Conditions: Homozygous Familial Hypercholesterolemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 69
Healthy volunteers: no

Brief summary:
The primary objective of the study is to demonstrate the reduction of low-density lipoprotein cholesterol (LDL-C) with alirocumab subcutaneous (SC) every 2 weeks (Q2W) in comparison to placebo after 12 weeks of treatment.

The secondary objectives of the study are:

* To evaluate the effect of alirocumab 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 participants with 15%, 30%, and 50% LDL-C reductions, Lp(a), HDL-C, triglycerides \[TG\]) in participants with HoFH
* To evaluate the safety and tolerability of alirocumab SC Q2W in participants with HoFH
* To assess the pharmacokinetics of alirocumab SC Q2W in participants with HoFH
* To assess the potential development of anti-drug (alirocumab) antibodies

Detailed description:

Arms:
arm 1: Alirocumab SC every 2 weeks (Q2W) from baseline (day 1) through week 10 during the double-blind treatment period

Starting at week 12, and continuing through week 22, participants will receive open-label alirocumab SC Q2W arm 2: Matching placebo SC Q2W from baseline through week 10 during the double-blind treatment period

Starting at week 12, and continuing through week 22, participants will receive open-label alirocumab SC Q2W

Interventions: intervention 1: Alirocumab intervention 2: Placebo
Intervention descriptions: intervention 1: Alirocumab SC Q2W intervention 2: Matching placebo SC Q2W

Protocol document:
Prot_000.pdf: 
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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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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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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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 
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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 
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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 
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2015 
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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 
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2008 
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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. 
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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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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 
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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. 
                                        VV-RIM-00067475-1.0 Approved - 04 Jan 2019 GMT-5:00
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Clinical Study Protocol 
R727-CL-1628 Amendment 3 
 
Regeneron Pharmaceuticals, Inc. 
Page 73 of 73  
CONFIDENTIAL 
Signature of Sponsor’s Responsible Officers 
(Scientific/Medical Monitor, Regulatory Representative, Clinical Study Team Lead, and 
Biostatistician) 
To the best of my knowledge, this protocol accurately describes the conduct of the study. 
Study Title: 
A 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

SAP_001.pdf: 
Clinical and Regulatory Development 
Biostatistics and Data Management 
STATISTICAL ANALYSIS PLAN 
VERSION: Final 
Document’s type 
Document Reference 
Effective Date 
Page 
Standard 
BDM-STD-ST4-1.0 
December 15, 2008 
1/83 
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: 
R727-CL-1628 
Investigational Product: 
REGN727/SAR236553 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Statistician: 
 
Clinical Trial Manager: 
 
Clinical Study Director: 
 
Version/Date:  
v1.0 / August 7, 2019 
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NCT03156621


Regeneron Pharmaceuticals, Inc.                                                                Protocol: R727-CL-1628 (alirocumab) 
Statistical Analysis Plan                                                                                                                      August 7, 2019 
 
CONFIDENTIAL 
Page 2 of 83 
The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting.  
 
See appended electronic signature page 
Study Biostatistician   
) 
 
See appended electronic signature page 
Study Pharmacokinetics 
) 
 
See appended electronic signature page 
Study Bioanalytical Sciences (
) 
 
See appended electronic signature page 
Study Medical Director 
) 
 
See appended electronic signature page 
Project Biostatistician  
) 
 
See appended electronic signature page 
Head of BDM or designee 
(
 
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Regeneron Pharmaceuticals, Inc.                                                                Protocol: R727-CL-1628 (alirocumab) 
Statistical Analysis Plan                                                                                                                      August 7, 2019 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ...................................................7 
1. 
OVERVIEW ...............................................................................................................10 
1.1. 
Background/Rationale ................................................................................................10 
1.2. 
Study Objectives .........................................................................................................10 
1.2.1. 
Primary Objectives .....................................................................................................10 
1.2.2. 
Secondary and Exploratory Objectives .......................................................................10 
1.2.3. 
Modifications from the Statistical Section of Protocol Amendment 3 .......................11 
1.2.4. 
Modifications from the Approved Statistical Analysis Plan ......................................11 
2. 
INVESTIGATING PLAN ..........................................................................................12 
2.1. 
Study Design and Randomization ...............................................................................12 
2.2. 
Sample Size and Power Considerations .....................................................................12 
2.3. 
Study Plan ...................................................................................................................14 
3. 
ANALYSIS POPULATIONS .....................................................................................15 
3.1. 
The Efficacy Analysis Sets .........................................................................................15 
3.1.1. 
Intent-to-treat Population ............................................................................................15 
3.1.2. 
Modified Intent-to-Treat .............................................................................................16 
3.2. 
Safety Analysis Set .....................................................................................................16 
3.3. 
The Anti-alirocumab Antibody Analysis Set ..............................................................16 
3.4. 
Pharmacokinetic Analysis Set ....................................................................................17 
3.5. 
Quality-of-life Analysis Set ........................................................................................17 
3.6. 
The Open-Label Analysis Set .....................................................................................17 
4. 
ANALYSIS VARIABLES .........................................................................................18 
4.1. 
Demographic and Baseline Characteristic Variables ..................................................18 
4.2. 
Medical History and Disease Characteristics .............................................................19 
4.3. 
Prior and Concomitant Medications ...........................................................................22 
4.4. 
Patient Disposition ......................................................................................................23 
4.5. 
Study Treatment Exposure and Compliance Variables ..............................................25 
4.6. 
Efficacy Variables .......................................................................................................26 
4.6.1. 
Primary Efficacy Variable ..........................................................................................27 
4.6.2. 
Key Secondary Efficacy Variables .............................................................................27 
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4.6.3. 
Other Secondary Efficacy Variables ...........................................................................28 
4.7. 
Safety Variables ..........................................................................................................28 
4.7.1. 
Adverse Events Variables ...........................................................................................28 
4.7.1.1. 
Adverse Events and Serious Adverse Events .............................................................29 
4.7.1.2. 
Adverse Events of Special Interest .............................................................................30 
4.7.1.3. 
Events Causing Death .................................................................................................31 
4.7.2. 
Clinical Laboratory Safety Variables ..........................................................................31 
4.7.3. 
Vital Sign Variables ....................................................................................................32 
4.7.4. 
Electrocardiogram Variables ......................................................................................32 
4.8. 
Other Variables ...........................................................................................................32 
4.9. 
Anti-alirocumab Anti-body Variables ........................................................................33 
4.10. 
Pharmacokinetic (PK) Variables ................................................................................34 
4.11. 
Quality-of-Life Variables ............................................................................................34 
4.12. 
Genomics Variables ....................................................................................................35 
5. 
STATISTICAL METHODS .......................................................................................36 
5.1. 
Demographics and Baseline Characteristics ...............................................................36 
5.2. 
Medical History and Disease Characteristics .............................................................36 
5.3. 
Prior and Concomitant Medications ...........................................................................38 
5.4. 
Subject Disposition .....................................................................................................39 
5.5. 
Extent of Study Treatment Exposure and Compliance ...............................................39 
5.5.1. 
Exposure to Investigational Product ...........................................................................39 
5.5.2. 
Measurement of Compliance ......................................................................................40 
5.6. 
Analysis of Efficacy Variables ...................................................................................40 
5.6.1. 
Analysis of Primary Efficacy Variable .......................................................................41 
5.6.1.1. 
Sensitivity to Stratification at Randomization ............................................................42 
5.6.1.2. 
Sensitivity to the Handling of Missing Data ...............................................................42 
5.6.1.3. 
Sensitivity to the Absence of Null/Null Mutations in Both LDL Alleles ...................44 
5.6.1.4. 
Sub-group Analyses ....................................................................................................44 
5.6.2. 
Analyses of Secondary Efficacy Variables .................................................................45 
5.6.2.1. 
Continuous Endpoints Anticipated to have a Normal Distribution ............................45 
5.6.2.2. 
Continuous Endpoints Anticipated to have a Non-normal Distribution .....................46 
5.6.2.3. 
Binary Endpoint Variables ..........................................................................................46 
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Statistical Analysis Plan                                                                                                                      August 7, 2019 
 
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5.6.2.4. 
Sensitivity Analyses of Key Secondary Endpoint Variables ......................................47 
5.6.2.5. 
Summary of Results by Time Point ............................................................................47 
5.6.3. 
Adjustment for Multiple Comparisons .......................................................................48 
5.7. 
Analysis of Safety Data...............................................................................................48 
5.7.1. 
Analysis of Adverse Events ........................................................................................50 
5.7.1.1. 
Patient Deaths .............................................................................................................52 
5.7.2. 
Analysis of Clinical Laboratory Variables ..................................................................53 
5.7.3. 
Analysis of Vital Sign Variables.................................................................................55 
5.7.4. 
Analysis of Electrocardiogram Variables ...................................................................56 
5.8. 
Analysis of Other Variables ........................................................................................56 
5.9. 
Analysis of Anti-alirocumab Antibody Variables ......................................................56 
5.10. 
Analysis of Pharmacokinetic Data ..............................................................................57 
5.11. 
Analysis of Genomics Variables .................................................................................57 
5.12. 
Analysis of Quality-of-Life Variables ........................................................................58 
6. 
DATA CONVENTIONS ............................................................................................59 
6.1. 
Definition of Baseline for Efficacy and Safety Variables ...........................................59 
6.2. 
Data Handling Conventions for Efficacy Variables ...................................................59 
6.3. 
General Data Handling Conventions ..........................................................................59 
6.4. 
General Missing Data Conventions ............................................................................60 
6.5. 
Visit Windows for Time Points ..................................................................................62 
6.6. 
Unscheduled Assessments ..........................................................................................62 
6.7. 
Pooling of Centers for Statistical Analyses ................................................................62 
6.8. 
Statistical Technical Issues .........................................................................................62 
7. 
TIMING OF STATISTICAL ANALYSES ................................................................63 
8. 
SOFTWARE ...............................................................................................................65 
9. 
REFERENCES ...........................................................................................................66 
10. 
APPENDIX .................................................................................................................67 
10.1. 
Summary of Statistical Analyses ................................................................................67 
10.2. 
Windows for Analysis Time Points ............................................................................67 
10.3. 
Criteria for Potential Clinical Significant Abnormalities (PCSA) .............................69 
10.4. 
EQ-5D Patient Questionnaire and Algorithme ...........................................................74 
10.5. 
List of MedDRA terms for CMQs ..............................................................................76 
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10.6. 
Detailed Description of the Multiple Imputation Procedure.......................................79 
10.7. 
Detailed Description of Pattern Mixture Model .........................................................80 
 
LIST OF TABLES 
Table 1: 
Definition of the Patient Status Regarding Hepatitis C Virus ....................................54 
Table 1a   Analysis Windows Definition for Double-Blind Period – All Endpoints 
Except Vital Signs ......................................................................................................67 
Table 1b  Analysis Windows Definition for Double-Blind Period – Vital Signs .......................68 
Table 2  
Analysis Windows Definition for Open-Label Period ................................................68 
Table 3    Selected PTS From SMQ “Optic Nerve Disorders” Including in the CMQ for 
Neurologic Events.......................................................................................................76 
Table 4  
CMQ “Neurocognitive Disorders – FDA’s Recommendation” .................................77 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................14 
Figure 2   Study DFI11565:  Calculated LDL-C Mean (+/- Se) Percent Change From 
Baseline .......................................................................................................................81 
Figure 3   Study R-727-Cl-1003: Calculated LDL-C Mean (+/- Se) Percent Change 
From Baseline .............................................................................................................81 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA 
Anti-alirocumab antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
Apo 
Apolipoprotein 
AST 
Aspartate aminotransferase 
ATC 
Anatomic therapeutic chemical 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CHD 
Coronary Heart Disease 
CI 
Confidence interval 
CMQ 
Company MedDRA query 
CV 
Cardiovascular 
DBP 
Diastolic blood pressure 
ECG 
Electrocardiogram 
e-CRF 
Electronic case record form 
eDISH 
Evaluation of drug-induced serious hepatotoxicity 
FAS 
Full analysis set 
GGT 
Gamma-glutamyl transferase 
HbA1c 
Glycated haemoglobin A1c 
HDL-C 
High density lipoprotein Cholesterol 
HLGT 
High level group term 
HLT 
High level term 
HoFH 
Homozygous familial hypercholesterolemia 
HR 
Heart rate 
hs-CRP 
High-sensitivity C-reactive protein 
IMP 
Investigational medicinal product 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ITT 
Intent-to-treat 
IVRS 
Interactive voice response system 
IWRS 
Interactive web response system 
LDH 
Lactate dehydrogenase 
LDL-C 
Low density lipoprotein cholesterol 
LLOQ 
Lower limit of quantification 
LLT 
Lowest level term 
LMT 
Lipid Modifying Therapy 
LOCF 
Last observation carried forward 
Lp(a) 
Lipoprotein a 
LS 
Least square 
MAR 
Missing-at-random 
MedDRA 
Medical dictionary for regulatory activities 
MI 
Myocardial infarction 
mITT 
Modified intent-to-treat 
MMRM 
Mixed effect model with repeated measures 
NMAR 
Not-missing-at-random 
PCSA 
Potentially Clinically significant abnormality 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PK 
Pharmacokinetic 
PT 
Preferred Term 
Q1 
First quartile 
Q2W 
Quoque 2 weeks 
Q3 
Third quartile 
RDW 
Red blood cell distribution width 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SBP 
Systolic blood pressure 
SC 
Subcutaneous 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
SD 
Standard deviation 
SE 
Standard error 
SMQ 
Standardized MedDRA query 
SOC 
System organ class 
TEAE 
Treatment emergent adverse event 
TG 
Triglycerides 
Total-C 
Total Cholesterol 
ULN 
Upper limit of normal range 
ULOQ 
Upper limit of quantification 
WHO-DD 
World Health Organization Drug Dictionary 
 
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Statistical Analysis Plan                                                                                                                     August 7, 2019 
 
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1. 
OVERVIEW 
This Statistical Analysis Plan (SAP) is intended to be a detailed description (expanding on the 
statistical analyses described in the protocol) of the definitions and statistical techniques to be 
used for the analyses of data collected in the R727-CL-1628 (ODYSSEY HoFH) study. This 
SAP will be finalized prior to the database lock for the first-step analysis to ensure the credibility 
of the study results by pre-specifying the statistical methods for analyses before unblinding of 
treatment assignments.  The content of this SAP is intended to be inclusive of both the first and 
second-step analyses described in the protocol.   
This plan may be revised during the study to accommodate protocol amendments and adapt to 
unexpected issues in study execution that may affect planned analyses. These revisions will be 
based on blinded data review, and a final plan will be issued prior to the first-step database lock 
(i.e. before treatment assignments become known). For the purposes of this document, 
REGN727/SAR236553 will be referred to as “alirocumab”.  
1.1. 
Background/Rationale 
The objective of this study is to evaluate the efficacy, safety and tolerability of alirocumab in 
patients with homozygous familial hypercholesterolemia (HoFH). Patients will be maintained on 
their background treatment throughout the study, supporting the choice of placebo for the control 
group.  Considering patients are already receiving maximally tolerated lipid modifying therapy 
(LMT) including lipid apheresis, the choice of a parallel-group placebo-controlled study design is 
appropriate to provide the most unbiased assessment of the efficacy and safety of alirocumab.  
1.2. 
Study Objectives 
1.2.1. 
Primary Objectives 
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. 
1.2.2. 
Secondary and Exploratory Objectives 
The secondary objectives of the study include: 
 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 
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 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 
The other objectives of the study include: 
 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 
1.2.3. 
Modifications from the Statistical Section of Protocol Amendment 3 
This SAP is based on Protocol R727-CL-1628 Amendment 3. The following modification from 
the protocol amendment 3 is made in this SAP: 
 The analysis for new onset of diabetes in Protocol Section 9.3.3 (Adverse Events of 
Special Interest) is deleted since the definition for new onset of diabetes is not 
appropriate for this short-term study. Instead, the analysis for diabetes mellitus or 
diabetic complications is added in Section 4.7.1.2. 
1.2.4. 
Modifications from the Approved Statistical Analysis Plan 
This is the first version of the Statistical Analysis Plan (SAP). 
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Statistical Analysis Plan                                                                                                                     August 7, 2019 
 
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2. 
INVESTIGATING PLAN 
2.1. 
Study Design and Randomization 
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 in the double-blind treatment period.  Randomization will be 
stratified by apheresis treatment status (Yes/No). 
The study will consist of up to 5 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 during which all patients will receive 
alirocumab.  Patients not continuing on to another lipid lowering study will undergo an 8-week 
follow-up period. 
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-step analysis database lock. 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 efficacy measures beyond week 12 time point. 
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.  
2.2. 
Sample Size and Power Considerations 
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, a 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 
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percent change in LDL-C of 20%, with a 5% two-sided significance level and assuming a 
standard deviation (SD) of 20%.  Assuming a 5% non-evaluable patient rate for the primary 
efficacy endpoint, the study sample size is 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 Guideline on Statistical Principles for Clinical Trials, 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) (6) 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) (6), 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 (e.g., 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 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. 
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2.3. 
Study Plan 
The study will consist of up to 5 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, a 
mandatory 12-week open-label treatment period, and an 8-week follow-up period (Figure 1).   
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 (Day 225) (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) 
 
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3. 
ANALYSIS POPULATIONS  
Two efficacy populations will be defined for this study, specifically the Intent-to-Treat (ITT) 
population and the Modified Intent-to-Treat population (mITT).  The primary efficacy analysis 
population is the ITT population.  Five additional patient populations are defined for safety, 
anti-drug (alirocumab) anti-body (ADA), pharmacokinetic (PK), quality-of-life, and open-label 
analyses. For the purposes of the definitions below, a patient is considered randomized to study 
treatment when they have been screened and received a double-blind treatment kit number 
allocated and recorded in the IVRS/IWRS database, regardless of whether the treatment kit was 
used or not.      
As with all trials, odd cases (usually rare) occur for patient eligibility in the analysis populations.  
The following are three common cases with the planned resolution of each type of case should 
they occur. 
 Patients administered study treatment without randomization or before randomization 
will not be considered as “randomized” and therefore will not be included in any 
analysis population. The safety experience from these patients will be reported 
separately. 
 For patients found to be randomized more than once in this trial, safety data from the 
first randomization will be included in the safety population, with safety data 
associated with the later randomization reported separately.  Inclusion of efficacy data 
from the patient randomized more than once in the two efficacy populations will be 
decided on a case-by-case basis prior to the unblinding of treatment assignments and 
documented in the study report. 
 Patients successfully randomized and administered study treatment, but later found to 
violate inclusion/exclusion criteria, will be included in all analyses with appropriate 
documentation for the protocol deviation.  
3.1. 
The Efficacy Analysis Sets 
3.1.1. 
Intent-to-treat Population 
The ITT population (also known as the full analysis set [FAS]) is defined as all randomized 
patients who had at least 1 measurement value for LDL-C before first dose of double-blind 
investigational study drug (i.e., baseline). 
Patients in the ITT population will be analyzed according to the treatment group allocated by 
randomization (i.e., as-randomized treatment group). 
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3.1.2. 
Modified Intent-to-Treat 
The mITT 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 (i.e., baseline). 
 Availability of at least 1 LDL-C value during the efficacy treatment period and within 
one of the analysis windows (defined in Appendix 10.2) 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. 
3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized patients who received any double-blind 
investigational study drug (safety population). Patients will be analyzed according to the 
treatment actually received (i.e. as-treated treatment group, placebo or alirocumab). Below are 
unusual cases with the resolution for each case. 
 Randomized patients for whom it is unclear whether they took the study drug will be 
included in the safety population as randomized. 
 For patients receiving study drug from more than 1 treatment group during the trial, 
the treatment group allocation for as-treated analysis will be the one in which the 
patient was treated with the highest number of injections. In case of the same number 
of injections of each treatment is received, the as-treated treatment group will be the 
as-randomized group. 
3.3. 
The Anti-alirocumab Antibody Analysis Set 
The anti-alirocumab antibody analysis of the double-blind period will be performed on all 
randomized and treated patients (safety population) with a sample at week 0 (baseline) and at 
least 1 evaluable sample for anti-alirocumab antibodies after the first dose of double-blind study 
treatment (ADA population). 
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3.4. 
Pharmacokinetic Analysis Set 
The pharmacokinetic analysis of the double-blind period will be performed on all randomized 
and treated patients (safety population) with at least 1 evaluable PK sample after the first dose of 
double-blind study treatments (PK population). 
3.5. 
Quality-of-life Analysis Set 
The analyses for quality of life of the double-blind period will be performed on all randomized 
and treated patients (safety population) with a baseline and at least 1 matching post-baseline 
evaluation for at least one of the 5 dimensions after the first dose of double-blind study treatment 
(quality-of-life population). 
3.6. 
The Open-Label Analysis Set 
For the open-label period, the open-label analysis population for all measurements (efficacy, 
safety, quality of life, 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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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristic Variables 
For each patient, demographic and baseline characteristics are obtained from the last available 
value up to the date and time of the first study treatment administration (i.e. baseline definition).  
For patients randomized and not treated, the baseline value is defined as the last available value 
obtained up to the date and time of randomization. 
All baseline safety and efficacy parameters (apart from those listed below) are presented along 
with the summary statistics in the safety and efficacy sections. 
Demographic Characteristics 
Demographic variables will include gender (Male, Female), race (White, Black or African 
American, Asian, American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, 
Other), age in years (quantitative and qualitative variable: <45, ≥45 to <65, ≥65 to <75, and ≥75 
years; and <65, and ≥65 years), and ethnicity (Hispanic or Latino, Not Hispanic or Latino). 
Baseline Characteristics 
Baseline variables will include body mass index (BMI in kg/m²: quantitative and qualitative 
variable defined as <30, ≥30), weight (kg), smoking status, alcohol habit, randomization strata as 
reported in the IVRS, randomization strata as reported from the e-CRF, apheresis schedule at 
randomization (QW, Q2W, NA), HoFH genotypes (homozygotes, compound heterozygotes, 
double heterozygotes) and LMT at randomization.  
Further baseline laboratory variables are defined below: 
 Lipid parameters - quantitative variables for all efficacy parameters  
 hs-CRP 
 Hepatitis B surface antigen 
 Hepatitis C antibody 
 LDL-C : <70, ≥ 70 to <100, ≥100 to <130, ≥130 to <160, ≥160 to <190, ≥190 mg/dL 
(<1.81, ≥ 1.81 to <2.59, ≥2.59 to <3.37, ≥3.37 to <4.14, ≥4.14 to <4.91, ≥4.91 
mmol/L) 
 HDL-C: <40, ≥40 mg/dL (<1.04, ≥1.04 mmol/L) 
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 Fasting TG: <150, ≥150 to <200, ≥200 mg/dL, and category ≥150 mg/dL for mixed 
dyslipidaemia (<1.7 , ≥1.7 to <2.3, ≥2.3 mmol/L, and category ≥ 1.7 mmol/L), 
 Lp(a): <30, ≥30 to <50, ≥50 mg/dL, and category ≥30 mg/dL (<0.3, ≥0.3 to <0.5, and 
≥0.5 g/L, and category ≥ 0.3 g/L). 
4.2. 
Medical History and Disease Characteristics  
As applicable, patient medical history, pre-listed or not in the e-CRF, will be dictionary coded by 
primary system organ class and preferred term using the Medical Dictionary for Regulatory 
Activities (MedDRA), specifically the MedDRA version in effect at the time of database lock for 
the analysis.  Medical history of interest will be assessed through cardiovascular history and risk 
factors (dedicated and pre-listed e-CRF variables of acute myocardial infarction, silent 
myocardial infarction, etc., with outcome of occurred/not occurred), subject medical allergic 
history (dedicated and pre-listed e-CRF variables of allergic rhinitis, chronic sinusitis,  etc., with 
outcome of occurred/not occurred), and family medical allergic history (dedicated and pre-listed 
e-CRF variables of allergic rhinitis, chronic sinusitis,  etc., with outcome of occurred/not 
occurred). Additional other medical history (i.e., not already collected in the pre-printed e-CRFs) 
and surgical history will also be coded and reported.  
Medical history of specific interest includes: 
 Coronary heart disease (CHD)  
 CHD risk equivalents  
 Cardiovascular (CV) risk factors other than hypercholesterolemia (hypertension, type 
2 diabetes, type 1 diabetes, family history of premature CHD). Smoking status will be 
summarized separately. 
 Family history of type 2 diabetes 
 Patient’s allergies (described using all pre-printed terms collected in the medical 
allergic history e-CRF page). 
Further for medical history variables, CHD, CHD risk equivalents, and CV risk factors are 
defined below, and will be based on items or combinations of items pre-listed in the dedicated 
medical history e-CRF page (unless otherwise specified). Patient status for primary and 
secondary CVD prevention is also defined below. 
CHD (regardless if it is ongoing or not) is defined as at least one of the following events: 
 Acute myocardial infarction 
 Silent myocardial infarction 
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 Unstable angina 
 Coronary revascularization procedure 
 Other clinically significant CHD diagnosed by invasive or non-invasive testing  
CHD risk equivalent (regardless if it is ongoing or not) is defined as at least one of the following 
events: 
 Peripheral arterial disease: See definition below.  
 Ischemic stroke 
 Chronic kidney disease 
 Known history of diabetes mellitus (type 1 or 2) AND 2 or more additional risk 
factors among: 
 History of ankle-brachial index ≤ 0.90 
 History of hypertension 
 History of microalbuminuria or macroalbuminuria or dipstick urinalysis at 
screening (week-2) with >2+ protein 
 History of pre–proliferative or proliferative diabetic retinopathy or laser treatment 
for diabetic retinopathy 
 Known family history of premature CHD  
As listed above, “Peripheral arterial disease” history is defined as follows, using combinations of 
the corresponding pre-listed medical history items of the e-CRF page “Cardiovascular history 
and cardiovascular risk factors”: 
 Intermittent claudication (linked to PAD) TOGETHER WITH ankle-brachial index ≤ 
0.90;  
Or 
 Intermittent claudication (linked to PAD) TOGETHER WITH peripheral 
revascularization procedure (angioplasty, stenting) for PAD or peripheral 
revascularization surgery (arterial bypass) for PAD; 
Or 
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 Critical limb ischemia TOGETHER WITH peripheral revascularization procedure 
(angioplasty, stenting) for PAD or thrombolysis for PAD or peripheral 
revascularization surgery (arterial bypass) for PAD. 
Secondary CVD prevention is defined as patients with any of the following history of CVD 
(other patients will be classified as primary CVD prevention): 
 History of CHD (as defined above) 
 History of ischemic stroke 
 History of PAD with severity criteria defined as one of the following events: 
 Intermittent claudication and ankle brachial index ≤ 0.90 
 Peripheral revascularization procedure (angioplasty, stenting) for PAD 
 Thrombolysis for PAD 
 Peripheral revascularization surgery (arterial bypass) for PAD 
 Critical limb ischemia  
CV Risk Factors are defined for this study as high risk and very high risk below. 
 Very high CV risk patients are defined as patients with CHD or CHD risk equivalents 
(ASCVD). 
 High CV risk patients are defined as all other patients. 
Hyperlipoproteinemia disease history will be assessed through diagnosis of HoFH, time from 
diagnosis to study randomization (years), confirmation of diagnosis (genotyping [Yes/No], 
clinical diagnosis [Yes/No], lipid modifying therapies history and received at randomization as 
detailed below.   
 Lipid modifying therapy history, as reported in the “History of 
Hypercholesterolemia/Statin Use” e-CRF page  
 Type of lipid-modifying therapy taken at screening (statin, fibrates, bile acid 
sequestrant, cholesterol absorption inhibitor, nicotinic acid and derivates, omega 3 
fatty acids ≥1000 mg/day, other). 
 Number of patients at screening on a maximal tolerated dose of stain. For those 
not on not statin or not taking the maximum tolerated dose, reason for not statin or 
not taking a maximum tolerated dose. 
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 Number of patients with a history of down-titration of statin dose due to 
tolerability issues 
 Number of patients with a history of changing to a different statin due to 
tolerability issues 
Lipid modifying therapies received at randomization will be derived from the prior and 
concomitant medication e-CRF pages by selecting medications with the type of lipid lowering 
medication tick box checked (“Statin” or “Other lipid modifying therapy”). 
 Background lipid modifying therapy at randomization as reported in the dedicated 
prior and concomitant medication e-CRF pages  
 Number of patients taking atorvastatin 40 to 80 mg, rosuvastatin 20 to 40 mg 
daily  
 Atorvastatin daily dose in mg (10, 20, 40, 80, Other) 
 Rosuvastatin daily dose in mg (5, 10, 20, 40, Other) 
 Simvastatin daily dose in mg (10, 20, 40, 80, Other) 
 Other statins 
 Any LMT other than statins 
 
Any LMT other than nutraceuticals (by chemical class and drug name) 
 
Nutraceuticals (Omega 3 fatty acids (<1000mg/day), Phytosterols, 
Psyllium/plantago, Policosanol, Other nutraceuticals) 
Details (i.e. statin names, doses) for patients who had received at least 2 statins the day of 
randomization will be listed.  
Apheresis history information such as the frequency, treatment technique used and time from the 
first apheresis procedure to the screening visit in years will be summarized. 
4.3. 
Prior and Concomitant Medications 
All medications taken from the time of informed consent/assent to the final study visit, including 
medications that were started before the study and are ongoing during the study, are to be 
reported in Concomitant Medications case report form page.  
All medications will be dictionary coded using the World Health Organization-Drug Dictionary 
(WHO-DD) to both an anatomic category and a therapeutic category, with the version in effect at 
the time of database lock for the analysis.  Drug names will be matched to respective 
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Anatomical-Therapeutic-Chemical (ATC) classification, although a drug can be matched to more 
than one ATC classification (i.e. patients can be counted in several categories for the same 
medication).  Definitions for deriving prior medications and concomitant medications are 
described below, with the understanding that a given medication can be simultaneously classified 
both as a prior and concomitant medication. 
 Prior medications are any medications the patient used within the time period between 
3 months prior to the screening visit up to the day before first study treatment 
administration.  Prior medications can be discontinued before first treatment 
administration or can be ongoing during the treatment phase. 
 Double-blind period concomitant medications are defined as any treatments received 
by the patient concomitantly with the double-blind study treatment, specifically from 
the first day of double-blind study treatment administration to the last day of double-
blind study treatment +70 days (for patients who do not continue into the open-label 
period). For patients entering the open-label period, concomitant medications will be 
truncated at the day before the first open-label study treatment administration. 
 Open-label period concomitant medications are defined as any treatments received by 
the patient concomitantly with the open-label study treatment, specifically from the 
first day of open-label study treatment administration to the last day of open-label 
study treatment +70 days. 
 Double-blind period post-treatment medications are those medications received by the 
patient during the time period starting from 71 days after the last double-blind study 
treatment injection and ending when the patient completes the study or begins 
treatment in the open-label period (whichever comes first) as applicable. 
 Open-label period post-treatment medications are those medications received by the 
patient during the time period starting from 71 days after the last open-label study 
treatment and ending when the patient completes the study. 
4.4. 
Patient Disposition 
Patient disposition includes the description of patient status at major milestone decisions in the 
study, as well as the patient analysis populations.   
For patient study status, patient double-blind treatment period milestone categories are defined 
below.  For all categories of patients, percentages will be calculated using the number of 
randomized patients as the denominator, with two exceptions.  Specifically, the two exceptions 
are for the screened and non-randomized categories, which will not have associated percentages 
shown.  
 Screened patients: The total patient counts will only be shown for pre-randomization 
information, and percentages will not be provided. 
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 Screen failure patients and reasons for screen failure: The total patient counts will 
only be shown for pre-randomization information, and percentages will not be 
provided. 
 Non-randomized but treated patients (include if applicable): The total patient counts 
will only be shown for pre-randomization information, and percentages will not be 
provided. 
 Randomized patients 
 Randomized but not treated patients and reason for not being treated (including 
patient’s decision for treatment period discontinuation) 
 Randomized and treated patients 
 Completed the double-blind study treatment period (i.e. as collected on the end of 
double blind treatment e-CRF) 
 Patients who did not complete the double-blind study treatment period and patient’s 
decision for treatment period discontinuation (as per e-CRF) 
 Patients who discontinued double-blind study treatment by main reason for permanent 
treatment discontinuation 
 Patients entering the open-label treatment period  
As defined in Section 3 of this document, the patient analysis populations for the double-blind 
period are: 
 Randomized population 
 Efficacy populations: ITT and mITT populations 
 Safety population 
 Anti-alirocumab antibody (ADA) population 
 Pharmacokinetic (PK) Population 
 Quality-of-life population 
For patient study status during the open-label period, patient open-label treatment period 
milestone categories are defined below.  For all categories of patients, percentages will be 
calculated using the number of patients in the open-label analysis population as the denominator. 
 Patients treated with open-label study treatment 
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 Completed the open-label study treatment period (i.e. as collected on the end of open 
label treatment e-CRF) 
 Patients who did not complete the open-label study treatment period and patient’s 
decision for treatment period discontinuation (as per e-CRF) 
 Patient ongoing in the open-label study treatment period (applicable for first-step 
analysis only) 
 Patients who discontinued open-label study treatment by main reason for permanent 
treatment discontinuation 
As defined in Section 3 of this document, the patient analysis population for the open-label 
period are: 
 Open-label analysis population 
4.5. 
Study Treatment Exposure and Compliance Variables 
Study treatment exposure variables for injections administered during the double-blind period are 
listed below with associated definitions: 
 Duration of double-blind study treatment 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. Values will be rounded to one decimal place. 
 The total number of double-blind study treatment injections by patient.  
 The following categories will be used for treatment exposure intervals: ≥1 day and <4 
weeks, ≥4 weeks and <8 weeks, ≥8 weeks and <10 weeks, ≥10 weeks.  
Study treatment exposure variables for injections administered during the open-label period are 
listed below with associated definitions: 
 Duration of open-label study treatment 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. Values 
will be rounded to one decimal place. 
 The total number of open-label alirocumab treatment injections by patient.  
 The following categories will be used for treatment exposure intervals: ≥1 day and <4 
weeks, ≥4 weeks and <8 weeks, ≥8 weeks and <10 weeks, ≥10 weeks.  
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Study treatment exposure variables combining double-blind and open-label periods are listed 
below for all patients who received alirocumab in the double-blind period: 
 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 following categories will be used for treatment exposure intervals: ≥1 day and <4 
weeks, ≥4 weeks and <8 weeks, ≥8 weeks and <12 weeks, ≥12 weeks and <16 weeks, 
≥16 weeks and <20 weeks, ≥20 weeks and <22 weeks, ≥22 weeks.  
Compliance will be assessed using the variables below with associated definitions. 
 The mean injection frequency for the double-blind study treatment injections will be 
defined for each patient as the average number of days between 2 consecutive 
injections, that is: (last double-blind injection date – first double-blind injection 
date) / (number of double-blind injections - 1) for patients receiving at least 2 
injections. 
 The mean injection frequency for the open-label study treatment injections will be 
defined for each patient as the average number of days between 2 consecutive 
injections, that is: (last open-label injection date – first open-label injection 
date) / (number of open-label injections - 1) for patients receiving at least 2 injections. 
All major and minor protocol deviations potentially impacting efficacy analyses, randomization 
and drug-dispensing irregularities, as well as other deviations, have been collected and reviewed 
on an ongoing basis throughout the study as described in the Protocol Deviation Definitions 
Document (PDDD).  Both monitoring collected and programmatically derived deviations are 
listed and defined in the PDDD. 
4.6. 
Efficacy Variables 
Efficacy will be assessed through the following lipid parameters: calculated LDL-C (using the 
Friedewald formula), measured LDL-C (obtained using the beta quantification method), total-C, 
HDL-C, TG, non-HDL-C (calculated by subtracting HDL-C from Total-C), Apo B, Apo A-1, the 
ratio of Apo B / Apo A-1, and Lp(a). All lipid parameters will be collected over the course of the 
study and sent to a central laboratory for evaluation, including scheduled and unscheduled blood 
draws. 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.    
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All lipid values obtained during the study (scheduled or unscheduled), regardless of fasting status 
(fasting or not fasting), can be used to provide a value for the primary and secondary efficacy 
endpoints, with the following exceptions: 
 Only fasting TG measurements will be included in the analysis. TG measurements 
with missing fasting status will be excluded from the analyses.  
 On the day of apheresis, any lipid values collected after start of the apheresis for the 
respective visit will be excluded from the efficacy analyses. 
All measurements will be assigned to analysis windows defined in Appendix 10.2 of this SAP, 
with the intent to provide an assessment for week 4 to week 24 time points. For all time points 
post-baseline, the value used for the analyses at a given time point (e.g. at week 12) is the value 
obtained within the corresponding analysis window. The baseline value is defined as the last 
available measurement obtained up to the date and time of the first double-blind study treatment 
injection. For patients randomized and not treated, the baseline value is defined as the last 
available value obtained up to the date and time of randomization.  
4.6.1. 
Primary Efficacy Variable 
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, 
using all LDL-C values regardless of adherence to treatment (ITT estimand).   
The percent change in LDL-C from baseline to week 12 is defined as: 100x (LDL-C value at 
week 12 - LDL-C value at baseline) / LDL-C value at baseline. 
4.6.2. 
Key Secondary Efficacy Variables 
The key secondary efficacy endpoints are: 
 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). 
 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). 
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 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). 
4.6.3. 
Other Secondary Efficacy Variables 
The other secondary efficacy endpoints are: 
 The percent change in LDL-C from baseline to week 12 in the modified (m)ITT 
population, using all LDL-C values 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 treatment 
injection up to 21 days after the last double-blind study treatment injection, or the first open-label 
alirocumab injection (if applicable), whichever comes first. 
4.7. 
Safety Variables 
Patient safety will be assessed through the collection of reported adverse events (AEs), clinical 
laboratory data, vital signs, and ECG. Unless otherwise noted, the baseline value is defined as the 
last available value before the first dose of double-blind study treatment. 
4.7.1. 
Adverse Events Variables  
The period of safety observation starts from the time when the patient gives informed consent 
and continues into the following periods: 
 The PRE-TREATMENT period: defined as the time from the signed informed 
consent up to the first double-blind study treatment injection. 
 The double-blind treatment-emergent adverse event (TEAE) period: defined as the 
time  from the first double-blind study treatment injection up to the day of the last 
double-blind study treatment injection + 70 days (10 weeks), or up to the day before 
first dose of open label investigational study drug administration, whichever is earlier. 
The double-blind TEAE period will include: 
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 The TREATMENT period is defined as the time from the first double-blind study 
treatment injection up to the day of last double-blind study treatment injection + 
21 days, as serum concentration of alirocumab >10 µg/mL is expected for 
approximately 21 days following administration of 150 mg.  Further, in previous 
studies, alirocumab concentrations declining below this concentration also 
showed  a decrease in effect on LDL-C. For patients entering into the open-label 
period, the treatment period will be truncated at the day before the first dose of 
open label investigational study drug administration. 
 The RESIDUAL TREATMENT period is defined as the time from the day of last 
double-blind study treatment injection + 22 days up to the day of last double-blind 
study treatment injection + 70 days (10 weeks), or up to the day before first dose 
of open label investigational study drug administration, whichever is earlier. 
 The open-label treatment-emergent adverse event (TEAE) period is defined as the 
time from first open label study treatment injection up to the day of the last open-label 
study treatment injection + 70 days. 
The open-label TEAE period will include: 
 The TREATMENT period is defined as the time from the first open-label study 
treatment injection up to the day of last open-label study treatment injection + 21 
days. 
 The RESIDUAL TREATMENT period is defined as the time from the day of last 
open-label study treatment injection + 22 days up to the day of last open-label 
study treatment injection + 70 days (10 weeks). 
 The POST-TREATMENT period: defined as starting the day after the end of the 
respective TEAE periods up to the patient’s end of study. 
4.7.1.1. 
Adverse Events and Serious Adverse Events 
Adverse events (including serious adverse events (SAE), AEs causing permanent treatment 
discontinuation, deaths, and AEs of special interest) are recorded from the time of signed 
informed consent until the end of study. All AEs diagnosed by the Investigator will be reported 
and described. 
All AEs will be dictionary coded by “lowest level term (LLT)”, “preferred term (PT)”, “high 
level term (HLT)”, “high level group term (HLGT)” and associated primary “system organ class 
(SOC)” using the version of MedDRA in effect at the time of database lock for the analysis. 
Adverse Event Observation Period  
 Pre-treatment AEs are AEs that developed or worsened or became serious during the 
pre-treatment period. 
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 Double-Blind and open-label treatment-emergent adverse events are AEs that 
developed or worsened or became serious during the respective TEAE period.  
 Double-Blind and open-label post-treatment AEs are AEs that developed or worsened 
or became serious during the post-treatment period. 
4.7.1.2. 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) are AEs (serious or non-serious) required to be 
monitored, documented, and managed in a pre-specified manner as described in the protocol. In 
this study, AESI are the following (their complete descriptions are provided in the protocol): 
 Local injection site reactions, selected using an e-CRF specific tick box on the AE 
page; 
 Allergic events: 
 General allergic events will be tabulated. Events will be selected using 
standardized MedDRA query (SMQ) “hypersensitivity” (broad and narrow) 
excluding the following preferred terms linked to local injection site reactions 
(“infusion site dermatitis”, “infusion site hypersensitivity”, “infusion site rash”, 
“infusion site urticaria”, “infusion site eczema”, “infusion site vasculitis”, 
“infusion site photosensitivity reaction”, “infusion site recall reaction”, “injection 
site dermatitis”, “injection site hypersensitivity”, “injection site rash”, “injection 
site urticaria”, “injection site eczema”,  “injection site vasculitis”, “injection site 
photosensitivity reaction”, and “injection site recall reaction”); 
 ALT ≥3 ULN in the case baseline ALT < ULN or ALT ≥2 times the baseline value in 
the case baseline ALT ≥ ULN, selected using laboratory data; 
 Neurologic events selected using SMQs “demyelination” (broad and narrow), 
“peripheral neuropathy” (broad and narrow), and “Guillain-Barre syndrome” (broad 
and narrow) excluding the following preferred terms: “acute respiratory distress 
syndrome”, “asthenia”, “respiratory arrest” and “respiratory failure” and including 
selected PTs from SMQ "optic nerve disorders" (see Appendix 10.5 Table 3 for the 
list of terms) 
 Symptomatic overdose with investigational medicine product, selected using HLT 
“Overdose” and the tick box “Symptomatic Overdose” in the e-CRF AE page. 
 Pregnancy of female patient/subject (including male subject’s partner), selected using 
appropriate MedDRA codes. 
 Neurocognitive events: 
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 Selected using a company MedDRA query (CMQ), based on the following 5 
HLGTs: “deliria (including confusion)”, “cognitive and attention disorders and 
disturbances”, “dementia and amnestic conditions”, “disturbances in thinking and 
perception”, and “mental impairment disorders”. 
 A second grouping of terms for neurocognitive events was defined based on 
Regulatory Agency request (see Appendix 10.5 Table 4 for the list of terms) 
 Cataract using HLT “Cataract conditions” 
In addition, the following grouping of events will be provided: 
 Hepatic disorder events using SMQ “Hepatic disorder” 
 Diabetes mellitus or diabetic complications using HLGT “diabetes complications” 
(including PTs pertaining to the secondary SOC included in the HLGT), HLT 
“diabetes mellitus”, and HLT “carbohydrate tolerance analyses (incl diabetes)” 
excluding PTs “blood glucose decreased” and “Glycosylated haemoglobin decreased” 
and including the PTs “hyperglycaemia”, “Hyperglycaemic unconsciousness” and 
“Hyperglycaemic seizure” from the HLT "Hyperglyceamic conditions NEC" 
4.7.1.3. 
Events Causing Death 
The observation periods for patient deaths are per the observation periods defined above.  
 Death on-treatment:  deaths occurring during the respective TEAE period (double-
blind or open-label), 
 Death post-treatment:  deaths occurring during the respective post-treatment period 
(double-blind or open-label). 
4.7.2. 
Clinical Laboratory Safety Variables 
Clinical laboratory tests will consist of blood analyses (including hematology and clinical 
chemistry) and urinalysis. Clinical laboratory values will be converted and analyzed in 
international units, including associated normal ranges provided by the central laboratory. 
International units will be used in all listings and tables. Clinical laboratory values in 
conventional (US) units will also be available in the database, with associated normal ranges 
(analyses can be provided upon request). Both actual test values and “change from baseline” 
values (defined as the post-baseline value minus the baseline value) will be used in the result 
summaries.  Potentially clinically significant abnormalities (PCSA) ranges will be applied to the 
laboratory test values as applicable (see Appendix 10.3 for PCSA definitions). 
Unless otherwise specified below, blood samples for clinical laboratories will be collected at 
week -2, week 0, and weeks 8, 12/or end of double-blind treatment visit, and week 24/or end of 
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open-label treatment visit. The laboratory parameters (excluding those considered as efficacy 
parameters) will be classified as follows: 
 Hematology: 
 Red blood cells and platelets:  hemoglobin, hematocrit, erythrocytes count, 
platelets count, reticulocyte count, red blood cell distribution width (RDW) 
 White blood cells: white blood cell count, neutrophils, lymphocytes, monocytes, 
basophils, eosinophils 
 Clinical chemistry: 
 Metabolism:  glucose, total protein, albumin, creatine phosphokinase 
 Electrolytes:  sodium, potassium, chloride, calcium, phosphorus, bicarbonate 
 Renal function:  creatinine, creatinine clearance, blood urea nitrogen, uric acid 
 Liver function  ALT, aspartate aminotransferases (AST), alkaline phosphatase 
(ALP), total bilirubin, LDH 
 Hepatitis screen:  anti-hepatitis-C antibody collected at week -2 and week 12, and 
hepatitis B surface antigen collected at week -2 
4.7.3. 
Vital Sign Variables 
Vital signs parameters will include weight (kg), heart rate (bpm), systolic and diastolic blood 
pressure (mmHg) in a sitting position for at least five minutes (arm used for blood pressure 
measurement is also collected). Both actual test values and “change from baseline” values 
(defined as the post-baseline value minus the baseline value) will be used in the result 
summaries.  Potentially clinically significant abnormalities (PCSA) ranges will be applied to the 
vital sign parameter values as applicable (see Appendix 10.3 for PCSA definitions). 
4.7.4. 
Electrocardiogram Variables 
Electrocardiograms were recorded automatically by the device at the Investigator site at week -2, 
week 12/or end of double-blind treatment visit, and week 24/or end of open-label treatment visit. 
Electrocardiogram assessments will be described as normal or abnormal.  
4.8. 
Other Variables 
Other assessment endpoints are listed and defined below.  As applicable, LDL-C will use the 
same definition as described in Section 4.6.1. 
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 The percent change in hs-CRP from baseline to weeks 12, and 24. Hs-CRP values 
greater or equal to 10 mg/L will be excluded from analyses in a second approach, 
since these are suggestive of concurrent infections (1). PCSA (potentially clinically 
significant abnormalities) criteria for hs-CRP are listed in Appendix 10.3. 
 The proportion of patients with two consecutives results, separated by at least 21 
days, of LDL-C <25 mg/dL (<0.65 mmol/L) (and again for LDL-C <15 mg/dL [< 0.39 
mmol/L]) during the double-blind period. 
 The proportion of patients with two consecutives results, separated by at least 21 
days, of LDL-C <25 mg/dL (<0.65 mmol/L) (and again for LDL-C <15 mg/dL [< 0.39 
mmol/L]) during the open-label period. 
 For the patients with two consecutive results as described above, the time to the first 
LDL-C <25 mg/dL (<0.65 mmol/L) (and again for LDL-C <15 mg/dL [< 0.39 
mmol/L]) during the respective treatment period (double-blind or open-label). 
 The change in the proportion of patients who meet US apheresis eligibility criteria 
from baseline to week 12 (Goldberg 2011) (7). 
 A patient is considered as meeting US apheresis eligibility criteria if LDL-C ≥ 300 
mg/dL (7.77 mmol/L). 
 The change in the proportion of patients who meet German apheresis eligibility 
criteria from baseline to week 12 (Schettler 2012) (8). 
 A patient with primary CVD prevention is considered as meeting German 
apheresis eligibility criteria if LDL-C > 160 mg/dL (4.2 mmol/L). 
 A patient with secondary CVD prevention is considered as meeting German 
apheresis eligibility criteria if LDL-C > 120 mg/dL (3.1 mmol/L). 
 Exploratory relationships between HoFH genotype status and lipid parameters. 
4.9. 
Anti-alirocumab Anti-body Variables 
Anti-drug (alirocumab) antibody (ADA) are assessed at baseline (before the first study treatment 
injection), at week 12/or end of double-blind treatment visit, and week 24/or end of open-label 
treatment visit. ADA measurements will be assigned to similar analysis windows as defined for 
efficacy endpoints in Appendix 10.2. As appropriate, patient frequencies and percentages will be 
depicted, and the percentages will be calculated based on the ADA population for the analysis of 
the double-blind period and based on the OLE population for the analysis of the open-label 
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The following variables will be described: 
 ADA response (Positive or Negative). For ADA positive: 
 Titer levels  
 Neutralizing status (Positive or Negative) 
 Pre-existing positive ADA defined as patients with positive ADA response at baseline 
with less than 4-fold increase in titer in the post-baseline period  
 Treatment-emergent positive ADA response defined as 1) Patients with no ADA 
positive response at baseline but with any positive response in the post-baseline 
period or 2) Patients with a positive ADA response at baseline and at least a 4-fold 
increase in titer in the post-baseline period. For treatment-emergent positive ADA, the 
following categories for ADA duration will be applied for the analysis of the double-
blind period: 
 A persistent positive response is a treatment-emergent ADA positive response 
detected in at least 2 consecutive post-baseline samples separated by at least a 
12-week period  
 An indeterminate duration positive response is defined as ADA present only at the 
last sampling time point  
 A transient positive response is defined as any treatment-emergent positive ADA 
response that is neither considered persistent nor indeterminate 
4.10. 
Pharmacokinetic (PK) Variables 
Samples of drug concentration measurements are collected at baseline (week 0), weeks 4, 8, 10, 
12, and 24. 
Pharmacokinetic variable is the total alirocumab concentration at each time point.  Alirocumab 
concentration, total and free PCSK9 concentration will be described following time windows as 
defined in Appendix 10.2 . 
4.11. 
Quality-of-Life Variables 
EQ-5D is a standardized and generic instrument for measuring the health status and health 
related quality of life for clinical and economic assessment (2). The EQ-5D instrument includes 5 
items corresponding to the following dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each item can take one of three responses: (1.) “no 
problem”, (2.) “some problems”, and (3.) “severe problems”. Overall health state is defined as a 
5-digit number and will be converted into a standard utility score ranging between - 0.594 
(representing severe problems) and 1 (representing no problem): the single index utility score, 
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using a regression model (2) (Appendix 10.4). If response to one or more dimensions is missing, 
the utility score will be missing.   
Quality of life endpoints include response to each EQ-5D item at week 12 and week 24.  The 
change in utility score from baseline will also be evaluated at each post-baseline week. 
4.12. 
Genomics Variables 
Plans for analysis of genomics data will be provided in a separate SAP.  
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5. 
STATISTICAL METHODS 
5.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group 
and overall for the study, as well as by treatment group and overall for the study within each of 
the stratification factor (IVRS/IWRS defined yes/no of apheresis treatment status).  Parameters 
described in Section 4.1 will be summarized for those patients randomized into the study, the 
safety population in the case of a 10% difference (in any treatment group) from the number of 
randomized patients, and again for the ITT population in the case of a 10% difference (in any 
treatment group) from the number of randomized patients.  
Continuous data will be summarized using the number of patients with data, mean, SD, median, 
minimum and maximum for each treatment group and for each of the strata. First quartile (Q1) 
and third quartile (Q3) will be also provided for baseline lipid parameters, and hs-CRP. 
Categorical and ordinal data will be summarized using the number and percentage of patients in 
each treatment group. 
Treatment group comparisons for demographic characteristics and disease characteristics will be 
provided for descriptive purposes (i.e., confirmation of the randomization process to equally 
distribute relevant patient background profiles among the two treatment groups) using the Fisher 
exact test for categorical data and the asymptotic one-way ANOVA test for Wilcoxon scores 
(Kruskal-Wallis test) for continuous data. As applicable, other safety baseline data is presented 
collectively in the descriptive statistics summary tables containing respective post-baseline data. 
For the open-label population, demographic and baseline characteristics will be summarized by 
all patients and by treatment group of the double-blind period (i.e., alirocumab, placebo) on the 
open-label population in the case of a 10% difference (in any treatment group of the double-blind 
period) from the number of randomized patients. Parameters described in Section 4.1 will be 
descriptively summarized for the open-label population. 
5.2. 
Medical History and Disease Characteristics 
Medical history and disease characteristics will be descriptively summarized by treatment group 
and overall for the study in patients randomized into the study. 
All reported patient’s medical history and surgical history will be presented by primary SOC and 
HLT.  The tables will be sorted by SOC internationally agreed order and decreasing patient 
frequency of HLT based on the overall incidence in the study.  In addition, all medical history of 
specific interest, as described in Section 4.2, will be summarized by patient incidence and 
percentage. 
For the patients with primary CVD prevention status (see definition in Section 4.2), the number 
(and percentage) of patients with the following comorbidities/risk factors will be tabulated: 
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 Diabetes mellitus with target organ damage (renal damage (microalbuminuria, or 
macroalbuminuria, moderate CKD) and/or retinopathy (pre-proliferative or 
proliferative diabetic retinopathy and/or laser treatment for diabetic retinopathy)), 
 Diabetes mellitus with 2 or more risk factors (see Section 4.2), 
 Family History of premature CHD 
 Hypertension, 
 Moderate CKD 
 Current smoker 
 At least 2 of the above comorbidities/risk factors 
In addition, smoking status will be summarized in patients with primary CVD prevention status. 
For the patients with a secondary prevention status, the CVD history will be described using the 
number (%) of patients with: 
 History of CHD (see Section 4.2) 
 History of ischemic stroke 
 History of PAD with severity criteria 
 Intermittent claudication and ankle brachial index ≤ 0.90 
 Peripheral revascularization procedure  (angioplasty, stenting) for PAD 
 Thrombolysis for PAD 
 Peripheral revascularization surgery (arterial bypass) for PAD 
 Critical limb ischemia 
Additionally: 
 The number (%) of patients with a secondary prevention status with 1 or more 
associated comorbidity among hypertension, diabetes mellitus, and/or moderate CKD 
will be summarized.  
 The number (%) of patients with history of CHD and 1 or more associated 
comorbidity among hypertension, diabetes mellitus, moderate CKD and/or other CVD 
(ischemic stroke, PAD) will be summarized. 
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For patient disease characteristics, as described in Section 4.2, continuous data will be 
summarized using the number of patients with data, mean, SD, median, minimum and maximum 
for the study and for each of the strata. Categorical and ordinal data will be summarized using the 
number and percentage of patients in the study and for each stratum.   
5.3. 
Prior and Concomitant Medications 
All prior medications, dictionary coded by WHO-DD, will be descriptively summarized by 
treatment group and overall for the study, for patients in the safety population. Summaries will 
present patient counts (and percentages) for all prior medications, by decreasing frequency of the 
overall incidence of ATC followed by therapeutic class.  In case of equal frequency across 
anatomic or therapeutic categories, alphabetical order will be used. Patients will be counted once 
in each ATC category (anatomic or therapeutic) linked to the medication, but may be counted 
several times for the same medication.   
All concomitant medications during the double-blind period, dictionary coded by WHO-DD, will 
be descriptively summarized by treatment group, for patients in the safety population. Summaries 
will present patient counts (and percentages) for the concomitant medication groups described in 
Section 4.3 for all concomitant medications (including statin, LMT, CV), by decreasing 
frequency of the alirocumab group incidence of ATC followed by therapeutic class.  In case of 
equal frequency across anatomic or therapeutic categories, alphabetical order will be used. 
Patients will be counted once in each ATC category (anatomic or therapeutic) linked to the 
medication, hence may be counted several times for the same medication.  Additionally, 
concomitant medications pre-specified as statin, LMT, and CV will be summarized by patient 
counts (and percentages) by therapeutic class or e-CRF pre-specified categories as appropriate 
and standardized medication name. Post-treatment medications will be summarized as described 
above for all medications. All concomitant and post-treatment medications for the open-label 
period, dictionary coded by WHO-DD, will be descriptively summarized by all patients and by 
treatment group of the double-blind period (i.e., alirocumab, placebo) on the open-label 
population. Summaries will present counts (and percentages) in the open-label population. 
LMT (statins and other LMTs) use after randomization will be summarized over time graphically 
by treatment group and LMTs intensity at randomization using the following categories: 
 atorvastatin 40 to 80 mg daily or rosuvastatin 20 to 40 mg daily or; 
 atorvastatin below 40 mg daily or rosuvastatin below 20 mg daily or simvastatin at 
any daily dose, 
 other statins, 
 LMT other than statin only, 
 no LMT.    
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The LMTs intensity at randomization is defined as: 
 patients treated at randomization with atorvastatin 40 to 80 mg daily or rosuvastatin 
20 to 40 mg daily (high intensity statin), 
 patients treated at randomization with atorvastatin below 40 mg daily or rosuvastatin 
below 20 mg daily or simvastatin at any daily dose (low intensity statin), 
 other statins, 
 non-statin LMT only, 
 no LMT.    
5.4. 
Subject Disposition 
Patient disposition includes the description of patient status at major milestone decisions in the 
study, as well as the patient analysis populations. 
Patient study status for the double-blind period will be summarized by treatment group and 
overall for the study (screened patients, screen failures, and non-randomized but treated patients 
only).  Summaries will provide the frequency (and percentage as applicable) of patients that met 
the criteria for the variables described in Section 4.4.  Exception listings will be generated for any 
subject treated but not randomized, randomized but not treated, and treated differently than 
randomized. 
Patient analysis populations will be summarized by treatment group, depicting frequencies (and 
percentages) of patients that met the criteria for each population described in Section 3.  
For the open-label period, the patient study status and patient analysis populations will be 
summarized by all patients and by treatment group of the double-blind period (i.e., alirocumab, 
placebo) on the open-label population for the variables described in Section 4.4. 
5.5. 
Extent of Study Treatment Exposure and Compliance 
The extent of study treatment exposure and study compliance parameters for the double-blind 
period described in Section 4.5 will be assessed and summarized by treatment group, for patients 
in the safety population. The extent of study treatment exposure and study compliance 
parameters for the open-label period described in Section 4.5 will be assessed and summarized 
by all patients and by treatment group of the double-blind period (i.e., alirocumab, placebo) on 
the open-label population. 
5.5.1. 
Exposure to Investigational Product 
Study treatment exposure for the double-blind period will be descriptively summarized for the 
treatment duration and patient injection total variables listed in Section 4.5. Treatment duration 
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will be summarized using the number of patients with data, mean, SD, median, minimum and 
maximum.  
For the open-label period, study treatment exposure will be descriptively summarized for the 
treatment duration and patient injection total variables listed in Section 4.5. Alirocumab dosing 
exposure in the open-label period will be summarized for all patients in the open-label 
population. Additionally, alirocumab dosing exposure will be summarized combining double-
blind and open-label periods for patients who received alirocumab in the double-blind period. 
5.5.2. 
Measurement of Compliance  
Study treatment compliance parameters will be descriptively summarized using the number of 
patients with data, mean, SD, median, minimum and maximum for the variables listed in 
Section 4.5.  According to protocol, cases of overdose are reported in the AE e-CRF pages and 
will be described in the AE analysis. 
Both monitored and derived protocol deviations will be summarized for major deviations (counts 
of deviations), patients (incurring a deviation by count and percentage), and by type of major 
deviation (patient count and percentage).  A patient listing of all major and minor protocol 
deviations will be provided. 
5.6. 
Analysis of Efficacy Variables 
For statistics where international and conventional units do not impact the results (e.g. means and 
least square (LS) means for percent changes from baseline, statistical testing for both percent and 
absolute changes from baseline, rates of patients below a threshold), derivations will be 
calculated and statistical models will be run using conventional units. For other statistics (e.g. 
descriptive statistics at baseline and over time, absolute changes from baseline), derivations will 
be presented in both international and conventional units. 
Statistical analyses for the primary efficacy endpoints and key secondary endpoints will be 
conducted in the double-blind period as described below, and will be completed during the step 1 
efficacy analyses (Section 7 ).  
With respect to the efficacy data in the open-label period, only descriptive efficacy analyses will 
be completed during the second-step analysis. During the open-label 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 (i.e., alirocumab, placebo).  Formal 
statistical testing is not planned.  Descriptive statistics will include the same parameters as 
described for each variable in the double-blind period. The same baseline (as defined in 
Section 4.6) will be used for the analyses of the double-blind and open-label periods.  
For patients receiving alirocumab in the double-blind period, a combined summary including 
both the double-blind and open-label period assessments may be considered, referencing the 
double-blind baseline for variable calculations.  Prolonged time between last dose of double-
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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. 
5.6.1. 
Analysis of Primary Efficacy Variable 
For the double-blind primary comparison of the alirocumab group to the placebo group, the 
percent change from baseline in LDL-C at week 12 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, and 12), treatment-by-time 
point interaction, and strata-by-time point interaction, as well as the continuous fixed covariates 
of baseline LDL-C value and baseline value-by-time point interaction.  
This model will be run using Statistical Analysis Software (SAS) mixed procedure with an 
unstructured correlation matrix to model the within-patient errors.  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. 
Within treatment group least-square means and standard errors will be adjusted using weights 
equal to the observed proportion of patients in strata variable levels across the study population 
(i.e. “population weight”), rather than equal weights.  Population weights are considered more 
appropriate that equal coefficients due to potential imbalances observed in the study population 
between levels of the randomization stratification factors.  
Model Assumption Checks 
Homogeneity of treatment effect across baseline LDL-C levels 
In order to check the homogeneity of treatment effect versus baseline LDL-C, the following 
interaction terms will be added in the primary MMRM model: 
 Treatment group * baseline LDL-C  
 Treatment group * time-point * baseline LDL-C 
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Within the framework of this model with interaction terms, a graph presenting the LS means 
difference versus placebo at week 12 and the corresponding 95% CI will be provided by baseline 
LDL-C value. 
Analysis of residuals: 
The analysis of the residuals of the MMRM will be primarily based on studentized residuals. It 
will include: 
 Normality of studentized residuals, presented graphically using histogram and QQ-
plot. 
 Plot of studentized residuals versus predicted values. 
 Distribution of studentized residuals, presented graphically using boxplots, within 
each category of the fixed categorical effects of the MMRM: 
 treatment group (alirocumab, placebo) 
 time point (weeks 4, 8, and 12) 
 treatment-by-time point interaction 
 randomization strata 
 randomization strata-by-time point interaction. 
5.6.1.1. 
Sensitivity to Stratification at Randomization 
In order to assess the robustness of the primary analysis to stratification mistakes made at the 
time of randomization (i.e. the stratum recorded in IVRS/IWRS differs from the actual stratum 
recorded in the e-CRF), the MMRM model will be re-run replacing the IVRS/IWRS strata with 
the e-CRF actual strata. 
5.6.1.2. 
Sensitivity to the Handling of Missing Data 
Sensitivity analyses will be conducted to assess the robustness of primary efficacy analysis with 
regards to handling of missing data (3).  
 Visual examination: 
 In order to explore the missing data pattern, post-baseline LDL-C observations (in the 
ITT population) will be described according to the following groups:  
1. 
Ldl-C available at week 12 (i.e. primary efficacy endpoint available), 
2. 
LDL-C available at week 8 but missing at week 12, 
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3. 
LDL-C available at week 4 but missing from week 8, 
4. 
LDL-C missing from week 4.  
A graph of mean LDL-C levels (respectively percent change from baseline in LDL-C) ± SE at 
baseline, and weeks 4, 8, and week 12 will be provided by missing data pattern, for each 
treatment group. 
 In the ITT population, demographic and baseline characteristics will be described 
within the missing data pattern number 1 versus the pooled others. P-values from 
Fisher exact test for categorical data and from asymptotic one-way ANOVA test for 
Wilcoxon scores (Kruskal-Wallis test) for continuous data, will be also provided, for 
descriptive purposes.  
Multiple Imputations:  
In addition to the MMRM method, the multiple imputation method (see Appendix 10.6  for more 
details) will be used to address missing values, in the randomized population, followed by the 
testing of treatment arms using an analysis of covariance (ANCOVA) model, with the intent to 
evaluate the robustness of the primary analysis using a different statistical method.  
Missing data from the randomized population will be imputed 100 times to generate 100 
complete data sets, using the MI SAS procedure (using Markov Chain Monte Carlo). The percent 
change from baseline at week 12 will be then derived from observed and imputed LDL-C at this 
time point. The 100 complete data sets will be then analyzed using an ANCOVA model with 
treatment group and randomization strata (as per IVRS/IWRS) as fixed effects, and the baseline 
LDL-C value as continuous covariate, and the MIANALYZE procedure will be used to generate 
valid statistical inferences by combining results from the 100 analyses using Rubin’s formulae 
(4).  
Pattern mixture model 
The MMRM model relies on the “missing-at-random” (MAR) assumption.  Because the 
possibility for a not-missing-at-random (NMAR) missingness mechanism can never be excluded, 
sensitivity analysis to explore the impact of non-ignorable missingness on the primary efficacy 
analysis will be conducted using the pattern mixture model approach as described below (see 
Appendix 10.7  for more details). 
In the pattern-mixture model approach, different imputation strategies will be applied to LDL-C 
values missing during the double-blind on-treatment period (i.e. within the time period from the 
first double-blind study treatment injection up to the day of last double-blind injection +21 days 
or day of the first open-label injection whichever comes first) versus LDL C values missing after 
treatment discontinuation (i.e. after the day of last double-blind injection +21 days) based on the 
following assumptions: 
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 Patients within 21 days of their last double-blind IMP injection would continue to 
show benefit from treatment similar to that observed at the scheduled time point.  
Therefore, LDL-C values missing during the on-treatment period (e.g., samples 
obtained out-side the specified window, no blood sample available although visit was 
performed, etc.) should be considered “Missing At Random” and imputed based on 
other on-treatment measurements. 
 Patients who stopped taking their study treatment no longer benefited from it after 
discontinuation, and thus tended to have LDL-C values returning to baseline.  
Therefore, LDL-C values missing after treatment discontinuation should be imputed 
based on patient’s own baseline value. 
Missing data from the randomized population will be imputed 100 times to generate 100 
complete data sets, using the approach described above.  The 100 completed datasets of observed 
and imputed LDL-C data will be used for primary efficacy analyses.  
The 100 complete datasets of observed and imputed LDL-C data at week 12 will be analyzed 
using an ANCOVA model with treatment group and randomization strata as fixed effect, and the 
baseline LDL C value as continuous covariate.  The MIANALYZE SAS procedure will be used 
to generate valid statistical inferences by combining results from the 100 analyses using Rubin’s 
formulae (4). 
5.6.1.3. 
Sensitivity to the Absence of Null/Null Mutations in Both LDL Alleles 
In order to assess the robustness of the primary analysis in patients excluding those with null/null 
mutations in both LDL alleles, the MMRM model will be re-run by excluding patients with 
null/null mutations in both LDL alleles in the ITT population. 
5.6.1.4. 
Sub-group Analyses 
To assess the homogeneity of the treatment effect across various subgroups, treatment-by-
subgroup factor, time point-by-subgroup factor and treatment-by time point-by subgroup factor 
interaction terms and a subgroup factor term will be added in the primary MMRM model. LS 
mean difference versus placebo at week 12 will be provided, as well as the corresponding SE and 
95% CI, within each subgroup. The significance level of the treatment-by-subgroup factor 
interaction term at week 12 will be also provided for each factor for descriptive purpose. Forest 
plots will be provided. In order to handle unbalances between randomization stratification factors 
levels, population weights will be used as for the primary analysis model.  
The following subgroups of interest will be evaluated, assuming there are enough patients in each 
subgroup level to perform the evaluation.  For the subgroup factors that are also randomization 
stratification factors, the IVRS strata will be used. 
 The baseline apheresis status (Yes, No) per IVRS, 
 Gender (Female, Male),  
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 Baseline HDL-C (<40, ≥40 mg/dL) (i.e. <1.04, ≥1.04 mmol/L), 
 Baseline fasting TGs (<150, ≥150 mg/dL) (i.e. <1.7, ≥1.7 mmol/L), to be performed 
also on the response variable percent change in fasting TGs from baseline to week 12. 
 Baseline Lp(a) (<30, ≥30 to <50, ≥50 mg/dL) (i.e. <0.3, ≥0.3 to <0.5, ≥0.5 g/L), 
 Statins with versus without other LMT at randomization, 
 Prior history of acute or silent myocardial infarction (MI) or ischemic stroke (Yes 
versus No), 
 Baseline total PCSK9 level (below the median, at or above the median) 
5.6.2. 
Analyses of Secondary Efficacy Variables 
The key secondary efficacy endpoints (defined in Section 4.6.2) and other secondary efficacy 
endpoints (described in Section 4.6.3) for the double-blind 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 Appendix 10.2  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 TGs, 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 percent change from baseline or absolute change from baseline for the ratio) 
and plots will be provided for other efficacy parameters:  Apo B, Apo A-1, ratio Apo B/Apo A-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). 
5.6.2.1. 
Continuous Endpoints Anticipated to have a Normal Distribution 
Continuous secondary variables defined in Section 4.6.2 and 4.6.3 anticipated to have a normal 
distribution (i.e. lipids other than TG and Lp(a)) will be analyzed using the same MMRM model 
as described for the primary endpoint.  Specifically, the model will contain the fixed categorical 
effects of treatment group, randomization strata (as per IVRS/IWRS), planned time points up to 
week 12, strata-by-time point and treatment-by-time point interaction, as well as, the continuous 
fixed covariates of corresponding baseline value and baseline value-by-time point interaction. 
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5.6.2.2. 
Continuous Endpoints Anticipated to have a Non-normal Distribution 
Continuous secondary efficacy variables defined  in Section 4.6.2 and 4.6.3 anticipated to have a 
non-normal distribution (i.e. TG and Lp(a)) will be analyzed using the same multiple imputation 
approach for handling of missing values as described for primary efficacy endpoint (and using 
the same time points in the imputation model as described above for Section 5.6.1.2), with data 
log-transformed before imputation process and then back transformed to create the imputed data 
sets using the TRANSFORM statement of SAS MI procedure. 
The percent change from baseline at time point of interest will be derived from observed and 
imputed lipid values at this time point. Multiple imputation will be followed by robust regression 
model (5) to compare treatment group differences, with the endpoint of interest as the response 
variable using M-estimation (using SAS ROBUSTREG procedure) with treatment group, 
randomization strata (as per IVRS/IWRS) and corresponding baseline value(s).  Combined 
means estimates for both treatment groups, as well as the differences of these estimates, with 
their corresponding SEs, 95% CIs and p-value will be provided through the SAS MIANALYZE 
procedure. 
5.6.2.3. 
Binary Endpoint Variables 
Binary secondary efficacy endpoints defined in Section 4.6.2 and 4.6.3 will be analyzed using the 
multiple imputation approach for handling of missing values as described for the primary 
efficacy endpoint (and using the same time points in the imputation model as described above for 
Section 5.6.1.2). 
The binary endpoint at time point of interest will be derived from observed and imputed lipid 
values at this time point. Multiple imputation will be followed by stratified logistic regression, 
(with strata defined as randomized in the IVRS/IWRS) using the strata option of the SAS logistic 
procedure. The logistic regression procedure will be used to compare treatment group 
differences, with the model containing treatment group and corresponding baseline value(s) as 
covariate, stratified by randomization strata defined as per IVRS/IWRS. Combined estimates of 
odds ratio versus placebo, 95% CI, and p-value will be obtained through the SAS MIANALYZE 
procedure. 
In the data dependent case such logistic regression is not applicable (e.g. the response rate is zero 
in one treatment arm and thus the maximum likelihood estimate may not exist), the last 
observation carried forward (LOCF) approach would be used for handling of missing values. 
Treatment effects would be compared using the stratified exact conditional logistic regression 
method, specifically using the strata option of the SAS logistic procedure (with strata defined as 
randomized in the IVRS/IWRS). In case the model would not converge with stratification 
variables, an unstratified exact logistic regression will be performed. The LOCF imputation 
method will consist of using the last value obtained up to the week 12 analysis window to impute 
the missing week 12 value. 
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In case of computing issues with exact logistic regression, the baseline level(s) will be entered in 
the model as a categorical variable(s) using quartiles. Exact odds ratio versus placebo, 95% CI, 
and p-value will be provided. 
5.6.2.4. 
Sensitivity Analyses of Key Secondary Endpoint Variables 
In order to assess the robustness of more clinically relevant between-group comparisons for the 
analyses of the key secondary endpoints during the efficacy treatment period, the same statistical 
approach as described above in Section 5.6.2 will be applied during the efficacy treatment period 
in the mITT population. 
5.6.2.5. 
Summary of Results by Time Point 
Central laboratory values (in conventional (US) and international units), percent change from 
baseline, and/or when appropriate absolute change from baseline (in conventional and 
international units), for LDL-C, Total-C, HDL-C, fasting TG, and non-HDL-C at weeks 4, 8, and 
week 12 time points will be summarized by treatment group in both the ITT and mITT 
populations as described below. Central laboratory values (in conventional (US) and 
international units), percent change from baseline, and/or when appropriate absolute change from 
baseline (in conventional and international units), for Lp(a), Apo-B, Apo-A1 and ratio Apo-
B/Apo-A1 (absolute change from baseline) at weeks 4, 8, and week 12 points will be 
summarized in the ITT and mITT populations as describe below:  
 For lipids other than TG and Lp(a): LS mean and SE for each treatment group, 
obtained from the same MMRM models as used for endpoints above and including 
planned time points (see Section 5.6.2.1) and with raw values, changes from baseline, 
and percent change from baseline as response variable in the model as appropriate.  
 For lipids other than TG and Lp(a):  Observed data raw values, change from baseline 
(as applicable), and percent change from baseline response variables will be 
summarized by patient counts, mean and SD for each treatment group at all planned 
time points. 
 For TG and Lp(a): mean and SE for each treatment group obtained from multiple 
imputation approach followed by the robust regression models as used for endpoints 
above and including planned time points (see Section 5.6.2.2) and with raw values or 
percent changes from baseline as response variable in the model as appropriate. 
 For TG and Lp(a): Observed data raw values and percent change from baseline 
response variables will be summarized by patient counts, mean and SD for each 
treatment group at all planned time points.  
For the open-label period, central laboratory values (in conventional (US) and international 
units), percent change from baseline, and/or when appropriate absolute change from baseline (in 
conventional and international units), LDL-C, Total-C, HDL-C, fasting TG, and non-HDL-C, 
Lp(a), Apo-B, Apo-A1 and ratio Apo-B/Apo-A1 (absolute change from baseline) at weeks 18, 
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and 24 time points will be summarized by patient counts, mean and SD by all patients and by 
treatment group of the double-blind period (i.e., alirocumab, placebo) on the open-label 
population. 
For patients receiving alirocumab in the double-blind period, central laboratory values (in 
conventional (US) and international units) including both the double-blind and open-label period 
assessments, percent change from baseline, and/or when appropriate absolute change from 
baseline (in conventional and international units), LDL-C, Total-C, HDL-C, fasting TG, and non-
HDL-C, Lp(a), Apo-B, Apo-A1 and ratio Apo-B/Apo-A1 (absolute change from baseline) at 
weeks 4, 8, 12, 18, and 24 time points will be summarized by patient counts, mean and SD by all 
patients. 
5.6.3. 
Adjustment for Multiple Comparisons 
In order to handle multiple key secondary endpoints during the double-blind 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 Sections 4.6.1 and 4.6.2. 
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 period. 
No further adjustments will be made for other secondary endpoints for which p-values will be 
provided for descriptive purpose only. 
No adjustment will be made for the first-step and second-step statistical analyses (Section 7), 
since the primary and key secondary endpoints will have been concluded at the time of the 
first-step analysis. 
5.7. 
Analysis of Safety Data 
The summary of safety results will be presented separately for the double-blind and open-label 
period. The double-blind period will be presented by treatment groups (alirocumab, placebo) on 
the safety population (Section 3.2). The open-label period will be presented by all patients and by 
treatment group of the double-blind period (i.e., alirocumab, placebo) on the open-label 
population (Section 3.3). No formal inferential testing will be performed for either period. 
Summaries will be descriptive in nature. All summaries of safety results described below will be 
presented for each period respectively, unless otherwise noted. 
General common rules 
All safety analyses will be performed, unless otherwise specified, using the following common 
rules: 
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 Safety data in patients who do not belong to the safety population (i.e., exposed but 
not randomized) will be listed separately. 
 For the analyses of both double-blind and open-label periods, the baseline value is 
defined as the last available value obtained up to the date and time of the first 
double-blind study treatment, except otherwise specified. 
 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 version 
dated January 2009 [Appendix 10.3]). Considering that the threshold defined in the 
PCSA list for monocytes and basophils can be below the ULN, the following PCSA 
criterion will be used for the PCSA analysis of monocytes and basophils:  
 PCSA criterion for monocytes: >0.7 Giga/L or >ULN (if ULN ≥0.7 Giga/L). 
 PCSA criterion for basophils: >0.1 Giga/L or >ULN (if ULN ≥0.1 Giga/L). 
 PCSA criteria will determine which patients had at least 1 PCSA during the TEAE 
period, taking into account all evaluations including nonscheduled or repeated 
evaluations. 
 The treatment-emergent PCSA denominator by treatment group for a given parameter 
will be based on the number of patients assessed for that given parameter at least once 
during the TEAE period. 
 All measurements, scheduled or unscheduled, fasting or not fasting, will be assigned 
to analysis windows defined in Appendix 10. 2, Table 1 and Table 2 in order to 
provide an assessment for week 4 to week 24 time points. 
 For quantitative safety parameters including central laboratory measurements and 
vital sign scores, descriptive statistics will be used to summarize results and change 
from  baseline values by visit, the last on-treatment value and the worst on-treatment 
value. The last on-treatment value is defined as the last post-baseline value collected 
during the respective treatment period (as defined in Section 4.7.1). The worst on-
treatment value is defined post-baseline as the nadir and/or the peak value collected 
during the respective treatment period, according to the direction (minimum or 
maximum) of the abnormality as defined in the PCSA list.  
 Analyses performed according to diabetes status will be done considering diabetic 
patients as patients with either type 1 or type 2 diabetes in the medical history e-CRF 
page (regardless of the ongoing status). 
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5.7.1. 
Analysis of Adverse Events  
In general, the primary focus of AE reporting will be on TEAEs presented in each of the study 
period, specifically the double-blind and open-label period.  Pre-treatment and post-treatment 
AEs will be provided separately.  
If an AE date/time of onset (occurrence, worsening, or becoming serious) is incomplete, an 
imputation algorithm will be used to classify the AE as pre-treatment, treatment-emergent, or 
post-treatment.  The algorithm for imputing date/time of onset will be conservative and will 
classify an AE as treatment-emergent unless there is definitive information to determine pre-
treatment or post-treatment status.  Details on classification of AEs with missing or partial onset 
dates are provided in Section 6.4. 
Adverse event incidence tables will present the number (n) and percentage (%) of patients 
experiencing an AE by SOC, HLGT (when applicable), HLT (when applicable), and PT.  
Multiple occurrences of the same event in the same patient will be counted only once in the 
tables within a treatment phase. For tables presenting severity of events, the worst severity will 
be chosen for patients with multiple instances of the same event. The denominator for 
computation of percentages is the safety population within each treatment group. 
The table of all TEAEs presented by SOC and PT will be sorted by the internationally agreed 
SOC order and decreasing frequency of PTs within SOCs (in the alirocumab group). This will 
define the presentation order for all other tables by SOC and PT, unless otherwise specified. The 
tables of AEs by SOC, HLGT, HLT and PT will be sorted by the SOC internationally agreed 
order and the other levels (HLGT, HLT, PT) will be presented in alphabetical order, unless 
otherwise specified.   
Analysis of all treatment-emergent adverse events 
The following TEAE summaries will be generated: 
 Overview of TEAEs, summarizing number (%) of patients with any 
 TEAE; 
 Serious TEAE; 
 TEAE leading to death; 
 TEAE leading to permanent treatment discontinuation. 
 All TEAEs by primary SOC, HLGT, HLT, and PT 
 Number (%) of patients experiencing common TEAE(s) presented by primary SOC, 
HLT and PT (HLT incidence ≥ 5 % in any treatment group), sorted by SOC 
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internationally agreed order and by alphabetic order for the other levels (HLT and 
PT); 
 All TEAEs by primary SOC and PT, sorted by the internationally agreed SOC order 
and by decreasing incidence of PTs within each SOC (in the alirocumab group).   
 All TEAEs by treatment group regardless of relationship in one column and, in the 
same table a second column with TEAEs related to alirocumab according to 
investigator’s opinion by primary SOC, HLGT, HLT and PT; 
 All TEAEs by maximal severity (i.e., mild, moderate or severe), presented by primary 
SOC and PT, sorted as defined above; 
Analysis of all treatment emergent serious adverse event(s) 
 All serious TEAEs by primary SOC, HLGT, HLT, and PT and by SOC/PT; Patient 
listings of serious TEAEs will be provided for the report appendix. 
 All serious TEAEs by treatment group regardless of relationship in one column and in 
the same table a second column with TEAEs related to alirocumab according to 
investigator’s opinion, by primary SOC, HLGT, HLT, and PT;  
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
 All TEAEs leading to permanent treatment discontinuation, by primary SOC, HLGT, 
HLT, and PT and by SOC/PT; Patient listings of TEAEs leading to permanent 
treatment discontinuation will be provided for the report appendix.  
Analysis of groupings of adverse events including selected adverse events of special interest 
 All grouping of TEAEs including adverse events of special interest, as listed in 
Section 4.7.1.2, will be presented by SMQ/CMQ and PT (when selection is based on 
SMQs/CMQs) and by SOC and PT (when selection is based on the e-CRF tick box or 
HLGT/HLT). The summaries will be sorted by decreasing incidence of PT within 
each SOC/SMQ (in the alirocumab group).  
 All TEAEs within diabetes grouping will be analyzed overall and according to the 
diabetic status at baseline. 
The following variables will also be tabulated for the local injection site reactions TEAEs: 
 Intensity of the event (mild, moderate, severe); 
 Number of events divided by the number of double-blind study treatment injections 
received; 
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 Time from first study treatment injection (double-blind or open-label depending on 
the analysis) to first injection site reaction; 
 Description of the highest intensity of each symptom recorded in the specific e-CRF 
page with table and bar chart.  
Post-treatment adverse events  
 All post-treatment AEs by primary SOC and PT, sorted by the internationally agreed 
SOC order and decreasing incidence of PTs (in the alirocumab group) within each 
SOC; 
 All post-treatment SAEs by primary SOC and PT, sorted by the sorting order defined 
above. 
Subgroup of patients with two consecutive LDL-C <25 mg/dL (<0.65 mmol/L) 
If applicable, similar summaries of TEAEs as those described above will be provided on the 
safety subgroup population of patients with two consecutive results of LDL-C <25 mg/dL (as 
defined in Section 4.8) in both treatment groups. Only TEAEs for which it will be confirmed or 
unclear that they occurred, worsened or became serious on the day or after the day the first level 
of LDL-C <25 mg/dL was observed will be considered in this summary.  These analyses will be 
restricted to the respective treatment periods.  The summaries of the subgroup of patients with 
two-consecutive LDL-C values <25 mg/dL in the double-blind treatment period will only 
consider TEAEs with a start date within the double-blind treatment period; summaries of the 
subgroup of patients with two-consecutive LDL-C values <25 mg/dL in the open-label period 
will only consider TEAEs with a start date within the open-label treatment period.  
5.7.1.1. 
Patient Deaths 
The following summaries of deaths will be generated. 
 Number (%) of patients who died by study period (TEAE and post-treatment in both 
the double-blind and open-label periods);  
 Deaths in nonrandomized patients or randomized but not treated patients; 
 TEAEs 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. 
Analysis of Adverse Event in the Open-Label Period 
For open-label period, summary of adverse events as described for the double-blind period will 
be used. 
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5.7.2. 
Analysis of Clinical Laboratory Variables 
Clinical laboratory parameter actual values (quantitative) and change from baseline values will 
be descriptively summarized at baseline and each post-baseline visit (collected up to the day of 
last dose of study treatment +21 days) by at least patient number, mean, median, Q1, Q3, SD, 
minimum and maximum for each treatment group. Additionally, laboratory parameter measures 
for last on-treatment values and worst on-treatment values will be summarized in a similar 
manner. Clinical laboratory parameters mean changes from baseline, with the corresponding SE, 
can be plotted at each visit by treatment group, in the case results warrant further investigation.  
These parameters will be presented by the biological functions defined in Section 4.7.2.  For 
glucose, only fasting samples will be included in the summaries. 
Individual patient laboratory parameter measurements will be additionally evaluated by PCSA 
criteria, specifically identifying patients with at least one post-baseline measurement that meets 
the PCSA criteria within the TEAE period.  The following additional project specific PCSA 
criteria will also be evaluated during the TEAE period: 
 Patients with a hemoglobin decrease from baseline ≥ 15 g/L. 
 Patients meeting the ALT increase defined in Section 4.7.1.2. 
 Glucose (quantitative summary and PCSA) will also be analyzed, overall and 
according to the diabetic status at baseline. 
Patients meeting the PCSA criteria at least once will be summarized by patient count (and 
percent) for a post-baseline PCSA measurement while accounting for the baseline PCSA status 
(PSCA normal/missing; PCSA abnormal), for each treatment group. For the appendix, this 
laboratory parameter PCSA table will be reproduced with patients meeting the PCSA criteria at 
least once during the TEAE period regardless of baseline PCSA status. These laboratory 
parameters will be presented by the biological functions defined in Section 4.7.2. Patient listings 
of laboratory measurements that meet PCSA criteria will be provided for the report appendix.  
For those laboratory parameters that don’t have an associated PCSA criteria, similar summary 
tables can be provided based on measurements outside the central laboratory normal ranges, if 
applicable. 
Hepatitis C antibody  
The number and percentage of patients with a post-baseline seroconversion for hepatitis C test 
will be provided by treatment group in post-baseline (including the TEAE and post TEAE 
periods) as well as in the TEAE period alone. Post-baseline seroconversion is defined for patients 
with a negative baseline status who had either a “positive RNA” or a “confirmed positive 
antibody with negative RNA” post-baseline status as defined in the table below. Other situations 
require case by case evaluation and will be described individually if relevant. 
The status as regards hepatitis C virus for a patient will be defined as follows for all evaluations 
(baseline and post-baseline).  
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Table 1: 
Definition of the patient status regarding hepatitis C virus 
 
Hepatitis C Antibody test result 
 
Negative 
Positive 
Reflexive testa – 
hepatitis C RNA test 
Not available or 
HCV RNA not 
detected 
HCV RNA 
detected 
HCV RNA not 
detectedb 
HCV RNA 
detected 
Not available 
Hepatitis C status – 
label 
Negative 
Positive RNA 
Negativeb 
Positive RNA 
Positive Ab – no 
RNA available 
a test performed at the same time or after the antibody test in pre-treatment period (for baseline evaluation), or post-baseline, respectively 
b For post-baseline evaluation, a second antibody test with a different type of assay is to be done at the same date or after the first antibody test. 
The result of this test will modify the final hepatitis C status of the patient in some cases (see details in the text below the table)  
The baseline evaluation will be based on tests performed during the pre-treatment period. 
In case of multiple hepatitis C tests available for the post-baseline evaluation, the positive status 
of the patient will be defined as follows:  
 “Positive RNA” status if at least 1 post-baseline positive RNA is detected, regardless 
of status of the patient at the end of treatment. 
 Else “Positive Ab – no RNA available” status if no post-baseline reflexive RNA test 
is available for at least 1 post-baseline positive antibody test. 
If no antibody test is available or with “indeterminate” as result pre-treatment or post-baseline 
respectively, the RNA test (if available) will be used alone to determine the status of the patient. 
If no RNA test is available then the hepatitis C status of the patient will be missing.   
The post-baseline status “confirmed positive antibody with negative RNA” will replace 
“Negative” status as defined above in the case where no RNA was detected post-baseline and the 
2 antibody tests surrounding the same visit (from 2 different types of assay) are positive.  
For a conservative approach, the post-baseline status “Positive Ab – no RNA available” will not 
be modified by the availability of a second antibody test from a different assay.  
For the description of the positive hepatitis C virus test during the TEAE period, all above rules 
will apply while replacing post-baseline by TEAE period. 
Drug-induced liver injury 
The liver function tests, namely AST, ALT, ALP, and total bilirubin, are used to assess possible 
drug-induced liver toxicity.  The proportion of patients with PCSA values or ALT increase as 
defined as AESI (see Section 4.7.1.2) during TEAE period by baseline status will be displayed by 
treatment group for each parameter. 
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An evaluation of drug-induced serious hepatotoxicity (eDISH) with the graph of distribution of 
peak values of ALT versus peak values of total bilirubin will also be presented using post-
baseline values during TEAE period. Note that the ALT and total bilirubin values are presented 
on a logarithmic scale. The graph will be divided into 4 quadrants with a vertical line 
corresponding to 3 x ULN for ALT and a horizontal line corresponding to 2 x ULN for total 
bilirubin. 
Listing of possible Hy’s law cases identified by treatment group (i.e., patients with any elevated 
ALT>3 x ULN, and associated with an increase in bilirubin >2 x ULN, concomitantly or not) 
with ALT, AST, ALP, total bilirubin, and if available direct and indirect bilirubin will be 
provided. 
The incidence of liver-related TEAEs will be summarized by treatment group. The selection of 
PTs will be based on SMQ Hepatic disorder (see Section 4.7.1.2).  
Analysis of Clinical Laboratory Variables in Open-Label Period 
For open-label period clinical laboratory parameters, summary tables as described for the 
double-blind period will be used. 
5.7.3. 
Analysis of Vital Sign Variables 
The vital sign actual values and change from baseline values obtained while sitting will be 
descriptively summarized at baseline and each post-baseline visit (collected up to the day of last 
dose of study treatment +21 days) by at least patient number, mean, median, Q1, Q3, SD, 
minimum and maximum for each treatment group. Additionally, vital sign measures for last on-
treatment value and worst on-treatment value will be summarized in a similar manner. Vital sign 
mean changes from baseline, with the corresponding SE, can be plotted at each visit by treatment 
group, in the case results warrant further investigation. 
Individual patient vital sign measurements (regardless of sitting position) will be additionally 
evaluated by PCSA criteria, specifically identifying patients with at least one post-baseline 
measurement that meets the PCSA criteria within the TEAE period.  Patients meeting the PCSA 
criteria at least once will be summarized by patient count (and percent) and treatment group.  
Patient listings of vial sign measurements that meet PCSA criteria will be provided for the report 
appendix.   
Analysis of Vital Sign Variables in Open-Label Period 
For open-label period vital sign parameters, summary tables as described for the double-blind 
period will be used. 
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5.7.4. 
Analysis of Electrocardiogram Variables 
ECG parameters will be described through an overall interpretation of ECG status. The count and 
percentage of patients with at least 1 abnormal post-baseline ECG during the TEAE period will 
be summarized by treatment group according to the following baseline status categories: 
 Normal/missing; 
 Abnormal 
5.8. 
Analysis of Other Variables 
The summary of other variables will be presented separately for the double-blind and open-label 
period. The double-blind period will be presented by treatment groups (alirocumab, placebo) on 
the safety population. The open-label period will be presented by all patients and by treatment 
group of the double-blind period (i.e., alirocumab, placebo) on the open-label population. No 
formal inferential testing will be performed for either period. Summaries will be descriptive in 
nature. All summaries of safety results described below will be presented for each period 
respectively, unless otherwise noted. 
All measurements, scheduled or unscheduled, fasting or not fasting, will be assigned to analysis 
windows in order to provide an assessment for week 4 to week 24 time points.   
Hs-CRP parameter (Section 4.8) will be summarized for the number of patients with data, mean, 
SD, median, minimum, maximum, Q1 and Q3 by analysis visit during the treatment period. The 
medians (with Q1-Q3) will be plotted for hs-CRP. Applying the PCSA criteria at any time during 
the TEAE period, the number of patients (and percentages) meeting the criteria will be 
summarized.  
Binary endpoints defined in Section 4.8 will be described through patient counts and percentages.  
The change in the proportion of patients who meet US apheresis eligibility criteria form baseline 
to week 12 (Section 4.8) will be summarized by treatment group on the safety population for the 
number of patients with data, mean, SD, median, minimum, and maximum. The change in the 
proportion of patients who meet German apheresis eligibility criteria form baseline to week 12 
will be summarized in a similar manner. 
Correlations between HoFH genotype status and lipid parameters will be explored (e.g., scatter 
plot). 
5.9. 
Analysis of Anti-alirocumab Antibody Variables 
The summary of ADA variables will be presented separately for the double-blind and open-label 
period. The double-blind period will be presented by treatment groups (alirocumab, placebo) on 
the ADA population. The open-label period will be presented by all patients and by treatment 
group of the double-blind period (i.e., alirocumab, placebo) on the open-label population. No 
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formal inferential testing will be performed for either period. Summaries will be descriptive in 
nature.  
ADA variables will be summarized, taking into account all samples regardless of timing in 
relation to injections.  ADA results will be summarized as follows: 
 ADA results (negative or positive) by time point  
 Neutralizing status (negative or positive) by time point for positive ADA  
 ADA titers using descriptive statistics (median, minimum and maximum) for positive 
ADA by time point  
 Number (%) of patients with pre-existing ADA and number (%) of patients with 
treatment-emergent ADA positive response  
 Number (%) of patients with persistent/indeterminate/transient treatment-emergent 
ADA positive response (only for the double-blind period) 
 Time to onset of treatment-emergent ADA positive response using descriptive 
statistics. 
Correlations between ADA parameters (e.g., titers, treatment-emergent ADA positive status, 
neutralizing status) and safety and/or efficacy endpoints will also be explored (e.g., scatter plot). 
5.10. 
Analysis of Pharmacokinetic Data 
Concentrations of total alirocumab in serum and total and free PCSK9 concentrations will be 
summarized on the PK population by treatment group and visit using descriptive statistics.  
Descriptive statistics could be provided by specific sub-groups (e.g., gender, BMI, age), as 
needed. 
Time profile for concentrations of total alirocumab and total and free PCSK9 will be provided by 
treatment group using graphs (mean ± SD or Median, as appropriate). Plots of the individual 
concentrations of alirocumab, and total and free PCSK9 may be presented versus actual time. 
Additional plots will be prepared, as deemed necessary (e.g., to explore the relationship with 
some safety or efficacy endpoints of interest). 
Concentrations of total alirocumab in serum and PCSK9 levels might be used for population PK 
modeling if considered necessary and the results of population PK modeling will be reported 
separately from the study report. 
5.11. 
Analysis of Genomics Variables 
Plans for the analysis of genomics data will be provided in a separate SAP. 
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5.12. 
Analysis of Quality-of-Life Variables 
The summary of quality-of-life variables will be presented separately for the double-blind and 
open-label period. The double-blind period will be presented by treatment groups (alirocumab, 
placebo) on the quality-of-life safety population. The open-label period will be presented by all 
patients and by treatment group of the double-blind period (i.e., alirocumab, placebo) on the 
open-label population. No formal inferential testing will be performed for either period. 
Summaries will be descriptive in nature. All summaries of safety results described below will be 
presented for each period respectively, unless otherwise noted. 
The analysis of data from EQ-5D instrument will be performed on the quality-of-life population. 
Baseline is defined as the visit at Day 1 or Visit 3 (week 0) evaluation. Analysis windows for 
efficacy parameters will be used to assign time point visits.  
Individual EQ-5D items 
Response for each one of the 5 EQ-5D items will be summarized for each treatment group using 
tables which will contain frequency and percentage of the patients reporting level 1 (no 
problems), level 2 (some problems) and level 3 (extreme problems) by analysis visit during the 
treatment period.  
EQ-5D utility score 
The raw value and the change from baseline of the utility score will be summarized using mean, 
median, Q1, Q3, SD, minimum and maximum for each post-baseline visit during the treatment 
period. Cumulative distribution functions for the change in utility score from baseline will be 
displayed by treatment groups at weeks 12 on the quality-of-life safety population.  
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis. 
6.1. 
Definition of Baseline for Efficacy and Safety Variables 
Unless otherwise specified, the baseline assessment is programmatically defined as the latest 
available measurement taken before first administration of double-blind study treatment. For 
patients randomized but not-treated, the baseline will be the last available measurement before 
randomization.  
6.2. 
Data Handling Conventions for Efficacy Variables 
Data handling conventions, including addressing missing data, is addressed for the efficacy 
endpoints in Sections 5.6.1 and 5.6.2. 
6.3. 
General Data Handling Conventions 
In general, the following formulas will be used for computation of parameters: 
Time from diagnosis 
Time from diagnosis (years) = (Date of informed consent – Date of diagnosis*) / 365.25.  
 (*):In case the month of diagnosis would be missing, it will be put equal to JANUARY if the year of diagnosis 
equals the year of informed consent; it will be put equal to JUNE otherwise. In the case the day is missing, the day 
will be put equal to 1st if the month and year of diagnosis equals the month and year of informed consent; otherwise 
it will be put equal to the 15th of the month. 
Date of last dose of study treatment 
The date of the last injection is equal to the last date of administration reported on injection 
administration case report form page, or missing if the last administration date is unknown.  
Renal function formulas  
Estimated GFR will be derived using the Modification of the Diet in Renal Disease (MDRD) 
equation: 
186.3 × (creatinine in µmol/L / 88.4)-1.154 × (age in years)-0.203 (x 0.742 if female, x 1.21 if race is 
"black or African American"). 
 
 
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Lipids variables, laboratory safety variables, hs-CRP 
For data below the lower limit of quantification (LLOQ) / limit of linearity, half of the lower 
limit value (i.e., LLOQ/2) will be used for quantitative analyses. For data above the upper limit 
of quantification (ULOQ) / limit of linearity, the upper limit value (i.e., ULOQ) will be used for 
quantitative analyses. 
6.4. 
General Missing Data Conventions 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified.  When relevant, the number of patients with missing data 
is presented. 
Handling of baseline definition if “time” of first double-blind study treatment administration 
or time of assessment at week 0 visit is missing 
If the time of the first double-blind study treatment administration or the time of assessment at 
week 0 visit is missing, then the baseline value is defined as the last available value obtained 
before or on the day of the double-blind first study treatment administration. 
Handling of computation of treatment duration and compliance if study treatment first or end 
of treatment date is missing  
If the last or first injection date is missing, the exposure duration and compliance will be left as 
missing. 
Handling of safety and efficacy analysis periods and survival analysis if end of study 
treatment date is missing  
If the last injection date for a treatment period (double-blind or open-label) is missing, then this 
date is imputed to the earliest between  
 the last day of the month and year, when applicable or else the 31st of December of 
the year,  
 the date of the end of treatment visit for the respective treatment period: 
 double-blind treatment period: week 12 visit for completer, early end of double-
blind treatment visit for patients who prematurely discontinued the study 
treatment, 
 open-label treatment period: week 24 visit for completer, early end of open-label 
treatment visit for patients who prematurely discontinued the study treatment, 
 the date of the last contact for the purpose of safety and efficacy analysis period start 
and/or end. 
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Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed.  If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior, concomitant, and post-treatment medication. 
Handling of adverse events with missing or partial date/time of onset, worsening, seriousness 
Missing or partial AE dates and times will be imputed so that if the partial AE date/time 
information does not indicate that the AE started prior to treatment or after the TEAE period, the 
AE will be classified as treatment-emergent. These data imputations are for categorization 
purpose only and will not be used in listings. No imputation is planned for date/time of AE 
resolution. 
Handling of adverse events when date and time of first study treatment administration is 
missing 
When the date and time of the study treatment administration is missing, all AEs that occurred on 
or after the day of randomization will be considered as TEAEs.  
When the time of the first study treatment administration is missing, all AEs that occurred on the 
day of the first study treatment administration will be considered as treatment-emergent AEs. 
Handling of missing assessment of relationship of adverse events to investigational medicinal 
product  
If the assessment of the relationship to study treatment is missing, then the relationship to study 
treatment has to be assumed as possibly related in the frequency tables, but no imputation should 
be done at the data level.  
Handling of potentially clinically significant abnormalities  
If a patient has a missing baseline value he will be grouped in the category “normal/missing at 
baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value and the other on a 
threshold value or a normal range, with the first condition being missing, the PCSA will be based 
only on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; e.g., for eosinophils the PCSA is >0.5 GIGA/L or 
>ULN if ULN ≥0.5 GIGA/L.  When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values. 
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6.5. 
Visit Windows for Time Points 
Visit windows will be programmatically imposed on those efficacy and safety measures 
repeatedly collected over the course of the study. These visit windows are derived from the 
number of days in study, specifically assigning day ranges to mimic the study assessment 
schedule provided in the protocol.  Data analyzed by time point (including efficacy, laboratory 
safety data, vital signs, ECG, quality of life, PK and ADA) will be summarized using the analysis 
windows given in Appendix 10.2. These analysis windows will be applicable for all analyses, 
and they are defined to provide more homogeneous data for time point-specific analyses. If 
multiple valid values of a variable exist within an analysis window, the nearest from the targeted 
study day will be selected. If the difference is a tie, the value after the targeted study day will be 
used. If multiple valid values of a variable exist within a same day, then the first value of the day 
will be selected when time is available, else the scheduled visit will be selected. 
6.6. 
Unscheduled Assessments 
For efficacy, safety laboratory data, vital signs, ECG, and ED-5D, unscheduled visit 
measurements may be used to provide a measurement for a time point, a baseline, a last or a 
worst value, if appropriate according to their definitions. The measurements may also be used to 
determine abnormal values and PCSA. 
6.7. 
Pooling of Centers for Statistical Analyses 
The randomization scheme was not stratified by center because the primary efficacy variable is 
centrally assessed and expected not to be influenced by the center when other factors such as diet 
are already controlled. Therefore, the center will not be added as factor in the primary analysis 
model. 
6.8. 
Statistical Technical Issues 
Not Applicable. 
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7. 
TIMING OF STATISTICAL ANALYSES  
Efficacy and safety analyses for this study will be performed in two steps, specifically for patient 
data collected up to the time the last patient completes efficacy assessments at week 12 (step 1 
consisting of the double-blind period) and at the end of the study (step 2 for the open-label 
period). No formal interim analysis for efficacy is planned since analyses of primary and key 
secondary efficacy endpoints will be final at the time of first-step analysis. Therefore, no 
multiplicity adjustment for multiple analyses is needed (see Section 5.6.3). The timing for patient 
data to be reported is defined below for each step: 
 First-step: efficacy analyses up to week 12 and interim safety analysis  
 This analysis will be conducted on all randomized patients when all patients will 
have all their lipid data up to week 12 analysis window collected and validated. 
 The efficacy analyses will be performed up to week 12 time point. Analyses of 
endpoints up to week 12 time point will correspond to the final analyses for these 
endpoints. Analysis of lipid parameters beyond week 12 will be descriptive.  
 The safety analyses will be performed on all safety data (double-blind and open-
label) collected up to the common cut-off date. For this analysis, the common cut-
off date is defined as date of the last week 12 visit. 
 Second-step: final analysis 
 This analysis will be conducted at the end of the study and will consist of the final 
analysis of efficacy data at time points beyond the week 12 time point and final 
safety analysis.  
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. The results of the first analysis will not be 
used to change the conduct of the ongoing study in any aspect. The first analysis will be used for 
the submission dossier to health authorities. 
Analyses methods and conventions described in the other sections of this SAP will be applied for 
all analyses as applicable. The following additional rules will apply for analyses performed at 
first-step analysis: 
 Any lipid assessments within analysis windows up to week 12 will be taken into 
account (may include few unscheduled lipid data soon after the cut-off date).  
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 Patients without end of treatment visit (double-blind or open-label) performed at the 
time of the cut-off date will be considered as ongoing and exposed up to the cut-off 
date. Therefore: 
 Patients who did not complete the respective treatment period nor prematurely 
discontinued the study treatment at cut-off date will be analyzed as “ongoing” in 
the disposition summary. 
 Their TEAE period and treatment period will end at the cut-off date. 
 Their treatment duration will be derived by considering date of cut-off as last 
injection date.  
 Analyses of number of injections, mean injection frequency, percentage of days with 
under/above-planned dosing and compliance will be performed up to the last injection 
reported in the e-CRF up to the cut-off date.  
 AEs occurring, worsening or becoming serious after the cut-off date will not be 
included in the analyses. However, any available outcome before database lock, 
regardless of timing in relation to the cut-off date, of an adverse event starting prior to 
the cut-off date will be taken into account. Medications, treatment 
discontinuations/completions and deaths occurring after the cut-off date will not be 
included in the analyses.  
 Post-treatment period, post-study period are not applicable for ongoing patients. 
Analyses of post-treatment AEs, post-study deaths and post-treatment medications 
will be performed for patients who either completed or prematurely discontinued the 
treatment before or at the cut-off date. 
 Analysis of status at last study contact and proportion of patients with insufficient 
follow-up will be provided for patients who either completed or prematurely 
discontinued the treatment before or at the cut-off date. 
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8. 
SOFTWARE 
All analyses will be generated using SAS Version 9.4 or higher. 
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9. 
REFERENCES 
1. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd, Criqui M, et al. 
Markers of inflammation and cardiovascular disease:  application to clinical and public 
health practice: A statement for healthcare professionals from the Centers for Disease 
Control and Prevention and the American Heart Association. Circulation. 2003 Jan 
28;107(3):499-511. 
2. Dolan P. Modeling valuations for EuroQol health states. Med Care. 1997 Nov; 
35(11):1095-108. 
3. Little RJ, D'Agostino R, Cohen ML, Dickersin K, Emerson SS, Farrar JT, et al. The 
prevention and treatment of missing data in clinical trials. N Engl J Med. 2012 Oct 
4;367(14):1355-60. doi: 10.1056/NEJMsr1203730. 
4. SAS Institute Inc. 2009. SAS/STAT ® 9.2 User’s Guide, Second Edition. Cary, NC: SAS 
Institute Inc. 
5. Mehrotra DV, Li X, Liu J, Lu K. Analysis of longitudinal clinical trials with missing data 
using multiple imputation in conjunction with robust regression. Biometrics. 2012 
Dec;68(4):1250-9. doi: 10.1111/j.1541-0420.2012.01780.x. 
6. 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. 
7. 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. 
8. 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. 
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10. 
APPENDIX 
10.1. 
Summary of Statistical Analyses 
Primary Efficacy Analysis: 
 
Analysis 
Statistical 
Supportive 
Subgroup 
Other 
Endpoint 
Populations 
Method 
Analysis 
Analysis 
Analyses 
Percent change 
from baseline in 
LDL-C at week 
12 
ITT 
MMRM 
Yes, 
including 
handling of 
missing data 
Yes 
1) On-treatment 
estimand 
2) Actual 
stratification factor 
3) Multiple 
Imputations + 
ANCOVA 
4) Pattern mixture 
model 
10.2. 
Windows for Analysis Time Points 
Below are the definitions for the visit windows programmatically imposed on measures 
repeatedly collected over the course of the study.  These visit windows reflect the study 
schedule of assessments as described in the protocol.  The visit windows are constructed 
using ranges applied to the number of days in study (study days) when the measure is 
collected.  Day 1 is defined as the first date of double-blind study treatment administration, 
and is labeled as baseline for most variables. Since the protocol specifies that measurements 
be collected before study treatment is administered on a given day, it is appropriate that 
baseline include Day 1. For randomized but not treated patients, Day 1 is the day of 
randomization.  
Table 1a Analysis Windows Definition for Double-Blind Period – All Endpoints Except 
Vital Signs 
Time point 
Targeted study day 
Analysis window in study days 
Week 4 
29 
15 to 42 
Week 8 
57 
43 to 70 
Week 12 
85 
71 to minimum of: 98 OR study day corresponding to 
the first open-label injection for patients entering open-
label period 
Study days are calculated from the day of first double-blind IMP injection, the day of first double-blind IMP injection being 
Day 1. For randomized but not treated patients, Day 1 is the day of randomization.  
 
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CONFIDENTIAL 
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Table 1b Analysis Windows Definition for Double-Blind Period – Vital Signs 
Time point 
Targeted study day 
Analysis window in study days 
Week 4 
29 
15 to 42 
Week 8 
57 
43 to 63 
Week 10 
71 
64 to 77 
Week 12 
85 
78 to minimum of: 98 OR study day corresponding to 
the first open-label injection for patients entering open-
label period 
Study days are calculated from the day of first double-blind IMP injection, the day of first double-blind IMP injection being 
Day 1. For randomized but not treated patients, Day 1 is the day of randomization.  
Table 2 Analysis Windows Definition for Open-Label Period 
Time point 
Targeted study day 
Analysis window in study days 
Week 18 
43 
22 to 63 
Week 24 
85 
64 to 105 
Study days are calculated from the day of first open-label IMP injection. The day of first open-label IMP injection being Day 
1.  
 
 
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Statistical Analysis Plan                                                                                                                     August 7, 2019 
 
CONFIDENTIAL 
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10.3. 
Criteria for Potential Clinical Significant Abnormalities (PCSA) 
Parameter 
PCSA 
Comments 
Clinical Chemistry 
ALT 
By distribution analysis : 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not in IU/L.  
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning zero can be 
deleted. 
AST 
By distribution analysis : 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not in IU/L.  
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning zero can be 
deleted. 
Alkaline Phosphatase 
>1.5 ULN 
Enzymes activities must be expressed in ULN, not in IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Total Bilirubin 
>1.5 ULN 
>2 ULN 
Must be expressed in ULN, not in µmol/L or mg/L. Categories are 
cumulative. 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Conjugated Bilirubin 
>35% Total Bilirubin and 
TBILI>1.5 ULN 
Conjugated bilirubin dosed on a case-by-case basis. 
ALT and Total Bilirubin 
ALT>3 ULN and TBILI>2 
ULN 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
To be counted within a same treatment phase, whatever the interval 
between measurement. 
CPK 
>3 ULN 
>10 ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning zero can be 
deleted. 
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Statistical Analysis Plan                                                                                                                     August 7, 2019 
 
CONFIDENTIAL 
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Parameter 
PCSA 
Comments 
Creatinine 
≥150 μmol/L (Adults) 
≥30% change from 
baseline 
≥100% change from 
baseline 
Benichou C., 1994. 
 
CLcr (mL/min) 
(Estimated creatinine clearance 
based on the Cokcroft-Gault 
equation)  
≥15 - <30 (severe 
decrease in GFR) 
≥30 - < 60 (moderate 
decrease in GFR) 
≥60 - <90 (mild decrease 
in GFR) 
≥ 90 (normal GFR) 
Use is optional. 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal function-study 
design, data analysis, and impact on dosing and labeling 
eGFR (mL/min/1.73m2) 
(Estimate of GFR based on an 
MDRD equation)  
 
≥15 - <30 (severe 
decrease in GFR) 
≥30 - < 60 (moderate 
decrease in GFR) 
≥60 - <90 (mild decrease 
in GFR) 
≥ 90 (normal GFR) 
Use is optional. 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal function-study 
design, data analysis, and impact on dosing and labeling 
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 μmol/L 
<120 μmol/L  
Harrison- Principles of internal Medicine 17th Ed., 2008. 
Blood Urea Nitrogen 
≥17 mmol/L 
 
Chloride 
<80 mmol/L 
>115 mmol/L 
 
Sodium 
≤129 mmol/L 
≥160 mmol/L 
 
Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
Lipasemia 
≥3 ULN 
 
Amylasemia 
≥3 ULN 
 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L 
(unfasted); ≥7 mmol/L 
(fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
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Statistical Analysis Plan                                                                                                                     August 7, 2019 
 
CONFIDENTIAL 
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Parameter 
PCSA 
Comments 
HbA1c 
>8% 
 
Albumin 
≤25 g/L 
 
CRP 
>2 ULN or >10 mg/L (if 
ULN not provided) 
 FDA Sept 2005. 
Hematology 
WBC 
<3.0 Giga/L (Non-Black); 
<2.0 Giga/L (Black) 
≥16.0 Giga/L 
Increase in WBC: not relevant. 
To be interpreted only if no differential count available. 
Lymphocytes 
>4.0 Giga/L 
 
Neutrophils 
<1.5 Giga/L (Non-
Black);<1.0 Giga/L 
(Black) 
International Consensus meeting on drug-induced blood cytopenias, 
1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L 
 
Basophils 
>0.1 Giga/L 
 
Eosinophils 
>0.5 Giga/L or >ULN (if 
ULN≥0.5 Giga/L) 
Harrison- Principles of internal Medicine 17th Ed., 2008. 
Hemoglobin 
≤115 g/L (Male); ≤95 g/L 
(Female) 
≥185 g/L (Male); ≥165 
g/L (Female) 
 
Decrease from Baseline 
≥20 g/L 
Criteria based upon decrease from baseline are more relevant than 
based on absolute value. Other categories for decrease from 
baseline can be used (≥30 g/L, ≥40 g/L, ≥50 g/L). 
Hematocrit 
≤0.37 v/v (Male) ; ≤0.32 
v/v (Female) 
≥0.55 v/v (Male) ; ≥0.5 
v/v (Female) 
 
RBC 
≥6 Tera/L 
Unless specifically required for particular drug development, the 
analysis is redundant with that of Hb. 
Otherwise, consider FDA criteria. 
Platelets 
<100 Giga/L 
≥700 Giga/L 
International Consensus meeting on drug-induced blood cytopenias, 
1991. 
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Regeneron Pharmaceuticals, Inc.                                                               Protocol: R727-CL-1628 (alirocumab) 
Statistical Analysis Plan                                                                                                                     August 7, 2019 
 
CONFIDENTIAL 
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Parameter 
PCSA 
Comments 
Urinalysis 
pH 
≤4.6 
≥8 
 
Vital signs 
HR 
≤50 bpm and decrease 
from baseline ≥20 bpm 
≥120 bpm and increase 
from baseline≥20 bpm 
To be applied for all positions (including missing) except 
STANDING. 
SBP 
≤95 mmHg and 
decrease from baseline 
≥20mmHg 
≥160 mmHg and 
increase from baseline 
≥20 mmHg 
To be applied for all positions (including missing) except 
STANDING. 
DBP 
≤45 mmHg and 
decrease from baseline 
≥10 mmHg 
≥110 mmHg and 
increase from baseline 
≥10 mmHg 
To be applied for all positions (including missing) except 
STANDING. 
Orthostatic Hypotension 
Orthostatic SDB 
Orthostatic DBP 
 
 
≤-20 mmHg 
≤-10 mmHg 
 
Weight 
≥5% increase from 
baseline  
≥5% decrease from 
baseline 
FDA Feb 2007. 
ECG 
Ref.: CPMP 1997 guideline. 
HR 
≤50 bpm and decrease 
from baseline ≥20 bpm 
≥120 bpm and increase 
from baseline ≥20 bpm 
 
PR 
≥220 ms and increase 
from baseline ≥20 ms 
 
QRS 
≥120 ms 
 
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Regeneron Pharmaceuticals, Inc.                                                               Protocol: R727-CL-1628 (alirocumab) 
Statistical Analysis Plan                                                                                                                     August 7, 2019 
 
CONFIDENTIAL 
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Parameter 
PCSA 
Comments 
QTc 
Borderline 
Prolonged* 
Additional 
 
Absolute values (ms)
 
 
Borderline: 431-450 ms 
(Male); 451-470 ms 
(Female) 
Prolonged: >450 ms 
(Male); >470 ms 
(Female) 
≥500 ms 
 
Increase from baseline 
Borderline: Increase 
from baseline 30-60 ms 
Prolonged:  Increase 
from baseline >60 ms 
To be applied to any kind of QT correction formula.  
 
 
 
*QTc prolonged and QTc>60 ms are the PCSA to be identified in 
individual subjects/patients listings. 
 
 
 
                                        VV-RIM-00084723-1.0 Approved - 14 Aug 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc.                                                               Protocol: R727-CL-1628 (alirocumab) 
Statistical Analysis Plan                                                                                                                     August 7, 2019 
 
CONFIDENTIAL 
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10.4. 
EQ-5D Patient Questionnaire and Algorithme 
 
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Statistical Analysis Plan                                                                                                                     August 7, 2019 
 
CONFIDENTIAL 
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EQ-5D Utility Score Algorithm 
Algorithm: UK based 
/*=========================================================================*/; 
/*  Aim                      : Derive the EQ5-D index (utility)            */; 
/*  Source for the algorithm : scoring EQ-5D health states (Rosalind Rabin */; 
/*            (cf. G:\_HE\PRO questionnaire\EQ5D\scoring\YorkTariffx.doc)  */; 
/*  Note                     : UK based population (Dolan, 1997)           */; 
/*=========================================================================*/; 
Answer to questions in numeric format, from 1 (no problem) to 3 (severe problem); Q1 
(mobility), Q2 (self-care), Q3 (usual activities), Q4 (pain/discomfort), Q5 (anxiety/depression) 
Result of the algorithm: Utility (EQ-5D utility score). 
If at least one of the answer to questions is missing then the utility score is missing. 
Start with Utility =1 and apply the following sequential algorithm. 
 
**********Mobility********* 
if Q1=2 then Utility = Utility - 0.069 
if Q1=3 then Utility = Utility - 0.314 
 
********Self-care********** 
if Q2=2 then Utility = Utility - 0.104 
if Q2=3 then Utility = Utility - 0.214 
 
******Usual activities***** 
if Q3=2 then Utility = Utility - 0.036 
if Q3=3 then Utility = Utility - 0.094 
 
*****Pain/discomfort****** 
if Q4=2 then Utility = Utility - 0.123 
if Q4=3 then Utility = Utility - 0.386 
 
*****Anxiety/depression***** 
if Q5=2 then Utility = Utility - 0.071 
if Q5=3 then Utility = Utility - 0.236 
 
if (Q1 ≠ 1 or Q2 ≠ 1 or Q3 ≠ 1 or Q4 ≠ 1 or Q5 ≠ 1) then Utility = Utility - 0.081 
if (Q1=3 or Q2=3 or Q3=3 or Q4=3 or Q5=3) then Utility = Utility - 0.269 
End of the sequential algorithm 
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Regeneron Pharmaceuticals, Inc.                                                               Protocol: R727-CL-1628 (alirocumab) 
Statistical Analysis Plan                                                                                                                     August 7, 2019 
 
CONFIDENTIAL 
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10.5. 
List of MedDRA terms for CMQs 
Table 3   Selected PTs from SMQ “Optic nerve disorders” including in the CMQ for 
neurologic events 
MedDRA Term Label 
Benign neoplasm of optic nerve 
Optic atrophy 
Optic discs blurred 
Optic nerve disorder 
Optic nerve injury 
Optic nerve neoplasm 
Optic nerve operation 
Optic neuropathy 
Papillitis 
Pseudopapilloedema 
Subacute myelo-opticoneuropathy 
Toxic optic neuropathy 
Visual evoked potentials abnormal 
Amaurosis fugax 
Blindness 
Blindness unilateral 
Colour blindness acquired 
Colour vision tests abnormal 
Cranial nerve injury 
Delayed myelination 
Fundoscopy abnormal 
Hemianopia 
Hemianopia heteronymous 
Hemianopia homonymous 
Loss of visual contrast sensitivity 
Neuro-ophthalmological test abnormal 
Night blindness 
Ophthalmological examination abnormal 
Optic pathway injury 
Optical coherence tomography abnormal 
Quadrantanopia 
Visual acuity reduced 
Visual acuity reduced transiently 
Visual acuity tests abnormal 
Visual field defect 
Visual field tests abnormal 
Visual impairment 
Visual pathway disorder 
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Regeneron Pharmaceuticals, Inc.                                                               Protocol: R727-CL-1628 (alirocumab) 
Statistical Analysis Plan                                                                                                                     August 7, 2019 
 
CONFIDENTIAL 
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Table 4 CMQ “Neurocognitive disorders – FDA’s recommendation” 
MedDRA level 
MedDRA Term Label 
PTCD 
Amnesia 
PTCD 
Amnestic disorder 
PTCD 
Anterograde Amnesia 
PTCD 
Behavioural and Psychiatric Symptoms of Dementia 
PTCD 
Change in sustained attention 
LLTCD 
Cognitive Deterioration 
PTCD 
Cognitive Disorder 
LLTCD 
Confusion 
LLTCD 
Confusion Aggravated 
PTCD 
Confusional State 
PTCD 
Delirium 
PTCD 
Dementia 
PTCD 
Dementia Alzheimer's type 
LLTCD 
Dementia Nos 
LLTCD 
Dementia Nos Aggravated 
LLTCD 
Dementia of the Alzheimer's type NOS 
PTCD 
Dementia with Lewy Bodies 
PTCD 
Disorientation 
PTCD 
Disturbance in attention 
PTCD 
Executive dysfunction 
PTCD 
Frontotemporal Dementia 
LLTCD 
Global Amnesia 
PTCD 
Illogical Thinking 
PTCD 
Impaired reasoning 
PTCD 
Incoherent 
PTCD 
Judgement impaired 
PTCD 
Memory Impairment 
PTCD 
Mental Impairment 
LLTCD 
Mental Impairment Nos 
LLTCD 
Mental State Abnormal Aggravated 
PTCD 
Mental Status Changes 
PTCD 
Mini Mental Status Examination Abnormal 
PTCD 
Presenile Dementia 
PTCD 
Retrograde Amnesia 
PTCD 
Senile Dementia 
LLTCD 
Senile Dementia Nos 
LLTCD 
Short-term Memory Loss 
PTCD 
Thinking Abnormal 
LLTCD 
Thinking Slowed 
PTCD 
Transient Global Amnesia 
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Regeneron Pharmaceuticals, Inc.                                                               Protocol: R727-CL-1628 (alirocumab) 
Statistical Analysis Plan                                                                                                                     August 7, 2019 
 
CONFIDENTIAL 
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MedDRA level 
MedDRA Term Label 
PTCD 
Vascular Dementia 
 
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Statistical Analysis Plan                                                                                                                     August 7, 2019 
 
CONFIDENTIAL 
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10.6. 
Detailed Description of the Multiple Imputation Procedure 
The following is a detailed description of the multiple imputation procedure which will be used 
for sensitivity analysis of primary efficacy endpoint as well as the analysis of the secondary 
efficacy endpoints. 
In general, the missing pattern is anticipated to be not monotone, a two-step approach will be 
used: 
 Step 1:  the MCMC method will be used in conjunction with the 
IMPUTE=MONOTONE option to create an imputed data set with a monotone 
missing pattern. 
 Step 2:  Using the monotone data set from step 1, missing data will be imputed using 
the regression method. 
The imputation model for step 1 will include the treatment group and the values of the analyzed 
parameter at baseline and planned time-points up to week 12. 
The imputation model for step 2 will include the same variables as in step 1 with the following 
additional variables: 
 the randomization strata (apheresis treatment status strata); 
 age, BMI, and gender (age and BMI included as continuous variables). 
Non-continuous variables included in the imputer’s model (i.e., treatment group, randomization 
strata and gender) are not expected to be missing. 
In addition, for continuous efficacy variables anticipated to have a non-normal distribution 
(i.e. TG and Lp(a)), data will be log-transformed before imputation process and then 
back-transformed to create the imputed data sets using the TRANSFORM statement of SAS MI 
procedure. 
For variables other than those continuous efficacy variables anticipated to have a non-normal 
distribution (i.e. TG and Lp(a)), for each simulation leading to negative imputed value, another 
value will be redrawn using MINIMUM option of MI SAS procedure. 
The number of imputations (100) will be informally verified by replicating sets of 100 
imputations and checking whether the combined results are stable. If not stable, the number of 
imputations will be increased and informally checked as above, and thus continued until stable 
estimates are obtained. 
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Regeneron Pharmaceuticals, Inc.                                                               Protocol: R727-CL-1628 (alirocumab) 
Statistical Analysis Plan                                                                                                                     August 7, 2019 
 
CONFIDENTIAL 
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10.7. 
Detailed Description of Pattern Mixture Model 
As a sensitivity analysis of the primary efficacy endpoint (i.e. percent change from baseline to 
Week 12 in  LDL-C), a pattern-mixture model approach will be used, with a different imputation 
strategy applied for missing LDL-C values during the on-treatment period (i.e. within the time 
period from the first double-blind IMP injection up to the day of the last double-blind injection 
+21 days or to the day before the first open-label injection, whichever comes first) and missing  
LDL-C values after treatment discontinuation (i.e. after the day of last injection +21 days) based 
on the following assumptions: 
 Patients within 21 days of their last IMP injection would continue to show benefit 
from treatment similar to that observed at the scheduled time point. Therefore, LDLC 
values missing during the on-treatment period will be considered “Missing At 
Random” and imputed using a model estimated using all samples collected on 
treatment. 
 Patients who stopped taking their study treatment no longer benefited from it in the 
future, and thus tended to have LDL-C values returning to baseline. Thus LDL-C 
values missing after treatment discontinuation will be imputed based on patient’s own 
baseline value. 
The assumptions for this approach are based on the following considerations: 
 Missing values during the on-treatment period are mostly consecutive to: 
 Visits performed outside of the pre-specified time-window  
 No blood sample available although visit was done 
 LDL-C not measurable due to technical reasons 
In addition, these missing data are often intermittent, i.e. followed by LDL-C values collected at 
subsequent visits. It is therefore considered reasonable to assume that these missing data were 
“At Random”. 
Phase 2 studies DFI11565 and R727-CL-1003 included a prospective assessment of calculated 
LDL-C during the follow-up period after a 12-week treatment period. These studies showed that 
after treatment discontinuation, the average calculated LDL-C returned to baseline level within 4 
weeks after ceasing Praluent treatment (see Figure 2 and Figure 3). 
 
 
 
 
 
 
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Regeneron Pharmaceuticals, Inc.                                                               Protocol: R727-CL-1628 (alirocumab) 
Statistical Analysis Plan                                                                                                                     August 7, 2019 
 
CONFIDENTIAL 
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Figure 2 - Study DFI11565:  calculated LDL-C mean (+/- SE) percent change from baseline 
 
Figure 3 - Study R-727-CL-1003: calculated LDL-C mean (+/- SE) percent change 
from baseline 
 
Missing LDL-C values will be imputed 100 times to generate 100 complete data sets. The 
percent change from baseline to Week 12 will be derived from observed and imputed LDL-C at 
this time point. The completed data sets will be analyzed using an analysis of covariance 
(ANCOVA) model with treatment group and randomization strata as fixed effects, and the 
baseline LDL-C value as continuous covariate. The results from the 100 analyses will be 
combined using Rubin’s formulae. If necessary, the number of imputations (100) will be 
increased until stable estimates are obtained. 
                                        VV-RIM-00084723-1.0 Approved - 14 Aug 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc.                                                               Protocol: R727-CL-1628 (alirocumab) 
Statistical Analysis Plan                                                                                                                     August 7, 2019 
 
CONFIDENTIAL 
Page 82 of 83 
Imputation of missing data during the on-treatment period 
Missing LDL-C values during the on-treatment period will be imputed from other on-treatment 
measurements assuming Missing At Random, using SAS® MI procedure. 
Only LDL-C values collected during the on-treatment period will be included in the imputation 
model. This way, missing LDL-C values during the on-treatment period will be imputed based 
solely on observed on-treatment LDL-C values. 
The imputation model will include the treatment arm, baseline LDL-C value, and all LDL-C 
values at pre-specified visits. Since the pattern of missing data will necessarily be non-monotone, 
a Monte-Carlo Markov Chain (MCMC) method will be used. A minimum value of 0 will be 
specified in order to avoid negative imputed LDL-C values. 
A sample SAS code is provided below: 
proc mi data=DATAIN out=DATAOUT nimpute=100 minimum=0; 
  mcmc impute=monotone; 
  var ARM LDL_BASE LDL_W4 LDL_W8 LDL_W12; 
run; 
As stated above, the input dataset DATAIN will include only LDL-C values collected during the 
on-treatment period. Any LDL-C values collected during the post-treatment period will be 
excluded from the input dataset. In practice, the MI procedure will generate imputed values for 
all missing values (whether on-treatment or post-treatment), but only imputed values during the-
on-treatment period will be kept in the final datasets that will be analyzed using ANCOVA. 
Imputed values during the post-treatment period will be discarded and replaced by imputed 
values described in the next paragraph. 
Imputation of missing data after treatment discontinuation 
Missing LDL-C values during the post-treatment period will be imputed assuming LDL-C values 
would on average return to baseline values. 
For each patient, missing post-treatment LDL-C values will be imputed 100 times, using a 
random draw from a normal distribution, with mean equal to patient’s own baseline value and 
variance equal to the conditional variance at the specific time-point, given the baseline value. 
Let Y0 and Y1 denote the LDL-C at baseline and at the specific time-point respectively. Since Y0 
and Y1 are assumed to have a bivariate normal distribution, the conditional variance of Y1 given 
Y0 is: 
)
1(
)
(
2
2
1
0
0
1




y
Y
Y
Var
 
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Regeneron Pharmaceuticals, Inc.                                                               Protocol: R727-CL-1628 (alirocumab) 
Statistical Analysis Plan                                                                                                                     August 7, 2019 
 
CONFIDENTIAL 
Page 83 of 83 
Where 
2
1
 denotes the variance of Y1 and ρ the coefficient of correlation between Y0 and Y1. 
The conditional variance will be estimated from observed data within the same treatment arm at 
the specific time-point. 
During the random generation process, a minimum value of 0 will also be applied in order to 
avoid negative imputed LDL-C values.  
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