Conditions: Hypercholesterolemia
Keywords: Hyperlipidemias Dyslipidemias Lipid Metabolism Disorders
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2176
Healthy volunteers: no

Brief summary:
The main purpose of this study is to evaluate the effect on mental state (known as "neurocognitive function") with use of Praluent.

Detailed description:

Arms:
arm 1: Praluent Regimen - Administration through subcutaneous injection arm 2: Placebo matching Praluent - Administration through subcutaneous injection

Interventions: intervention 1: Praluent (Alirocumab) intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
EudraCT Number:  2016-003189-16 
IND Number: 105574 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Effect of Praluent 
on Neurocognitive Function in Patients with Heterozygous Familial Hypercholesterolemia 
or with Non-Familial Hypercholesterolemia at High and Very High Cardiovascular Risk 
Compound: 
Praluent 
Clinical Phase: 
4 
Protocol Number: 
R727-CL-1532 
Protocol Version: 
R727-CL-1532.05 
Amendment 5 Date of Issue: 
See appended electronic signature page 
Amendment 4 Date of Issue: 
17 May 2017 
Amendment 3 Date of Issue: 
10 January 2017 
Amendment 2 Date of Issue: 
08 August 2016 
Amendment 1 Date of Issue: 
13 April 2016 
Original Date of Issue: 
23 October 2015 
Scientific/Medical Monitor: 
  
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road  
Tarrytown, NY 10591 
  
 
 
 
 
 
 
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CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 5 
The main purpose of this amendment is to correct that optional laboratory evaluations are 
mandatory. Other minor edits and corrections were also made.  
The table below outlines changes made in this amendment and indicates sections that were 
changed. 
Change 
Section Changed 
Corrected that certain laboratory evaluations 
should be performed at the end of study visit 
even in the absence of clinically relevant 
abnormal values in these parameters at 
previous visits 
Table 1 Schedule of Events 
Footnote 10 
Minor edits and corrections  
 Clarified that medication history to 
be collected is limited to 
medication history related to 
lipid-modifying therapy 
 Clarified definition of non-high 
density lipoprotein 
 Specified that research samples 
should be serum and plasma 
 
 Specified that adverse events of 
special interest (AESI) should be 
reported 
 Completed sentence 
 
Section 6.1 Demographic and Baseline 
Characteristics 
Section 7.6.1 Procedures Performed only at 
the Screening/Baseline Visit 
Section 6.2.3 Secondary Efficacy Endpoints 
Table 1 Schedule of Events 
Section 7.6.7.1 Use and Storage of Research 
Samples 
 
Section 7.6.4.5 Reporting Adverse Events of 
Special Interest 
Appendix 4 Drugs on the Anticholinergic 
Burden Scale, Note #7 
 
 
 
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CONFIDENTIAL 
 
Amendment 4 
The following table outlines the changes made to the protocol and the affected sections: 
Change 
Section Changed 
Added coronary calcium scan as a clarification of possible 
diagnostic methods to document history of coronary heart 
disease 
Section 4.2.1 Inclusion Criteria 
(#2av) 
Revised exclusion criteria to enhance enrollment (#5), to provide 
a definition for “as needed” (pro re nata [PRN]) use (#6), to 
provide comprehensive list of exclusionary medications (#6), to 
clarify “hyperthyroidism/or hypothyroidism” (#8), and to remove 
history of serious allergic reactions (such as anaphylaxis) as this 
is not included in the approved drug labeling (#11) 
Section 4.2.2 Exclusion Criteria 
(#5, #6, #8, #11) 
Clarified procedures to follow if emergency unblinding is 
required 
Section 5.5.2 Emergency 
Unblinding 
Added collection of menstrual cycle data in the study to facilitate 
meaningful analysis of reproductive hormone data 
Table 1 Schedule of Events (row 
added; new footnote #6 added) 
Clarified the visits (days on which blood samples are not 
collected) when study drug may be administered prior to study 
assessments to provide more flexibility in drug administration.  
Table 1 Schedule of Events 
(footnote #7) 
Added collection of a laboratory sample for hepatitis B surface 
antigen and hepatitis C antibody at the end-of-study visit 
Table 1 Schedule of Events 
Section 7.6.4.3 Laboratory Testing 
Removed the requirement that patients be identified by their 
initials on case report forms (CRFs) and other documents 
submitted to the sponsor to preserve patient confidentiality 
Section 13.3 Patient 
Confidentiality and Data Protection 
Removed gabapentin from the list of exclusionary medications 
since use of gabapentin won’t impact interpretation of study 
endpoints 
Appendix 3 Mood Stabilizers, 
Antipsychotics, and Medications to 
Treat Dementia 
Provided a more comprehensive list of medications for 
calculating the anticholinergic burden (ACB) 
Appendix 4 Drugs on the 
Anticholinergic Burden Scale 
Made minor editorial changes 
Table 1 Schedule of Events  
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CONFIDENTIAL 
Amendment 3 
The main purpose of this amendment is to incorporate the following changes requested during the 
regulatory review via the Voluntary Harmonization Procedure (VHP). 
 To add a history of serious allergic reactions and severe hepatic impairment as 
exclusion criteria. 
 To provide the list of highly effective contraception methods in accordance with 
recommendations of the Clinical Trial Facilitation Group (CTFG). 
 To describe the procedure to be followed if emergency unblinding of a patient by the 
investigator is required during the study. 
 To indicate that any patient with 2 consecutive LDL-C levels that are increased >25% 
compared to the randomization visit LDL-C level may receive rescue treatment if no 
reason for LDL-C levels above the threshold value can be determined. 
 To add mild cognitive impairment and dementia as reasons for potential permanent 
discontinuation of study drug. 
 To define what constitutes the end of the study. 
Amendment 2 
The overall purpose of this amendment is to address inconsistencies, provide clarifications and 
correct errors as follows: 
 A EudraCT number belonging to a different study was erroneously used in the original 
protocol.  The EudraCT number was corrected and replaced in this amendment. 
 To clarify that the last study drug administration is week 94 and not week 96. 
 To revise the total number of site locations from up to 600 to up to 300. 
 To add study milestones. 
 To add the proportion of patients reaching LDL-C <50 (1.29 mmol/L) mg/dL as a 
secondary efficacy endpoint because it is the criterion for dose adjustment. 
 To clarify gonadal hormone levels for female and male patients. 
 To add GDS-S and MoCA to the Schedule of Events table. 
 To add that limited clinical data are available on the impact of very low circulating 
LDL on neurocognitive function. 
 To allow study drug administration prior to performing study assessments at visit 4. 
 To allow unscheduled neurocognitive testing during visits when a neurocognitive AE 
is reported and the CANTAB test is not planned or in the case of early treatment 
discontinuation. 
 To modify reasons for permanent discontinuation of study drug. 
 To add new onset of diabetes as an AE of interest. 
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 To revise the list of AE causality evaluation factors for the “not related” category. 
 To more precisely define Neurocognitive Events of Special Interest. 
 To add electronic systems used to process and/or collect data. 
 To clarify that the sponsor may not implement a change in the design or operation of 
the protocol/ICF without a heath authority and/or IRB/EC approved amendment. 
 To make editorial changes corrections, and clarifications. 
Amendment 1 
The purpose of this amendment is incorporate changes made based on feedback received from the 
FDA and to address inconsistencies in the original version. 
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CONFIDENTIAL 
CLINICAL STUDY PROTOCOL SYNOPSIS 
TITLE 
A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Effect of 
Praluent on Neurocognitive Function in Patients with Heterozygous Familial 
Hypercholesterolemia or with Non-Familial Hypercholesterolemia at High and Very 
High Cardiovascular Risk 
SITE LOCATIONS 
 Principal Investigator 
Multinational, up to 300 sites  
Multicenter  
OBJECTIVES 
The primary objective of the study is to evaluate neurocognitive function with use of 
Praluent after 96 weeks of treatment versus placebo.  
The secondary objectives are: 
 To evaluate the effect of Praluent in comparison with placebo on lipoproteins 
 To evaluate the safety and tolerability of Praluent 
STUDY DESIGN 
This is a randomized, double-blind, placebo controlled trial to evaluate neurocognitive 
function in patients with heterozygous familial hypercholesterolemia (heFH), or in 
non-familial hypercholesterolemia (FH) patients, at high or very high cardiovascular 
risk.  
Patients will be randomized in a 1:1 ratio to receive either placebo or 75 mg Praluent 
every 2 weeks (Q2W). Randomization will be stratified by age (<65 or ≥65) and by 
statin use (no statin, low lipophilicity of the concomitant statin, or high lipophilicity 
of the concomitant statin). 
The study consists of the following 2 periods: 
 A screening period of up to 3 weeks.  
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. 
 A double-blind treatment period of 96 weeks.  
On day 1 (baseline), after completion of study assessments and after collection of 
blood samples, and as soon as possible after the patient is randomized into the 
study, the first dose of study drug will be administered.  The patient will be 
monitored at the clinical site for 30 minutes after the first dose. Subsequent doses 
of study drug must be administered Q2W. The last dose of study drug will be 
administered at week 94. 
Patients’ neurocognitive function will be assessed every 6 months. 
The dose of study drug will be increased (using a blinded process) at the week 12 
visit in patients whose low-density lipoprotein (LDL) cholesterol (LDL-C) levels 
are ≥50 mg/dL (1.3 mmol/L) at week 8.  Those patients who are randomized to 
Praluent will receive Praluent 150 mg Q2W at week 12 and until end of study. All 
patients randomized to placebo will continue to receive placebo. 
Lipid results will be blinded for specimens obtained after randomization.  No 
attempts should be made by the investigator or patient to have the patient’s lipid 
values evaluated independently from the time of randomization until the last study 
visit. 
Patients should be on a on a stable regimen of lipid-modifying therapy (LMT; 
including a maximally-tolerated dose of statin, unless statin-intolerant) for 28 days 
prior to screening, as well as on a stable diet.  Patients will be asked to maintain both 
their statin dose and diet from screening to the end of the study. 
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CONFIDENTIAL 
POPULATION 
 
 Sample Size 
Approximately 2170 patients are planned to be randomized: placebo, 1085; Praluent 
75 mg Q2W/up-titrate 150 mg Q2W, 1085.  
 Target Population 
The study population consists of patients with heFH or non-FH patients at high or very 
high cardiovascular risk. High or very high cardiovascular risk patients include 
patients with coronary heart disease (CHD), non-CHD cardiovascular disease (CVD), 
and other risk factors.  Patients must have had a history of CHD without adequate 
control of their hypercholesterolemia with LDL-C ≥70 mg/dL, or all other patients 
with LDL-C ≥100 mg/dL, and be on a maximally-tolerated dose of statin (unless they 
are statin-intolerant).  
TREATMENTS 
 
 Study Drug 
Praluent 
 Dose/Route/Schedule 
75 mg /subcutaneous (SC)/Q2W for 94 weeks* 
*If LDL-C is ≥50 mg/dL (1.3 mmol/L) at week 8, Praluent dose will be increased to 
150 mg Q2W at week 12  
 Placebo  
 Dose/Route/Schedule: 
Placebo matching Praluent 
SC/Q2W for 94 weeks 
ENDPOINTS 
 
 Primary 
The primary outcome measure is the change in Cambridge Neuropsychological Test 
Automated Battery (CANTAB) cognitive domain Spatial Working Memory (SWM) 
strategy score from baseline to week 96. 
 Secondary Endpoints 
Exploratory neurocognitive outcome measures to further assess neurocognitive 
function in the CANTAB domains are provided below for each patient: 
 Paired Associates Learning (PAL) at week 96 defined as both a PAL z-score 
change from baseline and PAL raw score change from baseline, following the 
definitions and rules provided for the primary neurocognitive endpoint 
 Reaction Time (RTI) at week 96 defined as both a RTI z-score change from 
baseline and RTI raw score change from baseline, following the definitions and 
rules provided for the primary neurocognitive endpoint 
 SWM between-errors score at week 96 defined as both a SWM between-errors 
z-score change from baseline and SWM between-errors raw score change from 
baseline, following the definitions and rules provided for the primary 
neurocognitive endpoint 
 Global Composite score at week 96 change from baseline is defined as (the 
average of the following 4 measures at week 96: SWM strategy z-score, PAL 
z-score, RTI z-score, and the SWM between-errors z-score) minus the average of 
the same 4 z-score measures at baseline 
Secondary efficacy endpoints are: 
 The percent change in calculated LDL-C, apolipoprotein (Apo) B, 
non-high-density 
lipoprotein 
 
cholesterol 
(non-HDL-C), 
and 
total 
cholesterol (Total-C) from baseline to weeks 12, 24, 48, 72, and 96 
 The percent change in lipoprotein a [Lp(a)], HDL-C, triglyceride (TG), and 
Apo A-1 from baseline to weeks 12, 24, 48, 72, and 96 
 The proportion of patients reaching LDL-C <70 mg/dL (1.81 mmol/L) at 
weeks 12, 24, 48, 72 and 96. 
 The proportion of patients reaching LDL-C <50 mg/dL (1.29 mmol/L) at weeks 
12, 24, 48, 72, and 96 
Other Endpoints 
 Anti-drug antibody status (positive/negative) and titers assessed at the end of the 
study. 
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CONFIDENTIAL 
 Gonadal hormone levels (for female patients - estradiol, follicle-stimulating 
hormone (FSH) and luteinizing hormone (LH); for male patients - testosterone, 
FSH and LH) 
PROCEDURES AND 
ASSESSMENTS 
The CANTAB will include the following 3 tests which will take approximately 
25 minutes to complete: SWM, PAL and RTI. In addition, efficacy of Praluent will be 
assessed by clinical laboratory evaluation of lipid levels. 
Overall safety will be assessed by monitoring/evaluation of treatment-emergent 
adverse events (TEAEs), physical examinations, blood pressure and heart rate, and 
clinical safety laboratory tests at prespecified time points.  
Blood samples will be collected for determination of anti-drug antibody levels at 
predetermined time points. Research samples and samples for exploratory biomarker 
analysis will be collected. 
STATISTICAL PLAN 
The primary neurocognitive analysis is a statistical evaluation of the noninferiority of 
the Praluent 75 mg Q2W/up-titrate 150 mg Q2W dose regimen to placebo for the 
primary endpoint of change in SWM strategy z-score from baseline to week 96 in the 
primary safety population. The 2-sided 95% confidence interval (CI) for the mean 
treatment difference at week 96 will be determined using an appropriate contrast 
statement in a mixed-effect model with repeated measures (MMRM).  The upper CI 
limit will be compared to the noninferiority margin which is defined as 0.2 and the 
noninferiority will be declared if the upper CI limit is below the noninferiority margin. 
To further understand the effects of Praluent on cognitive function and support the 
primary neurocognitive analysis, the 3 domain endpoints (specifically PAL, RTI, and 
SWM between-error scores) and the Global Composite score will also be evaluated 
for noninferiority at week 96 in the primary safety population. These 4 measures will 
not be evaluated for superiority. 
For secondary efficacy endpoints of lipids, descriptive summaries and analyses will 
be performed in the intent-to-treat (ITT) population (for ITT analysis) and the 
modified intent-to-treat (mITT) population (for on-treatment analysis). P-values for 
the testing of study treatment effect will be provided for descriptive purposes only 
(nominal p-values). 
The general safety analysis will be based on the safety analysis population (safety 
analysis set [SAF]). The safety variables include reported TEAEs and other safety 
information (ie, clinical laboratory evaluations, vital signs). The summary of safety 
results will be presented by the 2 treatment groups (placebo, and Praluent 75 mg 
Q2W/up-titrate 150 mg Q2W). No formal inferential testing will be performed. 
Summaries will be descriptive in nature. 
STUDY DURATION 
Each patient is planned to participate in the study for approximately 99 weeks 
(3 weeks of screening and 96 weeks of treatment). 
As committed to FDA, the study is expected to complete August, 2020, and a final 
study report will be submitted December, 2020. 
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CONFIDENTIAL 
TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................6 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................15 
1. 
INTRODUCTION AND RATIONALE .....................................................................18 
1.1. 
Introduction .................................................................................................................18 
1.2. 
Rationale .....................................................................................................................21 
1.2.1. 
Rationale for Study Design .........................................................................................21 
1.2.2. 
Rationale for Dose Selection ......................................................................................21 
2. 
STUDY OBJECTIVES ..............................................................................................22 
3. 
STUDY DESIGN .......................................................................................................23 
3.1. 
Study Description and Duration .................................................................................23 
3.2. 
Planned Interim Analysis ............................................................................................24 
3.3. 
Study Committees .......................................................................................................24 
3.3.1. 
Neurocognitive Events Review Committee ................................................................24 
4. 
SELECTION OF PATIENTS.....................................................................................25 
4.1. 
Number of Patients Planned .......................................................................................25 
4.2. 
Study Population .........................................................................................................25 
4.2.1. 
Inclusion Criteria ........................................................................................................25 
4.2.2. 
Exclusion Criteria .......................................................................................................26 
4.3. 
Replacement of Patients .............................................................................................28 
5. 
STUDY TREATMENTS............................................................................................29 
5.1. 
Injection Training .......................................................................................................29 
5.2. 
Investigational and Reference Treatments ..................................................................29 
5.3. 
Background Treatment ...............................................................................................30 
5.4. 
Dose Modification ......................................................................................................30 
5.5. 
Method of Treatment Assignment ..............................................................................30 
5.5.1. 
Blinding ......................................................................................................................30 
5.5.2. 
Emergency Unblinding ...............................................................................................31 
5.6. 
Treatment Logistics and Accountability .....................................................................31 
5.6.1. 
Packaging, Labeling, and Storage ..............................................................................31 
5.6.2. 
Supply and Disposition of Treatments .......................................................................32 
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5.6.3. 
Treatment Accountability and Compliance ................................................................32 
5.7. 
Concomitant Medications ...........................................................................................32 
5.7.1. 
Allowed Concomitant Medications ............................................................................33 
5.7.2. 
Prohibited Medications ...............................................................................................33 
5.7.3. 
Rescue Treatment for LDL-C Increase >25% ............................................................33 
6. 
STUDY VARIABLES................................................................................................33 
6.1. 
Demographic and Baseline Characteristics ................................................................33 
6.2. 
Primary and Secondary Endpoints..............................................................................34 
6.2.1. 
Primary Neurocognitive Endpoint ..............................................................................34 
6.2.2. 
Exploratory Neurocognitive Endpoints ......................................................................34 
6.2.3. 
Secondary Efficacy Endpoints ....................................................................................35 
6.2.4. 
Other Endpoints ..........................................................................................................35 
7. 
STUDY SCHEDULE OF EVENTS AND VISIT DESCRIPTIONS.........................35 
7.1. 
Schedule of Events .....................................................................................................35 
7.2. 
Study Visit Descriptions .............................................................................................39 
7.2.1. 
Unscheduled Visits .....................................................................................................39 
7.3. 
Handling of Study Drug Discontinuation and Patient Withdrawal from the 
Study ...........................................................................................................................39 
7.3.1. 
Study Drug Discontinuation .......................................................................................39 
7.3.1.1. 
Reasons for Temporary Discontinuation of Study Drug ............................................39 
7.3.1.2. 
Reasons for Permanent Discontinuation of Study Drug .............................................39 
7.4. 
Patient Withdrawal from the Study ............................................................................40 
7.4.1. 
Early Termination from the Study ..............................................................................40 
7.5. 
Replacement of Patients .............................................................................................40 
7.6. 
Study Procedures ........................................................................................................41 
7.6.1. 
Procedures Performed only at the Screening/Baseline Visit ......................................41 
7.6.2. 
Neurocognitive Assessment Battery Procedures ........................................................41 
7.6.2.1. 
CANTAB ....................................................................................................................41 
7.6.3. 
Efficacy Procedures ....................................................................................................41 
7.6.3.1. 
Lipid Panel ..................................................................................................................41 
7.6.4. 
Safety Procedures .......................................................................................................41 
7.6.4.1. 
Blood Pressure and Heart Rate ...................................................................................41 
7.6.4.2. 
Physical Examination .................................................................................................42 
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CONFIDENTIAL 
7.6.4.3. 
Laboratory Testing ......................................................................................................43 
7.6.4.4. 
Adverse Event Information Collection .......................................................................44 
7.6.4.5. 
Reporting Adverse Events of Special Interest ............................................................44 
7.6.5. 
Anti-Drug Antibody Procedures .................................................................................45 
7.6.6. 
Other Assessments ......................................................................................................45 
7.6.6.1. 
Review of Diet ............................................................................................................45 
7.6.6.2. 
Collection of Menstrual Cycle Data ...........................................................................45 
 
 
 
 
 
 
8. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................46 
8.1. 
Definitions ..................................................................................................................46 
8.1.1. 
Adverse Event .............................................................................................................46 
8.1.2. 
Serious Adverse Event ................................................................................................46 
8.2. 
Recording and Reporting Adverse Events ..................................................................47 
8.2.1. 
Deaths .........................................................................................................................48 
8.2.2. 
Pregnancy and Other Events that Require Accelerated Reporting .............................48 
8.2.3. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................48 
8.2.4. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results .............................49 
8.2.5. 
Follow-up ....................................................................................................................49 
8.3. 
Evaluation of Severity and Causality .........................................................................49 
8.3.1. 
Evaluation of Severity ................................................................................................49 
8.3.1.1. 
Adverse Events (Excluding Local Injection Site Reactions) ......................................49 
8.3.1.2. 
Local Injection Site Reactions ....................................................................................50 
8.3.2. 
Evaluation of Causality ...............................................................................................50 
8.3.2.1. 
Causality Evaluation Factors ......................................................................................50 
8.4. 
Investigator Alert Notification ....................................................................................51 
9. 
STATISTICAL PLAN................................................................................................51 
9.1. 
Statistical Hypothesis ..................................................................................................51 
9.2. 
Determination of Sample Size ....................................................................................51 
9.3. 
Analysis Sets ...............................................................................................................52 
9.3.1. 
Safety Analysis Sets ...................................................................................................52 
9.3.1.1. 
Safety Population ........................................................................................................52 
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9.3.1.2. 
Primary Safety Population ..........................................................................................52 
9.3.2. 
Efficacy Analysis Set ..................................................................................................52 
9.3.2.1. 
Intent-to-Treat .............................................................................................................52 
9.3.2.2. 
Modified Intent-to-Treat .............................................................................................53 
9.3.3. 
Other Analysis Set ......................................................................................................53 
9.4. 
Patient Disposition ......................................................................................................53 
9.5. 
Statistical Methods ......................................................................................................54 
9.5.1. 
Demography and Baseline Characteristics .................................................................54 
9.5.2. 
Safety and Efficacy Analyses .....................................................................................54 
9.5.2.1. 
Primary Neurocognitive Analysis ...............................................................................54 
9.5.2.2. 
Exploratory Neurocognitive Analyses ........................................................................55 
9.5.2.3. 
Secondary Efficacy Analyses .....................................................................................55 
9.5.2.4. 
Multiplicity Considerations ........................................................................................56 
9.5.2.5. 
General Safety Analyses .............................................................................................56 
9.5.2.6. 
Adverse Events ...........................................................................................................57 
9.5.2.7. 
Laboratory Data and Vital Signs ................................................................................58 
9.5.2.8. 
Treatment Exposure ....................................................................................................59 
9.5.2.9. 
Treatment Compliance ................................................................................................60 
9.5.2.10. 
Analysis of Other Endpoints .......................................................................................60 
10. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS .....................................60 
10.1. 
Data Management .......................................................................................................60 
10.2. 
Electronic Systems ......................................................................................................60 
11. 
STUDY MONITORING ............................................................................................61 
11.1. 
Monitoring of Study Sites ...........................................................................................61 
11.2. 
Source Document Requirements ................................................................................61 
11.3. 
Case Report Form Requirements ................................................................................61 
12. 
AUDITS AND INSPECTIONS .................................................................................61 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................62 
13.1. 
Good Clinical Practice Statement ...............................................................................62 
13.2. 
Informed Consent .......................................................................................................62 
13.3. 
Patient Confidentiality and Data Protection ...............................................................63 
13.4. 
Institutional Review Board/Ethics Committee ...........................................................63 
14. 
PROTOCOL AMENDMENTS ..................................................................................63 
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15. 
END OF STUDY DEFINITION ................................................................................63 
16. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................64 
16.1. 
Premature Termination of the Study ...........................................................................64 
16.2. 
Close-out of a Site ......................................................................................................64 
17. 
STUDY DOCUMENTATION ...................................................................................64 
17.1. 
Certification of Accuracy of Data ...............................................................................64 
17.2. 
Retention of Records ..................................................................................................64 
18. 
CONFIDENTIALITY ................................................................................................65 
19. 
FINANCING AND INSURANCE .............................................................................65 
20. 
PUBLICATION POLICY ..........................................................................................65 
21. 
REFERENCES ...........................................................................................................66 
22. 
INVESTIGATOR’S AGREEMENT ..........................................................................68 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................80 
 
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LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................36 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................24 
 
LIST OF APPENDICES 
Appendix 1. Simon Broome Register Diagnostic Criteria for Heterozygous Familial 
Hypercholesterolemia .................................................................................................69 
Appendix 2. WHO Criteria (Dutch Lipid Network Clinical Criteria) for Diagnosis of 
Heterozygous Familial Hypercholesterolemia ...........................................................70 
Appendix 3. Mood Stabilizers, Antipsychotics and Medications to Treat Dementia .................71 
Appendix 4. Drugs on the Anticholinergic Burden Scale ...........................................................72 
Appendix 5. Definition of Cardiovascular Disease Risk Categories ..........................................74 
Appendix 6. Summary of TLC Diet for High Cholesterol ..........................................................75 
Appendix 7. Assessment of Local Injection Site Reactions........................................................76 
Appendix 8. Geriatric Depression Scale short form ...................................................................77 
Appendix 9. Montreal Cognitive Assessment .............................................................................78 
Appendix 10. LDL-C Rescue Medication Principles..................................................................79 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACB 
Anticholinergic burden 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
Apo 
Apolipoprotein 
AST 
Aspartate aminotransferase 
CANTAB 
Cambridge Neuropsychological Test Automated Battery 
CHD 
Coronary heart disease 
CI 
Confidence interval 
CPK 
Creatine phosphokinase 
CRF 
Case report form (paper or electronic) 
CT 
Computed tomography 
CTFG 
Clinical Trial Facilitation Group 
CRO 
Contract research organization 
CVD 
Cardiovascular disease 
EC 
Ethics committee 
EDC 
Electronic data capture 
eCRF 
Electronic case report form 
eGFR 
Estimated Glomerular Filtration Rate 
FH 
Familial hypercholesterolemia 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GDS-S 
Geriatric Depression Scale short form 
HbA1c 
Hemoglobin A1c 
HDL 
High-density lipoprotein 
HDL-C 
High-density lipoprotein cholesterol 
heFH 
Heterozygous familial hypercholesterolemia 
HIV 
Human immunodeficiency virus 
hs-CRP 
High-sensitivity C-reactive protein 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
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IVRS 
Interactive voice response system 
IWRS 
Interactive web response system 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LDL-C 
Low-density lipoprotein cholesterol 
LDLR 
Low-density lipoprotein receptor 
LH 
Luteinizing hormone 
LMT 
Lipid-modifying therapy 
LOCF 
Last observation carried forward 
Lp(a) 
Lipoprotein a 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent-to-treat 
MMRM 
Mixed-effect model with repeated measures 
MoCA 
Montreal Cognitive Assessment 
MRI 
Magnetic resonance imaging 
NCEP ATP 
National Cholesterol Education Program-Adult Treatment Panel  
Non-HDL-C 
Non-high-density lipoprotein cholesterol 
PAL 
Paired Associates Learning 
PCSA 
Potentially clinically significant abnormal value 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PRN 
Pro re nata 
PT 
Preferred term 
Q2W 
Every 2 weeks 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
RTI 
Reaction Time 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Software 
SC 
Subcutaneous 
SOC 
System organ class 
SWM 
Spatial Working Memory 
TEAE 
Treatment-emergent adverse event 
TG 
Triglyceride 
Total-C 
Total cholesterol 
TSH 
Thyroid-stimulating hormone 
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ULN 
Upper limit of normal 
VHP 
Voluntary Harmonization Procedure 
WBC 
White blood cell 
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1. 
INTRODUCTION AND RATIONALE 
Praluent® is a human monoclonal antibody that binds proprotein convertase subtilisin/kexin type 
9 (PCSK9) to inhibit its function. All relevant information concerning the compound is available 
in the latest version of the Investigator’s Brochure. Praluent was approved in the US on 
July 24, 2015 for use, in addition to diet and maximally tolerated statin therapy, in adult patients 
with heterozygous familial hypercholesterolemia (heFH) or patients with clinical atherosclerotic 
cardiovascular disease (CVD) such as heart attacks or strokes, who require additional lowering of 
low-density lipoprotein (LDL) cholesterol (LDL-C).  Praluent was approved in the EU on 
23 September 2015 for use in adults with primary hypercholesterolemia (heterozygous familial 
and non-familial) or mixed dyslipidemia, as an adjunct to diet in combination with a statin or statin 
with other lipid lowering therapies in patients unable to reach LDL-C goals with the maximum 
tolerated dose of a statin, or alone or in combination with other lipid-lowering therapies in patients 
who are statin-intolerant or for whom a statin is contraindicated. 
Praluent is also referred to as alirocumab, REGN727 or SAR236553. In the context of the 
R727-CL-1532 clinical study protocol, it will be referred to as Praluent. 
1.1. 
Introduction 
This is a randomized, double-blind, placebo controlled trial to evaluate neurocognitive function in 
patients with heFH, or in non-familial hypercholesterolemia (FH) patients, at high or very high 
cardiovascular risk. To objectively evaluate neurocognitive function, the Cambridge 
Neuropsychological Test Automated Battery (CANTAB) will be employed. In addition, this study 
will evaluate the effect of Praluent on LDL-C, various lipid sub-fractions, and overall safety. 
Studies (trials and observational) have linked midlife and late-life cardiovascular risk factors to 
cognitive function (Joas 2012, Mielke 2010, Reijmer 2012). A recent epidemiological study has 
also shown that cumulative exposure to cardiovascular risk factors from early to middle adulthood, 
especially above guideline-recommended targets, was associated with worse cognition in midlife 
(Yaffe 2014). This was a prospective study of 3381 adults (age, 18 to 30 years at baseline) with 
25 years of follow-up. Assessment of cognitive function was performed at year 25 (2010 to 2011) 
with the Digit Symbol Substitution Test, Stroop Test, and Rey Auditory Verbal Learning Test 
analyzed with standardized z scores. The primary predictor was 25-year cumulative exposure 
estimated by areas under the curve for resting systolic and diastolic blood pressures, fasting blood 
glucose, and total cholesterol (Total-C). Higher cumulative systolic and diastolic blood pressures 
and fasting blood glucose were consistently associated with worse cognition on all 3 tests. These 
associations were significant, primarily for exposures above recommended guidelines; cognitive 
test z scores were between 0.06 and 0.30 points less, on average, for each 1-standard deviation 
increase in risk factor area under the curve after adjustment for age, race, sex, and education 
(p<0.05 for all). Fewer significant associations were observed for cholesterol. 
Although accumulating data from observational studies suggest that cardiovascular risk factors 
may be modifiable risk factors for cognitive impairment (Kivipelto 2001, Whitmer 2005), 
randomized controlled trials targeting the treatment of these conditions, including hypertension, 
dyslipidemia, and diabetes mellitus have reported mixed results (Shepardson 2011, Staessen 2011, 
Morris 2012). 
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Additionally, in 2012, the Food and Drug Administration expanded its advice on statin risks to 
include memory loss or confusion. Review of published data on statins does not suggest an adverse 
effect of statins on cognition, but the strength of available evidence is limited, particularly 
regarding high dose statins (Richardson 2013). In addition, highly lipophilic statins with specific 
pharmacokinetic properties (atorvastatin, simvastatin) appear to confer a significantly greater risk 
of adverse cognitive effects compared to other lipophilic statins and those with hydrophilic 
solubility properties (Sahebzamani 2014). 
The brain synthesizes or re-uses up to 95% of its cholesterol requirements (Pfrieger 2011), thus, 
limiting the potential biological impact of low-circulating LDL-C on central nervous system 
function. Moreover, LDL particles have not been reported to cross the blood-brain barrier. 
Consequently, low levels of circulating LDL-C are unlikely to affect central nervous system 
cholesterol metabolism and function. Moreover, monoclonal antibodies, including Praluent, would 
not cross the blood brain barrier and are unlikely to have direct effects on the brain.  However, 
limited clinical data are available on the impact of very low circulating LDL on neurocognitive 
function. 
Neurocognitive events were reported overall at a low incidence in the phase 3 Praluent 
development program. Analysis of neurocognitive events using a predetermined set of adverse 
event (AE) terms from both the placebo- and ezetimibe-controlled pools did not reveal an 
imbalance for any particular event in double-blind studies up to 18 months of treatment with 
Praluent. 
Cambridge Neuropsychological Test Automated Battery Assessment 
The proposed neurocognitive test battery (CANTAB) targets key cognitive domains commonly 
affected by pharmacological manipulation, including psychomotor processing speed, visual 
episodic memory, working memory, and executive function. The CANTAB has been widely used 
as a tool for assessment of patterns of cognitive function in a wide variety of neurological and 
psychiatric disorders such as dementia, schizophrenia, depression, and Parkinson’s Disease 
(De Jager 2005, Bartok 2005, Weiland-Friedler 2004, Foltynie 2003). These tests have been 
employed extensively in clinical trials and have been shown to be sensitive to pharmacological 
manipulation in healthy individuals, both in compounds inducing cognitive deficits (Rusted 1988, 
Jäkälä 1999, Harmer 2001, Ryan 2006), and those showing procognitive effects (Elliott 1997, 
Greig 2005, Randall 2005, Attwood 2007).  
All tests in the battery are nonverbal and culturally neutral and suitable for use in nonliterate or 
multicultural populations. This also facilitates the use of the battery in multinational trials as data 
will be valid regardless of cultural background. The CANTAB is self-administered using a 
computer and touch sensitive monitor, which allows immediate feedback. Parallel modes and 
automatic stimuli randomization ensure participants can be re-tested over time for longitudinal 
studies. Inter-rater variance is greatly reduced with standardized test delivery and CANTAB tests 
also have translational utility, meaning that data can be compared directly to preclinical findings. 
CANTAB Connect Research software has been validated for use on all iPad Air devices and is 
fully Good Clinical Practice (GCP)-compliant, meeting regulations for computerized systems used 
in clinical research and 21 CFR Part 11. 
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The proposed CANTAB includes the following 3 tests which will take approximately 25 minutes 
to complete: Spatial Working Memory (SWM), Paired Associates Learning (PAL), and Reaction 
Time (RTI).  
Spatial Working Memory  
Spatial Working Memory requires retention and manipulation of visuospatial information, and 
assesses the ability of the participant to retain spatial information and manipulate it in working 
memory.  This is a self-ordered task that has notable executive function demands, and measures 
strategy use as well as errors.  These are reported as 2 separate end points: between search errors, 
reflecting the cognitive domain of working memory; and a score reflecting the use of a consistent 
search strategy, reflecting the cognitive domain of executive function.  A number of colored boxes 
are presented on the screen, and the computer hides a token in these boxes one at a time.  The 
participant is instructed to touch the boxes in turn to search for the token that has been hidden.  
When a token is found it should be placed in a home area on the right side of the screen.  The 
participant then searches for more tokens until the same number of tokens as the number of colored 
boxes has been found.  The key task instruction is that the computer will never hide a token in the 
same colored box twice in the same problem.  As the test progresses, so it becomes more difficult.  
Spatial Working Memory performance is impaired by damage to the prefrontal cortex, especially 
the dorsolateral prefrontal cortex.  Similarly, in neuroimaging studies in healthy volunteers, SWM 
performance is associated with activations in the dorsolateral and mid ventrolateral prefrontal 
cortex. 
Paired Associates Learning  
Paired Associates Learning assesses visual memory and new learning, and is a sensitive tool for 
accurate assessment of episodic memory.  Boxes are displayed on the screen and open in turn to 
reveal a number of patterns.  Participants are instructed to try to remember the location in which 
each pattern was shown.  After all the boxes have been opened, each pattern is then shown in the 
center of the screen in a randomized order, and the participant touches the box in which the pattern 
was located.  If an error is made, all the patterns are re-presented to remind the participant of their 
locations.  As the test progresses so the stages become more difficult, the number of patterns to be 
remembered will increase up to a maximum of 8 patterns.  For participants who fail to complete 
all levels, an adjusted total is calculated that allows for errors predicted in the stages that were not 
attempted.  Successful performance of the PAL test is dependent on functional integrity of the 
temporal lobe, particularly the entorhinal cortex.  
Reaction Time  
Reaction Time provides assays of motor and mental response speeds, as well as measures of 
movement time, RTI, and response accuracy.  In this 5-choice RTI task the participant holds down 
a button at the bottom of the screen until a yellow spot appears in 1 of 5 circles at the top of the 
screen.  They must then release the button and touch inside the circle where the yellow spot 
appeared as quickly as they can. Practice trials are included to familiarize participants with the 
task. 
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1.2. 
Rationale 
1.2.1. 
Rationale for Study Design 
The primary goal of this study is to evaluate neurocognitive function in heFH patients and non-FH 
patients at high or very high cardiovascular risk receiving Praluent compared with placebo after 
96 weeks of treatment. The 96-week treatment duration is considered sufficient to evaluate the 
effect of Praluent on neurocognitive function. 
1.2.2. 
Rationale for Dose Selection 
This study will use the 75 mg Praluent every 2 weeks (Q2W) regimen, the recommended starting 
dose for Praluent in the US (or usual starting dose in EU), with an increase to 150 mg Q2W at 
week 12 (using a blinded process) if LDL-C is ≥50 mg/dL (1.3 mmol/L) at week 8. This is the 
titration threshold being used in ODYSSEY OUTCOMES, an ongoing study assessing the effect 
of Praluent on major cardiovascular events. It is supported by findings from post-hoc analyses of 
the PROVE-IT, TNT and JUPITER trials, aiming to achieve an LDL-C level within the 
‘physiologic ideal’ zone. 
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2. 
STUDY OBJECTIVES 
The primary objective of the study is to evaluate neurocognitive function with use of Praluent after 
96 weeks of treatment versus placebo.  
The secondary objectives are: 
 To evaluate the effect of Praluent in comparison with placebo on lipoproteins 
 To evaluate the safety and tolerability of Praluent 
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3. 
STUDY DESIGN 
3.1. 
Study Description and Duration 
This is a randomized, double-blind, placebo controlled trial to evaluate neurocognitive function in 
patients with heFH, or in non-FH patients, at high or very high cardiovascular risk.  
Patients will be randomized in a 1:1 ratio to receive either placebo or 75 mg Praluent Q2W. 
Randomization will be stratified by age (<65 or ≥65) and by statin use (no statin, low lipophilicity 
of the concomitant statin, or high lipophilicity of the concomitant statin). 
The study consists of the following 2 periods, which are shown schematically in Figure 1. 
 A screening period of up to 3 weeks. 
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. 
 A double-blind treatment period of 96 weeks. 
On day 1 (baseline), after completion of study assessments and after collection of blood 
samples, and as soon as possible after the patient is randomized into the study, the first 
dose of study drug will be administered. The patient will be monitored at the clinical 
site for 30 minutes after the first dose. Subsequent doses of study drug must be 
administered Q2W. The last dose of study drug will be administered at week 94.  
Patients’ neurocognitive function will be assessed every 6 months. 
The dose of study drug will be increased (using a blinded process) at the week 12 visit 
in patients whose LDL-C levels are ≥50 mg/dL (1.3 mmol/L) at week 8. Those patients 
who are randomized to Praluent will receive Praluent 150 mg Q2W at week 12 and 
until end of study. All patients randomized to placebo will continue to receive placebo. 
Lipid results will be blinded for specimens obtained after randomization. No attempts 
should be made by the investigator or patient to have the patient’s lipid values evaluated 
independently from the time of randomization until the last study visit.  
Patients should be on a stable regimen of lipid-modifying therapy (LMT) (including a 
maximally-tolerated dose of statin, unless statin-intolerant) for 28 days prior to 
screening, as well as on a stable diet. Patients will be asked to maintain both their statin 
dose and diet from screening to the end of the study. 
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Figure 1: 
Study Flow Diagram 
 
Screening 
visit 
Screening 
Period 
(up to 3 
weeks) 
W-1 
W8 
W0 
W-3 
Injection 
training 
visit 
W12 
N=1085 
N=1085 
Double-Blind Treatment Period (96 weeks)  
W24 
R
Placebo for alirocumab SC Q2W 
 
Diet (NCEP-ATPIII TLC or equivalent diet) and maximally tolerated statin/other LMT daily dose   
Alirocumab 75mg Q2W up-titrated at W12 to 150mg SC Q2W if  
LDL-C ≥ 50 mg/dL at W8 
 
Cognitive Battery tests to be assessed at W-3, W0, W24, W48, W72 and W96 
W36 
W48 
W60 
W72 
W84 
W96 
 
3.2. 
Planned Interim Analysis 
No interim analysis is planned. 
3.3. 
Study Committees  
3.3.1. 
Neurocognitive Events Review Committee 
The neurocognitive events review committee is composed of experts in the field of cognition, 
independent from the sponsor and the investigators. This committee will be responsible for 
defining, validating, and classifying (in a blinded fashion) AEs of interest possibly related to 
cognition impairment.  
A charter and an operational manual will specify the procedures and criteria used for review of 
these events. 
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4. 
SELECTION OF PATIENTS  
4.1. 
Number of Patients Planned 
Approximately 2170 patients are planned. The patients will be randomized as follows, stratified 
by age (<65 or ≥65) and by statin use (no statin, or low lipophilicity of the concomitant statin, or 
high lipophilicity of the concomitant statin):  
 Placebo: 1085 patients 
 Praluent 75 mg Q2W/up-titrate 150 mg Q2W: 1085 patients 
This will be a multinational study. The planned number of sites is up to 300. 
4.2. 
Study Population 
The study population consists of patients with heFH or non-FH patients at high or very high 
cardiovascular risk. Patients must have had a history of CHD without adequate control of their 
hypercholesterolemia with LDL-C ≥70 mg/dL, or all other patients with LDL-C ≥100 mg/dL, and 
be on a maximally-tolerated dose of statin (unless they are statin-intolerant).  
4.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Men and women ≥ age 40 and ≤ age 85 
2. Patients with heFH (see Appendix 1 and Appendix 2 for diagnosis criteria) or non-FH 
patients at high or very high cardiovascular risk  
High and very high cardiovascular risk patients include patients with coronary heart disease 
(CHD), non-CHD CVD, and other risk factors. Definitions for CHD, non-CHD CVD, and 
other risk factors: 
a. A documented history of CHD (includes 1 or more of the following): 
i. 
Acute myocardial infarction 
ii. 
Silent myocardial infarction 
iii. 
Unstable angina 
iv. 
Coronary 
revascularization 
procedure 
(eg, 
percutaneous 
coronary 
intervention or coronary artery bypass graft surgery) 
v. 
Clinically significant CHD diagnosed by invasive or non-invasive testing (eg, 
coronary angiography, stress test using treadmill, stress echocardiography, 
coronary calcium scan, or nuclear imaging). 
b. Non-CHD CVD (includes 1 or more of the following criteria): 
vi. 
Documented previous ischemic stroke with a focal ischemic neurological 
deficit that persisted more than 24 hours, considered as being of 
atherothrombotic origin. Computed tomography (CT) or magnetic resonance 
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imaging (MRI) must have been performed to rule out hemorrhage and 
non-ischemic neurological disease. 
vii. 
Peripheral arterial disease 
viii. 
Abdominal aortic aneurysm 
ix. 
Atherosclerotic renal artery stenosis 
x. 
Carotid artery disease (transient ischemic attacks or >50% obstruction of a 
carotid artery) 
c. Other risk factors 
xi. 
Documented moderate chronic kidney disease as defined by 30≤ Estimated 
Glomerular Filtration Rate (eGFR) <60 mL/min/1.73 m2 for 3 months or 
more, including the screening visit 
xii. 
Type 1 or type 2 diabetes mellitus  
xiii. 
A calculated 10-year fatal CVD risk SCORE ≥5% (ESC/EAS Guidelines for 
the management of dyslipidemias, Perk 2012) 
* For CVD risk categories, see Appendix 5. 
3. Patients with history of CHD not having adequate control of their hypercholesterolemia 
with LDL-C ≥70 mg/dL, or all other patients with LDL-C ≥100 mg/dL 
4. Patients have been on a maximally-tolerated dose of statin for at least 28 days prior to the 
screening visit (all statins are allowed), unless they are statin-intolerant. Statin intolerance 
is defined as the inability to tolerate at least 2 statins: 1 statin at the lowest daily starting 
dose (defined as rosuvastatin 5 mg, atorvastatin 10 mg, simvastatin 10 mg, lovastatin 
20 mg, pravastatin 40 mg, fluvastatin 40 mg, or pitavastatin 2 mg), AND another statin at 
any dose, due to skeletal muscle-related symptoms, other than those due to strain or trauma, 
such as pain, aches, weakness, or cramping that began or increased during statin therapy 
and stopped when statin therapy was discontinued. For these patients, the 
maximally-tolerated dose of statin is defined as 0 mg. 
5. Patients must have successfully completed the Motor Screening Task 
6. Patients must be willing and able to comply with clinic visits and study-related procedures. 
7. Patients must provide signed informed consent. 
4.2.2. 
Exclusion Criteria 
1. Patients with known Alzheimer’s disease or other dementia, schizophrenia, bipolar 
disorder, severe depression (≥11 score of the Geriatric Depression Scale short form [GDS-
S; Appendix 8]), cognitive impairment (<26 score of the Montreal Cognitive Assessment 
[MoCA]; Appendix 9]), or patients with a sleep disorder requiring daily pharmacological 
treatment  
2. Patients >85 year old  
3. Patient with a hemorrhagic stroke within last 5 years 
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4. Patients with planned major surgery or carotid stenting 
5. Patients who have previously participated in a clinical trial involving a PCSK9 antibody, 
or had any exposure to a PCSK9 antibody 
Note:  If patients had previously participated in a clinical trial involving a PCSK9 antibody, 
and it was subsequently determined that they had been in a placebo group, then this 
exclusion criterion does not apply. 
6. Patients treated with medications listed in Appendix 3, and/or with medications adding up 
to an anticholinergic burden (ACB) of 3 and above (see Appendix 4) within 3 months prior 
to the screening visit 
Note:  Medications listed in Appendix 4 used “as needed”/pro re nata (PRN), ≤2 times per 
week should not be included in calculating the ACB score. 
7. Patients with a history of substance abuse (alcohol or drug) or substance dependence 
meeting the DSM-IV criteria within 12 months prior to the screening visit 
(American Psychiatric Association 2000) 
8. Signs and symptoms of hyperthyroidism or hypothyroidism (thyroid replacement therapy 
is permitted, if stable for 12 weeks prior to screening and patient is documented to be 
euthyroid) 
9. History of a myocardial infarction, unstable angina leading to hospitalization, coronary 
artery bypass graft surgery, percutaneous coronary intervention, uncontrolled cardiac 
arrhythmia, carotid surgery or stenting, stroke, transient ischemic attack, or carotid 
revascularization within 3 months prior to the screening visit, or endovascular procedure 
or surgical intervention for peripheral vascular disease within 3 months prior to the 
screening visit 
10. eGFR <30 mL/min/1.73 m2 according to 4-variable Modification of Diet in Renal Disease 
Study equation (calculated by a central lab). 
11. Any condition or situation, including other significant mental or neurological disorders 
that, in the investigator’s opinion, may confound the study results, or may interfere 
significantly with the patient’s participation in the study. 
12. Pregnant or breastfeeding women 
13. Women of childbearing potential* who are unwilling to practice highly effective 
contraception prior to the initial dose/start of the first treatment, during the study, and for 
at least 6 months after the last dose. 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**. 
*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 tubal ligation. 
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**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. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject.  
14. A positive human immunodeficiency virus (HIV) test 
15. Patients with severe hepatic impairment (Child-Pugh Class C) 
4.3. 
Replacement of Patients 
Patients prematurely discontinued from the study will not be replaced. 
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5. 
STUDY TREATMENTS 
The study treatment is 1 subcutaneous (SC) injection Q2W of 1 mL, as follows: 
 Placebo group: 1 injection of placebo Q2W 
 Praluent 75 mg Q2W/up-titrate 150 mg Q2W: 1 injection of 75 mg Q2W Praluent with 
an increase to 1 injection of 150 mg Q2W at week 12 (using a blinded process) if LDL-
C is ≥50 mg/dL (1.3 mmol/L) at week 8 
The 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 (see Section 5.1).  
On day 1 (baseline), after completion of study assessments and after collection of blood samples, 
and as soon as possible after the patient is randomized into the study, the first dose of double-blind 
study drug will be administered in the clinic.  The patient will be monitored at the clinical site for 
30 minutes after the first dose. Subsequent doses of study drug must be administered Q2W.  
Doses of study drug should be administered at approximately the same time of day (based upon 
patient preference) throughout the study.  It is acceptable for dosing to fall within a window of 
±3 days. 
In the event an injection is delayed by more than 7 days or completely missed, the patient should 
return to the original schedule of 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 study drug. 
5.1. 
Injection Training 
After study eligibility is confirmed, the patient or caregiver will be trained to self-inject/inject 
using placebo at visit 2.  Injection training can be done at visit 3 (as an alternative to or in addition 
to visit 2) using placebo.  All patients and caregivers who will inject study drug must be trained 
by the study staff.  
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. 
5.2. 
Investigational and Reference Treatments 
Sterile Praluent drug product is supplied at a concentration of 75 mg/mL or 150 mg/mL in 
histidine, pH 6.0, polysorbate 20, and sucrose in a prefilled pen. 
Placebo matching Praluent is supplied in the same formulation as Praluent, without the addition of 
protein, in a prefilled pen. 
In case of disruption of supply of prefilled pens, patients will be switched to the use of prefilled 
syringes of placebo, 75 mg and 150 mg, with 1 injection of 1 mL for each of these doses. Should 
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disruption occur, site staff will train all patients/caregivers on the correct administration using the 
prefilled syringe. 
5.3. 
Background Treatment 
Patients should be on their maximally tolerated dose of statin as defined in inclusion criterion 4 
(Section 4.2.1).  The statin dose should remain stable throughout the entire study, from screening 
to the end of study visit.  If a patient is not taking the maximally allowed dose (per the label for 
that region or country), or if the patient is statin intolerant, a justification should be provided in the 
electronic case report form (e-CRF). 
Background treatment with LMTs is allowed for all patients (those who are using concomitant 
statins and for those who are not).  The background LMT dose should remain stable throughout 
the entire study, from screening to the end of study visit. 
5.4. 
Dose Modification 
In patients whose LDL-C levels are ≥50 mg/dL (1.3 mmol/L) at week 8 (visit 4), the dose will be 
increased in a double-blind manner beginning at week 12 (visit 5), as follows: 
 Placebo group: no change; placebo Q2W 
 Praluent 75 mg Q2W group: 150 mg Praluent Q2W 
To maintain the blind, the sites and the sponsor’s operational team will be blinded to LDL-C results 
and to dose modification. 
5.5. 
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. 
Study drug will be packaged in accordance with this list. 
Patients will be randomly assigned to receive placebo or Praluent 75 mg Q2W in a 1:1 ratio 
stratified by age (<65 or ≥65) and by statin use (no statin, low lipophilicity of the concomitant 
statin, or high lipophilicity of the concomitant statin). 
Depending on each site’s preference, the centralized treatment allocation system can be accessed 
by the IVRS or the IWRS. 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. The treatment kit allocated at week 12 for patients 
randomized to the Praluent treatment groups will be based on their week 8 LDL-C level (see 
Section 5.4). 
5.5.1. 
Blinding 
Study patients, the principal investigators, and study site personnel will remain blinded to all 
randomization assignments throughout the double-blind portion of 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. 
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Lipid results from blood samples collected after the randomization visit will not be communicated 
to the sites, and the sponsor’s operational team will not have access to these laboratory results until 
after the final database lock.  
Sites and the sponsor’s operational team will be blinded to changes in treatment dose in the event 
a patient meets a criterion for a change in dose. 
Blinded 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) results 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 
final database lock. 
Information on unblinding is provided in Section 5.5.2. 
5.5.2. 
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 must notify Regeneron and/or designee before unblinding the 
patient, whenever possible. 
5.6. 
Treatment Logistics and Accountability 
5.6.1. 
Packaging, Labeling, and Storage 
A medication numbering system will be used in labeling blinded investigational study drug 
provided in individual prefilled pens. Lists linking medication numbers with product lot numbers 
will be maintained by the groups (or companies) responsible for study drug packaging. In order to 
maintain the blind, the 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 at the injection training visit or at 
the baseline visit. A second placebo prefilled pen can be used before randomization if the 
patient/caregiver requires additional injection training. 
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. 
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5.6.2. 
Supply and Disposition of Treatments 
Study drug will be shipped at a temperature of 2ºC to 8ºC to the investigator or designee as needed 
during the study. At specified time points during the study (ie, interim site monitoring visits), at 
the site close-out visit, and after drug reconciliation and documentation by the site monitor, all 
opened and unopened study drug will be returned to the sponsor or designee according to directions 
provided in the study manual. 
Study drug will be dispensed to each patient and transported to the patient’s home. Study drug will 
be stored, prepared, and administered by the patient/caregiver according to instructions provided 
to each patient/caregiver. 
5.6.3. 
Treatment Accountability and Compliance 
All accountability and compliance records must be made available for inspection by the sponsor 
and regulatory agency inspectors. Photocopies must be provided to the sponsor at the conclusion 
of the study. 
Patients will complete a dosing log to document compliance with study drug administration. 
Measures taken to ensure and document 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 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 e-CRF pages, 
according to data recorded in the treatment log form. 
 The monitor will check the data consistency among e-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 study 
drug will be established with the investigator or designee and countersigned by the investigator 
and the monitoring team. 
5.7. 
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 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. 
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Any treatment administered from the time of informed consent to the end of the study will be 
considered concomitant medication. This includes medications that were started before the study, 
and are ongoing during the study. 
5.7.1. 
Allowed Concomitant Medications 
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 before the 
screening visit and during the screening period. The dose and regimen must remain stable during 
the double-blind treatment period (see Section 5.7.3). 
5.7.2. 
Prohibited Medications 
Commercially-available PCSK9 antibodies are prohibited from the initial screening visit until the 
end of the study visit. 
Sleep-aid medications are prohibited the night before the baseline visit, or the week 24, week 48, 
week 72, or week 96 visits. If the patient used such medication, the visit should be rescheduled as 
soon as possible. 
5.7.3. 
Rescue Treatment for LDL-C Increase >25% 
An LDL-C increase >25% compared with the randomization visit LDL-C on 2 consecutive 
occasions (Section 7.6.3.1) will generate an alert that the patient may require rescue therapy.  The 
investigator should determine whether a reasonable explanation exists for insufficient LDL-C 
control (such as an alternative medical cause like corticosteroid use, etc.), and in particular should 
ensure that 
 Compliance with diet is appropriate 
 Compliance with background LMT is appropriate and ongoing 
 Study treatment is given as planned 
If any of the above factors can reasonably explain the insufficient LDL-C control, the investigator 
should stress the absolute need to be compliant with all treatments and, if necessary, organize a 
specific interview with a qualified nutrition professional and stress the absolute need to be 
compliant with diet, and perform a blinded LDL-C assessment within 1 to 2 months prior to 
initiating rescue treatment. 
Rescue treatment may be initiated as outlined in Appendix 10, in the event that no reason for LDL-
C above the threshold value can be found. 
6. 
STUDY VARIABLES 
6.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, gender, weight, height, 
etc.), disease characteristics including prior medication history related to LMT, and medical 
history. 
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6.2. 
Primary and Secondary Endpoints 
6.2.1. 
Primary Neurocognitive Endpoint 
The primary outcome measure is the change in CANTAB cognitive domain SWM strategy score 
from baseline to week 96.  Two definitions will be provided for this endpoint, specifically: 
 SWM strategy z-score change from baseline is defined for each patient as: week 96 
SWM strategy z-score minus the patient’s baseline SWM strategy z-score.  The change 
from baseline SWM strategy z-score is used for the primary analysis evaluation of 
noninferiority.  A lower score denotes better SWM function (ie, less impairment). 
 A patient’s SWM strategy z-score at week 96 is defined as: (week 96 SWM strategy 
raw score minus the SWM strategy mean baseline score) divided by the SWM 
strategy baseline standard deviation.  The SWM strategy mean baseline score and 
the SWM strategy baseline standard deviation are calculated using patients in both 
treatment groups (ie, Praluent and placebo). 
 The SWM strategy z-score at baseline is defined for each patient in the same 
manner as the calculation for the SWM strategy z-score at week 96, replacing the 
patient’s week 96 raw score with the patient’s baseline raw score. 
 SWM strategy raw score change from baseline is defined for each patient as: week 96 
SWM strategy raw score minus the patient’s SWM strategy baseline score.  The SWM 
strategy raw score change from baseline is provided descriptively for clinical 
interpretation of function at week 96.  Lower change from baseline raw scores reflect 
better SWM performance (ie, less impairment). 
The baseline SWM strategy score is the last score obtained before the first dose of study treatment. 
The SWM Strategy score at week 96 is the score obtained within the week 96 analysis window 
and during the treatment-emergent adverse event (TEAE) period. The TEAE period is defined as 
the time from the first double-blind study treatment injection up to 70 days after the last 
double-blind study treatment injection. The analysis window used to allocate a time point to a 
measurement will be defined in the statistical analysis plan (SAP). 
6.2.2. 
Exploratory Neurocognitive Endpoints 
Exploratory neurocognitive outcome measures to further assess neurocognitive function in the 
CANTAB domains are provided below for each patient: 
 PAL at week 96 defined as both a PAL z-score change from baseline and PAL raw 
score change from baseline, following the definitions and rules provided for the 
primary neurocognitive endpoint 
 RTI at week 96 defined as both a RTI z-score change from baseline and RTI raw score 
change from baseline, following the definitions and rules provided for the primary 
neurocognitive endpoint 
 SWM between-errors score at week 96 defined as both an SWM between-errors z-score 
change from baseline and SWM between-errors raw score change from baseline, 
following the definitions and rules provided for the primary neurocognitive endpoint 
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 Global Composite score at week 96 change from baseline is defined as (the average of 
the following 4 measures at week 96: SWM strategy z-score, PAL z-score, RTI z-score, 
and the SWM between-errors z-score) minus the average of the same 4 z-score 
measures at baseline  
Standard outcome measures to assess general safety include overall AEs, SAEs (includes patient 
death), AEs causing discontinuation, adverse events of special interests (AESI), review of 
neurocognitive AEs, vital signs and laboratory values. 
6.2.3. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are provided below. For those efficacy endpoints described as 
percent change from baseline at a given visit, the definition is: 100 multiplied (post-baseline visit 
measurement – baseline measurement) divided by the baseline measurement. 
The baseline measurements are the last values obtained before the first dose of study treatment. 
The secondary efficacy endpoint at a given visit is the measurement obtained within the analysis 
window of the visit and during the main efficacy period. The main efficacy period is defined as 
the time from the first double-blind study treatment injection up to the upper limit of the week 96 
analysis window. 
All secondary efficacy endpoints (scheduled or unscheduled) may be used to provide a value for 
the efficacy endpoint, if appropriate, according to above definition. The analysis window used to 
allocate a time point to a measurement will be defined in the SAP: 
 The percent change in calculated LDL-C, apolipoprotein (Apo) B, non-high-density 
lipoprotein cholesterol (non-HDL-C), and Total-C from baseline to weeks 12, 24, 48, 
72, and 96 
 The percent change in lipoprotein a [Lp(a)], HDL-C, triglyceride (TG), and Apo A-1 
from baseline to weeks 12, 24, 48, 72, and 96 
 The proportion of patients reaching LDL-C <70 mg/dL (1.81 mmol/L) at weeks 12, 24, 
48, 72 and 96 
 The proportion of patients reaching LDL-C <50 mg/dL (1.29 mmol/L) at weeks 12, 24, 
48, 72, and 96 
6.2.4. 
Other Endpoints 
 Anti-drug antibody status (positive/negative) and titers assessed at the end of the study 
 Gonadal hormone levels (for female patients - estradiol, follicle-stimulating hormone 
(FSH) and luteinizing hormone (LH); for male patients - testosterone, FSH and LH) 
7. 
STUDY SCHEDULE OF EVENTS AND VISIT DESCRIPTIONS 
7.1. 
Schedule of Events 
Study assessments and procedures are presented by study period and visit in Table 1. 
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Table 1: 
Schedule of Events 
 
Screening Period 
Double-Blind Treatment Period (DBTP) 
Baseline 
EOS 
 
Visit 1 
Visit 21 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
Visit 12 
Day 
d-21 to 
d-8 
d-7 
d1 
d57 
d85 
d169 
d253 
d337 
d421 
d505 
d589 
d673 
Visit Window (days) 
 
+/-7d 
0 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-7d 
Week 
W-3 
W-11 
W01 
W8 
W12 
W24 
W36 
W48 
W60 
W72 
W84 
W96 
Screening/Baseline: 
Study informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
X 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Measured height 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
IVRS/IWRS contact 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GDS-S and MoCA 
X 
 
 
 
 
 
 
 
 
 
 
 
Motor Screening Task 
X 
 
 
 
 
 
 
 
 
 
 
 
HIV testing 
X 
 
 
 
 
 
 
 
 
 
 
 
Treatment:  
Injection training 
 
X2 
X2 
 
 
 
 
 
 
 
 
 
Administer study drug  
 
 
X3 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study drug kit dispensation4 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Kit return 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diet: 
Review of diet5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Assessments:7 
Blood pressure and pulse rate 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body weight 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
Physical exam 
X 
 
 
 
 
 
 
 
 
 
 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neurocognitive Battery8 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
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Screening Period 
Double-Blind Treatment Period (DBTP) 
Baseline 
EOS 
 
Visit 1 
Visit 21 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
Visit 12 
Day 
d-21 to 
d-8 
d-7 
d1 
d57 
d85 
d169 
d253 
d337 
d421 
d505 
d589 
d673 
Visit Window (days) 
 
+/-7d 
0 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-3d 
+/-7d 
Week 
W-3 
W-11 
W01 
W8 
W12 
W24 
W36 
W48 
W60 
W72 
W84 
W96 
Menstrual Cycle: 
Collection of menstrual cycle data6 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
Laboratory Testing:7 
Lipid panel9 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Hematology 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
Chemistry 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
Gonadal hormones10 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
Creatine phosphokinase (CPK) 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
Liver panel 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
Hepatitis B surface antigen 
X 
 
 
 
 
 
 
 
 
 
 
X 
Hepatitis C antibody 
X 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy test (WOCBP) 
S 
 
U 
 
U 
U 
U 
U 
U 
U 
U 
U 
Urinalysis11 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
HbA1c 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
hs-CRP 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
ADA sample 
 
 
X 
 
 
 
 
X 
 
 
 
X 
Research samples (serum and plasma) 
 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
ADA = anti-drug antibody, CPK = creatine phosphokinase, EOS = end of study, F/U = follow-up, HbA1c = hemoglobin A1c, hs-CRP = high-sensitivity 
C-reactive protein, S = serum, TSH = thyroid-stimulating hormone, U = urine, WOCBP = women of childbearing potential 
1. Visit 2 is optional. 
2. Injection training will be performed with the patient and/or caregiver at visit 2, at visit 3, or at visits 2 and 3 using placebo. Refer to Section 5.1 for 
additional information on injection training. 
3. The patient or caregiver will administer the first dose of double-blind study drug in the clinic on day 1. The patient will be monitored for 30 minutes after 
the first dose. Subsequent doses of study drug must be administered Q2W. Study drug will be administered at home between week 84 and week 94. The 
last dose of study drug will be administered at home at week 94.  Patients will come into the clinic for the last study visit at week 96. 
4. Injection supplies and the dosing log will be provided to the patient. 
5. See Appendix 6 for diet. 
6. Menstrual cycle data will be collected for women of childbearing potential who are not on hormonal contraceptives. 
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7. On days when a clinic visit coincides with a dosing day (visits 3, and 8), blood samples (including ADA samples) will be collected after study assessments 
are performed and before the dose of study drug is administered. At visits 4, 5, 6, 7, 9, 10, and 11, study drug may be administered prior to study 
assessments. 
8. If a neurocognitive AE is reported during the visits when the test is not planned or in case of early treatment discontinuation, an unscheduled 
neurocognitive battery test will be performed. 
9. Samples will be tested for Total-C, calculated LDL-C, HDL-C, TG, and non-HDL-C, Apo B, Apo A-1, Apo B/Apo A-1 ratio, and Lp(a).  
10. For female patients – estradiol, follicle-stimulating hormone (FSH) and luteinizing hormone (LH); for male patients – testosterone, FSH and LH. 
11. Dipstick and, if abnormal, microscopy. 
 
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7.2. 
Study Visit Descriptions 
For all visits after the randomization visit, if the visit 1 date is changed, then the next visit should 
take place according to the original study schedule. 
Alcohol consumption within 48 hours and intense physical exercise within 24 hours preceding 
blood sampling are discouraged.  
7.2.1. 
Unscheduled Visits  
All attempts should be made to keep patients on the study schedule. Unscheduled visits may be 
necessary to repeat testing or for a proper follow-up.  
7.3. 
Handling of Study Drug Discontinuation and Patient Withdrawal 
from the Study  
7.3.1. 
Study Drug Discontinuation 
Study drug should be continued whenever possible. In the event 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 prematurely discontinue study drug should remain in the study and undergo all 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 the 
assessments that are normally done at the end of study (EOS) visit (this should take place within 
5 days of discontinuation of study drug, if possible), and then resume the original study schedule 
until end of study.  
Assessment of patients who do not consent to remain in the study after discontinuation of study 
drug should be managed according to Section 7.4.1. 
7.3.1.1. 
Reasons for Temporary Discontinuation of Study Drug 
Temporary discontinuation of study drug may be considered by the investigator because of 
suspected AEs, including allergic events related to the dose of study drug. Reinitiating study drug 
dosing will be done under close and appropriate clinical and/or laboratory monitoring. 
Temporary discontinuation of study drug is defined as 1 or more scheduled injections that are not 
administered to the patient as decided by the investigator. 
7.3.1.2. 
Reasons for Permanent Discontinuation of Study Drug 
Patients should permanently discontinue study drug for the following reasons: 
 Pregnancy, intention for pregnancy, or no longer with effective contraceptive method 
of birth control (females enrolled in this study, only) 
 Acute injection reaction of clinical concern 
 SAE (or non-serious but severe in intensity) of hypersensitivity reaction considered 
related to study drug 
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 At patient request 
 If, in the investigator's opinion a patient’s cognition deteriorates to the degree of Mild 
Cognitive Impairment (MCI), or dementia, the investigator will seek diagnostic 
confirmation from the required specialist per local practice. If diagnosis is confirmed, 
study drug may be discontinued  
 If, in the investigator's opinion, continuation of study drug dosing would be detrimental 
to the patient's well being 
 Intercurrent condition that requires discontinuation of study drug 
 At the specific request of the sponsor 
 Patient receives double-blind treatment before randomization 
The IVRS/IWRS should be notified when a patient prematurely discontinues study treatment. 
Note: Patients who discontinue study treatment should be encouraged to continue to participate in 
the study and, at a minimum, return for the primary endpoint assessment at week 96. 
7.4. 
Patient 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 sponsor have the right to withdraw a patient from the study in the event of an 
intercurrent illness, AE, treatment failure, protocol violation, and for administrative or other 
reasons. An excessive rate of withdrawals would render the study uninterpretable; therefore, 
unnecessary withdrawal of patients should be avoided. 
7.4.1. 
Early Termination from the Study 
If for any reason the patient refuses to continue the study, the patient should undergo an 
unscheduled visit with assessments normally planned at the end of study visit (it should take place 
within 5 days of treatment discontinuation, if possible). The patient should be followed until 
recovery or stabilization of any AE. An end of study visit can take place with assessments as 
specified in the end of study visit after the premature discontinuation of study drug (see Table 1). 
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). 
7.5. 
Replacement of Patients 
Patients who are prematurely discontinued from the study will not be replaced. 
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7.6. 
Study Procedures  
7.6.1. 
Procedures Performed only at the Screening/Baseline Visit 
Medical/surgical history, medication history related to lipid-modifying therapy, demographics, 
height, hepatitis B surface antigen and hepatitis C antibody testing, HIV testing, serum pregnancy 
testing, GDS-S and MoCA, and the Motor Screening Task will be performed for the purpose of 
determining study eligibility or characterizing the baseline population. 
7.6.2. 
Neurocognitive Assessment Battery Procedures 
7.6.2.1. 
CANTAB 
The CANTAB will be performed at time point according to Table 1 and includes the following 3 
tests, which will take approximately 25 minutes to complete: SWM, PAL, and RTI. Training will 
be done at screening. Additional details will be provided in the study manual. 
7.6.3. 
Efficacy Procedures 
All laboratory samples will be collected before the dose of study drug is administered. 
Alcohol consumption within 48 hours or intense physical exercise within 24 hours preceding blood 
sampling is discouraged. 
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. 
Detailed procedures of sample preparation, storage, and shipment are provided in the laboratory 
manual. 
7.6.3.1. 
Lipid Panel  
Blood samples for the lipid panel (Total-C, TG, HDL-C, non-HDL-C, calculated LDL-C, Apo B, 
Apo A-1, Apo B/Apo A-1 ratio, and Lp(a)) will be collected at time points according to Table 1. 
Lipid results from blood samples obtained after the randomization visit will not be communicated 
to the investigators.  Sites will be notified if the following occurs: LDL-C increase >25% compared 
with the randomization visit LDL-C value in 2 consecutive LDL-C assessments.  The patient 
should be managed according to Section 5.7.3. 
7.6.4. 
Safety Procedures 
7.6.4.1. 
Blood Pressure and Heart Rate 
Blood pressure and heart rate will be assessed at time points according to Table 1. 
Note: in case of high blood pressure values at screening, the investigator is responsible for the 
optimization of the patient’s treatment to achieve blood pressure targets as defined by local 
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guidelines or the Seventh Report of the Joint National Committee on Prevention, Detection, 
Evaluation, and Treatment of High Blood Pressure (Chobanian 2003). 
7.6.4.2. 
Physical Examination 
A thorough and complete physical examination, including height and weight, will be performed at 
the first screening visit (visit 1).  Additional physical exams will be performed at other 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. 
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Body Weight and Height 
Body weight should be obtained at time points according to Table 1, with the patient wearing 
undergarments or very light clothing and no shoes, and with an empty bladder.  The same scale 
should be used throughout the study. 
The use of calibrated balance scales is recommended, if possible.  Self-reported weights are not 
acceptable; patients must not read the scales themselves. 
Height should be measured at screening; self-reported heights are not acceptable. 
7.6.4.3. 
Laboratory Testing 
All laboratory samples (including ADA samples) will be collected after assessments are performed 
and before a dose of study drug is administered at visits that correspond with a dosing day.  At 
visit 4, study drug may be administered prior to study assessments. 
Samples for laboratory testing will be collected at time points according to Table 1 and analyzed 
by a central laboratory during the study.  Detailed instructions for blood sample collection are in 
the laboratory manual provided to study sites.  Specific tests are listed below. 
Blood Chemistry 
Sodium 
Total protein 
Potassium 
Creatinine 
Chloride 
Blood urea nitrogen 
Bicarbonate 
Lactate dehydrogenase (LDH) 
Calcium 
Phosphorus 
Glucose 
Uric acid 
Albumin 
Gamma-glutamyl transpeptidase 
 
Hematology 
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Platelet count  
 
Basophils 
Reticulocyte count 
 
Eosinophils 
RBC distribution width 
 
Urinalysis 
Color 
Glucose 
RBCs 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBCs 
Yeast 
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Other Laboratory Tests 
Pregnancy testing (serum or urine) will be performed at time points according to Table 1. 
Samples for the liver panel (alanine aminotransferase [ALT], aspartate aminotransferase [AST], 
alkaline phosphatase, and total bilirubin), hepatitis C antibody, hepatitis B surface antigen, 
hemoglobin A1c (HbA1c), creatine phosphokinase (CPK), thyroid-stimulating hormone (TSH), 
high-sensitivity 
C-reactive 
protein 
(hs-CRP), 
and 
gonadal 
hormones 
(for 
female 
patients - estradiol, follicle-stimulating hormone [FSH] and luteinizing hormone [LH]; for male 
patients – testosterone, FSH and LH) will be collected at time points according to Table 1. 
Abnormal Laboratory Values and Laboratory Adverse Events 
 All laboratory values must be reviewed by the investigator or authorized designee. 
 Significantly abnormal tests 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 AEs are provided in Section 8.2.4. 
7.6.4.4. 
Adverse Event Information Collection 
The investigator (or designee) will record all AEs that occur during the study from the time the 
informed consent is signed through the last study visit. Information on follow-up for AEs is 
provided in Section 8.2.5. Abnormalities in laboratory results, vital signs, or electrocardiograms 
(ECGs) are to be recorded as AEs, as outlined in Section 8.2.4. 
The definition of an AE and SAE, and information on the determination of severity and 
relationship to treatment are provided in Section 8. 
7.6.4.5. 
Reporting Adverse Events of Special Interest 
The sponsor should be notified within 24 hours after the site learns about the following AEs of 
interest (the reporting function of the e-CRF should be used to report the event): 
 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 are allergic in nature and 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 
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 Cataracts 
 New onset of diabetes 
7.6.5. 
Anti-Drug Antibody Procedures 
Samples for ADA assessments will be collected in the clinic after all visit assessments have been 
completed, 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 study drug is administered.  Detailed 
procedures of sample preparation, storage, and shipment are provided in the laboratory manual. 
To maintain the blind of the study, ADA samples will be collected from all patients, including 
those who received only placebo. 
The Regeneron Sample Analysis group will analyze the ADA samples. 
7.6.6. 
Other Assessments 
7.6.6.1. 
Review of Diet 
Patients will be following a diet equivalent to the Nation Cholesterol Education Program-Adult 
Treatment Panel (NCEP-ATP III TLC) diet at the screening visit and will be asked to continue the 
dietary plan until the last study visit.  Patients will be queried about compliance with the dietary 
plan during the double-blind treatment period, at time points according to Table 1. 
Details are provided in the study reference manual and in Appendix 6. 
7.6.6.2. 
Collection of Menstrual Cycle Data 
Menstrual cycle data will be collected for women of childbearing potential who are not on 
hormonal contraceptives at time points according to Table 1. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
8.1. 
Definitions 
8.1.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug which may or 
may not have a causal relationship with the study drug. Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease, which is 
temporally associated with the use of a study drug, whether or not considered related to the study 
drug.  
An AE also includes any worsening (ie, any clinically significant change in frequency and/or 
intensity) of a preexisting condition that is temporally associated with the use of the study drug. 
8.1.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death – includes all deaths, even those that appear to be completely unrelated 
to study drug (eg, a car accident in which a patient is a passenger). 
 Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event. This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
 Requires in-patient hospitalization or prolongation of existing hospitalization. 
In-patient hospitalization is defined as admission to a hospital or an emergency room 
for longer than 24 hours. Prolongation of existing hospitalization is defined as a 
hospital stay that is longer than was originally anticipated for the event, or is prolonged 
due to the development of a new AE as determined by the investigator or treating 
physician. 
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 Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions). 
 Is a congenital anomaly/birth defect. 
 Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent 1 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). 
8.2. 
Recording and Reporting Adverse Events 
All SAEs, regardless of assessment of causal relationship to study drug must be reported to the 
sponsor (or designee) as follows: 
 Telephone the sponsor (or designee) at the contact information provided in the SAE 
completion guidelines, within 24 hours of learning of the event 
 Complete the SAE form utilizing the AE e-CRF in the electronic data capture (EDC) 
system and submit within 24 hours of learning of the event 
The sponsor (or designee) will provide the investigators with blank SAE forms, which are to be 
completed in the event that access to the EDC system is not available. Once the EDC system is 
available, the SAE information must be entered within 24 hours of the system availability. 
Information not available at the time of the initial report must be documented in the EDC within 
24 hours of receipt of the new information. Substantiating data such as relevant hospital or medical 
records and diagnostic test reports may also be requested. 
The investigator must promptly report to the Institutional Review Board (IRB)/Ethics Committee 
(EC) all unanticipated problems involving risks to patients. This includes death from any cause 
and all SAEs related to the use of the study drug. It is recommended that all SAEs be reported to 
the IRB/EC, regardless of assessed causality. 
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/early termination visit - the SAE 
will be reported to the sponsor.  The investigator should make every effort to obtain 
follow-up information on the outcome until the event is considered chronic and/or 
stable. 
 SAE with an onset day greater than 30 days from the end of study/early termination 
visit - only fatal SAEs and those deemed by the investigator to be drug-related SAEs 
will be reported to the sponsor.  The investigator should make every effort to obtain 
follow-up information on the outcome of a drug-related SAE until the event is 
considered chronic and/or stable. 
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8.2.1. 
Deaths 
Any AE that results in death is considered an SAE.  Deaths that occur from the time the patient 
signs the ICF until 70 days after dosing must be reported to the appropriate IRB/EC and to 
Regeneron Pharmacovigilance and Risk Management (or designee) within 24 hours of learning of 
the death.  The reporting procedures detailed in Section 8.2 should be followed. 
Any available autopsy reports and relevant medical reports must be sent to the sponsor (or 
designee) as soon as possible. 
8.2.2. 
Pregnancy and Other Events that Require Accelerated Reporting 
The following events also require reporting to the sponsor (or designee) within 24 hours of learning 
of the event: 
Overdose: 
An overdose (accidental or intentional) is an event suspected by the investigator or 
spontaneously notified by the patient (not based on systematic injection counts), 
and defined as at least twice of the intended dose within the intended therapeutic 
interval; to be reported using the corresponding screens in the e-CRF using the term 
“symptomatic OVERDOSE (accidental [or intentional]).”  The patient should be 
monitored and appropriate symptomatic treatment instituted. 
and/or, 
Accidental or intentional administration of the study drug at a frequency higher 
than that allowed by the study protocol, if associated with an AE. 
Pregnancy: 
Although it is not considered an AE, it is the responsibility of the investigator to 
report to the sponsor (or designee) by telephone within 24 hours, any pregnancy 
occurring in a female patient or partner of a male patient (if permitted by the female 
partner and by local regulatory policies), during the study or within 70 days 
following the last dose of study drug. Study drug will be discontinued in female 
study participants who become pregnant, per Section 7.3.1.2.  The sponsor will 
provide the investigator with a Pregnancy Tracking Form that is to be completed 
by the study site on a monthly basis and faxed to the sponsor (or designee).  The 
investigator will follow the pregnancy until delivery, or longer. If the pregnancy 
continues to term (delivery), the health of the infant must also be reported to the 
sponsor (or designee). 
Information on AEs of interest that requires accelerated reporting is provided in Section 7.6.4.5. 
Whenever possible and practical, a blood sample to potentially measure plasma drug levels should 
be obtained upon the development of any SAE or unusual AE that is judged related to study 
treatment. 
8.2.3. 
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. All SAEs leading to a patient’s withdrawal from the study must 
be reported as outlined in Section 8.2. 
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8.2.4. 
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/study drug, significant additional 
concomitant drug treatment, or other therapy 
Contact the medical monitor in the event the investigator feels that an abnormal test finding should 
be reported as an AE, although it does not meet any of the above criteria. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an 
AE.  Any abnormal test result that is determined to be an error does not require reporting as an 
AE. 
Evaluation of severity of laboratory abnormalities will be assessed according to the scale outlined 
in Section 8.3.1. 
8.2.5. 
Follow-up 
Adverse event information will be collected until the end of study visit, or the early termination 
visit if the patient withdraws consent. 
The investigator must make every effort to obtain follow-up information on the outcome of any 
SAE until the event is considered chronic and/or stable. 
8.3. 
Evaluation of Severity and Causality 
8.3.1. 
Evaluation of Severity 
8.3.1.1. 
Adverse Events (Excluding Local Injection Site Reactions) 
The severity of each AE (excluding local injection site reactions, see Section 8.3.1.2) will be 
graded by the investigator using a 3-point scale (mild, moderate, or severe) and reported in detail 
as indicated on the e-CRF and/or SAE form, as appropriate. 
 Mild: Does not interfere in a significant manner with the patient’s normal functioning 
level. It may be an annoyance.  Prescription drugs are not ordinarily needed for relief 
of symptoms, but may be given because of personality of the patient. 
 Moderate: Produces some impairment of functioning but is not hazardous to health. It 
is uncomfortable or an embarrassment.  Treatment for symptom may be needed. 
 Severe: Produces significant impairment of functioning or incapacitation and is 
a definite hazard to the patient’s health.  Treatment for symptom may be given and/or 
patient hospitalized. 
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If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
8.3.1.2. 
Local Injection Site Reactions 
The severity of local injection site reactions will be graded by the investigator using a 4-point scale 
(mild, moderate, severe, or very severe) adapted from the toxicity grading scale table from the 
Food and Drug Administration Draft Guidance for Industry:  Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials dated April 2005.  
Local injection site reactions will be reported in detail as indicated on the e-CRF and/or SAE form, 
as appropriate. 
The complete severity grading scale for assessing local injection site reactions is provided in 
Appendix 7. 
8.3.2. 
Evaluation of Causality 
The relationship of AEs to study drug is a clinical decision that will be made based on all available 
information, by the investigator, who will answer the following question: 
Is there a reasonable possibility that the AE was caused by the study drug? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by the study 
drug 
Related: 
There is a reasonable possibility that the event may have been caused by the study 
drug (ie, a causal relationship cannot reasonably be ruled out) 
The investigator will provide a comment on the SAE reporting form to explain the basis of the 
causality assessment for SAEs. 
8.3.2.1. 
Causality Evaluation Factors 
Factors to consider when determining the relationship of an AE to study drug are included below. 
Not Related: 
 Existence of a clear alternative explanation or nonplausibility (eg, the patient is struck 
by an automobile when there is no indication that the drug caused disorientation, or 
cancer diagnosed a few days after first drug administration) 
 Due to external causes such as other treatment(s) being administered 
 Due to the patient’s disease state or clinical condition 
 Does not follow a reasonable temporal sequence following the time of administration 
of the dose of study drug 
 Does not reappear or worsen when dosing with study drug is resumed (ie, negative 
re-challenge) 
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Related: 
 Could not be explained by other treatment(s) being administered 
 Could not be explained by the patient’s disease state or clinical condition 
 Follows a reasonable temporal sequence following the time of administration of the 
dose of study drug 
 Resolves or improves after discontinuation of study drug 
 Reappears or worsens when dosing with study drug is resumed (ie, positive 
re-challenge) 
 Known to be a response to the study drug based upon preclinical data or prior clinical 
data 
 Known to be strongly associated with drug exposure (eg, angioedema, Stevens-Johnson 
Syndrome) 
8.4. 
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, is unexpected based on the 
Investigator’s Brochure, and has a reasonable suspected causal relationship to the study drug). 
9. 
STATISTICAL PLAN 
9.1. 
Statistical Hypothesis 
Let μ0 and μ1 be the population means of the change in SWM strategy z-score from baseline to 
week 96 under placebo and Praluent, respectively. For the primary and exploratory neurocognitive 
variables, the following null and alternative hypotheses will be assessed for noninferiority:  
H0 : μ1 - μ0 ≥ NI margin 
versus 
H1 : μ1 - μ0 < NI margin 
Age (dichotomized by <65 or ≥65) and by statin use (no statin, low lipophilicity of the concomitant 
statin, or high lipophilicity of the concomitant statin) will be the 2 stratification factors for patient 
randomization, and will be accounted for in the statistical modeling for neurocognitive function 
assessment. 
9.2. 
Determination of Sample Size 
To demonstrate the noninferiority of the Praluent 75 mg Q2W/up-titrate 150mg Q2W dose 
regimen relative to placebo for the primary endpoint of mean change in SWM strategy z-score 
from baseline to week 96, the sample size for this study is calculated to be 1085 patients per 
treatment group. This sample size is based on the noninferiority margin of 0.2 for the primary 
outcome measure. Specifically, a worsening in the SWM strategy z-score of 0 to 0.2 at the group 
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level (small effect size) would not be considered clinically meaningful. Whereas a worsening of 
0.3 to 0.5 (or greater), a small-to-medium effect size, might be considered clinically relevant, 
indicating increased cognitive impairment (Roiser 2015). Therefore, a noninferiority margin of 0.2 
on the SWM strategy z-score change from baseline is a conservative estimate of the largest 
clinically meaningless mean difference between Praluent and placebo treatment groups. 
Additionally, the assumed mean difference between the treatment groups is 0 and the standard 
deviation is 1.0 (the standard deviation is obtained from the Cambridge Cognition internal 
normative data). To achieve 95% power using a 2-sided 95% confidence interval (CI) approach 
(2-sided alpha=0.05), the sample size is calculated to require 651 patients per treatment group. 
Assuming dropout rate of 20% in the first year and 25% in the second year, the sample size is 
increased to 1085 patients per treatment group.  
The nQuery Advisor 7.0 was used for the sample size calculations. 
9.3. 
Analysis Sets 
9.3.1. 
Safety Analysis Sets 
9.3.1.1. 
Safety Population 
The safety population will be defined as all patients randomized and exposed to at least 1 dose of 
study drug, regardless of the amount of treatment administered. Patients will be analyzed according 
to the treatment received (placebo or Praluent 75 mg Q2W/up-titrate 150 mg Q2W). 
9.3.1.2. 
Primary Safety Population 
The primary safety population used to analyze the neurocognitive endpoints will be defined as 
patients from the safety population who had an assessment of the SWM strategy score at baseline, 
and at least 1 score measured during the TEAE period. The TEAE period is defined as the first 
double-blind treatment dose to last dose of double-blind treatment + 70 days (10 weeks). Patients 
will be analyzed according to the treatment actually received. 
In addition: 
 Randomized patients for whom it is unclear whether they took the study drug will be 
included in the safety population as randomized. 
 For patients receiving study drug from more than 1 treatment group during the trial, the 
treatment group allocation for as-treated analysis will be Praluent. 
9.3.2. 
Efficacy Analysis Set 
9.3.2.1. 
Intent-to-Treat 
The intent-to-treat (ITT) population is defined as all randomized patients who had an evaluable 
secondary efficacy endpoint. The endpoint is evaluable when the following 2 conditions are met: 
 Availability of at least 1 measurement value for calculated LDL-C before first dose of 
study drug (ie, baseline) 
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 Availability of at least 1 measurement value for calculated LDL-C within 1 of the 
analysis windows during the main efficacy period; the main efficacy period is defined 
as the time from the first double-blind study treatment injection up to the upper limit 
of the week 96 analysis window 
Patients in the ITT population will be analyzed according to the treatment group allocated by 
randomization (ie, as-randomized treatment group). 
9.3.2.2. 
Modified Intent-to-Treat 
The modified intent-to-treat (mITT) population (also known as the full analysis set) is defined as 
the all randomized population who took at least 1 dose or part of a dose of study drug and have an 
evaluable secondary efficacy endpoint.  The endpoint is considered as evaluable when both of the 
following conditions are met: 
 Availability of at least 1 measurement value for calculated LDL-C before first dose of 
study drug (ie, baseline) 
 Availability of at least 1 calculated LDL-C value during the efficacy treatment period 
and within 1 of the analysis windows up to week 96; 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 
Patients in the mITT population will be analyzed according to the treatment group allocated by 
randomization. 
9.3.3. 
Other Analysis Set 
The anti-drug 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. 
9.4. 
Patient Disposition 
Screened patients are defined as any patient who originally met the inclusion criteria and signed 
the informed consent. 
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 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, safety data from the first randomization will be 
included in the safety population, with safety data associated with the later randomization reported 
separately.  Since this is expected to be a rare event, inclusion of efficacy data from 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. 
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9.5. 
Statistical Methods 
9.5.1. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively for the 2 treatment 
groups in the safety population. Continuous variables will be summarized with mean, Q1, median, 
Q3, standard deviation, minimum, and maximum. Categorical variables will be summarized with 
frequency and percentage. 
9.5.2. 
Safety and Efficacy Analyses 
9.5.2.1. 
Primary Neurocognitive Analysis 
The primary neurocognitive analysis is a statistical evaluation of the noninferiority of the Praluent 
75 mg Q2W/up-titrate 150 mg Q2W dose regimen to placebo for the primary endpoint of change 
in SWM strategy z-score from baseline to week 96 in the primary safety population.  The 2-sided 
95% CI for the mean treatment difference at week 96 will be determined using an appropriate 
contrast statement in a mixed-effect model with repeated measures (MMRM).  The upper CI limit 
will be compared to the noninferiority margin which is defined as 0.2 and the noninferiority will 
be declared if the upper CI limit is below the noninferiority margin.  
In the case noninferiority is achieved for the primary neurocognitive function endpoint 
comparison, superiority of the primary neurocognitive function endpoint will be assessed using 
the same upper CI limit calculated for the primary comparison.  Specifically, the upper CI limit 
will be compared to zero and superiority will be declared if the upper CI limit is below zero.  A 
statistical multiplicity adjustment is not needed, since this process of noninferiority achievement 
followed by superiority assessment using the same 95% upper CI limit on the primary endpoint 
corresponds to a simple closed test procedure (EMA/CPMP/EWP/482/99 – 27July 2000). 
The MMRM model will include the fixed categorical effects of treatment group (placebo, 
Praluent), both randomization strata (as per IVRS/IWRS), time point (weeks 24, 48, 72, and 96), 
treatment-by-time point interaction, and strata-by-time point interaction, as well as the continuous 
covariate of baseline SWM strategy raw score value and baseline value-by-time point interaction.  
Post-baseline assessments within a patient’s TEAE period will be included in the analysis and 
missing data are accounted for by the MMRM model.  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 96 for both treatment groups with 
their corresponding standard errors. 
To support the clinical interpretation of the primary neurocognitive analysis, the SWM strategy 
raw score change from baseline to week 96 in the primary safety population will also be 
descriptively provided using the MMRM analysis method described above (at least includes least 
squares mean and 95% CI).  
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Robustness of this statistical method will be assessed via sensitivity analyses detailed in the SAP, 
including different methodologies for missing data (multiple imputation and potentially pattern 
mixture modeling). 
9.5.2.2. 
Exploratory Neurocognitive Analyses 
To further understand the effects of Praluent on cognitive function and support the primary 
neurocognitive analysis, the 3 domain endpoints (specifically PAL, RTI, and SWM between-error 
scores) and the Global Composite score will also be evaluated for noninferiority at week 96 in the 
primary safety population.  These 4 measures will not be evaluated for superiority.  The analysis 
method (MMRM) and noninferiority evaluation approach (evaluation of the 95% CI for the mean 
treatment difference at week 96) described for the primary neurocognitive analysis will also be 
used for the 3 domain’s z-scores change from baseline and the Global Composite score change 
from baseline.  To support the clinical interpretation of the 3 domains, the raw score change from 
baseline to week 96 in the primary safety population will also be descriptively provided using the 
MMRM analysis method. 
The 4 domain endpoint scores (including the primary neurocognitive endpoint) and the Global 
Composite scores will be descriptively summarized by time point, and the details will be provided 
in the SAP. 
9.5.2.3. 
Secondary Efficacy Analyses 
For secondary efficacy endpoints of lipids (defined in Section 6.2.3), descriptive summaries and 
analyses will be performed in the ITT population (for ITT analysis) and the mITT population (for 
on-treatment analysis). P-values for the testing of study treatment effect will be provided for 
descriptive purposes only (nominal p-values). 
For descriptive summaries, percent change from baseline in calculated LDL-C, Total-C, HDL-C, 
TG, non-HDL-C, Apo B, Apo A-1, and Lp(a) 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.  The time profile of each 
parameter will be plotted by treatment group with the corresponding standard errors. For TG and 
Lp(a), summary statistics will include Q1 and Q3. 
Multiple types of measurements are planned to be analyzed during the trial, specifically continuous 
measurements expected to have a normal distribution (eg, percent change in calculated LDL-C), 
continuous measurements expected to have a non-normal distribution (eg, TG), and binary 
measurements (eg, proportion of patients reaching LDL-C <70 mg/dL). 
I. Continuous Endpoints Anticipated to have a Normal Distribution 
Continuous secondary efficacy variables, defined in Section 6.2.3, 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 method as described for the primary neurocognitive endpoint.  Specifically, the 
model will contain fixed categorical effects of treatment group, both randomization strata, planned 
time points up to week 96 (specific time points are weeks 8, 12, 24, 48, 72, and 96), 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.  
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II. Continuous Endpoints Anticipated to have a Non-Normal Distribution 
Continuous secondary efficacy endpoints, defined in Section 6.2.3, 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 
the 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 standard error estimates.  The combined mean difference between the 
treatment groups will be provided with the standard error, 95% CI, and p-value. 
III. Binary Endpoints 
Binary secondary efficacy endpoints, defined in Section 6.2.3, will be analyzed in the analysis 
populations using stratified logistic regression (using the strata option of the SAS logistic 
procedure) with treatment group and randomization strata as main effect and corresponding 
baseline value(s) as the 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 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 group and thus the maximum likelihood estimate may not exist), the last 
observation carried forward (LOCF) approach would be used for handling of missing values and 
an exact conditional logistic regression would be performed to compare treatment effects.  The 
LOCF imputation method will consist of using the last value obtained up to the applicable time 
point window (weeks 12, 24, 48, 72, and 96 as applicable) to impute the missing week value. 
9.5.2.4. 
Multiplicity Considerations 
Adjustments to the alpha level for the purposes of multiple testing are not applicable for this safety 
study. The exploratory neurocognitive and secondary efficacy lipid endpoints are supportive of the 
primary analysis and not hypothesis-testing.  Any statistical testing is for descriptive purposes only 
(ie, any p-values provided are nominal). 
9.5.2.5. 
General Safety Analyses 
The general safety analysis will be based on the safety analysis population (SAF).  The summary 
of safety results will be presented by the 2 treatment groups (placebo and Praluent 75 mg Q2W/up-
titrate 150 mg Q2W). No formal inferential testing will be performed.  Summaries will be 
descriptive in nature. 
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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 study 
treatment. 
9.5.2.6. 
Adverse Events 
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®).  The verbatim text, the preferred term (PT), and 
the system organ class (SOC) will be provided in patient listings. 
Definitions 
For safety variables, the following observation periods are defined: 
 The pretreatment period is defined as the time from signing the ICF to before the first 
dose of study treatment. 
 The TEAE period is defined as the time from the first dose of study treatment to the 
last dose of study treatment + 70 days (10 weeks) (residual effect of treatment is 
expected until 10 weeks after the last dose of study drug). 
 The post-treatment observation period is defined as the time from the day after the end 
of the TEAE period up to the last study visit. 
Pretreatment AEs are defined as those that developed, worsened, or became serious during the 
pretreatment period. 
Treatment-emergent adverse events are defined as those that developed, worsened, or became 
serious during the TEAE period. 
Post-treatment AEs are defined as those that developed, worsened, or became serious during the 
post-treatment period. 
Analysis 
Adverse event incidence tables will be presented by (at least) SOCs sorted by internationally 
agreed order, and PTs sorted by decreasing frequency in the Praluent group.  The number (n) and 
percentage (%) of patients experiencing an AE will be shown.  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 a treatment phase.  Data 
conventions for missing or partial AE dates will be addressed in the SAP.  The denominator for 
computation of percentages is the safety population 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 prespecified 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 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.  
Kaplan-Meier curves will be provided. 
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Death 
The following death summaries will be generated: 
 Number (%) of patients who died by study period (TEAE and post-study) summarized 
on the safety population by treatment received 
 Death in nonrandomized patients or randomized and not treated patients 
 TEAE leading to death (death as an outcome on the AE e-CRF page as reported by the 
investigator) by (at least) SOCs sorted by internationally agreed order, and PTs sorted 
by decreasing frequency in the Praluent group, showing the number (n) and percentage 
(%) of patients 
Drug-Induced Liver Injury 
Liver function tests, namely ALT, AST, alkaline phosphatase, and total bilirubin, are used to assess 
possible drug-induced liver toxicity.  The proportion of patients with potentially clinically 
significant abnormal values (PCSAs) at any post-baseline visit by baseline status will be displayed 
by treatment group for each parameter.  A graph of distribution of peak values of ALT versus peak 
values of total bilirubin will also be presented (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 upper limit of normal (ULN) for ALT and a horizontal line corresponding to 
2 x ULN for total bilirubin. 
The incidence of liver-related AEs will be summarized by treatment group.  The selection of PTs 
will be based on a standardized MedDRA query hepatic disorder. Time to liver-related treatment 
discontinuation and time to liver death may also be provided based on the hepatic disorder 
standardized MedDRA query. 
Neurocognitive Events of Special Interest: 
Neurocognitive events are defined in this study as AESI, specifically, neurocognitive AEs (serious 
or nonserious) required to be monitored, documented, and managed in a prespecified manner as 
described in this protocol.  The number and percentage of patients experiencing a neurocognitive 
event will be summarized for each treatment group by SOC and PT.  Time-to-event analyses could 
also be performed (if relevant, based on the number of events).  In addition, the neurocognitive 
event rate in patients with 2 consecutive results separated by at least 21 days, and with only 1 such 
event for calculated LDL-C <25 mg/dL, and calculated LDL-C <15 mg/dL, will be assessed. 
9.5.2.7. 
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 study 
treatment. 
 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. 
 The 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, 
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including unscheduled or repeated evaluations. The number of all such patients will be 
the numerator for the PCSA percentage. 
 Treatment period: the treatment period used for quantitative analysis (laboratory results 
and vital signs) is defined as the time from first dose of study treatment to the last dose 
of study treatment + 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 
standing 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 (on-treatment PCSAs) will be 
summarized by treatment group, whatever the baseline level and/or according to the following 
baseline categories: 
 Normal/missing 
 Abnormal according to PCSA criteria 
For laboratory parameters for which PCSA criteria is not defined, similar table(s) using the normal 
range could be provided. 
Hepatitis C Test 
The number and percentage of patients with an observed seroconversion for hepatitis C test will 
be provided by treatment group. 
9.5.2.8. 
Treatment Exposure 
The duration of treatment exposure will be calculated for each treatment group.  The following 
measures of exposure will be summarized: 
 Duration of Praluent exposure in weeks, defined as (last study treatment dosing date 
+14 minus first study treatment dosing date)/7, regardless of unplanned intermittent 
discontinuations 
 The total number of injections by patient 
Treatment exposure duration, measured in weeks, will be summarized by at least mean, median, 
standard deviation, and minimum/maximum.  The categorical data of maximum number of 
injections will be summarized by patient counts and percentages. 
The number (n) and percentage (%) of patients with an up-titration (a change in dose) in the 
Praluent group will be provided for the overall safety population. 
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9.5.2.9. 
Treatment Compliance 
Study treatment compliance will be assessed by treatment group using the following parameter:  
 The injection frequency will be defined for each patient as the average number of days 
between 2 injections, that is: (last dose date minus first dose date)/(number of injections 
minus 1) 
These parameters will be summarized descriptively (N, mean, standard deviation, median, 
minimum and maximum). 
9.5.2.10. Analysis of Other Endpoints 
All analyses for other endpoints will be performed on the safety population.  The baseline value 
is defined as the last available value before first dose of study drug. 
Exploratory variables, such as those defined in Section 6.2.4, will be summarized by time points 
using number of available data, mean, standard deviation, median, minimum, and maximum for 
each treatment group. 
The antibody status (positive/negative) and antibody titers will be summarized by treatment group 
and visit using descriptive statistics.  If appropriate, correlations between antibody titers, safety 
and/or efficacy endpoints will be provided by graphical methods. 
The number and percentage of patients with 2 consecutive results separated by at least 21 days for 
calculated LDL-C <25 mg/dL and calculated LDL-C <15 mg/dL will be provided by treatment 
group. 
Further details will be provided in the SAP. 
10. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
10.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation, cleaning, correcting, and 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, applicable baseline findings, medication, and medical history/surgical history) 
will be done using internationally recognized and accepted dictionaries.  
The e-CRF data for this study will be collected with an EDC tool. 
10.2. 
Electronic Systems 
Electronic systems used to process and/or collect data in this study will include the following: 
 IVRS/IWRS system – randomization, study drug supply 
 EDC system – data capture 
 SAS – statistical review, analysis, and reporting 
 AWARE, Business Objects XI – pharmacovigilance activities 
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 Central laboratory – data capture 
 Cambridge Cognition – data capture 
11. 
STUDY MONITORING 
11.1. 
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.  In accordance with ICH guidelines, the monitor 
will compare the e-CRF entries with the appropriate source documents.  Additional review may 
include, but is not limited to, patient ICFs, documentation of patient recruitment and follow-up, 
AEs, SAEs, and concomitant therapy; as well as records of study drug dispensing, compliance, 
and accountability.  A copy of the drug dispensing log must be provided to the sponsor upon 
request. 
11.2. 
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 e-CRF (throughout this protocol, 
CRF refers to either a paper CRF or an electronic CRF).  Case report forms and source documents 
must be available at all times for inspection by authorized representatives of the sponsor and 
regulatory authorities. 
11.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on e-CRFs by trained site 
personnel.  An e-CRF must be completed for 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 e-CRF page 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 e-CRF will be entered in the e-CRF by the investigator or an authorized 
designee.  All changes, including date and person performing the corrections, will be available via 
a system-generated audit trail.  For corrections made via data queries, a reason for any alteration 
must be provided. 
12. 
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 
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 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, 
e-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. 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1. 
Good Clinical Practice Statement 
It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory 
requirements. 
13.2. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC.  A copy of the IRB/EC -approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient prior to his/her participation in the study and after the 
aims, methods, objectives, and potential hazards of the study have been explained to the patient in 
a 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. 
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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. 
13.3. 
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 e-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. 
13.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve: 
 The protocol, ICF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
 Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the 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. 
14. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design or operation of the protocol or ICF without 
a health authority and/or IRB/EC-approved amendment. 
15. 
END OF STUDY DEFINITION 
The last patient last visit constitutes the end of study. 
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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 investigators 
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), 
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 e-CRFs must be signed 
by the investigator. This certification form accompanies each set of e-CRFs.  The signed form will 
be provided to the sponsor with the final set of e-CRFs for each patient. 
17.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of e-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 
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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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(4th Text Revision ed.) Washington, DC: American Psychiatric Association. 
Attwood AS, Higgs S, Terry P (2007): Differential responsiveness to caffeine and perceived 
effects of caffeine in moderate and high regular caffeine consumers. Psychopharmacology (Berl) 
190: 469–477. 
Bartok E, Berecz R, Galub T et al. Cognitive functions in prepsychotic patients. Prog 
Neuropsychopharmacol Biol Psychiatry, 29 (2005), pp. 621–625 
Chobanian AV1, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. The Seventh 
Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of 
High Blood Pressure: the JNC 7 report. JAMA. 2003 May 21;289(19):2560-72. 
Epub 2003 May 14. 
De Jager, A.D. Blackwell, M.M. Budge, B.J. Sahakian et al. Predicting cognitive decline in healthy 
older adults. Am J Geriatr Psychiatry. 2005; 13:735-40. 
Elliott R, Sahakian BJ, Matthews K, Bannerjea A, Rimmer J, Robbins TW (1997): Effects of 
methylphenidate on spatial working memory and planning in healthy young adults. 
Psychopharmacology (Berl) 131: 196–206. 
The European Agency for the Evaluation of Medicinal Products, the Committee for Proprietary 
Medicinal Products (CPMP). Points to Consider on Switching between Superiority and 
Non-Inferiority. EMA/CPMP/EWP/482/99 – 27July 2000. 
Foltynie T, Brayne CEG, Robbins TW et al. The cognitive ability of an incident cohort of 
Parkinson's patients in the UK. THe CamPaiGN study. Brain 2003; 127: 550-60. 
Greig NH, Sambamurti K, Yu Q, Brossi A, Bruinsma GB, Lahiri DK (2005): An Overview of 
Phenserine Tartrate, A Novel Acetylcholinesterase Inhibitor for the Treatment of Alzheimer’s 
Disease. Curr Alzheimer Res 2: 281–290. 
Harmer CJ, McTavish SFB, Clark L, Goodwin GM, Cowen PJ (2001): Tyrosine depletion 
attenuates dopamine function in healthy volunteers. Psychopharmacology (Berl) 154: 105–111. 
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Impairs 
Choice 
Reaction 
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Performance 
in 
Young 
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Volunteers. 
Neuropsychopharmacology 21: 495–502. 
Joas E, Bäckman K, Gustafson D. Blood pressure trajectories from midlife to late life in relation 
to dementia in women followed for 37 years. Hypertension. 2012 Apr;59(4):796-801 
Kivipelto M, Helkala EL et al. Midlife vascular risk factors and Alzheimer's disease in; later life: 
longitudinal, population based study. BMJ; 2001:322;1447-1451. 
Mielke MM, Zandi PP, Shao H et al. The 32-year relationship between cholesterol and dementia 
from midlife to late life. Neurology. 2010 Nov 23;75(21):1888-95. 
Morris JK, Burns JM,. Insulin: an emerging treatment for Alzheimer's disease dementia? Curr 
Neurol Neurosci Rep. 2012 Oct;12(5):520-7. 
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Perk J. European Guidelines on cardiovascular disease prevention in clinical practice 
(version 2012).  The Fifth Joint Task Force of the European Society of Cardiology and Other 
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Association for Cardiovascular Prevention & Rehabilitation (EACPR).  2012, 33 (13):1635-701 
Eur. Heart J. 
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J Clin Psychopharmacol. 25(2):175-9. 
Reijmer YD, van den Berg E, Dekker JM et al. Development of vascular risk factors over 15 years 
in relation to cognition: the Hoorn Study. J Am Geriatr Soc. 2012 Aug;60(8):1426-33 
Richardson K, Schoen M, French B, et al. Statin and Cognitive function. A systematic review. Ann 
Intern Med. 2013; 159: 688-697 
Roiser JP, Pradeep J, Nathan PJ, Mander AP, Adusei G, Zavitz KH, Blackwell AD. Assessment 
of Cognitive Safety in Clinical Development. Manuscript accepted for publication 2015.  
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memory in healthy young volunteers. Psychopharmacology (Berl) 96: 145–152. 
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Sahebzamani FM, Munro CL, Marroquin OC, Diamond DM, Keller E, et al. Examination of the 
FDA Warning for Statins and Cognitive Dysfunction. J Pharmacovigilance 2014;2:141 
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Weiland-Friedler P, Erickson K, Wladeck T et al. Evidence of continuing neuropsychological 
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Whitmer RA, Sidney S, Selby J et al. Midlife cardiovascular risk factors and risk of dementia in 
late life. Neurology. 2005 Jan 25;64(2):277-81. 
Yaffe K, Vittinghoff E, Pletcher MJ et al. Early adult to midlife cardiovascular risk factors and 
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22. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: A Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Effect of Praluent on Neurocognitive Function in Patients with Heterozygous Familial 
Hypercholesterolemia or with Non-Familial Hypercholesterolemia at High and Very High 
Cardiovascular Risk, 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. SIMON BROOME REGISTER DIAGNOSTIC CRITERIA 
FOR HETEROZYGOUS FAMILIAL 
HYPERCHOLESTEROLEMIA 
Definite familial hypercholesterolemia is defined as: 
 Total-C >6.7 mmol/l (260 mg/dL) or LDL cholesterol above 4.0 mmol/l (155 mg/dL) 
in a child <16 years or Total-C >7.5 mmol/l (290 mg/dL) or LDL cholesterol above 
4.9 mmol/l (190 mg/dL) in an adult. (Levels either pre-treatment or highest on 
treatment) 
PLUS 
 Tendon xanthomas in patient, or in 1st degree relative (parent, sibling, child), or in 
2nd degree relative (grandparent, uncle, aunt) 
OR 
 DNA-based evidence of an LDL receptor mutation or familial defective Apo B-100 
Possible familial hypercholesterolemia is defined as: 
 Total-C >6.7 mmol/l (260 mg/dL) or LDL cholesterol above 4.0 mmol/l (155 mg/dL) 
in a child <16 years or Total-C >7.5 mmol/l (290 mg/dL) or LDL cholesterol above 
4.9 mmol/l (190 mg/dL) in an adult. (Levels either pre-treatment or highest on 
treatment) 
And at least one of the following: 
 Family history of myocardial infarction below 50 years of age in 2nd degree relative 
or below 60 years of age in 1st degree relative. 
Family history of raised cholesterols >7.5 mmol/l (290 mg/dL) in adult 1st or 2nd degree relative 
or >6.7 mmol/l (260 mg/dL) in child or sibling under 16 years of age. 
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APPENDIX 2. WHO CRITERIA (DUTCH LIPID NETWORK CLINICAL 
CRITERIA) FOR DIAGNOSIS OF HETEROZYGOUS 
FAMILIAL HYPERCHOLESTEROLEMIA 
Diagnostic Scoring for Heterozygous Familial Hypercholesterolemia 
Family history 
a 
First degree relative with known premature (men <55 yrs, women <60 yrs) coronary and vascular disease. 
1 
b 
First degree relative with known LDL-cholesterol >95th percentile for age and sex. 
 
and/or 
a 
First degree relative with tendon xanthomata and/or arcus cornealis. 
2 
b 
Children below 18 yrs. with LDL-cholesterol >95th percentile for age and sex. 
 
 
 
 
Clinical history 
a 
Patient has premature (men <55 yrs, women <60 yrs) coronary artery disease 
2 
b 
Patient has premature (men <55 yrs, women <60 yrs) cerebral or peripheral vascular disease. 
1 
 
 
 
Physical examination 
a 
Tendon xanthomata 
6 
b 
Arcus cornealis below the age of 45 yrs. 
4 
 
 
 
Laboratory analysis 
 
 
mmol/L 
mg/dL 
 
a 
LDL-cholesterol 
>8.5 
>330 
8 
b 
LDL-cholesterol 
6.5-8.4 
250-329 
5 
c 
LDL-cholesterol 
5.0-6.4 
190-249 
3 
d 
LDL-cholesterol 
4.0-4.9 
155-189 
1 
 
(HDL-cholesterol and triglycerides are normal) 
 
 
 
 
DNA-analysis 
a 
Functional mutation low-density lipoprotein receptor gene present 
8 
 
 
 
Diagnosis of heFH is: 
Certain When 
>8 points 
Probable When 
6-8 points 
Possible When 
3-5 points 
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APPENDIX 3. MOOD STABILIZERS, ANTIPSYCHOTICS AND 
MEDICATIONS TO TREAT DEMENTIA 
(Exclusionary medications, regardless of indication for use) 
Mood Stabilizers 
Antipsychotics 
Dementia Treatment 
Lithium 
Risperidone 
Donepezil 
Valproic Acid 
Olanzapine 
Galantamine 
Topiramate 
Quetiapine 
Rivastigmine 
Lamotrigine 
Clozapine 
Memantine 
Divalproex 
Ziprasidone 
 
Valproate 
Aripiprazole 
 
Oxcarbazine 
Lurasidone 
 
Riluzole 
Asenapine 
 
Carbamazepine 
Pailperidone 
 
 
Iloperidone 
 
 
Haloperidol 
 
 
Fluphenazine 
 
 
Chlorpromazine 
 
 
Perphenazine 
 
 
Pimozide 
 
 
Thiothixine 
 
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APPENDIX 4. 
DRUGS ON THE ANTICHOLINERGIC BURDEN 
SCALE 
(A total ACB scale score of three or more is considered exclusionary) 
ACB Score 1 (mild)  
ACB Score 2 (moderate) 
ACB Score 3 (severe) 
Alimemazine 
Amantadine 
Amitriptyline 
Alprazolam 
Belladonna alkaloids 
Amoxapine 
Alverine 
Cyclobenzaprine 
Atropine 
Aripiprazole 
Cyproheptadine 
Benztropine 
Asenapine 
Loxapine 
Brompheniramine 
Atenolol 
Meperidine 
Carbinoxamine 
Beclometasone dipropionate 
Methotrimeprazine 
Chlorpheniramine 
Benzodiazepines 
Molindone 
Chlorpromazine 
Bupropion hydrochloride 
Nefopam 
Clemastine 
Captopril 
Oxcarbazepine 
Clomipramine 
Cetirizine 
Pethidine hydrochloride 
Clozapine 
Chlorthalidone 
 
Darifenacin 
Cimetidine hydrochloride 
 
Desipramine 
Clidinium 
 
Dicyclomine 
Clorazepate 
 
Dimenhydrinate 
Clonazepam 
 
Diphenhydramine 
Opiates 
 
Doxepin 
Colchicine 
 
Fesoterodine 
Desloratadine 
 
Flavoxate 
Dextropropoxyphene 
 
Hydroxyzine 
Digoxin 
 
Hyoscyamine 
Dipyridamole 
 
Imipramine 
Disopyramide phosphate 
 
Meclizine 
Fentanyl 
 
Methocarbamol 
Fluvoxamine 
 
Nortriptyline 
Furosemide 
 
Olanzapine 
Hydralazine 
 
Orphenadrine 
Hydrocortisone 
 
Oxybutynin 
Iloperidone 
 
Paroxetine 
Isosorbide preparations 
 
Perphenazine 
Levocetirizine 
 
Procyclidine 
Loperamide 
 
Promazine 
Loratidine 
 
Promethazine 
Metoprolol 
 
Propentheline 
Morphine 
 
Propiverine 
Nifedipine 
 
Pyrilamine 
Paliperidone 
 
Quetiapine 
Prednisone/Prednisolone 
 
Scopolamine 
Quinidine 
 
Solifenacin 
Ranitidine 
 
Thioridazine (withdrawn) 
Risperidone 
 
Tolterodine 
Sertraline 
 
Trifluoperazine 
Theophylline 
 
Trihexyphenidyl 
Timolol maleate 
 
Trimipramine 
Trazodone 
 
Trospium 
Triamterene 
 
 
Venlafaxine 
 
 
Warfarin 
 
 
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Notes: 
1. Certain medicines eg Risperidone (mild ACB), Quetiapine (severe ACB) and Olanzapine 
(severe ACB) were licensed after 1990 and therefore not prescribed to the original CFAS 
cohort. 
2. Brand names may conceal generic drug names. 
3. Some combination medicines contain anticholinergic drugs. 
4. This list is indicative and some related medicines were taken by patients in the CFAS study; 
if appropriate these related medicines were given an ACB score based on the ACB of the 
related medicine in the Aging Health publication (see Reference 1 below). 
5. Medications listed in Appendix 4 used “as needed”/pro re nata (PRN), ≤2 times per week 
should not be included in calculating the ACB score 
6. All products that include metoprolol (eg, metoprolol succinate [Toprol XL] or metoprolol 
tartrate [Lopressor]) should be scored “1.” 
7. All opiate products (eg, oxycodone, hydrocodone, tramadol, etc) should be scored as “1.” 
References: 
1. Boustani MA, Campbell NL, Munger S, Maidment I, Fox GC. Impact of anticholinergics 
on the aging brain: a review and practical application. Aging Health. 2008;4(3):311-20. 
2. Campbell N, Boustani M, Limbil T, Ott C, et al.  The cognitive impact of anticholinergics: 
a clinical review. Clinical Interventions in Aging. 2009;4(1):225-33 
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APPENDIX 5. DEFINITION OF CARDIOVASCULAR DISEASE RISK 
CATEGORIES 
 Very high CV risk is defined as a history of documented CHD, ischemic stroke, 
transient ischemic attack, carotid artery occlusion >50% without symptoms, carotid 
endarterectomy or carotid artery stent procedure, peripheral arterial disease, abdominal 
aortic aneurysm, renal artery stenosis, renal artery stent procedure, type 1 or type 2 
diabetes mellitus with target organ damage. 
A history of documented CHD includes 1 or more of the following: 
 Acute myocardial infarction 
 Silent myocardial infarction 
 Unstable angina 
 Coronary revascularization procedure (eg, percutaneous coronary intervention or 
coronary artery bypass graft surgery). 
 Clinically significant CHD diagnosed by invasive or non-invasive testing (such as 
coronary angiography, stress test using treadmill, stress echocardiography or 
nuclear imaging) 
 High CV risk is defined as a calculated 10-year fatal CVD risk SCORE ≥5% 
(ESC/EAS 2012), moderate chronic kidney disease, type 1 or type 2 diabetes mellitus 
without target organ damage, or heFH. 
 Moderate CV risk is defined as a calculated 10-year fatal CVD risk SCORE ≥1 and 
<5% (ESC/EAS 2012). 
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APPENDIX 6. 
SUMMARY OF TLC DIET FOR HIGH CHOLESTEROL 
 
Total Fat 
25% - 35% total calories* 
Saturated fat* 
< 7% total calories 
Polyunsaturated fat 
up to 10% total calories 
Monounsaturated fat 
up to 20% total calories 
Carbohydrates† 
50% - 60% total calories* 
Protein 
~15% total calories 
Cholesterol 
< 200 mg/day (5.172 mmol/day) 
Plant Sterols 
2g 
Soluble Fiber such as psyllium 
10g - 25g 
* ATP III allows an increase of total fat to 35 percent of total calories and a reduction in carbohydrate to 50 percent 
for persons with the metabolic syndrome. Any increase in fat intake should be in the form of either polyunsaturated 
or monounsaturated fat. Trans-fatty acids are another LDL-raising fat that should be kept at a low intake. 
† Carbohydrate should derive predominantly from foods rich in complex carbohydrates including grains—especially 
whole grains—fruits, and vegetables. 
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CONFIDENTIAL 
APPENDIX 7. ASSESSMENT OF LOCAL INJECTION SITE 
REACTIONS 
Reaction to 
Injectable 
Product 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Very Severe 
(Grade 4) 
Pain 
Does not interfere 
with activity 
Interferes with activity 
or repeated use of 
non-narcotic pain 
reliever 
Prevents daily activity or 
repeated use of narcotic 
pain reliever 
Emergency Room 
(ER) visit or 
hospitalization 
Tenderness 
Mild pain to touch 
Pain with movement 
Significant pain at rest 
ER visit or 
hospitalization 
Erythema/ 
Redness* 
2.5 – 5 cm 
5.1 – 10 cm 
>10 cm 
Necrosis or 
exfoliative 
dermatitis 
Swelling** 
2.5 – 5 cm and does 
not interfere with 
activity 
5.1 – 10 cm or interferes 
with activity 
> 10 cm or prevents 
daily activity 
Necrosis 
Itching 
Does not interfere 
with activity 
Interferes with activity 
or repeated use of topical 
or systemic treatment 
Prevents daily activity or 
leads to other significant 
dermatologic conditions 
(such as infection, 
scarring, etc.) 
Emergency Room 
(ER) visit or 
hospitalization 
Other (Please 
specify)*** 
No modification of 
daily activities and/or 
does not require 
symptomatic 
treatment. 
Hinders normal daily 
activities and/or requires 
symptomatic treatment. 
Prevents daily activities 
and requires 
symptomatic treatment. 
Emergency Room 
(ER) visit or 
hospitalization 
* In addition to grading the measured local reaction at the greatest single diameter, the measurement should be 
recorded as a continuous variable. 
**Swelling should be evaluated and graded using the functional scale as well as the actual measurement. 
***Please specify the other signs or symptoms (for example, hematoma, discoloration, re-activation, etc.). 
ADAPTED from the toxicity grading scale table from the FDA Draft Guidance for Industry: 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials April 2005 
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APPENDIX 8. 
GERIATRIC DEPRESSION SCALE SHORT FORM 
 
 
 
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APPENDIX 9. 
MONTREAL COGNITIVE ASSESSMENT 
 
 
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APPENDIX 10. LDL-C RESCUE MEDICATION PRINCIPLES 
If no reason for LDL-C above the threshold value can be found, or if appropriate action fails to 
decrease LDL-C below the threshold value, rescue medication may be introduced.  The 
effectiveness of any such changes will be made based on lack of rescue threshold from blinded 
lipid testing at the next routinely scheduled lab draw. 
Patients per protocol already receive a maximum tolerated dose of statin, so statin uptitration or 
switch will not be an option. 
For further LDL-C lowering, the investigator may consider adding: 
 A cholesterol absorption inhibitor (ezetimibe), or  
 A bile acid-binding sequestrant (the resins cholestyramine and colestipol, or 
colesevelam, a nonabsorbable polymer) 
The following lipid modifying agents may also be considered: 
 Fenofibrate 
Note:  Caution should be exercised when combining fibrates with other cholesterol 
lowering medications such as statins because of the risk of myopathy.  When a fibrate 
is combined with a statin, fenofibrate is the fibrate of choice because it does not affect 
statin glucuronidation. 
 Nicotinic acid (niacin) 
Note:  Niacin raises blood glucose but has been shown to be effective in modifying 
lipid disorders in people with diabetes if glucose control is maintained. 
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CONFIDENTIAL 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Medical/Study Director, 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 Study to Evaluate the 
Effect of Praluent on Neurocognitive Function in Patients with 
Heterozygous Familial Hypercholesterolemia or with Non-Familial 
Hypercholesterolemia at High and Very High Cardiovascular Risk 
Protocol Number: 
R727-CL-1532 
Protocol Version:  R727-CL-1532 Amendment 5 
See appended electronic signature page 
Sponsor’s Responsible Medical/Study Director 
 
 
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-00051258-1.0 Approved - 17 Jul 2018 GMT-5:00


Signature Page for VV-RIM-00051258 v1.0
Signature Page for VV-RIM-00051258 v1.0 Approved
Approval
Approval
Approval
Approval
                                        VV-RIM-00051258-1.0 Approved - 17 Jul 2018 GMT-5:00

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 
1/75 
Title: 
A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Effect of Praluent® on Neurocognitive Function in Patients with 
Heterozygous Familial Hypercholesterolemia or with Non-Familial 
Hypercholesterolemia at High and Very High Cardiovascular Risk 
Protocol: 
R727-CL-1532 
Investigational Product: 
Praluent® (REGN727/SAR236553) 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Statistician: 
 
Clinical Trial Manager: 
 
Clinical Study Director: 
 
Version/Date:  
V1.0 / May 5, 2020   
VV-RIM-00109809-1.0 Approved - 08 May 2020 GMT-5:00
NCT03694197 


Regeneron Pharmaceuticals, Inc.                                                                     Protocol: R727-CL-1532 (Praluent) 
Statistical Analysis Plan                                                                                                                         May 5, 2020 
 
CONFIDENTIAL 
Page 2 of 75 
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.  
 
Regeneron Study Biostatistician  
 
(
) 
 
Regeneron Study Bioanalytical Sciences 
(
) 
 
Regeneron Study Medical Director            (
  
 
Regeneron Project Biostatistician 
 
) 
 
Sanofi Project Biostatistician               
(
) 
 
Sanofi Global  Project Head for Praluent 
) 
 
Sanofi Therapeutic Area Head, Diabetes and Cardiovascular Medicine and Development 
Innovation 
 
 
 
 
(
) 
 
                                        VV-RIM-00109809-1.0 Approved - 08 May 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc.                                                                     Protocol: R727-CL-1532 (Praluent) 
Statistical Analysis Plan                                                                                                                         May 5, 2020 
 
CONFIDENTIAL 
Page 3 of 75 
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 
Head of BDM or designee (
 
 
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Regeneron Pharmaceuticals, Inc.                                                                     Protocol: R727-CL-1532 (Praluent) 
Statistical Analysis Plan                                                                                                                         May 5, 2020 
 
CONFIDENTIAL 
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Regeneron Pharmaceuticals, Inc.                                                                     Protocol: R727-CL-1532 (Praluent) 
Statistical Analysis Plan                                                                                                                         May 5, 2020 
 
CONFIDENTIAL 
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Regeneron Pharmaceuticals, Inc.                                                                     Protocol: R727-CL-1532 (Praluent) 
Statistical Analysis Plan                                                                                                                         May 5, 2020 
 
CONFIDENTIAL 
Page 6 of 75 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...................................................10 
1. 
OVERVIEW ...............................................................................................................12 
1.1. 
Background/Rationale ................................................................................................12 
1.2. 
Study Objectives .........................................................................................................12 
1.2.1. 
Primary Objectives .....................................................................................................12 
1.2.2. 
Secondary and Exploratory Objectives .......................................................................12 
1.2.3. 
Modifications from the Statistical Section of Protocol Amendment 5 .......................12 
1.2.4. 
Modifications from the Approved Statistical Analysis Plan ......................................12 
2. 
INVESTIGATING PLAN ..........................................................................................13 
2.1. 
Study Design and Randomization ...............................................................................13 
2.2. 
Sample Size and Power Considerations .....................................................................13 
2.3. 
Study Plan ...................................................................................................................13 
3. 
ANALYSIS POPULATIONS .....................................................................................15 
3.1. 
Safety Analysis Sets ....................................................................................................15 
3.1.1. 
Safety Population ........................................................................................................15 
3.1.2. 
Primary Safety Analysis Set .......................................................................................16 
3.2. 
The Efficacy Analysis Sets .........................................................................................16 
3.2.1. 
Intent-to-Treat Population ...........................................................................................16 
3.2.2. 
Modified Intent-to-Treat Population ...........................................................................16 
3.3. 
The Anti-Drug Antibody 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 ...........................................................................23 
4.4. 
Patient Disposition ......................................................................................................23 
4.5. 
Study Treatment Exposure and Compliance Variables ..............................................25 
4.6. 
Primary and Secondary Endpoints ..............................................................................25 
4.6.1. 
Primary Neurocognitive Endpoint ..............................................................................25 
4.6.2. 
Exploratory Neurocognitive Endpoint ........................................................................26 
4.6.3. 
Secondary Efficacy Variable.......................................................................................27 
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4.7. 
Safety Variables ..........................................................................................................27 
4.7.1. 
Adverse Events Variables ...........................................................................................27 
4.7.1.1. 
Adverse Events and Serious Adverse Events .............................................................28 
4.7.1.2. 
Adverse Events of Special Interest .............................................................................29 
4.7.1.3. 
Events Causing Death .................................................................................................31 
4.7.2. 
Clinical Laboratory Safety Variables ..........................................................................31 
4.7.3. 
Vital Sign Variables ....................................................................................................32 
4.8. 
Other Variables ...........................................................................................................32 
4.9. 
Anti-Drug Antibody Variables ...................................................................................33 
 
 
5. 
STATISTICAL METHODS .......................................................................................34 
5.1. 
Demographics and Baseline Characteristics ...............................................................34 
5.2. 
Medical History and Disease Characteristics .............................................................34 
5.3. 
Prior and Concomitant Medications ...........................................................................36 
5.4. 
Patient Disposition ......................................................................................................37 
5.5. 
Extent of Study Treatment Exposure and Compliance ...............................................37 
5.5.1. 
Exposure to Investigational Product ...........................................................................37 
5.5.2. 
Measurement of Compliance ......................................................................................38 
5.6. 
Analyses of Primary and Secondary Endpoints ..........................................................38 
5.6.1. 
Analyses of Primary Neurocognitive Variable ...........................................................38 
5.6.1.1. 
Sensitivity to Stratification at Randomization ............................................................40 
5.6.1.2. 
Sensitivity to the Handling of Missing Data ...............................................................40 
5.6.1.3. 
Sub-group Analyses ....................................................................................................42 
5.6.2. 
Analyses of Exploratory Neurocognitive Variables ...................................................42 
5.6.3. 
Analyses of Secondary Efficacy Variables .................................................................43 
5.6.3.1. 
Continuous Endpoints Anticipated to Have a Normal Distribution ...........................43 
5.6.3.2. 
Continuous Endpoints Anticipated to Have a Non-normal Distribution ....................44 
5.6.3.3. 
Binary Endpoint Variables ..........................................................................................44 
5.6.3.4. 
Summary of Results by Time Point ............................................................................45 
5.6.4. 
Adjustment for Multiple Comparisons .......................................................................45 
5.7. 
Analysis of Safety Data...............................................................................................46 
5.7.1. 
Analysis of Adverse Events ........................................................................................47 
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5.7.1.1. 
Patient Deaths .............................................................................................................50 
5.7.2. 
Analysis of Clinical Laboratory Variables ..................................................................50 
5.7.3. 
Analysis of Vital Sign Variables.................................................................................53 
5.8. 
Analysis of Other Variables ........................................................................................53 
5.9. 
Analysis of Anti-Drug Antibody Variables ................................................................54 
 
 
6. 
DATA CONVENTIONS ............................................................................................56 
6.1. 
Definition of Baseline for Efficacy and Safety Variables ...........................................56 
6.2. 
Data Handling Conventions for Primary and Secondary Endpoints ...........................56 
6.3. 
General Data Handling Conventions ..........................................................................56 
6.4. 
General Missing Data Conventions ............................................................................57 
6.5. 
Visit Windows for Time Points ..................................................................................58 
6.6. 
Unscheduled Assessments ..........................................................................................59 
6.7. 
Pooling of Centers for Statistical Analyses ................................................................59 
6.8. 
Statistical Technical Issues .........................................................................................59 
7. 
TIMING OF STATISTICAL ANALYSES ................................................................60 
8. 
SOFTWARE ...............................................................................................................61 
9. 
REFERENCES ...........................................................................................................62 
10. 
APPENDIX .................................................................................................................63 
10.1. 
Summary of Statistical Analyses ................................................................................63 
10.2. 
Windows for Analysis Time Points ............................................................................63 
10.3. 
Criteria for Potential Clinical Significant Abnormalities (PCSA) .............................65 
10.4. 
List of MedDRA terms for CMQs ..............................................................................69 
10.5. 
Detailed Description of the Multiple Imputation Procedure.......................................71 
10.6. 
Detailed Description of the Pattern Mixture Model ...................................................72 
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LIST OF TABLES 
Table 1: 
Definition of the patient status regarding hepatitis C virus ........................................52 
Table 2: 
Analysis Windows Definition – All Endpoints Except Lipids or Vital Signs ............63 
Table 3: 
Analysis Windows Definition – Lipids ......................................................................64 
Table 4: 
Analysis Windows Definition – Vital Signs ...............................................................64 
Table 5: 
Selected PTs from SMQ “Optic nerve disorders” including in the CMQ for 
neurologic events ........................................................................................................69 
Table 6: 
CMQ “Neurocognitive disorders – FDA’s recommendation” ....................................70 
Table 7: 
CMQ “Type 1 or Type 2 diabetes” .............................................................................71 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................14 
 
 
 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ACB 
Anticholinergic burden 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
Apo 
Apolipoprotein 
AST 
Aspartate aminotransferase 
CANTAB 
Cambridge Neuropsychological Test Automated Battery 
CHD 
Coronary heart disease 
CI 
Confidence interval 
CPK 
Creatine phosphokinase 
CRF 
Case report form (paper or electronic) 
CT 
Computed tomography 
CTFG 
Clinical Trial Facilitation Group 
CRO 
Contract research organization 
CVD 
Cardiovascular disease 
EC 
Ethics committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
eGFR 
Estimated Glomerular Filtration Rate 
FH 
Familial hypercholesterolemia 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
HDL 
High-density lipoprotein 
HDL-C 
High-density lipoprotein cholesterol 
heFH 
Heterozygous familial hypercholesterolemia 
HIV 
Human immunodeficiency virus 
hs-CRP 
High-sensitivity C-reactive protein 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IVRS 
Interactive voice response system 
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IWRS 
Interactive web response system 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LDL-C 
Low-density lipoprotein cholesterol 
LMT 
Lipid-modifying therapy 
LOCF 
Last observation carried forward 
Lp(a) 
Lipoprotein a 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent-to-treat 
MMRM 
Mixed-effect model with repeated measures 
MoCA 
Montreal Cognitive Assessment 
MRI 
Magnetic resonance imaging 
NCEP ATP 
National Cholesterol Education Program-Adult Treatment Panel  
Non-HDL-C 
Non-high-density lipoprotein cholesterol 
PAL 
Paired Associates Learning 
PCSA 
Potentially clinically significant abnormal value 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PT 
Preferred term 
Q2W 
Every 2 weeks 
RBC 
Red blood cell 
RTI 
Reaction Time 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Software 
SC 
Subcutaneous 
SOC 
System organ class 
SWM 
Spatial Working Memory 
TEAE 
Treatment-emergent adverse event 
TG 
Triglyceride 
Total-C 
Total cholesterol 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
WBC 
White blood cell 
 
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1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study 
results by pre-specifying the statistical approaches for the analysis of study data prior to 
unblinding of treatment assignments and database lock. The SAP is intended to be a 
comprehensive and detailed description of the strategy and statistical methods to be used in 
the analysis of data collected in the R727-CL-1532 study.  
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 of the study data, and a final plan will be issued prior to 
the database lock (i.e. before treatment assignments become known).   
1.1. 
Background/Rationale 
The primary goal of this study is to evaluate neurocognitive function in heFH patients and 
non-FH patients at high or very high cardiovascular risk receiving Praluent compared with 
placebo after 96 weeks of treatment. The 96-week treatment duration is considered sufficient 
to evaluate the effect of Praluent on neurocognitive function. 
Praluent is also referred to as alirocumab, REGN727 or SAR236553. In the context of the 
R727-CL-1532 SAP, it will be referred to as Praluent.  
1.2. 
Study Objectives 
1.2.1. 
Primary Objectives 
The primary objective of the study is to evaluate neurocognitive function with use of Praluent 
after 96 weeks of treatment versus placebo. 
1.2.2. 
Secondary and Exploratory Objectives 
The secondary objectives are: 
• To evaluate the effect of Praluent in comparison with placebo on lipoproteins 
• To evaluate the safety and tolerability of Praluent 
1.2.3. 
Modifications from the Statistical Section of Protocol Amendment 5 
N/A. 
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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2. 
INVESTIGATING PLAN 
2.1. 
Study Design and Randomization 
This is a randomized, double-blind, placebo-controlled trial to evaluate neurocognitive 
function in patients with Heterozygous familial hypercholesterolemia (heFH), or in non-
familial hypercholesterolemia (non-FH) patients, at high or very high cardiovascular risk.  
Patients will be randomized in a 1:1 ratio to receive either placebo or 75 mg Praluent Q2W. 
Randomization will be stratified by age (<65 or ≥65) and by statin use (no statin, low 
lipophilicity of the concomitant statin, or high lipophilicity of the concomitant statin).  
2.2. 
Sample Size and Power Considerations 
To demonstrate the noninferiority of the Praluent 75 mg Q2W/up-titrate 150mg Q2W dose 
regimen relative to placebo for the primary endpoint of mean change in Spatial Working 
Memory (SWM) strategy z-score from baseline to week 96, the sample size for this study is 
calculated to be 1085 patients per treatment group. This sample size is based on the 
noninferiority margin of 0.2 for the primary outcome measure. Specifically, a worsening in 
the SWM strategy z-score of 0 to 0.2 at the group level (small effect size) would not be 
considered clinically meaningful. Whereas a worsening of 0.3 to 0.5 (or greater), a small-to-
medium effect size, might be considered clinically relevant, indicating increased cognitive 
impairment (Roiser 2015). Therefore, a noninferiority margin of 0.2 on the SWM strategy z-
score change from baseline is a conservative estimate of the largest clinically meaningless 
mean difference between Praluent and placebo treatment groups. Additionally, the assumed 
mean difference between the treatment groups is 0 and the standard deviation is 1.0 (the 
standard deviation is obtained from the Cambridge Cognition internal normative data). To 
achieve 95% power using a 2-sided 95% confidence interval (CI) approach (2-sided 
alpha=0.05), the sample size is calculated to require 651 patients per treatment group. 
Assuming dropout rate of 20% in the first year and 25% in the second year, the sample size is 
increased to 1085 patients per treatment group. 
2.3. 
Study Plan 
The study consists of the following 2 periods, which are shown schematically in Figure 1. 
• A screening period of up to 3 weeks. 
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. 
• A double-blind treatment period of 96 weeks. 
On day 1 (baseline), after completion of study assessments and after collection of 
blood samples, and as soon as possible after the patient is randomized into the 
study, the first dose of study drug will be administered. The patient will be 
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monitored at the clinical site for 30 minutes after the first dose. Subsequent doses 
of study drug must be administered Q2W. The last dose of study drug will be 
administered at week 94.  
Patients’ neurocognitive function will be assessed every 6 months. 
The dose of study drug will be increased (using a blinded process) at the week 12 
visit in patients whose LDL-C levels are ≥50 mg/dL (1.3 mmol/L) at week 8. 
Those patients who are randomized to Praluent will receive Praluent 150 mg 
Q2W at week 12 and until end of study. All patients randomized to placebo will 
continue to receive placebo. 
Lipid results will be blinded for specimens obtained after randomization. No 
attempts should be made by the investigator or patient to have the patient’s lipid 
values evaluated independently from the time of randomization until the last study 
visit.  
Patients should be on a stable regimen of lipid-modifying therapy (LMT) (including a 
maximally-tolerated dose of statin, unless statin-intolerant) for 28 days prior to screening, as 
well as on a stable diet. Patients will be asked to maintain both their statin dose and diet from 
screening to the end of the study. 
Figure 1: 
Study Flow Diagram 
 
Screening 
visit 
Screening 
Period 
(up to 3 
weeks) 
W-1 
W8 
W0 
W-3 
Injection 
training 
visit 
W12 
N=1085 
N=1085 
Double-Blind Treatment Period (96 weeks)  
W24 
R
Placebo for alirocumab SC Q2W 
 
Diet (NCEP-ATPIII TLC or equivalent diet) and maximally tolerated statin/other LMT daily dose   
Alirocumab 75mg Q2W up-titrated at W12 to 150mg SC Q2W if  
LDL-C ≥ 50 mg/dL at W8 
 
Cognitive Battery tests to be assessed at W-3, W0, W24, W48, W72 and W96 
W36 
W48 
W60 
W72 
W84 
W96 
 
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3. 
ANALYSIS POPULATIONS  
In accordance with guidance from the International Conference of Harmonization of 
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline 
ICH E9 Statistical Principles for Clinical Trials (ICH, 1998), below are the patient 
populations defined for statistical analysis. The Primary Safety Analysis Set will be the main 
analysis set for primary endpoint 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. 
Safety Analysis Sets 
3.1.1. 
Safety Population 
The safety population (SAF) will be defined as all patients randomized and exposed to at 
least 1 dose of study drug, regardless of the amount of treatment administered. Patients will 
be analyzed according to the treatment received (placebo or Praluent 75 mg Q2W/up-titrate 
150 mg Q2W). 
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3.1.2. 
Primary Safety Analysis Set 
The primary safety population (PSAF) used to analyze the neurocognitive endpoints will be 
defined as patients from the safety population who had an assessment of the SWM strategy 
score at baseline, and at least 1 score measured during the TEAE period. The TEAE period is 
defined as the first double-blind treatment dose to last dose of double-blind treatment + 70 
days (10 weeks). Patients will be analyzed according to the treatment actually received. 
In addition: 
• Randomized patients for whom it is unclear whether they took the study drug will 
be included in the safety population as randomized. 
• For patients receiving study drug from more than 1 treatment group during the 
trial, the treatment group allocation for as-treated analysis will be Praluent.  
3.2. 
The Efficacy Analysis Sets 
3.2.1. 
Intent-to-Treat Population 
The intent-to-treat (ITT) population is defined as all randomized patients who had an 
evaluable secondary efficacy endpoint. The endpoint is evaluable when the following 2 
conditions are met: 
• Availability of at least 1 measurement value for calculated LDL-C before first 
dose of study drug (ie, baseline) 
• Availability of at least 1 measurement value for calculated LDL-C within 1 of the 
analysis windows during the main efficacy period; the main efficacy period is 
defined as the time from the first double-blind study treatment injection up to the 
upper limit of the week 96 analysis window 
Patients in the ITT population will be analyzed according to the treatment group allocated by 
randomization (ie, as-randomized treatment group). 
3.2.2. 
Modified Intent-to-Treat Population 
The modified intent-to-treat (mITT) population is defined as the all randomized population 
who took at least 1 dose or part of a dose of study drug and have an evaluable secondary 
efficacy endpoint.  The endpoint is considered as evaluable when both of the following 
conditions are met: 
• Availability of at least 1 measurement value for calculated LDL-C before first 
dose of study drug (ie, baseline) 
• Availability of at least 1 calculated LDL-C value during the efficacy treatment 
period and within 1 of the analysis windows up to week 96; the efficacy treatment 
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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 
Patients in the mITT population will be analyzed according to the treatment group allocated 
by randomization. 
3.3. 
The Anti-Drug Antibody Analysis Set 
The anti-drug (Praluent) antibody (ADA) 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 (ADA population). 
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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. 
The following variables will be summarized:  
Demographic Characteristics 
• Sex (Male, Female) 
• Race (White, Black or African American, Asian, American Indian or Alaska 
Native, Native Hawaiian or Other Pacific Islander, Other) 
• Age in years (quantitative and qualitative variable: <45, ≥45 to <65, ≥65 to <75, 
and ≥75 years; and <65, and ≥65 years) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown) 
Baseline Characteristics 
• Baseline Weight (kg) 
• Baseline Height (cm) 
• Baseline Body mass index (BMI) in kg/m² (quantitative and qualitative variable 
defined as <30, ≥30)  
• Randomization Strata as Reported in IVRS 
• Randomization Strata as Reported from eCRF 
• Tobacco Use (current, past, never) 
• Alcohol Use (current, past, never) 
• LMT at Randomization 
• Female Menopausal Status 
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Baseline Disease Characteristics 
• Lipid parameters - quantitative variables for all efficacy parameters  
• LDL-C: <70, ≥ 70 to <100, ≥100 to <130, ≥130 to <160, ≥160 to <190, ≥190 
mg/dL (<1.81, ≥1.81, <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) 
• 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,  
≥0.5 g/L, and category >=0.3 g/L) 
• HbA1c both quantitative variable and qualitative variable defined as: <5.7%, 
≥5.7% to <6.5%, ≥6.5% 
• hs-CRP 
• Hepatitis B surface antigen 
• Hepatitis C antibody 
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  
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• 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 
• 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 
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− 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 
• 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. 
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Hyperlipoproteinemia disease history will be assessed through diagnosis of HeFH, 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 statin. For 
those not on not statin or not taking the maximum tolerated dose, reason for 
not statin or not taking a maximum tolerated dose. 
− 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) 
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Details (i.e. statin names, doses) for patients who had received at least 2 statins the day of 
randomization will be listed. 
Statin use (no statin, low lipophilicity of the concomitant statin, or high lipophilicity of the 
concomitant statin) as per IVRS and as per eCRF will be summarized together with other 
baseline characteristics (Section 4.1). 
4.3. 
Prior and Concomitant Medications 
All medications (including statin, non-statin LMT, CV, and Other) taken from the time of 
informed consent to the end of the study, including medications that were started before the 
study and are ongoing during the study, will be reported in Concomitant Medications CRF.  
All medications will be dictionary coded using the World Health Organization-Drug 
Dictionary (WHO-DD) to both an anatomic category and a therapeutic category, with the 
version in effect at the time of the database lock.  Drug names will be matched to respective 
Anatomical-Therapeutic-Chemical (ATC) classification, although a drug can be matched to 
more than one ATC classification (i.e. patients can be counted in several categories for the 
same medication).    
Definitions for deriving prior medications, concomitant and post-treatment 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. 
• Concomitant medications are defined as any treatments received by the patient 
concomitantly with the study treatment, specifically from the first day of study 
treatment administration to the last day of study treatment +70 days. Concomitant 
medications do not include medications started during the post-treatment period. 
• Post-treatment medications are those medications administered to the patient 
during the time period starting from 71 days after the last study treatment 
administration and ending when the patient terminates 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, the following 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. 
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• Screened patients:  The total patient counts will only be shown for 
pre-randomization information, and percentages will not be provided 
• Screen failure patients and reasons for screen failure: The total patient counts will 
only be shown for pre-randomization information. 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  
• Patients complete 96 weeks of double-blind treatment period (at least 94 weeks of 
exposure and visit W96 performed) 
• Patients completed the study treatment period (i.e. as collected on the End of 
Double Blind Treatment eCRF) 
• Patients who did not complete the study treatment period and patient’s decision 
for treatment period discontinuation (as per the End of Double Blind Treatment 
eCRF) 
• Patients who discontinued study treatment by main reason for permanent 
treatment discontinuation (as per the End of Double Blind Treatment eCRF)  
• Patients completed the study (i.e. as collected on the Study Completion eCRF) 
• Patients who early terminated the study (as per the Study Completion eCRF) 
• Patients who early terminated the study by main reason for early termination (as 
per the Study Completion eCRF) 
• Patients who will participate in the Open Label Extension Study 
• Status at last study contact 
As defined in Section 3. of this document, the patient analysis populations are: 
• Randomized population 
• Safety Population (SAF) 
• Primary Safety Population (PSAF) 
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• Intent-to-Treat Population (ITT) 
• Modified Intent-to-Treat Population (mITT) 
• The Anti-alirocumab Antibody Population (ADA) 
4.5. 
Study Treatment Exposure and Compliance Variables 
Study treatment exposure variables are listed below with associated definitions: 
• Patient duration of study treatment exposure in weeks defined as: (last study 
treatment administration date +14 – first study treatment administration date )/7, 
regardless of intermittent discontinuations.  
• The following categories will be used for treatment exposure intervals: ≥1 day 
and <4 weeks, ≥4 weeks and <8 weeks, ≥8 weeks and <12 weeks, ≥12 weeks and 
<16 weeks, ≥16 weeks and <20 weeks, ≥20 weeks and <24 weeks, ≥24 weeks and 
<28 weeks, ≥28 weeks and <32 weeks, ≥32 weeks and <36 weeks, ≥36 weeks and 
<40 weeks, ≥40 weeks and <44 weeks, ≥44 weeks and <48 weeks, …….,  
≥92 weeks and <96 weeks,  ≥96 weeks. 
• The total number of study treatment injections by patient.  
• Patients with up-titration are defined as up-titration according to IVRS/IWRS 
week 12 transaction with at least 1 injection of alirocumab 150 mg following 
up-titration decision. 
Compliance will be assessed using the following variables with associated definitions: 
• For each patient, the mean injection frequency for study treatment injections will 
be defined as the average number of days between 2 consecutive injections, that 
is: (last injection date – first injection date) / (number of injections - 1) for patients 
receiving at least 2 injections. 
All important and minor protocol deviations potentially impacting primary endpoint, 
randomization and drug-dispensing irregularities, as well as other deviations, will be 
collected and reviewed on an ongoing basis throughout the study as described in the Protocol 
Deviation Plan (PDP).  Both monitoring-collected and programmatically derived deviations 
are listed and defined in the PDP. 
4.6. 
Primary and Secondary Endpoints 
4.6.1. 
Primary Neurocognitive Endpoint 
The primary outcome measure is the change in CANTAB cognitive domain SWM strategy 
score (SWMS) from baseline to week 96.  Two definitions will be provided for this endpoint, 
specifically: 
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• SWM strategy z-score change from baseline is defined for each patient as: week 
96 SWM strategy z-score minus the patient’s baseline SWM strategy z-score.  The 
change from baseline SWM strategy z-score is used for the primary analysis 
evaluation of noninferiority.  A lower score denotes better SWM function (ie, less 
impairment). 
− A patient’s SWM strategy z-score at week 96 is defined as: (week 96 SWM 
strategy raw score minus the SWM strategy mean baseline score) divided by 
the SWM strategy baseline standard deviation.  The SWM strategy mean 
baseline score and the SWM strategy baseline standard deviation are 
calculated using patients in both treatment groups (ie, Praluent and placebo). 
− The SWM strategy z-score at baseline is defined for each patient in the same 
manner as the calculation for the SWM strategy z-score at week 96, replacing 
the patient’s week 96 raw score with the patient’s baseline raw score. 
• SWM strategy raw score change from baseline is defined for each patient as: week 
96 SWM strategy raw score minus the patient’s SWM strategy baseline score.  
The SWM strategy raw score change from baseline is provided descriptively for 
clinical interpretation of function at week 96.  Lower change from baseline raw 
scores reflect better SWM performance (ie, less impairment). 
The baseline SWM strategy score is the last score obtained before the first dose of study 
treatment. The SWM Strategy score at week 96 is the score obtained within the week 96 
analysis window and during the treatment-emergent adverse event (TEAE) period. The 
TEAE period is defined as the time from the first double-blind study treatment injection up to 
70 days after the last double-blind study treatment injection. The analysis window used to 
allocate a time point to a measurement is defined in Appendix 10.2 of this SAP. 
4.6.2. 
Exploratory Neurocognitive Endpoint 
Exploratory neurocognitive outcome measures to further assess neurocognitive function in 
the CANTAB domains are provided below for each patient: 
• Paired Associates Learning (PAL) at week 96 defined as both a PAL z-score 
change from baseline and PAL raw score change from baseline, following the 
definitions and rules provided for the primary neurocognitive endpoint 
• Reaction Time (RTI) at week 96 defined as both a RTI z-score change from 
baseline and RTI raw score change from baseline, following the definitions and 
rules provided for the primary neurocognitive endpoint 
• SWM between-errors score (SWMBE) at week 96 defined as both an SWM 
between-errors z-score change from baseline and SWM between-errors raw score 
change from baseline, following the definitions and rules provided for the primary 
neurocognitive endpoint 
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• Global Composite score at week 96 change from baseline is defined as (the 
average of the following 4 measures at week 96: SWM strategy z-score, PAL 
z-score, RTI z-score, and the SWM between-errors z-score) minus the average of 
the same 4 z-score measures at baseline  
4.6.3. 
Secondary Efficacy Variable 
The secondary efficacy endpoints are provided below. For those efficacy endpoints described 
as percent change from baseline at a given visit, the definition is: 100 multiplied 
(post-baseline visit measurement – baseline measurement) divided by the baseline 
measurement. 
The baseline measurements are the last values obtained before the first dose of study 
treatment. 
The secondary efficacy endpoint at a given visit is the measurement obtained within the 
analysis window of the visit and during the main efficacy period. The main efficacy period is 
defined as the time from the first double-blind study treatment injection up to the upper limit 
of the week 96 analysis window. 
All secondary efficacy endpoints (scheduled or unscheduled) may be used to provide a value 
for the efficacy endpoint, if appropriate, according to above definition. 
• The percent change in calculated LDL-C, apolipoprotein (Apo) B, 
non-high-density lipoprotein cholesterol (non-HDL-C), and Total-C from baseline 
to weeks 12, 24, 48, 72, and 96 
• The percent change in lipoprotein a [Lp(a)], HDL-C, triglyceride (TG), and Apo 
A-1 from baseline to weeks 12, 24, 48, 72, and 96 
• The proportion of patients reaching LDL-C <70 mg/dL (1.81 mmol/L) at weeks 
12, 24, 48, 72 and 96 
• The proportion of patients reaching LDL-C <50 mg/dL (1.29 mmol/L) at weeks 
12, 24, 48, 72, and 96 
4.7. 
Safety Variables 
Patient safety will be assessed through the collection of reported adverse events (AEs), 
clinical laboratory data, and vital signs. Unless otherwise noted, the baseline value is defined 
as the last available value before the first dose 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: 
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• The PRE-TREATMENT period: defined as the time from the signed informed 
consent up to the first study treatment injection. 
• The treatment-emergent adverse event (TEAE) period: defined as the time from 
the first study treatment injection up to the day of the last study treatment injection 
+ 70 days (10 weeks), as residual effect of Praluent is expected until 10 weeks 
after last dose of study treatment. 
The TEAE period will include: 
− The TREATMENT period is defined as the time from the first study treatment 
injection up to the day of last 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.  
− The RESIDUAL TREATMENT period is defined as the time from the day of 
last study treatment injection + 22 days up to the day of last study treatment 
injection + 70 days (10 weeks). 
• The POST-TREATMENT period: defined as starting the day after the end of the 
TEAE periods (i.e., 71 days after the last study treatment injection) 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. 
• Treatment-emergent adverse events (TEAEs) are AEs that developed or worsened 
or became serious during the TEAE period.  
• Post-treatment AEs are AEs that developed or worsened or became serious during 
the post-treatment period. 
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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 preferred terms linked to local injection site reactions (i.e. preferred 
terms containing “injection site” or “infusion site”) 
• 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: 
− 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 (FDA CMQ) (see Appendix 10.5, Table 4 for the 
list of terms) 
• Cataract using HLT “Cataract conditions” 
• New onset of diabetes (NOD) will be assessed in patients without diabètes at 
baseline: 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 in Appendix 10.4, Table 7) 
and/or 
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− 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 
Analyses of NOD events will also be provided using the tick box on the e-CRF AE page as 
an exploratory approach in patients without Diabètes at baseline. 
In addition, the following grouping of events will be provided: 
• Hepatic disorder events using SMQ “Hepatic disorder” 
• Diabetes mellitus or diabetic complications using 1/ the HLGT “diabetes 
complications” (including PTs pertaining to the secondary SOC included in the 
HLGT),2/ the HLT “diabetes mellitus”, 3/ the HLT “carbohydrate tolerance 
analyses (incl diabetes)” excluding PTs “blood glucose decreased” and 
“Glycosylated haemoglobin decreased” and 4/ from the HLT "Hyperglyceamic 
conditions NEC" only the following PTs “hyperglycaemia”, “Hyperglycaemic 
unconsciousness” and “Hyperglycaemic seizure”  
Neurocognitive Events of Special Interest 
Neurocognitive events are defined in this study as AESI, specifically, neurocognitive AEs 
(serious or nonserious) required to be monitored, documented, and managed in a 
pre-specified manner as described in this protocol. The neurocognitive events will be 
adjudicated by the neurocognitive events review committee which is composed of experts in 
the field of cognition, independent from the sponsor and the investigators. This committee 
will be responsible for defining, validating, and classifying (in a blinded fashion) AEs of 
interest possibly related to cognition impairment. A charter and an operational manual will 
specify the procedures and criteria used for review of these events.  
The committee will adjudicate whether a neurocognitive event identified by investigator or 
the CMQs is indeed a neurocognitive event (Yes/No). 
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The committee will also adjudicate whether possible etiology of the neurocognitive event is 
identified. 
• Yes: means that there is a clear alternative explanation for the neurocognitive 
event. 
• No: means that there is no clear alternative explanation for the neurocognitive 
event, and it might be study related. 
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 TEAE period, 
• Death post-treatment:  deaths occurring during the post-treatment period. 
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 
the protocol scheduled visits, and visits will be assigned to the Analysis Windows 
(See Appendix 10.2). The laboratory parameters (excluding those considered as efficacy 
parameters) will be classified as follows: 
• Hematology: 
− Red blood cells and platelets:  hemoglobin, hematocrit, erythrocytes count, 
platelets count, reticulocyte count, ery. mean corpuscular Hemoglobin (MCH), 
ery. mean corpuscular HGB concentration (MCHC), ery. mean corpuscular 
volume (MCV) 
− White blood cells: white blood cell count, neutrophils, lymphocytes, 
monocytes, basophils, eosinophils 
• Clinical chemistry: 
− Metabolism:  glucose, total protein, albumin, creatine phosphokinase 
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− Electrolytes:  sodium, potassium, chloride, calcium, phosphorus, bicarbonate 
− Renal function:  creatinine, creatinine clearance, blood urea nitrogen (BUN), 
uric acid 
− Liver function:  alanine Aminotransferase (ALT), aspartate aminotransferases 
(AST), alkaline phosphatase (ALP), GGT, bilirubin, LDH 
• Hepatitis screen:  anti-hepatitis-C antibody and hepatitis B surface antigen 
collected at week -3 and week 96. 
4.7.3. 
Vital Sign Variables 
Vital signs parameters will include height (cm), weight (kg), heart rate (bpm), systolic and 
diastolic blood pressure (mmHg) after resting at least five minutes. Both actual test values 
and “change from baseline” values (defined as the post-baseline value minus the baseline 
value) will be provided for protocol specified visits and visits will be assigned to the Analysis 
Windows (See Appendix 10.2). Potentially clinically significant Abnormalities (PCSA) 
ranges will be applied to the vital sign parameter values as applicable (see Appendix 10.3 for 
PCSA definitions).  
4.8. 
Other Variables 
Other assessment endpoints are listed and defined below. Protocol schedule visits will be 
assigned to the Analysis Windows (See Appendix 10.2).   
• The percent change in hs-CRP from baseline to protocol specified visits. 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 infection(1). PCSA (potentially 
clinically significant abnormalities) criteria for hs-CRP are listed in 
Appendix 10.3. 
• The absolute change in HbA1c (%) from baseline to protocol specified visits.  
PCSA criteria for HbA1c are listed in Appendix 10.3. 
• The proportion of patients with two consecutives results, separated by at least 21 
days, of calculated LDL-C <25 mg/dL (<0.65 mmol/L) (and again for calculated 
LDL-C <15 mg/dL [< 0.39 mmol/L]) during the treatment period. 
• The proportion of patients with at least one result of calculated LDL-C <25 mg/dL 
(<0.65 mmol/L) (and again for calculated LDL-C <15 mg/dL [< 0.39 mmol/L]) 
during the treatment period. 
• For the patients with two consecutive results as described above, the time to the 
first calculated LDL-C <25 mg/dL (<0.65 mmol/L) (and again for calculated 
LDL-C <15 mg/dL [< 0.39 mmol/L]) during the treatment period. 
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• Gonadal hormone levels (for female patients - estradiol, follicle-stimulating 
hormone (FSH) and luteinizing hormone (LH); for male patients - testosterone, 
FSH and LH) 
4.9. 
Anti-Drug Antibody Variables 
Anti-drug (Praluent) antibody (ADA) are assessed at baseline (before the first study treatment 
injection), at weeks 48 and 96. ADA measurements will be assigned to the analysis windows 
as defined in Appendix 10.2. As appropriate, patient frequencies and percentages will be 
depicted, and the percentages will be calculated based on the ADA population. 
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: 
− 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 
 
 
  
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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 safety population.  Parameters described in Section 4.1 will be 
summarized for the safety population, the primary safety population in the case of a 10% 
difference (in any treatment group) from the number of safety population, and again for the 
ITT population in the case of a 10% difference (in any treatment group) from the number of 
safety population.  
Continuous data will be summarized using the number of patients with data, mean, SD, 
median, minimum and maximum for each treatment group. First quartile (Q1) and third 
quartile (Q3) will be also provided for baseline lipid parameters, HbA1c 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 Chi-squaretest 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. 
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 safety population. 
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: 
• 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), 
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• 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. 
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.   
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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 treatment 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, non-statin 
LMT, CV), by decreasing frequency of the Praluent 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, 
non-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.  
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, or other statins, 
• LMT other than statin only, 
• no LMT.    
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), or other statins, 
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• non-statin LMT only, 
• no LMT.    
5.4. 
Patient Disposition 
Patient disposition includes the description of patient status at major milestone decisions in 
the study, as well as the patient analysis populations. 
Patient study status 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.  
5.5. 
Extent of Study Treatment Exposure and Compliance 
The extent of study treatment exposure and study compliance parameters for the treatment 
period described in Section 4.5 will be assessed and summarized by treatment group, for 
patients in the safety population.  
5.5.1. 
Exposure to Investigational Product 
Study treatment exposure for the treatment period will be descriptively summarized for the 
treatment duration and total number of injections as described in Section 4.5. Treatment 
duration will be summarized using the number of patients with data, mean, SD, median, 
minimum and maximum. Categorized 4-week intervals of treatment duration will be 
summarized descriptively by counts and percentages. 
The incidence of premature study treatment discontinuation (irrespective of the reason) and 
premature treatment discontinuation due to AEs will be presented graphically by treatment 
group in the safety population using the Kaplan-Meier method. 
Patient Up-titration 
The number and percentage of patients with an up-titration in the Praluent group will be 
described.  Patients with an up-titration are defined as up-titrated according to IVRS/IWRS 
Week 12 transaction with at least one injection of alirocumab 150 mg following the 
up-titration decision. 
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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 important deviations 
(counts of deviations), patients (incurring a deviation by count and percentage), and by type 
of important deviation (patient count and percentage).  A patient listing of all major and 
minor protocol deviations will be provided. 
5.6. 
Analyses of Primary and Secondary Endpoints 
5.6.1. 
Analyses of Primary Neurocognitive Variable 
The primary neurocognitive analysis is a statistical evaluation of the noninferiority of the 
Praluent 75 mg Q2W/up-titrate 150 mg Q2W dose regimen to placebo for the primary 
endpoint of change in SWM strategy z-score from baseline to week 96 in the primary safety 
population.  The 2-sided 95% CI for the mean treatment difference at week 96 will be 
determined using an appropriate contrast statement in a mixed-effect model with repeated 
measures (MMRM).  The upper CI limit will be compared to the noninferiority margin which 
is defined as 0.2 and the noninferiority will be declared if the upper CI limit is below the 
noninferiority margin.  
In the case noninferiority is achieved for the primary neurocognitive function endpoint 
comparison, superiority of the primary neurocognitive function endpoint will be assessed 
using the same upper CI limit calculated for the primary comparison.  Specifically, the upper 
CI limit will be compared to zero and superiority will be declared if the upper CI limit is 
below zero.  A statistical multiplicity adjustment is not needed, since this process of 
noninferiority achievement followed by superiority assessment using the same 95% upper CI 
limit on the primary endpoint corresponds to a simple closed test procedure 
(EMA/CPMP/EWP/482/99 – 27July 2000). 
The MMRM model will include the fixed categorical effects of treatment group (placebo, 
Praluent), both randomization strata (as per IVRS/IWRS), time point (weeks 24, 48, 72, and 
96), treatment-by-time point interaction, and strata-by-time point interaction, as well as the 
continuous covariate of baseline SWM strategy raw score value and baseline value-by-time 
point interaction.  Post-baseline assessments within a patient’s TEAE period will be included 
in the analysis and missing data are accounted for by the MMRM model.  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.  
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This model will provide baseline adjusted least-squares means estimates at week 96 for both 
treatment groups with their corresponding standard errors. 
To support the clinical interpretation of the primary neurocognitive analysis, the SWM 
strategy raw score change from baseline to week 96 in the primary safety population will also 
be provided using the MMRM analysis method described above (at least includes least 
squares mean and 95% CI).  
Model Assumption Checks 
Homogeneity of treatment effect across baseline SWM strategy z-score 
In order to check the homogeneity of treatment effect versus baseline SWM strategy z-score, 
the following interaction terms will be added in the primary MMRM model: 
• Treatment group * baseline SWM strategy z-score  
• Treatment group * time-point * baseline SWM strategy z-score 
Within the framework of this model with interaction terms, a graph presenting the LS means 
difference versus placebo at week 96 and the corresponding 95% CI will be provided by 
baseline SWM strategy z-score 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 (Praluent, placebo) 
− time point (weeks 24, 48, 72, and 96) 
− treatment-by-time point interaction 
− randomization strata 
− randomization strata-by-time point interaction. 
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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 analysis with 
regards to handling of missing data (3).  
Visual examination: 
• In order to explore the missing data pattern, post-baseline SWM strategy z-score 
observations during the TEAE period (in the primary safety population) will be 
described according to the following groups:  
− SWM strategy z-score available at week 96 (i.e. primary endpoint available), 
− SWM strategy z-score available at week 72 but missing at week 96, 
− SWM strategy z-score available at week 48 but missing from week 72, 
− SWM strategy z-score available at week 24 but missing from week 48, 
− SWM strategy z-score missing from week 24. 
A graph of mean SWM strategy z-score (respectively change from baseline in SWM strategy 
z-score) ± SE at baseline, and weeks 8, 12, 24, 48, 72, and week 96 will be provided by 
missing data pattern, for each treatment group. 
• In the primary safety population, demographic and baseline characteristics will be 
described within the missing data pattern number 1 versus the pooled others. P-
values from Chi-square 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 10.5 for 
more details) will be used to address missing values, in the primary safety 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 primary safety population will be imputed 100 times to generate 100 
complete data sets, using the MI SAS procedure (using Markov Chain Monte Carlo). The 
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percent change from baseline at week 96 will be then derived from observed and imputed 
SWM strategy z-score 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 SWM strategy z-score 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 neurocognitive endpoint analysis will be conducted using the pattern mixture model 
approach as described below (see Appendix 10.6 for more details). 
In the pattern-mixture model approach, different imputation strategies will be applied to the 
primary neurocognitive endpoint (i.e. CANTAB cognitive domain SWM strategy z-score 
change from baseline to Week 96) values missing during TEAE period (i.e. within the time 
period from the first double-blind IMP injection up to the day of the last double-blind 
injection +70 days) in contrast to those missing after the TEAE period. Presented below are 
the reasons for considering differences in the impact of alirocumab dependent on the timing 
of the last study treatment administration: 
• Patients who discontinued study treatment due to adjudicated neurocognitive 
events but are still within the TEAE period would continue to show impact from 
treatment similar to that observed for other patients who also had adjudicated 
neurocognitive events.  
      Note: The neurocognitive events recorded on the AE eCRF by the investigator are 
defined below, by any of the following programmatical procedures: 
− Sponsor neurocognitive events CMQ; 
− FDA neurocognitive events CMQ; 
− Investigator identified NC events, as entered in the eCRF.   
• Patients who discontinued study treatment due to reasons other than adjudicated 
neurocognitive events but are still within the TEAE period would continue to 
show impact from treatment similar to that observed for patients without any 
adjudicated neurocognitive events.  
• Patients who discontinued study treatment (alirocumab or placebo) but are after 
the TEAE period would no longer be impacted by study treatment, and thus would 
have SWMS values similar to patients receiving placebo. 
Missing data from the primary safety population will be imputed 100 times to generate 100 
complete data sets, using the approach described above.  The 100 completed datasets of 
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observed and imputed LDL-C data will be used for primary neurocognitive endpoint 
analyses.  
The 100 complete datasets of observed and imputed SWMS data at week 96 will be analyzed 
using an ANCOVA model with treatment group and randomization strata as fixed effect, and 
the baseline SWMS 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. 
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 96 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 96 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 age group (<65, ≥65) per IVRS, 
• The statin use strata per IVRS (no statin, low lipophilicity of the concomitant 
statin, high lipophilicity of the concomitant statin), 
• Gender (Female, Male) 
5.6.2. 
Analyses of Exploratory Neurocognitive Variables 
To further understand the effects of Praluent on cognitive function and support the primary 
neurocognitive analysis, the 3 domain endpoints (specifically PAL, RTI, and SWM between 
error scores) and the Global Composite score will also be evaluated for noninferiority at week 
96 in the primary safety population.  These 4 measures will not be evaluated for superiority.  
The analysis method (MMRM) and noninferiority evaluation approach (evaluation of the 
95% CI for the mean treatment difference at week 96) described for the primary 
neurocognitive analysis will also be used for the 3 domain’s z-scores change from baseline 
and the Global Composite score change from baseline.  To support the clinical interpretation 
of the 3 domains, the raw score change from baseline to week 96 in the primary safety 
population will also be provided using the MMRM analysis method. 
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The 4 domain endpoint scores (including the primary neurocognitive endpoint) and the 
Global Composite scores will be summarized by time point (weeks 24, 48, 72, and 96) for the 
primary safety population as described below: 
• For the 4 domain’s z-score: 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 5.6.1) and with z-score values, changes from baseline in 
the model as appropriate.  
• For the 4 domain’s raw score and the Global Composite score: 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 5.6.1) and with 
raw score values, changes from baseline in the model as appropriate. 
The 4 domain endpoint scores (including the primary neurocognitive endpoint) and the 
Global Composite scores will also be summarized descriptively by time point. 
Descriptive statistics by time point for the SWM Strategy z-score and raw score will be 
provided for patients with 2 consecutive LDL-C < 25 mg/dL results separated by at least 21 
days, or with 2 consecutive LDL-C < 15 mg/dL results separated by at least 21 days, if 
applicable (i.e., with enough patients). 
5.6.3. 
Analyses of Secondary Efficacy Variables 
For secondary efficacy endpoints of lipids (defined in Section 4.6.3), descriptive summaries 
and analyses will be performed in the ITT population (for ITT analysis) and the mITT 
population (for on-treatment analysis). P-values for the testing of study treatment effect will 
be provided for descriptive purposes only (nominal p-values). 
For descriptive summaries, percent change from baseline in calculated LDL-C, Total-C, 
HDL-C, TG, non-HDL-C, Apo B, Apo A-1, and Lp(a) 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.  The time profile of each parameter will be plotted by treatment group with the 
corresponding standard errors. For TG and Lp(a), summary statistics will include Q1 and Q3. 
Multiple types of measurements are planned to be analyzed during the trial, specifically 
continuous measurements expected to have a normal distribution (eg, percent change in 
calculated LDL-C), continuous measurements expected to have a non-normal distribution 
(eg, TG), and binary measurements (eg, proportion of patients reaching LDL-C <70 mg/dL). 
5.6.3.1. 
Continuous Endpoints Anticipated to Have a Normal Distribution 
Continuous secondary efficacy variables, defined in Section 4.6.3, 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 method as described for the primary neurocognitive 
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endpoint (Section 4.6.1).  Specifically, the model will contain fixed categorical effects of 
treatment group, both randomization strata, planned time points up to week 96 (specific time 
points are weeks 8, 12, 24, 48, 72, and 96), 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.  
5.6.3.2. 
Continuous Endpoints Anticipated to Have a Non-normal Distribution 
Continuous secondary efficacy endpoints, defined in Section 4.6.3, 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 the covariate.  Missing values will be addressed using the same multiple imputation 
approach as described for primary neurocognitive 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 variables in the multiple imputation 
model will at least include the same variables as used in the robust regression model.   
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 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. 
5.6.3.3. 
Binary Endpoint Variables 
Binary secondary efficacy endpoints, defined in Section 4.6.3, will be analyzed in the analysis 
populations using stratified logistic regression (using the strata option of the SAS logistic 
procedure) with treatment group and randomization strata as main effect and corresponding 
baseline value(s) as the covariate.  Missing values will be addressed using the same multiple 
imputation approach as described for primary neurocognitive endpoint (and using the same 
time points in the imputation model as described above for Section 5.6.1.2).  The variables in 
the multiple imputation model will at least include the same variables as used in the robust 
regression model.   
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. 
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In the data dependent case that the logistic regression method is not applicable (eg, the 
response rate is zero in 1 treatment group 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). The LOCF imputation method will 
consist of using the last value obtained up to the applicable time point window (weeks 8, 12, 
24, 48, 72, and 96 as applicable) to impute the missing week value. In case the model would 
not converge with stratification variables, an unstratified exact logistic regression will be 
performed.  
5.6.3.4. 
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,  non-HDL-C, Lp(a), Apo-B, 
Apo-A1 and ratio Apo-B/Apo-A1 (absolute change from baseline) at weeks 8, 12, 24, 48, 72, 
and 96 time points will be summarized by treatment group in both the ITT and mITT 
populations as described 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 5.6.3.1) 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 5.6.3.2) 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.  
5.6.4. 
Adjustment for Multiple Comparisons 
Adjustments to the alpha level for the purposes of multiple testing are not applicable for this 
safety study. The exploratory neurocognitive and secondary efficacy lipid endpoints are 
supportive of the primary analysis and not hypothesis-testing.  Any statistical testing is for 
descriptive purposes only (ie, any p-values provided are nominal). 
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5.7. 
Analysis of Safety Data 
The summary of safety results will be presented by treatment groups (Praluent, placebo) on 
the safety population (Section 3.1). No formal inferential testing will be performed. 
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: 
• Safety data in patients who do not belong to the safety population (i.e., exposed 
but not randomized) will be listed separately. 
• The baseline value is defined as the last available value obtained up to the date 
and time of the first 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 2 in order to 
provide an assessment for week 8 to week 96 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 
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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.  
• For exploratory purposes, specific safety analyses could also be provided 
according to up-titration status, ie, according to whether the patients remained on 
the alirocumab 75 mg Q2W doses or whether they were up titrated to 150 mg 
Q2W. These analyses will be exploratory and descriptive (no formal comparison 
per dose) as it is expected that there could be inherent differences in the baseline 
characteristics between those patients titrating to 150 mg Q2W and those 
remaining on the alirocumab 75 mg Q2W doses. In order to reduce the bias of this 
analysis, the period before the up-titration time point (planned at Week 12) will be 
analyzed separately since only the alirocumab 75 mg Q2W doses are proposed for 
this time period and consequently the early events occurring before Week 12 can 
only be attributed to those doses. Therefore, the descriptive analysis per dose will 
include any safety events occurring from the first injection post Week 12 
IVRS/IWRS transaction to the end of the TEAE period. Baseline characteristics of 
patients receiving each dose will be summarized. 
• 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). 
5.7.1. 
Analysis of Adverse Events  
In general, the primary focus of AE reporting will be on TEAEs.  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 Praluent 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 
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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 
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 Praluent 
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; 
• The event rate per patient-year (the number of patients with an event in question 
divided by total patient-years) will be provided for all TEAEs by SOC and PT.  
For a patient with event, patient year is censored at time of first event; for patient 
without event, it corresponds to length of TEAE period; 
• Kaplan-Meier curves will be provided, when appropriate, for time from first dose 
of study treatment to the first occurrence of selected TEAEs as well as incidence 
rates at 24, 48, 72, and 96 weeks of exposure.  Patients without any event will be 
censored at the end of the TEAE period.  Selected TEAEs could be AESIs (e;g 
neurocognitive events), or TEAE related to any clinically significant signal that 
needs further characterization; 
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• The frequency of selected AEs by SOC and PT over time during the treatment 
period (number of patients experiencing AE and percentage by patient-months) 
will be provided by time intervals defined as:  ≤24 weeks, >24 to ≤48 weeks, >48 
to ≤72 weeks, >72 to ≤96 weeks, using the PROC LIFETEST with the actuarial 
method.  Only the first event will be counted. 
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;  
• The event rate per patient-year will be provided for all serious TEAEs by SOC 
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 Praluent group).  
• Neurocognitive events adjudicated by the neurocognitive events review committee 
will also be summarized by primary SOC and PT. They will also be summarized 
according to the adjudication of possible etiology of the neurocognitive events 
(Yes/No) (Section 4.7.1.2).  
• All TEAEs within diabetes grouping will be analyzed overall and according to the 
diabetic status at baseline (i.e., in patients With and without diabètes 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 study treatment injections received; 
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• Time from first study treatment injection 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.  
Description of symptoms and possible etiologies for General Allergic Reaction TEAE 
reported by investigator (using the tick box), will be presented. 
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 Praluent 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)and LDL-C 
<15 mg/dL [< 0.39 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.   
In addition, the neurocognitive event rate in patients with 2 consecutive results separated by 
at least 21 days, and with only 1 such event for calculated LDL-C <25 mg/dL, and calculated 
LDL-C <15 mg/dL, will be assessed. 
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);  
• 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 the safety population. 
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 
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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 
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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. 
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).  
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 vital sign measurements that meet PCSA criteria will be provided 
for the report appendix.  
5.8. 
Analysis of Other Variables 
The summary of other variables will be presented by treatment groups (Praluent, placebo) on 
the safety population. No formal inferential testing will be performed for either period. 
Summaries will be descriptive in nature.  
All measurements, scheduled or unscheduled, fasting or not fasting, will be assigned to 
analysis windows in order to provide an assessment for week 8 to week 96 time points.   
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Hs-CRP and HbA1c parameters (Section 4.8) will be summarized by treatment group for the 
number of patients with data, mean, SD, median, minimum, and maximum (for hs-CRP, Q1 
and Q3 will be also provided) by analysis visit during the treatment period. For HbA1c, 
summaries will also be provided according to diabetes mellitus status at baseline. The time 
profile will be plotted by treatment group for HbA1c showing the means and the 
corresponding SEs, while medians (with Q1-Q3) will be plotted for hs-CRP. Applying the 
PCSA criteria to these variables at any time during the TEAE period, the number of patients 
(and percentages) meeting the criteria will be summarized by treatment group. 
The gonadal hormone parameters (Section 4.8) will be summarized by treatment group for 
the number of patients with data, mean, SD, median, minimum, and maximum by analysis 
visit during the treatment period. For FSH and LH, the summaries will be performed for all 
patients, female patients, and male patients. Estradiol will be summarized for female patients 
only, and testosterone will be summarized for male patients only. Summary tables will also 
be provided for gonadal hormone parameters based on measurements outside the central 
laboratory normal ranges, if applicable. 
In order to minimize confounding factors with menopause or exogenous estrogens, the 
summaries of estradiol, FSH, and LH for female patients will be repeated by excluding 
patients who were receiving hormone replacement therapy, were ≥50 years, or had FSH 
levels ≥25 IU/L at baseline. 
For male patients, the summaries of testosterone, FSH, and LH will be repeated by excluding 
patients who were receiving testosterone supplementation or had LH levels ≥15 IU/L at 
baseline. 
Binary endpoints defined in Section 4.8 will be described through patient counts and 
percentages.  Kaplan-Meier curves will be provided for the variables assessing time to first 
occurrence of an event (i.e., calculated LDL-C related outcome).  Patients not meeting the 
event will be censored at the end of the treatment period.  For the analysis of the time to the 
first of the two consecutive LDL-C events, patients without post-baseline LDL-C result or 
with only one post-baseline LDL-C result will not be included in the analysis. 
5.9. 
Analysis of Anti-Drug Antibody Variables 
The summary of ADA variables will be presented by treatment groups (Praluent, placebo) on 
the ADA population. No formal inferential testing will be performed. 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  
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• 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 
• Time to onset of treatment-emergent ADA positive response using descriptive 
statistics. 
• Number (%) of patients with at least 1 neutralizing ADA. 
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). 
 
 
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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 study treatment. For patients 
randomized but not-treated, the baseline will be the last available measurement before 
randomization.  
6.2. 
Data Handling Conventions for Primary and Secondary 
Endpoints 
Data handling conventions, including addressing missing data, is addressed for the primary 
and secondary endpoints in Section 5.6.1, 5.6.2, and 5.6.3. 
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 study treatment administration or time of 
assessment at week 0 visit is missing 
If the time of the first 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 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 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 (week 96 visit for completer, early end of 
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. 
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. 
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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. 
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 
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schedule provided in the protocol.  Data analyzed by time point (including efficacy, 
laboratory safety data, vital signs, physical examinations, 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, physical examinations, and ADA, 
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  
There are no interim analyses planned. Therefore, no multiplicity adjustment for multiple 
analyses is needed (see Section 5.6.4). 
The statistical analysis will be conducted at the end of the study and will consist of the final 
analysis of primary and secondary endpoints and final safety analysis. 
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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. Robert J. Frerichs ∗, Holly A. Tuokko A comparison of methods for measuring 
cognitive change in older adults. Archives of Clinical Neuropsychology 20 (2005) 
321–333. doi:10.1016/j.acn.2004.08.002 
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10. 
APPENDIX 
10.1. 
Summary of Statistical Analyses 
Primary Neurocognitive Endpoint Analysis: 
 
Analysis 
Statistical 
Supportive 
Subgroup 
Other 
Endpoint 
Populations 
Method 
Analysis 
Analysis 
Analyses 
Change from 
baseline to week 
96 in SWM 
strategy z-score  
Primary 
Safety 
Population 
MMRM 
Yes, 
including 
handling of 
missing data 
Yes 
1) Actual 
stratification factor 
2) Multiple 
Imputations + 
ANCOVA 
3) 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 2: 
Analysis Windows Definition – All Endpoints Except Lipids or Vital 
Signs 
Time point 
Targeted study day 
Analysis window in study days 
Week 24 
169 
85 to 252 
Week 48 
337 
253 to 420 
Week 72 
505 
421 to 588 
Week 96 
673 
589 to 756 
Study days are calculated from the day of first IMP injection, the day of first IMP injection being Day 1. For randomized but 
not treated patients, Day 1 is the day of randomization.  
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Table 3: 
Analysis Windows Definition – Lipids 
Time point 
Targeted study day 
Analysis window in study days 
Week 8 
57 
29 to 70 
Week 12 
85 
71 to 126 
Week 24 
169 
127 to 252 
Week 48 
337 
253 to 420 
Week 72 
505 
421 to 588 
Week 96 
673 
589 to 756 
Study days are calculated from the day of first IMP injection, the day of first IMP injection being Day 1. For randomized but 
not treated patients, Day 1 is the day of randomization.  
Table 4: 
Analysis Windows Definition – Vital Signs 
Time point 
Targeted study day 
Analysis window in study days 
Week 8 
57 
29 to 70 
Week 12 
85 
71 to 126 
Week 24 
169 
127 to 210 
Week 36 
253 
211 to 294 
Week 48 
337 
295 to 378 
Week 60 
421 
379 to 462 
Week 72 
505 
463 to 546 
Week 84 
589 
547 to 630 
Week 96 
673 
631 to 714 
Study days are calculated from the day of first IMP injection, the day of first IMP injection being Day 1. For randomized but 
not treated patients, Day 1 is the day of randomization.  
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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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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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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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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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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. 
 
 
10.4. 
List of MedDRA terms for CMQs 
Table 5: 
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 
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MedDRA Term Label 
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 
Table 6: 
CMQ “Neurocognitive disorders – FDA’s recommendation” 
MedDRA level 
MedDRA Term Label 
PTCD 
Amnesia 
PTCD 
Amnestic disorder 
PTCD 
Anterograde Amnesia 
PTCD 
 Neuropsychiatric symptoms 
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 
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MedDRA level 
MedDRA Term Label 
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 
PTCD 
Vascular Dementia 
Table 7: 
CMQ “Type 1 or Type 2 diabetes” 
MedDRA Term Label 
Preferred Term Code 
Diabetes mellitus 
10012601 
Diabetes mellitus inadequate control 
10012607 
Insulin resistant diabetes 
10022491 
Diabetes mellitus malnutrition-related 
10050197 
Diabetes mellitus management 
10051599 
Insulin-requiring type 2 diabetes mellitus 
10053247 
 
Type 1 diabetes mellitus 
10067584 
Type 2 diabetes mellitus 
10067585 
Fulminant type 1 diabetes mellitus 
10072628 
10.5. 
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 endpoint as well as the analysis of the secondary 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. 
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• 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 96. 
The imputation model for step 2 will include the same variables as in step 1 with the following 
additional variables: 
• the randomization strata (age and statin use 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. 
10.6. 
Detailed Description of the Pattern Mixture Model 
As a sensitivity analysis of the primary neurocognitive endpoint (i.e. CANTAB cognitive domain 
SWM strategy z-score change from baseline to Week 96), a pattern-mixture model approach will 
be used to explore missing data patterns. Specifically, a different imputation strategy is planned 
for missing SWMS values during the TEAE period (i.e. within the time period from the first 
double-blind IMP injection up to the day of the last double-blind injection +70 days) in contrast 
to those missing after the TEAE period.  Presented below are the reasons for considering 
differences in the impact of alirocumab dependent on the timing of the last study treatment 
administration:  
• Patients who discontinued study treatment due to adjudicated neurocognitive events 
but are still within the TEAE period would continue to show impact from treatment 
similar to that observed for other patients who also had adjudicated neurocognitive 
events.  
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Note: The neurocognitive events recorded on the AE eCRF by the investigator are 
defined below, by any of the following programmatical procedures: 
− Sponsor neurocognitive events CMQ; 
− FDA neurocognitive events CMQ; 
− Investigator identified NC events, as entered in the eCRF. 
• Patients who discontinued study treatment due to reasons other than adjudicated 
neurocognitive events but are still within the TEAE period would continue to show 
impact from treatment similar to that observed for patients without any adjudicated 
neurocognitive events.  
• Patients who discontinued study treatment (alirocumab or placebo) but are after the 
TEAE period would no longer be impacted by study treatment, and thus would have 
SWMS values similar to patients receiving placebo. 
In addition, SWMS data missing prior to last study treatment administration (i.e., intermittent 
missing) are considered “Missing At Random”. 
Missing SWMS values from the primary safety population will be imputed 100 times to generate 
100 complete data sets. The change from baseline to Week 96 will be derived from observed and 
imputed SWMS 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 SWMS 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. 
Imputation Strategy 1: Missing data during the TEAE period for patients who 
discontinued study treatment due to adjudicated neurocognitive events 
The imputation strategy for missing SWMS values following discontinuation of study treatment 
due to adjudicated neurocognitive events but still within the TEAE period, is to impute by 
patients who had at least one adjudicated neurocognitive event during the TEAE period. 
Specifically, data collected during the TEAE period for patients who had at least one adjudicated 
neurocognitive event during the TEAE period will be used to impute missing data.  
For each patient, missing SWMS values will be imputed 100 times, using a random draw from a 
normal distribution, with mean equal to the mean of the observed SWMS values, and variance 
equal to the conditional variance of observed SWMS values given the baseline value, at the 
specific time-point from patients in the same treatment group who had adjudicated 
neurocognitive events during the TEAE period. 
Let Y0 and Y1 denote the SWMS 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: 
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)
1(
)
(
2
2
1
0
0
1


−
=
= y
Y
Y
Var
 
Where 
2
1
 denotes the variance of Y1 and ρ the coefficient of correlation between Y0 and Y1. 
During the random generation process, a minimum value of 4 and a maximum of 28 will also be 
applied in order to avoid imputed SWMS values out of range.  
Imputation Strategy 2: Imputation of missing data during the TEAE period for patients 
who discontinued study treatment due to reasons other than adjudicated neurocognitive 
events 
The imputation strategy for missing SWMS values following discontinuation of study treatment 
due to reasons other than adjudicated neurocognitive event, but still within the TEAE period, is 
to impute by patients who did not have any adjudicated neurocognitive events during the TEAE 
period. Specifically, data collected during the TEAE period for patients who did not have any 
adjudicated neurocognitive events during the TEAE period will be used to impute missing data.  
For each patient, missing SWMS values will be imputed 100 times, using a random draw from a 
normal distribution, with mean equal to the mean of the observed SWMS values, and variance 
equal to the conditional variance of observed SWMS values given the baseline value, at the 
specific time-point from patients in the same treatment group who did not have any adjudicated 
neurocognitive events during the TEAE period. 
Let Y0 and Y1 denote the SWMS 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
 
Where 
2
1
 denotes the variance of Y1 and ρ the coefficient of correlation between Y0 and Y1. 
During the random generation process, a minimum value of 4 and a maximum of 28 will also be 
applied in order to avoid imputed SWMS values out of range.  
 
Imputation of missing data after the TEAE period 
The imputation strategy for missing SWMS values following discontinuation of study treatment, 
and after the TEAE period, is to impute by patients who are in the placebo treatment group. 
Specifically, all data collected (whether during TEAE period or after TEAE period) for patients 
who are in the placebo treatment group will be used to impute missing data. 
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For each patient, missing SWMS values will be imputed 100 times, using a random draw from a 
normal distribution, with mean equal to the mean of the observed SWMS values , and variance 
equal to the conditional variance of observed SWMS values given the baseline value, at the 
specific time-point from patients in the placebo treatment group. 
Let Y0 and Y1 denote the SWMS 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
 
Where 
2
1
 denotes the variance of Y1 and ρ the coefficient of correlation between Y0 and Y1. 
During the random generation process, a minimum value of 4 and a maximum of 28 will also be 
applied in order to avoid imputed SWMS values out of range. 
 
                                        VV-RIM-00109809-1.0 Approved - 08 May 2020 GMT-5:00


Signature Page for VV-RIM-00109809 v1.0
Signature Page for VV-RIM-00109809 v1.0 Approved
ESig Approval
ESig Approval
ESig Approval
ESig Approval
ESig Approval
                                        VV-RIM-00109809-1.0 Approved - 08 May 2020 GMT-5:00