A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Alirocumab in Patients With Homozygous Familial Hypercholesterolemia
Phase: PHASE3
Conditions: Homozygous Familial Hypercholesterolemia
Sponsor: Regeneron Pharmaceuticals

IND Number: 105574 
EudraCT: 2017-000351-95 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP STUDY TO EVALUATE THE EFFICACY AND 
SAFETY OF ALIROCUMAB IN PATIENTS WITH HOMOZYGOUS 
FAMILIAL HYPERCHOLESTEROLEMIA  
Compound: 
Alirocumab (Praluent®) 
Study Name 
ODYSSEY HoFH 
Clinical Phase: 
3b 
Protocol Number: 
R727-CL-1628 
Protocol Version: 
R727-CL-1628 Amendment 3 
Amendment 3 Date of Issue: 
See appended electronic signature page 
Amendment 2 Date of Issue: 
11 Jul 2017 
Amendment 1 Date of Issue: 
29 Mar 2017 
Original Date of Issue: 
08 Feb 2017 
Scientific/Medical Monitor: 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
 
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NCT03156621

Clinical Study Protocol 
R727-CL-1628 Amendment 3 
 
Regeneron Pharmaceuticals, Inc. 
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CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 3 
The table below summarizes the changes to the protocol and the affected sections. 
Rationale for Change 
Sections Changed  
To increase the number of patients from 54 to 
approximately 74, the protocol includes a 
provision to re-estimate the sample size after 
approximately 75% of the patients reach the 
week 12 visit in the double-blind treatment 
period to ensure adequate power in case of a 
larger-than-expected variability in the data.  The 
sample size adjustment process was 
implemented and due to the variability observed, 
a decision was made to increase the sample size. 
Clinical Study Protocol Synopsis:  Study design 
Clinical Study Protocol Synopsis: Population 
Clinical Study Protocol Synopsis: Statistical Plan 
Section 5.1 Study Description and Duration 
Section 6.1 Number of Patients Planned 
Section 10.2 Justification of Sample Size 
 
The ITT population definition is revised to 
remove the requirement of a post-baseline 
measurement (ie, “availability of at least 1 
measurement value for LDL-C within 1 of the 
analysis windows in the double-blind period up 
to week 12”), per regulatory agency feedback. 
Section 10.3.1 Efficacy Analysis Sets 
Added a reference to footnote 6 for the PK 
sample. 
Table 1 Schedule of Events 
 
Amendment 2 
The table below summarizes the changes to the protocol and the affected sections. 
Rationale for Change 
Sections Changed  
Added EQ-5D QOL questionnaire and an 
EQ-5D objective and exploratory endpoint to 
allow assessment of quality of life in this 
population 
Section 2.3 Other Objectives 
Section 4.2.4 Other Endpoints 
Table 1 Schedule of Events 
Section 8.2.3.1 EuroQol-5 Questionnaire 
Exclude adolescents as a separate pediatric study 
is planned 
Clinical Study Protocol Synopsis: Study Design, Population, and 
Procedures & Assessments 
Section 3.2.1 Rationale for Study Design 
Section 3.2.2 Rationale for Dose Selection 
Section 4.2.3 Safety Endpoints 
Section 6.2 Study Population 
Section 6.2.1 Inclusion Criteria 
Section 6.2.2 Exclusion Criteria 
Table 1 Schedule of Events 
Section 8.1.1 Footnotes for Schedule of Events Table 
Section 8.2.4.2 Physical Examination 
Section 10.4.1 Patients Disposition 
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CONFIDENTIAL 
Rationale for Change 
Sections Changed  
Section 13 Audits and Inspections 
Section 14.2 Informed Consent 
Section 14.3 Patient Confidentiality and Data Protection 
Section 14.4 Institutional Review Board/Ethics Committee 
Section 15 Protocol Amendments 
Section 17.2 Retention of Records 
Modified ADA variables to align with other 
studies 
Section 4.4 Anti-Drug Antibody Variables 
Section 10.3.4 Other Analysis Sets 
Extended the treatment-emergent adverse event 
(TEAE) period from +21 days to +70 days to 
obtain additional safety information since 
alirocumab has not been studied previously in 
patients with HoFH 
Section 8.1.2 Early Termination Visit 
Section 10.4.4.1 Adverse Events 
Clarified language for apheresis requirements 
and collection of clinical laboratory samples 
relative to the timing of apheresis procedures 
Section 5.1 Study Description and Duration 
Section 6.2.1 Inclusion Criteria #4 
Section 7.3 Run-in (optional) and Background Treatment(s) 
Section 8.1.1 Footnotes for Schedule of Events Table 
Added a criterion excluding patients with 
LDL-C level <70 mg/dL as this is the goal for 
FH patients. Consequently, patients already at 
goal will be excluded. 
Added criterion excluding members of the 
clinical site study team and/or his/her immediate 
family 
Section 6.2.2 Exclusion Criteria 
Added an instruction for a follow-up call at 
week 32 to capture AEs and concomitant 
medications because the TEAE period was 
extended from +21 days to +70 days (10 weeks) 
and added 8-week follow-up period for patients 
not continuing in another lipid lowering study 
Clinical Study Protocol Synopsis 
Section 5.1 Study Description and Duration 
Figure 1 Study Flow Diagram 
Table 1 Schedule of Events 
Section 8.1.1 Footnotes for Schedule of Events Table 
Added provision for a retention manual to be 
provided to the sites to improve adherence with 
assessments as planned in the protocol and 
minimize missing data for patients who 
discontinue the study treatment early 
Section 6.3 Premature Withdrawal from the Study 
Section 7.4.2 Study Drug Discontinuation 
Section 8.1.2 Early Termination Visit 
Added assessment for hepatitis C to end of 
double-blind treatment period and end of open-
label treatment period to assess for 
seroconversion 
Section 8.1 Schedule of Events 
Section 8.2.1 Procedures Performed Only at the 
Screening/Baseline Visit  
Section 8.2.4.4 Laboratory Testing 
Provided a definition for “new onset diabetes” 
as this is an adverse event of special interest 
(AESI) 
Section 9.3.3 Adverse Events of Special Interest 
Clarified text concerning availability of 
additional studies after completion of the open-
label treatment period into which patients may 
Section 5.1 Study Description and Duration 
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CONFIDENTIAL 
Rationale for Change 
Sections Changed  
choose to enroll and continue to receive 
alirocumab 
Updated description of the method to account 
for missing data 
Section 10.4.3.1 Primary Efficacy Analysis 
Edits/Clarifications 
Section 1 Introduction 
Section 3.2.1 Rationale for Study Design 
Section 5.1.1 End of Study Definition 
Section 6.2.1 Inclusion Criteria 
Section 6.2.2 Exclusion Criteria 
Section 9.3.3 Adverse Events of Special Interest 
Section 10.4.4.1 Adverse Events 
Amendment 1 
The purpose of this amendment is to update the following areas: add a blinded sample size 
adjustment to the statistical methods, refine the diagnostic criteria for HoFH, update the safety 
monitoring of adolescents by adding additional assessments, require mutation status for those on 
LDL apheresis to be known prior to screening, correct inconsistencies, and make additional 
editorial changes throughout the protocol. 
The statistical methods section on justification of sample size is being updated to allow for a 
blinded sample size adjustment.  During the study, the actual blinded pooled standard deviation for 
LDL-C will be determined by an independent, unblinded statistician and, if a larger-than-expected 
standard deviation is observed, a sample size re-estimation analysis will be performed.  This 
analysis will not be binding and any potential changes to the sample size will be implemented 
through a protocol amendment. 
The inclusion/exclusion criteria are being updated to allow the inclusion of patients considered to 
be double heterozygotes, defined as having different mutations on 2 different alleles affecting 
LDLR function.  These patients, along with true homozygotes and compound heterozygotes, are 
considered to be part of the patient population defining HoFH.  Additionally, the use of skin 
fibroblast LDL receptor activity as part of the clinical criteria to diagnosis HoFH is being removed 
based on feedback that the assessment is rarely done in clinical practice. 
The safety monitoring of adolescents is being updated to add an additional height assessment at 
the end of the study and assess Tanner stages throughout the double-blind and open-label treatment 
periods. 
The genotyping requirement is being updated such that for all patients on LDL apheresis whose 
HoFH genotype status is unknown prior to enrollment, it should be determined prior to entering 
the screening period.  This change is being made to mitigate the risk of inadvertently enrolling a 
patient with null/null mutations in both LDLR alleles. 
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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................14 
1. 
INTRODUCTION ......................................................................................................16 
2. 
STUDY OBJECTIVES ..............................................................................................18 
2.1. 
Primary Objective .......................................................................................................18 
2.2. 
Secondary Objective(s) ...............................................................................................18 
2.3. 
Other Objectives .........................................................................................................18 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................18 
3.1. 
Hypothesis ..................................................................................................................18 
3.2. 
Rationale .....................................................................................................................19 
3.2.1. 
Rationale for Study Design .........................................................................................19 
3.2.2. 
Rationale for Dose Selection ......................................................................................19 
3.2.3. 
Benefit / Risk Assessment ..........................................................................................20 
4. 
STUDY VARIABLES................................................................................................21 
4.1. 
Demographic and Baseline Characteristics ................................................................21 
4.2. 
Primary and Secondary Endpoints..............................................................................21 
4.2.1. 
Primary Endpoint ........................................................................................................21 
4.2.2. 
Secondary Efficacy Endpoints ....................................................................................21 
4.2.2.1. 
Key Secondary Efficacy Endpoints ............................................................................21 
4.2.2.2. 
Other Secondary Efficacy Endpoints ..........................................................................22 
4.2.3. 
Safety Endpoints .........................................................................................................22 
4.2.4. 
Other Endpoints ..........................................................................................................22 
4.3. 
Pharmacokinetic Variables .........................................................................................22 
4.4. 
Anti-Drug Antibody Variables ...................................................................................23 
5. 
STUDY DESIGN .......................................................................................................24 
5.1. 
Study Description and Duration .................................................................................24 
5.1.1. 
End of Study Definition ..............................................................................................26 
5.2. 
Planned Interim Analysis ............................................................................................26 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............26 
6.1. 
Number of Patients Planned .......................................................................................26 
6.1.1. 
Rescreening of Patients ...............................................................................................26 
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6.2. 
Study Population .........................................................................................................26 
6.2.1. 
Inclusion Criteria ........................................................................................................26 
6.2.2. 
Exclusion Criteria .......................................................................................................27 
6.3. 
Premature Withdrawal from the Study .......................................................................30 
6.4. 
Replacement of Patients .............................................................................................30 
7. 
STUDY TREATMENTS............................................................................................30 
7.1. 
Injection Training .......................................................................................................30 
7.2. 
Investigational and Reference Treatments ..................................................................31 
7.3. 
Run-in (optional) and Background Treatment(s) .......................................................31 
7.4. 
Dose Modification and Study Treatment Discontinuation Rules ...............................32 
7.4.1. 
Dose Modification ......................................................................................................32 
7.4.2. 
Study Drug Discontinuation .......................................................................................32 
7.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................32 
7.4.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................33 
7.5. 
Management of Acute Reactions ................................................................................33 
7.5.1. 
Acute Injection Reactions ...........................................................................................33 
7.5.1.1. 
Systemic Injection Reactions ......................................................................................33 
7.6. 
Method of Treatment Assignment ..............................................................................33 
7.6.1. 
Blinding ......................................................................................................................33 
7.6.2. 
Emergency Unblinding ...............................................................................................34 
7.7. 
Treatment Logistics and Accountability .....................................................................34 
7.7.1. 
Packaging, Labeling, and Storage ..............................................................................34 
7.7.2. 
Supply and Disposition of Treatments .......................................................................35 
7.7.3. 
Treatment Accountability ...........................................................................................35 
7.7.4. 
Treatment Compliance ................................................................................................36 
7.8. 
Concomitant Medications ...........................................................................................36 
7.8.1. 
Prohibited Medications and Procedures .....................................................................36 
7.8.2. 
Permitted Medications and Procedures ......................................................................36 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................37 
8.1. 
Schedule of Events .....................................................................................................37 
8.1.1. 
Footnotes for the Schedule of Events Table ...............................................................41 
8.1.2. 
Early Termination Visit ..............................................................................................41 
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8.1.3. 
Unscheduled Visits .....................................................................................................42 
8.2. 
Study Procedures ........................................................................................................42 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................42 
8.2.2. 
Efficacy Procedures ....................................................................................................42 
8.2.2.1. 
Lipid Panel ..................................................................................................................43 
8.2.3. 
Quality of Life Procedures ..........................................................................................43 
8.2.3.1. 
EuroQol-5 Questionnaire ............................................................................................43 
8.2.4. 
Safety Procedures .......................................................................................................43 
8.2.4.1. 
Vital Signs ..................................................................................................................43 
8.2.4.2. 
Physical Examination .................................................................................................43 
8.2.4.3. 
Electrocardiogram .......................................................................................................43 
8.2.4.4. 
Laboratory Testing ......................................................................................................43 
8.2.5. 
Pharmacokinetic and Anti-Drug Antibody Procedures ..............................................45 
8.2.5.1. 
Drug Concentration Measurements and Samples .......................................................45 
8.2.5.2. 
Anti-Drug Antibody Measurements and Samples ......................................................45 
8.2.6. 
HoFH Genetic Testing ................................................................................................45 
8.2.7. 
Research Samples .......................................................................................................45 
8.2.7.1. 
Biomarker Procedures ................................................................................................45 
 
 
 
 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................46 
9.1. 
Obligations of Investigator .........................................................................................46 
9.2. 
Obligations of Sponsor ...............................................................................................46 
9.3. 
Definitions ..................................................................................................................47 
9.3.1. 
Adverse Event .............................................................................................................47 
9.3.2. 
Serious Adverse Event ................................................................................................47 
9.3.3. 
Adverse Events of Special Interest .............................................................................48 
9.4. 
Recording and Reporting Adverse Events ..................................................................49 
9.4.1. 
Adverse Events ...........................................................................................................49 
9.4.2. 
Serious Adverse Events ..............................................................................................49 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor ...................................50 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................50 
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9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results .............................50 
9.4.6. 
Follow-up ....................................................................................................................51 
9.5. 
Evaluation of Severity and Causality .........................................................................51 
9.5.1. 
Evaluation of Severity ................................................................................................51 
9.5.2. 
Evaluation of Causality ...............................................................................................52 
9.6. 
Safety Monitoring .......................................................................................................53 
9.7. 
Investigator Alert Notification ....................................................................................53 
10. 
STATISTICAL PLAN................................................................................................53 
10.1. 
Statistical Hypothesis ..................................................................................................54 
10.2. 
Justification of Sample Size........................................................................................54 
10.3. 
Analysis Sets ...............................................................................................................55 
10.3.1. 
Efficacy Analysis Sets ................................................................................................55 
10.3.2. 
Safety Analysis Set .....................................................................................................55 
10.3.3. 
The Open-Label Analysis Set .....................................................................................55 
10.3.4. 
Other Analysis Sets .....................................................................................................56 
10.4. 
Statistical Methods ......................................................................................................56 
10.4.1. 
Patients Disposition ....................................................................................................56 
10.4.2. 
Demography and Baseline Characteristics .................................................................56 
10.4.3. 
Efficacy Analyses .......................................................................................................57 
10.4.3.1. 
Primary Efficacy Analysis ..........................................................................................57 
10.4.3.2. 
Secondary Efficacy Analysis ......................................................................................57 
10.4.3.3. 
Other Efficacy Endpoints ...........................................................................................59 
10.4.3.4. 
Multiplicity Considerations ........................................................................................59 
10.4.4. 
Safety Analysis ...........................................................................................................59 
10.4.4.1. 
Adverse Events ...........................................................................................................59 
10.4.4.2. 
Laboratory Data and Vital Signs ................................................................................61 
10.4.4.3. 
Treatment Exposure ....................................................................................................62 
10.4.4.4. 
Treatment Compliance ................................................................................................62 
10.4.5. 
Analysis of Drug Concentration Data .........................................................................63 
10.4.6. 
Analysis of Pharmacodynamics Data .........................................................................63 
10.4.7. 
Analysis of Anti-Drug Antibody Data ........................................................................63 
10.5. 
Timing of Statistical Analysis ....................................................................................63 
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10.6. 
Additional Statistical Data Handling Conventions .....................................................63 
10.7. 
Statistical Considerations Surrounding the Premature Termination of a Study .........64 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS .....................................64 
11.1. 
Data Management .......................................................................................................64 
11.2. 
Electronic Systems ......................................................................................................64 
12. 
STUDY MONITORING ............................................................................................64 
12.1. 
Monitoring of Study Sites ...........................................................................................64 
12.2. 
Source Document Requirements ................................................................................64 
12.3. 
Case Report Form Requirements ................................................................................65 
13. 
AUDITS AND INSPECTIONS .................................................................................65 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................65 
14.1. 
Good Clinical Practice Statement ...............................................................................65 
14.2. 
Informed Consent/Assent ...........................................................................................66 
14.3. 
Patient Confidentiality and Data Protection ...............................................................66 
14.4. 
Institutional Review Board/Ethics Committee ...........................................................66 
15. 
PROTOCOL AMENDMENTS ..................................................................................67 
16. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................67 
16.1. 
Premature Termination of the Study ...........................................................................67 
16.2. 
Close-out of a Site ......................................................................................................67 
17. 
STUDY DOCUMENTATION ...................................................................................68 
17.1. 
Certification of Accuracy of Data ...............................................................................68 
17.2. 
Retention of Records ..................................................................................................68 
18. 
CONFIDENTIALITY ................................................................................................68 
19. 
FINANCING AND INSURANCE .............................................................................68 
20. 
PUBLICATION POLICY ..........................................................................................68 
21. 
REFERENCES ...........................................................................................................69 
22. 
INVESTIGATOR’S AGREEMENT ..........................................................................71 
 
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LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................38 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................26 
 
LIST OF APPENDICES 
Appendix 1: Factors to Consider in Assessing the Relationship of Adverse Events to 
Study Drug and Study Conduct or Injection Procedure, Study Procedure, or 
Background Treatment, etc. ........................................................................................72 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to 
Evaluate the Efficacy and Safety of Alirocumab in Patients with 
Homozygous Familial Hypercholesterolemia 
Site Location(s) 
Multinational  
Multicenter  
Objective(s) 
Primary Objective 
The primary objective of the study is to demonstrate the reduction of 
low-density lipoprotein cholesterol (LDL-C) with alirocumab 150 mg 
subcutaneous (SC) every 2 weeks (Q2W) in comparison to placebo after 12 
weeks of treatment. 
Secondary Objective(s) 
The secondary objectives of the study are: 
 
To evaluate the effect of alirocumab 150 mg Q2W on other lipid 
parameters (ie, apolipoprotein [Apo] A-1 and B, non-high-density 
lipoprotein cholesterol [non-HDL-C], total-cholesterol [TC], 
proportion of patients with 15%, 30%, and 50% LDL-C reductions, 
Lp(a), HDL-C, triglycerides [TG]) in patients with HoFH 
 
To evaluate the safety and tolerability of alirocumab 150 mg SC 
Q2W in patients with HoFH 
 
To assess the pharmacokinetics of alirocumab 150 mg SC Q2W in 
patients with HoFH 
 
To assess the potential development of anti-drug (alirocumab) 
antibodies 
Study Design 
This is a randomized, double-blind, placebo-controlled, parallel-group study 
to evaluate the efficacy and safety of alirocumab in patients with HoFH. 
Approximately 74 patients will be randomized in a 2:1 ratio to receive either 
alirocumab 150 mg SC Q2W or matching placebo.  Randomization will be 
stratified by apheresis treatment status.  
The study will consist of up to 4 periods:  a 4-week optional run-in, a 2-
week screening period, a 12-week double-blind treatment period, and a 
mandatory 12-week open-label treatment period.  Patients not continuing on 
to another lipid-lowering study will also undergo an 8-week follow-up 
period. 
The optional run-in will last up to 4 weeks and will be available for those 
patients whose background therapy or apheresis schedule and/or apheresis 
settings have not been stable prior to screening. Additionally, all patients on 
LDL apheresis must be diagnosed based on genotype and, if genotype 
information has not been determined previously, they can enter the run-in to 
allow time, if needed, to determine their mutation status. 
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The 2-week screening period will be used to determine eligibility and 
provide training on appropriate SC injection techniques.  
All patients who meet the inclusion criteria and none of the exclusion criteria 
will enter the 12-week double-blind treatment period.  The first injection of 
double-blind study drug will occur on day 1 (baseline), and the last injection 
of double-blind study drug will occur on day 71 (week 10).  
Following the completion of the 12-week double-blind treatment period, all 
patients will enter a 12-week open-label treatment period.  The first injection 
of open-label alirocumab will occur on day 85 (week 12) and the last 
injection of open-label alirocumab will occur on day 155/week 22.  After 
completion of the 12-week open-label treatment period, all patients who 
have successfully completed this study may have the opportunity to 
participate in an additional lipid-lowering clinical trial.  
Study Duration 
This is a 24-week study, excluding the optional 4-week run-in period and 
the 2-week screening period. 
Population 
The study population will consist of male and female patients, ≥18 years of 
age diagnosed with HoFH. 
 
Sample Size: 
Approximately 74 patients 
 
Target Population: 
Males and females ≥18 years of age diagnosed with HoFH, except patients 
known to have null/null mutations in both LDLR alleles. 
Treatment(s) 
 
 
Study Drug 
 
Dose/Route/Schedule: 
Alirocumab 150 mg SC every 2 weeks from day 1 through week 12 (end of 
double-blind treatment period, last double-blind injection at week 10).  
Regardless of treatment assignment in the double-blind treatment period, all 
patients will receive open-label alirocumab 150 mg SC Q2W starting at 
week 12 and continuing through week 24 (last injection in the open-label 
period at week 22). 
 
Reference Drug 
 
Dose/Route/Schedule: 
Placebo SC Q2W 
 
Background 
Treatment 
 
Dose/Route/Schedule: 
Not Applicable 
Endpoint(s) 
 
 
Primary: 
The primary endpoint is the percent change in LDL-C from baseline to 
Week 12. 
 
Secondary: 
 
The percent change in Apo B from baseline to week 12 (intent-to-
treat [ITT] estimand). 
 
The percent change in non-HDL-C from baseline to week 12 
(ITT estimand). 
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 
The percent change in TC from baseline to week 12 (ITT estimand). 
 
Proportion of patients with ≥15% reduction in LDL-C at week 12 
(ITT estimand). 
 
Proportion of patients with ≥30% reduction in LDL-C at week 12 
(ITT estimand). 
 
The percent change in Lp(a) from baseline to week 12 
(ITT estimand). 
 
Proportion of patients with ≥50% reduction in LDL-C at week 12 
(ITT estimand). 
 
The percent change in HDL-C from baseline to week 12 
(ITT estimand). 
 
The percent change in fasting TG from baseline to week 12 
(ITT estimand). 
 
The percent change in Apo A-1 from baseline to week 12 
(ITT estimand). 
Procedures and Assessments 
The efficacy of alirocumab will be assessed by clinical laboratory evaluation 
of lipid levels.  
Overall 
safety 
will 
be 
assessed 
by 
monitoring/evaluation 
of 
treatment-emergent adverse events, physical examinations, vital signs, 
electrocardiograms, and clinical safety laboratory tests at specified time 
points.  
Blood samples will be collected for determination of alirocumab 
concentration and anti-alirocumab antibody levels at predetermined time 
points.  Research samples will be collected. 
Statistical Plan 
Patients will be randomized in the double-blind treatment period to 
alirocumab or placebo in a ratio of 2:1 respectively, with the primary 
efficacy hypothesis comparing the alirocumab-treated group to the placebo 
group at week 12.  For the primary efficacy hypothesis during the 
double-blind treatment period, an initial total sample size of 51 patients (34 
patients in the alirocumab-treated group and 17 patients in the placebo 
group) will have 90% power to detect a difference in mean percent change 
in LDL-C of 20%, with a two-sided significance level and assuming a 
standard deviation of 20%.  Taking into account a 5% non-evaluable patient 
rate for the primary efficacy endpoint, the initial study sample size is 
increased to 54 patients (36 patients in the alirocumab-treated group and 18 
patients in the placebo group). 
Following the Blinded Sample Size Adjustment process, the total study 
sample size will increase to approximately 74 patients, adding 
approximately 20 patients to the initial study sample size. 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
Apo 
Apolipoprotein 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
BW 
Body weight 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic) 
CRO 
Contract research organization 
CV 
Cardiovascular 
CVD 
Cardiovascular disease 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EOS 
End of the study 
FH 
Familial hypercholesterolemia 
GCP 
Good Clinical Practice 
HDL-C 
High-density lipoprotein cholesterol 
HeFH 
Heterozygous familial hypercholesterolemia  
HoFH 
Homozygous familial hypercholesterolemia 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IVRS/IWRS 
Interactive voice response system/ Interactive web response system 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LDL-C 
Low-density lipoprotein cholesterol 
LDLR 
Low-density lipoprotein receptor 
LDLRAP1 
LDL receptor adaptor protein 1 
LMT 
Lipid Modifying Therapy 
Lp(a) 
Lipoprotein(a) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 
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mITT 
Modified intent-to-treat 
MMRM 
Mixed-effect model with repeated measures 
NOD 
New onset of diabetes 
OTC 
Over-the-counter  
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PK 
Pharmacokinetic 
PT 
Preferred term 
Q2W 
Every 2 weeks 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Software 
SC 
Subcutaneous 
SD 
Standard deviation 
SOC 
System organ class 
TC 
Total cholesterol 
TEAE 
Treatment-emergent adverse event 
TG 
Triglycerides 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
WBC 
White blood cell 
 
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1. 
INTRODUCTION 
Familial hypercholesterolemia (FH) is an inherited disorder of lipid metabolism that predisposes 
a person to premature severe cardiovascular disease (CVD) (Kolansky 2008).  It can be either an 
autosomal dominant or an autosomal recessive disease that results from mutations in the 
low-density lipoprotein receptor (LDLR), or in 3 associated genes: proprotein convertase 
subtilisin/kexin type 9 (PCSK9), apolipoprotein B (Apo B), and LDL receptor adaptor protein 1 
(LDLRAP1), with a similar phenotype and varying severity.  Mutations in LDLR, PCSK9, and 
Apo B have a dominant mode of transmission, while mutations in LDLRAP1 have a recessive 
mode of transmission (http://omim.org/entry/143890, http://omim.org/entry/603813). 
Homozygous familial hypercholesterolemia (HoFH) is a rare, serious condition genetically 
defined to include individuals with the same mutation(s) in both LDLR, ApoB, or PCSK9 alleles 
(true homozygotes), different mutations in each allele of the same gene (compound heterozygotes), 
or different mutations on different genes (double heterozygotes).  Phenotypically, the severity of 
HoFH depends on the amount of residual LDLR activity, historically categorized as either 
receptor-negative (<2% of normal LDLR activity) or receptor-defective (2% to 25% of normal 
LDLR activity) based on the amount of activity in skin fibroblasts.  The genetic definition used in 
the current study will include all individuals considered to be true homozygotes, compound 
heterozygotes, or double heterozygotes.  However, those individuals with null LDLR mutations in 
both alleles will be excluded because it is expected that alirocumab will not be efficacious in those 
patients, as has already been shown with another PCSK9 inhibitor, evolocumab (Raal 2015). 
Patients with HoFH have severe hypercholesterolemia (500-1000 mg/dL, 12.95-25.9 mmol/L), 
resulting in lifelong exposure to high levels of plasma LDL-C and increased risk of developing 
atherosclerosis at a highly accelerated rate, often manifesting within the first 2 decades of life. 
Persistently high levels of LDL-C can also lead to cutaneous and tendon xanthomas, valvular and 
supravalvular stenosis (Kolansky 2008).  This accelerated atherosclerosis results in premature 
cardiovascular disease (CVD) and an increased risk of a cardiovascular (CV) event.  A recent 
observational study of HoFH patients demonstrated that the mean age for first major CV event was 
20 years (Kolansky 2008). 
The initial goal of drug therapy in adult patients with FH is to achieve LDL-C reduction ≥50% 
(Goldberg 2011).  If this is achieved, therapy is escalated with an aim to achieve an LDL-C of 
<100 mg/dL (2.59 mmol/L) in the absence of coronary artery disease or other major risk factors 
or <70 mg/dL (<1.81 mmol/L) in the presence of coronary artery disease or other major risk factors 
(Watts 2014).  However, management of elevated LDL-C in patients with HoFH is challenging 
with the current existing treatment options.  Patients with HoFH generally have a poor response to 
conventional drug therapies, resulting in extremely elevated LDL-C levels that are often refractory 
to pharmacologic management thus requiring the need to initiate LDL apheresis. 
Statins inhibit cholesterol synthesis by inhibiting 3-hydroxy-3-methyl-glutaryl coenzyme 
reductase and are used as first-line therapy in HoFH patients because they have been proven to 
reduce CV mortality in non-FH patients. High-dose statins have demonstrated a mean reduction 
in LDL-C of 18-22% in patients with HoFH (Lipitor Product insert, Crestor Product insert, 
Zocor Product insert).  Compare this with the 50-60% reductions seen in the non-FH population; 
it is clear that patients with mutations resulting in little or no LDL receptor function may not have 
as robust a response to statins. Patients with HoFH tend to be refractory to statins because the 
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mechanism of action generally lowers LDL-C levels through up-regulation of the hepatic LDL 
receptor.  Nonetheless, despite the near total loss of functional LDL receptors in HoFH patients, 
statins are still used as first line therapy in order to maximize residual receptor activity (Raal 2000, 
Marais 2008, Raal 1997). 
Ezetimibe, a cholesterol absorption inhibitor has been shown to provide an additional 14-21% 
LDL-C reduction when added to high dose statins (Gagné 2002), but many patients treated with 
the combination of high dose statin and ezetimibe remain far from their target LDL-C.  Newer 
therapies, i.e., mipomersen and lomitapide, have been approved for use in patients with HoFH, 
and can provide an additional ~25% and 40% reduction in LDL-C, respectively, when used along 
with other LMTs).  However, these new therapies are not commercially available in all countries 
and are associated with increases in hepatic fat content, elevated markers of liver injury, frequent 
injection site reactions that can be of severe intensity (mipomersen) or poorly tolerated 
gastrointestinal adverse effects (lomitapide) (Raal 2010, Cuchel 2013). 
Mechanical removal of LDL-C using LDL apheresis is an option, but may lower the quality of life 
in patients and present other challenges (Schiel 1995).  Low-density lipoprotein apheresis is a 
costly procedure that is invasive and burdensome for patients.  Many patients must travel a 
significant distance for this procedure, which is administered over 3 hours and must be given every 
week to every 4 weeks, depending on the patient’s LDL-C level and CV risk.  In addition, this 
procedure may require placement of a shunt for frequent vascular access, although peripheral veins 
are used for vascular access in approximately 85% of cases.  Low-density lipoprotein apheresis is 
generally well tolerated, but may result in hypotension, hypocalcemia, allergic reactions, and an 
acute decrease in serum protein levels.  The quality of life in patients undergoing apheresis in 
addition to lipid-lowering drugs was lower compared with patients treated only with lipid-lowering 
drugs (Schiel 1995).  Patients on a LMT regimen who require apheresis to lower LDL-C, may 
benefit from the addition of alirocumab to their current LDL-C lowering therapies by reducing or 
eliminating the need for apheresis. 
Recently, 2 PCSK9 inhibitors (alirocumab and evolocumab) have been approved to lower LDL-C 
in patients with heterozygous familial hypercholesterolemia (HeFH) and one PCSK9 inhibitor 
(evolocumab) has been approved to lower LDL-C in patients with HoFH (Praluent Product insert, 
Repatha Product insert).  In the non-FH and HeFH patient populations, the addition of alirocumab 
on top of background LMT resulted in LDL-C reductions of 45-60%.  For example, in the Odyssey 
FH 1 and FH 2 studies comparing alirocumab on top of maximally tolerated statins (with or without 
other LMTs, including ezetimibe) in patients with HeFH and LDL-C ≥70 mg/dL with a history of 
myocardial infarction (MI)/stroke or LDL-C ≥100 mg/dL without a history of MI/stroke, treatment 
with alirocumab reduced LDL-C by up to a mean of 48.8% after 24 weeks (Kastelein 2015).  
Efficacy with another PCSK9 inhibitor, evolocumab, has also been seen in the difficult-to-treat 
HoFH population, although the response has not been as robust.  The TESLA-B study compared 
evolocumab on top of statins (with or without other LMTs, including ezetimibe) in patients with 
HoFH and showed a mean percent reduction in LDL-C at week 12 of 23.1%. (Raal 2015).  
Additionally, because PCSK9 inhibitors reduce LDL-C by increasing the number of hepatic LDL 
receptors, evolocumab therapy did not reduce LDL-C in patients with LDL receptor-negative 
mutations in both alleles (Raal 2015, Repatha Product Insert). 
The primary purpose of this study is to evaluate the efficacy, safety and tolerability of alirocumab 
in patients with HoFH (excluding those patients with null/null mutations in both LDLR alleles). 
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Additional background information on the investigational study drug and development program is 
provided in the Investigator's Brochure.  For countries where alirocumab is approved, additional 
information can be found in the local country's prescribing information. 
2. 
STUDY OBJECTIVES  
2.1. 
Primary Objective 
The primary objective of the study is to demonstrate the reduction of LDL-C with alirocumab 
150 mg subcutaneous (SC) every 2 weeks (Q2W) in comparison to placebo after 12 weeks of 
treatment. 
2.2. 
Secondary Objective(s) 
The secondary objectives of the study are: 
 To evaluate the effect of alirocumab 150 mg Q2W on other lipid parameters (i.e., 
apolipoprotein [Apo] A-1 and B, non-high-density lipoprotein cholesterol 
[non-HDL-C], total cholesterol [TC], proportion of patients with 15%, 30%, and 50% 
LDL-C reductions, Lp(a), HDL-C, triglycerides [TG]) in patients with HoFH 
 To evaluate the safety and tolerability of alirocumab 150 mg SC Q2W in patients with 
HoFH 
 To assess the pharmacokinetics (PK) of alirocumab 150 mg SC Q2W in patients with 
HoFH 
 To assess the potential development of anti-drug (alirocumab) antibodies 
2.3. 
Other Objectives 
 Genotype information will be collected for all patients to characterize HoFH mutation 
status in order to explore potential differences in efficacy and safety 
 To assess the effect of alirocumab on eligibility for apheresis (using German and US 
apheresis criteria) 
 To assess the effect of alirocumab on quality of life using the EQ-5D QOL 
questionnaire 
3. 
HYPOTHESIS AND RATIONALE  
3.1. 
Hypothesis 
Treatment with alirocumab for 12 weeks will result in a greater percent reduction in LDL-C from 
baseline than placebo treatment in patients with HoFH who are not already receiving PCSK9 
targeted therapy. 
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3.2. 
Rationale 
3.2.1. 
Rationale for Study Design 
Patients with HoFH have persistently elevated LDL-C, which is a contributing factor to a number 
of health concerns, principally accelerated atherosclerosis resulting in premature CV disease.  
Despite treatment with LMTs such as pharmacological agents including statins, and mechanical 
removal of lipids by LDL apheresis, many patients with HoFH remain far from their LDL-C 
treatment goal.  In a cohort study, the age of first CVD event was in the third decade of life in 
HoFH (Raal 2011).  While this is later than the early teen years as seen before implementation of 
medical regimens such as statins, the need for more intensive treatments remain in order to delay 
the onset of CVD and occurrence of events. 
This study is intended to demonstrate the efficacy and safety of alirocumab in patients with HoFH.  
The study population will include individuals ≥18 years of age.  Diagnosis of HoFH will be based 
on either genotyping data or clinical criteria.  The genetic definition will include all individuals 
considered to be true homozygotes, compound heterozygotes, or double heterozygotes for 
mutations in the LDLR, ApoB, PCSK9, or LDLRAP1 genes.  In this study, however, individuals 
with history null/null LDLR mutations will be excluded because PCSK9 inhibitors, including 
alirocumab, will not be efficacious in those patients.  This was confirmed in the evolocumab HoFH 
study (TESLA-B, TASSIG), where patients with null/null LDLR mutation status were treated with 
evolocumab, but did not have any response or had a minimal response to treatment. 
Percent change in LDL-C from baseline will be the primary endpoint.  Low-density lipoprotein 
cholesterol is an accepted surrogate endpoint for CV risk and has repeatedly been used as the 
primary endpoint for approval of multiple other HoFH treatments.  This study is designed as a 
placebo controlled trial with the addition of alirocumab on top of patients’ existing treatment 
regimens of maximally tolerated LMT, including lipid apheresis.  This study will utilize an 
optional run-in period for those patients that have not yet achieved a stable background treatment 
regimen that will be required to be maintained throughout the double-blind treatment period.  An 
add-on design is appropriate because removal of any therapies from the patient’s existing treatment 
regimen will lead to an increase in LDL-C and possibly contribute to the serious CV sequelae seen 
in this disease.  Treatment duration of 12 weeks for the primary endpoint will allow alirocumab to 
achieve steady state and exert its full effect on LDL-C.  An additional 12-week open-label 
treatment period in which all patients will be administered alirocumab will allow further 
assessment of safety in this population. 
3.2.2. 
Rationale for Dose Selection 
Alirocumab 75 mg and 150 mg SC Q2W are the approved doses and is currently authorized in 40 
countries worldwide (including the US, European Union, Canada, Norway, Iceland, Brazil, and 
Japan).  The 150 mg SC Q2W dose has demonstrated saturation of free PCSK9 through the dosing 
interval and provides maximum efficacy.  The need for a higher starting dose in hard-to-treat 
patients as characterized by a higher baseline LDL-C was seen in the Odyssey FH1, FH2 and 
HIGH FH studies.  The Odyssey FH1 and FH2 studies enrolled patients with HeFH not controlled 
on maximally tolerated statins (with or without ezetimibe) and evaluated the addition of 
alirocumab 75 mg SC Q2W, with a possible up-titration to 150 mg SC Q2W, on LDL-C.  
Approximately 40% of the patients needed their dose titrated from 75 mg SC Q2W to 150 mg SC 
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Q2W, and the need for titration was a reflection of the baseline LDL-C value.  Patients requiring 
up-titration had a mean LDL-C of 160 mg/dL (4.14 mmol/L) at baseline vs. 118 mg/dL (3.05 
mmol/L) in those patients not requiring titration.  The Odyssey HIGH FH study included patients 
with HeFH receiving maximally tolerated statin therapy and baseline LDL-C levels ≥160 mg/dL 
(4.14 mmol/L) and used a starting dose of 150 mg SC Q2W.  At this higher starting dose, 
alirocumab was able to reduce LDL-C by approximately 45.7% from baseline (Ginsberg 2016).  
Because patients with HoFH are proven to be a hard-to-treat population compared to non-FH and 
HeFH patients and will have a very high baseline LDL-C far from their target level, the dose of 
alirocumab proposed for this study is the highest approved dose, 150 mg SC Q2W. 
In addition to being efficacious, alirocumab has a favorable safety profile.  Overall, the most 
commonly occurring treatment-emergent adverse events (TEAEs), reported in a higher proportion 
of patients in the alirocumab group compared to placebo (ie, incidence ≥2.0% in the alirocumab 
group) were: injection site reaction (7.2% vs 5.1%), nasopharyngitis (11.3% vs 11.1%), influenza 
(5.7% vs 4.6%), myalgia (4.3% vs 3.4%), urinary tract infection (4.8% vs 4.6%), diarrhea (4.7% 
vs 4.4%) and bronchitis (4.3% vs 3.8%) (Praluent Product Insert).  No differences in the safety 
profile have been observed between the two approved doses of 75 mg and 150 mg.  
It is expected that treatment with alirocumab 150 mg Q2W in patients with HoFH already receiving 
maximally tolerated LMT or LDL apheresis will be well-tolerated and have an acceptable safety 
profile while providing maximal LDL-C lowering effect. 
3.2.3. 
Benefit / Risk Assessment  
Patients with HoFH have extremely high LDL-C levels, are far from their target LDL-C, and will 
require significant reductions in LDL-C.  Despite the approval of newer treatments including 
lomitapide and mipomersen, the need for more intensive therapies remain.  PCSK9 inhibitors are 
a new addition to the armamentarium of LMT that has proven to profoundly decrease LDL-C.  In 
TESLA-B, evolocumab on top of statins (with or without ezetimibe) in patients with HoFH showed 
a 23.1% mean reduction in LDL-C at week 12 (Raal 2014).  In the Odyssey HIGH FH study, 
alirocumab reduced LDL-C by approximately 45.7% in patients with HeFH receiving maximally 
tolerated statin therapy and baseline LDL-C levels ≥160 mg/dL (4.14 mmol/L) (Ginsberg 2016).  
Based on these data, it is expected that the addition of alirocumab to existing treatments will lead 
to significant LDL-C reductions in the HoFH population.  The body of evidence from the statin 
literature shows that the relationship between LDL-C reduction and CV event reduction is 
approximately linear and for every 1 mmol/L (38.7 mg/dL) reduction in LDL-C there is a 
corresponding 22% risk reduction in CV events (Cholesterol Treatment Trialists’ Collaboration 
2010).  Within the context of this study in the HoFH patient population, even a modest reduction 
in LDL-C may translate into significant benefit for these patients. 
It is also expected that treatment with alirocumab will be well tolerated and have an acceptable 
safety profile.  The accumulated safety information show that the most commonly occurring 
TEAEs with alirocumab were nasopharyngitis, injection site reactions, influenza, myalgia, 
musculoskeletal pain, and contusion.  Moreover, the rates of these adverse events (AEs) were 
relatively low, ranging from 11.3% to 2.1% for the alirocumab treatment group (vs 11.1% - 1.6% 
in the placebo group) (Praluent Product Insert). 
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Taken together, these data show that the benefit/risk assessment of treatment with alirocumab in 
the HoFH populations is favorable.  
4. 
STUDY VARIABLES  
4.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (age, race, weight, height, etc), disease 
characteristics including lipid levels, mutation status, medical history, medication history and 
apheresis schedule (if applicable) for each patient. 
4.2. 
Primary and Secondary Endpoints 
4.2.1. 
Primary Endpoint 
The primary efficacy endpoint is the percent change in LDL-C from baseline to week 12 in the 
ITT population for alirocumab 150 mg Q2W as compared with placebo in patients with HoFH.  
The percent change in LDL-C from baseline to week 12 is defined as:  
100 x (LDL-C value at week 12 -LDL-C value at baseline) 
LDL-C value at baseline 
For LDL-C analysis, both calculated and measured LDL-C values will be taken into account.  In 
case both calculated and measured LDL-C values are available for the same sampling time point, 
the measured LDL-C will be considered.  The baseline LDL-C value will be the last LDL-C value 
obtained before the first dose of double-blind-study drug. For randomized but not-treated patients, 
baseline will be defined as the last value before randomization.  The LDL-C at week 12 will be 
the LDL-C value obtained within the week 12 analysis window, regardless of adherence to 
treatment (ITT estimand). 
All calculated and measured LDL-C values (scheduled or unscheduled, fasting or not fasting) may 
be used for the primary efficacy endpoint, if appropriate, according to the above definition.  The 
analysis window used to allocate a time point to a measurement will be defined in the statistical 
analysis plan (SAP). 
4.2.2. 
Secondary Efficacy Endpoints 
4.2.2.1. 
Key Secondary Efficacy Endpoints 
 The percent change in Apo B from baseline to week 12 (ITT estimand). 
 The percent change in non-HDL-C from baseline to week 12 (ITT estimand). 
 The percent change in total cholesterol from baseline to week 12 (ITT estimand). 
 Proportion of patients with ≥15% reduction in LDL-C at week 12 (ITT estimand). 
 Proportion of patients with ≥30% reduction in LDL-C at week 12 (ITT estimand). 
 The percent change in Lp(a) from baseline to week 12 (ITT estimand). 
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 Proportion of patients with ≥50% reduction in LDL-C at week 12 (ITT estimand). 
 The percent change in HDL-C from baseline to week 12 (ITT estimand). 
 The percent change in fasting TG from baseline to week 12 (ITT estimand). 
 The percent change in Apo A-1 from baseline to week 12 (ITT estimand). 
The same definition and rules apply to these key secondary efficacy endpoints as are applied to 
the primary efficacy endpoint.  
4.2.2.2. 
Other Secondary Efficacy Endpoints 
 The percent change in LDL-C from baseline to week 12 in the modified (m)ITT 
population (Section 10.3.1), using all LDL-C values within the week 12 analysis 
window and during the efficacy treatment period (on-treatment estimand). 
 The percent change in Apo B, non-HDL-C, TC, Lp(a), HDL-C, fasting TG and Apo 
A-1 from baseline to week 12 (on-treatment estimand). 
 Proportion of patients with ≥15% reduction, ≥30% reduction, and ≥50% reduction in 
LDL-C at week 12 (on treatment estimand). 
 The absolute change in the ratio of Apo B/Apo A-1 from baseline to week 12 (ITT 
estimand). 
The efficacy treatment period is defined as the time from the first double-blind study drug injection 
up to 21 days after the last double-blind study drug injection, or the first open-label alirocumab 
injection (if applicable), whichever comes first. 
4.2.3. 
Safety Endpoints 
 Safety parameters (AEs, laboratory data, vital signs, and electrocardiogram [ECG]) 
assessed throughout the study. 
4.2.4. 
Other Endpoints 
 Exploratory relationships between HoFH genotype status and lipid parameters. 
 The change in the proportion of patients who meet US apheresis eligibility criteria 
from baseline to week 12 (Goldberg 2011). 
 The change in the proportion of patients who meet German apheresis eligibility 
criteria from baseline to week 12 (Schettler 2012). 
 Response of each EQ-5D item, index score, and change of index score from baseline 
through week 12. 
4.3. 
Pharmacokinetic Variables 
The PK variable will be alirocumab serum concentration collected at specified sampling time. 
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4.4. 
Anti-Drug Antibody Variables 
Anti-drug (alirocumab) antibody status will be assessed. 
 Total patients negative in the ADA assay at all time points. 
 Pre-existing immunoreactivity - defined as either an anti-drug antibody (ADA) positive 
response in the assay at baseline with all post-dose ADA results negative, OR a positive 
response at baseline with all post-treatment ADA responses less than 4-fold baseline 
titer levels. 
 Treatment emergent - defined as either any post-dose positive ADA response when 
baseline results are negative, OR any post-dose positive ADA response that is at least 
4-fold over the baseline level when baseline is positive in the ADA assay. 
Samples positive in the ADA assay will be assessed for titer. 
 Titer category 
 Low (titer <1,000) 
 Moderate (1,000≤ titer ≤10,000) 
 High (titer >10,000) 
Samples positive in the ADA assay will be assessed for neutralizing activity. 
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5. 
STUDY DESIGN 
5.1. 
Study Description and Duration 
This is a randomized, double-blind, placebo-controlled, parallel-group study to evaluate the 
efficacy and safety of alirocumab in patients with HoFH. 
Approximately 74 patients will be randomized in a 2:1 ratio to receive either alirocumab 150 mg 
SC Q2W or matching placebo.  Randomization will be stratified by apheresis treatment status 
(Yes/No).  
The study will consist of up to 4 periods: an optional 4-week run-in period (for patients whose 
background medical LMT regimen or apheresis schedule and/or apheresis settings have not been 
stable prior to screening), a 2-week screening period, a 12-week double-blind treatment period, 
and a mandatory 12-week open-label treatment period (Figure 1).  Patients not continuing on to 
another lipid lowering study will also undergo an 8-week follow-up period. 
Optional Run-in: 
Apheresis therapy - Patients who are undergoing apheresis therapy must be on a stable weekly or 
every other week schedule.  Patients whose schedule or apheresis settings that have not been stable 
for at least 8 weeks before the screening visit will enter a 4-week run-in period before the screening 
period. After the 4-week run-in period, patients whose lipid-apheresis schedule/settings remain 
stable (and have been stable for at least 8 weeks in total) will be eligible to enter the 2-week 
screening period.  Additionally, all patients on LDL apheresis must be diagnosed based on 
genotype and, if genotype information has not been determined previously, they can enter the run-
in to allow time, if needed, to determine their mutation status. 
Lipid-modifying therapy - Patients who are on background LMT that has not been stable for at 
least 4 weeks before the screening visit will enter a 4-week run-in period to stabilize their LMT 
before entering the screening period.  Patients who have not been on a stable dose of mipomersen 
for 6 months prior to screening or on a maximum tolerated dose of lomitapide for 12 weeks prior 
to screening are excluded. 
Screening: 
Once on a stable background regimen as defined above, patients will enter a 2-week screening 
period.  Initial eligibility will be determined during this screening period by standard screening 
procedures.  A DNA sample will be collected for HoFH mutation status. 
Patients should be on a stable low fat or heart-healthy diet throughout the duration of the study, 
starting at screening through the end of the double-blind treatment period and through the 
open-label treatment period. 
Patients’ exercise regimen should remain stable throughout the duration of the study, from 
screening, through the end of the double-blind treatment period and through the open-label 
treatment period. 
The patient or caregiver will be trained to self-inject/inject using a dose of placebo during the 
screening period or at the first visit of the double-blind treatment period. 
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Double-blind Treatment: 
Patients who meet all inclusion criteria and who meet none of the exclusion criteria will be 
randomized in a 2:1 ratio to receive: 
alirocumab 150 mg SC Q2W 
OR 
matching placebo SC Q2W 
Study drug administration during the double-blind treatment period will start on the day of 
randomization and will be administered immediately after completion of the LDL apheresis 
procedure (if applicable).  For those patients not undergoing LDL apheresis, administration of 
study drug must be made after all samples for clinical laboratory evaluation have been obtained.  
The last injection during the double-blind treatment period will be on day 71/week 10. 
For all patients undergoing LDL apheresis, all samples for clinical laboratory evaluation must be 
obtained immediately prior to the LDL apheresis procedure and prior to administration of study 
drug.  Given the impact of LDL apheresis on lipid parameters, it is important to match the time of 
the baseline activities with the timing of the week 12 activities.  This would mean that timing 
between the baseline sample collection relative to the most recently completed LDL apheresis 
procedure should match the timing of the week 12 sample collection relative to the most recently 
completed LDL apheresis procedure. 
For all patients who are not undergoing apheresis, all samples for clinical laboratory evaluation 
must be obtained prior to administration of investigational medical product.  The efficacy of 
alirocumab will be assessed by clinical laboratory evaluation of lipid levels at pre-specified time 
points throughout the study. 
Patients who are receiving LMT or who are undergoing apheresis should maintain stable LMT and 
a stable apheresis schedule (as applicable) throughout the duration of the study, from screening 
through the end of the open-label treatment period/end-of-study visit (week 24). 
Patients who prematurely discontinue study drug during the double-blind treatment period should 
be encouraged to remain in the study and undergo all double-blind study visits and procedures 
with the exception of dosing with study drug.  At the time of study drug discontinuation, the patient 
should have, as soon as possible, an unscheduled visit with assessments normally planned at the 
end of the double-blind treatment visit (this should take place within 5 days of discontinuation of 
study drug, if possible). 
Open-label Treatment: 
To provide further safety data in this rare patient population, all patients will participate in an open-
label treatment period.  Regardless of treatment assignment in the double-blind treatment period, 
patients will receive open-label study drug (alirocumab 150 mg SC Q2W) starting at week 12 (day 
85) and continuing through week 24 (end of open-label treatment period, last injection of study 
drug on day 155/week 22).  Patients who are receiving LMT or who are undergoing LDL apheresis 
should continue a stable dose and regimen and a stable LDL apheresis schedule and settings (as 
applicable) throughout the duration of the open-label treatment period. 
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Upon completion of the open-label treatment period, the sponsor may offer each patient the 
opportunity to participate in an additional lipid-lowering clinical trial.  The patient and investigator 
may decline participation in further treatment trials. 
Patients who do not participate in another lipid-lowering study will undergo an 8-week follow-up 
period.  A follow-up phone call will be made at week 32 (corresponding to the 70 day follow-up) 
to collect AE and concomitant medication information. 
Figure 1: 
Study Flow Diagram 
 
Optional 
Run-in 
Screening 
Double-Blind 
Treatment 
Open-Label Treatment 
Follow-up Phone Call 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
 
End of Double-Blind 
 
End of Open-Label 
End of Study 
(Day -42) 
(Day –14) 
(Day 1) 
 
(Day 85) 
 
(Day 169) 
(Day 225) 
5.1.1. 
End of Study Definition 
The end of study definition for this study is the last visit of the last patient. 
5.2. 
Planned Interim Analysis  
No interim analysis is planned. 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
6.1. 
Number of Patients Planned 
Approximately 74 patients with a 2:1 randomization to alirocumab and placebo are planned. 
6.1.1. 
Rescreening of Patients 
Patients who do not meet eligibility criteria during the initial screening may rescreen only once.  
Patients who are rescreened after the screening window ends must re-consent for study 
participation and repeat all screening procedures. 
Patients who do not meet all eligibility criteria during the initial screening, and are still within the 
screening window, may retest those assessments that did not meet eligibility criteria once.  
6.2. 
Study Population  
The study population will consist of male and female patients, ≥18 years of age diagnosed with 
HoFH, except patients known to have null/null mutations in both LDLR alleles.  
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 years of age at the time of the screening visit.  
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2. Diagnosis of HoFH by at least 1 of the following genotype or clinical criteria (all patients 
on LDL apheresis must be diagnosed based on genotype): 
a. Documented homozygous or compound heterozygous mutations in both LDLR alleles 
Note: Patients with known null mutations in both LDLR alleles are excluded (see 
Exclusion Criteria) 
b. Presence of homozygous or compound heterozygous mutations in Apo B, PCSK9 or 
LDLRAP1 
c. Presence of double heterozygous mutations, ie, mutations on different genes in the 
LDLR, Apo B or PCSK9 alleles  
d. Untreated TC >500 mg/dL (12.93 mmol/L) and TG <300 mg/dL (3.39 mmol/L) 
AND 
Both parents with history of TC >250 mg/dL (6.46 mmol/L) OR cutaneous or 
tendinous xanthoma before age 10 
3. Receiving a stable dose of a statin at the screening visit 
Note:  Patients who are not able to tolerate a statin or if statins were found to be ineffective 
may be included in the study but the reason should be documented in the case report form 
(CRF). 
4. If undergoing LDL apheresis, must have initiated LDL apheresis at least 3 months prior to 
screening and must have been on a stable weekly (every 7 days) or every other week (every 
14 days) schedule or stable settings for at least 8 weeks 
5. Willing to maintain a stable low fat or heart-healthy diet for the duration of the study 
6. Willing and able to comply with clinic visits and study related procedures 
7. Provide signed informed consent 
6.2.2. 
Exclusion Criteria  
A patient who meets any of the following criteria will be excluded from the study: 
1. Documented evidence of a null mutation in both LDLR alleles 
2. Use of a PCSK9 inhibitor within 10 weeks from screening visit 
3. Background medical LMT that has not been stable for at least 4 weeks (6 weeks for 
fibrates, 24 weeks for mipomersen, 12 weeks for maximum tolerated dose of lomitapide) 
before the screening visit 
Patients will have the option to enter the optional run-in period.  Once the patient is stable 
on his/her background medical LMT for the appropriate amount of time, the patient may 
enter the screening period. 
4. LDL apheresis schedule/apheresis settings that have not been stable for at least 8 weeks 
before the screening visit or an apheresis schedule/settings that is not anticipated to be 
stable over the next 24 weeks 
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Patients will have the option to enter the optional run-in period.  Once the patient is stable 
on his/her background lipid apheresis schedule/settings for the appropriate amount of time, 
the patient may enter the screening period. 
5. Use of nutraceuticals or over-the-counter (OTC) therapies known to affect lipids, at a 
dose/amount that has not been stable for at least 4 weeks prior to the screening visit or 
between the screening and randomization visits. 
Patients will have the option to enter the optional run-in period. Once the patient is stable 
on his/her nutraceuticals or OTC therapies for the appropriate amount of time, the patient 
may enter the screening period. 
6. Presence of any clinically significant uncontrolled endocrine disease known to influence 
serum lipids or lipoproteins.  This may include newly diagnosed (within 3 months prior to 
randomization visit [week 0/day 1]) diabetes mellitus, or signs and symptoms of 
hypothyroidism. 
Note:  Patients on thyroid replacement therapy can be included if the dosage of replacement 
therapy has been stable for at least 12 weeks prior to screening and the thyroid stimulating 
hormone (TSH) level is within the normal range at the screening visit 
7. Unstable weight (variation >5 kg) within 2 months prior to the screening visit (week -2)  
8. Initiation of a new diet or major change to a previous diet within 4 weeks prior to screening  
9. Chronic use of systemic corticosteroids, unless on a stable regimen of 10 mg daily 
prednisone equivalent or less for at least 6 weeks prior to randomization  
Note:  topical, intra-articular, nasal, inhaled and ophthalmic steroid therapies are not 
considered as ‘systemic’ and are allowed 
10. Use of estrogen or testosterone therapy unless the regimen has been stable in the past 
6 weeks prior to the screening visit and there are no plans to change the regimen during the 
study 
11. Systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg at the 
screening visit (1 repeat measurement is allowed) 
12. LDL-C level <70 mg/dL (1.81 mmol/L) at the screening visit 
13. History of a MI, unstable angina leading to hospitalization, coronary artery bypass graft 
surgery, percutaneous coronary intervention, uncontrolled cardiac arrhythmia, carotid 
surgery or stenting, stroke, transient ischemic attack, valve replacement surgery, carotid 
revascularization, endovascular procedure or surgical intervention for peripheral vascular 
disease within 3 months prior to the screening visit 
14. History of New York Heart Association (NYHA) class IV heart failure within 12 months 
before screening 
15. History of cancer within the past 2 years, except for adequately treated basal cell skin 
cancer, squamous cell skin cancer, or in situ cervical cancer 
16. Use of any active investigational drugs within 1 month or 5 half-lives prior to the screening 
visit, whichever is longer 
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17. Conditions/situations such as: 
 Any clinically significant abnormality identified at the time of screening that, in the 
judgment of the investigator or any sub-investigator, would preclude safe completion 
of the study or constrain endpoints assessment; eg, major systemic diseases, patients 
with short life expectancy 
 Considered by the investigator or any sub-investigator as inappropriate for this study 
for any reason, eg: 
 Deemed unable to meet specific protocol requirements, such as scheduled visits 
 Deemed unable to tolerate injections as per the patient or the investigator 
 Investigator or any sub-investigator, pharmacist, study coordinator, other study 
staff or relative thereof directly involved in the conduct of the protocol, etc. 
 Presence of any other conditions (eg, geographic or social), either actual or 
anticipated, that the investigator feels would restrict or limit the patient’s 
participation for the duration of the study 
18. Laboratory findings during screening period (not including randomization labs): 
 Hepatitis B surface antigen and/or Hepatitis C antibody (associated with a positive 
HCV RNA polymerase chain reaction) at the screening visit 
 Positive serum beta-human chorionic gonadotropin (hCG) or urine pregnancy test in 
women of childbearing potential 
 Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 (calculated by central 
lab) 
 Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 x upper limit 
of normal (ULN) (1 repeat lab is allowed) 
 Unexplained serum creatine phosphokinase CPK >5 x ULN (1 repeat lab is allowed) 
19. Known hypersensitivity to monoclonal antibody therapeutics 
20. Member of the clinical site study team and/or his/her immediate family 
21. Pregnant or breastfeeding women 
22. Women of childbearing potential* who are unwilling to practice highly effective 
contraception prior to the initial dose/start of the first treatment and for the duration of the 
study. Highly effective contraceptive measures include stable use of combined (estrogen 
and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or 
progestogen-only hormonal contraception (oral, injectable, implantable) associated with 
inhibition of ovulation initiated 2 or more menstrual cycles prior to screening; intrauterine 
device (IUD); intrauterine hormone releasing system (IUS); bilateral tubal ligation; 
vasectomized partner; and or sexual abstinence**. 
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*Postmenopausal women must be amenorrheic for at least 12 months in order not to be 
considered of childbearing potential.  Pregnancy testing and contraception are not 
required for women with documented hysterectomy or oophorectomy. 
**Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatments.  
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. 
The investigator should make the best effort to contact any patient (eg, contacting patient’s family 
or private physician, reviewing available registries or health care database) who fails to return to 
the site and to determine health status, including vital status at a minimum.  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). 
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 will not be replaced. 
7. 
STUDY TREATMENTS  
The investigational study drug injections will be provided in prefilled pens and will be 
administered SC into the abdomen, thigh, or outer area of the upper arm.  The patient or caregiver 
will use placebo for injection training at the clinical site. 
7.1. 
Injection Training 
After study eligibility is confirmed, the patient or caregiver will be trained to self-inject/inject 
using placebo. 
Injection training can be done during the screening period or at baseline (visit 2) using placebo.  
All patients and caregivers who will inject the investigational study drug must be trained by the 
study staff.  
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Investigators will have the option of providing a second placebo dose to patients who require 
additional injection training before randomization.  The patient and/or investigator may elect to 
inject the additional dose of placebo at home or at the study site. 
7.2. 
Investigational and Reference Treatments 
Double-blind-Treatment: 
Study drug administration during the double-blind treatment period will start on the day of 
randomization and will be administered immediately after completion of the LDL apheresis 
procedure (if applicable).  For those patients not undergoing LDL apheresis, administration of the 
investigational study drug must be made after all samples for clinical laboratory evaluation have 
been obtained. The last injection of double-blind study drug will occur on day 71/week 10. 
If a dose is missed, the patient will be instructed to administer the injection within 7 days from the 
missed dose. If the missed dose is not administered within 7 days, the patient will be instructed to 
skip the dose and resume the original schedule.  
Patients will be randomized in a 2:1 ratio to receive: 
 alirocumab 150 mg SC Q2W 
OR 
 matching placebo SC Q2W 
Sterile alirocumab drug product will be supplied at a concentration of 150 mg/mL in a prefilled 
pen. 
Placebo will also be supplied in a prefilled pen. 
Open-label Treatment: 
To provide further safety data in this rare patient population, all patients will receive open-label 
investigational study drug (alirocumab 150 mg SC Q2W), starting at week 12 and continuing 
through week 24 (end-of open-label treatment period/EOS visit, last injection at week 22) 
regardless of treatment assignment in the double-blind treatment period.  Patients who are 
receiving LMT or who are undergoing apheresis should continue a stable dose and regimen and a 
stable apheresis schedule and settings (as applicable) throughout the duration of the open-label 
treatment period.  
Sterile alirocumab drug product will be supplied at a concentration of 150 mg/mL in a prefilled 
pen. 
7.3. 
Run-in (optional) and Background Treatment(s) 
Apheresis therapy - Patients who are undergoing apheresis therapy without a stable weekly or 
every other week schedule or stable settings for at least 8 weeks before the screening visit will 
enter a 4-week optional run-in period before the screening period.  After the 4-week run-in period, 
patients whose lipid apheresis schedule/settings remain stable will be eligible to enter the 2-week 
screening period.  Additionally, all patients on LDL apheresis must be diagnosed based on 
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genotype and, if genotype information has not been determined previously, they can enter the run-
in to allow time, if needed, to determine their mutation status.  
Lipid modifying therapy - Patients who are on background LMT that has not been stable for at 
least 4 weeks before the screening visit will enter a 4-week run-in period to stabilize their LMT.  
Patients who have not been on a stable dose of mipomersen within 6 months prior to screening or 
a maximum tolerated dose of lomitapide for 12 weeks prior to screening are excluded. 
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 
Study drug should be continued whenever possible.  In the event the investigational study drug 
dosing is stopped, it should be determined if the stop can be made temporarily; permanent 
discontinuation should be a last resort.  In any case, the patient should remain in the study as long 
as possible. 
Patients who permanently discontinue study drug during the double-blind treatment period should 
remain in the study and undergo all double-blind study visits and procedures with the exception of 
dosing with study drug.  At the time of study drug discontinuation, the patient should have, as soon 
as possible, an unscheduled visit with assessments normally planned at end of double-blind 
treatment visit (this should take place within 5 days of discontinuation of study drug, if possible). 
Then, patients should resume the original study schedule until the end of the double-blind 
treatment period and all efforts should be made to perform the week 12 assessments at week 12.  
The original study schedule will continue until the end of the study visit (ie, follow-up phone call 
visit). 
Patients who permanently discontinue study drug during the open-label period should have, as 
soon as possible, an unscheduled visit with assessments normally planned at the end of the 
open-label treatment period (this should take place within 5 days of discontinuation of the study 
drug, if possible).  Upon completion of this visit, the original study schedule will resume until end 
of study (ie, follow-up phone visit). 
Assessment of patients who do not consent to remain in the study after discontinuation of the 
investigational study drug should be managed according to Section 8.1.2. 
7.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
Patients should permanently discontinue study drug for the following reasons: 
 For female patients, individuals that have become pregnant, are actively trying to 
become pregnant, or discontinue use of protocol-defined methods of effective birth 
control 
 Acute injection reaction of clinical concern 
 At patient request 
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 If, in the investigator's opinion, continuation of the investigational study drug dosing 
would be detrimental to the patient's well being 
 Intercurrent condition that requires discontinuation of the investigational study drug 
 At the specific request of the sponsor 
 Patient receives double-blind treatment before randomization 
7.4.2.2. 
Reasons for Temporary Discontinuation of Study Drug 
Temporary discontinuation of the investigational study drug may be considered by the investigator 
because of suspected AEs, including allergic events related to the dose of the investigational study 
drug.  Reinitiating the investigational study drug dosing will be done under close and appropriate 
clinical and/or laboratory monitoring. 
Temporary discontinuation of the investigational study drug is defined as 1 or more scheduled 
injections that are not administered to the patient as decided by the investigator. 
7.5. 
Management of Acute Reactions  
7.5.1. 
Acute Injection Reactions 
7.5.1.1. 
Systemic Injection Reactions 
Acute systemic reactions following injection of the investigational study drug (subcutaneous [SC]) 
should be treated using clinical judgment to determine the appropriate response according to 
typical clinical practice.  
7.6. 
Method of Treatment Assignment  
The randomized list of treatment kit numbers will be generated centrally.  An interactive voice 
response system (IVRS) and/or interactive web response system (IWRS) will be used in this study.  
The investigational study drug will be packaged in accordance with this list. 
Patients will be randomly assigned to receive alirocumab 150 mg or matching placebo in a 
2:1 ratio, stratified by LDL apheresis treatment status (on vs off treatment). 
The treatment kit numbers will be allocated using the centralized treatment allocation system at 
the randomization visit, at weeks specified in Table 1 as re-supply visits, and at unscheduled visits, 
if needed.  
7.6.1. 
Blinding 
Study patients, the investigators, and study site personnel will remain blinded to all randomization 
assignments throughout the study.  The Regeneron Study Director, Medical Monitor, Study 
Monitor, and any other Regeneron and contract research organization (CRO) personnel who are 
in regular contact with the study site will remain blinded to all patient randomization assignments. 
Lipid results from blood samples collected after the randomization visit will not be communicated 
to the sites, and the sponsor’s operational team will not have access to these laboratory results until 
after the completion of the double-blind treatment period and the first-step analysis.  
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Blinded investigational study drug kits coded with a medication numbering system will be used.  
In order to maintain the blind, lists linking these codes with product lot numbers will not be 
accessible to individuals involved in study conduct. 
Anti-drug antibody (ADA) will not be communicated to the sites, and the sponsor’s operational 
team will not have access to results associated with patient identification until after the database 
lock after completion of the double-blind treatment period. 
While the study is ongoing, it is anticipated that unblinded data, after the first step analysis 
(Section 10.5), will be submitted to health authorities.  Sponsor representatives who will conduct 
and review such data analyses for submission to the health authorities will not be part of the study 
operational team from that point forward, and patient level results will not be provided to the study 
sites.  The analysis process, the measures used to protect the blind and the integrity of the study, 
and a communication plan and confidentially agreement will be described in a separate document. 
7.6.2. 
Emergency Unblinding  
Unblinding of treatment assignment for a patient may be necessary due to a medical emergency or 
any other significant medical event (eg, pregnancy). 
 If unblinding is required: 
 Only the investigator will make the decision to unblind the treatment assignment. 
 Only the affected patient will be unblinded. 
 The designated study pharmacist(s)/designee at the study site will provide the 
treatment assignment to the investigator.  If there is no study pharmacist, the 
investigator for the site will unblind the patient  
 The investigator will notify Regeneron and/or designee before unblinding the 
patient, whenever possible 
Treatment assignment is not to be provided to site personnel at any time during the conduct of the 
study, except in the case of a true emergency.  In the event that there is no study pharmacist, the 
individual at the site fulfilling that role will be the only unblinded member of the site personnel. 
7.7. 
Treatment Logistics and Accountability 
7.7.1. 
Packaging, Labeling, and Storage  
A medication numbering system will be used to label blinded investigational study drug.  Lists 
linking medication numbers with product lot numbers will be maintained by the groups (or 
companies) responsible for the investigational study drug packaging.  In order to maintain the 
blind, these lists will not be accessible to individuals involved in study conduct. 
Training kits containing 1 placebo prefilled pen will be provided to the sites for patient/caregiver 
injection training that will be performed before randomization during the screening period or at 
the baseline visit.  A second placebo prefilled pen can be used before randomization if the 
patient/caregiver requires additional injection training. 
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Study drug will be refrigerated at the site at a temperature of 2ºC to 8ºC.  Storage temperature will 
be logged.  Detailed storage instructions are provided in the study 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 investigational study drug should be returned to the 
sponsor or designee. 
The investigational study drug will be dispensed to each patient.  The investigational study drug 
will be stored, prepared, and administered by the patient/caregiver according to instructions 
provided to each patient/caregiver. 
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 investigational study drug.  
These records should contain the dates, quantity, and study medication 
 dispensed to each patient, 
 returned from each patient (if applicable), and 
 disposed of at the site or returned to the sponsor or designee 
Patients will complete a dosing log to document compliance with the investigational study drug 
administration.  Measures taken to ensure and document the investigational study drug 
accountability and compliance are as follows: 
 The investigator or designee will obtain via IVRS/IWRS the treatment kit number(s) 
and will dispense the treatment kit(s) to the patient 
 Accountability is to be verified during the investigational study drug kit re-supply visits 
only.  The used and unused kit(s) should be brought to these visits for accountability 
purposes. 
 All kits, including used and unused kits, are to be returned by the patient at the 
designated visit. An unused kit contains all of the unused prefilled pens.  A used kit is 
one from which the patient has removed 1 or more prefilled pens.  A used prefilled pen 
is one that has been removed from the kit with the intention of administration, including 
those injections that have been partially or fully injected.  The patient should discard 
all used prefilled pens into the sharps container and never put used prefilled pens back 
into the used kit. 
 All sharps containers should be returned to the site by the patient 
 The investigator/study coordinator will enter data in the appropriate CRF pages, 
according to data recorded in the treatment log form 
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 The monitor will check the data consistency among CRF pages, treatment log form and 
returned unused prefilled pens of a corresponding kit 
All treatments kits will be retrieved by the sponsor.  A detailed treatment log of the returned 
investigational study drug will be established with the investigator or designee and countersigned 
by the investigator and the monitoring team. 
7.7.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the sponsor 
and regulatory agency inspectors.  Patients will complete a dosing log to document compliance 
with the investigational study drug administration. 
7.8. 
Concomitant Medications 
Concomitant medications should be kept to a minimum during the study.  If considered necessary 
for the patient’s welfare and unlikely to interfere with the investigational study drug, concomitant 
medications (other than those that are prohibited during the study) may be given at the discretion 
of the investigator, at a stable dose when possible. 
Any treatments administered from the time of informed consent/assent to the final study visit will 
be considered concomitant medications.  This includes medications that were started before the 
study and are ongoing during the study. 
7.8.1. 
Prohibited Medications and Procedures 
Use of a PCSK9 inhibitor within 10 weeks from the screening visit is prohibited. 
Initiation of or changes to the LDL apheresis schedule and/or settings (if applicable) or background 
medical LMT from the initial screening visit until the end of study visit is prohibited. 
Use of continuous estrogen or testosterone hormone replacement therapy is prohibited unless the 
regimen has been stable in the past 6 weeks prior to the screening visit. 
Chronic use of systemic corticosteroids, unless on a stable regimen of 10 mg daily prednisone 
equivalent or less for at least 6 weeks prior to randomization, is prohibited.  Note: topical, 
intra-articular, nasal, inhaled and ophthalmic steroid therapies are not considered as ‘systemic’ and 
are allowed. 
7.8.2. 
Permitted Medications and Procedures 
Lipid modifying therapies, nutraceuticals, and over-the-counter therapies that may affect lipids are 
allowed only if they have been used at a stable dose and regimen for at least 4 weeks (6 months 
for mipomersen, 12 weeks for the maximum tolerated dose of lomitapide) before the screening 
visit.  The dose and regimen must remain stable until the end of study visit. 
Low-density lipoprotein apheresis is allowed only if the schedule/settings have been stable for at 
least 8 weeks before the screening visit and will remain stable until the end of study visit. 
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8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
8.1. 
Schedule of Events 
Study assessments and procedures are presented by study period and visit in Table 1. 
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Table 1: 
Schedule of Events 
 
Optional 
Run-in 
Screenin
g Period 
Double-Blind Treatment Period 
Open-label Treatment 
Period 
Follow-up10  
Study Procedure 
Run-in 
Visit 1a 
Screenin
g 
Visit 1 
Baseline 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
End of 
Double-Blind 
Treatment 
Visit 6 
Visit 7 
End of Open-
Label 
Treatment 
Visit 8 
End of Study 
Phone Visit 9 
Day 
-42 to -14 
-14 to -1 
1(±1) 
29(±5/
±19) 
57(±5/
±19) 
71(±5/±
19) 
85(±3/±19)  
127(±7) 
169(±3/±19)  
225(±5) 
Week 
-6 to -2 
-2 to -1 
0 
4 
8 
10 
12 
18 
24 
32 
Screening/Baseline: 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
Informed Consent/Assent1 
X 
X 
 
 
 
 
 
 
 
 
Pharmacogenomics 
Consent/Assent 
 
X 
 
 
 
 
 
 
 
 
Medical/Surgical History, 
Alcohol habits, Smoking 
habits 
 
X 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
Treatment: 
Injection training2 
 
X 
X 
 
 
 
 
 
 
 
Investigational study drug 
kit dispensation 
 
 
X 
X 
 
 
X 
X 
 
 
Administer SC 
double-blind 
investigational study drug 3 
 
 
X 
X 
X 
X 
 
 
 
 
Administer open-label 
investigational study drug3 
 
 
 
 
 
 
X 
X 
 
 
Kit return 
 
 
 
X 
X 
 
 
X 
X 
 
Review of dosing log 
 
 
 
X 
X 
 
 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy: 
Lipid panel4 
 
X 
X 
X 
X 
 
X 
X 
X 
 
Specialty lipid panel4 
 
 
X 
X 
X 
 
X 
 
X 
 
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Optional 
Run-in 
Screenin
g Period 
Double-Blind Treatment Period 
Open-label Treatment 
Period 
Follow-up10  
Study Procedure 
Run-in 
Visit 1a 
Screenin
g 
Visit 1 
Baseline 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
End of 
Double-Blind 
Treatment 
Visit 6 
Visit 7 
End of Open-
Label 
Treatment 
Visit 8 
End of Study 
Phone Visit 9 
EQ-5D 
 
 
X 
 
 
 
X 
 
X 
 
Safety 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
 
X 
 
 
 
 
X 
 
X 
 
Body weight 
X 
X 
 
 
 
 
X 
 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Electrocardiogram5 
 
X 
 
 
 
 
X 
 
X 
 
Laboratory Testing: 
Hematology6 
 
X 
X 
 
X 
 
X 
 
X 
 
Blood chemistry6 
 
X 
X 
 
X 
 
X 
 
X 
 
Creatine Phosphokinase6 
 
X 
X 
 
X 
 
X 
 
X 
 
Hepatitis B surface 
antigen6 
 
X 
 
 
 
 
 
 
 
 
Hepatitis C antibody6 
 
X 
 
 
 
 
X 
 
X 
 
Serum pregnancy test 
 
X 
 
 
 
 
 
 
  
 
Urine pregnancy test (done 
locally) 
X 
 
 
 
 
 
X 
 
X 
 
Urinalysis 
 
X 
X 
 
X 
 
X 
 
X 
 
TSH 
 
X 
 
 
 
 
 
 
 
 
hs-CRP6 
 
X 
X 
 
 
 
X 
 
X 
 
Research samples6 
 
 
X 
X 
X 
 
X 
 
X  
 
Mandatory DNA 
collection for HoFH 
Genetic Testing7 
X 
X 
 
 
 
 
 
 
 
 
PK/Drug Concentration and ADA Samples: 
PK Sample6 
 
 
X 
X 
X 
X 
X 
 
X 
 
ADA Sample6 
 
 
X 
 
 
 
X 
 
X 
 
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Optional 
Run-in 
Screenin
g Period 
Double-Blind Treatment Period 
Open-label Treatment 
Period 
Follow-up10  
Study Procedure 
Run-in 
Visit 1a 
Screenin
g 
Visit 1 
Baseline 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
End of 
Double-Blind 
Treatment 
Visit 6 
Visit 7 
End of Open-
Label 
Treatment 
Visit 8 
End of Study 
Phone Visit 9 
 
 
 
 
X 
 
 
 
 
 
 
 
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8.1.1. 
Footnotes for the Schedule of Events Table  
1. Informed consent/assent will be obtained either at Visit 1a (for patients who need the 
optional run-in time) or at Visit 1 (for the patients who do not need optional run-in). 
2. Injection training will be performed with the patient and/or caregiver during the screening 
period or at baseline using placebo. 
3. After the investigational study drug administration (double-blind and open-label), patients 
will need to be monitored for 30 minutes. 
4. Lipid panel will consist of:  total-C, LDL-C, HDL-C, TG, non-HDL-C.  Specialty lipid 
panel will consist of: ApoB, Apo A-1, ratio Apo B/Apo A-1, and Lp(a).  Lipid panels 
should be collected after an approximately 8 hour fast. 
5. ECG should be performed before blood samples are collected. 
6. On days when a clinic visit coincides with a dosing day, all blood samples (including ADA 
samples) will be collected immediately prior to LDL apheresis (if applicable) and before 
the investigational study drug administration, but after study assessments are performed.  
PK samples will also be used for free and total PCSK9 analysis. 
7. Sample should be obtained prior to randomization and will be used to determine HoFH 
mutation status.  Patients on apheresis may collect this during visit 1a. 
 
 
 
. 
9. Visit window is ±3 days for patients not on apheresis and +1 day for patients on apheresis.  
Every attempt should be made to ensure all samples are collected immediately prior to LDL 
apheresis. The timing between the baseline sample collection relative to the most recently 
completed LDL apheresis procedure should match the timing of the week 12 sample 
collection relative to the most recently completed LDL apheresis procedure. Depending on 
the duration between the LDL apheresis procedure and sample collection, the visit window 
may not apply. 
10. This visit is only for patients who do not participate in another lipid-lowering study. 
8.1.2. 
Early Termination Visit 
If for any reason the patient refuses to continue the study, the patient should undergo an 
unscheduled visit as soon as possible with assessments normally planned at the end of double-blind 
treatment visit if the patient is in the double-blind treatment period (week 12 visit assessments); if 
the patient is in the open-label treatment visit, then the end of the open-label treatment assessments 
should be used (week 24 visit assessments).  This visit should take place within 5 days of treatment 
discontinuation, if possible.  The patient should be followed for at least 70 days 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. 
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8.1.3. 
Unscheduled Visits 
All attempts should be made to keep the 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: 
 medical/surgical history 
 medication history 
 demographics 
 hepatitis B surface antigen 
 serum pregnancy testing 
On day 1, after completion of study assessments, collection of blood samples, LDL apheresis (if 
applicable), and the first dose of double-blind investigational study drug will be administered. The 
patient will be monitored at the clinical site for 30 minutes after the first dose. Subsequent doses 
of the investigational study drug must be administered subcutaneously Q2W. Doses of the 
investigational study drug should be administered at approximately the same time of day (based 
upon patient preference) throughout the study. After day 1, it is acceptable for dosing to fall within 
a window of ± 5 days, with the exception of the week 10 and week 22 doses, which will have a ± 
3 day dosing window for patients not on apheresis and a +1 day dosing window for patients on 
apheresis since there are key efficacy assessments at week 12 and week 24. 
In the event an injection is delayed by more than 7 days or completely missed, the patient should 
return to the original schedule of the investigational study drug dosing without administering 
additional injections.  If the delay is less than or equal to 7 days from the missed date, the patient 
should administer the delayed injection and then resume the original dosing schedule.  Site 
personnel will provide the patient/caregiver with detailed instructions for transport, storage, 
preparation, and administration of the investigational study drug. 
8.2.2. 
Efficacy Procedures  
Total cholesterol, HDL-C, TG, Apo B, Apo A-1, and Lp(a) will be directly measured by the central 
laboratory.  Low-density lipoprotein cholesterol will be calculated using the Friedewald formula.  
If TG values exceed 400 mg/dL (4.52 mmol/L), or if calculated LDL-C values are below 15 mg/dL, 
then the central lab will reflexively measure LDL-C using the beta quantification method.  Non-
HDL-C will be calculated by subtracting HDL-C from the Total-C.  The Apo B/Apo A-1 ratio will 
be calculated. 
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8.2.2.1. 
Lipid Panel 
Blood samples for the lipid panel and specialty lipid panel will be collected at time points 
according to Table 1.  See Section 8.2.4.4 Laboratory Testing for a list of what is included in the 
lipid panel and special lipid panel.  
8.2.3. 
Quality of Life Procedures 
8.2.3.1. 
EuroQol-5 Questionnaire 
The EQ-5D is a standardized measure of health status developed by the EuroQol Group in order 
to provide a simple, generic measure of health for clinical and economic appraisal.  The EQ-5D as 
a measure of health related quality of life, defines health in terms of 5 dimensions: mobility, self-
care, usual activities, pain/discomfort, anxiety/depression.  Each dimension has 3 ordinal levels of 
severity: “no problem” (1), “some problems” (2), “severe problems” (3).  Overall health state is 
defined as a 5-digit number. Health states defined by the 5-dimensional classification can be 
converted into corresponding index scores that quantify health status, where 0 represents “death” 
and 1 represents “perfect health.” 
8.2.4. 
Safety Procedures  
8.2.4.1. 
Vital Signs 
Vital signs, including blood pressure and heart rate will be collected at time points according to 
Table 1. 
8.2.4.2. 
Physical Examination 
A thorough and complete physical examination will be performed at time points according to 
Table 1.  Body weight will be collected 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. 
8.2.4.3. 
Electrocardiogram 
Electrocardiogram should be performed before blood is drawn during the visits requiring blood 
draws.  A standard 12-lead ECG will be performed with the patient in the supine position after 
resting quietly for 10 minutes at time points according to Table 1.  Heart rate will be recorded from 
the ventricular rate and the PR, QRS, RR and QT intervals will be recorded.  The ECG strips or 
reports will be retained with the source. 
8.2.4.4. 
Laboratory Testing 
All laboratory samples (including ADA samples) will be collected after assessments are performed 
and before a dose of the investigational study drug is administered at visits that correspond with 
a dosing day.  Alcohol consumption within 48 hours or intense physical exercise within 24 hours 
preceding blood sampling is discouraged.  Samples for laboratory testing will be collected at time 
points according to Table 1 and analyzed by a central laboratory during the study.  Lipid panel 
samples will be collected after 8 hour fasting.  Detailed instructions for blood sample collection 
are in the laboratory manual provided to study sites.  Tests include:  
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Lipid Panel and Specialty Lipid Panel 
Total cholesterol 
Apo B 
 
Triglyceride 
Apo A-1 
 
Calculated LDL-C 
Apo B/Apo A-1 ratio 
 
HDL-C 
Lp(a) 
 
Non-HDL-C 
 
 
 
Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin 
Potassium 
Creatinine 
Uric acid 
Chloride 
Blood urea nitrogen (BUN) 
Creatine phosphokinase (CPK) 
Carbon dioxide 
Aspartate aminotransferase (AST) 
 
Calcium 
Alanine aminotransferase (ALT) 
 
Glucose 
Alkaline phosphatase 
 
Albumin 
Lactate dehydrogenase (LDH) 
 
Hematology 
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
Urinalysis 
Color 
Glucose 
RBC 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBC 
Yeast 
Other Laboratory Tests 
Pregnancy testing (serum and urine) will be performed at time points according to Table 1. 
Pregnancy testing (urine) will be assessed locally at time points according to Table 1. 
Samples for the liver panel (ALT, AST, alkaline phosphatase, and total bilirubin), high-sensitivity 
C-reactive protein (hs-CRP) will be collected at time points according to Table 1.  
A sample for hepatitis B surface antigen, hepatitis C antibody, and TSH will be collected at 
screening. Samples for hepatitis C antibody will be collected at time points according to 
Table 1.Abnormal Laboratory Values and Laboratory Adverse Events 
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 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. 
8.2.5. 
Pharmacokinetic and Anti-Drug Antibody Procedures 
8.2.5.1. 
Drug Concentration Measurements and Samples 
Samples for drug concentration will be collected at time points listed in Table 1. 
 
8.2.5.2. 
Anti-Drug Antibody Measurements and Samples 
Samples for ADA assessment will be collected at time points listed in Table 1. 
At visits that take place on dosing days, all samples for ADA assessments will be collected before 
a dose of the investigational study drug is administered. 
To maintain the blind of the study, ADA samples will be collected from all patients, including 
those who received only placebo. 
. 
8.2.6. 
HoFH Genetic Testing 
A sample will be collected for mandatory HoFH genetic testing to characterize the mutation status 
of each patient as listed in Table 1. 
8.2.7. 
Research Samples 
Samples for exploratory research will be collected as allowed by local regulations to study PCSK9 
levels, PCSK9 function, effects of PCSK9 inhibition with a monoclonal antibody, and mechanisms 
of hyperlipidemia and heart disease. 
Research sampling will be collected at time points according to Table 1.  Research samples will 
be coded to maintain patient confidentiality. 
8.2.7.1. 
Biomarker Procedures 
Biomarker samples will be collected at time points according to Table 1 as part of the Research 
Samples.  Biomarker measurements will be performed in matrix, for example, serum samples to 
determine effects on biomarkers of indication or relevant physiological and pathogenic processes. 
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The biomarkers studied will be ones believed to be relevant to the pathophysiology of indication 
target engagement, mechanism of action and possible toxicities.  Biomarkers studied may include 
but not limited to PCSK9.  
 
. 
Biomarkers results will be reported separately from the clinical study report. 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
. 
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 the patient.  This includes death from any cause 
and all serious adverse events (SAEs) related to the use of the investigational 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 investigational study drug (suspected 
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unexpected serious adverse reaction), to the health authorities, IRBs/ECs as appropriate, and to the 
investigators. 
Any AE not listed as an expected event in the prescribing information or Investigators Brochure 
for alirocumab or in this protocol will be considered as unexpected.  Any worsening of or new 
onset of symptoms related to the patient’s CVD, which occur during the screening/washout period 
prior to the investigational 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 investigational 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. 
9.3. 
Definitions 
9.3.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered an investigational study drug, 
which may or may not have a causal relationship with the investigational 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 the investigational study drug, whether 
or not considered related to the investigational 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 
investigational 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 the investigational study drug (eg, a car accident in which a patient is a passenger). 
 Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event.  This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
 Requires in-patient hospitalization or prolongation of existing hospitalization.  
In-patient hospitalization is defined as admission to a hospital or an emergency room 
for longer than 24 hours.  Prolongation of existing hospitalization is defined as a 
hospital stay that is longer than was originally anticipated for the event, or is prolonged 
due to the development of a new AE as determined by the investigator or treating 
physician. 
 Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions). 
 Is a congenital anomaly/birth defect 
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 Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent one of the other serious outcomes listed above (eg, 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse). 
Criteria for reporting SAEs must be followed for these events.  See Section 9.4 for more 
information on recording and reporting SAEs. 
9.3.3. 
Adverse Events of Special Interest 
An adverse event of special interest (serious or non-serious) is one of scientific and medical 
concern specific to the sponsor’s product or program, for which ongoing monitoring and rapid 
communication by the investigator to the sponsor can be appropriate.  Such an event might warrant 
further investigation in order to characterize and understand it.  Depending on the nature of the 
event, rapid communication by the trial sponsor to other parties (e.g., regulators) might also be 
warranted (Section 9.4.3). 
Adverse events of special interest for this study include the following: 
 Increase in ALT: ALT ≥3 x ULN (if baseline ALT <ULN), or ALT ≥2 times the 
baseline value (if baseline ALT ≥ ULN) 
 Allergic events and/or local injection site reactions that require consultation with 
another physician for further evaluation 
 Pregnancy 
 Symptomatic overdose with investigational medicinal product 
 Neurologic events that require additional examinations/procedures and/or referral to a 
specialist 
 Neurocognitive events 
 Cataracts 
 New onset of diabetes 
The definition of new onset of diabetes (NOD) will be the following: 
 Type 1 or type 2 diabetes TEAE (grouping of Medical Dictionary for Regulatory 
Activities [MedDRA®] terms will be specified in the SAP) 
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and/or 
 At least 2 values of HbA1c ≥6.5% during the TEAE period 
NOTE: For patients with only a single measurement available during the TEAE period, 
a single value ≥6.5% will be considered and qualify the patient as NOD by default. 
For patients with several HbA1c measurements but only with the last one ≥6.5%, this 
single value ≥6.5% will be considered and qualify the patient as NOD by default 
and/or 
 At least 2 values of fasting plasma glucose (FPG) ≥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 FPG 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 
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/assent 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 the investigational 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 30 days of the last dose 
of the investigational study drug if the patient terminated early from the study, the SAE 
will be reported to the sponsor.  The investigator should make every effort to obtain 
follow-up information on the outcome until the event is considered recovered, chronic 
and/or stable, or fatal. 
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 SAE with an onset day greater than 30 days from the end of study/early termination 
visit - only fatal SAEs and those deemed by the investigator to be drug-related SAEs 
will be reported to the sponsor.  The investigator should make every effort to obtain 
follow-up information on the outcome of a drug-related SAE until the event is 
considered recovered, chronic and/or stable, or fatal. 
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 the investigational study drug within the intended therapeutic 
window, if associated with an AE, 
Pregnancy: 
Although pregnancy is not considered an AE, it is the responsibility of the 
investigator to report to the sponsor (or designee), within 24 hours of identification, 
any pregnancy occurring in a female or female partner of a male study patient, 
during the study or within 30 days of the last dose of the investigational study drug.  
Any complication of pregnancy affecting a female study patient or female partner 
of a male study patient, and/or fetus and/or newborn that meets the SAE criteria 
must be reported as an SAE.  Outcome for all pregnancies should be reported to the 
sponsor. 
Adverse Events of Special Interest: All adverse events of special interest, serious and 
nonserious, must be reported with 24 hours of identification using the same 
reporting process as the SAE reporting, per Section 9.4.2. 
Refer to the study manual for the procedures to be followed. 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study 
All AEs that lead to a patient’s withdrawal from the study must be reported to the sponsor’s 
medical monitor within 30 days. 
Refer to the study 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 
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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 recovered, chronic 
and/or stable, or fatal. 
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. 
Injection Site Reactions 
The severity of injection site reactions will be graded according to the following scale (semi-colon 
indicates “or” within description of grade): 
 Mild:  Pain that does not interfere with activity; mild discomfort to touch; <5 cm of 
erythema or induration that does not interfere with activity 
 Moderate:  Pain that requires repeated use of non-narcotic pain reliever >24 hours or 
interferes with activity; discomfort with movement; 5.1 cm to 10 cm erythema or 
induration or induration that interferes with activity 
 Severe:  Pain that requires any use of narcotic pain reliever or that prevents daily 
activity; significant discomfort at rest; >10 cm erythema or induration; prevents daily 
activity; requires ER visit or hospitalization; necrosis or exfoliative dermatitis 
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9.5.2. 
Evaluation of Causality 
Relationship of Adverse Events to Study Drug: 
The relationship of AEs to the investigational study drug will be assessed by the blinded 
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 investigational study 
drug? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by the 
investigational study drug 
Related: 
There is a reasonable possibility that the event may have been caused by the 
investigational study drug 
A list of factors to consider when assessing the relationship of AEs to the investigational study 
drug is provided in Appendix 1. 
The investigator should justify the causality assessment of each SAE. 
Relationship of Adverse Events to Study Conduct: 
The relationship of AEs to study conduct will be assessed by the blinded investigator, and will be 
a clinical decision based on all available information.  The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by study conduct? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by study 
conduct 
Related: 
There is a reasonable possibility that the event may have been caused by study 
conduct 
A list of factors to consider when assessing the relationship of AEs to study conduct is provided 
in Appendix 1. 
The investigator should justify the causality assessment of each SAE. 
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The relationship of AEs to injection procedure, study procedure, or background treatment, etc. will 
be assessed by the (include "blinded" or "masked" here, if appropriate) investigator, and will be a 
clinical decision based on all available information.  The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by the injection procedure, 
study procedure, or background treatment, etc.? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by the 
injection procedure, study procedure, or background treatment, etc. 
Related: 
There is a reasonable possibility that the event may have been caused by the 
injection procedure, study procedure, or background treatment, etc. 
A list of factors to consider in assessing the relationship of AEs to injection procedure, study 
procedure, or background treatment, etc.is provided in Appendix 1. 
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 (e.g., 
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 alirocumab 
prescribing information or Investigators Brochure or this protocol, and has a reasonable suspected 
causal relationship to the medicinal/investigational 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 after the double-blind period completion. 
Analysis variables are listed in Section 4. 
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10.1. 
Statistical Hypothesis  
Let μ0 and μ1 be the population means of the percent change from baseline in LDL-C at week 12 
under placebo and alirocumab, respectively for the primary analysis. For the primary and main 
efficacy variables, the following null hypothesis and alternative will be tested: 
H0 : μ0 = μ1 versus H1 : μ0 ≠ μ1 
10.2. 
Justification of Sample Size 
Patients will be randomized in the double-blind treatment period to alirocumab or placebo in a 
ratio of 2:1 respectively, with the primary efficacy hypothesis comparing the alirocumab-treated 
group to the placebo group at week 12.  For the primary efficacy hypothesis during the 
double-blind treatment period, an initial total sample size of 51 patients (34 patients in the 
alirocumab-treated group and 17 patients in the placebo group) will have 90% power to detect a 
difference in mean percent change in LDL-C of 20%, with a two-sided significance level and 
assuming a standard deviation (SD) of 20%.  Taking into account a 5% non-evaluable patient rate 
for the primary efficacy endpoint, the initial study sample size is increased to 54 patients 
(36 patients in the alirocumab-treated group and 18 patients in the placebo group). 
Following the Blinded Sample Size Adjustment process (see below for details), the total study 
sample size will increase to approximately 74 patients, adding approximately 20 patients to the 
initial study sample size. 
Blinded Sample Size Adjustment 
Referencing the ICH E9 regulatory guidance, the study sample size may be re-estimated after 
approximately 75% of the patients reach the week 12 visit in the double-blind treatment period to 
ensure adequate power in case of a larger-than-expected variability in the data.  The sample size 
re-estimation will be based on the actual blinded pooled standard deviation (adjusted as described 
in Kieser 2003) for the primary efficacy measure.  Since the patients’ post-baseline LDL-C levels 
are masked to all study participants (patients, site personnel, and sponsor staff), the blinded pooled 
standard deviation will be calculated by a designated unblinded CRO statistician who will have 
access to the lipid data.  As mentioned in Kieser and Friede (Kieser 2003), the blinded sample size 
re-estimation does not affect type I error materially for continuous endpoints. 
This re-estimation procedure will assess the need for an increase in sample size and will maintain 
the initial planned enrollment if the procedure yields a smaller sample size (restricted 
recalculation).  The result of this procedure is non-binding, since the decision to increase the 
sample size will also take into account other study execution factors (eg, availability of patients).  
In the case the re-estimated sample size is implemented, a protocol amendment will document the 
modification. 
The blinded sample size adjustment process was implemented in October 2018 when 
approximately 75% of the patients reached the week 12 visit. The Kieser adjusted pooled standard 
deviation for LDL-C percent change from baseline was calculated at Week 12 to be 35%, which 
is larger than the protocol initial planned standard deviation of 20%. Applying the Kieser adjusted 
pooled standard deviation of 35 (while keeping all other assumptions as described in the protocol), 
the sample size would increase to 156 patients. With this large sample size increase, enrollment of 
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additional patients with HoFH, a rare disease, depends on the operational feasibility to identify 
eligible patients. After an assessment to identify eligible patients, a total sample size of 156 patients 
is not operationally feasible, but an additional 20 patients is considered realistic. Maintaining all 
other initial sample size assumptions, a new sample size of approximately 74 patients yields 61% 
power to detect a treatment group difference in mean percent change in LDL-C of 20%. Taking 
into account the conservative nature of the assumptions for the initial protocol sample size 
calculation, the new study sample size of approximately 74 patients will be implemented. 
10.3. 
Analysis Sets 
10.3.1. 
Efficacy Analysis Sets 
Intent-to-Treat Primary Efficacy Analysis Set: 
The primary efficacy analysis population is the ITT population (also known as the full analysis 
set), defined as all randomized patients who had at least 1 measurement value for LDL-C before 
the first dose of double blind investigational study drug (ie, baseline). 
Patients in the ITT population will be analyzed according to the treatment group allocated by 
randomization (i.e., as-randomized treatment group). 
Modified Intent-to-Treat Analysis Set: 
The modified (m)ITT population is defined as the all randomized population who took at least 1 
dose or part of a dose of double-blind investigational study drug and has an evaluable primary 
endpoint.  The endpoint is considered as evaluable when both of the following conditions are met: 
 Availability of at least 1 measurement value for LDL-C before first dose of 
double-blind investigational study drug (ie, baseline). 
 Availability of at least 1 LDL-C value during the efficacy treatment period and within 
one of the analysis windows in the double-blind period up to week 12.  The efficacy 
treatment period is defined as the time from the first double-blind investigational 
study drug injection up to 21 days after the last double-blind investigational study 
drug injection, or the first dose of the open-label investigational study drug, 
whichever is earlier. 
Patients in the mITT population will be analyzed according to the treatment group allocated by 
randomization. 
10.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized patients who received any double-blind 
investigational 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. 
The Open-Label Analysis Set 
For the open-label treatment period, the open-label extension population for all measurements 
(efficacy, safety, PK and ADA) will be defined as those patients who received at least 1 dose or 
part of a dose of open-label investigational study drug alirocumab. 
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10.3.4. 
Other Analysis Sets 
For the double-blind treatment period, the PK and the ADA analyses will be performed on all 
randomized patients who received any double-blind investigational study drug, and further: 
 The PK population will also require at least 1 non-missing result after the first dose of 
double-blind investigational study drug. 
 The anti-alirocumab antibody analysis will be performed on all treated patients (safety 
population) with a blood sample at week 0 (baseline) and at least 1 evaluable blood 
sample for anti-alirocumab antibodies after the first dose of study drug. 
10.4. 
Statistical Methods 
For continuous variables, descriptive statistics will include the following information: the number 
of patients reflected in the calculation (n), mean, median, SD, minimum, and maximum. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
10.4.1. 
Patients Disposition 
Screened patients are defined as any patient who signed the ICF (informed assent form). 
Randomized patients consist of all screened patients with a double-blind treatment kit number 
allocated and recorded in the IVRS/IWRS database, regardless of whether the treatment kit was 
used or not.  Patients treated in the double-blind treatment period without being randomized, or 
treated with a double-blind treatment kit before the randomization will not be considered as 
randomized and will not be included in any analysis population.  The safety experience of patients 
treated and not randomized will be reported separately. 
For any patient randomized more than once during the double-blind treatment period, safety data 
from the first randomization will be included in the double-blind safety population, with the safety 
data associated with the later randomization reported separately.  Since this is expected to be a rare 
event, inclusion of efficacy data from the patient randomized more than once in the efficacy 
population will be decided on a case-by-case basis prior to the unblinding of treatment 
assignments, and will be documented in the clinical study report. 
Lastly, patients in the open-label treatment period consist of all double-blind treated patients who 
receive any amount of open-label alirocumab treatment. 
10.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group on 
the randomized population for the double-blind treatment period and again on the open-label 
population for the open-label treatment period (which will also include the patient total). 
Continuous variables will be summarized with mean, median, SD, minimum, and maximum. 
Categorical variables will be summarized with frequency and percentage. 
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10.4.3. 
Efficacy Analyses 
10.4.3.1. Primary Efficacy Analysis 
For the double-blind primary comparison of the alirocumab treated group to the placebo treated 
group, the percent change from baseline in LDL-C at week 12, as defined in Section 4.2.1 will be 
analyzed in the ITT population using a mixed-effect model with repeated measures (MMRM) 
approach.  All post-baseline data available within week 4 to week 12 analysis windows will be 
used and missing data are accounted for by the MMRM model.  The model will include the fixed 
categorical effects of treatment group (alirocumab versus placebo), randomization strata 
(undergoing apheresis treatment [Yes vs. No] per IVRS/IWRS), time point (weeks 4, 8, 10, 12), 
and treatment-by-time point interaction, strata-by-time point interaction, as well as the continuous 
fixed covariates of baseline LDL-C value and baseline value-by-time point interaction.  Model 
assumptions for normality will be explored prior to the analysis testing. 
This model will be run using Statistical Analysis Software (SAS) mixed procedure with an 
unstructured correlation matrix to model the within-patient errors.  Parameters will be estimated 
using restricted maximum likelihood method with the Newton-Raphson algorithm.  Denominator 
degrees of freedom will be estimated using Satterthwaite’s approximation.  This model will 
provide baseline adjusted least-squares means estimates at week 12 for both treatment groups with 
their corresponding standard errors. 
Let µ0 and µ1 be the population means of the percent change from baseline in LDL-C at week 12 
under placebo and alirocumab, respectively.  The hypothesis that will be tested is “H0: µ0 =µ1” 
versus “H1: µ0≠µ1”.  Therefore, the alirocumab treated group will be compared to the placebo 
group using an appropriate contrast statement tested at the 2-sided 0.05 level, with corresponding 
least squares estimate of mean difference, SE and 95% confidence interval. 
Robustness of this statistical method will be assessed via sensitivity analyses detailed in the SAP, 
including a different methodology to assess the potential violation of the missing-at-random 
assumption, specifically a pattern mixture model (PMM). For the PMM, the imputation model will 
account for the differing missing value patterns based on LDL-C collected in the presence or 
absence of study treatment administration for those patients randomized into the study. 
10.4.3.2. Secondary Efficacy Analysis 
The key secondary efficacy endpoints (defined in Section 4.2.2.1) and other secondary efficacy 
endpoints (described in Section 4.2.2.2 for the double-blind treatment period, descriptive 
summaries and analyses will be performed in the ITT population or mITT population, 
corresponding to the specified estimand for the endpoint. 
For descriptive summaries, percent change, and when appropriate, absolute change from baseline 
in LDL-C, total-C, HDL-C, TG, and non-HDL-C will be provided at each time point for each 
treatment group.  All measurements, scheduled or unscheduled, will be assigned to analysis 
windows defined in the SAP in order to provide an assessment for these time points.  Laboratory 
assessments other than the ones provided by the central laboratory will be excluded.  For TG, 
measurements on not fasting patients will be excluded.  The time profile of each parameter will be 
plotted by treatment group with the corresponding standard errors.  Similar tables (with either 
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percent change from baseline or absolute change from baseline for the ratio) and plots will be 
provided for other efficacy parameters: ApoB, ApoA-1, ratio ApoB/ApoA-1, Lp(a). 
Multiple types of measurements are planned to be analyzed during differing time points in the trial, 
specifically continuous measurements expected to have a normal distribution (example: percent 
change in LDL-C), continuous measurements expected to have a non-normal distribution 
(example: TG), and binary measurements (example: proportion of patients with at least 30% 
reduction in LDL-C). 
I. 
Continuous endpoints anticipated to have a normal distribution 
Continuous secondary variables defined in Section 4.2.2 anticipated to have a normal distribution 
(ie, lipids other than TG and Lp(a)) will be analyzed in the analysis populations using the same 
MMRM model as for the primary endpoint.  Specifically, the model will contain fixed categorical 
effects of treatment group, randomization strata, planned time points up to week 12, strata-by-time 
point interaction and treatment-by-time point interaction, as well as the continuous fixed covariates 
of corresponding baseline value and baseline value-by-time point interaction. 
II. 
Continuous endpoints anticipated to have a non-normal distribution 
Continuous secondary efficacy endpoints defined in Section 4.2.2, anticipated to have a 
non-normal distribution (ie, TG and Lp(a)), will be analyzed in the analysis populations using a 
robust regression model (ie, ROBUSTREG SAS procedure with M-estimation option) with 
treatment group and randomization strata as main effect and corresponding baseline value(s) as 
covariate.  Missing values will be addressed using a multiple imputation approach, which will be 
described in the SAP.  The variables in the multiple imputation model will at least include the 
same variables as used in the robust regression model.  The treatment group combined means will 
be provided with respective SE estimates.  The combined mean difference between the treatment 
groups will be provided with the SE, 95% confidence interval and p-value. 
III. 
Binary endpoints 
Binary secondary efficacy endpoints defined in Section 4.2.2 will be analyzed in the analysis 
populations using stratified logistic regression (using the strata option of the SAS logistic 
procedure) with treatment group as main effect and corresponding baseline value(s) as covariate, 
stratified by randomization factor (as per IVRS). Missing values will be addressed using a multiple 
imputation approach which will be described in the SAP.  The variables in the multiple imputation 
model will at least include the same variables as used in the logistic regression model.  Treatment 
effects will be compared and the combined odds ratio estimate between the treatment groups, with 
their corresponding 95% CIs and p-value will be provided. In the data dependent case that the 
logistic regression method is not applicable (eg, the response rate is zero in 1 treatment arm and 
thus the maximum likelihood estimate may not exist), the last observation carried forward 
approach would be used for handling of missing values and an exact conditional logistic regression 
would be performed to compare treatment effects.  The last observation carried forward imputation 
method will consist of using the last value obtained up to the week 12 time window to impute the 
missing week 12 value. 
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10.4.3.3. Other Efficacy Endpoints 
During the open-label treatment period, efficacy variables will be explored through descriptive 
statistics at each scheduled visit for the total patients administered open-label study treatment 
(total), as well as by the patient subgroups of study treatment received in the double-blind treatment 
period (ie, alirocumab, placebo).  Formal statistical testing is not planned.  Descriptive statistics 
will include the same parameters as described for each variable in the double-blind treatment 
period. 
For patients receiving alirocumab in the double-blind treatment period, a combined summary 
including both the double-blind and open-label treatment period assessments may be considered, 
referencing the double-blind baseline for variable calculations.  Prolonged time between last dose 
of double-blind treatment and first dose of open-label treatment will need to be taken into 
consideration when combining longitudinal efficacy data.  Again, formal testing is not planned 
due to the absence of control group. 
10.4.3.4. Multiplicity Considerations 
In order to handle multiple key secondary endpoints during the double-blind treatment period for 
the comparison of the alirocumab group and the placebo group, the overall type-I error will be 
controlled by the use of a hierarchical inferential approach. Statistical significance of the 
double-blind primary parameter at the 0.05 alpha level is required before drawing inferential 
conclusions about first key secondary parameter. Inferential conclusions about successive key 
secondary parameters require statistical significance of the prior one.  The hierarchy testing 
sequence is the order of endpoints as presented in Section 4.2.2.1. 
This fixed hierarchical approach will ensure a strong control of the overall type-I error rate at the 
0.05 level during the double-blind treatment period. 
No further adjustments will be made for other secondary endpoints for which p-values will be 
provided for descriptive purpose only. 
10.4.4. 
Safety Analysis 
No formal inferential testing is planned for safety analyses.  Summaries will be descriptive in 
nature.  All safety analyses will be performed on the safety population using the following common 
rule: 
 The baseline value is defined as the last available value before the first dose of the 
investigational study drug. 
10.4.4.1. Adverse Events  
All AEs reported in this study will be coded using the currently available version of the MedDRA.  
The verbatim text, the preferred term (PT), and the system organ class (SOC) will be provided in 
the patient listings. 
Definitions 
For safety variables, the following observation periods are defined: 
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 The pretreatment period is defined as the time from signing the ICF to before the first 
dose of double-blind investigational study drug. 
 The double-blind TEAE observation period is defined as the time from first dose of 
double-blind investigational study drug to the last dose of double-blind investigational 
study drug + 70 days, or up to the day before first dose of open-label investigational 
study drug administration, whichever is earlier. 
 The open-label TEAE observation period is defined as the time from first open-label 
study treatment administration to the last open-label study treatment administration 
+ 70 days. 
 The post-treatment observation period is defined as the time from the day after the end 
of the respective TEAE periods up to the patient’s end of study. 
 Pre-treatment AEs are defined as those that developed, worsened, or became serious 
during the pre-treatment period. 
 Double-blind and open-label TEAEs are defined as those that developed, worsened, or 
became serious during the respective TEAE periods. 
 Double-blind and open-label post-treatment AEs are defined as those that developed, 
worsened, or became serious during the post-treatment period. 
Analysis 
Treatment-emergent and post treatment AEs in both the double-blind and open-label study periods 
will be summarized in incidence tables by (at least) SOC (sorted by internationally agreed order), 
and PT (sorted by decreasing frequency, and the number (n) and percentage (%) of patients 
experiencing an AE).  The high level group term and high level term can be added in alphabetical 
order, as applicable.  Multiple occurrences of the same event in the same patient will be counted 
only once in the tables within the TEAE period.  Data conventions for missing or partial AE dates 
will be addressed in the SAP.  The denominator for computation of percentages is the safety set 
within each treatment group. 
Adverse event incidence tables will be provided by treatment group for all types of TEAEs:  all 
TEAEs, all TEAEs of interest (defined with a PT or a pre-specified grouping), TEAE by severity, 
all treatment-emergent SAEs, and all TEAEs leading to permanent treatment discontinuation. 
If any clinically significant signal is detected and further characterization is needed, or for AEs of 
clinical interest, selected TEAEs will be analyzed using a time-to-event approach (Kaplan Meier 
methodology) to account for the differential exposure time in all patients. Time from the first dose 
of the investigational study drug to the first occurrence of the event will be calculated (only the 
first event will be counted).  Patients without any event will be censored at the end of the TEAE 
period. 
Death 
The following death summaries will be generated: 
 Number (%) of patients who died by study period (TEAE and post treatment in both 
the double-blind and open-label study periods) 
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 Death in nonrandomized patients or randomized and not treated patients 
 TEAE leading to death (death as an outcome on the AE CRF page, as reported by the 
investigator) by (at least) SOC (sorted by internationally agreed order), and PT (sorted 
by decreasing frequency, showing the number (n) and percentage (%) of patients) for 
both the double-blind and open-label study periods 
10.4.4.2. Laboratory Data and Vital Signs 
The following definitions will be applied to laboratory parameters and vital signs: 
 The baseline value is defined as the last available value before first dose of double-blind 
investigational study drug. 
 The PCSA 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. 
 PCSA criteria will determine which patients had at least 1 PCSA during the TEAE 
period, taking into account all evaluations performed during the TEAE period, 
including unscheduled or repeated evaluations.  The number of all such patients will 
be the numerator for the PCSA percentage. 
 Double-blind treatment period:  the treatment period used for quantitative analysis 
(laboratory results and vital signs) in the double-blind period is defined as the time 
from the first double-blind dose of the investigational study drug to the last 
double-blind dose of the investigational study drug + 21 days, or up to the first 
open-label dose of the investigational study drug, whichever comes first. 
 Open-label treatment period:  the treatment period used for quantitative analysis 
(laboratory results and vital signs) in the open-label study period is defined as the time 
from the first open-label dose of the investigational study drug to the last open-label 
dose of the investigational study drug + 21 days. 
Summary statistics (including mean, median, Q1, Q3, standard error, minimum and maximum) of 
all laboratory variables and all vital sign parameters (raw data and changes from baseline) will be 
calculated for each visit, last and worst value assessed during the treatment period, and presented 
by treatment group.  For selected parameters, mean changes from baseline with the corresponding 
standard error will be plotted over time (at same time points) in each treatment group. 
The incidence of PCSAs at any time during the TEAE period will be summarized by treatment 
group for the double-blind study period, and by all patients and by the as-treated treatment group 
for the open-label study period, whatever the baseline level and/or according to the following 
baseline categories: 
 Normal/missing 
 Abnormal according to PCSA criterion or criteria 
For laboratory parameters for which PCSA criterion is not defined, similar table(s) using the 
normal range could be provided. 
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Hepatitis C Test 
The number and percentage of patients with an observed seroconversion for the hepatitis C test 
will be provided by treatment group for the double-blind study period, and by all patients and also 
by treatment group of double-blind period for the open-label study period. 
10.4.4.3. Treatment Exposure 
The double-blind duration of treatment exposure will be calculated for each of the 2 treatment 
arms as: 
 Duration of alirocumab exposure in weeks defined as: (last double-blind study 
treatment administration date + 14 – first double-blind study treatment administration 
date)/7, regardless of unplanned intermittent discontinuations. 
 The total number of double-blind treatment injections by patient. 
The double-blind study treatment duration of exposure, measured in weeks, will be summarized 
by at least mean, median, SD, and minimum/maximum.  The categorical data of number of 
injections will be summarized by patient counts and percentages. 
The OLE duration of treatment exposure will be calculated for each of the 2 treatment arms of the 
double-blind period as well as patient total: 
 Duration of open-label alirocumab exposure in weeks defined as: (last open-label 
alirocumab treatment administration date + 14 – first open-label alirocumab treatment 
administration date)/7, regardless of unplanned intermittent discontinuations. 
 The total number of open-label alirocumab treatment injections by patient. 
The open-label duration of exposure measured in weeks will be summarized by at least mean, 
median, SD, and minimum/maximum.  The categorical data of number of injections will be 
summarized by patient counts and percentages. 
The combined duration of treatment exposure for patients who received the alirocumab treatment 
in the double-blind period is calculated as: 
 Combined duration of alirocumab exposure in weeks defined as: double-blind 
treatment exposure plus open-label treatment exposure, regardless of unplanned 
intermittent discontinuations.  
 Combined total number of alirocumab treatment injections by patient defined as: total 
number of double-blind injections plus total number of open-label injections for each 
patient. 
The combined duration of exposure measured in weeks will be summarized by at least mean, 
median, SD, and minimum/maximum.  The categorical data of number of injections will be 
summarized by patient counts and percentages. 
10.4.4.4. Treatment Compliance 
Compliance during the double-blind period will be assessed using the following parameter:  The 
injection frequency will be defined for each patient as the average number of days between 2 
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injections, that is: (last dose date – first dose date)/(number of injections -1) for patients receiving 
at least 2 injections. 
The parameter will be summarized descriptively (N, mean, SD, median, min and max). 
10.4.5. 
Analysis of Drug Concentration Data 
Descriptive statistics of concentrations of alirocumab will be provided by treatment group.  Plots 
of the individual concentrations of alirocumab will be presented versus actual time (linear and log 
scales).  Plots of the mean or median concentrations of alirocumab will be presented by time 
point (linear and log scales). 
10.4.6. 
Analysis of Pharmacodynamics Data 
Descriptive statistics of concentrations of total PCSK9 and free PCSK9 will be provided by 
treatment group.  Plots of the individual concentrations of total and free PCSK9 will be presented 
versus actual time (linear and log scales).  Plots of the mean or median concentrations of total and 
free PCSK9 will be presented by time point (linear and log scales). 
10.4.7. 
Analysis of Anti-Drug Antibody Data 
The ADA status and ADA titers will be summarized by treatment group and visit using descriptive 
statistics.  If appropriate, correlations between ADA titers, safety and/or efficacy endpoints will 
be provided. 
10.5. 
Timing of Statistical Analysis  
The analyses will be conducted in 2 steps.  The first analysis will be conducted as soon as all 
patients have been randomized and all data through week 12 (double-blind period) have been 
collected and validated; this will consist of the final analysis of the double-blind primary and 
secondary efficacy endpoints.  The safety analysis will be performed on all safety data collected 
and validated at the time of the first analysis. 
Since the double-blind primary efficacy measure data collection will have been concluded at the 
time of this first analysis, the significance level for the study remains at 0.05.  This first analysis 
may be used for the submission to health authorities or other interested parties. 
The second analysis will be performed with the data from the open-label treatment period and will 
consist of the final analysis for the safety and exploratory efficacy measures. 
The results of the first analysis will not be used to change the conduct of the ongoing study in any 
aspect.  Individuals involved in the first step analysis of the study will not be involved in the 
conduct of the study afterwards; individual patient identification will not be released to anyone 
who is directly involved in the conduct of the study.  The first step analysis process, the measures 
used to protect the blind and the integrity of the study, the communication plan, and the 
confidentiality agreement will be described in a separate document. 
10.6. 
Additional Statistical Data Handling Conventions 
Additional data handling conventions will be described in the statistical analysis plan. 
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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/ophthalmic 
history) will be done using internationally recognized and accepted dictionaries. 
The CRF data for this study will be collected with an electronic data capture (EDC). 
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, investigational study drug supply 
 EDC system – data capture 
 Statistical Analysis Software – statistical review and analysis 
 Pharmacovigilance safety database 
12. 
STUDY MONITORING  
12.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, CRO monitor) will visit each site prior to enrollment of 
the first patient, and periodically during the study. 
12.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). 
The investigator must keep all source documents on file with the CRF.  Case report forms and 
source documents must be available at all times for inspection by authorized representatives of the 
sponsor and regulatory authorities. 
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12.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic CRFs within 
the EDC system by trained site personnel.  All required CRFs must be completed for each and 
every patient enrolled in the study.  After review of the clinical data for each patient, the 
investigator must provide an electronic signature.  A copy of each patient CRF casebook is to be 
retained by the investigator as part of the study record and must be available at all times for 
inspection by authorized representatives of the sponsor and regulatory authorities. 
Corrections to the CRF will be entered in the CRF by the investigator or an authorized designee.  
All changes, including date and person performing corrections, will be available via the audit trail, 
which is part of the EDC system.  For corrections made via data queries, a reason for any alteration 
must be provided. 
13. 
AUDITS AND INSPECTIONS  
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities.  Should this occur, the investigator is responsible for: 
 Informing the sponsor of a planned inspection by the authorities as soon as notification 
is received, and authorizing the sponsor’s participation in the inspection 
 Providing access to all necessary facilities, study data, and documents for the inspection 
or audit 
 Communicating any information arising from inspection by the regulatory authorities 
to the sponsor immediately 
 Taking all appropriate measures requested by the sponsor to resolve the problems found 
during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, CRFs, 
medical records, correspondence, ICFs, IRB/EC files, documentation of certification and quality 
control of supporting laboratories, and records relevant to the study maintained in any supporting 
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 ICH guidelines for GCP and applicable regulatory 
requirements. 
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14.2. 
Informed Consent/Assent 
The principles of informed consent and assent 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 the investigational 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. 
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 
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 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 
16. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
16.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely.  Reasons may include efficacy, 
safety, or futility, among others.  Should the sponsor decide to terminate the study, the 
investigator(s) will be notified in writing. 
16.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
Investigator’s Decision 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at least 
30 days’ notice.  The final decision should be made through mutual agreement with the sponsor.  
Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing.  
Reasons may include the following, among others: 
 The investigator has received all items and information necessary to perform the study, 
but has not enrolled any patient within a reasonable period of time 
 The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
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breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines 
 The total number of patients required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB/EC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection of 
the patients’ interests. 
17. 
STUDY DOCUMENTATION 
17.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the CRF must be signed 
electronically by the investigator.  This signed declaration accompanies each set of patient’s final 
CRF that will be provided to the sponsor. 
17.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of CRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
regulatory authorities.  The investigator must consult with the sponsor before discarding or 
destroying any essential study documents following study completion or discontinuation.  Records 
must be destroyed in a manner that ensures confidentiality. 
If the investigator's personal situation is such that archiving can no longer be ensured, the 
investigator must inform the sponsor and the relevant records will be transferred to a mutually 
agreed-upon destination. 
18. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
19. 
FINANCING AND INSURANCE  
Financing and insurance information is provided as a separate agreement. 
20. 
PUBLICATION POLICY 
The publication policy is provided as a separate agreement. 
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21. 
REFERENCES 
Cholesterol Treatment Trialists’ Collaboration 2010.  http://www.cttcollaboration.org 
Crestor Product insert:  www.crestor.com 
Cuchel M, Meagher EA, du Toit Theron H, Blom DJ, Marais AD. Et al., Efficacy and safety of a 
microsomal triglyceride transfer protein inhibitor in patients with homozygous familial 
hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet. 2013 Jan 
5;381(9860):40-6. 
Gagné C, Bays HE, Weiss SR, Mata P, Quinto K, Melino M, Cho M, Musliner TA, Gumbiner B; 
Ezetimibe Study Group. Efficacy and safety of ezetimibe added to ongoing statin therapy for 
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of 
patients 
with 
primary 
hypercholesterolemia. 
Am 
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Cardiol. 
2002 Nov 15;90(10):1084-91. 
Ginsberg HN, Rader DJ, Raal FJ, Guyton JR, Baccara-Dinet MT, Lorenzato C, Pordy R, Stroes E. 
Efficacy and Safety of Alirocumab in Patients with Heterozygous Familial Hypercholesterolemia 
and LDL-C of 160 mg/dl or Higher. Cardiovasc Drugs Ther. 2016; 30(5):473-483. 
Goldberg AC, Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, Robinson JG, et al., Familial 
hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: 
clinical guidance from the National Lipid Association Expert Panel on Familial 
Hypercholesterolemia. J Clin Lipidol. 2011 Jun;5(3 Suppl):S1-8.  
Kastelein JJ, Ginsberg HN, Langslet G, Hovingh GK, Ceska R, Dufour R. et al., ODYSSEY FH I 
and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial 
hypercholesterolaemia. 
Eur 
Heart 
J. 
2015 
Nov 
14;36(43):2996-3003. 
doi: 
10.1093/eurheartj/ehv370. 
Kieser M, Friede T. Simple procedures for blinded sample size adjustment that do not affect the 
type I error rate. Stat Med. 2003; 22(23): 3571-81. 
Kolansky DM, Cuchel M, Clark BJ, Paridon S, McCrindle BW, Wiegers SE. et al., Longitudinal 
evaluation and assessment of cardiovascular disease in patients with homozygous familial 
hypercholesterolemia. 
Am 
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2008 
Dec 
1;102(11):1438-43. 
doi: 
10.1016/j.amjcard.2008.07.035. 
Lipitor Product insert:  www.lipitor.com  
Marais AD, Raal FJ, Stein EA, Rader DJ, Blasetto J, Palmer M, Wilpshaar W. A dose-titration and 
comparative study of rosuvastatin and atorvastatin in patients with homozygous familial 
hypercholesterolaemia. Atherosclerosis. 2008 Mar;197(1):400-6. 
Marais AD, Raal FJ, Stein EA, et al. A dose-titration and comparative study of rosuvastatin and 
atorvastatin in patients with homozygous familial hypercholesterolaemia. Atherosclerosis 2008; 
197: 400–06. 
Praluent Product insert. www.praluent.com  
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Raal FJ, Giugliano RP, Sabatine MS, Koren MJ, Langslet G, Bays H, Blom D. et al., Reduction in 
lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of 
more than 1,300 patients in 4 phase II trials. J Am Coll Cardiol. 2014;63(13):1278-88. doi: 
10.1016/j.jacc.2014.01.006 
Raal FJ, Honarpour N, Blom DJ, Hovingh GK, Xu F, Scott R, Wasserman SM, Stein EA; TESLA 
Investigators. 
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homozygous 
familial 
hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. 
Lancet. 2015;385(9965):341-50. doi: 10.1016/S0140-6736(14)61374-X. 
Raal FJ, Pappu AS, Illingworth DR, Pilcher GJ, Marais AD, Firth JC, Kotze MJ, Heinonen TM, 
Black DM. Inhibition of cholesterol synthesis by atorvastatin in homozygous familial 
hypercholesterolaemia. Atherosclerosis. 2000 Jun;150(2):421-8. 
Raal FJ, Pilcher GJ, Illingworth DR, Pappu AS, Stein EA, Laskarzewski P. et al., Expanded-dose 
simvastatin is effective in homozygous familial hypercholesterolaemia. Atherosclerosis. 
1997 Dec;135(2):249-56. 
Raal FJ, Pilcher GJ, Panz VR, van Deventer HE, Brice BC, Blom DJ, Marais AD. Reduction in 
mortality in subjects with homozygous familial hypercholesterolemia associated with advances in 
lipid-lowering therapy. Circulation. 2011 Nov 15;124(20):2202-7. 
Raal FJ, Santos RD, Blom DJ, Marais AD, Charng MJ, Cromwell WC. et al., Mipomersen, an 
apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients 
with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled 
trial. Lancet. 2010 Mar 20;375(9719):998-1006.  
Repatha Product insert: www.repatha.com  
Schiel R, Bambauer R, Müller UA. Four years' treatment efficacy of patients with severe 
hyperlipidemia. Lipid lowering drugs versus 
LDL-apheresis. 
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1995 Dec;18(12):786-93. 
Schiel R, Bambauer R, Muller UA. Four years’ treatment efficacy of patients with severe 
hyperlipidemia. Lipid lowering drugs versus LDL apheresis. Int J Artif Organs 1995;18:786-793 
Schettler V, Neumann CL, Hulpke-Wette M, Hagenah GC, Schulz EG, Wieland E, German 
Apheresis Working Group, Current view: indications for extracorporeal lipid apheresis treatment. 
Clin Res Cardiol Suppl. 2012 Jun;7:15-9. 
Watts GF, Gidding S, Wierzbicki AS, Toth PP, Alonso R, Brown WV. et al.  Integrated guidance 
on the care of familial hypercholesterolemia from the International FH Foundation. J Clin Lipidol. 
2014;8(2):148-72. 
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22. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: A Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of Alirocumab in Patients with 
Homozygous Familial Hypercholesterolemia, Amendment 2, 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: Factors to Consider in Assessing the Relationship of Adverse Events to Study 
Drug and Study Conduct or Injection Procedure, Study Procedure, or 
Background Treatment, etc. 
Is there a reasonable possibility that the event may have been caused by the investigational study 
drug or study conduct or injection procedure, study procedure, or background treatment, etc.? 
No: 
 due to external causes such as environmental factors or other treatment(s) being 
administered 
 due to the patient’s disease state or clinical condition 
 do not follow a reasonable temporal sequence following the time of administration of 
the dose of the investigational study drug or injection procedure, study procedure, or 
background treatment, etc. 
 do not reappear or worsen when dosing with the investigational study drug or injection 
procedure, study procedure, or background treatment, etc.is resumed 
 are not a suspected response to the investigational study drug or injection procedure, 
study procedure, or background treatment, etc. based upon preclinical data or prior 
clinical data 
Yes: 
 could not be explained by environmental factors or other treatment(s) being 
administered 
 could not be explained by the patient’s disease state or clinical condition 
 follow a reasonable temporal sequence following the time of administration of the dose 
of the investigational study drug or injection procedure, study procedure, or 
background treatment, etc. 
 resolve or improve after discontinuation of the investigational study drug or injection 
procedure, study procedure, or background treatment, etc. 
 reappear or worsen when dosing with the investigational study drug or injection 
procedure, study procedure, or background treatment, etc. is resumed 
 are known or suspected to be a response to the investigational study drug or injection 
procedure, study procedure, or background treatment, etc. based upon preclinical data 
or prior clinical data 
NOTE:  This list is not exhaustive. 
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Signature of Sponsor’s Responsible Officers 
(Scientific/Medical Monitor, Regulatory Representative, Clinical Study Team Lead, and 
Biostatistician) 
To the best of my knowledge, this protocol accurately describes the conduct of the study. 
Study Title: 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to 
Evaluate the Efficacy and Safety of Alirocumab in Patients with 
Homozygous Familial Hypercholesterolemia 
Protocol Number: 
R727-CL-1628 
 
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-00067475-1.0 Approved - 04 Jan 2019 GMT-5:00
VV-TMF-1164593 - 1.0 - Approved

Signature Page for VV-RIM-00067475 v1.0
Signature Page for VV-RIM-00067475 v1.0 Approved
ESig Approval
ent
02-Jan-2019 18:36:49 GMT+0000
ESig Approval
02-Jan-2019 18:39:08 GMT+0000
ESig Approval
03-Jan-2019 14:44:29 GMT+0000
ESig Approval
04-Jan-2019 20:20:21 GMT+0000
                                        VV-RIM-00067475-1.0 Approved - 04 Jan 2019 GMT-5:00
VV-TMF-1164593 - 1.0 - Approved