned Interim Analysis ............................................................................................38 
5.3. 
Study Committees .......................................................................................................38 
5.3.1. 
Independent Data Monitoring Committee ..................................................................38 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............39 
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CONFIDENTIAL 
6.1. 
Number of Patients Planned .......................................................................................39 
6.2. 
Study Population .........................................................................................................39 
6.2.1. 
Inclusion Criteria ........................................................................................................39 
6.2.2. 
Exclusion Criteria .......................................................................................................40 
6.3. 
Premature Withdrawal from the Study .......................................................................42 
6.4. 
Replacement of Patients .............................................................................................43 
7. 
STUDY TREATMENTS............................................................................................43 
7.1. 
Investigational and Reference Treatments ..................................................................43 
7.2. 
Run-in Treatment(s) ....................................................................................................43 
7.3. 
Pretreatment(s) ............................................................................................................43 
7.4. 
Dose Modification and Study Treatment Discontinuation Rules ...............................43 
7.4.1. 
Dose Modification ......................................................................................................43 
7.4.2. 
Study Drug Discontinuation .......................................................................................43 
7.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................44 
7.4.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................44 
7.4.2.3. 
Management of Suspected Cases of Acute Pancreatitis .............................................44 
7.5. 
Management of Acute Reactions ................................................................................45 
7.5.1. 
Acute Infusion Reactions ............................................................................................45 
7.5.1.1. 
Interruption of the Infusion .........................................................................................45 
7.5.1.2. 
Termination of the Infusion ........................................................................................45 
7.6. 
Method of Treatment Assignment ..............................................................................46 
7.6.1. 
Blinding ......................................................................................................................46 
7.6.2. 
Emergency Unblinding ...............................................................................................46 
7.7. 
Treatment Logistics and Accountability .....................................................................47 
7.7.1. 
Packaging, Labeling, and Storage ..............................................................................47 
7.7.2. 
Supply and Disposition of Treatments .......................................................................47 
7.7.3. 
Treatment Accountability ...........................................................................................47 
7.7.4. 
Treatment Compliance ................................................................................................47 
7.8. 
Concomitant Medications ...........................................................................................47 
7.8.1. 
Prohibited Medications ...............................................................................................48 
7.8.2. 
Permitted Medications and Procedures ......................................................................48 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................48 
8.1. 
Schedule of Events .....................................................................................................48 
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CONFIDENTIAL 
8.1.1. 
Footnotes for the Schedule of Events Table ...............................................................53 
8.1.2. 
Early Termination Visit ..............................................................................................54 
8.1.3. 
Unscheduled Visits .....................................................................................................55 
8.2. 
Study Procedures ........................................................................................................55 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................55 
8.2.2. 
Efficacy Procedures ....................................................................................................55 
8.2.3. 
Daily Symptom Questionnaire and Symptom/Dietary Impact Questionnaire ...........55 
8.2.4. 
Imaging .......................................................................................................................56 
8.2.4.1. 
18F-FDG-PET ..............................................................................................................56 
8.2.4.2. 
Magnetic Resonance Imaging .....................................................................................58 
8.2.5. 
Safety Procedures .......................................................................................................61 
8.2.5.1. 
Vital Signs ..................................................................................................................61 
8.2.5.2. 
Physical Examination .................................................................................................61 
8.2.5.3. 
Electrocardiogram .......................................................................................................61 
8.2.5.4. 
Laboratory Testing ......................................................................................................61 
8.2.6. 
Pharmacokinetic and Anti-Drug Antibody Procedures ..............................................62 
8.2.6.1. 
Drug Concentration Measurements and Samples .......................................................62 
8.2.6.2. 
Anti-Drug Antibody Measurements and Samples ......................................................62 
8.2.7. 
Biomarker Procedures ................................................................................................63 
8.2.8. 
Biochemical Measures of Pancreatic Health ..............................................................63 
 
 
8.2.9.1. 
Genomics Study ..........................................................................................................63 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................64 
9.1. 
Obligations of Investigator .........................................................................................64 
9.2. 
Obligations of Sponsor ...............................................................................................64 
9.3. 
Definitions ..................................................................................................................65 
9.3.1. 
Adverse Event .............................................................................................................65 
9.3.2. 
Serious Adverse Event ................................................................................................65 
9.3.3. 
Infusion Reactions ......................................................................................................65 
9.4. 
Recording and Reporting Adverse Events ..................................................................66 
9.4.1. 
Adverse Events ...........................................................................................................66 
9.4.2. 
Serious Adverse Events ..............................................................................................66 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor ...................................66 
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CONFIDENTIAL 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................67 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results .............................68 
9.4.6. 
Follow-up ....................................................................................................................68 
9.5. 
Evaluation of Severity and Causality .........................................................................68 
9.5.1. 
Evaluation of Severity ................................................................................................68 
9.5.2. 
Evaluation of Causality ...............................................................................................69 
9.6. 
Safety Monitoring .......................................................................................................70 
9.7. 
Investigator Alert Notification ....................................................................................70 
10. 
STATISTICAL PLAN................................................................................................70 
10.1. 
Statistical Hypothesis ..................................................................................................71 
10.2. 
Justification of Sample Size........................................................................................71 
10.3. 
Analysis Sets ...............................................................................................................71 
10.3.1. 
Full Analysis Set .........................................................................................................71 
10.3.2. 
Safety Analysis Set .....................................................................................................72 
10.3.3. 
Pharmacokinetics Analysis Set ...................................................................................72 
10.3.4. 
Anti-Drug Antibody Analysis Set ..............................................................................72 
10.4. 
Statistical Methods ......................................................................................................72 
10.4.1. 
Patient Disposition ......................................................................................................72 
10.4.2. 
Demography and Baseline Characteristics .................................................................72 
10.4.3. 
Efficacy Analyses .......................................................................................................72 
10.4.3.1. 
Primary Efficacy Analysis ..........................................................................................72 
10.4.3.2. 
Secondary and Exploratory Efficacy Analysis ...........................................................74 
10.4.4. 
Analysis of Symptoms ................................................................................................74 
10.4.5. 
Safety Analysis ...........................................................................................................74 
10.4.5.1. 
Adverse Events ...........................................................................................................74 
10.4.5.2. 
Other Safety ................................................................................................................75 
10.4.5.3. 
Treatment Exposure ....................................................................................................75 
10.4.5.4. 
Treatment Compliance ................................................................................................76 
10.4.6. 
Analysis of Drug Concentration Data .........................................................................76 
10.4.7. 
Analysis of Anti-Drug Antibody Data ........................................................................76 
10.4.8. 
Analysis of Biomarker Data .......................................................................................76 
10.4.9. 
Timing of Statistical Analysis ....................................................................................76 
10.4.9.1. 
First Step:  Main Efficacy and Safety Analysis ..........................................................76 
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10.4.9.2. 
Second Step:  Final Efficacy and Safety Analysis ......................................................76 
10.5. 
Interim Analysis ..........................................................................................................76 
10.6. 
Additional Statistical Data Handling Conventions .....................................................77 
10.7. 
Statistical Considerations Surrounding the Premature Termination of a Study .........77 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS .....................................77 
11.1. 
Data Management .......................................................................................................77 
11.2. 
Electronic Systems ......................................................................................................78 
12. 
STUDY MONITORING ............................................................................................78 
12.1. 
Monitoring of Study Sites ...........................................................................................78 
12.2. 
Source Document Requirements ................................................................................78 
12.3. 
Case Report Form Requirements ................................................................................78 
13. 
AUDITS AND INSPECTIONS .................................................................................78 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................79 
14.1. 
Good Clinical Practice Statement ...............................................................................79 
14.2. 
Informed Consent .......................................................................................................79 
14.3. 
Patient Confidentiality and Data Protection ...............................................................80 
14.4. 
Institutional Review Board/Ethics Committee ...........................................................80 
15. 
PROTOCOL AMENDMENTS ..................................................................................80 
16. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................80 
16.1. 
Premature Termination of the Study ...........................................................................80 
16.2. 
Close-out of a Site ......................................................................................................81 
17. 
STUDY DOCUMENTATION ...................................................................................81 
17.1. 
Certification of Accuracy of Data ...............................................................................81 
17.2. 
Retention of Records ..................................................................................................81 
18. 
CONFIDENTIALITY ................................................................................................82 
19. 
FINANCING AND INSURANCE .............................................................................82 
20. 
PUBLICATION POLICY ..........................................................................................82 
21. 
REFERENCES ...........................................................................................................83 
22. 
INVESTIGATOR’S AGREEMENT ..........................................................................92 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................99 
 
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CONFIDENTIAL 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................49 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................36 
Figure 2: 
18F-FDG PET showing decrease of signal in areas of AIP inflammation 
(pancreas, salivary glands and retroperitoneum) after up to 2 months of 
prednisolone treatment (0.5 mg/kg, baseline on the left, post-treatment on 
the right) (Lee 2009). ..................................................................................................57 
Figure 3: 
Axial CT and co-registered PET images from 2 patients.  Patient A showed 
low 18F-FDG uptake in the region of the carotid plaque, while Patient B had 
high uptake in the region of the carotid plaque.  The uptake difference was 
consistent with high inflammatory infiltration in the atherosclerotic plaque 
of patient B compared to patient A as determined from excised tissue 
samples. ......................................................................................................................58 
Figure 4: 
ADC values as measured by DW-MRI differentiate normal pancreas from 
acute pancreatic disease states.  ~20% difference between normal and mild 
acute pancreas.  Kruskal-Wallis test across cohorts (P < 0.001).  Sample 
Size: Normal (N=15), mild acute (N=13) and necrotizing acute (N=8) 
pancreas (de Freitas Tertulino 2015). .........................................................................60 
Figure 5: 
Axial T2-weighted MRI with fat-suppression demonstrated intrapancreatic 
threadlike hyperintense structures consistent with interlobular septal 
inflammation (arrows).  Data collected from a 42-year-old male, acute 
pancreatitis patient (Xiao 2010).  Boxplots of the control (N=51) and acute 
pancreatitis (N=117) groups shows higher T2 values in the patient cohort 
owing to presence of edematous pancreatic tissue.  Calculation of the ROC 
curve demonstrated good diagnostic value of T2 MRI for diagnosis of acute 
pancreatitis (Tang 2016). ............................................................................................60 
 
LIST OF APPENDICES 
Appendix 1. Known LPL and APOC2 Null (Total Loss of Function) Mutations ......................93 
Appendix 2. Factors to Consider in Assessing the Relationship of Adverse Events to 
Study Drug and Study Conduct ..............................................................................98 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Phase 2, Randomized, Placebo-Controlled Study of Safety and Efficacy, 
Following Repeat-Dose Administration of Evinacumab (anti-ANGPTL3) in 
Patients with Severe Hypertriglyceridemia (sHTG) at Risk for Acute 
Pancreatitis 
Site Locations 
 
Principal Investigator 
The study will be conducted at approximately 20 study sites globally. 
PI to be determined.  
Objective(s) 
Primary Objective:  
The primary objective of the study is to determine the change in triglycerides 
(TG) levels following 12 weeks of repeated intravenous (IV) doses of 
evinacumab in the subset of patients with a documented history of sHTG 
(TG ≥1000 mg/dL [11.3 mmol/L]), a TG level of at least 500 mg/dL 
(5.6 mmol/L) at screening, a history of acute pancreatitis and without loss 
of function (LOF) mutations in genes in the lipoprotein lipase (LPL) 
pathway; and to assess whether a reduction in TG of at least 40% from the 
baseline placebo period has been achieved. 
Secondary Objectives: 
 
To determine the percent change from baseline in TG levels 
following 2 to 24 weeks of repeated IV doses of evinacumab 
overall and in subgroups with homozygous or compound 
heterozygous LOF mutations, heterozygous LOF mutations, 
and without LOF mutations in genes in the LPL pathway  
 
To assess changes in patient reported abdominal and 
gastrointestinal 
(GI) 
symptoms, 
dietary 
habits, 
and 
symptom/dietary impact measures 
 
To assess the degree of pancreatic injury/inflammation 
through 18F-2-Fluoro-2-Deoxy-D glucose positron emission 
tomography (18F-FDG-PET) imaging at baseline (placebo 
run-in) and change from baseline following 12 weeks of 
treatment with evinacumab as assessed by 
18F-FDG 
standardized uptake values SUVmax and SUVmean  
 
To assess the degree of pancreatic injury/inflammation 
through diffusion weighted-magnetic resonance imaging 
(DW-MRI) at baseline and the change from baseline following 
12 and 24 weeks of treatment with evinacumab as assessed by 
apparent diffusion coefficient (ADC) 
 
To evaluate total evinacumab and total ANGPTL3 
concentrations, and anti-drug antibody (ADA) during the 
evinacumab treatment and follow-up periods 
 
To evaluate the safety and tolerability of evinacumab 
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Study Design 
This is a phase 2, randomized, placebo-controlled study designed to evaluate 
the efficacy and safety of repeated doses of evinacumab in adult patients 
with severe hypertriglyceridemia. Up to approximately 50 patients will be 
enrolled, randomized 2:1 to receive evinacumab or placebo. 
The study consists of a screening period of up to 37 days (which includes 
day -66 to day -59 [visit 1], day -58 to -52 [visit 1b], and day -51 to -39 
[visit 2]), a baseline/single-blind placebo run in period (day -28 to day -1), 
a 12-week double-blind treatment period (day 1 to day 85), a single-blind 
12-week treatment period (day 86 to day 169), and an off-treatment 
follow-up period (week 24 [day 170] to week 44 [day 309]). 
The following cohorts will be enrolled based upon information (or lack of 
information) on genotype in the patient’s medical history at screening: 
Cohort 1:  Familial Chylomicronemia Syndrome (FCS) due to complete 
LPL deficiency.  Approximately 6 to 9 patients will be enrolled.  This cohort 
consists of patients: 
 
With known homozygous or compound heterozygous null 
LPL, GPIHBP1, or APOC2 LOF mutations. 
Cohort 2:  Multifactorial chylomicronemia with partial LPL deficiency. 
Approximately 9 to 12 patients will be enrolled. This cohort consists of 
patients: 
 
with known heterozygous null LPL, GPIHBP1, or APOC2 
LOF mutations, or 
 
with uncharacterized or known non-null LOF LPL pathway 
gene mutations (LPL, APOC2, APOA5, LMF1 and 
GPIHBP1)  
Cohort 3:  Multifactorial chylomicronemia. Approximately 15 to 27 patients 
will be enrolled. This cohort consists of patients not included in cohorts 1 or 
2 above:  
 
with other monogenic or polygenic causes of sHTG 
(eg, CGKR, CREB3L3, E2/E2 dysbetalipoproteinemia), or  
 
without genotype information 
For all patients who are enrolled, LPL pathway genotype will also be 
confirmed using exome sequencing. 
Screening (Day -66 to Day -29) 
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. 
Patients who do not meet eligibility criteria during the initial screening may 
rescreen only once; only the assessments that did not meet eligibility criteria 
initially are required to be repeated, if rescreening occurs within the 
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screening period. Patients who are rescreened after the screening window 
ends must re-consent for study participation and repeat all screening 
procedures. 
After confirmation of eligibility at visit 2, all patients will receive an 
IV bolus of 60 IU of heparin per kg of body weight and a blood sample will 
be collected to assess baseline LPL level enzyme activity. 
Assignment into 1 of the 3 cohorts and enrollment into the study will occur 
at visit 3 for patients meeting eligibility criteria. 
If enrollment into a specific cohort has reached the maximum number 
allowed, the patient will not be eligible for enrollment. 
Baseline/Single-Blind Placebo Run-in Period (Day -28 to Day -1) 
Principal investigators, study site personnel, and the Regeneron study team 
will be unblinded to treatment, but study patients will not. On day -28, all 
patients will receive a single IV placebo infusion. Patients will be closely 
monitored for a minimum of 120 minutes after IV administration of placebo 
on day -28. 
Double-Blind Treatment Period (Day 1 to Day 85) 
Principal investigators, study site personnel, study patients and the 
Regeneron study team will all be blinded to treatment during the 
double-blind treatment period. 
Patients will be randomized 2:1 (evinacumab:placebo) to receive either 
evinacumab administered IV at a dose of 15 mg/kg or matching placebo 
every 4 weeks (±4 days) on days 1, 29, and 57. Patients will be closely 
monitored for a minimum of 120 minutes after IV administration of 
evinacumab or matching placebo on days 1, 29, and 57. 
Stable doses of other triglyceride-lowering therapies such as fibrates, statins, 
Omega-3s, and niacin are allowed during the study. Patients may not take 
Glybera®, mipomersen, or lomitapide during the study. 
Efficacy and safety procedures and completion of the pancreatitis daily 
symptom questionnaire and symptom/dietary impact questionnaire will be 
performed as outlined in the Schedule of Events. Imaging correlates of 
pancreatic health will be assessed by 18F-FDG PET, by DW-MRI, and by 
T2-MRI. 
Serum samples for the determination of total evinacumab, total ANGPTL3, 
and anti-drug (anti-evinacumab) antibodies will be collected as outlined in 
the Schedule of Events. 
Serum and plasma samples will be collected for analysis of additional 
biomarkers, including amylase and lipase. 
Single-Blind Treatment Period (Day 86 to Day 169) 
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All patients who complete the double-blind treatment period will receive 
evinacumab administered IV at a dose of 15 mg/kg every 4 weeks (± 4 days) 
on days 85, 113, and 141. 
Stable doses of other triglyceride-lowering therapies, such as fibrates, 
statins, Omega-3s, and niacin are allowed during the study. Glybera®, 
mipomersen, or lomitapide are prohibited during the study. 
Efficacy and safety procedures and completion of the pancreatitis daily 
symptom questionnaire and symptom/dietary impact questionnaire will be 
performed as outlined in the schedule of events. Patients should fast for a 
minimum of 8 hours prior to any blood draws. Imaging correlates of 
pancreatic health will be assessed by DW-MRI. 
Serum samples for the determination of total evinacumab, total ANGPTL3, 
and anti-drug (anti-evinacumab) antibodies will be collected. 
Serum and plasma samples will be collected for analysis of additional 
biomarkers, including amylase and lipase. 
Off-Drug Treatment Follow-up Period (Day 170 to Day 309 
[End-of-Study]) 
Efficacy and safety procedures will be performed as outlined in the Schedule 
of Events. 
Throughout the Study 
Patients will 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 and the female partners (of childbearing potential) of 
male patients will be monitored throughout the study and for 24 weeks post 
the last dose of study drug. 
Study Duration 
The duration of the study for a patient is approximately 337 days (48 weeks), 
excluding the screening period. 
Population 
 
 
Sample Size: 
Up to approximately 50 adult male and female patients will be enrolled in 
the study. 
 
Target Population: 
The study population will be males and females ≥18 to 75 years of age with 
a history of fasting TG ≥1000 mg/dL, a fasting TG ≥500 mg/dL during 
screening, and a history of acute pancreatitis. Efforts will be made to select 
sites with a large population of well-characterized patients who have 
previously undergone gene sequencing and other procedures to understand 
the etiology of the HTG. 
Treatment(s) 
 
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Study Drug 
 
Dose/Route/Schedule: 
Double-Blind Treatment Period:  Patients will be randomized to receive 
either evinacumab 15 mg/kg or matching placebo administered IV every 
4 weeks (±4 days) on days 1, 29, and 57. 
 
 
 
 
 
Placebo 
 
Route/Schedule: 
Single-Blind Treatment Period:  Patients will receive evinacumab 
administered IV at a dose of 15 mg/kg every 4 weeks (±4 days) on days 85, 
113, and 141. 
On day -28, all patients will receive an IV placebo infusion. Placebo 
matching evinacumab will be prepared in the same formulation as 
evinacumab, without the addition of protein 
Endpoint(s) 
 
 
Primary: 
The primary endpoint is the percent lowering of TG levels from baseline 
following 12 weeks of repeated IV doses of evinacumab in the subset of 
patients with a documented history of sHTG (TG ≥1000 mg/dL 
[11.3 mmol/L]), a TG level of at least 500 mg/dL (5.6 mmol/L) at screening, 
a history of acute pancreatitis and without LOF mutations in  genes in the 
LPL pathway. (For patients randomized to evinacumab, baseline is defined 
as the period prior to the double-blind period; for patients randomized to 
placebo, baseline is defined as the period prior to the single-blind period). 
 
Secondary: 
The secondary endpoints of the study are: 
 
Percent TG lowering from baseline following 2 to 24 weeks of 
repeated IV doses of evinacumab overall and in subgroups with 
homozygous 
or 
compound 
heterozygous 
LOF 
mutations, 
heterozygous LOF mutations, and without LOF mutations in genes 
in the LPL pathway.  
 
Changes in patient reported abdominal and GI symptoms, dietary 
habits, and symptom/dietary impact measures 
 
Degree of pancreatic injury/inflammation through 18F-FDG-PET 
imaging at baseline (placebo run-in) and change from baseline 
following 12 weeks of treatment with evinacumab as assessed by 
18F-FDG SUVmax and SUVmean 
 
Degree of pancreatic injury/inflammation through DW-MRI at 
baseline (placebo run-in period) and change from baseline following 
12 and 24 weeks of treatment with evinacumab as assessed by ADC 
 
The 
total 
evinacumab 
concentrations, 
total 
ANGPTL3 
concentrations, and ADA during the evinacumab treatment and 
follow-up periods 
 
Incidence and severity of treatment-emergent adverse event (TEAEs), 
serious adverse events (SAEs), laboratory abnormalities, and other 
safety variables in patients treated with evinacumab 
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Procedures and Assessments 
Safety for all patients will be monitored via adverse events (AEs) reported 
by the patients (including patient reported outcomes on the questionnaires) 
or observed by the investigator, physical examinations, vital signs (heart 
rate, systolic and diastolic blood pressure, weight, and body temperature), 
clinical laboratory tests (biochemistry, amylase, lipase, hematology, 
urinalysis), and standard 12-lead electrocardiogram automatic reading (HR, 
PR, QRS, and QT-intervals, and QTc). 
Efficacy will be assessed by measurement of lipids and lipoproteins. 
Serum samples for the determination of total evinacumab and total 
ANGPTL3 concentrations, and anti-drug (anti-evinacumab) antibodies 
(ADA) will be collected. 
Serum and plasma samples will be collected for analysis of additional 
biomarkers, including amylase and lipase. 
Imaging correlates of pancreatic health will be assessed by 18F-FDG PET, 
by DW-MRI, and T2-weighted MRI. 
Statistical Plan 
Descriptive statistics are planned for the primary and secondary outcome 
measures collected in this study. Statistical analyses will explore data 
collected across all patients, as well as those patients in the genotype 
subgroups (as applicable for pharmacodynamic measures). 
Primary analysis: 
The primary analysis is based on percent change from baseline over 
12 weeks of evinacumab treatment for the assessment of probability 
(computed from the likelihood function based on the observed data, which 
is equivalent to Bayesian posterior probability with uninformative prior) that 
the mean TG change ≥40% (considered to be a clinically meaningful 
change) using study data, the point estimates of TG changes between the 
placebo run-in period and each observation week will be calculated using a 
Mixed effect Model for Repeated Measures (MMRM) method in the full 
analysis set population. A natural log transformation will be applied to the 
TG levels prior to analysis, aiming to provide a relatively normal data 
distribution (residuals will be examined for normality prior to proceeding 
with the analysis). The MMRM model will assess within-patient treatment 
comparisons (using an unstructured covariance matrix), while accounting 
for baseline TG, study visit, and baseline TG by study visit interaction. Note 
that study visits will be adjusted to start of evinacumab in order to pool data 
from both randomized groups of patients for this analysis. Since the 
comparison of study visits yields the within-patient comparisons of study 
treatments (ie, week 12 [after 12 weeks of treatment with evinacumab] 
compared to baseline at week 0 [after 4 weeks of treatment with placebo] in 
patients randomized to evinacumab and week 24 [after 12 weeks of 
treatment with evinacumab] compared to baseline at week 12 in patients 
randomized to placebo), contrast and estimate statements will be used to 
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assess treatment effects (least squares [LS] means with confidence intervals) 
and comparisons (LS mean ratio with confidence interval). Within-patient 
comparisons will include all patients, as well as analyses for the genotype 
subgroups (to assess relationship with amount of TG reduction while on 
evinacumab). A graph will depict the relationship of TG over time for each 
genotype subgroup. Details on the subgroup analyses will be defined in the 
statistical analysis plan (SAP). Both percent change and raw TG will be 
descriptively summarized by study visit. In the event the MMRM model 
covariance matrix does not converge or normality is not achieved with the 
natural log transformation, then other transformations will be explored, 
including ranks. 
Using the estimate of the log TG mean ratio (week 12/baseline at week 0 for 
patients randomized to evinacumab and week 24/baseline at week 12 for 
those randomized to placebo) and the log of the standard deviation derived 
from the MMRM model, the PP will be calculated using the target change 
from baseline of 40% reduction (ie, log 0.6) in patients without LOF 
mutations in genes in the LPL pathway. For the probability calculation (ie, 
Pr [log TG mean ratio (post/pre)] < log 0.6 conditional on this study’s TG 
results), a non-informative normal distribution prior and a normal 
distribution of the data is assumed. The probability calculation will yield the 
probability that the actual mean percent decrease is at least the target 40% 
value, based on the OBSERVED results from the patients without LOF 
mutations in genes in the LPL pathway. 
Nominal p-values for testing mean change from baseline >0 and ≥40% at 
each time point in each cohort may be computed for information purposes. 
Since this is an exploratory study, control of the overall type-I error is not 
applicable for statistical testing. Any p-values provided for outcome 
measures are for descriptive purposes only. 
Safety data will be summarized. 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA 
Anti-Drug Antibody 
ADC 
Apparent diffusion coefficient 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AIP 
Auto immune pancreatitis 
ALT 
Alanine aminotransferase 
ANGPTL3 
Angiopoietin-like 3 
APO 
Apolipoprotein 
AP 
Acute pancreatitis 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CABG 
Coronary Artery Bypass Grafting 
CI 
Confidence Interval 
CM 
Chylomicrons 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CV 
Cardiovascular 
CVD 
Cardiovascular disease 
DW-MRI 
Diffusion Weighted-Magnetic Resonance Imaging 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
FAS 
Full analysis set 
FCS 
Familial Chylomicronemia Syndrome 
FFA 
Free fatty acids 
18F-FDG PET 
18F-2-Fluoro-2-Deoxy-D glucose positron emission tomography 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HDL 
High-density lipoprotein 
HDL-C 
High-density lipoprotein cholesterol 
HTG 
Hypertriglyceridemia 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IRB 
Institutional Review Board 
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IV 
Intravenous 
IWRS 
Interactive web response system 
Ki 
Incorporation rate 
Kpatlak  
Patlak clearance rate 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LDL-C 
Low-density lipoprotein cholesterol 
LOF 
Loss of function 
LPL 
Lipoprotein lipase 
LS 
Least squares 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect model for repeated measures 
MRI 
Magnetic resonance imaging 
PCI 
Percutaneous Coronary Interventions 
PK 
Pharmacokinetic 
PP 
Posterior probability 
PRO 
Patient-Reported Outcomes 
PT 
Preferred term 
Q4W 
Every 4 weeks 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Software 
SC 
Subcutaneous 
SD 
Standard Deviation 
sHTG 
Severe hypertriglyceridemia 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
SUV 
Standardized uptake value 
TBR 
Target to background ratio 
TE 
Echo times 
TEAE 
Treatment-emergent adverse event 
TG 
Triglycerides 
TIA 
Transient Ischemic Attack 
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T2-MRI 
T2-weighted magnetic resonance imaging 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
VLDL 
Very-low-density lipoproteins 
WBC 
White blood cell 
WES 
Whole exome sequencing 
WOCBP 
Women of childbearing potential 
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1. 
INTRODUCTION 
Elevated levels of serum triglycerides (TG) are associated with the development of cardiovascular 
disease (CVD) and acute pancreatitis (AP). Studies suggest that mild to moderate elevations in TG 
levels are an independent risk factor for the development of CVD (Hokanson 1996), and recent 
studies have demonstrated that genetic loss of function (LOF) variants which result in lower TG 
levels (eg, apolipoprotein C3 (APOC3), ANGPTL3, and ANGPTL4 LOF genetic variants) are 
associated with a decreased risk of myocardial infarction (Musunura 2010, Stitziel 2016, 
Dewey 2016, Crosby 2014, Dewey 2017). Patients with severe elevations in TG levels 
(>1000 mg/dL) are at increased risk of pancreatitis and current lipid guidelines recommend 
lifestyle interventions and medications to lower TG levels to prevent AP (Berglund 2012, 
Jacobson 2015). In most patients who develop AP secondary to sHTG, the condition is mild and 
self-limiting, but approximately 20% of patients suffer severe attacks associated with prolonged 
hospitalization and significant morbidity and mortality. 
Patients with sHTG often require robust reductions in TG to lower the risk of acute pancreatitis, 
and a substantial proportion of patients have persistent hypertriglyceridemia, despite the use of 
multiple medications to lower TG. Current available therapies for lowering TG (eg, statins, 
fibrates, niacin, omega-3 fatty acids) can provide 20% to 50% reductions in TG in some patients, 
and minimal effects in other patients, especially patients with mutations in genes in the lipoprotein 
lipase (LPL) pathway (Brisson 2010). Patients with TG >1000 mg/dl typically have 
chylomicronemia that may be either multifactorial (polygenic & environmental) in origin or due 
to the presence of highly penetrant gene mutations in the LPL pathway (Brown 2012, 
Minicocci 2012) as observed in Familial Chylomicronemia Syndrome (also known as Fredrickson 
Type 1 Hyperlipidemia). 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 or other genes that modulate the enzymatic activity of 
LPL, such as APOC2, and APOA5, LMF1 and GPIHBP1, lead to varying levels of loss of LPL 
functional activity and elevated levels of plasma TG and especially 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 a clear significant 
unmet medical need for additional treatment options for patients with sHTG to further lower TG 
levels and the risk of pancreatitis. 
Angiopoietin-like 3 acts as a natural inhibitor of LPL and has recently emerged as a potential 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, LDL-C and high-
density lipoprotein-cholesterol (HDL-C) (Minicocci 2013). Deficiency of ANGPTL3 has also 
been reported to be associated with decreased serum free fatty acids (FFA) and increased insulin 
sensitivity in patients who are homozygous for LOF mutations in ANGPTL3 (Robciuc 2013). 
Humans carrying these variants have otherwise appeared healthy and have a reduced risk of 
coronary artery disease (Dewey 2017). 
Evinacumab (REGN1500) is a human IgG4 monoclonal antibody specific for ANGPTL3 and is 
being developed for treatment of dyslipidemia including hypertriglyceridemia (HTG) and 
hypercholesterolemia. Evinacumab has been studied in approximately 100 individuals with 
elevations in LDL-C and TG and has been generally well tolerated up to single doses of 20 mg/kg 
intravenous (IV), and in multiple subcutaneous (SC) doses up to 450 mg administered weekly and 
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20 mg/kg IV administered every 4 weeks for approximately 8 weeks. After single doses, 
evinacumab lowered TG up to ~80% in participants with TG <1000 mg/dL and lowered LDL-C 
up to 27% in participants with TG <500 mg/dL. In a multiple ascending dose study, evinacumab 
robustly lowered TG (up to ~72%) and LDL-C (up to ~34%) in patients with TG (150 – 
500 mg/dL) and LDL-C >100 mg/dl and had a long durability of treatment effect. However, TG 
lowering was highly variable in a small cohort of patients with TG >1000 mg/dl given a single 
dose of evinacumab (4 patients received 250 mg SC and 2 patients received 20 mg/kg IV). 
Although certain individuals exhibited the rapid and substantial lowering of TG (up to 90%), some 
of the patients with underlying LPL and other mutations did not show robust lowering following 
single doses of evinacumab. The reason for the mixed response was not clear. Three out of the 
6 patients treated with evinacumab and 1 placebo-treated patient in the cohort of patients with 
baseline TG >1000 mg/dL had an occurrence of acute pancreatitis during the study. These serious 
adverse events (SAEs) were not considered related to evinacumab since all of the patients had a 
history of prior pancreatitis episodes, had other underlying etiologies, and the events occurred 
70 days or later after the single dose of antibody when antibody levels were low or undetectable. 
The current study is a phase 2 randomized placebo-controlled study of the effects of multiple doses 
of evinacumab (anti-ANGPTL3) on safety, on plasma lipids and pancreatic disease biomarkers in 
patients with sHTG with a history of acute pancreatitis. There are 2 principal aims of this study. 
The first aim is to evaluate the safety and TG lowering effects of evinacumab in patients with 
various causes of sHTG including homozygous/heterozygous LPL gene LOF mutations, mutations 
in other genes in the LPL pathway, and other polygenic/environmental causes of severely elevated 
TGs. Analyses of the treatment effects among individuals with or without mutations in LPL 
pathway related genes and across a range of baseline LPL functional activity measurements will 
allow for a better understanding of the population(s) who will have robust lowering of TG with 
evinacumab treatment. The second aim of the study is to determine whether patients with sHTG 
and a history of acute pancreatitis have subclinical evidence of ongoing pancreatic inflammation 
with or without symptoms. Ongoing pancreatic inflammation may increase the risk of recurrent 
acute pancreatitis. This novel hypothesis will be tested in a population of patients with a prior 
history of pancreatitis. Patients with a relatively recent history of pancreatitis (eg, within the past 
10 years) will be enrolled to select for a high-risk population that may be more likely to have 
ongoing pancreatic disease. If patients in this rare patient population, with severe 
hypertriglyceridemia with a recent history of pancreatitis cannot be enrolled in a reasonable period 
of time, the study sponsor may allow investigators to enroll patients with history of pancreatitis at 
any time in the past without the requirement of a time specification. A thorough evaluation of 
Patient Reported Outcomes (PRO) (eg, patient symptoms, dietary habits), plasma biomarkers and 
imaging of the pancreas at baseline and after treatment will be performed. In addition, the effects 
of treatment with evinacumab on pancreatic inflammation biomarkers and the incidence of acute 
pancreatitis will also be assessed. 
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 Objectives 
The primary objective of the study is to determine the change in TG levels following 12 weeks of 
repeated IV doses of evinacumab in the subset of patients with a documented history of sHTG 
(TG ≥1000 mg/dL [11.3 mmol/L]), a TG level of at least 500 mg/dL (5.6 mmol/L) at screening, a 
history of acute pancreatitis and without LOF mutations in genes in the lipoprotein lipase (LPL) 
pathway; and to assess whether a reduction in TG of at least 40% from the baseline placebo period 
has been achieved. 
2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
 To determine the percent change from baseline in TG levels following 2 to 24 weeks 
of repeated IV doses of evinacumab overall and in subgroups with homozygous or 
compound heterozygous LOF mutations, heterozygous LOF mutations, and without 
LOF mutations in genes in the LPL pathway   
 To assess changes in patient reported abdominal and gastrointestinal (GI) symptoms, 
dietary habits, and symptom/dietary impact measures  
 To assess the degree of pancreatic injury/inflammation through 18F-2-Fluoro-2-Deoxy-
D glucose positron emission tomography (18F-FDG-PET) imaging at baseline (placebo 
run-in) and change from baseline following 12 weeks of treatment with evinacumab as 
assessed by 18F-FDG standardized uptake values SUVmax and SUVmean 
 To assess the degree of pancreatic injury/inflammation through diffusion 
weighted-magnetic resonance imaging (DW-MRI) at baseline and the change from 
baseline following 12 and 24 weeks of treatment with evinacumab as assessed by 
apparent diffusion coefficient (ADC) 
 To evaluate the total evinacumab and total ANGPTL3 concentrations, and anti-drug 
antibody (ADA) during the evinacumab treatment and follow-up periods 
 To evaluate the safety and tolerability of evinacumab 
2.3. 
Exploratory Objectives 
 To assess the degree of pancreatic injury/inflammation in the placebo run-in period and 
following treatment with evinacumab, as assessed by biochemical markers (amylase 
and pancreatic lipase activity [measured without lipemia interference], hsCRP, IL-6, 
and other inflammation markers) 
 To evaluate the effect of evinacumab compared to placebo on the incidence of recurrent 
acute pancreatitis overall and in subgroups with homozygous or compound 
heterozygous LOF mutations, heterozygous LOF mutations, and without LOF 
mutations in genes in the LPL pathway  
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 To assess medical visits/hospitalizations for abdominal pain or pancreatitis, medical 
visits/hospitalizations for pancreatitis, and medical visits/hospitalizations for 
cardiovascular disease  
 To assess the degree of pancreatic injury/inflammation through T2-weighted magnetic 
resonance imaging (T2-MRI) at baseline and the change from baseline following 12 
and 24 weeks of treatment with evinacumab as assessed by T2 intensity and T2 
relaxation time 
 To 
assess 
the 
degree 
of 
pancreatic 
injury/inflammation 
through 
18F-2-Fluoro-2-Deoxy-D glucose positron emission tomography (18F-FDG-PET) 
imaging at baseline (placebo run-in) and change from baseline following 12 weeks of 
treatment with evinacumab as assessed by 18F-FDG Ki or Kpatlak 
 To evaluate the percent change from baseline of other lipid parameters (eg, total 
cholesterol [TC], TG, non-HDL-C, LDL-C, HDL-C, APOB, FFA, APOA-I) and 
lipoprotein subfraction composition (eg, chylomicrons [CM], VLDL, IDL, LDL 
[low-density lipoprotein], HDL [high-density lipoprotein], particle cholesterol, TG 
content, and apolipoprotein composition) after ultracentrifugation 
 To evaluate change from baseline in metabolic parameters (fasting blood glucose, 
insulin, C-peptide, HbA1c) after 12 and 24 weeks of evinacumab treatment  
 To evaluate change from baseline in post heparin LPL activity after evinacumab 
treatment. 
 To evaluate changes in 18F-FDG-PET in atherosclerotic plaque (target to background 
ratio [TBR]) in carotids and/or aorta 
 To evaluate change from baseline in MRI liver fat signal 
3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypothesis 
In patients with a documented history of sHTG (TG ≥1000 mg/dL [11.3 mmol/L]), a TG level of 
at least 500 mg/dL (5.6 mmol/L) at screening, a history of acute pancreatitis, and without LOF 
mutations in genes in the LPL pathway, 12 weeks of IV evinacumab administered monthly will 
reduce serum TG levels from baseline by a mean of at least 40%. 
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
Principal aims: 
This is a phase 2, multicenter, partial-blind, placebo run-in, randomized, placebo-controlled fixed-
sequence study, to evaluate the efficacy and safety of repeated doses of evinacumab administered 
IV for the treatment of patients with a history of sHTG (fasting TGs ≥1000 mg/dL) with a baseline 
TG >500 mg/dL at screening and a history of acute pancreatitis. The primary aim of the study is 
to evaluate the intrapatient change from baseline in triglyceride concentrations following treatment 
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with evinacumab in patients with multifactorial and polygenic causes of sHTG as well as in 
patients with reduced LPL functional activity due to LOF mutations in LPL pathway-related genes. 
A key secondary aim is to determine whether patients with sHTG at high risk for pancreatitis have 
evidence of subclinical pancreatic disease as assessed by a panel of plasma/serum biomarkers, 
imaging biomarkers, and PROs and whether these biomarkers will be impacted by treatment with 
evinacumab. 
Benefit/Risk Assessment: 
Elevated blood levels of TGs have been associated with the development of both CVD and acute 
pancreatitis. Current therapies for lowering TGs (eg, weight reduction, lifestyle changes, statins, 
fibrates, omega-3 fatty acids) have limited efficacy and/or tolerability issues. Recent studies have 
demonstrated that patients with genetic LOF mutations that decrease the activity of LPL can result 
in severe elevations in TG. Because ANGPTL3 acts as a natural inhibitor of LPL, blockade of 
ANGPTL3 and preventing LPL inhibition is a potential target for the treatment of elevated levels 
of TGs. Importantly, no identified safety risks from the absence of ANGPTL3 have been reported 
for the few individuals who are homozygous for LOF mutations in ANGPTL3 (Musunuru 2010, 
Minicocci 2012). In fact, recent studies have demonstrated that genetic LOF variants which result 
in lower TG levels (eg, APOC3, ANGPTL3, and ANGPTL4 LOF genetic variants) are associated 
with a decreased risk of myocardial infarction (Musunuru 2010, Stitziel 2016, Dewey 2016, 
Crosby 2014, Dewey 2017). A therapeutic targeted to ANGPTL3 could provide beneficial changes 
in the lipid profile and ultimately in the cardiovascular (CV) risk for patients. Additionally, 
significant reductions in TGs would also benefit the patient with severe elevations in TGs at risk 
for pancreatitis. Thus, a significant unmet need exists for additional and improved methods for 
treating elevated TG levels. 
Evinacumab has been evaluated in 3 clinical studies and has been generally well tolerated with no 
significant clinical safety findings observed to date. No important identified risks have been 
established. The important potential risks with evinacumab (based on preclinical evaluation, 
mechanism of action, or risks associated with monoclonal antibody [mAbs] in general) include 
systemic hypersensitivity reactions, immunogenicity, and embryofetal toxicity. For the potential 
embryofetal toxicity risk, there is a strict risk mitigation plan, including requirements for consistent 
use of contraception for sexually active male study participants and sexually active female study 
participants of child-bearing potential. Currently, the available safety data along with the risk 
minimization and management activities for all important potential risks support the continued 
development of this compound. 
Population: 
Three different cohorts will be enrolled to evaluate the TG lowering effects of evinacumab in the 
setting of varying levels of LPL functional activity. Since the mechanism of action of evinacumab 
is to block an endogenous inhibitor of LPL activity in plasma, it is important to understand whether 
evinacumab will lower TG when the LPL pathway and functional LPL activity is compromised 
due to partial or total loss of functional mutations in the LPL and LPL pathways genes. Since 
genetic, environmental factors such as diet and alcohol and disease modifiers (eg, diabetes) can 
have an impact on LPL functional activity variability, enrollment of patients according to genotype 
will ensure that the patient population includes patients with a wide range of baseline LPL 
functional activity. Enrollment of patients at specialized centers, where genetic testing to identify 
genetic causes of HTG is routinely performed, will be encouraged, and enrollment into the 3 
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cohorts will be controlled via the Interactive Web Response System (IWRS). If genetic 
information is not available in a patient’s medical history, the patient will be enrolled into cohort 
3.  
The study will enroll up to approximately 50 adult male and female patients at approximately 
20 sites globally. Efforts will be made to select sites with a large population of well characterized 
patients who have previously undergone gene sequencing and other procedures to understand the 
etiology of the HTG. 
The following cohorts will be enrolled based upon the patient’s genotype: 
Cohort 1:  Familial Chylomicronemia Syndrome (FCS) due to complete LPL deficiency. 
Approximately 6 to 9 patients will be enrolled. This cohort consists of patients: 
 with known homozygous or compound heterozygous null LPL, GPIHBP1, or APOC2 
LOF mutations  
Cohort 2:  Multifactorial chylomicronemia with partial LPL deficiency.  Approximately 9 to 12 
patients will be enrolled. This cohort consists of patients: 
 with known heterozygous null LPL, GPIHBP1, or APOC2 LOF mutations, or 
 with uncharacterized or known non-null LOF LPL pathway gene mutations (LPL, 
APOC2, APOA5, LMF1 and GPIHBP1)  
Cohort 3:  Multifactorial chylomicronemia. Approximately 15 to 27 patients will be enrolled. This 
cohort consists of patients not included in cohorts 1 or 2 above:  
 with other monogenic or polygenic causes of sHTG (eg, CGKR, CREB3L3, E2/E2 
dysbetalipoproteinemia) or  
 without genotype information 
Lipoprotein lipase activity will be measured in all patients at baseline and at the end of treatment. 
Lipoprotein lipase enzyme activity will be measured using the assay developed by Imamura 
(Imamura 2008) in fasting plasma collected from patients during the screening period, after the 
patient has received an IV bolus of 60 IU of heparin per kg of body weight. Lipoprotein lipase is 
bound to the luminal side of capillary endothelium by glycosoaminoglycans and the infusion of 
heparin is required for the disassociation of the bound LPL into the circulation. This will allow a 
comparison of the treatment effects in different subgroups of patients with varying genetic LOF 
variants and LPL functional activity. Whole Exome Sequencing (WES) will be done to ascertain 
or confirm any genetic mutations in LPL and other genes in the LPL pathway (LMF1, APOC2, 
APOA5, etc). 
Patients with a history of pancreatitis due to HTG will be enrolled to increase the probability of 
observing abnormalities in pancreatic biomarkers at baseline and treatment-related changes in 
patient-reported outcomes (eg, chronic abdominal complaints, symptom/dietary impact measures), 
circulating plasma/serum pancreatic/inflammation markers and noninvasive pancreatic imaging 
inflammation biomarkers. Questionnaires will be administered to patients to evaluate for clinical 
symptoms of pancreatic inflammation such as nausea, vomiting, abdominal distention, abdominal 
pain, loss of appetite, and/or self-imposed dietary restrictions. Amylase and lipase, which are 
typically elevated during episodes of AP, will be measured. Levels of IL6 and C-reactive protein, 
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frequently elevated during acute pancreatitis episodes, and a panel of inflammation markers will 
be measured at baseline and post-treatment. Evaluation of subclinical pancreatic injury will be 
performed using 18F-FDG-PET and DW-MRI and T2-MRI. 18F-2-Fluoro-2-Deoxy-D glucose PET 
is a molecular imaging modality that has demonstrated high sensitivity in the in vivo detection of 
glycolytic tissues, including tumors and inflammatory foci. Although 18F-FDG-PET has not been 
used in this particular setting, it has been utilized to assess low-level pancreatic injury in other 
settings such as autoimmune pancreatitis (AIP), atherosclerosis and infection (Ozaki 2008, 
Shreve 1998, Tahara 2007, Vos 2006, Lee 2009, Shigekawa 2010). 18F-FDG PET will be 
performed at baseline and at week 12 (12 weeks after blinded treatment with evinacumab or 
placebo). A combination DW-MRI and T2-MRI will also be used to assess pancreatic health at 
baseline and following treatment with evinacumab. Compared to healthy pancreatic tissue, 
inflammatory tissue is characterized as having restricted water diffusion (decreased ADCs), while 
necrotic tissue corresponds to less restricted water diffusion (increased ADCs). With respect to the 
T2-MRI signal, edematous or inflammatory tissue is hypothesized to possess higher T2-weighted 
signal intensities in addition to longer T2 relaxation times as a result of higher water content. The 
implementation of DW-MRI and T2-MRI has been used to assess pancreatic health across 
pancreatic disease states, including acute, chronic and autoimmune pancreatitis as well as 
pancreatic cancer (de Freitas Tertulino 2015, Xiao 2010, Tang 2016). DW-MRI and T2-MRI will 
be performed at the beginning of the placebo run-in period, prior to the randomization visit at the 
end of the double-blind treatment period (week 12), and at the end of the single blind evinacumab 
treatment period (week 24). 
Study Design: 
The current fixed sequence study has a 4-week screening phase, a 4-week single-blind placebo run 
in phase to obtain additional baseline lipid data, a 12-week double-blind, placebo controlled phase, 
a 12-week single blind active treatment phase, and an off drug observation phase. Patients with 
sHTG are very rare and genetically diverse; therefore, it is important to study safety and treatment 
response in all patients enrolled. 
The single-blind placebo run-in period allows for measurement of change from baseline in TG in 
patients randomized to placebo. The double-blind period allows for an unbiased assessment of the 
safety of evinacumab compared to placebo. The single-blind period allows for analysis of a 
treatment effect in patients randomized to placebo. A single-blind period is preferred over an open-
label period to allow for unbiased collection of patient reported outcomes by the study participants.  
Since fasting TG are highly variable in this population, the geometric mean of TG measurements 
obtained at specific time-points (day -28, day -14 and week 0) will be used for pre-treatment 
comparison for the 12-week double blind period. For patients receiving placebo during the double-
blind treatment period, the geometric mean obtained at specific time points (week 6, 8, and 12) 
will be used as the baseline measurements for the single-blind evinacumab treatment period. A 
placebo controlled double-blind period will allow an unbiased assessment of safety of evinacumab 
versus placebo. Furthermore, offset kinetics will be observed in patients following withdrawal of 
active study medication. 
3.2.2. 
Rationale for Dose Selection 
An IV dose of 15 mg/kg was selected to test the efficacy of evinacumab with once-monthly 
administration for this study. The 15 mg/kg IV dose is within the range of doses that has been 
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shown to be generally well tolerated and markedly efficacious in patients with TG levels of 
≥150 mg to 450 mg/dL (Group A) and ≥450 to 1000 mg/dL (Group B) in the single-dose 
first-in-human study (Study R1500-HV-1214). Ninety to 100 mg/L of evinacumab appears to be 
the serum concentration of antibody associated with saturation of the target-mediated pathway and 
to achieve maximal or near-maximal TG lowering. The PK of evinacumab is non-linear, consistent 
with target-mediated elimination. An evinacumab concentration of >100 mg/L is maintained for 
approximately 2 weeks for a 10 mg/kg IV dose and for 4 weeks for a 20 mg/kg IV dose with a 
non-linear PK consistent with target mediated elimination. Pharmacokinetics simulation shows 
that 15 mg/kg IV will maintain evinacumab concentration above 100 mg/L for 1 month during the 
24-week treatment period. Total ANGPTL3 (drug antibody complex) concentration data showed 
possible target saturation with a limited duration at 20 mg/kg which supports selection of the 
15 mg/kg IV monthly regimen. Fifteen mg/kg of evinacumab administered monthly is therefore 
predicted to provide serum evinacumab concentrations that exceed that required to saturate the 
target-mediated pathway over the dosing interval. 
4. 
STUDY VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height, etc), 
disease characteristics including detailed cardiovascular and pancreatitis history, medication 
history, daily symptom Questionnaire, Symptom and Dietary Impact Questionnaire, and screening 
laboratory measurements for each patient. 
4.2. 
Primary and Secondary Endpoints 
4.2.1. 
Primary Endpoint 
The primary endpoint is the percent lowering of TG levels from baseline following 12 weeks of 
repeated IV doses of evinacumab in the subset of patients with a documented history of sHTG (TG 
>1000 mg/dL [11.3 mmol/L]), a TG level of at least 500 mg/dL (5.6 mmol/L) at screening, a 
history of acute pancreatitis, and without LOF mutations in genes in the LPL pathway. (For 
patients randomized to evinacumab, baseline is defined as the period prior to the double-blind 
period; for patients randomized to placebo, baseline is defined as the period prior to the 
single-blind period.) 
4.2.2. 
Secondary Endpoints 
The secondary endpoints of the study are: 
 Percent TG lowering from baseline following 2 to 24 weeks of repeated IV doses of 
evinacumab overall and subgroups with homozygous or compound heterozygous LOF 
mutations, heterozygous LOF mutations, and without LOF mutations in genes in the 
LPL pathway  
 Changes in patient reported abdominal and GI symptoms, dietary habits, and 
symptom/dietary impact measures 
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 Degree of pancreatic injury/inflammation through 18F-FDG-PET imaging at baseline 
(placebo run-in) and change from baseline following 12 weeks of treatment with 
evinacumab as assessed by 18F-FDG standardized uptake values SUVmax and SUVmean 
 Degree of pancreatic injury/inflammation through DW-MRI at baseline (placebo run-in 
period) and the change from baseline following 12 and 24 weeks of treatment with 
evinacumab as assessed by ADC 
 The total evinacumab concentrations, total ANGPTL3 concentrations, and ADA during 
the evinacumab treatment and follow-up periods 
 Incidence and severity of treatment-emergent adverse event (TEAEs), SAEs, 
laboratory abnormalities, and other safety variables in patients treated with evinacumab 
4.2.3. 
Exploratory Endpoints 
The exploratory endpoints of the study are:  
 Change from baseline in pancreatic injury/inflammation in the placebo run-in period 
and following treatment with evinacumab as assessed by biochemical markers 
(amylase, lipase, hsCRP, IL-6 and other inflammatory markers)  
 Incidence of recurrent acute pancreatitis overall and in subgroups with homozygous or 
compound heterozygous LOF mutations, heterozygous LOF mutations, and without 
LOF mutations in genes in the LPL pathway  
 Incidence of medical visits/hospitalizations for abdominal pain or pancreatitis, medical 
visits/hospitalizations for pancreatitis, and medical visits/hospitalizations for 
cardiovascular disease 
 Degree of pancreatic injury/inflammation through T2-MRI at baseline (placebo run-in 
period) and the change from baseline following 12 and 24 weeks of treatment with 
evinacumab as assessed by T2 intensity and T2 relaxation time 
 Degree of pancreatic injury/inflammation through 18F-FDG-PET imaging at baseline 
(placebo run-in) and change from baseline following 12 weeks of treatment with 
evinacumab as assessed by 18F-FDG Ki or Kpatlak 
 Percent change from baseline in lipid parameters (eg, TC, TG, non-HDL-C, LDL-C, 
HDL-C, APOB, FFA, APOA-I) and lipoprotein subfraction composition (eg, CM, 
VLDL, IDL, LDL, HDL, particle cholesterol, TG content, and apolipoprotein 
composition) after ultracentrifugation at 16 weeks and 28 weeks 
 Change from baseline in metabolic parameters (fasting blood glucose, insulin, 
C-peptide, HbA1c) after 12 and 24 weeks of evinacumab treatment 
 Percent change from baseline in post heparin LPL activity after evinacumab treatment 
overall and by LPL gene mutations 
 Change from baseline in 18F-FDG-PET in atherosclerotic plaque (TBR) in carotids 
and/or aorta 
 Change from baseline in liver fat fraction as measured by MRI 
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4.3. 
Pharmacokinetic Variables 
Pharmacokinetic variables may include, but are not limited to, the following: 
 Total evinacumab concentrations in serum over time 
 Cmax  
 Ctrough 
4.4. 
Anti-Drug Antibody Variables 
Anti-drug antibody variables include status (positive or negative) and titer as follows:  
 Treatment emergent - defined as any post-dose positive ADA assay response when the 
pre-dose baseline ADA results are negative 
 Treatment-boosted - defined as any post-dose positive ADA assay response that has 
titer at least 9-fold over the pre-dose baseline titer when pre-dose baseline ADA results 
are positive 
The definition of persistent and transient ADA will be defined a priori in the statistical analysis 
plan (SAP). 
 Titer values 
 Titer category 
 Low (titer <1,000) 
 Moderate (1,000≤ titer ≤10,000) 
 High (titer >10,000) 
Samples positive in the ADA assay will be assessed for neutralizing activity. 
5. 
STUDY DESIGN 
5.1. 
Study Description and Duration 
This is a phase 2, randomized, placebo-controlled, study designed to evaluate the efficacy and 
safety of repeated doses of evinacumab in adult patients with severe HTG. Up to approximately 
50 patients will be enrolled, randomized 2:1 (evinacumab:placebo) to receive evinacumab or 
placebo. 
The study consists of a screening period of up to 37 days (which includes day -66 to day -59 [visit 
1], day -58 to -52 [visit 1b], and day -51 to -39 [visit 2]), a baseline/single-blind placebo run in 
period (day -28 to day -1), a 12-week double-blind treatment period (day 1 to day 85), a single-
blind 12-week treatment period (day 86 to day 169), and an off-treatment follow-up period (week 
24 [day 170] to week 44 [day 309]). 
The following cohorts will be enrolled based upon information (or lack of information) on 
genotype in the patient’s medical history at screening: 
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1. Cohort 1:  FCS due to complete LPL deficiency. Approximately 6 to 9 patients will be 
enrolled.  This cohort consists of patients: 
 with known homozygous or compound heterozygous null LPL, GPIHBP1, or APOC2 
LOF mutations 
2. Cohort 2:  Multifactorial chylomicronemia with partial LPL deficiency. Approximately 9 
to 12 patients will be enrolled. This cohort consists of patients: 
 with known heterozygous null LPL, GPIHBP1, or APOC2 LOF mutations, or 
 with uncharacterized or known non-null LOF LPL pathway gene mutations (LPL, 
apoC2, apoA5, LMF1 and GPIHBP1) 
3. Cohort 3:  Multifactorial chylomicronemia. Approximately 15 to 27 patients will be 
enrolled. This cohort consists of patients not included in cohorts 1 or 2 above:  
 with other monogenic or polygenic causes of sHTG (eg, CGKR, CREB3L3, E2/E2 
dysbetalipoproteinemia), or 
 without genotype information 
A study flow diagram is in Figure 1. 
Figure 1: 
Study Flow Diagram 
 
Screening (Day -66 to Day -29) 
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. Patients who do not meet eligibility criteria during the initial screening 
may rescreen only once; only the assessments that did not meet eligibility criteria initially are 
required to be repeated, if rescreening occurs within the screening period. Patients who are 
rescreened after the screening window ends must re-consent for study participation and repeat all 
screening procedures. 
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After confirmation of eligibility at visit 2, all patients will receive an IV bolus of 60 IU of heparin 
per kg of body weight and a blood sample will be collected to assess baseline level of LPL enzyme 
activity. 
Assignment into 1 of the 3 cohorts and enrollment into the study will occur at visit 3 for patients 
meeting eligibility. 
If enrollment into a specific cohort has reached the maximum number allowed, the patient will not 
be eligible for enrollment. 
Baseline/Single-Blind Placebo Run-in Period (Day -28 to Day -1) 
Principal investigators, study site personnel, and the Regeneron study team will be unblinded to 
treatment, but study patients will not. On day -28, all patients will receive a single IV placebo 
infusion. Patients will be closely monitored for a minimum of 120 minutes after IV administration 
of placebo on day -28. 
Double-Blind Treatment Period (Day 1 to Day 85) 
Principal investigators, study site personnel, study patients and the Regeneron study team will all 
be blinded to treatment during the double-blind treatment period. 
Patients will be randomized 2:1 (evinacumab:placebo) to receive either evinacumab administered 
IV at a dose of 15 mg/kg or matching placebo every 4 weeks (±4 days) on days 1, 29, and 57. 
Patients will be closely monitored for a minimum of 120 minutes after IV administration of 
evinacumab or matching placebo on days 1, 29, and 57. 
Stable doses of other triglyceride-lowering therapies, such as fibrates, statins, omega-3s, and niacin 
are allowed during the study.  Patients may not take Glybera®, mipomersen, or lomitapide during 
the study. 
Efficacy and safety procedures and completion of the pancreatitis daily symptom questionnaire 
and symptom/dietary impact questionnaire will be performed as outlined in the schedule of events. 
Imaging correlates of pancreatic health will be assessed by 18F-FDG PET, by DW-MRI, and by 
T2-MRI. 
Serum samples for the determination of total evinacumab, total ANGPTL3, and anti-drug 
(anti-evinacumab) antibodies (ADA) will be collected. 
Serum and plasma samples will be collected for analysis of additional biomarkers, including 
amylase and lipase. 
Single-Blind Treatment Period (Day 86 to Day 169) 
All patients who complete the double-blind treatment period will receive evinacumab administered 
IV at a dose of 15 mg/kg every 4 weeks (± 4 days) on days 85, 113, and 141. 
Stable doses of other triglyceride-lowering therapies, such as fibrates, statins, omega-3s, and niacin 
are allowed during the study. Glybera®, mipomersen, or lomitapide are prohibited during the study. 
Efficacy and safety procedures and completion of the pancreatitis daily symptom questionnaire 
and symptom/dietary impact questionnaire will be performed as outlined in the schedule of events. 
Patients should fast for a minimum of 8 hours prior to any blood draws. Imaging correlates of 
pancreatic health will be assessed by DW-MRI. 
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Serum samples for the determination of total evinacumab, total ANGPTL3, and anti-drug 
(anti-evinacumab) antibodies (ADA) will be collected. 
Serum and plasma samples will be collected for analysis of additional biomarkers, including 
amylase and lipase. 
Off-Drug Treatment Follow-up Period (Day 170 to Day 309 [End-of-Study]) 
Efficacy and safety procedures will be performed as outlined in the Schedule of Events. 
Throughout the Study 
Patients will 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 and of female 
partners (of child-bearing potential) of male patients will be monitored throughout the study and 
for 24 weeks post the last dose of study drug. 
5.1.1. 
End of Study Definition 
The end of study for this study is defined as the last visit of the last patient. 
5.2. 
Planned Interim Analysis  
Interim analyses may be conducted during the course of the study by the unblinded team to assess 
efficacy, safety, and futility. If the timing of this analysis falls within a few weeks of the first-step 
analysis, only the first-step analysis will be performed. Enrollment (up to a maximum of 
approximately 50 patients) may be halted if the incidence of pancreatitis is much lower than 
anticipated, making the evaluation of a treatment effect on pancreatitis futile. Details of the interim 
analysis will be provided in the SAP. 
5.3. 
Study Committees 
5.3.1. 
Independent Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC), composed of members who are 
independent from the sponsor and the study investigators, will monitor patient safety by 
conducting formal reviews of accumulated safety data that will be blinded by treatment group; if 
requested, the IDMC may have access to the treatment allocation code or any other requested data 
for the purposes of a risk-benefit assessment. 
The IDMC will provide the sponsor with appropriate recommendations on the conduct of the 
clinical study to ensure the protection and safety of the patients enrolled in the study. The IDMC 
will also institute any measures that may be required for ensuring the integrity of the study results 
during the study execution. 
All activities and responsibilities of the IDMC are described in the IDMC charter. 
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6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
6.1. 
Number of Patients Planned 
The study will enroll up to approximately 50 patients at approximately 20 study sites globally. 
6.2. 
Study Population 
The study population will be males and females ≥18 to 75 years of age with a history of fasting 
TG ≥1000 mg/dL, a fasting TG ≥500 mg/dL during screening, and a history of pancreatitis. The 
study will enroll up to approximately 50 adult male and female patients at approximately 20 sites 
globally.  Efforts will be made to select sites with a large population of well-characterized patients 
who have previously undergone gene sequencing and other procedures to understand the etiology 
of the HTG. 
The following LPL pathway cohorts will be enrolled based upon the patient’s genotype: 
1. Cohort 1:  FCS due to complete LPL deficiency. Approximately 6 to 9 patients will be 
enrolled. This cohort consists of patients: 
 With known homozygous or compound heterozygous null LPL, GPIHBP1, or APOC2 
LOF mutations 
2. Cohort 2:  Multifactorial chylomicronemia with partial LPL deficiency. Approximately 
9 to 12 patients will be enrolled. This cohort consists of patients: 
 with known heterozygous null LPL, GPIHBP1, or APOC2 LOF mutations, or 
 with uncharacterized or known non-null LOF LPL pathway gene mutations (LPL, 
APOC2, APOA5, LMF1 and GPIHBP1) 
3. Cohort 3:  Multifactorial chylomicronemia. Approximately 15 to 27 patients will be 
enrolled. This cohort consists of patients not included in cohorts 1 or 2 above:  
 with other monogenic or polygenic causes of sHTG (eg, CGKR, CREB3L3, E2/E2 
dysbetalipoproteinemia), or 
 without genotype information 
6.2.1. 
Inclusion Criteria  
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Males and females ≥18 to 75 years of age at screening 
2. Previous documentation in the patient’s medical records of a fasting serum TG 
measurement ≥ 1000 mg/dL (11.3 mmol/L) on more than 1 occasion, and all fasting 
TG values >500 mg/dL (5.6 mmol/L) at screening 
NOTE:  TGs will be measured at least twice and at least 4 days apart during the screening 
period.  
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3. History of a hospitalization and diagnosis of acute pancreatitis in the past 10 years. 
(Sponsor may elect to drop the time specification if sufficient enrollment does not occur 
within a reasonable period of time).  
4. On a stable lipid-modifying diet with or without medications (eg, statins, niacin, omega-3 
fatty acids). Lipid-modifying diet and doses of medications should be stable for at least 4 
weeks (6 weeks for fibrates, 8 weeks for PCSK9 inhibitors) prior to screening 
5. BMI index of 18-40 kg/m2 
6. Willing to consume no more than an average of 2 standard alcoholic drinks per day and a 
maximum of 15 standard alcoholic drinks per week for the duration of the study. (A 
standard alcoholic drink is the equivalent of 12 ounces (355 mL) of beer, 5 ounces 
(148 mL) of wine, or 1.5 ounces (44 mL) of hard liquor) 
7. Willing to refrain from consumption of alcohol for 24 hours prior to each study visit 
8. Willing to refrain from cigarette smoking for 24 hours prior to each study visit 
9. Willing to consistently maintain previously recommended diet and exercise regimen for 
duration of the study 
10. Willing and able to comply with clinic visits and study-related procedures 
11. Provide signed informed consent 
12. Able to understand and complete study-related questionnaires 
6.2.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. A hospital or clinic discharge diagnosis of acute pancreatitis within 12 weeks of screening 
2. Lipid apheresis or plasma exchange treatment within the last 4 weeks or plans to undergo 
apheresis or plasma exchange during the time frame of the study 
3. History of class 3/4 heart failure at any time in the past, or hospitalization for heart failure, 
diagnosis of a myocardial infarction, stroke, TIA, unstable angina, CABG, PCI, carotid 
surgery/stenting within 3 months before the screening visit 
4. History of bleeding disorders, esophageal varices, heparin induced thrombocytopenia, or 
contraindications to receiving heparin (eg, allergic reaction to heparin) 
5. New clinically significant findings on 12-lead electrocardiogram (ECG) that would place 
the patient at risk or interfere with participation in the study 
6. Dose(s) of any permitted concomitant medications that have changed in the time period 
prior to screening as described in Section 7.8.2 
7. Presence of any clinically significant uncontrolled endocrine disease known to influence 
serum lipids or lipoproteins 
NOTE:  Patients on thyroid replacement therapy are eligible if the dosage of thyroxine has 
been stable for at least 12 weeks prior to screening visit 
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8. Use of systemic corticosteroids, unless used as replacement therapy for pituitary/adrenal 
disease (in which case must be a stable regimen for at least 6 weeks prior to the screening 
visit) 
NOTE:  Topical, intra-articular, nasal, inhaled and ophthalmic steroid therapies are not 
considered as ‘systemic’ and are allowed 
9. Calculated eGFR <45 ml/min (according to 4-variable MDRD study equation) 
10. History of drug or alcohol abuse (including binge drinking which typically involves 
consumption of approximately 4 drinks for women and 5 drinks for men in a few hours) 
within 1 year of screening 
11. Exposure to another investigational drug or therapy within 30 days or within at least 5 half-
lives (whichever is longer) prior to the screening visit 
12. Blood donation of any volume within 1 month prior to administration of study drug 
13. Known hypersensitivity to monoclonal antibody therapeutics. Known sensitivity to any of 
the components of the investigational product formulation  
14. History of malignancy within 5 years prior to screening (other than successfully treated 
nonmetastatic cutaneous squamous cell or basal cell carcinoma and or localized carcinoma 
in situ of the cervix) 
15. Any medical or psychiatric condition that, in the opinion of the investigator, would place 
patient at risk, interfere with participation in the study or interfere with the interpretation 
of the study results (eg, cirrhosis or chronic active hepatitis, nephrotic syndrome, 
uncontrolled diabetes, uncontrolled hypertension) 
16. Previous treatment with Glybera® in the past 5 years or treatment with lomitapide or 
mipomersen in the past 6 months 
17. Positive serum hCG pregnancy test at the screening visit 
18. Creatine phosphokinase (CPK) >3x upper limit of normal (ULN) at the screening visit 
19. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3x ULN 
20. Thyroid-stimulating hormone (TSH) >1.5 ULN or < lower limit of normal 
21. Platelet count <75,000 
22. Any patient who is the investigator or any sub-investigator, research assistant, study 
coordinator, or other staff directly involved in the conduct of the protocol, or a family 
member of staff involved in the conduct of the protocol 
23. Pregnant or breast feeding women 
24. Women of childbearing potential (WOCBP)* who are unwilling to practice a highly 
effective birth control method prior to the initial dose, during the study, and for 24 weeks 
after the last dose of study drug. Highly effective contraceptive measures include: 
 Stable use of combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to 
screening: 
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 oral 
 intravaginal 
 transdermal 
 Stable use of progestogen-only hormonal contraception associated with inhibition of 
ovulation initiated 2 or more menstrual cycles prior to screening: 
 oral 
 injectable 
 implantable  
 intrauterine device (IUD)  
 intrauterine hormone-releasing system (IUS)  
 bilateral tubal ligation 
 Vasectomized partner. Note: Vasectomized partner is a highly effective birth control 
method provided that the partner is the sole sexual partner of the woman of child 
bearing potential trial participant and that the vasectomized partner has received 
medical assessment of the surgical success 
 Sexual abstinence. Note: Sexual abstinence is considered a highly effective method 
only if defined as refraining from heterosexual intercourse during the entire period of 
risk associated with study treatments.  
*Postmenopausal women must be amenorrheic for at least 12 months in order not to be 
considered of childbearing potential. Postmenopausal status will be confirmed by 
measurement of follicle-stimulating hormone (FSH). Pregnancy testing and contraception are 
not required for women with documented hysterectomy and/or oophorectomy. 
25. Men who are sexually active with WOCBP and are unwilling to consistently use condoms 
during the study drug treatment period and for 24 weeks after the last injection of study 
drug, regardless of vasectomy status. Sperm donation is prohibited during the study and 
for up to 24 weeks after the last injection of study drug. 
6.3. 
Premature Withdrawal from the Study 
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and/or sponsor have the right to withdraw a patient from the study if it is no longer 
in the interest of the patient to continue in the study, or if the patient’s continuation in the study 
places the scientific outcome of the study at risk (eg, if a patient does not or cannot follow study 
procedures). An excessive rate of withdrawals would render the study uninterpretable; therefore, 
unnecessary withdrawal of patients should be avoided.  The site will be provided a retention 
manual outlining the best practices for patient retention. 
Patients who are withdrawn prematurely from the study will be asked to complete study 
assessments, as described in Section 8.1.2. 
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Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 7.4.2. 
6.4. 
Replacement of Patients 
Patients prematurely discontinued from the study/ study drug will not be replaced. 
7. 
STUDY TREATMENTS 
7.1. 
Investigational and Reference Treatments 
Sterile evinacumab drug product will be provided in a 20 mL single-use glass vial at a 
concentration of 150 mg/mL. 
Double-Blind Treatment Period:  Patients will be randomized to receive either evinacumab 
15 mg/kg or matching placebo administered IV every 4 weeks (±4 days) on days 1, 29, and 57. 
Single-Blind Treatment Period:  All patients will receive evinacumab administered IV at a dose 
of 15 mg/kg every 4 weeks (±4 days) on days 85, 113, and 141. 
Instructions on management of infusion reactions are provided in Section 7.5. 
Instructions on dose preparation are provided in the pharmacy manual. 
7.2. 
Run-in Treatment(s) 
On day -28, all patients will receive an IV placebo infusion. Placebo will be supplied in vials that 
match evinacumab, but do not contain the protein. 
7.3. 
Pretreatment(s) 
After confirmation of eligibility, patients will receive an IV bolus of 60 IU of heparin per kg of 
body weight at screening visit 2. 
7.4. 
Dose Modification and Study Treatment Discontinuation Rules 
7.4.1. 
Dose Modification 
Dose modification for an individual patient is not allowed. 
7.4.2. 
Study Drug Discontinuation 
Patients who permanently discontinue from study drug before entering the double-blind treatment 
period (day 1, week 0) will be contacted to assess any adverse events (AEs) but will not be asked 
to return for the remaining study visits. 
Patients who permanently discontinue from study drug during the double-blind treatment period 
will be asked to return to the clinic within 5 days for an early termination visit consisting of week 
12 study assessments; these patients will then enter the off-drug treatment follow-up period. 
Patients who are permanently withdrawn from study drug during the single-blind treatment period 
will be asked to return to the clinic for an early termination visit consisting of week 24 study 
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assessments. After the early termination visit, patients will enter the off-drug treatment follow-up 
period. 
Patients who are unable or unwilling to attend the study visits as described above should still be 
followed for at least 24 weeks from the last dose of study drug or up to recovery or stabilization 
of any AE to be followed-up as specified in this protocol, whichever comes last. The assessments 
completed should include pregnancy testing for WOCBP. A final end of study visit should take 
place with assessments as specified in the end of study visit (ie, follow up visit) at 24 weeks after 
the premature discontinuation of study drug. 
Sexually active males and WOCBP who discontinue the study prematurely should be reminded at 
the early termination visit following treatment discontinuation to maintain the contraceptive 
measures (as described in Section 6.2.2) for 24 weeks after the last dose of study drug. At this visit, 
WOCBP will be provided a sufficient number of urine pregnancy tests with instructions to test for 
pregnancy 4 weeks after this visit and every 4 weeks (Q4W) thereafter. The patient will also be 
notified of Q4W follow-up phone calls to confirm continued contraception use, to obtain results 
of urine pregnancy tests, and to obtain information on whether pregnancy has occurred in WOCBP 
and in female partners of male patients. 
The investigator should make the best effort to contact any patient (eg, contacting patient’s family 
or private physician, review available registries or health care database) who fails to return to the 
site, and to determine health status. Attempts to contact such patients must be documented in the 
patient’s records (eg, times and dates of attempted telephone contact, receipt for sending a 
registered letter). 
7.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
Study drug dosing will be permanently stopped in the event of: 
 Evidence of pregnancy 
 Acute systemic injection reactions with AEs including, but not limited to, anaphylaxis, 
laryngeal/pharyngeal edema, severe bronchospasm, chest pain, seizure or severe 
hypotension 
 Withdrawal of patient consent 
7.4.2.2. 
Reasons for Temporary Discontinuation of Study Drug 
The investigator may temporarily discontinue study drug dosing at any time, even without 
consultation with the medical monitor if the urgency of the situation requires immediate action 
and if this is determined to be in the patient’s best interest. However, the Regeneron medical 
monitor should be contacted as soon as possible in any case of temporary or permanent study drug 
discontinuation. If a patient requires a prohibited medication at any time during the study, the 
principal investigator should contact the Regeneron medical monitor. Based on the discussions, 
study drug may be continued or temporarily or permanently discontinued. 
7.4.2.3. 
Management of Suspected Cases of Acute Pancreatitis 
Patients enrolled in this study have an increased risk of acute and recurrent pancreatitis due to 
HTG. A key objective of this study is to determine whether patients with sHTG have evidence of 
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subclinical pancreatitis by collecting information on abdominal symptoms and biochemical tests 
such as amylase and pancreatic lipase on a regular basis throughout the study.  Development of or 
worsening abdominal pain with or without elevations in amylase and/or pancreatic lipase may 
signify the development of acute pancreatitis in this susceptible population. Investigators may elect 
to perform additional diagnostic and laboratory testing.  If a clinical diagnosis of acute pancreatitis 
is made, investigators may elect to temporarily discontinue study drug. 
7.5. 
Management of Acute Reactions  
7.5.1. 
Acute Infusion Reactions 
Emergency equipment and medication for the treatment of infusion reactions must be available for 
immediate use. All infusion reactions must be reported as AEs (as defined in Section 9.4.1) and 
graded using the grading scales as instructed in Section 9.5.1. 
7.5.1.1. 
Interruption of the Infusion 
The infusion should be interrupted if any of the following AEs are observed: 
 cough 
 rigors/chills 
 rash, pruritus (itching) 
 urticaria (hives, welts, wheals) 
 diaphoresis (sweating) 
 hypotension 
 dyspnea (shortness of breath) 
 vomiting 
 flushing 
The reaction(s) should be treated symptomatically. If investigators feel there is a medical need for 
treatment or discontinuation of the infusion other than described above, they should use clinical 
judgment to provide the appropriate response according to typical clinical practice. 
7.5.1.2. 
Termination of the Infusion 
The infusion should be terminated and NOT restarted if any of the following AEs occur: 
 Anaphylaxis* 
 laryngeal/pharyngeal edema 
 severe bronchospasm 
 chest pain 
 seizure 
 severe hypotension 
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 other neurological symptoms (confusion, loss of consciousness, paresthesia, paralysis, 
etc) 
 any other symptom or sign that, in the opinion of the investigator, warrants 
discontinuation of the infusion 
*Consider anaphylaxis if the following is observed (Sampson 2006):  acute onset of an illness 
(minutes to several hours) with the involvement of the skin, mucosal tissue, or both (eg, 
generalized hives, pruritus or flushing, swollen lips-tongue-uvula AND AT LEAST ONE OF THE 
FOLLOWING: 
a. respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia); 
b. reduced blood pressure or associated symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, incontinence). 
7.6. 
Method of Treatment Assignment 
Up to approximately 50 patients will be treated in this partial-blind, randomized, 
placebo-controlled, fixed-sequence study; all will receive an IV placebo infusion on day -28.  
Patients will be randomized 2:1 to receive either evinacumab 15 mg/kg or matching placebo 
administered IV every 4 weeks (±4 days) on days 1, 29, and 57 (double-blind treatment period). 
All patients will receive evinacumab administered IV at a dose of 15 mg/kg every 4 weeks 
(±4 days) on days 85, 113, and 141, (single-blind treatment period). 
7.6.1. 
Blinding 
Study patients will remain blinded to the sequence of study drug administration in this partial-blind 
study. Investigators, Regeneron Study Director, Medical Monitor, Study Monitor, and any other 
Regeneron and contract research organization (CRO) personnel who are in regular contact with 
the study site will be blinded to treatment assignment during the double-blind treatment period of 
the study and blinded to blood lipid measurements during the double-blind and single-blind 
treatment periods. 
Selected individuals at Regeneron not involved in the conduct of the study may have access to 
unblinded data, as needed, for safety review or other data review. 
Although there is a slight color difference between the drug product and placebo product for IV 
infusion bag preparation, the color difference is not detectable when the investigational product is 
added to the IV infusion bag. Further details are provided in the pharmacy manual. 
7.6.2. 
Emergency Unblinding 
Unblinding of treatment assignment for a patient may be necessary due to a medical emergency 
or any other significant medical event (eg, pregnancy) during the double-blind treatment period. 
If unblinding is required: 
 Only the investigator will make the decision to unblind the treatment assignment. 
 Only the affected patient will be unblinded. 
 The investigator or their designee for the site will unblind the patient. 
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 The investigator will notify Regeneron and/or designee before unblinding the patient, 
whenever possible. 
Treatment assignment is not to be provided to site personnel at any time during the conduct of 
the study except in the case of a true emergency. 
7.7. 
Treatment Logistics and Accountability 
7.7.1. 
Packaging, Labeling, and Storage 
A medication numbering system will be used to label blinded investigational study drug. Lists 
linking medication numbers with product lot numbers will be maintained by the groups (or 
companies) responsible for study drug packaging. In order to maintain the blind, these lists will 
not be accessible to individuals involved in study conduct. 
Study drug will be stored at the site at a temperature of 2°C to 8°C; storage instructions will be 
provided in the pharmacy manual. 
7.7.2. 
Supply and Disposition of Treatments 
Study drug will be shipped at a temperature of 2°C to 8°C to the investigator or designee at regular 
intervals or as needed during the study. At specified time points during the study (eg, interim site 
monitoring visits), at the site close-out visit, and following drug reconciliation and documentation 
by the site monitor, all opened and unopened study drug will be returned to the sponsor or designee. 
7.7.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug.  These records 
should contain the dates, quantity, and study medication 
 dispensed to each patient, 
 returned from each patient (if applicable), and 
 returned to the sponsor or designee. 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
7.7.4. 
Treatment Compliance 
All 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. 
7.8. 
Concomitant Medications  
Any treatment administered from the time the informed consent is signed 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. 
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7.8.1. 
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, unless used as replacement therapy for pituitary/adrenal 
disease with a stable regimen for at least 6 weeks prior to the screening visit 
7.8.2. 
Permitted Medications and Procedures 
The use of medications and nutritional supplements known to lower triglycerides, including 
statins, fibrates, niacin, omega-3s are permitted as long as that therapy has been stable for at least 
4 weeks (6 weeks for fibrates, 8 weeks for PCSK9 inhibitors) prior to the screening visit. Patients 
should continue taking their background medical lipid-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. 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
8.1. 
Schedule of Events 
Study assessments and procedures are presented by study period and visit in Table 1. 
 
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Table 1: 
Schedule of Events 
 
Screening Period 
Placebo run-
in1/ Baseline 
Double-Blind Treatment Period2 
Single-Blind Treatment 
Period3 
Study Procedure 
Visit 
1 
Visit 
1b4 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
105 
Visit 
11 
Visit 
12 
End of 
Treat-
ment 
Visit 13 
Day 
-66 to 
-59 
-58 to  
-52 
-51 to  
-39 
-28 
+4d 
-14 
± 4d 
1 
± 4d 
15 
± 4d 
29 
± 4d 
43 
± 4d 
57 
± 4d 
85 
± 4d 
113 
± 4d 
141 
± 4d 
169 
± 5d 
Week 
 
 
 
 
 
0 
2 
4 
6 
8 
12 
16 
20 
24 
Screening/Baseline: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FT4, TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (for women only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/PTT, INR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort Assignment 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Heparin7 
 
 
X8 
 
 
 
 
 
 
 
 
 
 
X 
Administer Placebo 
 
 
 
X9,10 
 
 
 
 
 
 
 
 
 
 
Administer Study Drug (evinacumab or 
placebo) 
 
 
 
 
 
X9,10 
 
X9,10 
 
X9,10 
 
 
 
 
Administer evinacumab 
 
 
 
 
 
 
 
 
 
 
X9,10 
X9,10 
X9,10 
 
Concomitant Medications and treatment 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipids and lipoproteins11,12 
X13 
X13 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HbA1c, Insulin, C-peptide, and Homa11 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
Post-heparin LPL, EL, HL activity assay and 
HL mass assay11 
 
 
X14 
 
 
 
 
 
 
 
 
 
 
X 
Pre-heparin LPL and EL mass assay 11 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Train/dispense ePRO device 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Daily Symptom Questionnaire 
(Hypertriglyceridemia and Acute Pancreatitis 
Signs and Symptoms)15 
 
 
 
X 
 
X16 
 
X16 
 
X16 
X16 
X16 
X16 
X16 
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Screening Period 
Placebo run-
in1/ Baseline 
Double-Blind Treatment Period2 
Single-Blind Treatment 
Period3 
Study Procedure 
Visit 
1 
Visit 
1b4 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
105 
Visit 
11 
Visit 
12 
End of 
Treat-
ment 
Visit 13 
Day 
-66 to 
-59 
-58 to  
-52 
-51 to  
-39 
-28 
+4d 
-14 
± 4d 
1 
± 4d 
15 
± 4d 
29 
± 4d 
43 
± 4d 
57 
± 4d 
85 
± 4d 
113 
± 4d 
141 
± 4d 
169 
± 5d 
Week 
 
 
 
 
 
0 
2 
4 
6 
8 
12 
16 
20 
24 
Symptom/Dietary Impact Questionnaire 
(Hypertriglyceridemia and Acute Pancreatitis 
Dietary Behavior)15 
 
 
 
X 
 
X16 
 
X16 
 
X16 
X16 
X16 
X16 
X16 
Site review of questionnaires for compliance 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Safety: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
 
X 
X10 
X 
X10 
X 
X10 
X 
X10 
X10 
X10 
X10 
X 
Physical Examination 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
Weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram17 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Adverse Events18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Confirm required contraception use and 
reminder of pregnancy status reporting in 
women of child bearing potential and female 
partners of male patients19 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Remind male patients to use condoms 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology11 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Chemistry11 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test 
serum 
 
 
urine 
 
urine 
 
urine 
 
urine 
urine 
urine 
urine 
serum 
Urinalysis 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
Imaging and Other Assessments:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DW-MRI20  
 
 
 
X 
X 
 
 
 
 
 
X 
 
 
X 
18F-FDG-PET20 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
PK/Drug Concentration and ADA Samples: 
 
PK/Drug conc. Sample21 
 
 
 
 
 
X22 
 
X22 
 
X22 
X22 
 
X22 
X 
ADA sample 
 
 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
Biomarkers: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker serum/plasma 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Amylase, lipase11 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
APOC2, APOC3, APOA5, NEFA11 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
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Screening Period 
Placebo run-
in1/ Baseline 
Double-Blind Treatment Period2 
Single-Blind Treatment 
Period3 
Study Procedure 
Visit 
1 
Visit 
1b4 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
105 
Visit 
11 
Visit 
12 
End of 
Treat-
ment 
Visit 13 
Day 
-66 to 
-59 
-58 to  
-52 
-51 to  
-39 
-28 
+4d 
-14 
± 4d 
1 
± 4d 
15 
± 4d 
29 
± 4d 
43 
± 4d 
57 
± 4d 
85 
± 4d 
113 
± 4d 
141 
± 4d 
169 
± 5d 
Week 
 
 
 
 
 
0 
2 
4 
6 
8 
12 
16 
20 
24 
Inflammation Panel (eg, IL-1, IL-6, IL-8, 
TNFα) 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
hs-CRP 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
Lipid sub-fractions by UC  
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Genomic DNA sample: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood DNA sample 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
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Schedule of Events (continued) 
 
Off-Drug Treatment Follow-Up Period 
Study Procedure 
Visit 14 
Phone Call 
Visit 16 
Phone Call 
End of Study 
Visit 18 
Day 
197± 5d 
225± 5d 
253± 5d 
281± 5d 
309± 5d 
Week(s) 
28 
32 
36 
40 
44 
Treatment: 
 
 
 
 
 
Concomitant Medications and treatment 
X 
X 
X 
X 
X 
Efficacy: 
 
 
 
 
 
Lipids and lipoproteins11,12 
X 
 
X 
 
X 
HbA1c, Insulin, C-peptide, and Homa11 
 
 
 
 
X 
Daily Symptom Questionnaire (Hypertriglyceridemia and Acute 
Pancreatitis Signs and Symptoms)15 
X16 
 
X16 
 
X16 
Symptom/Dietary Impact Questionnaire (Hypertriglyceridemia and 
Acute Pancreatitis Dietary Behavior)15 
X 
 
X 
 
X 
Site review of responses to questionnaires 
X 
 
X 
 
X 
Safety: 
 
 
 
 
 
Vital Signs 
X 
 
X 
 
X 
Physical Examination 
 
 
 
 
X 
Weight 
X 
 
X 
 
X 
Electrocardiogram17 
 
 
 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
Confirm required contraception use and reminder of pregnancy status 
reporting in women of child bearing potential and female partners of 
male patients19 
X 
X 
X 
X 
X 
Remind male patients to use condoms 
X 
X 
X 
X 
 
Laboratory Testing: 
 
 
 
 
 
Hematology11 
X 
 
X 
 
X 
Blood Chemistry11 
X 
 
X 
 
X 
Pregnancy Test19 
Urine 
Urine 
urine 
urine 
serum 
Urinalysis 
 
 
 
 
X 
Imaging and Other Assessments:  
 
 
 
 
 
Amylase, lipase11 
X 
 
X 
 
X 
PK/Drug Concentration and ADA Samples: 
 
 
 
 
 
PK/Drug conc. Sample21 
X 
 
X 
 
X 
ADA sample 
 
 
 
 
X 
Biomarkers: 
 
 
 
 
 
Inflammation Panel (eg, IL-1, IL-6, IL-8, TNFα) 
 
 
 
 
X 
hs-CRP 
 
 
 
 
X 
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8.1.1. 
Footnotes for the Schedule of Events Table  
1. Patients who are permanently withdrawn from study drug before entering the double-blind 
treatment period (day 1, week 0) will be contacted to assess any AEs. 
2. Patients who are permanently withdrawn from the study drug during double-blind period 
will be asked to return to the clinic for an early termination visit consisting of week 12 
study assessments. After the early termination visit, patients will enter the off-drug 
treatment follow-up period. 
3. Patients who are permanently withdrawn from study drug during the single-blind treatment 
period will be asked to return to the clinic for an early termination visit consisting of week 
24 study assessments. After the early termination visit, patients will enter the off-drug 
treatment follow-up period. 
4. Visit 1b must occur at least 4 days after visit 1. 
5. Patients will undergo end of double-blind treatment period assessments at the week 12 
visit, which is the first visit of administration of single-blind evinacumab. 
6. Medical history should include detailed cardiovascular and pancreatitis history. 
7. The patient should be fasting for at least 8 hours prior to the post-heparin procedure for 
measurement of LPL activity. The patient should not consume any alcohol 48 hours prior 
to the post-heparin plasma blood draw. Heparin (60 U/kg body weight) should be 
administered IV by bolus injection. Venous blood should be collected 10 minutes after the 
bolus injection. Prior to discharge from the clinic, patients should then be observed for 1 
hour post-heparin administration for any AEs. 
8. Following the screening period and confirmation of eligibility, patients will receive an 
IV bolus of 60 IU of heparin per kg of body weight at visit 2. 
9. At dosing visits, all assessments (including urine or serum pregnancy tests for WOCBP) 
should be performed and all blood samples should be collected before the dose of study 
drug is administered. 
10. Vital signs should also be measured and AEs monitored pre-dose, at the end of study drug 
infusion, between 30 to 60 minutes post dose, and at approximately 120 minutes post dose. 
Patients will be closely monitored for a minimum of 120 minutes after IV administration 
of study drug. 
11. Patients should fast for a minimum of 8 hours prior to all blood draws. For patients with 
diabetes, investigators may hold a patient’s morning diabetes medications until labs are 
drawn and the patient has eaten. 
12. Lipids and lipoproteins, total cholesterol, LDL-C, HDL-C, TG, APOB, APOA1, and Lp(a) 
will be measured except at visit 1 and 1b. 
13. At visit 1 and visit 1b, only total cholesterol, LDL-C, HDL-C, and TG will be measured. 
14. Lipoprotein lipase level enzyme activity will be measured in fasting plasma collected at 
visit 2 only after eligibility has been confirmed by screening procedures at visit 1 and visit 
1b. 
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15. Questionnaires should be completed daily for 7 days prior to each visit except for visit 3 
(to be completed daily for the duration between visit 2 and visit 3). 
16. Patients should be reminded by phone call 1 week prior to their visit to complete 
questionnaires. 
17. Electrocardiogram should be performed before blood is drawn during visits that require 
blood draws. 
18. In addition to assessment of adverse events at each visit, investigators should also ask 
patients if they have had any changes in abdominal symptoms and/or medical clinic visits 
for abdominal symptoms. 
19. Confirm required contraception use and pregnancy status of female patients of childbearing 
potential and female partners (of child-bearing potential) of male patients will be monitored 
at clinic visits and by phone call for 24 weeks post the last dose of study drug. Women of 
childbearing potential will be provided urine pregnancy tests with instructions to test for 
pregnancy on days corresponding to phone call visits or Q4W if patients do not attend 
regularly scheduled visits. 
20. Imaging may be performed up to 1 week prior to the visit and may be on the same day of 
the visit (for visit 3, MRI can be done on the same day or up to 4 days after visit 3). If done 
on the day of the visit, vital signs, ECG and blood draws after an 8-hour fast should be 
completed prior to the imaging procedures. Imaging procedures should be performed prior 
to study drug infusion. 
21. PK samples will also be used for the analysis of total ANGPTL3. 
22. In addition to the PK sample collected prior to drug administration, a PK sample should be 
obtained immediately after the end of each infusion. 
8.1.2. 
Early Termination Visit 
Patients who are permanently withdrawn before entering the double-blind treatment period (day 
1, week 0) will be contacted to assess any adverse events. Patients who are permanently withdrawn 
from study drug during the double blind treatment period will be asked to return to the clinic for 
an early termination visit consisting of week 12 study assessments described in Table 1. After the 
early termination visit, patients will enter the off-drug treatment follow-up period as described in 
Table 1.  Patients who are permanently withdrawn from study drug during the single blind 
treatment period will be asked to return to the clinic for an early termination visit consisting of 
week 24 study assessments described in Table 1. After the early termination, patients will enter 
the off-drug treatment follow-up period as described in Table 1. Efforts should be made to contact 
patients by phone to assess for AEs for patients who do not wish to return for clinic visits (as 
described above) after discontinuation from study drug. 
All patients who prematurely discontinue study treatment (either in the double-blind period or in 
the single blind period) should be followed for at least 24 weeks from the last dose of study drug, 
and a final end of study visit can take place with assessments as specified in the end of study visit 
(ie, follow-up visit). 
Sexually active males and WOCBP who discontinue the study prematurely should be reminded at 
the unscheduled early termination visit following treatment discontinuation to maintain highly 
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effective contraceptive measures for 24 weeks (as described in Section 6.2.2) for 24 weeks after 
the last dose of study drug. At this visit, WOCBP will be provided a sufficient number of urine 
pregnancy tests with instructions to test for pregnancy 4 weeks after this visit and Q4W thereafter. 
The patient will also be notified of Q4W follow-up phone calls to confirm continued contraception 
use and pregnancy reporting, to obtain the results of the pregnancy tests, and to obtain information 
on whether pregnancy has occurred in WOCBP and in female partners of male patients. 
If a WOCBP is lost to follow-up, sites should attempt a minimum of 2 telephone calls. If the patient 
cannot be reached on the second attempt, a formal letter will be issued from the site to the patient 
that reminds the patient of the importance of continued use of highly effective contraception use 
for at least 6 months after the last dose of study drug. 
8.1.3. 
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. 
8.2. 
Study Procedures 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed for the sole purpose of determining study eligibility 
or characterizing the baseline population:  FT4, TSH, FSH (to verify postmenopausal status - for 
women only), and PT/PTT/INR. 
8.2.2. 
Efficacy Procedures 
Fasting blood samples will be collected at specified time points listed in Table 1 for assessment of 
the lipid profile, including plasma triglycerides, LDL-C by ultra-centrifugation, HDL-C, 
non-HDL-C, total cholesterol and other assays. The TG and total cholesterol will be assessed by 
an enzymatic colorimetric assay run on Beckman-Coulter chemistry analyzers. HDL-C will be 
assayed by precipitation, which involves precipitating all non-HDL-C (IDL, LDL and Lp[a]) using 
50kDa Dextran sulfate with magnesium ions as the precipitating agent followed by determination 
of the HDL-C in the supernatant on the Beckman-Coulter analyzers using an adapted method for 
determining total-cholesterol. Low-density lipoprotein cholesterol will be calculated after 
separation of the VLDL/CM sub-fraction by ultra-centrifugation, measurement of the cholesterol 
in the infranatant measured by the enzymatic colorimetric assay and subtraction of the HDL-C 
(also known as beta-quantification). APOA1 and APOB will be assessed by nephelometry on a 
Siemens BNII nephelometer. Serial ultra-centrifugation will be performed to separate lipoprotein 
subfractions (CM, VLDL, IDL, LDL, HDL) and lipids (eg, TG, cholesterol, phospholipids) and 
proteins (eg, APOB, A1, C2, C3, A5, etc) will be measured in the fractions by established methods. 
Samples for assessment of lipids and lipoproteins and HbA1c will be collected at time points 
according to Table 1. 
8.2.3. 
Daily Symptom Questionnaire and Symptom/Dietary Impact Questionnaire 
Patients will complete a daily symptom questionnaire recording sub-clinical/clinical 
pancreas-related symptoms such as nausea vomiting, abdominal distention, abdominal pain, loss 
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of appetite, and self-imposed dietary restrictions daily for 7 days prior to each visit except for visit 
3 (the questionnaire should be completed daily for the duration between visit 2 and visit 3) 
(Table 1). 
Patients will also complete a symptom/dietary impact questionnaire after the weekly signs and 
symptoms questionnaire daily for 7 days prior to each visit except for visit 3 (the questionnaire 
should be completed daily for the duration between visit 2 and visit 3) (Table 1). 
8.2.4. 
Imaging 
Imaging provides a non-invasive means of evaluating tissue-specific changes that may not be 
detectable by assays performed on blood samples. 18F-FDG PET provides a sensitive way to 
evaluate tissue-specific inflammatory changes. This is achieved through signal enhancement 
driven by increased blood vessel permeability and presence of hypermetabolic infiltrating immune 
cells. Pancreatic 18F-FDG PET signal may be susceptible to drastic changes in blood glucose, and 
could be affected by clearance changes of the tracer induced by therapeutic intervention. While 
the DW-MRI signal depends on the water diffusion through tissue and is not affected by the 
metabolic state of the patient, the T2-MRI signal in soft tissue is dependent upon the degree of 
localized water content. Respiratory motion artifacts and presence of abdominal fat may present 
challenges for quantitative MRI. Compared to other imaging modalities, there is more cross-
sectional published data on the utilization of MRI in acute pancreatic states. However, more 
examples in the literature exist where 18F-FDG PET was implemented to longitudinally assess 
pancreatic inflammation. Thus, both imaging modalities appear promising for the detection of 
pancreatic inflammation or injury. Taken together, these factors point to the advantage an imaging 
strategy where both modalities are incorporated, as they may each provide complementary 
information, or only one may be the primary source of pancreatic injury data due to 
technical/operational challenges that cannot be fully predicted at this time. 
8.2.4.1. 
18F-FDG-PET 
18F-FDG-PET will be performed at baseline (placebo run-in period) and following 12 weeks of 
study treatment (double-blind treatment period) as a method to measure inflammation in the 
pancreas. 
Although 18F-FDG-PET has not been used to detect subclinical pancreatic inflammation in patients 
with HTG, it has been utilized to assess low-level pancreatic injury in other settings. We plan to 
assess subclinical pancreatic injury through 18FDG-PET measures (maximal standardized uptake 
value, SUVmax, SUVmean, and incorporation rates, Ki or Kpatlak at baseline and following 12 weeks 
of treatment). Although 18FDG-PET has not been used in this particular setting, it has been utilized 
to assess low-level pancreatic injury in other settings. 18F-FDG PET is a molecular imaging 
modality that has demonstrated high sensitivity in the in vivo detection of glycolytic tissues, 
including tumors and inflammatory foci. 18F-FDG PET has been applied in a clinical setting to the 
assessment of inflammation for a variety of indications, including AIP, atherosclerosis and 
infection (Ozaki 2008, Shreve 1998, Glaudemans 2013,Tahara 2007, Vos 2006). 18F-FDG PET 
has shown the capability of measuring longitudinal patient inflammatory response in the context 
of AIP, where patients who present with pancreatitis symptoms and high baseline pancreatic PET 
signal were treated with corticosteroids. These studies demonstrated the within-patient 
normalization of PET signal after treatment (see Figure 2) (Lee 2009). While normal pancreas has 
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a PET uptake signal with an SUVmean = 2.0±0.5 (mean ± SD), patients with AIP show enhanced 
pancreatic PET uptake with an SUVmean = 4.0±1.2, providing a substantial signal window (SUV = 
a normalized measure of activity concentration in tissue, SUVmax is the maximum SUV within a 
region of interest). Given the test/re-test variability in PET signal (CV = 15%), a mean ~10% 
change in mean pancreatic SUV signal should be readily detectable in this study. Studies in patients 
undergoing corticosteroid treatment for AIP experienced consistent reductions of ~40% pancreatic 
signal and normalization of 18F-FDG pancreatic uptake (Lee 2009, Shigekawa 2010). A 30% 
reduction in 18F-FDG pancreas uptake should be deemed as clinically significant. In one study 
(N=12), 50% of patients with pancreatitis and positive 18F-FDG PET scans showed normal 
amylase and lipase levels (Shreve 1998), suggesting that 18F-FDG PET may have better sensitivity 
for detection of pancreatic inflammation than traditional markers of pancreatitis. 
Figure 2: 
18F-FDG PET showing decrease of signal in areas of AIP inflammation 
(pancreas, salivary glands and retroperitoneum) after up to 2 months of 
prednisolone treatment (0.5 mg/kg, baseline on the left, post-treatment on the 
right) (Lee 2009). 
 
18F-FDG PET has been shown to be able detect inflamed/vulnerable atherosclerotic plaque in the 
carotid of patients (Figure 3) (Tawakol 2006) and to detect ~15% reductions in signal following 
12 weeks of treatment with high-dose statin (versus low dose statin) in N=34 patients 
(Tawakol 2013). Since the acquisitions with 18F-FDG PET in the present study will include the 
neck and thoracic regions, it will be possible to assess suspect areas of atherosclerotic plaque in 
the carotid and aorta of patients. Reduction of signal (target to background ratio - TBR) in these 
areas would indicate a potential beneficial effect of ANGPTL3 inhibition on atherosclerotic 
lesions. ANGPTL3 inhibition in rodents has led to reductions in atherosclerotic plaque. Since 18F-
FDG-PET can detect inflammation in atherosclerotic lesions, we plan to explore imaging of the 
carotids and aorta before and after treatment, without any further isotope dosing or radiation 
exposure. 
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Figure 3: 
Axial CT and co-registered PET images from 2 patients.  Patient A showed 
low 18F-FDG uptake in the region of the carotid plaque, while Patient B had 
high uptake in the region of the carotid plaque.  The uptake difference was 
consistent with high inflammatory infiltration in the atherosclerotic plaque 
of patient B compared to patient A as determined from excised tissue 
samples. 
 
18F-FDG PET scans (including a low-dose CT scan) result in typical effective radiation doses of 7 
to 10 mSv per study for an adult (19 microSv/MBq) (ICRP 80). The maximum recommended 
allowed effective dose for a research patient in a single year is 50 mSv (21CFR361.1). Two 
18F-FDG PET studies would result in an approximate dose of 20 mSv, or 40% of the recommended 
maximum allowed dose. Risk and management of radiation exposure will be disclosed to patients 
in the informed consent form. 18F-FDG PET will be performed at week 2 and at week 16 (12 weeks 
after initiation of evinacumab treatment). 
8.2.4.2. 
Magnetic Resonance Imaging 
MRI will be used to assess pancreatic injury/inflammation at baseline and after treatment with 
evinacumab. With MRI, there is no ionizing radiation dose to the patient that would limit the 
number of imaging studies that could be performed. Pancreatic MRI is planned for day -28, week -
2, week 12 and week 24. Week 12 and 24 scans will allow for short-term and long-term 
inflammatory response assessments (Klauss 2015). During early stages of pancreatic injury or 
inflammation, acinar cell injury, activation of pancreatic stellate cells and an invasion by 
leukocytes, neutrophils and macrophages are all known to exist (Whitcomb 2004). Such intra-and 
extracellular pathological events modulate microstructural properties of affected pancreatic tissue, 
and in turn, alter the Brownian motion of water molecules in cellular compartment. In DW-MRI, 
the random diffusion of water molecules occurring within intracellular, extracellular and 
intravascular spaces is measured, enabling detection of macroscopic soft tissue pathology such as 
edema, necrosis and fibrosis. The apparent diffusion coefficient (ADC, units of mm2/sec) is a 
principal metric quantified in DW-MRI experiments, where ADC values can be mapped across a 
region of interest at a spatial resolution of ~3 x 3 x 5 mm3. Compared to healthy pancreatic tissue, 
inflammatory tissue is characterized as having restricted water diffusion (decreased ADCs), while 
necrotic tissue corresponds to less restricted water diffusion (increased ADCs). Normal pancreas 
ADCs are (1.77±0.32) X 103 mm2/sec while acute pancreatitis ADCs are (1.32±0.32) X 103 
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mm2/sec showing a significant window for measuring the projected inflammatory changes in the 
pancreas. Given a test/re-test variability of 18%, a signal change of 20% should be detectable in 
the present study. 
Measurement of ADCs has been used to assess pancreatic health across pancreatic disease states, 
including acute, chronic and autoimmune pancreatitis as well as pancreatic cancer. Confirming 
earlier observations, de Freitas Turtulino recently reported a ~20% difference in ADC between 
healthy (N=15) and mild acute (N=13) pancreas states (de Freitas Tertulino 2015) (Figure 4). 
Lower ADCs were also detected in indications possessing pancreatic inflammation such as in cases 
of chronic obstruction of the main pancreatic duct known to exist in pancreatic cancer 
(Hayano 2016). Here, a ~12% difference in ADCs between large and small main pancreatic duct 
diameter cohorts was observed (Mann-Whitney U test [P=0.03]). For review of implementation of 
DW-MRI in pancreatic disease see Barral 2015. 
DW-MRI can be combined with T2-weighted and T2 mapping MRI, the latter of which can further 
inform on the presence, but not clear differentiation of edema, hyperemia or inflammatory cell 
infiltration within a region of interest (Figure 5). Moreover, pancreatic lesions can be assesses in 
combination with whole organ or regional (head, neck, body and tail) pancreatic volume, which 
can be modulated in a disease state. In the current study, ADCs, T2-weighted intensities and T2 
relaxations times will be reported for the whole pancreas in addition for each pancreatic sub-region 
(head, neck, body and tail). Outside of disease states affecting pancreatic health, a combined 
diffusion-weighted and T2-MRI approach is commonly utilized for early detection of lesions 
following stroke, monitoring of hepatic metastases across oncology indications and detection of 
focal renal lesions known to exist in metabolic diseases such as chronic kidney disease. Thus, the 
combined DW-MRI and T2-MRI approach is commonly implemented and validated across 
multiple indications (Mashhood 2013). 
Magnetic resonance imaging is used in the measurement of hepatic fat fraction. A multi-echo 
gradient-recalled echo sequence acquiring axial images to cover the entire liver is recommended. 
The echo times shall be such that at successive echo times (TEs), fat and water alternate between 
out-of-phase and in-phase. To minimize motion artifacts, these should be acquired under breath 
hold (not to exceed 20 seconds), and 3 separate breath hold acquisitions covering different sections 
of the liver (superior-middle-inferior) will need to be acquired. The full acquisition should take 3 
to 5 minutes. 
 
 
 
 
 
 
 
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Figure 4: 
ADC values as measured by DW-MRI differentiate normal pancreas from 
acute pancreatic disease states.  ~20% difference between normal and mild 
acute pancreas.  Kruskal-Wallis test across cohorts (P < 0.001).  Sample Size: 
Normal (N=15), mild acute (N=13) and necrotizing acute (N=8) pancreas 
(de Freitas Tertulino 2015). 
 
 
Figure 5: 
Axial T2-weighted MRI with fat-suppression demonstrated intrapancreatic 
threadlike hyperintense structures consistent with interlobular septal 
inflammation (arrows).  Data collected from a 42-year-old male, acute 
pancreatitis patient (Xiao 2010).  Boxplots of the control (N=51) and acute 
pancreatitis (N=117) groups shows higher T2 values in the patient cohort 
owing to presence of edematous pancreatic tissue.  Calculation of the ROC 
curve demonstrated good diagnostic value of T2 MRI for diagnosis of acute 
pancreatitis (Tang 2016). 
 
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8.2.5. 
Safety Procedures 
8.2.5.1. 
Vital Signs 
Vital signs, including temperature, sitting blood pressure, pulse, and respiration will be collected 
pre-dose at time points according to Table 1. 
8.2.5.2. 
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. Medical history should include detailed cardiovascular 
and pancreatitis history. 
8.2.5.3. 
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. 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. 
8.2.5.4. 
Laboratory Testing 
Hematology, chemistry, urinalysis, 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. Tests will include: 
Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin 
Potassium 
Creatinine 
Total cholesterol* 
Chloride 
Blood urea nitrogen (BUN) 
Triglycerides 
Carbon dioxide 
Aspartate aminotransferase (AST) 
Uric acid 
Calcium 
Alanine aminotransferase (ALT) 
Creatine phosphokinase (CPK) 
Glucose 
Alkaline phosphatase 
Phosphorus 
Albumin 
Lactate dehydrogenase (LDH) 
Magnesium 
 
*(low-density lipoprotein [LDL] and high-density lipoprotein [HDL]) 
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Hematology 
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
Urinalysis 
Color 
Glucose 
RBC 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBC 
Yeast 
Other Laboratory Tests 
Samples will also be collected for assessment of LPL enzyme activity after administration of 
heparin at screening visit 2 and at visit 13. Other laboratory tests include HbA1C, insulin, 
C-peptide, Homa, inflammation biomarker panel (eg, hs-CRP, IL-1, IL-6, IL-8, and TNFα), 
amylase, lipase, APOC2, APOC3, APOA5, and NEFA, and lipid sub-fractions by UC. 
Abnormal Laboratory Values and Laboratory Adverse Events 
 All laboratory values must be reviewed by the investigator or authorized designee. 
 Significantly abnormal test results that occur after start of treatment must be repeated 
to confirm the nature and degree of the abnormality. When necessary, appropriate 
ancillary investigations should be initiated. If the abnormality fails to resolve or 
cannot be explained by events or conditions unrelated to the study medication or its 
administration, the medical monitor must be consulted. 
 The clinical significance of an abnormal test value, within the context of the disease 
under study, must be determined by the investigator. 
Criteria for reporting laboratory values as an AE are provided in Section 9.4.5. 
8.2.6. 
Pharmacokinetic and Anti-Drug Antibody Procedures 
8.2.6.1. 
Drug Concentration Measurements and Samples 
Samples for drug concentration will be collected at time points listed in Table 1.  
. 
8.2.6.2. 
Anti-Drug Antibody Measurements and Samples 
Serum samples for ADA assessment will be collected at time points listed in Table 1. They will 
be collected pre-dose on days when study drug is administered.
 
. 
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Patients who exhibit a treatment emergent or treatment boosted positive ADA assay response in 
their last sample analyzed will be followed until the titers are less than 240 or within 2 dilution 
steps from the pre-dose baseline titer levels. 
8.2.7. 
Biomarker Procedures 
Biomarker samples will be collected at time points according to Table 1. 
Lipoprotein lipase enzyme activity will be measured using the assay developed by Imamura et al, 
(Imamura 2008) in fasting plasma collected from patients at visit 2 (after eligibility has been 
confirmed by screening procedures at visit 1 and 1b and the patient has received an IV bolus of 60 
IU of heparin per kg of body weight), and at visit 13 (after administration of an IV bolus of 60 IU 
of heparin per kg of body weight). Lipoprotein lipase is bound to the luminal side of capillary 
endothelium by glycosoaminoglycans and the infusion of heparin is required for the disassociation 
of the bound LPL into the circulation. The heparin infusion is generally considered to be safe and 
well tolerated. 
8.2.8. 
Biochemical Measures of Pancreatic Health 
Amylase and pancreatic lipase are clinical measures of pancreatic health, which are elevated 
during episodes of AP and will be measured at every visit. Levels of IL6 and CRP have been 
demonstrated to be elevated during AP episodes and are considered exploratory measures due to 
limited clinical evidence and therefore will only be measured at baseline and during the treatment 
period. Research samples will be collected at every visit for any post-hoc analyses of biochemical 
markers for correlation with clinical symptoms of AP and may include trypsinogen, pancreatic 
isoamylase, pancreatic elastase, serum trypsin, phospholipase A2, carboxypeptidase B. 
 
 
 
 
 
. 
8.2.9.1. 
Genomics Study 
To better understand the response to inhibition of ANGPTL3 in patients with sHTG, this study 
will enroll patients with LPL deficiency (as assessed by genotype) as well as those with relatively 
intact LPL activity. Lipoprotein lipase deficiency can be caused by LOF mutations in LPL or other 
genes that modulate the enzymatic activity of LPL, such as APOC2, and APOA5. APOC2 serves 
as an activator protein of LPL and APOA5 is thought to stabilize the lipoprotein enzyme complex 
and enhance lipolysis. 
Loss of function mutations in LPL (eg, deletions or duplications) lead to levels of undetectable 
LPL activity and mass in plasma (Monsalve 1990) and heterozygotes who have a G215E mutation 
have mean levels of LPL at about 50% of normal though individually their levels overlap with 
normal levels (Wilson 1993). Other genetic causes of sHTG include homozygous mutations in 
LMF1 and GPIHBP1, which are genes in the LPL pathway. In a study of 86 sHTG patients (both 
Type 1 and Type 5 with TGs > 10 mmol/L), with a range of LPL enzyme activity levels, 35% had 
rare causative mutations in LPL, 11% had mutations in APOA5, APOC2, LMF1 and GPIHBP1, 
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and the rest had either common variants in these genes or no identified mutations 
(Surendran 2012). Based on the data from this Dutch study, not all LOF mutations in the LPL 
pathway resulted in diminished LPL enzyme activity. 
DNA will be collected for all patients and sequencing performed to confirm mutations if 
previously genotyped and analysis will be done to identify mutations in genes in the LPL pathway 
eg, LPL, APOC2, APOA5 as well as other genes known to be associated with sHTG. 
 
 
 
 
 
 
 
 
 
 
 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
9.1. 
Obligations of Investigator 
The investigator must promptly report to the Institutional Review Board (IRB)/Ethics Committee 
(EC) all unanticipated problems involving risks to patient. This includes death from any cause and 
all SAEs related to the use of the study drug. It is recommended that all SAEs be reported to the 
IRB/EC, regardless of assessed causality. 
9.2. 
Obligations of Sponsor 
During the course of the study, the sponsor will report in an expedited manner all SAEs that are 
both unexpected and at least reasonably related to the study drug (suspected unexpected serious 
adverse reaction [SUSAR]), to the health authorities, IRBs/ECs as appropriate, and to the 
investigators. 
Any AE not listed as an expected event in the Investigator’s Brochure or in this protocol will be 
considered as unexpected. Any worsening of or new onset of symptoms related to sHTG which 
occur during the screening period prior to study drug administration will be considered expected.  
In addition, the sponsor will report in an expedited manner all SAEs that are expected and at least 
reasonably related to the study drug to the health authorities, according to local regulations. 
At the completion of the study, the sponsor will report all safety observations made during the 
conduct of the trial in the clinical study report to health authorities and IRBs/ECs as appropriate. 
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9.3. 
Definitions 
9.3.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug, which may or 
may not have a causal relationship with the study drug. Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease, which is 
temporally associated with the use of a study drug, whether or not considered related to the study 
drug. 
An AE also includes any worsening (ie, any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug. 
9.3.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death - includes all deaths, even those that appear to be completely unrelated 
to study drug (eg, a car accident in which a patient is a passenger). 
 Is life-threatening - in the view of the investigator, the patient is at immediate risk of 
death at the time of the event. This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
 Requires in-patient hospitalization or prolongation of existing hospitalization.  
In-patient hospitalization is defined as admission to a hospital or an emergency room 
for longer than 24 hours. Prolongation of existing hospitalization is defined as a 
hospital stay that is longer than was originally anticipated for the event, or is prolonged 
due to the development of a new AE as determined by the investigator or treating 
physician. 
 Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions). 
 Is a congenital anomaly/birth defect 
 Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent one of the other serious outcomes listed above (eg, 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse). 
9.3.3. 
Infusion Reactions 
Infusion reactions are defined as any AE that occurs during the infusion or within 2 hours after the 
infusion is completed. All infusion reactions must be reported as AEs (defined in Section 9.4.1) 
and graded using the grading scales as instructed in Section 9.5.1. 
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9.4. 
Recording and Reporting Adverse Events 
9.4.1. 
Adverse Events 
The investigator (or designee) will record all AEs that occur from the time the informed consent 
is signed until the end of study. Refer to the study reference manual for the procedures to be 
followed. 
Information on follow-up for AEs is provided in Section 9.4.6. Laboratory, vital signs, or 
ECG abnormalities are to be recorded as AEs as outlined in Section 9.4.5. 
9.4.2. 
Serious Adverse Events 
All SAEs, regardless of assessment of causal relationship to study drug, must be reported to the 
sponsor (or designee) within 24 hours. Refer to the study reference manual for the procedure to be 
followed. 
Information not available at the time of the initial report must be documented in a follow-up report. 
Substantiating data such as relevant hospital or medical records and diagnostic test reports may 
also be requested. 
In the event the investigator is informed of an SAE after the patient completes the study, the 
following will apply: 
 SAE with an onset within 30 days of the end of study or within 24 weeks of last study 
drug administration if the patient terminated from the study early - the SAE will be 
reported to the sponsor. The investigator should make every effort to obtain follow-up 
information on the outcome until the event is considered chronic and/or stable. 
 SAE with an onset day greater than 30 days from the end of study or 24 weeks from 
the early termination visit for patients who terminate from the study early - only fatal 
SAEs and those deemed by the investigator to be drug-related SAEs will be reported 
to the sponsor. The investigator should make every effort to obtain follow-up 
information on the outcome of a drug-related SAE until the event is considered chronic 
and/or stable. 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of learning 
of the event: 
Symptomatic Overdose of Study Drug: 
Accidental or intentional overdose of at least 2 times 
the intended dose of study drug within the intended therapeutic window, if 
associated with an AE. 
Pregnancy: 
Although pregnancy is not considered an AE, it is the responsibility of the 
investigator to report to the sponsor (or designee), within 24 hours of identification, 
any pregnancy occurring in a female patient, or female partner of a male patient, 
during the study or within 24 weeks of the last dose of study drug. Any 
complication of pregnancy affecting a female study patient, or the female partner 
of a male study patient, and/or fetus and/or newborn that meets the SAE criteria 
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must be reported as an SAE. Outcome for all pregnancies should be reported to the 
sponsor. 
Adverse Events of Special Interest: 
All AESI, serious and nonserious, must be reported 
within 24 hours of identification using the same reporting process as for SAE 
reporting, per Section 9.4.2. Adverse events of special interest for this study include 
the following: 
 Anaphylactic reactions 
 Allergic reactions and/or local injection site reactions that require consultation with 
another physician for further evaluation 
 Increase in ALT or AST:  ≥3 x ULN (if baseline <ULN), or ≥2 times the baseline 
value (if baseline ≥ ULN) 
 Pregnancy 
 Symptomatic overdose with evinacumab 
 Neurocognitive events 
 New onset of diabetes: The definition of new onset of diabetes will be the following: 
 Type 1 or type 2 diabetes TEAE (grouping of Medical Dictionary for Regulatory 
Activities [MedDRA®] terms will be specified in the SAP) 
and/or 
 At least 2 values of HbA1c ≥6.5% during the TEAE period.  NOTE: For patients 
with only a single measurement available during the TEAE period, a single value 
≥6.5% will be considered and qualify the patient as new onset of diabetes by 
default. For patients with several HbA1c measurements but only with the last one 
≥6.5%, this single value ≥6.5% will be considered and qualify the patient as new 
onset of diabetes by default. 
and/or 
 At least 2 values of fasting glucose ≥126 mg/dL (7.0 mmol/L).  NOTE: For patients 
with only a single measurement available during the TEAE period, a single value 
≥126 mg/dL (7.0 mmol/L) will NOT be considered and will NOT qualify the patient 
as new onset of diabetes. For patients with several fasting glucose measurements but 
only with the last one ≥126 mg/dL (7.0 mmol/L), this single value ≥ 126 mg/dL 
(7.0 mmol/L) will NOT be considered and will NOT qualify the patient as new onset 
of diabetes 
 Pancreatitis 
Refer to the study manual for the procedures to be followed. 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study 
All AEs that lead to a patient’s withdrawal from the study must be reported to the sponsor’s 
medical monitor within 30 days. 
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Refer to the study reference manual for the procedures to be followed. 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results 
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE include: 
 the test result is associated with accompanying symptoms, and/or 
 the test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
 the test result leads to a change in dosing (outside of protocol-stipulated dose 
adjustments), discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy 
Contact the medical monitor in the event the investigator feels that an abnormal test finding should 
be reported as an AE, although it does not meet any of the above criteria. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an 
AE. Any abnormal test result that is determined to be an error does not require reporting as an AE. 
Evaluation of severity of laboratory abnormalities will be assessed according to the scale outlined 
in Section 9.5.1. 
9.4.6. 
Follow-up 
Adverse event information will be collected until the patient’s last study visit. 
Serious adverse event information will be collected until the event is considered chronic and/or 
stable. 
9.5. 
Evaluation of Severity and Causality 
9.5.1. 
Evaluation of Severity 
The severity of AEs will be graded according to the following scale: 
 Mild:  Does not interfere in a significant manner with the patient 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. 
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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. 
9.5.2. 
Evaluation of Causality 
Relationship of Adverse Events to Study Drug: 
The relationship of AEs to study drug will be assessed by the investigator, and will be a clinical 
decision based on all available information. The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by the study drug? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by the study 
drug 
Related: 
There is a reasonable possibility that the event may have been caused by the study 
drug 
A list of factors to consider when assessing the relationship of AEs to study drug is provided in 
Appendix 2. 
The investigator should justify the causality assessment of each SAE. 
Relationship of Adverse Events to Study Conduct: 
The relationship of AEs to study conduct will be assessed by the investigator, and will be a clinical 
decision based on all available information. The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by study conduct? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by study 
conduct 
Related: 
There is a reasonable possibility that the event may have been caused by study 
conduct 
A list of factors to consider when assessing the relationship of AEs to study conduct is provided 
in Appendix 2. 
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The investigator should justify the causality assessment of each SAE. 
Relationship of Adverse Events to study drug infusion:  
The relationship of AEs to the infusion procedure will be assessed by the investigator, and will be 
a clinical decision based on all available information. The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by the infusion procedure? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by the 
infusion procedure 
Related: 
There is a reasonable possibility that the event may have been caused by the 
infusion procedure 
A list of factors to consider in assessing the relationship of AEs to infusion procedure is provided 
in Appendix 2. 
The sponsor will request information to justify the causality assessment of SAEs, as needed. 
9.6. 
Safety Monitoring 
The investigator will monitor the safety of study patient at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP). Any questions or 
concerns should be discussed with the sponsor in a timely fashion. The sponsor will monitor the 
safety data from across all study sites. The medical monitor will have primary responsibility for 
the emerging safety profile of the compound, but will be supported by other departments 
(eg, Pharmacovigilance and Risk Management; Biostatistics and Data Management). Safety 
monitoring will be performed on an ongoing basis (eg, individual review of SAEs) and on a 
periodic cumulative aggregate basis. 
9.7. 
Investigator Alert Notification 
Regeneron (or designee) will inform all investigators participating in this clinical trial, as well as 
in any other clinical trial using the same investigational drug, of any SAE that meets the relevant 
requirements for expedited reporting (an AE that is serious, unexpected based on the Investigator’s 
Brochure or this protocol, and has a reasonable suspected causal relationship to the 
medicinal/study drug). 
10. 
STATISTICAL PLAN 
This section provides the basis for the SAP for the study. The SAP may be revised during the study 
to accommodate amendments to the clinical study protocol and to make changes to adapt to 
unexpected issues in study execution and data that may affect the planned analyses. The final SAP 
will be issued before the database is locked. 
Analysis variables are listed in Section 4. 
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10.1. 
Statistical Hypothesis  
There is no formal statistical hypothesis testing planned for this trial, as the primary objective is to 
estimate the magnitude of treatment effect on TG lowering. 
10.2. 
Justification of Sample Size 
Percent change in TG is analyzed based on log (post/pre) transformation, allowing for a normal 
distribution of the data. Standard deviations (SD) of raw percent changes up to 13% are akin to 
moderate SD on the log scale (30-40%). For the statistical precision calculations, a log-scale SD 
of 0.5 was used based on available evinacumab phase 1 data, and is assumed to be conservative. 
With N=10 patients, the 90% confidence interval (CI) for an estimated mean reduction in 
triglycerides of 40% is approximately 20% to 55%. With N=12, the CI is 22% to 54%. A sample 
size of 24 is considered adequate to analyze the percent change in TG in the 3 genetic cohorts. 
Assuming a 20% drop out rate, approximately 30 patients will be needed to assess TG. Additional 
patients (up to a maximum of approximately 50 patients) will be enrolled with the intent to explore 
the effect of evinacumab on development of pancreatitis. 
For the FDG-PET uptake signal SUVmax, prior data on steroid-treated patients yielded a natural 
log-scale SD of change of 0.66 (Shigekawa 2010). This yields 80% power to yield a statistically 
significant (alpha=0.05, 1-sided) change from baseline within the N=16 evinacumab-treated 
patients if the TRUE underlying geometric mean ratio (post/pre) is 0.65 (back-transformed from 
the log-scale; ~35% reduction). For comparison to the N=8 placebo-treated patients, assuming log-
scale SD=0.15 for placebo based on reproducibility data, and 0.66 for evinacumab, there is 80% 
power if the TRUE underlying geometric mean ratio (GMR) of GMR's (evinacumab post/pre 
divided by placebo post/pre) is 0.64 (~36% reduction). 
For the key MRI endpoint "mean f", which is the weighting coefficient between contrasting MRI 
regions (Klauss 2015) reported summary statistics which yield an SD estimate at most 5.96 for 
change from baseline. With this assumed SD, the N=24 patients with evinacumab post- and 
pre-values have 80% power to yield a statistically significant (alpha=0.05, 1-sided) change from 
baseline if the TRUE underlying mean change is 3.12 (~30% from baseline 10.5, which was 
observed by Klauss [Klauss 2015]). For the between-treatment comparison (N=16 evinacumab vs 
N=8 placebo), there is 80% power if the TRUE difference is 6.62 (~63% of the 10.5 baseline value 
observed by Klauss [Klauss 2015]). 
10.3. 
Analysis Sets 
10.3.1. 
Full Analysis Set 
The full analysis set (FAS) includes all randomized patients who receive any randomized study 
drug; it is based on the treatment assigned (as randomized). Only observed data will be 
analyzed/summarized; no missing data will be imputed. Efficacy endpoints and baseline 
characteristics will be analyzed using the FAS. 
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10.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized patients who received any randomized study 
drug; it is based on the treatment received (as treated). Treatment compliance/administration and 
all clinical safety variables will be analyzed using the SAF. 
10.3.3. 
Pharmacokinetics Analysis Set 
The PK analysis set includes all treated patients who received any randomized study drug and who 
had at least 1 non-missing result following the first dose of study drug. 
10.3.4. 
Anti-Drug Antibody Analysis Set 
The ADA analysis set includes all treated patients who had at least 1 qualified non-missing 
post-dose ADA result. 
10.4. 
Statistical Methods 
For continuous variables, descriptive statistics will include the following information:  the number 
of patients reflected in the calculation (n), mean and/or geometric mean, median, SD or log-scale 
SD, minimum, and maximum. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
10.4.1. 
Patient Disposition 
The following will be provided: 
 The total number of screened patients:  met the inclusion criteria regarding the target 
indication and signed the informed consent form (ICF) 
 The total number of patients in each analysis set (eg, FAS, provided in Section 10.3.1) 
 The total number of patients who discontinued the study, and the reasons for 
discontinuation 
 A listing of patients enrolled and treated with at least 1 dose of evinacumab, and 
patients enrolled but not treated with at least 1 dose of evinacumab 
 A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation 
10.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group, 
and by all patients combined. 
10.4.3. 
Efficacy Analyses 
10.4.3.1. Primary Efficacy Analysis 
The primary analysis is based on percent change from baseline in TG over 12 weeks of evinacumab 
treatment. For the assessment of probability (computed from the likelihood function based on the 
observed data, which is equivalent to Bayesian posterior probability with uninformative prior) that 
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mean TG percent change ≥40% (considered to be a clinically meaningful change) using study data, 
the point estimates of TG percent changes between the placebo run-in period and each observation 
week will be calculated using a Mixed-effect Model for Repeated Measures (MMRM) method in 
the FAS population. A natural log transformation will be applied to the TG levels prior to analysis, 
aiming to provide a relatively normal data distribution (residuals will be examined for normality 
prior to proceeding with the analysis). The MMRM model will assess within-patient treatment 
comparisons (using an unstructured covariance matrix), while accounting for baseline TG, study 
visit, and baseline TG by study visit interaction. Note that study visits will be adjusted to start of 
evinacumab in order to pool data from both randomized groups of patients for this analysis. Since 
the comparison of study visits yields the within-patient comparisons of study treatments (ie, week 
12 [after 12 weeks of treatment with evinacumab] compared to baseline at week 0 [after 4 weeks 
of treatment with placebo] for patients randomized to evinacumab and week 24 [after 12 weeks of 
treatment with evinacumab] compared to baseline at week 12 for those randomized to placebo), 
contrast and estimate statements will be used to assess treatment effects (least squares [LS means 
with confidence intervals) and comparisons (LS mean ratio with CI). Within-patient comparisons 
will include all patients, as well as analyses for the genotype subgroups (to assess relationship with 
amount of TG reduction while on evinacumab). A graph will depict the relationship of TG over 
time for each genotype subgroup. Details on the subgroup analyses will be defined in the SAP. 
Both percent change and raw TG will be descriptively summarized by study visit. In the event the 
MMRM model covariance matrix does not converge or normality is not achieved with the natural 
log transformation, then other transformations will be explored, including ranks. 
To reduce variability of TG baseline measurements, baseline at week 0 for patients randomized to 
active treatment is the geometric mean of the last 2 measurements during the placebo run-in (day 
-28, day -14) and week 0. Baseline at week 12 for patients switching from placebo to active is the 
geometric mean of the last 2 measurements during the placebo phase (weeks 6, 8) and first 
measurement prior to active infusion (week 12). Additional exploratory analyses may be carried 
out using the average of all available TG observations prior to first dose of active treatment, if no 
trend over time in those measurements is discernable. 
Using the estimate of the log TG mean ratio (week 12/baseline at week 0 for patients randomized 
to evinacumab and week 24/baseline at week 12 for those randomized to placebo) and the log of 
the standard deviation derived from the MMRM model, the PP will be calculated using the target 
percent change from baseline of 40% reduction (ie, log 0.6) in patients without LOF mutations in 
genes in the LPL pathway. For the probability calculation (ie, Pr [log TG mean ratio (post/pre)] < 
log 0.6 conditional on this study’s TG results), a non-informative normal distribution prior and a 
normal distribution of the data is assumed. The probability calculation will yield the probability 
that the actual mean percent decrease is at least the target 40% value, based on the OBSERVED 
results from the patients without LOF mutations in genes in the LPL pathway. 
This fixed sequence design assumes no carryover effect from the placebo run-in period into the 
active treatment period. This assumption will be verified by assessment of the time course of TG 
observations during the run-in period. A generally flat or non-decreasing trend over time in the 
placebo run-in period will be evidence of no carryover effect into the active treatment period and 
of a useful valid baseline benchmark against which to compare treatment effects based on within-
patient comparisons (active treatment period to placebo run-in period). As a sensitivity analysis, 
the TG reduction and posterior probability analyses of the combined sequence groups will be 
repeated using the same baseline at week 0. Note that the follow-up period is expected to have 
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carryover effects from the active treatment period and is included to estimate the time course of 
those effects. Such carryover effects may also be interpreted as evidence of treatment effects. 
Nominal p-values for testing mean change from baseline >0 and >40% at each time point in each 
cohort may be computed for information purposes. Since this is an exploratory study, control of 
the overall type-I error is not applicable for statistical testing. Any p-values provided for outcome 
measures are for descriptive purposes only. 
10.4.3.2. Secondary and Exploratory Efficacy Analysis 
Continuous secondary and exploratory endpoints will be analyzed similarly to the primary 
endpoint, except PP will not be computed. Binary endpoints will be summarized by counts and 
percents. Triglyceride mean percent change from baseline at each observation week will be 
summarized. Triglyceride mean percent change from baseline at each observation week will be 
analyzed and estimated for genetic mutations affecting LPL function (eg, homozygous LPL null 
[total LOF], heterozygous LPL null, with no LPL null gene mutations subgroups). 
For the FDG-PET endpoint, comparisons will be within the evinacumab-treated patients in the 
double-blind period (week 12 vs week -2 for post/pre) and between the treatment groups in the 
double-blind period (week 12 vs week -2 for evinacumab in comparison to week 12 vs week -2 
for placebo). In order to yield corresponding results, the MRI readout will be analyzed similarly 
as the FDG-PET endpoint. In addition, combining all evinacumab post/pre observations from the 
double-blind period (week 12 vs week -2) and the single-blind post/pre (week 24 vs week 12) for 
the patients who received placebo in the double-blind period, and post/pre (week 24 vs week -2 
and week 24 vs week 12) for patients randomized to evinacumab during the double-blind period. 
Summary statistics may be computed for time points beyond week 12 for the TG and continuous 
and exploratory endpoints in the patients randomized to evinacumab. 
Summary statistics will be computed for the End of Day symptom diary and the symptom and 
dietary impact measure. These measures will also be psychometrically analyzed; this will be 
outlined in a separate psychometric analysis plan. 
10.4.4. 
Analysis of Symptoms 
The signs and symptoms questionnaire along with the symptom/dietary impact questionnaire will 
be analyzed using total aggregate scores. 
10.4.5. 
Safety Analysis 
10.4.5.1. Adverse Events 
Definitions 
For safety variables, 3 observation periods are defined: 
 The pretreatment period is defined as the time from signing the ICF to before the first 
dose of study drug 
 The treatment period is defined as the day from first dose of randomized study drug to 
end of the study 
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 The double-blind treatment period is defined as the day from first dose of study drug 
in the double-blind treatment period to the day prior to the administration of 
single-blind evinacumab 
Treatment-emergent adverse events are defined as those that are not present at baseline or represent 
the exacerbation of a pre-existing condition during the on-treatment period. 
Analysis 
All AEs reported in this study will be coded using the currently available version of MedDRA. 
Coding will be to lowest level terms. The verbatim text, the preferred term (PT), and the primary 
system organ class (SOC) will be listed. 
Summaries of all TEAEs will include: 
 The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
 TEAEs by severity (according to the grading scale outlined in Section 9.5.1), presented 
by SOC and PT 
 TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
All deaths, SAEs and TEAEs overall and events leading to permanent treatment discontinuation 
will be listed will be listed. 
10.4.5.2. Other Safety 
Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiration rate) will be summarized by 
baseline and change from baseline to each scheduled assessment time with descriptive statistics. 
Laboratory Tests 
Laboratory test results by baseline, change from baseline to each scheduled assessment time, and 
number and percentage of patients with a potentially clinically significant value (PCSV) at any 
time point will be summarized with descriptive statistics  
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
Listings will be provided with flags indicating the out of laboratory range values. 
10.4.5.3. Treatment Exposure 
The duration of exposure during the study will be presented and calculated as: 
(Date of last evinacumab injection - date of first evinacumab injection) + 24 weeks (length of 
follow-up period) 
The number (%) of patients enrolled and exposed to evinacumab will be presented by specific time 
periods. The time periods of interest will be specified in the SAP. 
In addition, duration of exposure during the study will be summarized using number of patients, 
means, SD, minimums, medians, and maximums. A summary of the number of doses will be 
provided. 
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10.4.5.4. Treatment Compliance 
Treatment compliance will be assessed via the summary of treatment exposure as described in 
Section 10.4.5.3. 
10.4.6. 
Analysis of Drug Concentration Data 
Summary 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). 
10.4.7. 
Analysis of Anti-Drug Antibody Data 
Listings of ADA positivity and titers presented by patient, time point, and dose group will be 
provided. Prevalence of treatment-emergent and treatment-boosted ADA response will be assessed 
as absolute occurrence (N) and percent of patients (%), grouped by study cohorts. 
The influence of ADAs on drug concentrations will be evaluated. Assessment of impact of ADA 
on safety and efficacy may be provided. 
10.4.8. 
Analysis of Biomarker Data 
All exploratory biomarker data analyses will be performed on the FAS and no multiplicity 
adjustment is planned. Detailed analyses of exploratory biomarker endpoints will be provided in 
the SAP. 
10.4.9. 
Timing of Statistical Analysis 
The analyses will be conducted in 2 steps. 
10.4.9.1. First Step:  Main Efficacy and Safety Analysis 
The first analysis will be conducted when all enrolled patients have completed the double-blind 
period. This will consist of the final analysis of the primary and secondary endpoints up to 
week 12. The safety analysis will be performed on all safety data collected and validated at the 
time of the first analysis. 
10.4.9.2. Second Step:  Final Efficacy and Safety Analysis 
The second analysis will be conducted at the end of the study and will consist of the final analysis 
of week 44 efficacy endpoints and final safety analysis. 
10.5. 
Interim Analysis  
Interim analyses may be conducted during the course of the study by the unblinded team to assess 
efficacy, safety, and futility.  If the timing of this analysis falls within a few weeks of the first-step 
analysis, only the first-step analysis will be performed. Enrollment (up to a maximum of 
approximately 50 patients) may be halted if the incidence of pancreatitis is much lower than 
anticipated, making the evaluation of a treatment effect on pancreatitis futile. Details of the interim 
analysis will be described in the SAP. 
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10.6. 
Additional Statistical Data Handling Conventions 
The following analysis and data conventions will be followed: 
Definition of baseline: 
 The baseline assessment will be the latest, valid pre-dose assessment available. 
General rules for handling missing data:  
 If the start date of an AE or concomitant medication is incomplete or missing, it will 
be assumed to have occurred on or after the intake of study medication, except if an 
incomplete date (eg, month and year) clearly indicates that the event started prior to 
treatment. If the partial date indicates the same month or year of the intake of study 
medication date, then the start date by the study medication intake date will be imputed; 
otherwise, the missing day or month by the first day or the first month will be imputed. 
 No imputations for missing laboratory data, ECG data, vital signs data, or physical 
examination data will be made 
Visit windows: 
 Assessments taken outside of protocol allowable windows will be displayed according 
to the case report form (CRF) assessment recorded by the investigator 
Unscheduled assessments: 
 Extra assessments (laboratory data or vital signs associated with nonprotocol clinical 
visits or obtained in the course of investigating or managing AEs) will be included in 
listings, but not summaries. If more than 1 laboratory value is available for a given 
visit, the first observation will be used in summaries and all observations will be 
presented in listings 
10.7. 
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 16.1. 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
11.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation, cleaning, correcting, releasing) will be maintained and stored at Regeneron. 
A medical coding plan will specify the processes and the dictionary used for coding. All data 
coding (eg, AEs, baseline findings, medication, medical history/surgical history) will be done 
using internationally recognized and accepted dictionaries. 
The CRF data for this study will be collected using an electronic data capture (EDC) tool, Medidata 
Rave. 
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11.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
 IVRS/IWRS system – randomization, study drug supply 
 EDC system – data capture 
 Statistical Analysis System (SAS) – statistical review and analysis 
 Pharmacovigilance safety database 
12. 
STUDY MONITORING 
12.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, contract research organization) will visit each site prior to 
enrollment of the first patient, and periodically during the study. 
12.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). 
The investigator must keep all source documents on file with the CRF (throughout this protocol, 
CRF refers to either a paper CRF or an electronic CRF). Case report forms and source documents 
must be available at all times for inspection by authorized representatives of the sponsor and 
regulatory authorities. 
12.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic CRFs within 
the EDC system by trained site personnel. All required CRFs must be completed for each patient 
enrolled in the study. After review of the clinical data for each patient, the investigator must 
provide an electronic signature. A copy of each patient CRF casebook is to be retained by the 
investigator as part of the study record and must be available at all times for inspection by 
authorized representatives of the sponsor and regulatory authorities. 
13. 
AUDITS AND INSPECTIONS 
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities. Should this occur, the investigator is responsible for: 
 Informing the sponsor of a planned inspection by the authorities as soon as notification 
is received, and authorizing the sponsor’s participation in the inspection 
 Providing access to all necessary facilities, study data, and documents for the inspection 
or audit 
 Communicating any information arising from inspection by the regulatory authorities 
to the sponsor immediately 
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 Taking all appropriate measures requested by the sponsor to resolve the problems found 
during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, CRFs, 
medical records, correspondence, ICFs, IRB/EC files, documentation of certification and quality 
control of supporting laboratories, and records relevant to the study maintained in any supporting 
pharmacy facilities. Conditions of study material storage are also subject to inspection. In addition, 
representatives of the sponsor may observe the conduct of any aspect of the clinical study or its 
supporting activities both within and outside of the investigator's institution. 
In all instances, the confidentiality of the data must be respected. 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS 
14.1. 
Good Clinical Practice Statement 
It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with the International Council for Harmonisation (ICH) 
guidelines for GCP and applicable regulatory requirements. 
14.2. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC. A copy of the IRB/EC -approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient prior to his/her participation in the study and after the 
aims, methods, objectives, and potential hazards of the study have been explained to the patient in 
language that he/she can understand. The ICF should be signed and dated by the patient and by the 
investigator or authorized designee who reviewed the ICF with the patient. 
 Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF 
 Patients who can understand but who can neither write nor read will have the ICF read 
to them in presence of an impartial witness, who will sign and date the ICF to confirm 
that informed consent was given 
The original ICF must be retained by the investigator as part of the patient's study record, and a 
copy of the signed ICF must be given to the patient. 
If new safety information results in significant changes in the risk/benefit assessment, the ICF must 
be reviewed and updated appropriately. All study patients must be informed of the new information 
and provide their written consent if they wish to continue in the study. The original signed revised 
ICF must be maintained in the patient’s study record and a copy must be given to the patient. 
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14.3. 
Patient Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained. Patients should be identified by 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. 
14.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve: 
 The protocol, ICF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
 Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patients, in 
which case the IRB/EC should be informed as soon as possible 
 Ongoing studies on an annual basis or at intervals appropriate to the degree of risk 
In addition, the IRB/EC should be informed of any event likely to affect the safety of patients or 
the continued conduct of the clinical study. 
A copy of the IRB/EC approval letter with a current list of the IRB/EC members and their functions 
must be received by the sponsor prior to shipment of drug supplies to the investigator. The approval 
letter should include the study number and title, the documents reviewed, and the date of the 
review. 
Records of the IRB/EC review and approval of all study documents (including approval of ongoing 
studies) must be kept on file by the investigator. 
15. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an IRB/EC 
-approved amendment. Where required under local regulations, regulatory approval will also be 
sought. 
16. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
16.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely. Reasons may include efficacy, safety, 
or futility, among others. Should the sponsor decide to terminate the study, the investigator(s) will 
be notified in writing. 
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16.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close out a site prematurely. 
Investigator’s Decision 
The investigator must notify the sponsor of a desire to close out a site in writing, providing at least 
30 days’ notice. The final decision should be made through mutual agreement with the sponsor. 
Both parties will arrange the close out procedures after review and consultation. 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close out a study site in writing. Reasons 
may include the following, among others:  
 The investigator has received all items and information necessary to perform the study, 
but has not enrolled any patient within a reasonable period of time 
 The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines  
 The total number of patients required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB/EC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection of 
the patients’ interests. 
17. 
STUDY DOCUMENTATION 
17.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the eCRF must be signed 
electronically by the investigator. This signed declaration accompanies each set of patient final 
eCRF that will be provided to the sponsor. 
17.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of CRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
regulatory authorities. The investigator must consult with the sponsor before discarding or 
destroying any essential study documents following study completion or discontinuation. Records 
must be destroyed in a manner that ensures confidentiality. 
If the investigator's personal situation is such that archiving can no longer be ensured, the 
investigator must inform the sponsor and the relevant records will be transferred to a mutually 
agreed-upon destination. 
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18. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
19. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
20. 
PUBLICATION POLICY 
The publication policy is provided as a separate agreement. 
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22. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: A Phase 2, Randomized, Placebo-Controlled Study of Safety 
and Efficacy Following Repeat-Dose Administration of Evinacumab (anti-ANGPTL3) in Patients 
with Severe Hypertriglyceridemia (sHTG) at Risk for 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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APPENDIX 1. 
KNOWN LPL AND APOC2 NULL (TOTAL LOSS OF 
FUNCTION) MUTATIONS 
This list of LPL and APOC2 mutations is not comprehensive and is for reference only. Inclusion 
in the study is not limited to mutations in this list. 
LPL 
Variant  
HGVS 
Nomenclature 
Nucleotide 
Change 
State 
Reference 
1 
1 
Met-27Ile 
M1I 
3G>C 
Homozygous  
Yu XH 2006  
2 
1 
Trp-14Ter 
W14X 
42G>A 
Homozygous  
Nakamura T 1996  
3 
1 
pQ-12E>11X 
46_47del2 
Compound 
Heterozygous 
Wang J 2007  
4 
Intron 
IVS1+1G>C 
Homozygous  
Chimienti G 1992  
5 
Intron 
89-4_89-2del3 
Compound 
Heterozygous 
Hölzl B 2000  
6 
2 
133_143del11 
Compound 
Heterozygous 
Reina M 1992  
7 
2 
Cys27Ter 
C54X 
162C>A 
Compound 
Heterozygous 
Chan AO 2006  
8 
2 
183dup1 
Homozygous  
Benlian P AJHG 1996  
9 
2 
Asn43Ser 
N70S 
209A>G 
Homozygous  
Kobayashi J 1994   
10 
Intron 
IVS2+1G>A 
 
 
Homozygous  
Gotoda T 1991  
11 
Intron 
IVS2-1G>A 
Compound 
Heterozygous 
Hata A 1990  
12 
3 
Tyr61Ter 
Y88X 
264T>A 
Homozygous  
Gotoda T 1991 
13 
3 
Trp64Ter 
W91X 
272G>A 
Compound 
Heterozygous 
Sprecher DL 1992  
14 
3 
287_288del2 
Compound 
Heterozygous 
Foubert L 1998  
15 
3 
290_293del4ins
2 
Compound 
Heterozygous 
Benlian P 1996  
16 
3 
Tyr73Ter 
Y100X 
300A>C 
Compound 
Heterozygous 
Wilson DE 1993  
17 
3 
Arg75Ser 
R102S 
306A>C 
Compound 
Heterozygous 
Wilson DE 1993 
18 
3 
Trp86Arg 
W113R 
337T>C 
Compound 
Heterozygous 
Ishimura-Oka K 1992  
19 
3 
384del1ins6 
Homozygous  
Henderson HE  1990 
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Regeneron Pharmaceuticals, Inc. 
 
Page 94 of 99 
CONFIDENTIAL 
LPL 
Variant  
HGVS 
Nomenclature 
Nucleotide 
Change 
State 
Reference 
20 
3 
Gly105Arg 
G132R 
394G>A 
Compound 
Heterozygous 
Ikeda Y 2000  
21 
3 
Gln106Ter 
Q133X 
397c>t 
Homozygous  
Emi M AJHG 1990  
22 
4 
440_443del4 
Compound 
Heterozygous 
Ma Y  1993 
24 
4 
Gly139Ser 
G166S 
496G>A 
Homozygous  
Bijvoet S 1994  
25 
4 
Gly142Glu 
G169E 
506G>A 
Homozygous  
Ameis D 1991  
26 
4 
Gly154Ser 
G181S 
541G>A 
Homozygous  
Bruin T JLR 1993  
27 
5 
Gly154Val 
G181V 
542G>T 
Compound 
Heterozygous 
Ikeda Y 2001  
28 
5 
Asp156Asn 
D183N 
547G>A 
Compound 
Heterozygous 
Ma Y 1992 
29 
5 
Asp156Gly 
D183G 
548A>G 
Homozygous 
and Compound 
Heterozygous 
Ma Y 1992, Faustinella F 
1991 
30 
5 
Pro157Arg 
P184R 
551C>G 
Homozygous  
Bruin T  1992  
31 
5 
Ala158Thr 
A185T 
553G>A 
Homozygous  
Mailly F 1997  
32 
5 
Ala176Thr 
A203T 
607G>A 
Homozygous  
Beg OU 1990  
33 
5 
Asp180Glu 
D207E 
621C>G 
Homozygous  
Haubenwallner S 1993 
34 
5 
His183Asp 
H210D 
628C>G 
Compound 
Heterozygous 
Hölzl B 2000  
35 
5 
Gly188Arg 
G215R 
643G>A 
Homozygous  
Benlian P 1996  
36 
5 
Gly188Glu 
G215E 
644G>A 
Homozygous  
Emi M JBC 1990, 
Monsalve MV 1990 
37 
5 
Arg192Ter 
R219X 
655C>T 
Homozygous  
Zhang Q 1997  
38 
5 
Ser193Arg 
S220R 
658A>C 
Compound 
Heterozygous 
Mailly F 1997  
39 
5 
Ile194Thr 
I221T 
662T>C 
Homozygous  
Henderson HE 1991 
40 
5 
Gly195Glu 
G222E 
665G>A 
Homozygous  
Hata A 1992  
41 
5 
Asp204Glu 
D231E 
693C>G 
Homozygous  
Gotoda T 1991 
42 
5 
Ile205Ser 
I232S 
695T>G 
Homozygous  
Reina M 1992  
43 
5 
Pro207Leu 
P234L 
701C>T 
Homozygous 
and Compound 
Heterozygous 
Ma Y 1991, Yang Y 2007 
44 
5 
Cys216Ser 
C243S 
727T>A 
Compound 
Heterozygous 
Ma Y 1992  
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Regeneron Pharmaceuticals, Inc. 
 
Page 95 of 99 
CONFIDENTIAL 
LPL 
Variant  
HGVS 
Nomenclature 
Nucleotide 
Change 
State 
Reference 
45 
5 
742del1 
Homozygous  
Takagi A 1992  
46 
5 
Ile225Thr 
I252T 
755T>C 
Compound 
Heterozygous 
Henderson HE  1993  
47 
6 
Cys239Ter 
C266X 
798C>A 
Homozygous  
Takagi A 1994  
48 
6 
Cys239Trp 
C266W 
798C>G 
Homozygous  
Hoffmann MM 2000  
49 
6 
Arg243His 
R270H 
809G>A 
Homozygous 
and Compound 
Heterozygous 
Gotoda T 1991, Dichek HL 
1991  
50 
6 
Ser244Thr 
S271T 
811T>A 
Compound 
Heterozygous 
Hata A 1990  
51 
6 
Asp250Asn 
D277N 
829G>A 
Homozygous  
Ma Y 1992  
52 
6 
835_836del2 
Homozygous  
Mailly F 1997  
53 
6 
Ser251Cys 
S278C 
833C>G 
Compound 
Heterozygous 
Bijvoet SM 1996  
54 
6 
Leu252Val 
L279V 
835C>G 
Compound 
Heterozygous 
Chan L 2000  
55 
6 
Leu252Arg 
L279R 
836T>G 
Compound 
Heterozygous 
Chan L 2000,  
Ma Y 1994  
56 
6 
Ser259Arg 
S286R 
858T>A 
Homozygous  
Foubert L 1997  
57 
6 
Tyr262His 
Y289H 
865T>C 
Homozygous  
Rouis M 1996  
58 
6 
Cys264Tyr 
C291Y 
872G>A 
Homozygous  
Murugasu CG 1998  
59 
6 
Phe270Leu 
F297L 
891T>G 
Homozygous  
Takagi A  2000  
60 
6 
Leu276Phe 
L303F 
909G>C 
Homozygous  
Saika Y 2003  
61 
6 
Leu286Pro 
L313P 
938T>C 
Compound 
Heterozygous 
Benlian P 1996  
62 
6 
Tyr288Ter 
Y315X 
945T>A 
Homozygous  
Causeret  AS 2001  
63 
6 
953del1 
Compound 
Heterozygous 
Kobayashi J 1999  
64 
6 
Tyr302Ter 
Y329X 
987C>A 
Homozygous  
Bertolini S 2000  
65 
Intron 
IVS6-3C>A 
Homozygous 
and Compound 
Heterozygous 
Hölzl B 1994  
66 
8 
Trp382Ter 
W409X 
1227G>A 
Homozygous  
Gotoda T 1991 
67 
8 
1227del1 
Homozygous  
Gotoda T 1991, Maruyama 
T 2004  
68 
8 
1314_1315del2 
 
 
Homozygous  
Nierman MC 2006  
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Regeneron Pharmaceuticals, Inc. 
 
Page 96 of 99 
CONFIDENTIAL 
LPL 
Variant  
HGVS 
Nomenclature 
Nucleotide 
Change 
State 
Reference 
69 
Intron 
IVS8+2T>C 
Compound 
Heterozygous 
 Ikeda Y 2001 
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Regeneron Pharmaceuticals, Inc. 
 
Page 97 of 99 
CONFIDENTIAL 
LPL 
Variant  
HGVS 
Nomenclature 
Nucleotide 
Change 
State 
Reference 
APOC2 
Exon 
Variant/HGVS-
Nomenclature 
Nucleotide 
Change 
Mutation Type 
State 
Reference 
1 
Prom
7.5 kb promoter + ex. 1  
Deletion 
Gross Deletion 
 Homozygous Fu J 2013 
2 
Prom
-25 relative to transcription 
initiation site 
Regulatory 
Homozygous
3 
1 
M1V 
1A>G 
Missense 
Homozygous
4 
1 
R4X 
10C>T 
Nonsense 
Homozygous
5 
Intron 
55+1G>C 
55+1G>C 
Splicing 
Homozygous
6 
2 
70delC 
Small Deletion 
Homozygous
7 
2 
118delG 
Small Deletion 
Homozygous
8 
2 
K41T 
122A>C 
Missense 
Homozygous
9 
2 
W48R 
142T>C 
Missense 
Homozygous
10 
2 
Y59X 
177C>A 
Nonsense 
Homozygous
11 
2 
E60K 
178G>A 
Missense 
Homozygous
12 
3 
Y85X 
255C>A 
Nonsense 
Homozygous
 
13 
3 
270delT 
 
Small Deletion 
Homozygous
 
14 
3 
Q92X 
274C>T 
Nonsense 
Homozygous
15 
3 
274dupC 
 
Small Insertion 
 
 
16 
3 
L94P 
281T>C 
Missense 
Homozygous
 
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Page 98 of 99 
CONFIDENTIAL 
APPENDIX 2. 
FACTORS TO CONSIDER IN ASSESSING THE 
RELATIONSHIP OF ADVERSE EVENTS TO STUDY 
DRUG AND STUDY CONDUCT 
Is there a reasonable possibility that the event may have been caused by the study drug or study 
conduct? 
No: 
 due to external causes such as environmental factors or other treatment(s) being 
administered 
 due to the patient’s disease state or clinical condition 
 do not follow a reasonable temporal sequence following the time of administration of 
the dose of study  
 do not reappear or worsen when dosing with study drug is resumed 
 are not a suspected response to the study drug based upon preclinical data or prior 
clinical data 
Yes: 
 could not be explained by environmental factors or other treatment(s) being 
administered 
 could not be explained by the patient’s disease state or clinical condition 
 follow a reasonable temporal sequence following the time of administration of the dose 
of study drug  
 resolve or improve after discontinuation of study drug  
 reappear or worsen when dosing with study drug is resumed 
 are known or suspected to be a response to the study drug based upon preclinical data 
or prior clinical data 
NOTE:  This list is not exhaustive. 
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Page 99 of 99 
CONFIDENTIAL 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Scientific/Medical Monitor, Regulatory Representative, Clinical Study Team Lead, and 
Biostatistician) 
To the best of my knowledge, this protocol accurately describes the conduct of the study. 
Study Title: 
A Phase 2, Randomized, Placebo-Controlled Study of Safety and Efficacy, 
Following Repeat-Dose Administration of Evinacumab (anti-ANGPTL3) 
in Patients with Severe Hypertriglyceridemia (sHTG) at Risk for Acute 
Pancreatitis 
Protocol Number: 
R1500-HTG-1522 
Protocol Version: 
R1500-HTG-1522 Amendment 5 
See appended electronic signature page 
Sponsor’s Responsible Scientific/Medical Monitor 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Representative 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Team Lead 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
                                        VV-RIM-00089259-1.0 Approved - 15 Oct 2019 GMT-5:00


Signature Page for VV-RIM-00089259 v1.0
Signature Page for VV-RIM-00089259 v1.0 Approved
ESig Approval
ESig Approval
ESig Approval
ESig Approval
                                        VV-RIM-00089259-1.0 Approved - 15 Oct 2019 GMT-5:00

SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 
STATISTICAL ANALYSIS PLAN 
VERSION: FINAL
A Phase 2, Randomized, Placebo-controlled Study of Safety and Efficacy 
Following Repeat-dose Administration of Evinacumab (Anti-Angptl3) in 
Patients with Severe Hypertriglyceridemia (sHTG) at Risk for Acute 
Pancreatitis 
Compound: 
Evinacumab 
Protocol Number: 
R1500-HTG-1522 Version 4GB 
Clinical Phase:  
Phase 2 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician:  
 
Clinical Trial Manager: 
  
Study Medical Director: 
 
Version/Date:  
Final / May 17, 2019 
VV-RIM-00078988-1.0 Approved - 20 May 2019 GMT-5:00
NCT03452228


Regeneron Pharmaceuticals, Inc.                 
                Protocol: R1500-HTG-1522 4GB 
Statistical Analysis Plan 
Date: May 17, 2019 
 
Regeneron Pharmaceuticals Inc.                                                                              Page 2 of 62 
CONFIDENTIAL 
The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
 
 
See appended electronic signature page 
Study Biostatistician  (
 
 
 
See appended electronic signature page 
Study Clinical Pharmacologist 
) 
 
 
See appended electronic signature page 
Study Bioanalytical Sciences 
 
 
 
See appended electronic signature page 
Study Medical Director 
 
 
 
See appended electronic signature page 
Project Biostatistician (
 
 
 
See appended electronic signature page 
Head of BDM or designee 
 
 
                                        VV-RIM-00078988-1.0 Approved - 20 May 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc.                 
                Protocol: R1500-HTG-1522 4GB 
Statistical Analysis Plan 
Date: May 17, 2019 
 
Regeneron Pharmaceuticals Inc.                                                                              Page 3 of 62 
CONFIDENTIAL 
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 ................................13 
1.2.5. 
Revision History for Statistical Analysis Plan Amendments .....................................14 
2. 
INVESTIGATION PLAN ..........................................................................................14 
2.1. 
Study Design and Randomization ..............................................................................14 
2.2. 
Sample Size and Power Considerations .....................................................................15 
2.3. 
Study Plan ...................................................................................................................16 
3. 
ANALYSIS POPULATIONS ....................................................................................17 
3.1. 
Full Analysis Set .........................................................................................................17 
3.2. 
Double-Blind Safety Analysis Set ..............................................................................17 
3.3. 
Single-Blind Safety Analysis Set ................................................................................18 
3.4. 
Pharmacokinetic (PK) Analysis Set............................................................................18 
3.5. 
The Anti-evinacumab Antibody Analysis Set ............................................................18 
3.6. 
Patient-Reported Outcomes (PRO) Analysis Set .......................................................18 
3.7. 
PET Analysis Set ........................................................................................................18 
3.8. 
MRI Analysis Set ........................................................................................................18 
4. 
ANALYSIS VARIABLES .........................................................................................19 
4.1. 
Demographic and Baseline Characteristics ................................................................19 
4.2. 
Medical History ..........................................................................................................20 
4.3. 
Prior and Concomitant Medications ...........................................................................21 
4.4. 
Prohibited Medications and Procedures During Study ...............................................22 
4.5. 
Patient Disposition ......................................................................................................22 
4.6. 
Study Treatment Exposure and Compliance Variables ..............................................24 
4.7. 
Efficacy Variables ......................................................................................................25 
4.7.1. 
Primary Efficacy Variable ..........................................................................................25 
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Statistical Analysis Plan 
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Regeneron Pharmaceuticals Inc.                                                                              Page 4 of 62 
CONFIDENTIAL 
4.7.2. 
Lipids Variables ..........................................................................................................25 
4.7.3. 
Other Variables ...........................................................................................................26 
4.7.4. 
PET Variable(s) ..........................................................................................................26 
4.7.5. 
MRI Variable(s) ..........................................................................................................26 
4.8. 
Safety Variables ..........................................................................................................26 
4.8.1. 
Adverse Events Variables ...........................................................................................26 
4.8.1.1. 
Adverse Events and Serious Adverse Events .............................................................27 
4.8.1.2. 
Adverse Events of Special Interest .............................................................................27 
4.8.1.3. 
Events Causing Death .................................................................................................28 
4.8.1.4. 
Incidence of Recurrent Acute Pancreatitis .................................................................28 
4.8.1.5. 
Hospitalizations ..........................................................................................................28 
4.8.2. 
Laboratory Safety Variables .......................................................................................28 
4.8.3. 
Vital Signs ..................................................................................................................29 
4.8.4. 
12-Lead Electrocardiography (ECG) ..........................................................................29 
4.8.5. 
Physical Examination Variables .................................................................................29 
4.9. 
Pharmacokinetic Variables .........................................................................................29 
4.10. 
Anti-Drug (evinacumab) Antibody Variables (ADA) ................................................29 
4.11. 
PRO Variables ............................................................................................................30 
4.11.1. 
Number of pain and abdominal symptom free days and days where meals are 
avoided ........................................................................................................................31 
4.12. 
Biomarker Variable(s) ................................................................................................31 
5. 
STATISTICAL METHODS .......................................................................................32 
5.1. 
Demographics and Baseline Characteristics ...............................................................32 
5.2. 
Medical History ..........................................................................................................32 
5.3. 
Prior and Concomitant Medications ...........................................................................32 
5.4. 
Prohibited Medications ...............................................................................................33 
5.5. 
Patient Disposition ......................................................................................................33 
5.6. 
Extent of Study Treatment Exposure and Compliance ...............................................34 
5.6.1. 
Exposure to Investigational Product ...........................................................................34 
5.6.2. 
Study Treatment Compliance .....................................................................................34 
5.7. 
Analyses of Efficacy Variables ..................................................................................34 
5.7.1. 
Analysis of Primary Efficacy Variable .......................................................................34 
5.7.1.1. 
Sub-group Analyses ....................................................................................................35 
                                        VV-RIM-00078988-1.0 Approved - 20 May 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc.                 
                Protocol: R1500-HTG-1522 4GB 
Statistical Analysis Plan 
Date: May 17, 2019 
 
Regeneron Pharmaceuticals Inc.                                                                              Page 5 of 62 
CONFIDENTIAL 
5.7.2. 
Analyses of Lipids Variables ......................................................................................36 
5.7.3. 
Analysis of Other Variables ........................................................................................36 
5.7.4. 
Analysis of PET Variables ..........................................................................................37 
5.7.5. 
Analysis of MRI Variables .........................................................................................37 
5.8. 
Analysis of Safety Data ..............................................................................................37 
5.8.1. 
Adverse Events ...........................................................................................................38 
5.8.2. 
Analysis of Adverse Events of Special Interest ..........................................................40 
5.8.3. 
Analysis of Incidence of Recurrent Acute Pancreatitis ..............................................40 
5.8.4. 
Analysis of Hospitalizations .......................................................................................40 
5.8.5. 
Clinical Laboratory Measurements.............................................................................40 
5.8.6. 
Analysis of Vital Signs ...............................................................................................41 
5.8.7. 
Analysis of 12-Lead ECG ...........................................................................................42 
5.8.8. 
Physical Exams ...........................................................................................................42 
5.9. 
Analysis of Pharmacokinetic Variables ......................................................................42 
5.10. 
Analysis of Anti-evinacumab Antibody Variables .....................................................42 
5.11. 
Analysis of PRO Variables .........................................................................................43 
5.12. 
Analysis of Biomarker Variables ................................................................................44 
6. 
DATA CONVENTIONS ............................................................................................44 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................44 
6.2. 
Definition of Cohort Assignment ...............................................................................44 
6.3. 
Data Handling Convention for Missing Data .............................................................44 
6.4. 
Unscheduled Assessments ..........................................................................................45 
6.5. 
Statistical Technical Issues .........................................................................................45 
7. 
TIMING OF STATISTICAL ANALYSES ................................................................46 
8. 
SOFTWARE ...............................................................................................................47 
9. 
REFERENCES ...........................................................................................................48 
10. 
APPENDIX.................................................................................................................49 
10.1. 
Summary of Statistical Analyses ................................................................................49 
10.2. 
List of AESIs with Data Sources and Definitions of SMQ/CMQ ..............................50 
10.3. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................54 
10.4. 
Schedule of Time and Events .....................................................................................57 
10.4.1. 
Footnotes for the Schedule of Events Table ...............................................................61 
                                        VV-RIM-00078988-1.0 Approved - 20 May 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc.                 
                Protocol: R1500-HTG-1522 4GB 
Statistical Analysis Plan 
Date: May 17, 2019 
 
Regeneron Pharmaceuticals Inc.                                                                              Page 6 of 62 
CONFIDENTIAL 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................57 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................16 
 
 
                                        VV-RIM-00078988-1.0 Approved - 20 May 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc.                 
                Protocol: R1500-HTG-1522 4GB 
Statistical Analysis Plan 
Date: May 17, 2019 
 
Regeneron Pharmaceuticals Inc.                                                                              Page 7 of 62 
CONFIDENTIAL 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADA 
Anti-drug antibody 
ADC 
Apparent diffusion coefficient 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANGPTL3 
Angiopoietin-like 3 
APO  
Apolipoprotein 
AP 
Acute pancreatitis 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CABG 
Coronary Artery Bypass Grafting 
CI 
Confidence interval 
CM 
Chylomicrons 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CV 
Cardiovascular 
CVD 
Cardiovascular disease 
DBTP 
Double-blind treatment period 
DW-MRI 
Diffusion Weighted-Magnetic Resonance Imaging 
ECG 
Electrocardiogram 
EOT 
End of treatment 
FAS 
Full analysis set 
FCS 
Familial Chylomicronemia Syndrome 
FFA 
Free fatty acids 
18F-FDG PET 
18F-2-Fluoro-2-Deoxy-D glucose positron emission tomography 
FSH 
Follicle stimulating hormone 
GI 
Gastrointestinal 
HbA1c 
Hemoglobin A1c 
HDL 
High-density lipoprotein 
HDL-C 
High-density lipoprotein cholesterol 
HL 
Hepatic lipase 
HTG 
Hypertriglyceridemia 
ICH 
International Council for Harmonization 
ICF 
Informed consent form 
                                        VV-RIM-00078988-1.0 Approved - 20 May 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc.                 
                Protocol: R1500-HTG-1522 4GB 
Statistical Analysis Plan 
Date: May 17, 2019 
 
Regeneron Pharmaceuticals Inc.                                                                              Page 8 of 62 
CONFIDENTIAL 
IDMC 
Independent Data Monitoring Committee 
IV 
Intravenously 
IVRS 
Interactive voice response system 
Ki 
Incorporation rate 
Kpatlak  
Patlak clearance rate 
LDH 
Lactate dehydrogenase 
LDL-C 
Low-density lipoprotein cholesterol 
LDLR 
Low-density lipoprotein receptor 
LOF 
Loss of function 
Lp(a) 
Lipoprotein a 
LPL 
Lipoprotein lipase 
LS 
Least squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect model with repeated measures 
MRI 
Magnetic resonance imaging 
NMR 
Nuclear Magnetic Resonance 
PCI 
Percutaneous Coronary Interventions 
PCSV 
Potentially clinically significant value 
PET 
Positron emission tomography 
PK 
Pharmacokinetic 
PRO 
Patient-Reported Outcomes 
PT 
Preferred term 
Q4W 
Every 4 weeks 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SBTP 
Single-blind treatment period 
SD 
Standard deviation 
SE 
Standard error 
sHTG 
Severe hypertriglyceridemia 
SOC 
System organ class 
TBR 
Target to background ratio 
TC 
Total cholesterol 
TEAE 
Treatment-emergent adverse event 
                                        VV-RIM-00078988-1.0 Approved - 20 May 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc.                 
                Protocol: R1500-HTG-1522 4GB 
Statistical Analysis Plan 
Date: May 17, 2019 
 
Regeneron Pharmaceuticals Inc.                                                                              Page 9 of 62 
CONFIDENTIAL 
TG 
Triglycerides 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
VLDL 
Very-low-density lipoproteins 
WBC 
White blood cell 
 
                                        VV-RIM-00078988-1.0 Approved - 20 May 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc.                 
                Protocol: R1500-HTG-1522 4GB 
Statistical Analysis Plan 
Date: May 17, 2019 
 
Regeneron Pharmaceuticals Inc.                                                                              Page 10 of 62 
CONFIDENTIAL 
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-1522 study. 
The content of this SAP is inclusive of the interim, first, and second step analyses as described in 
the protocol. 
This plan may be revised during the study to accommodate protocol amendments and adapt to 
unexpected issues in study execution that may affect planned analyses. These revisions will be 
based on blinded data review, and a final plan will be issued prior to the first interim database 
lock (i.e. before any treatment assignments become known). For the purposes of this document, 
REGN1500 will be referred to as “evinacumab”. 
1.1. 
Background/Rationale 
Elevated levels of serum triglycerides (TG) are associated with the development of 
cardiovascular disease (CVD) and acute pancreatitis (AP). Studies suggest that mild to moderate 
elevations in TG levels are an independent risk factor for the development of CVD, and recent 
studies have demonstrated that genetic loss of function (LOF) variants which result in lower TG 
levels (eg, apolipoprotein C3 (APOC3), ANGPTL3, and ANGPTL4 LOF genetic variants) are 
associated with a decreased risk of myocardial infarction. Patients with severe elevations in TG 
levels (>1000 mg/dL) are at increased risk of pancreatitis and current lipid guidelines 
recommend lifestyle interventions and medications to lower TG levels to prevent AP.  
Angiopoietin-like 3 is the natural inhibitor of lipoprotein lipase (LPL) and has recently emerged 
as a potential 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, LDL-C and high-density lipoprotein-cholesterol (HDL-C). Deficiency of 
ANGPTL3 has also been reported to be associated with decreased serum free fatty acids (FFA) 
and increased insulin sensitivity in patients who are homozygous for LOF mutations in 
ANGPTL3. Humans carrying these variants have otherwise appeared healthy and have a reduced 
risk of coronary artery disease. 
Evinacumab (REGN1500) is a human IgG4 monoclonal antibody specific for ANGPTL3 and is 
being developed for treatment of dyslipidemia including hypertriglyceridemia (HTG) and 
hypercholesterolemia. Additional background information on the study drug and development 
program can be found in the Investigator’s Brochure. 
 
 
 
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1.2. 
Study Objectives  
1.2.1. 
Primary Objectives 
The primary objective of the study is to determine the change in TG levels following 12 weeks 
of repeated IV doses of evinacumab in the subset of patients with a documented history of sHTG 
(TG ≥1000 mg/dL [11.3 mmol/L]), a TG level of at least 500 mg/dL (5.6 mmol/L) at screening, 
a history of acute pancreatitis and without LOF mutations in genes in the LPL pathway; and to 
assess whether a reduction in TG of at least 40% from the baseline placebo period has been 
achieved. 
Regeneron and contract research organization (CRO) personnel who are in regular contact with 
the study site will be blinded to blood lipid measurements during the double-blind and 
single-blind treatment periods 
1.2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
 To determine the percent change from baseline in TG levels following 2 to 24 weeks 
of repeated IV doses of evinacumab overall and in subgroups with homozygous or 
compound heterozygous LOF mutations, heterozygous LOF mutations, and without 
LOF mutations in genes in the LPL pathway   
 To assess changes in patient reported abdominal and gastrointestinal (GI) symptoms, 
dietary habits, and symptom/dietary impact measures  
 To assess the degree of pancreatic injury/inflammation through 
18F-2-Fluoro-2-Deoxy-D glucose positron emission tomography (18F-FDG-PET) 
imaging at baseline (placebo run-in) and change from baseline following 12 weeks of 
treatment with evinacumab as assessed by 18F-FDG standardized uptake values 
SUVmax and SUVmean 
 To assess the degree of pancreatic injury/inflammation through diffusion 
weighted-magnetic resonance imaging (DW-MRI) at baseline and the change from 
baseline following 12 and 24 weeks of treatment with evinacumab as assessed by 
apparent diffusion coefficient (ADC) 
 To evaluate the total evinacumab and total ANGPTL3 concentrations, and 
treatment-emergent anti-drug antibody (ADA) incidence during the evinacumab 
treatment and follow-up periods 
 To evaluate the safety and tolerability of evinacumab 
1.2.3. 
Exploratory Objectives 
 To assess the degree of pancreatic injury/inflammation in the placebo run-in period 
and following treatment with evinacumab, as assessed by biochemical markers 
(amylase and pancreatic lipase activity [measured without lipemia interference], 
hs-CRP, IL-6, and other inflammation markers) 
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 To evaluate the effect of evinacumab compared to placebo on the incidence of 
recurrent acute pancreatitis overall and in subgroups with homozygous or compound 
heterozygous LOF mutations, heterozygous LOF mutations, and without LOF 
mutations in genes in the LPL pathway  
 To assess hospitalizations for abdominal pain, hospitalizations for pancreatitis, and 
hospitalizations for cardiovascular disease  
 To assess the degree of pancreatic injury/inflammation through T2-weighted 
magnetic resonance imaging (T2-MRI) at baseline and the change from baseline 
following 12 and 24 weeks of treatment with evinacumab as assessed by T2 intensity 
and T2 relaxation time 
 To assess the degree of pancreatic injury/inflammation through 
18F-2-Fluoro-2-Deoxy-D glucose positron emission tomography (18F-FDG-PET) 
imaging at baseline (placebo run-in) and change from baseline following 12 weeks of 
treatment with evinacumab as assessed by 18F-FDG Ki or Kpatlak 
 To evaluate the percent change from baseline of other lipid parameters (eg, total 
cholesterol [TC], TG, non-HDL-C, LDL-C, HDL-C, APOB, FFA, APOA-I) and 
lipoprotein subfraction composition (eg, chylomicrons [CM], VLDL, IDL, LDL 
[low-density lipoprotein], HDL [high-density lipoprotein], particle cholesterol, TG 
content, and apolipoprotein composition) after ultracentrifugation 
 To evaluate change from baseline in metabolic parameters (fasting blood glucose, 
insulin, C-peptide, HbA1c) after 12 and 24 weeks of evinacumab treatment  
 To evaluate change from baseline in post heparin LPL activity after evinacumab 
treatment. 
 To evaluate changes in 18F-FDG-PET in atherosclerotic plaque (target to background 
ratio [TBR]) in carotids and/or aorta 
 To evaluate change from baseline in MRI liver fat signal 
 To evaluate changes in the number and percentage of stomach pain, pain and 
abdominal symptom-free days, defined as the number and percentage of stomach pain 
free days, number of pain free days, and the number of abdominal symptom free 
days, as assessed by the HAP-SS.  
 To evaluate changes in the number and percentage of days where meals are avoided 
as assessed by the HAP-DB. 
 
 
 
 
 
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1.2.4. 
Modifications from the Statistical Section in the Final Protocol 
The summary of modifications is listed in the following table. 
Item Protocol Section 
Description 
1 
2.3 Exploratory Objective 
To assess medical visits/hospitalizations for 
abdominal pain or pancreatitis, medical 
visits/hospitalizations for pancreatitis, and 
medical visits/hospitalizations for 
cardiovascular disease  
SAP Section 1.2.3: 
Modified exploratory objective for medical 
visits/hospitalizations to remove medical visits 
because it is not captured in e-CRF (consistent 
across all evinacumab studies). 
2 
2.3 Exploratory Objective 
 
SAP Section 1.2.3, added two objectives: 
 To evaluate changes in the number and 
percentage of stomach pain, pain and 
abdominal symptom-free days, defined as 
the number and percentage of stomach pain 
free days, number of pain free days, and the 
number of abdominal symptom free days, 
as assessed by the HAP-SS.  
 To evaluate changes in the number and 
percentage of days where meals are 
avoided as assessed by the HAP-DB. 
3 
10.3.2 Safety Analysis Set 
The safety analysis set (SAF) includes all 
randomized patients who received any 
randomized study drug; it is based on the 
treatment received (as treated). Treatment 
compliance/administration and all clinical 
safety variables will be analyzed using the 
SAF. 
SAP Section 3.2 and 3.3: 
Safety Analysis Set was divided to double-
blind and single-blind period to be consistent 
with other evinacumab studies. 
4 
10.4.3.1 Primary Efficacy Analysis 
 “For the assessment of probability 
(computed from the likelihood function 
based on the observed data, which is 
equivalent to Bayesian posterior 
probability with uninformative prior) 
that mean TG percent change ≥40% ...” 
 “A natural log transformation will be 
applied to the TG levels prior to 
SAP Section 5.7.1: 
 For this proof-of-concept trial, estimates in 
TG change will be reviewed for 40% 
reduction supporting future drug 
development planning i.e., body of 
evidence review. Due to a lack of historical 
data in this indication, the application of 
posterior probability is not informative.  
 To provide further clarification, TG 
baseline definition was changed to the 
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analysis.”  
“To reduce variability of TG baseline 
measurements, baseline at week 0 for 
patients randomized to active treatment 
is the geometric mean of the last 2 
measurements during the placebo run-in 
(day -28, day -14) and week 0.” 
mean (arithmetic), since the log-
transformed geometric mean of 
measurements is equivalent to the 
arithmetic mean of log-transformed 
measurements. 
5 
10.4.3.2 Secondary and Exploratory 
Efficacy Analysis 
SAP Section 5.7.2, 5.9 to 5.12: 
 Analyses for each secondary and 
exploratory endpoint are specified in the 
corresponding sections for each endpoint. 
 The statement that “Continuous secondary 
and exploratory endpoints will be analyzed 
similarly to the primary endpoint” was 
deleted since for some continuous variables 
MMRM model may not converge due to 
the small number of visits/observations 
6  
10.4.5.3 Treatment Exposure 
The duration of exposure during the study 
will be presented and calculated as: 
(Date of last evinacumab injection - date of 
first evinacumab injection) + 24 weeks 
(length of follow-up period) 
SAP Section 4.6: 
Duration of exposure was divided to double-
blind and single-blind period and the duration 
definition was changed to “…+28 days/7” to be 
consistent with other evinacumab studies. 
1.2.5. 
Revision History for Statistical Analysis Plan Amendments 
This is the first version of Statistical Analysis Plan (SAP). 
2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
This is a phase 2, randomized, placebo-controlled, study designed to evaluate the efficacy and 
safety of repeated doses of evinacumab in adult patients with severe HTG. Up to approximately 
50 patients will be enrolled, randomized 2:1 (evinacumab:placebo) to receive evinacumab 
15 mg/kg IV every 4 weeks (Q4W) or matching placebo IV Q4W for the 12-week double-blind 
treatment period (DBTP). After completion of the DBTP, all patients will enter a 12-week 
single-blind treatment period (SBTP) and receive open-label evinacumab 15 mg/kg IV Q4W. 
Investigators, Regeneron Study Director, Medical Monitor, Study Monitor, and any other 
Regeneron and contract research organization (CRO) personnel who are in regular contact with 
the study site will be blinded to treatment assignment during the double-blind treatment period of 
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the study and blinded to blood lipid measurements during the double-blind and single-blind 
treatment periods. After SBTP, all patients will undergo a 24-week follow-up after the last dose 
of study treatment. 
The following cohorts will be enrolled based upon information (or lack of information) on 
genotype in the patient’s medical history at screening: 
1. Cohort 1:  FCS due to complete LPL deficiency. Approximately 6 to 9 patients will be 
enrolled.  This cohort consists of patients: 
 with known homozygous or compound heterozygous null LPL, GPIHBP1, or APOC2 
LOF mutations 
2. Cohort 2:  Multifactorial chylomicronemia with partial LPL deficiency. Approximately 9 
to 12 patients will be enrolled. This cohort consists of patients: 
 with known heterozygous null LPL, GPIHBP1, or APOC2 LOF mutations, or 
 with uncharacterized or known non-null LOF LPL pathway gene mutations (LPL, 
apoC2, apoA5, LMF1 and GPIHBP1) 
3. Cohort 3:  Multifactorial chylomicronemia. Approximately 15 to 27 patients will be 
enrolled. This cohort consists of patients not included in cohorts 1 or 2 above:  
 with other monogenic or polygenic causes of sHTG (eg, CGKR, CREB3L3, E2/E2 
dysbetalipoproteinemia), or 
 without genotype information 
2.2. 
Sample Size and Power Considerations 
Percent change in TG is analyzed based on log (post/pre) transformation, allowing for a normal 
distribution of the data. Standard deviations (SD) of raw percent changes up to 13% are akin to 
moderate SD on the log scale (30-40%). For the statistical precision calculations, a log-scale SD 
of 0.5 was used based on available evinacumab phase 1 data and is assumed to be conservative. 
With N=10 patients, the 90% confidence interval (CI) for an estimated mean reduction in 
triglycerides of 40% is approximately 20% to 55%. With N=12, the CI is 22% to 54%. A sample 
size of 24 is considered adequate to analyze the percent change in TG in the 3 genetic cohorts. 
Assuming a 20% drop out rate, approximately 30 patients will be needed to assess TG. 
Additional patients (up to a maximum of approximately 50 patients) will be enrolled with the 
intent to explore the effect of evinacumab on development of pancreatitis. 
For the FDG-PET uptake signal SUVmax, prior data on steroid-treated patients yielded a natural 
log-scale SD of change of 0.66 (Shigekawa 2010). This yields 80% power to yield a statistically 
significant (alpha=0.05, 1-sided) change from baseline within the N=16 evinacumab-treated 
patients if the TRUE underlying geometric mean ratio (post/pre) is 0.65 (back-transformed from 
the log-scale; ~35% reduction). For comparison to the N=8 placebo-treated patients, assuming 
log-scale SD=0.15 for placebo based on reproducibility data, and 0.66 for evinacumab, there is 
80% power if the TRUE underlying geometric mean ratio (GMR) of GMR's (evinacumab 
post/pre divided by placebo post/pre) is 0.64 (~36% reduction). 
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For the key MRI endpoint "mean f", which is the weighting coefficient between contrasting MRI 
regions (Klauss 2015), reported summary statistics yielded an SD estimate at most 5.96 for 
change from baseline. With this assumed SD, the N=24 patients with evinacumab post- and 
pre-values have 80% power to yield a statistically significant (alpha=0.05, 1-sided) change from 
baseline if the TRUE underlying mean change is 3.12 (~30% from baseline 10.5, which was 
observed by Klauss [Klauss 2015]). For the between-treatment comparison (N=16 evinacumab 
vs N=8 placebo), there is 80% power if the TRUE difference is 6.62 (~63% of the 10.5 baseline 
value observed by Klauss [Klauss 2015]). 
2.3. 
Study Plan 
The study consists of a screening period of up to 37 days (which includes day -66 to day -59 
[visit 1], day -58 to -52 [visit 1b], and day -51 to -39 [visit 2]), a placebo run-in period (day -28 
to day -1), a 12-week double-blind treatment period (day 1 to day 85), a single-blind 12-week 
evinacumab treatment period (day 86 to day 169), and an off-treatment follow-up period (week 
24 [day 170] to week 44 [day 309]). 
A study flow diagram is in Figure 1. 
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 primary efficacy analysis population is the full analysis set (FAS) 
population.  Additional patient populations are defined for safety, anti-drug (evinacumab) 
anti-body (ADA), pharmacokinetic (PK), total target (ANGPTL3), patient-reported outcomes 
(PRO), PET, MRI, biomarkers, and single-blind analyses. For the purposes of the definitions 
below, a patient is considered randomized to study treatment when they have been screened and 
received a double-blind treatment kit number allocated and recorded in the IVRS/IWRS 
database, regardless of whether the treatment kit was used or not.      
As with all trials, odd cases (usually rare) occur for patient eligibility in the analysis populations.  
The following are three cases with the planned resolution of each type of case should they occur. 
 Patients administered double-blind study treatment without randomization or before 
randomization will not be considered as “randomized” and therefore will not be 
included in any analysis population. The safety experience from these patients will be 
reported separately. 
 For patients found to be randomized more than once in this trial, safety data from the 
first randomization will be included in the safety population, with safety data 
associated with the later randomization reported separately.  Inclusion of efficacy data 
from the patient randomized more than once will be decided on a case-by-case basis 
prior to the unblinding of treatment assignments and documented in the study report. 
 Patients successfully randomized and administered double-blind study treatment, but 
later found to violate inclusion/exclusion criteria, will be included in all analyses with 
appropriate documentation for the protocol deviation.  
3.1. 
Full Analysis Set 
The full analysis set (FAS) includes all randomized patients who receive any double-blind study 
drug; it is based on the treatment assigned (as randomized). Only observed data will be 
analyzed/summarized; no missing data will be imputed.  
3.2. 
Double-Blind Safety Analysis Set 
The double-blind safety analysis set (SAF) considered for safety analyses will be the randomized 
population who received at least 1 dose or part of a dose of double-blind study drug. Patients will 
be analyzed according to the treatment received (placebo or evinacumab). In addition:   
 Randomized patients for whom it is unclear whether they took the study drug will be 
included in the safety population as randomized. 
 For patients receiving study drug from more than 1 treatment group during the 
double-blind period, the treatment group allocation for as-treated analysis will be 
evinacumab. 
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3.3. 
Single-Blind Safety Analysis Set 
The single-blind SAF considered for safety analyses will be the randomized population who 
received at least 1 dose or part of a dose of single-blind study drug.  
3.4. 
Pharmacokinetic (PK) Analysis Set 
The PK analysis set is defined as all randomized patients who received any study drug and have 
at least 1 non-missing measurement of evinacumab concentration following the first dose of the 
study drug.   Treatment assignments for the DBTP are based on the treatment received (placebo 
or evinacumab). 
The total target analysis set is defined as all randomized patients who received any study drug 
and have at least 1 non-missing measurement of total ANGPTL3 concentration following the 
first dose of study drug. Treatment assignments for the DBTP are based on the treatment 
received (placebo or evinacumab).  
3.5. 
The Anti-evinacumab Antibody Analysis Set 
The anti-evinacumab antibody (ADA) analysis set is defined as all randomized patients who 
received any study drug and have at least 1 non-missing ADA result following the first dose of 
study treatment. Treatment assignments for the DBTP are based on the treatment received 
(placebo or evinacumab). 
3.6. 
Patient-Reported Outcomes (PRO) Analysis Set  
The analyses of the PRO data in the respective treatment period (DBTP and SBTP) will be 
performed on all randomized patients who received any double-blind study treatment with a 
baseline and at least 1 non-missing post-baseline PRO evaluation. Treatment assignments for the 
DBTP are based on the treatment received (placebo or evinacumab).  
3.7. 
PET Analysis Set  
The analyses for PET will be performed on all randomized patients who received any double-
blind study treatment with a baseline and a post-baseline PET evaluation.  Treatment 
assignments are based on the treatment received (placebo or evinacumab). 
3.8. 
MRI Analysis Set  
The analyses for MRI in the respective treatment period (DBTP and SBTP) will be performed on 
all randomized patients who received any double-blind study treatment with a baseline and at 
least 1 post-baseline MRI evaluation.  Treatment assignments for the DBTP are based on the 
treatment received (placebo or evinacumab).  
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
For each patient, demographic and baseline characteristics, except TG, will be obtained from the 
last available value up to the date of the first double-blind study treatment administration (i.e. 
baseline definition). Baseline TG is defined as the mean of the last 2 measurements during the 
placebo run-in (day -28, day -14) and week 0. For patients randomized and not treated in 
R1500-HTG-1522, the baseline value is defined as the last available measurement prior to the 
date of randomization.  
All baseline safety and efficacy parameters (apart from those listed below) will be presented 
along with the summary statistics in the safety and efficacy sections. 
The following variables will be summarized:  
Demographic Characteristics 
 Sex (Male, Female) 
 Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other Pacific Islander, Not Reported, Other) 
 Age in years (quantitative and qualitative variable:  ≥18 to <45, ≥45 to <65, and ≥65) 
 Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not reported, Unknown) 
Baseline Characteristics 
 Baseline Weight (kg) 
 Baseline Height (cm) 
 Baseline Body mass index (BMI) in kg/m² (quantitative and qualitative variable 
defined as <30, ≥30) 
 Smoking Status (never, former, and current smoker) 
 Current alcohol consumption (yes/no) 
Baseline Disease Characteristics 
 Lipid parameters - quantitative variables for all efficacy parameters  
 HbA1c both quantitative variable and qualitative variable defined as: <5.7%, ≥5.7% 
to <6.5%, ≥6.5% 
 Hs-CRP 
 Lp(a): <30, ≥30 to <50, ≥50 mg/dL, and category ≥30 mg/dL (<75, ≥75 to <125, and 
≥125 nmol/L, and category ≥ 75 nmol/L)  
 Cohort assignment  
 Patient genotype  
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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, high level term, and preferred term using the Medical Dictionary for 
Regulatory Activities (MedDRA), specifically the MedDRA version in effect at the time of the 
first database lock. The medical history of interest collected on dedicated and pre-listed e-CRFs 
is: cardiovascular history and risk factors, and pancreatitis history. Primary and secondary CVD 
prevention, CV risk factors categorized by high and very high risk are also defined below from 
pre-defined risk factors collected on e-CRF. 
Medical history of interest is defined as the occurrence of these diseases: 
1. Coronary heart disease (CHD)  
2. CHD risk equivalents  
3. Cardiovascular (CV) risk factors other than hypercholesterolemia (hypertension, type 2 
diabetes, type 1 diabetes, family history of premature CHD).  
4. Family history of type 2 diabetes 
CHD and CHD risk equivalents will be derived from the respective e-CRF as follows: 
1. Coronary heart disease (CHD) (regardless if it is ongoing or not) is defined as the 
occurrence of at least one of the following events: 
 Acute myocardial infarction 
 Silent myocardial infarction 
 Angina (chronic stable or unstable) 
 Coronary revascularization procedure (e.g. PCI, CABG) 
2. CHD risk equivalent (regardless if it is ongoing or not) is defined as the occurrence of at 
least one of the following events: 
 Peripheral arterial disease (PAD)  
 Ischemic stroke 
 Chronic kidney disease (CKD) 
 Known history of diabetes mellitus (type 1 or 2) AND 2 or more additional risk 
factors among: 
 History of ankle-brachial index ≤ 0.90 
 History of hypertension 
 History of microalbuminuria or macroalbuminuria  
 History of proliferative diabetic retinopathy  
 Known family history of premature CHD  
Secondary CVD prevention is defined as patients with any of the following history of CVD 
(other patients will be classified as primary CVD prevention): 
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 History of CHD (as defined above) 
 History of ischemic stroke 
 History of PAD with severity criteria defined as one of the following events: 
 PAD and ankle brachial index ≤ 0.90 
 Peripheral revascularization procedure (angioplasty, stenting) for PAD 
 Thrombolysis for PAD 
 Peripheral revascularization surgery (arterial bypass) for PAD 
CV Risk Factors are defined for this study as high risk and very high risk below. 
 Very high CV risk patients are defined as patients with CHD or CHD risk 
equivalents. 
 High CV risk patients are defined as all other patients. 
4.3. 
Prior and Concomitant Medications 
All medications taken from the time of informed consent to the final study visit, including 
medications that were started before the study and are ongoing during the study, will be reported 
in Concomitant Medications CRF.  
All medications will be dictionary coded using the World Health Organization-Drug Dictionary 
(WHO-DD) to both an anatomic category and a therapeutic category, with the version in 
effect at the time of the first database lock.  Drug names will be matched to respective 
Anatomical-Therapeutic-Chemical (ATC) classification, although a drug can be matched to 
more than one ATC classification (i.e. patients can be counted in several categories for the same 
medication).   Prior medications, concomitant medications, and post-treatment medications are 
defined below and will be applied in the respective treatment periods (DBTP and SBTP). 
 Prior medications are defined as medications for which the stop date is before the date 
of the first DBTP study treatment administration. 
 Concomitant medications are defined as medications that are administered to the 
patients during the respective study treatment periods. Specifically: 
 Start date of the concomitant medication is on or after the first study treatment 
administration in respective study treatment periods (≥ DBTP Day 1 or ≥ SBTP 
Week 12); or 
 Start date of the concomitant medication is before the first study treatment 
administration in respective study treatment periods and is “Ongoing” during the 
treatment emergent period; or  
 Start date of the concomitant medication is before the first study treatment 
administration in respective study treatment periods, and the end date is on or 
after the first study treatment administration in respective study treatment periods 
(≥ DBTP Day 1 or ≥ SBTP Week 12). 
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The concomitant medication treatment emergent periods are defined as:  
 For concomitant medications in the DBTP, the treatment emergent period is defined 
from the first day of double-blind study treatment administration to the last day of 
double-blind study treatment +168 days (for patients who do not continue into the 
SBTP) or to the day before the first single-blind study treatment administration (for 
patients who enter the SBTP). 
 For concomitant medications in the SBTP, the treatment emergent period is defined 
from the first day of single-blind study treatment administration to the last day of 
single-blind study treatment +168 days. 
Note: In the case the start date is before first DBTP 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 7.8.1 of 
the protocol. They will be reviewed and identified by the study clinician and reported in protocol 
deviations.   
4.5. 
Patient Disposition 
Patient disposition will include the description of patient status at major milestone decisions in 
the study, as well as the patient analysis populations.   
For patient study status, patient double-blind treatment period milestone categories are defined 
below.  As applicable, percentages will be calculated using the number of randomized patients in 
the denominator, with two exceptions.  Specifically, the two exceptions will be for the screened 
and non-randomized categories, which will not have associated percentages shown.  
 The total number of screened patients, defined as originally having met the inclusion 
criteria and signed the ICF.  
 The total number of randomized patients, defined as all screened patients with a 
double-blind treatment kit number allocated and recorded in the IVRS database, 
regardless of whether the treatment kit was used. 
 The total number of patients randomized but not receiving study treatment. 
 The total number of patients randomized and receiving study treatment. 
 The total number of patients who completed the DBTP as collected on the End of 
Treatment e-CRF. 
 The total number of patients who completed the DBTP, defined as at least 12 weeks 
of study treatment exposure and visit week 12 performed. 
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 The total number of patients who prematurely discontinued study treatment during 
the double-blind period, and the reasons for discontinuation collected on the End of 
Treatment e-CRF. 
 The total number of patients who do not proceed into SBTP and complete the last 
study follow-up visit (i.e. End of Study/Visit 18). 
Patient SBTP milestone categories are defined below.  As applicable, percentages will be 
calculated using a denominator of the number of patients administer single-blind study treatment.  
 The total number of patients receiving single-blind study treatment. 
 The total number of patients ongoing in SBTP (applicable for the interim and first 
step analyses) 
 The total number of patients who completed the SBTP as collected on the End of 
Treatment e-CRF. 
 The total number of patients who completed the SBTP, defined as at least 24 weeks 
of study treatment exposure and week 24 visit performed. 
 The total number of patients who prematurely discontinued study treatment during 
the SBTP, and the reasons for discontinuation collected on the End of Treatment e-
CRF. 
 The total number of patients from SBTP who complete the last study follow-up visit 
(i.e. End of Study/Visit 18). 
The following patient populations for analyses are defined below: 
 Randomized population 
 Full analysis set population 
 Double-blind safety analysis set  
 Single-blind safety analysis set 
 Anti-evinacumab antibody (ADA) analysis set 
 Pharmacokinetic (PK) analysis set and total target analysis set 
 PRO analysis set 
 PET analysis set 
 MRI analysis set 
The following patient listings will provide the details from the patient disposition table. 
 A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized. 
 A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation. 
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4.6. 
Study Treatment Exposure and Compliance Variables 
Study treatment exposure variables for infusions administered during the DBTP are listed below 
with associated definitions: 
 Patient duration of double-blind study treatment exposure in weeks defined as: (last 
double-blind study treatment administration date +28 – first double-blind study 
treatment administration date)/7, regardless of unplanned intermittent 
discontinuations. Values will be rounded to one decimal place. 
 The total number of double-blind study treatment infusions by patient.  
 The following categories will be used for treatment exposure intervals: ≥1 day and 
<4 weeks, ≥4 weeks and <8 weeks, ≥8 weeks and <12 weeks, ≥12 weeks  
Study treatment exposure variables for infusions administered during the SBTP are listed below 
with associated definitions: 
 Patient duration of single-blind study treatment exposure in weeks defined as: (last 
single-blind evinacumab treatment administration date +28 – first single-blind 
evinacumab treatment administration date)/7, regardless of unplanned intermittent 
discontinuations. Values will be rounded to one decimal place. 
 The total number of single-blind evinacumab treatment infusions by patient.  
 The following categories will be used for treatment exposure intervals: ≥1 day and 
<4 weeks, ≥4 weeks and <8 weeks, ≥8 weeks and <12 weeks, ≥12 weeks  
Study treatment exposure variables combining DBTP and SBTP are listed below for all patients 
who received evinacumab in the DBTP: 
 Cumulative patient duration of evinacumab exposure in weeks defined as: 
double-blind treatment exposure plus single-blind treatment exposure, regardless of 
unplanned intermittent discontinuations. 
 Cumulative total number of evinacumab treatment infusions by patient defined as: 
total number of double-blind infusions plus total number of single-blind infusions.  
 The following categories will be used for cumulative patient treatment exposure 
intervals: ≥1 day and <4 weeks, ≥4 weeks and <8 weeks, ≥8 weeks and <12 weeks, 
≥12 weeks and <16 weeks, ≥16 weeks and <20 weeks, ≥20 weeks and <24 weeks, 
≥24 weeks 
With respect to patient treatment administration compliance, the study treatment is administered 
during the investigative site visits and therefore study compliance will be accessed by infusion 
frequency for respective treatment periods, specifically: 
 DBTP: for each patient as the average number of days between 2 infusions: (last 
double-blind dose date – first double-blind dose date) / (number of infusions in DBTP 
-1), for patients receiving at least 2 infusions. 
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  SBTP: for each patient as the average number of days between 2 infusions: (last 
single-blind dose date – first single-blind dose date) / (number of infusions in SBTP 
-1), for patients receiving at least 2 infusions. 
All important and minor protocol deviations potentially impacting efficacy analyses, 
randomization and drug-dispensing irregularities, as well as other deviations, will be collected 
and reviewed on an ongoing basis throughout the study as described in the Protocol Deviation 
Plan (PDP).  Both monitoring collected and programmatically derived deviations are listed and 
defined in the PDP. 
4.7. 
Efficacy Variables 
Efficacy will be assessed through the following measurements:  
 Lipids: LDL-C (Ultracentrifugation), HDL-C, total-C, fasting TG, non-HDL-C 
(calculated by subtracting HDL-C from Total-C), Apo B, Apo A1, Apo CIII, Apo 
B/Apo A1 ratio, and Lp(a) 
 Other variables: Hemoglobin A1c, hs-CRP, post heparin LPL activity, APOC2, 
APOA5, and metabolic parameters 
 Imaging: F-FDG-PET, DW-MRI, and T2-MRI 
The baseline value, unless noted otherwise, is defined as the last available measurement prior to 
the date of the first double-blind study treatment administration (applicable to measurement 
derivations during both DBTP and SBTP). For patients randomized and not treated, the baseline 
value is defined as the last available value prior to the date of randomization. 
4.7.1. 
Primary Efficacy Variable  
The primary endpoint is the percent lowering of TG levels from baseline following 12 weeks of 
repeated IV doses of evinacumab in the subset of patients with a documented history of sHTG 
(TG >1000 mg/dL [11.3 mmol/L]), a TG level of at least 500 mg/dL (5.6 mmol/L) at screening, 
a history of acute pancreatitis, and without LOF mutations in genes in the LPL pathway.  
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. 
Lipids Variables  
Potential clinical benefits of study treatment will be explored through the following lipids 
parameters: LDL-C (Ultracentrifugation), HDL-C, total-C, fasting TG, non-HDL-C, Apo B, Apo 
A1, Apo CIII, Apo B/Apo A1 ratio, and Lp(a). 
Baseline TG is defined as the mean of the last 2 measurements during the placebo run-in (day 
-28, day -14) and week 0. 
Lipids parameters will be collected in a fasted state over the course of the study at time points 
listed in Appendix 10.4, and sent to the central laboratory for evaluation, including scheduled 
and unscheduled blood draws. Both the absolute change from baseline and the percent change 
from baseline will be calculated for each lipids parameter, and derivations will be presented in 
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both international and conventional units. TG measurements with missing fasting status will be 
excluded from the summaries. 
4.7.3. 
Other Variables 
Other assessment endpoints are listed and defined below.  
 The change in hemoglobin A1c (HbA1c [%]) from baseline to post-baseline visits. 
 The percent change in hs-CRP from baseline over time 
 Post heparin LPL activity 
 Apolipoproteins: APOC2, APOA5 
 Metabolic parameters (fasting blood glucose, insulin, C-peptide, NEFA) 
4.7.4. 
PET Variable(s) 
The F-FDG PET endpoints are listed below: 
 Percent change in pancreatic 18F-FDG standardized uptake values SUVmax and 
SUVmean from baseline at week 12 
 Percent change in 18F-FDG-PET target to background ratio [TBR] in carotids and/or 
aorta atherosclerotic plaques at week 12 
 The change in pancreatic 18F-FDG Ki or Kpatlak from baseline at week 12 
4.7.5. 
MRI Variable(s) 
The MRI endpoints are listed below: 
 The change in apparent diffusion coefficient (ADC) in the pancreas from baseline to 
post-baseline visits 
 The change in T2 signal in the pancreas from baseline to post-baseline visits 
 The change in hepatic fat fraction from baseline to post-baseline visits 
The baseline value is defined as the mean of two measurements prior to the date of the first 
double-blind study treatment administration (applicable to measurement derivations during both 
DBTP and SBTP) 
4.8. 
Safety Variables 
Patient safety will be assessed through the collection of reported adverse events (AEs), clinical 
laboratory data, vital signs, and ECG. Unless otherwise noted, the baseline value is defined as 
the last available value before the first dose of double-blind study treatment. 
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: 
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 The PRE-TREATMENT period is defined from the day the ICF is signed to the day 
before the first dose of double-blind study treatment administration. 
 The double-blind treatment-emergent adverse event (TEAE) period is defined from 
the day of the first dose of double-blind study treatment administration to the day of 
the last dose of double-blind study treatment administration + 168 days (24 weeks) 
for those patients not proceeding into the  SBTP, or up to the day before the first dose 
of  single-blind study treatment administration for those patients proceeding into the  
SBTP. 
 The single-blind treatment-emergent adverse event (TEAE) period is defined from the 
day of the first single-blind study treatment administration to the day of the last 
single-blind study treatment administration + 168 days (24 weeks).  
 The POST-TREATMENT period is defined from the day after the end of the 
respective TEAE periods to the last study visit.  
4.8.1.1. 
Adverse Events and Serious Adverse Events 
Adverse events (including serious adverse events (SAE), AEs leading to treatment 
discontinuation, deaths, and AEs of special interest) are recorded from the time of signed 
informed consent until the end of study. All AEs identified by the Investigator will be reported 
and described. 
All AEs will be coded by “lowest level term (LLT)”, “preferred term (PT)”, “high level term 
(HLT)”, “high level group term (HLGT)” and associated primary “system organ class (SOC)” 
using the version of MedDRA in effect at the time of the first database lock. 
Adverse Event Observation Period  
 Pre-treatment AEs are AEs that developed or worsened or became serious during the 
pre-treatment period. 
 Double-blind and single-blind TEAEs are AEs that developed or worsened or became 
serious during the respective TEAE periods.  
 Post-treatment AEs are AEs that developed or worsened or became serious during the 
post-treatment period. 
4.8.1.2. 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) are AEs (serious or non-serious) required to be 
monitored, documented, and managed in a pre-specified manner. AESIs will be recorded on the 
adverse event e-CRF using dedicated tick boxes, and/or identified using standard MedDRA 
queries (SMQ), and/or company MedDRA queries (CMQ), and/or applicable laboratory 
assessments. Appendix 10.2 contains the definitions used to identify AESIs: 
The AESIs include the following: 
 Anaphylactic reactions (CRF) 
 General allergic events (SMQ) 
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 Infusion reactions (CRF) 
 Pregnancy (CRF) 
 Symptomatic overdose with investigational medicinal product (CRF) 
 Neurocognitive events (CMQ) 
 New onset of diabetes (NOD) (lab data) 
 Pancreatitis (CRF) 
4.8.1.3. 
Events Causing Death 
The observation periods for patient deaths are per the observation periods defined above.  
 Death on-treatment:  deaths occurring during the respective TEAE period 
(double-blind or single-blind), 
 Death post-treatment:  deaths occurring during the post-treatment period. 
4.8.1.4. 
Incidence of Recurrent Acute Pancreatitis 
Acute pancreatitis events are recorded in e-CRF as an AESI with event details captured in the 
complimentary e-CRF page. 
4.8.1.5. 
Hospitalizations 
Hospitalizations for abdominal pain, hospitalizations for pancreatitis, and hospitalizations for 
cardiovascular disease are recorded in AE e-CRF. 
4.8.2. 
Laboratory Safety Variables 
Clinical laboratory tests will consist of blood analyses (including hematology, clinical chemistry 
and other) and urinalysis. Clinical laboratory values will be converted and analyzed in both 
international units and US conventional units, with associated normal ranges provided by the 
central laboratory. Both actual test values and “change from baseline” values (defined as the 
post-baseline value minus the baseline value) will be used in the result summaries.  Potentially 
clinically significant values (PCSV) ranges will be applied to the laboratory test values as 
applicable (see Appendix 10.3 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. 
In addition, local laboratory tests for hematology will be summarized in the same manner as the 
central lab results.  
The laboratory parameters will be classified as follows: 
Hematology: 
 Red blood cells and platelets:  hemoglobin, hematocrit, erythrocytes count, red blood 
cells, platelets count, reticulocyte count, red blood indices 
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 White blood cells: white blood cells, neutrophils, lymphocytes, monocytes, basophils, 
eosinophils 
Clinical chemistry: 
 Metabolism:  glucose, total protein, albumin, creatine phosphokinase 
 Electrolytes:  sodium, potassium, chloride, calcium, bicarbonate 
 Renal function:  creatinine, blood urea nitrogen (BUN), uric acid 
 Liver function:  ALT, aspartate aminotransferases (AST), alkaline phosphatase 
(ALP), total bilirubin, LDH 
Urinalysis 
Urinalysis will include the following parameters: color, clarity, pH, specific gravity, ketones, 
protein, glucose, blood, bilirubin, leukocyte esterase, nitrite, WBC, RBC, hyaline and other casts, 
bacteria, epithelial cells, crystals, and yeast. 
4.8.3. 
Vital Signs 
Vital signs parameters will include weight (kg), heart rate (bpm), respiration (rpm), temperature 
(C or F), systolic and diastolic blood pressure (mmHg) after resting at least five minutes. Both 
actual test values and “change from baseline” values (defined as the post-baseline value minus 
the baseline value) will be provided for protocol specified visits. 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) 
Electrocardiograms will be recorded in the supine position after the patient has rested for at least 
10 min. Electrocardiogram assessments will be described as normal or abnormal. 
4.8.5. 
Physical Examination Variables 
Physical examination will be conducted at the protocol scheduled visits (See Appendix 10.4 for 
schedule of event). The result is an outcome of clinically significant (Yes/No, not examined). 
4.9. 
Pharmacokinetic Variables 
Pharmacokinetic (PK) variables include total evinacumab and total ANGPTL3 concentrations at 
each time point specified in the protocol (See Appendix 10.4 for schedule of event). 
4.10. 
Anti-Drug (evinacumab) Antibody Variables (ADA) 
Anti-drug antibody variables will include ADA status (positive or negative), titer and 
neutralizing antibody (NAb) status for samples analyzed at each time point specified in the 
protocol (See Appendix 10.4 for schedule of event). 
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4.11. 
PRO Variables 
The baseline value is defined as the last available measurement prior to the date of the first 
double-blind study treatment administration (applicable to measurement derivations during both 
DBTP and SBTP). 
The patient experience of symptoms and the impact on dietary behavior will be assessed with 
two de novo PRO measures: the Hypertriglyceridemia and Acute Pancreatitis Symptoms Scale 
(HAP-SS) and the Hypertriglyceridemia and Acute Pancreatitis Dietary Behavior questionnaire 
(HAP-DB). 
 Hypertriglyceridemia and Acute Pancreatitis Symptom Scale (HAP-SS) 
The HAP-SS is a 19-item measure of symptoms that has a 24-hour recall period. Four pain items 
are captured on a 0-10-point severity NRS, each scored 0=’No pain’ to 10=’Worst possible 
pain’, while the 15 non-pain items are captured on a 5-point frequency Likert scale, each scored 
from 1=’None of the time’ to 5=’All of the time’. The proposed structure of the measure is 
currently being tested and is yet to be finalized but currently consists of a total score and four 
domain scores: pain; abdominal symptoms; physical symptoms; other symptoms, each scored 0 
(no symptoms) to 100 (severe symptoms). 
The Pain domain includes the four items: item 1 - stomach pain average, item 2 - stomach pain at 
worst, item 3 - back pain at worst, item 4 - stomach pain after eating (possible score range:  0 to 
40). 
The Abdominal symptoms domain includes the 6 items: item 5 – bloated or swollen stomach, 
item 6 – nausea/feeling sick, item 7 – vomiting, item 8 – passed excessive gas, item 9 – loose 
stools/diarrhoea, item 10 – foul smelling, light-coloured or greasy stool (possible score range: 
6 to 30). 
The Physical symptoms domain includes 5 items: item 11 – fever or flu like symptoms, item 
12 - insomnia, item 13 – excessive sweating, item 14 – dizziness (light/headedness), item 
15 - racing heart rate (felt like your heart was racing) (possible score range 5 to 25). 
The Other symptoms domain includes 4 items: item 16 – fatigue, item 17 – loss of appetite, item 
18 – been hungry after eating, item 19 – felt full after eating a small amount (possible score 
range 4 to 20). 
Each item will be calculated at each evaluation/visit as the mean of the item scores over the 
seven days previous to the visit; each domain score at each evaluation/visit will be calculated as 
the sum of the mean component item scores. Each domain score will then be transformed onto a 
0-100 scale, with the total score being the sum of the four domain scores (0-400), also then 
transformed to a 0-100 scale. 
To transform to a 0-100 scale the following algorithm will be applied: 
Transformed score = 100 x (score – minimum possible score) / (maximum – minimum possible 
score). 
 Dietary behavior questionnaire (HAP-DB)  
The HAP-DB is a 6-item measure of dietary behavior that has a 24-hour recall period. The items 
in the measure are all captured on a 5-point frequency Likert scale, each scored from 1=’None of 
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the time’ to 5=’All of the time’. The proposed structure of the measure is currently being tested 
and is yet to be finalized but currently consists of a dietary impact total score, ranging from 6 (no 
impact) to 30 (severe impact). 
The six HAP-DB items are: item 1 – amount of food eaten, item 2 – fatty or greasy food, item 
3 – carbohydrates, item 4 – sugar or sugary foods, item 5 – alcohol intake, item 6 – skipped 
meal. 
Each item will be calculated at each evaluation/visit as the mean of the item scores over the 
seven days previous to the visit. The total score will be calculated as the sum of the six item 
scores and then transformed to a 0-100 score. 
To transform to a 0-100 scale the following algorithm will be applied: 
Transformed score = 100 x (score – minimum possible score) / (maximum – minimum possible 
score).  
4.11.1. 
Number of pain and abdominal symptom free days and days where meals are 
avoided 
Exploratory endpoints of the frequency of stomach pain (on average, and at its worse), pain 
(stomach pain, back pain, stomach pain at its worst after eating), and abdominal symptom free 
days at each evaluation/visit will be defined as the number and percentage of stomach pain free 
days, number and percentage of pain free days, and the number and percentage of abdominal 
symptom free days over the seven days prior to the visit, as assessed by the HAP-SS: 
 A stomach pain free day will be determined if the patient scores 0 - ‘No Pain’ on both 
of the HAP-SS stomach pain items 1 and 2. 
 A pain free day will be determined if the patient scores 0 - ‘No Pain’ on all of the 
HAP-SS pain items 1, 2, 3 and 4.   
 An abdominal symptom free day will be determined if the patient scores 1 - ‘None of 
the time’ to all the HAP-SS abdominal symptoms items 5-10. 
An additional exploratory endpoint of the number of days where meals are avoided will be 
assessed as the number of days where all meals are skipped as assessed by the HAP-DB: 
 A day where all meals are avoided will be determined if the patient scores 5 - ‘All of 
the time’ to item 6 in HAP-DB, skipped meals. 
4.12. 
Biomarker Variable(s) 
The biomarker endpoints include the following: 
 Biochemical markers (amylase, lipase, IL-1, IL-6, IL-8 and TNFa) 
 LPL concentration, Hepatic Lipase activity and concentration, Endothelial Lipase 
activity and concentration 
 Lipoprotein subfraction composition after ultracentrifugation: chylomicrons (CM), 
VLDL, IDL, LDL (low-density lipoprotein), HDL (high-density lipoprotein) and TG 
content. 
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 Apolipoprotein composition per lipid subfraction by ultra-centrifugation 
 Lipoprotein concentration parameters determined by Nuclear Magnetic Resonance 
(NMR) 
5. 
STATISTICAL METHODS 
5.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group 
and overall for the study, as well as by treatment group and overall within each cohort in the 
FAS population. 
Continuous data will be summarized using the number of patients with data, mean, SD, median, 
Q1, Q3, minimum and maximum for each treatment group. Categorical and ordinal data will be 
summarized using the number and percentage of patients in each treatment group. 
For the single-blind safety population, demographic and baseline characteristics will be 
summarized by all patients and by treatment group of the DBTP (i.e., evinacumab, placebo).  
5.2. 
Medical History  
Medical history will be descriptively summarized by treatment group and overall for the study, 
as well as by treatment group and overall within each cohort in the FAS population. 
All reported patient’s medical history will be presented by primary SOC and HLT.  The tables 
will be presented by SOC sorted alphabetically and decreasing patient frequency of HLT based 
on the overall incidence in the study.  In addition, all medical history of specific interest, primary 
and secondary CVD prevention including corresponding criteria, as described in Section 4.2, will 
be summarized by patient incidence and percentage. 
The number (%) of patients will be summarized by CVD prevention status (i.e. primary and 
secondary CVD prevention status).  
In addition, smoking status will be summarized in patients with primary CVD prevention status. 
For patient disease characteristics, as described in Section 4.2, continuous data will be 
summarized using the number of patients with data, mean, SD, median, Q1, Q3, minimum and 
maximum for the study. Categorical and ordinal data will be summarized using the number and 
percentage of patients in the study.   
5.3. 
Prior and Concomitant Medications  
All prior medications, dictionary coded by WHO-DD, will be descriptively summarized by 
treatment group and overall for the study, as well as by treatment group and overall within each 
cohort for patients in the double-blind safety population. Summaries will present patient counts 
(and percentages) for all prior medications, by decreasing frequency of the overall incidence of 
ATC followed by therapeutic class.  In case of equal frequency across anatomic or therapeutic 
categories, alphabetical order will be used. Patients will be counted once in each ATC category 
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(anatomic or therapeutic) linked to the medication but may be counted several times for the same 
medication.  
All concomitant medications during the DBTP, dictionary coded by WHO-DD, will be 
descriptively summarized by treatment group, for patients in the double-blind safety population. 
Summaries will present patient counts (and percentages) for the concomitant medication groups 
described in Section 4.3 for all concomitant medications, by decreasing frequency of the 
evinacumab group incidence of ATC followed by therapeutic class.  In case of equal frequency 
across anatomic or therapeutic categories, alphabetical order will be used. Patients will be 
counted once in each ATC category (anatomic or therapeutic) linked to the medication, hence 
may be counted several times for the same medication.   Post-treatment medications will be 
summarized as described above for all medications. 
For the SBTP, concomitant and post-treatment medications will be dictionary coded by 
WHO-DD and will be descriptively summarized as described for the DBTP. Medications will be 
summarized for all patients and by treatment group of the DBTP (i.e., evinacumab, placebo) for 
patient in the single-blind safety population. Summaries will present patient counts (and 
percentages). 
5.4. 
Prohibited Medications  
Listing of prohibited medications will be provided for the patients in the double-blind safety 
analysis set for the DBTP and SBTP. 
5.5. 
Patient Disposition 
Patient disposition includes the description of patient status at major milestone decisions in the 
study, as well as the patient analysis populations. 
Patient study status for the DBTP will be summarized by treatment group and overall for the 
study, as well as by treatment group and overall within each cohort (screened patients, screen 
failures, and non-randomized but treated patients only).  Summaries will provide the frequency 
(and percentage as applicable) of patients that met the criteria for the variables described in 
Section 4.5.  Exception listings will be generated for any patient treated but not randomized, 
randomized but not treated, and treated differently than randomized. 
DBTP patient analysis populations will be summarized by treatment group, depicting frequencies 
(and percentages) of patients that met the criteria for each population described in Section 3.  
For the SBTP, the patient study status and patient analysis populations will be summarized by all 
patients and by treatment group of the DBTP (i.e., evinacumab, placebo) on the single-blind 
safety population for the variables described in Section 4.5  
For both the DBTP and SBTP, the incidence of premature study treatment discontinuation 
(irrespective of the reason) and premature treatment discontinuation due to AEs will be presented 
graphically by treatment group in the respective safety analysis set using the Kaplan-Meier 
method. 
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5.6. 
Extent of Study Treatment Exposure and Compliance 
The extent of study treatment exposure for the DBTP described in Section 4.6 will be assessed 
and summarized by treatment group, for patients in the double-blind safety analysis set. The 
extent of study treatment exposure for the SBTP described in Section 4.6 will be assessed and 
summarized for all patients and by treatment group of the DBTP (i.e., evinacumab, placebo) for 
patients in the single-blind safety analysis set. 
5.6.1. 
Exposure to Investigational Product 
Study treatment exposure in the DBTP and SBTP will be descriptively summarized for treatment 
duration and total number of infusions as described in Section 4.6. Treatment duration and total 
number of infusions will be summarized using the number of patients with data, mean, SD, Q1, 
Q3, median, minimum and maximum.  
Additionally, evinacumab dosing exposure will be summarized cumulatively across the study, 
combining DBTP and SBTP for patients who received evinacumab in the DBTP. 
5.6.2. 
Study Treatment Compliance 
Both monitored and derived protocol deviations will be summarized for important deviations 
(counts of deviations), patients (incurring a deviation by count and percentage), and by type of 
important deviation (patient count and percentage). A patient listing of all important and minor 
protocol deviations will be provided. 
Descriptive statistics of the infusion frequency will be summarized. A patient listing will be 
provided for those patients with incomplete or interrupted infusions. Cases of study treatment 
overdose will be reported in the AE e-CRF page and will be described in the adverse event 
analysis.  
5.7. 
Analyses of Efficacy Variables 
For statistics where international and conventional units do not impact the results (e.g. means and 
least square (LS) means for percent changes from baseline, rates of patients below a threshold), 
derivations will be calculated and statistical models will be run using conventional units. For 
other statistics (e.g. descriptive statistics at baseline and over time, absolute changes from 
baseline), derivations will be presented in both international and conventional units. 
Statistical analyses for the primary efficacy endpoint will be conducted as described below and 
will be completed during the final efficacy analysis (Section 7). Only measurements collected at 
the protocol scheduled time point (as defined by e-CRF visit label) will be used for the analyses. 
5.7.1. 
Analysis of Primary Efficacy Variable 
The primary efficacy analysis will assess within-patient percent change in TG over 12 weeks of 
evinacumab treatment (double-blind period for patients randomized to evinacumab and 
single-blind period for patients randomized to placebo). 
The point estimates of TG percent changes between the placebo period and each observation 
week will be calculated using a Mixed-effect Model for Repeated Measures (MMRM) method in 
the FAS population. A natural log transformation will be applied to the TG levels prior to 
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analysis, aiming to provide a relatively normal data distribution (residuals will be examined for 
normality prior to proceeding with the analysis). The MMRM model will assess within-patient 
treatment comparisons (using an unstructured covariance matrix), while accounting for baseline 
TG, study visit, and baseline TG by study visit interaction. Note that study visits will be adjusted 
to start of evinacumab in order to pool data from both randomized groups of patients for this 
analysis. Since the comparison of study visits yields the within-patient comparisons of study 
treatments (ie, week 12 [after 12 weeks of treatment with evinacumab] compared to baseline at 
week 0 [after 4 weeks of treatment with placebo] for patients randomized to evinacumab and 
week 24 [after 12 weeks of treatment with evinacumab] compared to baseline at week 12 for 
those randomized to placebo), contrast and estimate statements will be used to assess treatment 
effects (least squares [LS] means with confidence intervals) and comparisons (LS mean ratio 
with CI). Within-patient comparisons will include all patients. In the event the MMRM model 
covariance matrix does not converge or normality is not achieved with the natural log 
transformation, then other transformations will be explored, including ranks. 
To reduce variability of TG baseline measurements, baseline at week 0 for patients randomized 
to active treatment is the mean of the 3 log-transformed measurements at day -28, day -14, and 
week 0. Baseline at week 12 for patients switching from placebo to active is the mean of 
3 log-transformed measurements at weeks 6, 8, and 12. Additional exploratory analyses may be 
carried out using the average of all available TG observations prior to first dose of active 
treatment, if no trend over time in those measurements is discernable. 
The estimate of the log TG mean ratio (week 12/baseline at week 0 for patients randomized to 
evinacumab and week 24/baseline at week 12 for those randomized to placebo) and the log of the 
standard deviation derived from the MMRM model (ie., LS mean ratio with CI) based on 
observed results from the patients without LOF mutations in genes in the LPL pathway will be 
reviewed for 40% reduction. 
5.7.1.1. 
Sub-group Analyses 
To assess the homogeneity of the treatment effect across various subgroups, treatment-by-
subgroup factor, time point-by-subgroup factor and treatment-by time point-by subgroup factor 
interaction terms and a subgroup factor term will be added in the primary MMRM model. 
Within-patient contrast and estimate statements will be used to assess treatment effects (least 
squares [LS means with confidence intervals) and comparisons (LS mean ratio with CI). In order 
to handle imbalances between subgroup factors levels, population weights will be used in the 
analysis model.  
The following subgroups of interest will be evaluated, assuming there are enough patients in 
each subgroup level to perform the evaluation.   
 Cohort assignment (1,2 and 3) as defined at the time of the analysis 
A graph will depict the mean (+/- SE) TG concentrations over time for each genotype subgroup. 
Nominal p-values for testing mean change from baseline >0 and >40% at each time point in each 
cohort may be computed for information purposes. Since this is an exploratory study, control of 
the overall type-I error is not applicable for statistical testing. Any p-values provided for 
outcome measures are for descriptive purposes only. 
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5.7.2. 
Analyses of Lipids Variables  
Descriptive statistical analyses for the lipids defined in Section 4.7.2 will be summarized by 
treatment group and overall for the study, as well as by treatment group and overall within each 
cohort in the FAS population. 
For descriptive summaries, percent change, and/or when appropriate, absolute change from 
baseline in conventional (US) and international units will be provided for lipids (LDL-C, Apo B, 
total-C, TG, non-HDL-C, Lp(a), Apo CIII, Apo A-1, and ratio Apo B/Apo A-1) at each protocol 
scheduled time point (as defined by e-CRF visit label) for each treatment group. For TGs, 
measurements on not-fasting patients will be excluded. Observed lipid values will be used, ie, 
imputation of missing values is not planned. For the evinacumab treated group, within-patient 
testing of endpoints with a non-normal distribution will use the Wilcoxon signed-rank test and 
endpoints with a normal distribution will use the paired t-test to evaluate the mean differences 
between baseline and each protocol visit. The p-value will be provided for descriptive purposes 
only. 
Figures will be produced to support the summary tables for percent change and/or when 
appropriate absolute change from baseline. The plot will contain mean percent change +/- 
standard error (SE) through the study visits for each lipid variable (except TG and Lp(a)) by 
treatment group. For TG and Lp(a), plots will contain the median percent and /or absolute 
change from baseline along with quartiles (Q1 and Q3) over time by treatment group. 
In addition, all lipids measurements (scheduled and unscheduled) will be included in patient 
listing. 
During the SBTP, efficacy variables will be explored through descriptive statistics at each 
protocol scheduled visit for the total patients administered single-blind study treatment (total), as 
well as by the patient subgroups of study treatment received in the double-blind treatment period 
(i.e., evinacumab, placebo).  Descriptive statistics will include the observed values of the same 
parameters as described for each variable in the DBTP, for patients in the single-blind safety 
analysis set.  
For patients receiving evinacumab in the DBTP, a combined summary including both the DBTP 
and SBTP assessments may be considered, referencing the double-blind baseline for variable 
calculations.  Prolonged time between last dose of double-blind treatment and first dose of 
single-blind treatment will need to be taken into consideration when combining longitudinal 
efficacy data. Descriptive statistics will include the observed values of the same parameters as 
described for each variable in the DBTP, for patients in the double-blind safety analysis set.  
5.7.3. 
Analysis of Other Variables 
Descriptive statistical analyses for other endpoints (described in Section 4.7.3) will be 
summarized by treatment group and overall for the study, as well as by treatment group and 
overall in the FAS population. For summary tables, only protocol scheduled measurements (as 
defined by e-CRF visit label) will be included. Patient listings will include all measurements, 
scheduled and unscheduled. 
The summary of results for other variables will be presented separately for the DBTP and SBTP, 
unless otherwise noted. Summaries for the DBTP will be presented by treatment groups 
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(evinacumab, placebo) containing patients from the double-blind safety analysis set. Summaries 
for the SBTP will be presented by all patients and by treatment group in DBTP (i.e., evinacumab, 
placebo), for patients in the single-blind safety analysis set. No formal inferential testing will be 
performed for either period. Summaries will be descriptive in nature.  
Hs-CRP and HbA1c parameters will be summarized at each protocol-scheduled visit. The 
medians (with Q1-Q3) will be plotted for hs-CRP and HbA1c. Applying the PCSV criteria at any 
time during the TEAE period, the number of patients (and percentages) meeting the criteria will 
be summarized.  
Similar tables, except PCSV criteria, will be provided for post heparin LPL activity, APOC2, 
APOA5, and metabolic parameters. 
5.7.4. 
Analysis of PET Variables 
Descriptive statistical analyses for the PET variables defined in Section 4.7.4 will be summarized 
by treatment group and overall for the study, as well as by treatment group and overall within 
each cohort in the PET population. 
For descriptive summaries, raw values, percent change, and/or when appropriate, absolute 
change from baseline will be provided for PET variables at each protocol scheduled time point 
(as defined by e-CRF visit label) for each treatment group. Missing values will not be imputed. 
For the evinacumab treated group, within-patient testing of endpoints with a non-normal 
distribution will use the Wilcoxon signed-rank test and endpoints with a normal distribution will 
use the paired t-test to evaluate the mean differences between baseline and each protocol visit. 
The p-value will be provided for descriptive purposes only 
5.7.5. 
Analysis of MRI Variables 
Descriptive statistical analyses for the MRI variables defined in Section 4.7.5 will be 
summarized by treatment group and overall for the study, as well as by treatment group and 
overall within each cohort in the MRI population. 
For descriptive summaries, raw values, percent change, and/or when appropriate, absolute 
change from baseline will be provided for MRI variables at each protocol scheduled time point 
(as defined by e-CRF visit label) for each treatment group. Missing values will not be imputed. 
For the evinacumab treated group, within-patient testing of endpoints with a non-normal 
distribution will use the Wilcoxon signed-rank test and endpoints with a normal distribution will 
use the paired t-test to evaluate the mean differences between baseline and each protocol visit. 
The p-value will be provided for descriptive purposes only 
5.8. 
Analysis of Safety Data 
The summary of safety results will be presented separately for the DBTP and SBTP, unless 
otherwise noted. Safety summaries for the DBTP will be presented by treatment groups 
(evinacumab, placebo), as well as by treatment group within each cohort containing patients 
from the double-blind safety analysis set. Safety summaries for the SBTP will be presented by all 
patients and by treatment group in DBTP (i.e., evinacumab, placebo), for patients in the 
single-blind safety analysis set. No formal inferential testing will be performed for either period. 
Summaries will be descriptive in nature.  
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General common rules 
All safety analyses will be performed, unless otherwise specified, using the following common 
rules: 
 Safety data in patients who do not belong to the safety analysis set (i.e., exposed but 
not randomized) will be listed separately. 
 PCSV values are defined as abnormal values considered medically important by the 
Sponsor according to predefined criteria/thresholds based on literature review and 
defined by the Sponsor for clinical laboratory tests and vital signs (PCSV version 
dated January 2009 [Appendix 10.3]). 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 
respective TEAE periods, taking into account all evaluations including unscheduled 
or repeated evaluations. 
 For summary tables, only protocol scheduled measurements (as defined by e-CRF 
visit label) will be included. Patient listings will include all measurements, scheduled 
and unscheduled. 
 The treatment-emergent PCSV denominator by treatment group for a given parameter 
will be based on the number of patients assessed for that given parameter at least once 
during the respective TEAE periods. 
 For quantitative safety parameters including central laboratory measurements and 
vital sign scores, descriptive statistics will be used to summarize observed values and 
change from baseline values by visit.  
5.8.1. 
Adverse Events  
In general, the primary focus of AE reporting will be on TEAEs summarized in respective TEAE 
periods, specifically the DBTP and SBTP.  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 6.2. 
Adverse event incidence tables will present the number (n) and percentage (%) of patients 
experiencing an AE by SOC and PT.  Multiple occurrences of the same event in the same patient 
will be counted only once in the tables within a treatment phase (TEAE or post-treatment AE). 
For tables presenting severity of events, the worst severity will be chosen for patients with 
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multiple instances of the same event. The denominator for computation of percentages is the 
respective safety analysis set within each treatment group. 
AE incidence tables will present data by SOC sorted alphabetically and PT sorted by decreasing 
frequency of the evinacumab treated group and summarize the number (n) and percentage (%) of 
patients experiencing an AE. 
Analysis of all treatment-emergent adverse events 
The following TEAE summaries will be generated: 
 Overview of TEAEs, summarizing number (%) of patients with any 
 TEAE; 
 Serious TEAE; 
 TEAE leading to death; 
 TEAE leading to permanent treatment discontinuation. 
 All TEAEs by primary SOC and PT 
 Number (%) of patients experiencing any TEAE(s) presented by primary SOC and PT  
 All TEAEs relationship (related/not related) to evinacumab 
 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 and PT 
 Patient listings of serious TEAEs will be provided in the report appendix 
 All Serious TEAEs relationship (related/not related) to evinacumab 
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
 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 
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. 
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Hepatic Disorder 
Hepatic disorder events will be defined using the SMQ drug-related hepatic disorder 
(comprehensive search).  
 All hepatic disorder TEAEs by 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, if applicable.  AESI are defined by SMQ, CMQ, dedicated e-CRF, or 
lab data as described in Appendix 10.2.   
The following variables will also be tabulated for infusion reactions TEAEs: 
 Intensity of the event (mild, moderate, and severe); 
 Number of events divided by the number of study treatment administrations received 
in respective treatment periods; 
 Time from first study treatment administration (DBTP or SBTP depending on the 
analysis) to first infusion reaction; 
5.8.3. 
Analysis of Incidence of Recurrent Acute Pancreatitis 
Acute pancreatitis event incidence table will present the number (n) and percentage (%) of 
patients experiencing such event.  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). 
The denominator for computation of percentages is the respective safety analysis set within each 
treatment group. 
5.8.4. 
Analysis of Hospitalizations 
Hospitalizations event (defined in Section 4.8.1.5) incidence table will present the number (n) 
and percentage (%) of patients experiencing such event.  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). The denominator for computation of percentages is the respective safety 
analysis set within each treatment group. 
5.8.5. 
Clinical Laboratory Measurements  
For respective treatment period (DBTP and SBTP), clinical laboratory parameter actual values 
(quantitative) and change from baseline values will be descriptively summarized at baseline and 
each post-baseline visit (collected up to the day of last dose of study treatment +28 days) by at 
least patient number, mean, median, Q1, Q3, SD, minimum and maximum. Clinical laboratory 
parameters mean changes from baseline, with the corresponding SE, can be plotted at each visit 
in the case results warrant further investigation.  These parameters will be presented by the 
biological functions defined in Section 4.8.2.  For glucose, only fasting samples will be included 
in the summaries. 
Individual patient laboratory parameter measurements will be additionally evaluated by PCSV 
criteria (See Appendix 10.3), specifically identifying patients with at least one post-baseline 
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measurement that meets the PCSV criteria within the respective TEAE periods. These laboratory 
parameters will be presented by the biological functions defined in Section 4.8.2. The incidence 
of PCSVs at any time during the respective TEAE periods will be summarized regardless of the 
baseline level, and again according to the following baseline categories: 
 Normal (according to PCSV criterion/criteria)/missing 
 Abnormal according to PCSV criterion or criteria 
Patient listings of laboratory measurements that meet PCSV criteria will be provided for the 
report appendix.  For those laboratory parameters that don’t have an associated PCSV criteria, 
similar summary tables can be provided based on measurements outside the central laboratory 
normal ranges, if applicable. 
Drug-induced liver injury 
For respective treatment period (DBTP and SBTP), an evaluation of drug-induced serious 
hepatotoxicity (eDISH) with the graph of distribution of peak values of ALT versus peak values 
of total bilirubin will also be presented using post-baseline values during respective TEAE 
periods. Note that the ALT and total bilirubin values are presented on a logarithmic scale. The 
graph will be divided into 4 quadrants with a vertical line corresponding to 3 x ULN for ALT 
and a horizontal line corresponding to 2 x ULN for total bilirubin. 
Patient listing of possible Hy’s law cases identified by treatment group (i.e., patients with any 
elevated ALT>3 x ULN, and associated with an increase in bilirubin >2 x ULN, concomitantly 
or not) with ALT, AST, ALP, total bilirubin, and if available direct and indirect bilirubin will be 
provided. 
5.8.6. 
Analysis of Vital Signs 
For respective treatment period (DBTP and SBTP), the vital sign actual values and change from 
baseline values obtained while sitting will be descriptively summarized at baseline and each 
post-baseline visit (collected up to the day of last dose of study treatment +28 days) by at least 
patient number, mean, median, Q1, Q3, SD, minimum and maximum. Vital sign mean changes 
from baseline, with the corresponding SE, can be plotted at each visit in the case results warrant 
further investigation. 
Individual patient vital sign measurements (regardless of sitting position) will be additionally 
evaluated by PCSV criteria, specifically identifying patients with at least one post-baseline 
measurement that meets the PCSV criteria within the TEAE period.  The incidence of PCSVs at 
any time during the respective TEAE periods will be summarized regardless of the baseline 
level, and again according to the following baseline categories: 
 Normal (according to PCSV criterion/criteria)/missing 
 Abnormal according to PCSV criterion or criteria 
Patient listings of vital sign measurements that meet PCSV criteria will be provided for the 
report appendix.   
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5.8.7. 
Analysis of 12-Lead ECG 
For respective treatment period (DBTP and SBTP), ECG parameters will be described through 
an overall interpretation of ECG status (e.g. normal, abnormal [clinically significant (Yes/No)]). 
The count and percentage of patients with at least 1 abnormal post-baseline ECG during the 
respective TEAE period will be summarized according to the following baseline status 
categories: 
 Normal/missing; 
 Abnormal 
5.8.8. 
Physical Exams 
A list of patients with any clinically significant abnormality results will be generated. 
5.9. 
Analysis of Pharmacokinetic Variables 
Descriptive statistics for concentrations of total evinacumab and total ANGPTL3 will be 
presented. Mean concentrations of each analyte will be tabulated by visit and treatment group, 
with concentrations below the LLOQ set to zero. 
Plots of the mean concentrations (linear and log scales) will be presented by nominal sampling 
time. Plots of the individual concentrations (linear and log scales) will be presented by actual 
sampling time. In the linear-scaled plots, concentrations below the LLOQ will be set to zero; in 
the log-scaled plots, concentrations below the LLOQ will be imputed as LLOQ/2. 
When appropriate, relationship between concentrations of evinacumab and concentration of total 
ANGPTL3 (target engagement), percentage of TG reduction or other biomarkers may be 
evaluated descriptively.  
5.10. 
Analysis of Anti-evinacumab Antibody Variables 
The ADA variables described in Section 4.10 will be summarized using descriptive statistics 
by dose/cohort group in the ADA analysis set. Listings of ADA positivity and titers presented 
by patient, time point, and study treatment received will be provided. Incidence of 
treatment-emergent ADA will be assessed as absolute occurrence (N) and percent of patients 
(%), grouped by study treatment received. 
The influence of ADA on drug concentrations will be evaluated. Assessment of impact of ADA 
on safety and efficacy may be provided.  
Anti-drug antibody status (negative or positive) and titer over the study duration may be 
classified as follows:  
 Negative - negative in the ADA assay at all time points 
 Pre-existing immunoreactivity -  a positive response in the ADA assay at baseline 
with all post first double-blind dose results negative in the ADA assay, or a positive 
response at baseline with all post-first dose responses less than 9-fold of the baseline 
titer levels 
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 Treatment emergent response is defined as a positive response in the ADA assay post 
first double-blind dose when baseline results are negative or missing.  The treatment 
emergent responses will be further characterized as Persistent, Indeterminate or 
Transient and further categorized as follows:  
 Persistent - Treatment emergent ADA positive response with two or more 
consecutive ADA positive sampling time points separated by greater than 
16-week period (based on nominal sampling time), with no ADA negative 
samples in between, regardless of any missing samples.  
 Indeterminate - A positive result in the ADA assay at the last collection time point 
analyzed only, regardless of any missing samples 
 Transient - a treatment emergent ADA positive assay response that is not 
considered persistent or indeterminate regardless of any missing samples 
 Treatment boosted response - defined as a positive response in the ADA assay post 
first dose, that is at least 9-fold over baseline titer levels when baseline results are 
positive 
 Titer category for subjects, by maximum ADA titer value: 
 Low (titer <1,000) 
 Moderate (1,000≤ titer ≤10,000) 
 High (titer >10,000) 
 NAb status (positive or negative) 
5.11. 
Analysis of PRO Variables 
Descriptive statistical analyses for the PRO variables defined in Section 4.11 will be summarized 
by treatment group and overall for the study, as well as by treatment group and overall within 
each cohort in the PRO population. 
Only measurements collected within 14 days prior to the protocol scheduled time point (as 
defined by e-CRF visit label) will be assigned to that visit and used for the analyses. If more than 
7 days of data are collected during this period, only 7 days of the data (closest to the visit date) 
will be used.  PRO evaluation at the visit is considered non-missing if a patient completes the 
questionnaire for at least four days for this visit. Missing PRO evaluations will not be imputed. 
A cross-sectional analysis will be performed for each available PRO variable for the SBTP and 
the DBTP. The HAP-SS and HAP-DB domains and total scores including change from baseline 
will be reported at each time point. The number of patients with non-missing values, mean, 
standard deviation, median, Q1, Q3, minimum value, and maximum value will be reported. 
Summaries for the DBTP will be presented by treatment groups (evinacumab, placebo). 
Summaries for the SBTP will be presented by all patients and by treatment group in DBTP (i.e., 
evinacumab, placebo).  
During the DBTP the difference in change score from baseline between the treatment groups will 
be calculated and presented as the number of patients with non-missing values, mean, 95% 
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confidence interval (if data is normally distributed), standard error, median, Q1, Q3, minimum 
value, and maximum value at each time point. No formal inferential testing will be performed. 
Summaries will be descriptive in nature.  
The number and percentage of stomach pain, pain, and abdominal symptom free days, and 
avoidance of meals, at each evaluation/visit (calculated over the seven days prior to the visit), 
will be presented at each time point for all patients (SBTP) and for each treatment arm (DBTP). 
To take account of varying numbers of completed HAP-SS and HAP-DB scores over the seven 
days prior to each visit (minimum number = 4, maximum number = 7), percentage scores will be 
calculated using both a denominator of 7 and a denominator of the number of days of available 
data. 
5.12. 
Analysis of Biomarker Variables 
Descriptive statistical analyses for the biomarker variables defined in Section 4.12 will be 
summarized by treatment group and overall for the study, as well as by treatment group and 
overall within each cohort in the FAS population. 
For descriptive summaries, percent change, and/or when appropriate, absolute change from 
baseline will be provided for biomarker variables at each protocol scheduled time point (as 
defined by e-CRF visit label) for each treatment group. Missing values will not be imputed.  
In addition, all biomarker measurements (scheduled and unscheduled) will be included in patient 
listing. 
6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis.  
6.1. 
Definition of Baseline for Efficacy/Safety Variables 
Unless otherwise specified, the baseline assessment is programmatically defined as the last 
available measurement prior to the date of the first double-blind study treatment administration. 
For patients randomized and not treated, the baseline value is defined as the last available value 
prior to the date of randomization. 
6.2. 
Definition of Cohort Assignment 
Cohort assignment (1,2, and 3) as defined at the time of the analysis will be used for all statistical 
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 and Time of First/Last Study Treatment 
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Since the study drug is administered at the site, the date and time of study drug administration 
are filled in e-CRF. No missing data is expected. Date of first/last administration is the first/last 
start date of study drug filled in e-CRF. 
Adverse Event 
If the intensity of a TEAE is missing, it will be classified as “severe” in the frequency tables by 
intensity of TEAEs. If the assessment of relationship of a TEAE to the investigational product is 
missing, it will be classified as related to the investigational product. 
When the partial AE date/time information does not indicate that the AE started prior to study 
treatment or after the TEAE period, the AE will be classified as treatment-emergent. 
Medication/Procedure 
No imputation of medication/procedure start/end dates or times will be performed.  If a 
medication date or time is missing or partially missing and it cannot be determined whether it 
was taken prior or concomitantly or stopped prior to the first study treatment administration, it 
will be considered as concomitant medication/procedure. 
Potentially Clinically Significant Value (PCSV) 
If a patient has a missing baseline value, this patient will be grouped in the category 
“normal/missing at baseline.” 
For PCSVs with 2 conditions, one based on a change from baseline value and the other on a 
threshold value or a normal range, with the first condition being missing, the PCSV will be based 
only on the second condition. 
For a PCSV defined on a threshold and/or a normal range, this PCSV will be derived using this 
threshold if the normal range is missing; e.g., for eosinophils the PCSV is >0.5 giga/L or >ULN 
if ULN ≥0.5 giga/L.  When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSVs. 
6.4. 
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. 
6.5. 
Statistical Technical Issues 
Not Applicable. 
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7. 
TIMING OF STATISTICAL ANALYSES 
The analyses will be conducted in 2 steps: 
 First step: Main Efficacy and Safety Analysis 
The first analysis will be conducted when all enrolled patients have completed the 
double-blind period. This will consist of the final analysis of the primary and 
secondary endpoints up to week 12. The safety analysis will be performed on all 
safety data collected and validated at the time of the first analysis. 
 Second-step: Final Efficacy and Safety analysis 
The second analysis will be conducted at the end of the study and will consist of the 
final analysis of week 44 efficacy endpoints and final safety analysis 
Interim Analyses  
Interim analyses may be conducted during the course of the study by the unblinded team to 
assess efficacy, safety, and futility.  If the timing of this analysis falls within a few weeks of the 
first-step analysis, only the first-step analysis will be performed. Enrollment (up to a maximum 
of approximately 50 patients) may be halted if the incidence of pancreatitis is much lower than 
anticipated, making the evaluation of a treatment effect on pancreatitis futile. The following 
interim analysis is planned:  
 The interim analysis will be conducted when the first 9 randomized patients have 
been administered study treatment in cohort 1 and have completed the double-blind 
period (i.e., week 12 visit). This will consist of the final data contributing to the 
analysis of the applicable variables up to week 12 for these 9 patients. In general, 
interim analysis will include only limited number of outputs applicable for the small 
sample size. For lipid variables, only descriptive summaries (without within-patient 
tests) in conventional units will be provided. Other variables (defined in 
Section 4.7.3) biomarkers, ECG, and PRO variables will not be included. Imaging 
and PK/ADA may be included in the analyses depending on the availability. For 
general labs and vital signs only PCSV summary tables will be included. The safety 
analysis will be performed for these 9 patients on all safety data collected and 
validated at the time of the first interim analysis. The interim analysis results will be 
used for the future program development. 
The results of the interim analyses will not be used to change the conduct of the 
ongoing study in any aspect. Individuals involved in the interim analysis of the study 
will not be involved in the conduct of the study afterwards; individual patient 
identification will not be released to anyone who is directly involved in the conduct of 
the study.  The interim analysis processes, the measures used to protect the blind and 
the integrity of the study, the communication plan, and the confidentiality agreement 
will be described in separate documents. 
Additional interim analyses may be conducted if decided by the study team. 
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Analyses methods and conventions described in the other sections of this SAP will be applied for 
all analyses as applicable. The following additional rules will apply for analyses performed at 
interim and first step analyses: 
 Patients without end of treatment visit performed at the time of the cut-off date will 
be considered as ongoing and exposed up to the cut-off date. Therefore: 
 Patients who did not complete the respective treatment period nor prematurely 
discontinued the study treatment at cut-off date will be analyzed as “ongoing” in 
the disposition summary. 
 Their TEAE period and treatment period will end at the cut-off date. 
 Their treatment duration will be derived by considering date of cut-off as last 
administration date.  
 Analyses of number of administrations, and mean administration frequency will be 
performed up to the last administration reported in the e-CRF up to the cut-off date.  
 AEs occurring, worsening or becoming serious after the cut-off date will not be 
included in the analyses. However, any available outcome before database lock, 
regardless of timing in relation to the cut-off date, of an adverse event starting prior to 
the cut-off date will be taken into account. Medications, treatment 
discontinuations/completions and deaths occurring after the cut-off date will not be 
included in the analyses.  
 Post-treatment period, and post-study period are not applicable for ongoing patients. 
Analyses of post-treatment AEs, post-study deaths and post-treatment medications 
will be performed for patients who either completed or prematurely discontinued the 
treatment before or at the cut-off date. 
 Analysis of status at last study contact and proportion of patients with insufficient 
follow-up will be provided for patients who either completed or prematurely 
discontinued the treatment before or at the cut-off date. 
8. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or higher. 
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9. 
REFERENCES 
1. ICH. (1996, July 30). ICH Harmonized tripartite guideline: Structure and content of 
clinical study reports (E3). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
2. ICH. (1997, July 17). ICH Harmonized tripartite guideline: General considerations for 
clinical trials (E8). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
3. ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for 
clinical trials (E9). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
4. Klauss M, Maier-Hein K, Tjaden C, Hackert T, Grenacher L, Stieltjes B. IVIM DW-MRI 
of autoimmune pancreatitis: therapy monitoring and differentiation from pancreatic 
cancer. Eur Radiol. 2015 DOI 10.1007/s00330-015-4041-4. 
5. Shigekawa M, Yamao K, Sawaki A, Hara K, Takagi T, Bhatia V, Nishio M, Tamaki T, 
El-Amin H, Sayed Zel A, Mizuno N. Is (18)F-fluorodeoxyglucose positron emission 
tomography meaningful for estimating the efficacy of corticosteroid therapy in patients 
with autoimmune pancreatitis? J Hepatobiliary Pancreat Sci. 2010 17(3): 269-274. 
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10. 
APPENDIX 
10.1. 
Summary of Statistical Analyses 
Primary Efficacy Analysis: 
Endpoint 
Analysis 
Population 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Percent lowering of TG levels 
from 
baseline 
following 
12 weeks of repeated IV doses 
of evinacumab in the subset of 
patients with a documented 
history 
of 
sHTG 
(TG 
>1000 mg/dL [11.3 mmol/L]), a 
TG level of at least 500 mg/dL 
(5.6 mmol/L) at screening, a 
history of acute pancreatitis, and 
without LOF mutations in genes 
in the LPL pathway.  
 
 FAS 
MMRM 
 No 
Yes 
 
No 
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10.2. 
List of AESIs with Data Sources and Definitions of SMQ/CMQ  
AESI 
Using an e-CRF specific 
tick box on AE page 
Using Standard MedDRA Query (SMQ)/company 
MedDRA Query (CMQ) or lab data 
Anaphylactic reactions   
 
Yes 
No 
General allergic events  No 
SMQ “hypersensitivity” (broad and narrow) excluding the 
following preferred terms linked to local injection site 
reactions (“infusion site dermatitis”, “infusion site 
hypersensitivity”, “infusion site rash”, “infusion site 
urticaria”, “injection site dermatitis”, “injection site 
hypersensitivity”, “injection site rash”, “injection site 
urticaria”, “injection site vasculitis”) plus “idiopathic 
angioedema” 
Infusion reactions  
Yes 
No 
Pregnancy 
Yes 
No 
Symptomatic overdose 
with investigational 
medicinal product 
Yes 
No 
Neurocognitive events 
No 
CMQ for neurocognitive events as defined based on 
Regulatory Agency request for another lipid lowering 
program (See Table 4 in Appendix 10.2 for the list of terms) 
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New onset of diabetes 
(NOD) 
No 
 
At least 2 values of HbA1c ≥6.5% during the 
TEAE period. NOTE: For patients with only a 
single measurement available during the TEAE 
period, a single value ≥6.5% will be considered 
and qualify the patient as NOD by default. For 
patients with several HbA1c measurements but 
only with the last one ≥6.5%, this single value 
≥6.5% will be considered and qualify the patient as 
NOD by default. 
OR 
 
At least 2 values of fasting glucose ≥126 mg/dL 
(7.0 mmol/L). NOTE: For patients with only a 
single measurement available during the TEAE 
period, a single value ≥126 mg/dL (7.0 mmol/L) 
will NOT be considered and will NOT qualify the 
patient as NOD. For patients with several fasting 
glucose measurements but only with the last one 
≥126 mg/dL (7.0 mmol/L), this single value ≥ 126 
mg/dL (7.0 mmol/L) will NOT be considered and 
will NOT qualify the patient as NOD. 
Pancreatitis 
Yes 
No 
 
Table 4 CMQ “Neurocognitive disorders – FDA’s recommendation” 
MedDRA level 
MedDRA Term Label 
PTCD 
Amnesia 
PTCD 
Amnestic disorder 
PTCD 
Anterograde Amnesia 
PTCD 
Behavioural and Psychiatric Symptoms of Dementia 
PTCD 
Change in sustained attention 
LLTCD 
Cognitive Deterioration 
PTCD 
Cognitive Disorder 
LLTCD 
Confusion 
LLTCD 
Confusion Aggravated 
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MedDRA level 
MedDRA Term Label 
PTCD 
Confusional State 
PTCD 
Delirium 
PTCD 
Dementia 
PTCD 
Dementia Alzheimer's type 
LLTCD 
Dementia Nos 
LLTCD 
Dementia Nos Aggravated 
LLTCD 
Dementia of the Alzheimer's type NOS 
PTCD 
Dementia with Lewy Bodies 
PTCD 
Disorientation 
PTCD 
Disturbance in attention 
PTCD 
Executive dysfunction 
PTCD 
Frontotemporal Dementia 
LLTCD 
Global Amnesia 
PTCD 
Illogical Thinking 
PTCD 
Impaired reasoning 
PTCD 
Incoherent 
PTCD 
Judgement impaired 
PTCD 
Memory Impairment 
PTCD 
Mental Impairment 
LLTCD 
Mental Impairment Nos 
LLTCD 
Mental State Abnormal Aggravated 
PTCD 
Mental Status Changes 
PTCD 
Mini Mental Status Examination Abnormal 
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MedDRA level 
MedDRA Term Label 
PTCD 
Presenile Dementia 
PTCD 
Retrograde Amnesia 
PTCD 
Senile Dementia 
LLTCD 
Senile Dementia Nos 
LLTCD 
Short-term Memory Loss 
PTCD 
Thinking Abnormal 
LLTCD 
Thinking Slowed 
PTCD 
Transient Global Amnesia 
PTCD 
Vascular Dementia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10.3. 
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 
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 
CrCl (mL/min) 
(Estimated creatinine 
clearance based on the 
Cokcroft-Gault equation) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
eGFR (mL/min/1.73m2) 
(Estimate of GFR based on 
an MDRD equation)  
 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
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Parameter 
PCSV 
Uric Acid 
   Hyperuricemia: 
   Hypouricemia: 
 
>408 µmol/L 
<120 µmol/L 
Blood Urea Nitrogen 
≥17 mmol/L 
Chloride 
<80 mmol/L 
>115 mmol/L 
Sodium 
129 mmol/L 
 160 mmol/L 
Potassium 
< 3  mmol/L 
 5.5 mmol/L 
Glucose 
   Hypoglycaemia 
   Hyperglycaemia 
 
 3.9 mmol/L and < LLN 
  7 mmol/L (fasted);  11.1 mmol/L (unfasted) 
HbA1c 
>8% 
Albumin 
≤25 g/L 
CRP 
> 2 ULN or 
 >10 mg/L, if ULN not provided 
Hematology 
WBC 
< 3.0 Giga/L (3000/ mm3) (Non-Black) 
< 2.0 Giga/L (2000/ mm3) (Black) 
≥16.0 Giga/L (16000/ mm3) 
 
Lymphocytes 
>4.0 Giga/L 
Neutrophils 
< 1.5 Giga/L (1500/ mm3) (Non-Black) 
< 1.0 Giga/L (1000/ mm3) (Black) 
Monocytes 
>0.7 Giga/L 
Eosinophils 
> 0.5 Giga/L (500/ mm3) 
or > ULN if ULN  0.5 Giga/L 
Hemoglobin 
≤115 g/L (Male); ≤95 g/L (Female) 
≥185 g/L (Male); ≥165 g/L (Female) 
Decrease from Baseline ≥15 g/L 
Decrease from Baseline ≥20 g/L 
 
Hematocrit 
≤0.37 v/v (Male) ; ≤0.32 v/v (Female) 
≥0.55 v/v (Male) ; ≥0.5 v/v (Female) 
RBC 
≥6 Tera/L 
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Parameter 
PCSV 
Platelets 
< 100 Giga/L (100 000/mm3) 
≥700 Giga/L (700000/mm3) 
Urinalysis 
pH 
≤4.6 
≥8 
Vital signs 
HR 
 50 bpm and decrease from baseline  20 bpm 
 120 bpm and increase from baseline  20 bpm 
SBP 
 95 mmHg and decrease from baseline  20 mmHg 
 160 mmHg and increase from baseline  20 mmHg 
DBP 
Young and elderly patients 
 45 mmHg and decrease from baseline  10 mmHg 
 110 mmHg and increase from baseline  10 mmHg 
Weight 
5% increase versus baseline 
5% decrease versus baseline 
ECG parameters 
HR 
 50 bpm and decrease from baseline  20 bpm 
 120 bpm and increase from baseline  20 bpm 
PR 
≥220 ms and increase from baseline ≥20 ms 
QRS 
 120 ms 
QTc 
Borderline 
Prolonged* 
Additional 
Absolute values (ms) 
Borderline  
      431-450 ms (Male) 
      451-470 ms (Female) 
Prolonged* 
       > 450 ms (Male)        
       > 470 ms (Female) 
       QTc   ≥500 ms            
 
Increase versus baseline (Males and Females) 
Borderline 
 30-60 ms 
Prolonged * 
 > 60 ms 
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10.4. 
Schedule of Time and Events 
Table 1: 
Schedule of Events 
 
Screening Period 
Placebo run-
in1/ Baseline 
Double-Blind Treatment Period2 
Single-Blind Treatment 
Period3 
Study Procedure 
Visit 
1 
Visit 
1b4 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
105 
Visit 
11 
Visit 
12 
End of 
Treat-
ment 
Visit 13 
Day 
-66 to 
-59 
-58 to  
-52 
-51 to  
-39 
-28 
+4d 
-14 
± 4d 
1 
± 4d 
15 
± 4d 
29 
± 4d 
43 
± 4d 
57 
± 4d 
85 
± 4d 
113 
± 4d 
141 
± 4d 
169 
± 5d 
Week 
 
 
 
 
 
0 
2 
4 
6 
8 
12 
16 
20 
24 
Screening/Baseline: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FT4, TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (for women only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/PTT, INR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort Assignment 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Heparin7 
 
 
X8 
 
 
 
 
 
 
 
 
 
 
X 
Administer Placebo 
 
 
 
X9,10 
 
 
 
 
 
 
 
 
 
 
Administer Study Drug (evinacumab or 
placebo) 
 
 
 
 
 
X9,10 
 
X9,10 
 
X9,10 
 
 
 
 
Administer evinacumab 
 
 
 
 
 
 
 
 
 
 
X9,10 
X9,10 
X9,10 
 
Concomitant Medications and treatment 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipids and lipoproteins11,12 
X13 
X13 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HbA1c, Insulin, C-peptide, and Homa11 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
Post-heparin LPL, endothelial lipase (EL), 
hepatic lipase (HL) activity assay and HL mass 
assay11 
 
 
X14 
 
 
 
 
 
 
 
 
 
 
X 
Pre-heparin LPL and EL mass assay11 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Train/dispense ePRO device 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Daily Symptom Questionnaire 
 
 
 
X 
 
X16 
 
X16 
 
X16 
X16 
X16 
X16 
X16 
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Screening Period 
Placebo run-
in1/ Baseline 
Double-Blind Treatment Period2 
Single-Blind Treatment 
Period3 
Study Procedure 
Visit 
1 
Visit 
1b4 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
105 
Visit 
11 
Visit 
12 
End of 
Treat-
ment 
Visit 13 
Day 
-66 to 
-59 
-58 to  
-52 
-51 to  
-39 
-28 
+4d 
-14 
± 4d 
1 
± 4d 
15 
± 4d 
29 
± 4d 
43 
± 4d 
57 
± 4d 
85 
± 4d 
113 
± 4d 
141 
± 4d 
169 
± 5d 
Week 
 
 
 
 
 
0 
2 
4 
6 
8 
12 
16 
20 
24 
(Hypertriglyceridemia and Acute Pancreatitis 
Signs and Symptoms)15 
Symptom/Dietary Impact Questionnaire 
(Hypertriglyceridemia and Acute Pancreatitis 
Dietary Behavior)15 
 
 
 
X 
 
X16 
 
X16 
 
X16 
X16 
X16 
X16 
X16 
Site review of questionnaires for compliance 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Safety: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
 
X 
X10 
X 
X10 
X 
X10 
X 
X10 
X10 
X10 
X10 
X 
Physical Examination 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
Weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram17 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Adverse Events18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Confirm required contraception use and 
reminder of pregnancy status reporting in 
women of child bearing potential and female 
partners of male patients19 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology11 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Chemistry11 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test 
serum 
 
 
urine 
 
urine 
 
urine 
 
urine 
urine 
urine 
urine 
serum 
Urinalysis 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
Imaging and Other Assessments:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DW-MRI20  
 
 
 
X 
X 
 
 
 
 
 
X 
 
 
X 
18F-FDG-PET20 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
PK/Drug Concentration and ADA Samples: 
 
PK/Drug conc. Sample21 
 
 
 
 
 
X22 
 
X22 
 
X22 
X22 
 
X22 
X 
ADA sample 
 
 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
Biomarkers: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker serum/plasma 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Amylase, lipase11 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Statistical Analysis Plan                                                                                                                                                Date: May 17, 2019 
 
Regeneron Pharmaceuticals Inc.                                                                                                                                          Page 59 of 62 
CONFIDENTIAL 
 
Screening Period 
Placebo run-
in1/ Baseline 
Double-Blind Treatment Period2 
Single-Blind Treatment 
Period3 
Study Procedure 
Visit 
1 
Visit 
1b4 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
105 
Visit 
11 
Visit 
12 
End of 
Treat-
ment 
Visit 13 
Day 
-66 to 
-59 
-58 to  
-52 
-51 to  
-39 
-28 
+4d 
-14 
± 4d 
1 
± 4d 
15 
± 4d 
29 
± 4d 
43 
± 4d 
57 
± 4d 
85 
± 4d 
113 
± 4d 
141 
± 4d 
169 
± 5d 
Week 
 
 
 
 
 
0 
2 
4 
6 
8 
12 
16 
20 
24 
APOC2, APOC3, APOA5, NEFA11 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Inflammation Panel (eg, IL-1, IL-6, IL-8, 
TNFα) 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
hs-CRP 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
Lipid sub-fractions by UC  
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Genomic DNA sample: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood DNA sample 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
                                        VV-RIM-00078988-1.0 Approved - 20 May 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc.                                                                                                             Protocol: R1500-HTG-1522 4GB 
Statistical Analysis Plan                                                                                                                                                Date: May 17, 2019 
 
Regeneron Pharmaceuticals Inc.                                                                                                                                          Page 60 of 62 
CONFIDENTIAL 
Schedule of Events (continued) 
 
Off-Drug Treatment Follow-Up Period 
Study Procedure 
Visit 14 
Phone Call 
Visit 16 
Phone Call 
End of Study 
Visit 18 
Day 
197± 5d 
225± 5d 
253± 5d 
281± 5d 
309± 5d 
Week(s) 
28 
32 
36 
40 
44 
Treatment: 
 
 
 
 
 
Concomitant Medications and treatment 
X 
X 
X 
X 
X 
Efficacy: 
 
 
 
 
 
Lipids and lipoproteins11,12 
X 
 
X 
 
X 
HbA1c, Insulin, C-peptide, and Homa11 
 
 
 
 
X 
Daily Symptom Questionnaire (Hypertriglyceridemia and Acute 
Pancreatitis Signs and Symptoms)15 
X16 
 
X16 
 
X16 
Symptom/Dietary Impact Questionnaire (Hypertriglyceridemia and 
Acute Pancreatitis Dietary Behavior)15 
X 
 
X 
 
X 
Site review of responses to questionnaires 
X 
 
X 
 
X 
Safety: 
 
 
 
 
 
Vital Signs 
X 
 
X 
 
X 
Physical Examination 
 
 
 
 
X 
Weight 
X 
 
X 
 
X 
Electrocardiogram17 
 
 
 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
Confirm required contraception use and reminder of pregnancy status 
reporting in women of child bearing potential and female partners of 
male patients19 
X 
X 
X 
X 
X 
Laboratory Testing: 
 
 
 
 
 
Hematology11 
X 
 
X 
 
X 
Blood Chemistry11 
X 
 
X 
 
X 
Pregnancy Test19 
Urine 
Urine 
urine 
urine 
serum 
Urinalysis 
 
 
 
 
X 
Imaging and Other Assessments:  
 
 
 
 
 
Amylase, lipase11 
X 
 
X 
 
X 
PK/Drug Concentration and ADA Samples: 
 
 
 
 
 
PK/Drug conc. Sample21 
X 
 
X 
 
X 
ADA sample 23 
 
 
 
 
X 
Biomarkers: 
 
 
 
 
 
Inflammation Panel (eg, IL-1, IL-6, IL-8, TNFα) 
 
 
 
 
X 
hs-CRP 
 
 
 
 
X 
                                        VV-RIM-00078988-1.0 Approved - 20 May 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R1500-HTG-1522 4GB 
Statistical Analysis Plan 
Date: May 17, 2019 
 
Regeneron Pharmaceuticals Inc.                                                                              Page 61 of 62 
CONFIDENTIAL 
10.4.1. 
Footnotes for the Schedule of Events Table  
1. Patients who are permanently withdrawn from study drug before entering the 
double-blind treatment period (day 1, week 0) will be contacted to assess any AEs. 
2. Patients who are permanently withdrawn from the study drug during double-blind period 
will be asked to return to the clinic for an early termination visit consisting of week 12 
study assessments. After the early termination visit, patients will enter the off-drug 
treatment follow-up period. 
3. Patients who are permanently withdrawn from study drug during the single-blind 
treatment period will be asked to return to the clinic for an early termination visit 
consisting of week 24 study assessments. After the early termination visit, patients will 
enter the off-drug treatment follow-up period. 
4. Visit 1b must occur at least 4 days after visit 1. 
5. Patients will undergo end of double-blind treatment period assessments at the week 12 
visit, which is the first visit of administration of single-blind evinacumab. 
6. Medical history should include detailed cardiovascular and pancreatitis history. 
7. The patient should be fasting for at least 8 hours prior to the post-heparin procedure for 
measurement of LPL activity. The patient should not consume any alcohol 48 hours prior 
to the post-heparin plasma blood draw. Heparin (60 U/kg body weight) should be 
administered IV by bolus injection. Venous blood should be collected 10 minutes after 
the bolus injection. Prior to discharge from the clinic, patients should then be observed 
for 1 hour post-heparin administration for any AEs. 
8. Following the screening period and confirmation of eligibility, patients will receive an 
IV bolus of 60 IU of heparin per kg of body weight at visit 2. 
9. At dosing visits, all assessments (including urine or serum pregnancy tests for WOCBP) 
should be performed and all blood samples should be collected before the dose of study 
drug is administered. 
10. Vital signs should also be measured and AEs monitored pre-dose, at the end of study 
drug infusion, between 30 to 60 minutes post dose, and at approximately 120 minutes 
post dose. Patients will be closely monitored for a minimum of 120 minutes after 
IV administration of study drug. 
11. Patients should fast for a minimum of 8 hours prior to all blood draws. For patients with 
diabetes, investigators may hold a patient’s morning diabetes medications until labs are 
drawn and the patient has eaten. 
12. Lipids and lipoproteins, total cholesterol, LDL-C, HDL-C, TG, APOB, APOA1, and 
Lp(a) will be measured except at visit 1 and 1b. 
13. At visit 1 and visit 1b, only total cholesterol, LDL-C, HDL-C, and TG will be measured. 
14. Lipoprotein lipase level enzyme activity will be measured in fasting plasma collected at 
visit 2 only after eligibility has been confirmed by screening procedures at visit 1 and 
visit 1b. 
                                        VV-RIM-00078988-1.0 Approved - 20 May 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R1500-HTG-1522 4GB 
Statistical Analysis Plan 
Date: May 17, 2019 
 
Regeneron Pharmaceuticals Inc.                                                                              Page 62 of 62 
CONFIDENTIAL 
15. Questionnaires should be completed daily for 7 days prior to each visit except for visit 3 
(to be completed daily for the duration between visit 2 and visit 3). 
16. Patients should be reminded by phone call 1 week prior to their visit to complete 
questionnaires. 
17. Electrocardiogram should be performed before blood is drawn during visits that require 
blood draws. 
18. In addition to assessment of adverse events at each visit, investigators should also ask 
patients if they have had any changes in abdominal symptoms and/or medical clinic visits 
for abdominal symptoms. 
19. Confirm required contraception use and pregnancy status of female patients of 
childbearing potential and female partners (of child-bearing potential) of male patients 
will be monitored at clinic visits and by phone call for 24 weeks post the last dose of 
study drug. Women of childbearing potential will be provided urine pregnancy tests with 
instructions to test for pregnancy on days corresponding to phone call visits or Q4W if 
patients do not attend regularly scheduled visits. 
20. Imaging may be performed up to 1 week prior to the visit and may be on the same day of 
the visit (for visit 3, MRI can be done on the same day or up to 4 days after visit 3). If 
done on the day of the visit, vital signs, ECG and blood draws after an 8-hour fast should 
be completed prior to the imaging procedures. Imaging procedures should be performed 
prior to study drug infusion. 
21. PK samples will also be used for the analysis of total ANGPTL3. 
22. In addition to the PK sample collected prior to drug administration, a PK sample should 
be obtained immediately after the end of each infusion. 
 
 
                                        VV-RIM-00078988-1.0 Approved - 20 May 2019 GMT-5:00


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                                        VV-RIM-00078988-1.0 Approved - 20 May 2019 GMT-5:00