Clinical trial NCT02715726
Conditions: Hypercholesterolemia
Sponsor: Sanofi
Start date: 2016-07-27; Completion date: 2018-08-06
Enrollment: 615 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

To demonstrate the reduction of low-density lipoprotein cholesterol (LDL-C) by alirocumab as add-on therapy to stable maximally tolerated daily statin therapy in comparison to ezetimibe 10 mg daily after 24 weeks of treatment in Asia in participants with hypercholesterolemia at high cardiovascular (CV) risk.

Secondary Objectives:

* To evaluate the effect of alirocumab 75 mg in comparison with ezetimibe 10 mg on LDL-C after 12 weeks of treatment.
* To evaluate the effect of alirocumab on other lipid parameters: e.g., apolipoprotein B (Apo B), non-high density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), lipoprotein a (Lp\[a\]), HDL-C, triglycerides (TG), apolipoprotein A-1 (Apo A-1).
* To evaluate the safety and tolerability of alirocumab.
* To evaluate the development of anti-alirocumab antibodies.
* To evaluate the pharmacokinetics (PK) of alirocumab.

Detailed description:
The maximum study duration was 35 weeks per participant, which included a screening period of up to 3 weeks, a 24-week randomized treatment period, and an 8-week post-treatment follow-up period.

Arms: arm 1: Oral ezetimibe 10 mg capsule once daily with or without food for 24 weeks and subcutaneous placebo injection for alirocumab every 2 weeks (Q2W) for 22 weeks added to lipid modifying therapy (LMT). arm 2: Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe once daily with or without food added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C level was \>=70 milligrams per deciliter (mg/dL) (1.81 millimoles per liter \[mmol/L\]) at Week 8.
Interventions: intervention 1: Alirocumab intervention 2: Placebo for alirocumab intervention 3: ezetimibe intervention 4: placebo for ezetimibe intervention 5: atorvastatin intervention 6: rosuvastatin intervention 7: simvastatin
Intervention descriptions: intervention 1: Pharmaceutical form:solution Route of administration: subcutaneous intervention 2: Pharmaceutical form:solution Route of administration: subcutaneous intervention 3: Pharmaceutical form:capsule Route of administration: oral intervention 4: Pharmaceutical form:capsule Route of administration: oral intervention 5: Pharmaceutical form:tablet Route of administration: oral intervention 6: Pharmaceutical form:tablet Route of administration: oral intervention 7: Pharmaceutical form:tablet Route of administration: oral

Protocol documents:
Prot_001.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-003152 VERSION N°2.0 (28-JUN-2013)
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 01 
COMPOUND: alirocumab (SAR236553/REGN727) 
A Randomized, Double-Blind, Parallel Group Study to Evaluate the Efficacy and 
Safety of Alirocumab (SAR236553/REGN727) Versus Ezetimibe in Asia in High 
Cardiovascular Risk Patients with Hypercholesterolemia Not Adequately 
Controlled With Their Statin Therapy 
STUDY NUMBER: EFC13889 
STUDY NAME: ODYSSEY EAST 
VERSION DATE / STATUS: 17-Dec-2015 / Approved 
CLINICAL STUDY DIRECTOR: 
 (
) 
Protocol Amendment 01 
Version number: 1 (electronic 1.0) 
Date : 17-Dec-2015 
Clinical Trial Protocol 
Version number: 1 (electronic 1.0) 
Date : 25-Mar-2014 
EudraCT or IND number : UTN U1111-1150-8859 
(electronic 1.0)
NCT02715726


Amended Clinical Trial Protocol 01  
17-Dec-2015 
SAR236553/REGN727-EFC13889 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 2 
NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE  
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
  
Company: 
Address: 
 
 
 
 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
(electronic 
 
 
 
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Amended Clinical Trial Protocol 01  
17-Dec-2015 
SAR236553/REGN727-EFC13889 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 3 
CLINICAL TRIAL SUMMARY 
 
COMPOUND: Alirocumab (SAR236553/REGN727) STUDY No: EFC13889 
TITLE 
A Randomized, Double-Blind, Parallel Group Study to Evaluate the Efficacy 
and Safety of Alirocumab (SAR236553/REGN727) Versus Ezetimibe in Asia 
in High Cardiovascular Risk Patients With Hypercholesterolemia Not 
Adequately Controlled With Their Statin Therapy 
INVESTIGATOR/TRIAL LOCATION 
China, India and other Asia countries; Multi-center 
PHASE OF DEVELOPMENT 
Phase 3 
STUDY OBJECTIVE(S) 
 
Primary objective 
• 
To demonstrate the reduction of low-density lipoprotein cholesterol 
(LDL-C) by alirocumab as add-on therapy to stable maximally 
tolerated daily statin therapy in comparison with ezetimibe 10 mg 
daily after 24 weeks of treatment in Asia in patients with 
hypercholesterolemia at high cardiovascular (CV) risk.  
Key Secondary objective(s)  
• 
To evaluate the effect of alirocumab 75 mg in comparison with 
ezetimibe 10 mg on LDL-C after 12 weeks of treatment 
• 
To evaluate the effect of alirocumab on other lipid parameters: 
eg, Apolipoprotein (Apo) B, non-high-density lipoprotein cholesterol 
(non-HDL-C), total cholesterol (TC), lipoprotein a (Lp[a]), 
high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and 
Apo A-1  
• 
To evaluate the safety and tolerability of alirocumab 
• 
To evaluate the development of anti-alirocumab antibodies 
• 
To evaluate the pharmacokinetics (PK) of alirocumab 
STUDY DESIGN 
This is a randomized, double-blind, double-dummy, unbalanced (2:1, 
alirocumab: ezetimibe), parallel-group, multi-center study.  Randomization will 
be stratified according to prior history of myocardial infarction (MI) or ischemic 
stroke [Yes/No], high-intensity statin treatment (Yes defined as atorvastatin 
40 to 80 mg or rosuvastatin 20 to 40 mg, No for simvastatin whatever the 
dose daily, atorvastatin below 40 mg daily or rosuvastatin below 20 mg daily), 
and Country. 
After randomization, patients will receive double-blind, double-dummy study 
treatment (either alirocumab or ezetimibe) over a period of 24 weeks on top of 
stable maximally tolerated daily statin therapy. A dose up-titration of 
alirocumab from 75 mg to 150 mg may occur at Week 12 for patients 
randomized to alirocumab (see below).   
The study consists of: 
• 
A screening period of up to 3 weeks, including an intermediate visit 
during which the patient or another designated person (such as 
spouse, relative, etc) will be trained to self-inject/inject with 
a placebo for alirocumab. 
• 
A double-blind, double-dummy treatment period of 24 weeks with 
either A or B below: 
(electronic 
 
 
 
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Amended Clinical Trial Protocol 01  
17-Dec-2015 
SAR236553/REGN727-EFC13889 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 4 
A) Alirocumab 75 mg subcutaneous (SC) every 2 weeks (Q2W) + 
Placebo for ezetimibe by mouth (PO) daily.  At Week 12, patients 
will, in a blinded manner, either: 
- 
Continue alirocumab 75mg Q2W + placebo for ezetimibe PO 
daily, if the Week 8 LDL-C is <70 mg/dL (1.81 mmol/L).  
OR 
- 
Dose up-titrate to alirocumab 150 mg Q2W + placebo for 
ezetimibe PO daily, if the Week 8 LDL-C is ≥70 mg/dL 
(1.81 mmol/L).   
Lipid values obtained at Week 8 for the purpose of up-titration will not be 
communicated to investigators to maintain the blind.  The continuation of the 
75 mg dose or dose up-titration to the 150 mg dose will occur automatically 
through Interactive Voice Response System (IVRS) or Interactive Web 
Response System (IWRS) without site or patient awareness. 
OR 
B) Placebo for alirocumab subcutaneous Q2W + ezetimibe 10 mg PO 
daily    
• 
A follow-up period of 8 weeks after the end of double-blind 
treatment period (DBTP) 
The lipid results obtained from specimens collected after randomization will 
be masked to maintain blinding. 
No attempts should be made by the investigator or patient to routinely have 
the patient’s lipid values independently evaluated after randomization until the 
follow up visit. 
Patients should be on a stable diet (National Cholesterol Education Program 
Adult Treatment Panel III (NCEP ATP III) Therapeutic Lifestyle Changes 
(TLC) diet or equivalent) throughout the entire study duration from screening 
to the follow-up visit.  
Daily dose of statin should be stable throughout the whole study duration 
from screening to the follow-up visit.   
Fibrates, other than fenofibrate, are not allowed during the study. 
During the double-blind period, modification to the statin therapy or addition of 
other lipid modifying therapy (LMT) is allowed only under the following 
circumstances: 
• 
Exceptional circumstances (such as muscle symptoms) per the 
Investigator’s judgment 
• 
Patient meets the pre-specified TG alert (TG ≥500 mg/dL 
[5.65 mmol/L]). Lab alerts will be sent.  
STUDY POPULATION  
Main selection criteria 
Main Inclusion Criteria  
I01. 
Patients with hypercholesterolemia and established coronary heart 
disease (CHD) or CHD risk equivalents who are not adequately 
controlled with a maximally tolerated daily dose of statin* at a stable 
dose for at least 4 weeks prior to the screening visit (Week -3). 
*Definition of maximally tolerated dose (any of the following are acceptable):    
- 
Atorvastatin 40 mg to 80 mg daily  
- 
Rosuvastatin 20 mg to 40mg daily 
- 
Simvastatin 40 mg daily 
(electronic 
 
 
 
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Amended Clinical Trial Protocol 01  
17-Dec-2015 
SAR236553/REGN727-EFC13889 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 5 
- 
Patients not able to be on any of the above statin doses should 
be treated with the dose of daily atorvastatin, rosuvastatin or 
simvastatin which is considered appropriate for the patient as 
per the investigator's judgment or concerns. Some examples of 
acceptable reasons for a patient taking a lower statin dose 
include, but are not limited to: adverse effects on higher doses, 
advanced age, low body mass index (BMI), local prescribing 
information, concomitant medications and comorbid conditions 
such as impaired glucose tolerance/impaired fasting glucose. 
The reason(s) will need to be documented in the case report 
form. 
Main Exclusion Criteria 
E01. 
Patients without established CHD or CHD risk equivalents 
E02. 
LDL-C <70 mg/dL (<1.81 mmol/L) at the screening visit (Week -3) in 
patients with history of documented CV disease  
E03. 
LDL-C <100 mg/dL (<2.59 mmol/L) at the screening visit (Week -3) 
in patients without history of documented CV disease 
NOTE – Cardiovascular disease (CVD) is defined as CHD, ischemic stroke or 
peripheral arterial disease (PAD) as described in Section 7.1  
E04. 
Change in statin dose or dose regimen from screening to 
randomization 
E05. 
Currently taking a statin other than atorvastatin, rosuvastatin or 
simvastatin  
E06. 
Atorvastatin, rosuvastatin or simvastatin is not taken daily or not 
taken at a registered dose 
E07. 
Daily doses above atorvastatin 80 mg, rosuvastatin 40 mg or 
simvastatin 40 mg 
E08. 
Use of cholesterol absorption inhibitor (ie, ezetimibe), omega-3 fatty 
acid (at doses ≥1000 mg daily), nicotinic acid, fibrates, bile 
acid-binding sequestrant, or red yeast rice products in the past 
4 weeks prior to screening visit (Week -3) 
E09. 
Fasting serum TG >400 mg/dL (>4.52 mmol/L) at the screening 
period 
Total expected number of patients 
 
 
Expected number of sites 
Approximately 600 randomized patients (400:200, alirocumab:ezetimibe). 
At least 110 patients in total from pre-selected sites will have PK analysis 
during the study, in order to have 60 patients on alirocumab treatment (at 
least 30 Chinese and 24 Indian patients). 
Approximately 69 sites. 
STUDY TREATMENT(s) 
 
Investigational medicinal 
product(s) 
 
Formulation 
Alirocumab  
 
Sterile alirocumab drug product supplied at a concentration of 75 mg/mL 
and/or 150 mg/mL in histidine, pH 6.0, polysorbate 20, and sucrose. 
Route(s) of administration 
Subcutaneous (SC) injection in the abdomen 
Dose regimen 
• 
75 mg Q2W  
OR 
(electronic 
 
 
 
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Amended Clinical Trial Protocol 01  
17-Dec-2015 
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Version number: 1 
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Page 6 
• 
75 mg Q2W up to Week 12 followed by 150 mg Q2W from Week 12 
onwards 
At Week 12, in a blinded manner managed by IVRS/IWRS process, the 
patient will either continue alirocumab 75 mg Q2W if the Week 8 LDL-C is 
<70 mg/dL (1.81 mmol/L) or up-titrate to alirocumab 150 mg Q2W if Week 8 
LDL-C is ≥70 mg/dL (1.81 mmol/L).  
Placebo  
 
Formulation 
Placebo for alirocumab  
• 
Sterile solution consisting of histidine, pH 6.0, polysorbate 20, and 
sucrose 
Route(s) of administration 
SC in the abdomen 
Dose regimen 
N/A 
Investigational medicinal 
product(s) 
 
Formulation 
Ezetimibe 10 mg 
 
ezetimibe 10 mg tablets -over encapsulated 
Route(s) of administration 
PO 
Dose regimen 
10 mg daily 
Placebo 
 
Formulation 
Placebo for ezetimibe 
 
capsules to match ezetimibe 
Route(s) of administration 
PO 
Dose regimen 
N/A 
ENDPOINT(S) 
 
Primary endpoint 
• 
The percent change in calculated LDL-C from baseline to Week 24 
in the intent-to-treat (ITT) population, using all LDL-C values 
regardless of adherence to treatment (ITT estimand) 
Secondary endpoint(s)  
• 
The percent change in calculated LDL-C from baseline to Week 24 
in the modified ITT (mITT) population, using all LDL-C values during 
the efficacy treatment period (on-treatment estimand)   
• 
The percent change in calculated LDL-C from baseline to Week 12 
(ITT and on-treatment estimands) 
• 
The percent change in Apo B from baseline to Week 24 (ITT and 
on-treatment estimands)  
• 
The percent change in non-HDL-C from baseline to Week 24  (ITT 
and on-treatment estimands) 
• 
The percent change in TC from baseline to Week 24 (ITT estimand) 
• 
The percent change in Apo B, non-HDL-C, TC from baseline to 
Week 12 (ITT estimand) 
• 
The proportion of patients reaching calculated LDL-C <70 mg/dL 
(1.81 mmol/L) at Week 24 (ITT and on-treatment estimands) 
• 
The percent change in Lp(a), HDL-C, fasting TG and  Apo A-1 from 
baseline to Week 24 (ITT estimand) 
• 
The percent change in Lp(a), HDL-C, fasting TG and  Apo A-1 from 
baseline to Week 12 (ITT estimand) 
(electronic 
 
 
 
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Amended Clinical Trial Protocol 01  
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Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 7 
Other Secondary Efficacy Endpoints 
• 
The proportion of patients with calculated LDL-C <100 mg/dL 
(2.59 mmol/L) at Week 12 and Week 24 (ITT estimand) 
• 
The proportion of patients reaching calculated LDL-C <70 mg/dL 
(1.81 mmol/L) at Week 12 (ITT estimand) 
• 
The absolute change in calculated LDL-C (mg/dL and mmol/L) from 
baseline to Week 12 and Week 24 (ITT estimand) 
• 
The absolute change in ratio Apo B/Apo A-1 from baseline to 
Week 12 and Week 24 (ITT estimand) 
• 
The proportion of patients with Apo B <80 mg/dL (0.8 g/L) at 
Week 12 and Week 24 (ITT estimand) 
• 
The proportion of patients with non-HDL-C <100 mg/dL 
(2.59 mmol/L) at Week 12 and Week 24 (ITT estimand) 
• 
The proportion of patients with non-HDL-C <130 mg/dL 
(3.37 mmol/L) at Week 12 and Week 24 (ITT estimand) 
• 
The proportion of patients with calculated LDL-C <70 mg/dL 
(1.81 mmol/L) and/or ≥50% reduction from baseline in calculated 
LDL-C (if calculated LDL-C ≥70 mg/dL [1.81 mmol/L]) at Week 12 
and Week 24 (ITT estimand) 
• 
The proportion of patients with ≥50% reduction in calculated LDL-C 
at Week 12 and Week 24 (ITT estimand) 
• 
The absolute change in ratio TC/HDL-C from baseline to Week 12 
and Week 24 (ITT estimand) 
• 
The percent change in TC from baseline to Week 12 and 24 
(on-treatment estimand) 
• 
The percent change in Apo B from baseline to Week 12 
(on-treatment estimand) 
• 
The percent change in non-HDL-C from baseline to Week 12 
(on-treatment estimand) 
• 
The percent change in Lp(a) from baseline to Week 12 and 24 
(on-treatment estimand)   
• 
The proportion of patients reaching calculated LDL-C <100 mg/dL 
(2.59 mmol/L) at Week 24 (on-treatment estimand) 
Safety Endpoints 
• 
Safety parameters (adverse events [AEs]) (including adjudicated 
CV events), laboratory data, vital signs assessed throughout the 
study. 
Other Endpoints 
• 
Anti-alirocumab antibodies assessed throughout the study. 
• 
Serum alirocumab concentration assessed throughout the study. 
• 
The absolute change in glycated Hemoglobin A1c (HbA1c) from 
baseline to Week 12 and 24. 
(electronic 
 
 
 
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Amended Clinical Trial Protocol 01  
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Page 8 
ASSESSMENT SCHEDULE 
Patient assessments in the screening period 
• 
On-site visits: Week -3 (screening visit), Week -1 (injection training 
visit).  
Patient assessments in the double-blind treatment period 
• 
On-site visits: Day 1/Week 0 (randomization visit), Week 4, Week 8, 
Week 12, Week 16, Week 24 (end of treatment visit) 
Patient assessments in the follow-up period 
• 
On-site visit: Week 32 (8 weeks after the end of treatment visit) 
STATISTICAL CONSIDERATIONS 
 
Sample Size Determination 
A total sample size of 96 patients (64 in alirocumab and 32 in ezetimibe arms) 
will have 95% power to detect a difference in mean percent change in LDL-C 
of 20% with a 0.05 two-sided significance level and assuming a common 
standard deviation (SD) of 25% and all these patients having an evaluable 
primary endpoint. 
Nevertheless, to meet registration requirement and provide safety 
documentation in participating countries the final total sample size will be 600 
with a randomization ratio 2:1 (alirocumab: 400, ezetimibe: 200). 
Analysis Population 
Randomized population includes any patients who have been allocated to a 
randomized treatment regardless of whether the treatment kit was used or 
not. 
The primary efficacy analysis population will be the ITT population, defined as 
the randomized population who had an evaluable primary endpoint. The 
primary endpoint will be considered evaluable when both of the following 
conditions are met: 
- 
The baseline calculated LDL-C value is available.  
- 
At least one calculated LDL-C value is available within one of 
analysis window up to Week 24. 
The mITT population is defined as all randomized patients who took at least 
one dose or part of dose of the double-blind investigational medicinal product 
(IMP) (injection or capsule) and had an evaluable primary efficacy endpoint 
during the efficacy treatment period. The primary efficacy endpoint will be 
considered evaluable when both of the following conditions are met: 
• 
The baseline calculated LDL-C value is available  
• 
At least one calculated LDL-C value is available during the efficacy 
treatment period and within one of the analysis windows up to Week 
24. 
The efficacy treatment period will be defined as: 
• 
The time period from the first double-blind IMP (injection or capsule, 
whichever comes first) up to 21 days after the last double-blinded 
IMP injection or the day of last capsule intake + 3 days, whichever 
comes first 
Patients in the ITT and mITT populations will be analyzed according to the 
treatment group allocated by randomization. 
The safety population consists of the randomized population who actually 
received at least one dose or partial dose of IMP (injection or capsule). The 
(electronic 
 
 
 
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Amended Clinical Trial Protocol 01  
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Property of the Sanofi Group - strictly confidential 
Page 9 
safety population will be analyzed according to the treatment actually 
received. 
Primary Analysis 
The percent change in calculated LDL-C from baseline to Week 24 will be 
analyzed in the ITT population using mixed-effect model with repeated 
measures (MMRM) approach to handle missing data. All post-baseline data 
available within Week 4 to Week 24 analysis window will be used 
(on-treatment and off-treatment through Week 24).  
The model will include the fixed categorical effects of treatment group 
(alirocumab versus ezetimibe), time point (Week 4, Week 8, Week 12, 
Week 16, Week 24),randomization strata, treatment-by-time point interaction 
and strata-by time point interaction, as well as, the continuous fixed 
covariates of baseline LDL-C value and baseline value-by-time point 
interaction. Alirocumab will be compared to ezetimibe using appropriate 
contrasts, and the 95% confidence interval (CI) of the difference will be 
provided. 
Analysis of key secondary efficacy endpoints 
A hierarchical procedure will be used to control the type I error and handle 
multiple endpoints. If the primary endpoint analysis is significant at the 5% 
alpha level, key secondary endpoints will be tested sequentially, using the 
order defined in section “Key secondary efficacy endpoints”. 
Continuous secondary endpoints anticipated to have a normal distribution 
(ie, lipids other than Lp[a] and TG), will be analyzed using the same MMRM 
model as for the primary endpoint with the continuous fixed covariates of 
corresponding baseline value and baseline value-by-time point interaction. 
Continuous secondary endpoints anticipated to have a non-normal distribution 
(ie, Lp[a] and TG) will be analyzed using multiple imputation approach for 
handling of missing values followed by robust regression. 
Binary secondary endpoints will be analyzed using multiple imputation 
approach for handling of missing values followed by logistic regression. 
Safety Analysis 
Safety analysis (AE [including adjudicated CV events], laboratory, vital signs 
will be descriptive), based on the safety population. The safety analysis will 
focus on Treatment Emergent Adverse Events (TEAE) period, defined as the 
time from the first double-blind IMP dose to the last dose of double-blind IMP 
injection + 70 days (10 weeks).   
DURATION OF STUDY PERIOD  
(per patient)  
Approximately 35 weeks (screening: 3 weeks, DBTP: 24 weeks, and follow-
up period: 8 weeks).    
(electronic 
 
 
 
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Amended Clinical Trial Protocol 01  
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STUDY COMMITTEES 
Steering Committee:  
 Yes    
  No 
Data Monitoring Committee: 
 Yes    
 No 
The independent Data Monitoring Committee (DMC) is implemented in order 
to monitor patient safety by conducting formal reviews of accumulated safety 
data.  The DMC will provide the Sponsor with appropriate recommendations 
on the conduct of the clinical trial to ensure the protection and the safety of 
the enrolled patients in the study. 
Adjudication Committee:  
 Yes    
 No 
The Cardiovascular Events Adjudication Committee (CEC) will be responsible 
for defining, validating and classifying, in a blinded fashion, pre-specified 
cardiovascular events and all death. Classification of events will be as 
follows: CHD death, non-fatal MI, fatal and non-fatal ischemic stroke, 
unstable angina requiring hospitalization, congestive heart failure requiring 
hospitalization, and ischemia-driven coronary revascularisation procedure. In 
addition, the classification of the cause of all deaths will occur.  All events for 
adjudication will be defined in the adjudication Charter.     
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1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
 
 
* Every effort should be made to ensure that the screening window is as short as possible and ideally within two weeks. 
(electronic 
 
 
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1.2 
STUDY FLOW CHART 
 
     
Screening period    
Double-blind Treatment Period 
Follow-up period 
Day (D) / Week (W) / Month (M)  
W-3  
(D-21 to -8) 
W-1 
 (D-7) 
W0 
 (D1) 
W4 
 (D29) 
W8 
 (D57) 
W12  
(D85)  
W16  
(D113) 
W24  
(D169)  
End of Treatment 
W32 
(D225) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Visit Window (Days) 
 
±7 
+3 
±7 
±7 
±3 
±7 
±3 
±7 
Design: 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Patient demography 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
Xd 
 
 
 
 
 
 
Medical/family//surgical history, alcohol 
habits, smoking habits 
X 
 
 
 
 
 
 
 
 
Prior medication history 
X 
 
 
 
 
 
 
 
 
Physical examination  
 
 
Xd 
 
 
 
 
X 
Xa 
Body weight 
X 
 
Xd 
 
 
X 
 
X 
X 
Measured height 
X 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
Patient diary dispensation / review / 
Collectione 
 
 
X 
X 
X 
X 
X 
X 
 
IVRS/IWRS contact 
X 
X 
X 
 
 
X 
 
X 
X 
Treatment: 
 
 
 
 
 
 
 
 
 
Injection training  
 
Xb 
Xc 
 
 
 
 
 
 
Review diet 
 
 
Xd 
 
 
X 
 
X 
 
(electronic 
 
 
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Screening period    
Double-blind Treatment Period 
Follow-up period 
Day (D) / Week (W) / Month (M)  
W-3  
(D-21 to -8) 
W-1 
 (D-7) 
W0 
 (D1) 
W4 
 (D29) 
W8 
 (D57) 
W12  
(D85)  
W16  
(D113) 
W24  
(D169)  
End of Treatment 
W32 
(D225) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Visit Window (Days) 
 
±7 
+3 
±7 
±7 
±3 
±7 
±3 
±7 
Double-blind IMP kit dispensatione 
 
 
X 
 
 
X 
 
 
 
The time of the first injection of the IMP 
 
 
X 
 
 
 
 
 
 
Compliance check of IMP (review 
patient diary and treatment kit) and data 
collection on IMP administration 
 
 
 
X 
X 
X 
X 
X 
 
Concomitant medication 
X 
X 
Xd 
X 
X 
X 
X 
X 
X 
Vital signs: 
 
 
 
 
 
 
 
 
 
Heart rate (HR), blood pressure (BP) 
X 
X 
Xd 
X 
X 
X 
X 
X 
X 
Safety: 
 
 
 
 
 
 
 
 
 
AEs / SAEs recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead electrocardiogram (ECG) 
X 
 
 
 
 
 
 
X 
 
Laboratory Testing - Efficacy 
 
 
 
 
 
 
 
 
 
TC,calculated LDL-C, HDL-C, TG, non-
HDL-Cf 
X 
 
Xd 
X 
X 
X 
X 
X 
 
Apo B, Apo A-1, Apo B/Apo A-1 ratio 
and Lp(a) 
 
 
Xd 
 
 
X 
 
X 
 
Laboratory Testing - Safety 
 
 
 
 
 
 
 
 
 
Hematology and chemistryg 
X 
 
Xd 
 
 
X 
 
X 
Xa 
Creatine phosphokinase (CPK) 
X 
 
Xd 
 
 
X 
 
X 
Xa 
Liver panelh 
X 
 
Xd 
X 
X 
X 
X 
X 
Xa 
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Screening period    
Double-blind Treatment Period 
Follow-up period 
Day (D) / Week (W) / Month (M)  
W-3  
(D-21 to -8) 
W-1 
 (D-7) 
W0 
 (D1) 
W4 
 (D29) 
W8 
 (D57) 
W12  
(D85)  
W16  
(D113) 
W24  
(D169)  
End of Treatment 
W32 
(D225) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Visit Window (Days) 
 
±7 
+3 
±7 
±7 
±3 
±7 
±3 
±7 
Hepatitis B surface antigen 
X 
 
 
 
 
 
 
 
 
Hepatitis C antibody 
X 
 
 
 
 
 
 
Xi 
 
Serum pregnancy testj 
X 
 
 
 
 
 
 
 
 
Urine pregnancy testj 
 
 
Xd 
 
 
X 
 
X 
X 
Urinalysis 
X 
 
Xd 
 
 
X 
 
X 
Xa 
Laboratory Testing - Other 
 
 
 
 
 
 
 
 
 
HbA1c 
X 
 
 
 
 
X 
 
X 
Xa 
Thyroid-stimulating hormone (TSH) 
X 
 
 
 
 
 
 
 
 
Anti-alirocumab antibodiesk 
 
 
X 
X 
 
X 
 
X 
Xl 
Library samplesm 
 
 
Xd 
X 
 
X 
 
X 
 
PK samplesk, n 
 
 
X 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
a To be obtained at the follow up visit only in case of clinically relevant abnormal values for these parameters(or clinically relevant abnormal finding for physical examination)  at the end of double-blind treatment visit. 
b Injection training at screening period visit Week -1 is performed with placebo.  Investigators will have the option of providing a second placebo for alirocumab for patients who require additional self-injection training 
prior to randomization, e.g. the patient or investigator may elect to have the patient inject at home or at the study site. 
c Injection training at randomization visit Week 0/Day 1 is performed at the site by the patient or a trained designated person with double-blind study treatment kit allocated by IVRS/IWRS. Further training with a 
double-blind treatment can be done between Week 0 and 4 and at additional scheduled or unscheduled visits, as per patient or investigator’s judgment. 
d To be performed before randomization. 
e Along with kit dispensation, the treatment administration package should be given as well as the IMP diary and injection instruction manual, as needed. 
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f 
LDL-C will also be measured (via the beta-quantification method) at Week 0 and Week 24 
g Hematology includes: complete blood cell count (CBC) including red blood cell distribution width (RDW) and reticulocyte count, hematocrit, hemoglobin (Hb), red blood cell count, white blood cell count with 
differential count and platelets. Chemistry includes: glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, urea nitrogen, creatinine, uric acid, lactate dehydrogenase (LDH), total protein, 
albumin, and gamma-glutamyl transferase (γGT).   
h Liver panel: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and total bilirubin. 
i 
Positive HCV antibody results for the W24 assessment will be followed up with confirmatory test.   
j 
Women of Child Bearing Potential (WOCBP) only.   
k PK and anti-alirocumab antibodies collections are to be done prior to the IMP injection.  
l 
Patients who have a titer at or above 240 for anti-alirocumab antibody at follow up visit will have additional antibody sample(s), at 6 to 12 months after the last dose and thereafter, about every 3 to 6 months until 
titer returns below 240. 
m Library samples should be collected, as permitted by local regulatory policies. They may be stored for up to 10 years or as permitted by local regulatory policies, whichever is shorter, for exploratory research of 
PCSK9 levels, PCSK9 function, effect(s) of PCSK9 inhibition with a monoclonal antibody, lipoprotein sub-fraction, inflammation, and cardiovascular risk markers (eg, lipoprotein–associated phospholipase A2). 
n An additional random PK sample to be collected 5 days (± 2) after dosing, on or after week 22. 
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2 
TABLE OF CONTENTS 
1 
FLOW CHARTS.............................................................................................................................11 
1.1 
GRAPHICAL STUDY DESIGN ......................................................................................................11 
1.2 
STUDY FLOW CHART ..................................................................................................................12 
2 
TABLE OF CONTENTS ................................................................................................................16 
3 
LIST OF ABBREVIATIONS ..........................................................................................................22 
4 
INTRODUCTION AND RATIONALE.............................................................................................24 
5 
STUDY OBJECTIVES ...................................................................................................................31 
5.1 
PRIMARY.......................................................................................................................................31 
5.2 
SECONDARY ................................................................................................................................31 
6 
STUDY DESIGN ............................................................................................................................32 
6.1 
DESCRIPTION OF THE PROTOCOL...........................................................................................32 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................34 
6.2.1 
Duration of study participation for each patient .............................................................................34 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................34 
6.3 
STUDY COMMITTEES..................................................................................................................34 
7 
SELECTION OF PATIENTS..........................................................................................................36 
7.1 
INCLUSION CRITERIA..................................................................................................................36 
7.2 
EXCLUSION CRITERIA ................................................................................................................37 
7.2.1 
Exclusion criteria related to study methodology ............................................................................37 
7.2.2 
Exclusion criteria related to the active comparator and/or mandatory background therapies.......40 
7.2.3 
Exclusion criteria related to the current knowledge of alirocumab ................................................40 
8 
STUDY TREATMENTS .................................................................................................................42 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) ..........................................................................42 
8.1.1 
Route and method of administration..............................................................................................42 
8.1.2 
Timing of administration.................................................................................................................43 
8.2 
NON-INVESTIGATIONAL MEDICINAL PRODUCT(S) .................................................................44 
8.3 
BLINDING PROCEDURES............................................................................................................44 
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8.3.1 
Methods of blinding........................................................................................................................44 
8.3.1.1 
Lipid parameters ............................................................................................................................44 
8.3.1.2 
Anti-alirocumab antibodies.............................................................................................................44 
8.3.1.3 
Pharmacokinetics measurements..................................................................................................45 
8.3.1.4 
Committees....................................................................................................................................45 
8.3.2 
Randomization code breaking during the study.............................................................................45 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................46 
8.5 
DOSE UP-TITRATION...................................................................................................................47 
8.6 
PACKAGING AND LABELING ......................................................................................................47 
8.7 
STORAGE CONDITIONS AND SHELF LIFE................................................................................48 
8.8 
RESPONSIBILITIES ......................................................................................................................48 
8.8.1 
Treatment accountability and compliance......................................................................................49 
8.8.2 
Return and/or destruction of treatments ........................................................................................49 
8.9 
CONCOMITANT MEDICATION.....................................................................................................50 
8.9.1 
Management of background lipid modifying therapy / Rescue therapy.........................................50 
8.9.2 
Contraception.................................................................................................................................51 
8.9.3 
Prohibited concomitant medications ..............................................................................................51 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................52 
9.1 
EFFICACY ENDPOINTS ...............................................................................................................52 
9.1.1 
Primary efficacy endpoint...............................................................................................................52 
9.1.2 
Secondary efficacy endpoints ........................................................................................................52 
9.1.2.1 
Key secondary efficacy endpoints .................................................................................................52 
9.1.2.2 
Other secondary efficacy endpoints...............................................................................................53 
9.1.3 
Efficacy assessment method .........................................................................................................54 
9.1.3.1 
Lipid parameters ............................................................................................................................54 
9.2 
SAFETY ENDPOINTS ...................................................................................................................54 
9.2.1 
Adverse event ................................................................................................................................55 
9.2.2 
Safety laboratory............................................................................................................................56 
9.2.3 
Vital signs measurement................................................................................................................56 
9.3 
OTHER ENDPOINTS.....................................................................................................................56 
9.3.1 
Anti-alirocumab antibody assessments .........................................................................................56 
9.3.1.1 
Sampling time ................................................................................................................................56 
9.3.1.2 
Sampling procedure.......................................................................................................................56 
9.3.1.3 
Bioanalytical method......................................................................................................................57 
9.3.2 
Glycated hemoglobin A1c ..............................................................................................................57 
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9.3.3 
Pharmacokinetic variables .............................................................................................................57 
9.3.3.1 
Sampling time ................................................................................................................................57 
9.3.3.2 
Sampling procedure.......................................................................................................................58 
9.3.3.3 
Bioanalytical method......................................................................................................................58 
9.3.4 
Pharmacogenetic Samples ............................................................................................................58 
10 
STUDY PROCEDURES ................................................................................................................60 
10.1 
VISIT SCHEDULE..........................................................................................................................63 
10.1.1 
Screening Period............................................................................................................................63 
10.1.1.1 Screening Visit (Visit1/Week -3 /Day -21 up to -8) ........................................................................63 
10.1.1.2 Injection-training Visit at Screening (Visit 2/Week -1/Day -7 ± 7) ..................................................64 
10.1.2 
Double-Blind Double-Dummy Treatment Period (Study Site Visits)..............................................65 
10.1.2.1 Randomization Visit (Visit 3/Week 0/Day 1 + 3) ............................................................................65 
10.1.2.2 Visit 4/ Week 4, Visit 5/ Week 8 and Visit 7/Week 16 (Day 29, 57 and 113 ± 7)...........................66 
10.1.2.3 Visit 6/Week 12 (Day 85 ± 3): ........................................................................................................67 
10.1.2.4 Unscheduled PK visit / 5 days (± 2) after Week 22 IMP injection or after (optional) .....................68 
10.1.2.5 Visit 8/Week 24 (Day 169 ± 3): End of treatment visit ...................................................................68 
10.1.3 
Follow-Up Period............................................................................................................................69 
10.1.3.1 Follow-Up Visit (Visit 9/ Week 32/ Day 225 ± 7) ............................................................................69 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................70 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................71 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) ...........................71 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) ...........................71 
10.3.3 
List of criteria for permanent treatment discontinuation.................................................................71 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................72 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................73 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................73 
10.4.1 
Definitions of adverse events.........................................................................................................73 
10.4.1.1 Adverse event ................................................................................................................................73 
10.4.1.2 Serious adverse event ...................................................................................................................73 
10.4.2 
Adverse event of special interest...................................................................................................74 
10.4.3 
General guidelines for reporting adverse events ...........................................................................75 
10.4.4 
Instructions for reporting serious adverse events ..........................................................................75 
10.4.5 
Guidelines for reporting adverse events of special interest...........................................................76 
10.4.5.1 Reporting of adverse events of special interest (AESI) with immediate notification......................76 
10.4.5.2 Reporting of adverse events of special interest (AESI) without immediate notification.................77 
10.4.6 
Guidelines for management of specific laboratory abnormalities ..................................................78 
10.4.6.1 Hemoglobin decrease ....................................................................................................................78 
10.5 
OBLIGATIONS OF THE SPONSOR .............................................................................................79 
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10.6 
SAFETY INSTRUCTIONS .............................................................................................................80 
10.6.1 
Local tolerability (Local Injection Site Reactions) ..........................................................................80 
10.6.2 
Allergic adverse events..................................................................................................................80 
10.6.2.1 Allergic adverse events with cutaneous involvement ....................................................................80 
10.6.2.2 Acute allergic Injection Reactions..................................................................................................81 
10.6.3 
Cardiovascular events....................................................................................................................81 
10.6.4 
Laboratory alert related to TG rescue............................................................................................82 
10.7 
ADVERSE EVENTS MONITORING..............................................................................................82 
11 
STATISTICAL CONSIDERATIONS..............................................................................................83 
11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................83 
11.2 
DISPOSITION OF PATIENTS .......................................................................................................83 
11.3 
ANALYSIS POPULATIONS...........................................................................................................83 
11.3.1 
Efficacy populations .......................................................................................................................83 
11.3.1.1 Intent–to-treat population ...............................................................................................................84 
11.3.1.2 Modified Intent–to-treat (mITT) population.....................................................................................84 
11.3.2 
Safety population ...........................................................................................................................84 
11.3.3 
Other analysis population ..............................................................................................................85 
11.4 
STATISTICAL METHODS .............................................................................................................85 
11.4.1 
Extent of study treatment exposure and compliance.....................................................................85 
11.4.1.1 Extent of investigational medicinal product exposure....................................................................85 
11.4.1.2 Compliance ....................................................................................................................................85 
11.4.2 
Analyses of efficacy endpoints.......................................................................................................86 
11.4.2.1 Analysis of primary efficacy endpoint(s) ........................................................................................86 
11.4.2.2 Analysis of secondary efficacy endpoint(s)....................................................................................86 
11.4.2.3 Multiplicity considerations ..............................................................................................................88 
11.4.3 
Analyses of safety data..................................................................................................................88 
11.4.3.1 Adverse events ..............................................................................................................................89 
11.4.3.2 Laboratory and vital signs ..............................................................................................................90 
11.4.4 
Analyses of other endpoints...........................................................................................................90 
11.4.5 
Analyses of pharmacokinetic variables..........................................................................................91 
11.4.6 
Analyses of pharmacogenomics variables ....................................................................................91 
11.5 
INTERIM ANALYSIS......................................................................................................................91 
12 
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................92 
12.1 
ETHICAL AND REGULATORY STANDARDS ..............................................................................92 
12.2 
INFORMED CONSENT .................................................................................................................92 
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12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) ..............92 
13 
STUDY MONITORING...................................................................................................................94 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).......................................................................94 
13.2 
RESPONSIBILITIES OF THE SPONSOR.....................................................................................94 
13.3 
SOURCE DOCUMENT REQUIREMENTS....................................................................................94 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS AND ADDITIONAL REQUEST .............95 
13.5 
USE OF COMPUTERIZED SYSTEMS..........................................................................................95 
14 
ADDITIONAL REQUIREMENTS...................................................................................................96 
14.1 
CURRICULUM VITAE....................................................................................................................96 
14.2 
RECORD RETENTION IN STUDY SITES ....................................................................................96 
14.3 
CONFIDENTIALITY .......................................................................................................................96 
14.4 
PROPERTY RIGHTS.....................................................................................................................97 
14.5 
DATA PROTECTION.....................................................................................................................97 
14.6 
INSURANCE COMPENSATION....................................................................................................97 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES .................................98 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE............................................................................................................................................98 
14.8.1 
By the Sponsor...............................................................................................................................98 
14.8.2 
By the Investigator .........................................................................................................................99 
14.9 
CLINICAL TRIAL RESULTS ..........................................................................................................99 
14.10 
PUBLICATIONS AND COMMUNICATIONS .................................................................................99 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................100 
16 
BIBLIOGRAPHIC REFERENCES...............................................................................................101 
17 
APPENDICES..............................................................................................................................106 
APPENDIX A. 
SUMMARY OF TLC DIET FOR HIGH CHOLESTEROL..................................................106 
APPENDIX B. 
THE STAGES OF HEART FAILURE – NYHA CLASSIFICATION...................................107 
APPENDIX C. 
SUMMARY OF ADVERSE EVENT REPORTING INSTRUCTIONS ...............................108 
APPENDIX D. 
GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI....................................................................................................110 
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APPENDIX E. 
GUIDELINES FOR HEMOGLOBIN (HB) DECREASE >=1.5 G/DL.................................115 
APPENDIX F. DNA STORAGE SAMPLES..............................................................................................116 
APPENDIX G. ASSESSMENT OF LOCAL INJECTION SITE REACTIONS...........................................118 
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3 
LIST OF ABBREVIATIONS 
 
ADA: 
anti-drug antibody 
AEs: 
adverse events 
AESI: 
adverse event of special Interest 
ALP: 
alkaline phosphatase  
ALT: 
alanine aminotransferase 
Apo: 
apolipoprotein 
AST: 
aspartate aminotransferase  
BMI: 
body mass index  
BP: 
blood pressure 
CABG: 
coronary artery bypass graft surgery  
CBC: 
complete blood cell count  
CEC: 
Cardiovascular Events Adjudication Committee 
CHD: 
coronary heart disease 
CI: 
confidence intervals 
CIB: 
clinical investigator’s brochure  
CKD: 
chronic kidney disease 
CPK: 
Creatine phosphokinase 
CV: 
cardiovascular 
CVD: 
cardiovascular disease  
DBTP: 
double-blind treatment period 
DMC: 
Data Monitoring Committee  
DNA: 
deoxyribonucleic acid  
DRF: 
discrepancy resolution form  
ECG: 
electrocardiogram 
e-CRF: 
electronic case record form 
FH: 
familial hypercholesterolemia  
GCP: 
good clinical practice  
Hb: 
hemoglobin 
HbA1c: 
glycated hemoglobin A1c 
HDL-C: 
high density lipoprotein cholesterol  
HLGT: 
high level group term  
HLT: 
high level term  
HMG CoA: 
3-hydroxy-3-methyl-glutaryl-CoA reductase 
HR: 
heart rate 
ICF: 
informed consent form  
ICH: 
International Conference on Harmonization 
IEC: 
Independent Ethics Committee  
IMP: 
investigational medicinal product 
IRB: 
Institutional Review Board 
ITT: 
intent-to-treat 
IV: 
intravenous 
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IVRS: 
interactive voice response system 
IWRS: 
interactive web response system 
LDH: 
lactate dehydrogenase  
LDL-C: 
low density lipoprotein cholesterol  
LDL-R: 
low density lipoprotein receptor  
LMT: 
lipid modifying therapy  
LOCF: 
last Observation Carried Forward 
Lp(a): 
lipoprotein a  
LTT: 
lowest level term  
MedDRA: 
medical dictionary for regulatory activities 
MI: 
myocardial infarction  
MMRM: 
mixed effect model with repeated measures 
mRNA: 
messenger ribonucleic acid 
NCEP ATP III: national cholesterol education program adult treatment panel III  
NIMP: 
non investigational medicinal products  
non-HDL-C: 
non-high-density lipoprotein cholesterol 
NYHA: 
New York Heart Association  
PAD: 
peripheral arterial disease  
PCI: 
percutaneous coronary intervention  
PCSK9: 
proprotein convertase subtilisin kexin type 9  
PK: 
pharmacokinetics 
PO: 
by mouth = per os 
PT: 
preferred term  
Q2W: 
every 2 weeks 
Q4W: 
every 4 weeks  
RDW: 
red blood cell distribution width  
SAEs: 
serious adverse events 
SAP: 
Statistical Analysis Plan 
SC: 
subcutaneous 
SD: 
standard deviation 
SE: 
standard errors 
SNP: 
single nucleotide polymorphisms  
SOC: 
system organ class  
SUSAR: 
suspected unexpected serious adverse reaction 
TC: 
total cholesterol  
TEAE: 
treatment emergent adverse events  
TG: 
triglycerides 
TLC: 
therapeutic lifestyle changes  
TSH: 
thyroid stimulating hormone  
WOCBP: 
women of child bearing potential  
γGT: 
gamma glutamyl transferase 
 
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4 
INTRODUCTION AND RATIONALE 
Alirocumab is a fully human monoclonal antibody that binds proprotein convertase subtilisin 
kexin type 9 (PCSK9). All relevant information concerning the compound is available in the latest 
version of the Clinical Investigator’s Brochure (CIB).  
Alirocumab is also referred to as SAR236553 or REGN727. However, for this study protocol 
(EFC13889), it will be referred to as alirocumab. 
Background on patient populations: 
This study will be performed in Asia and will include patients with high CV risk due to 
established coronary heart disease (CHD) or CHD risk equivalents and having 
hypercholesterolemia. 
Hypercholesterolemia, particularly an increase in low density lipoprotein cholesterol (LDL-C) 
levels, constitutes a major risk for the development of atherosclerosis and CHD (1), a leading 
cause of death and disability in the world (2). Cardiovascular mortality is projected to double 
globally between 1990 and 2020, with developing countries bearing about 80% of the increased 
disease burden (3). In general across Asia, along with the rapid urbanization and economic 
development during the past 20 years, there have been trends toward increases in serum total 
cholesterol (TC) levels and CHD mortality rates (4). As in western societies, there is a direct 
(continuous) relationship between plasma TC concentrations and CHD mortality, although the 
mean TC is lower in many Asian societies compared with western societies having higher 
proportions of Caucasians (4). The study published in 2012 showed serum TC and LDL-C levels 
were high and increasing in the Chinese population (5). 
LDL-C is identified as the primary target of cholesterol lowering therapy (6) and is accepted as a 
valid surrogate endpoint (7, 8, 9). Numerous studies have demonstrated that reducing LDL-C 
levels mainly via 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG CoA) inhibition, reduces the 
risk of CHD, with a strong direct relationship between LDL-C levels and CHD events; for each 
1 mmol/L (~40 mg/dL) reduction in LDL-C, cardiovascular disease (CVD) mortality and 
morbidity is lowered by 22% (10). Greater reductions in LDL-C produce greater reduction in 
events, and comparative data of intensive versus standard statin treatment suggest that the lower 
the LDL-C level, the greater the benefit in patients at very high cardiovascular risk (10, 11, 12, 
13).  
The Third Report of the National Cholesterol Education Program Adult Treatment Panel III 
(NCEP ATP III) in 2001(14) and the Third Joint Task Force of European and Other Societies on 
Cardiovascular Disease Prevention in Clinical Practice in 2003 (15) have recommended an LDL-
C level of less than 100 mg/dL as the goal of therapy for patients at high risk for CHD. On the 
basis of accumulating data with statins in CHD patients, the National Cholesterol Education 
Program in conjunction with the American Heart Association and the American College of 
Cardiology subsequently introduced in 2004 a more aggressive, but optional, LDL-C goal of less 
than 70 mg/dL (1.81 mmol/L) for patients at very high risk for CHD, even if baseline LDL-C 
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levels were below 100 mg/dL (16). The Task Force for the management of dyslipidemia of the 
European Society of Cardiology and the European Atherosclerosis society recently recommended  
in all patients at very high cardiovascular risk a LDL-C goal of less than 1.81 mmol/L (70 mg/dL) 
and/or ≥50% LDL-C reduction when target level cannot be reached (6). There is no specific 
guideline for dyslipidemia treatment to be applicable in whole Asia Pacific region. Generally, 
national guideline is in line with global guideline as in United States/European Union. 
Current LDL-C-lowering medications include statins, cholesterol absorption inhibitors 
(ie, ezetimibe), fibrates, niacin, and bile acid sequestrants; statins are the most commonly 
prescribed as they have shown a great ability to lower LDL-C and reduce CHD events. However 
despite these available treatments that can be also used in combination, many high risk patients 
fail to reach the guideline target level (17).  REALITY-Asia study found LDL-C goal attainment 
is low in Asia, particularly in patients with CHD/diabetes (18). The CEPHEUS Pan-Asian survey 
published in 2012 still showed a large proportion of patients in Asia with hypercholesterolemia on 
lipid-lowering drugs are not at recommended LDL-C levels by updated NCEP ATP III, LDL-C 
goal was attained  in 55.4% of high risk(<100 mg/dL), and only 34.9% of very high-risk patients 
(<70 mg/dL) (19). These data indicate a need for more effective treatments to help more patients 
in Aisa to achieve their guideline-recommended cholesterol treatment targets. 
Introduction to proprotein convertase subtilisin kexin type 9 (PCSK9): 
Proprotein convertase subtilisin kexin type 9 (PCSK9) belongs to the subtilisin family of serine 
proteases and is highly expressed in the liver. PCSK9 is involved in regulating the levels of the 
low-density lipoprotein receptor (LDL-R) protein (20, 21). Once PCSK9 is secreted into plasma it 
directly binds to the LDL-R and promotes its degradation. The increased degradation of LDLRs 
leads to a reduced LDL-C removal, and therefore, higher LDL-C circulating levels. Experiments 
with mice have shown that increasing PCSK9 protein levels decreases levels of LDL-R protein in 
the liver while PCSK9 knockout mice have increased levels of LDL-R in the liver (22, 23). In 
humans, PCSK9 mutations have been identified: the gain-of-function mutations are rare and cause 
an autosomal dominant form of severe hypercholesterolemia and premature CHD, whereas 
loss-of-function mutations are more common and are associated with reduced plasma levels of 
LDL-C and protection from CHD (24, 25).  
Therefore blocking PCSK9 binding to the LDL-R can potentially benefit patients with 
hypercholesterolemia by decreasing their plasma LDL-C levels. In addition, PCSK9 messenger 
ribonucleic acid (mRNA) and protein levels are increased in response to statins, potentially 
attenuating their cholesterol-lowering effect (26). 
Summary of select clinical studies with alirocumab: 
Phase 1 studies 
No safety signal was raised from completed Phase 1 studies. 
Results of 6 phase 1 studies showed that alirocumab administered to healthy subjects and patients 
by intravenous (IV) or subcutaneous (SC) administration was generally well-tolerated at all doses. 
No safety signal was raised from completed Phase 1 studies. Treatment Emergent Adverse Events 
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(TEAE) did not display a dose relationship. No pattern of AEs related to the drug was identified. 
In all the phase 1 studies, administration of alirocumab induced rapid, substantial, and sustained 
reductions from baseline in mean LDL-C, up to 60%. The magnitude and duration of the 
reductions were related to the dose.  
Larger doses of alirocumab were associated with greater and longer-lasting reductions in LDL-C. 
In study R727-CL-1001, the effects of SC doses of alirocumab as an add-on to stable doses of 
atorvastatin or given without concomitant statin were similar in patients with familial 
hypercholesterolemia (FH) and in patients with non-FH.  
Phase 2 studies 
Four Phase 2 studies (DFI11565, R727-CL-1003, DFI11566 and DFI12361) have been conducted 
in patients receiving a statin (with or without ezetimibe) as background therapy. Overall, a total of 
349 patients were exposed to at least one dose of alirocumab in the 4 phase 2 studies.  
Efficacy results: 
In both dose-finding studies, statistically significant decreases in percent change from baseline in 
LDL-C at 12 weeks were observed in all alirocumab groups compared to the placebo group. The 
greatest decrease was seen in the 150 mg every 2 weeks (Q2W) group, with a mean decrease from 
baseline of up to 72.4% (the least square mean difference versus placebo of -67.3% in DFI11565, 
-69.1% in DFI12361, -57.2% in R727-CL-1003; all p <0.0001) (27). Decreases observed with the 
doses administered Q2W were maintained from the first injection throughout the study. Large 
decreases in LDL-C from baseline to 12 weeks were also observed with doses administered every 
4 weeks (Q4W); however, the treatment effect was not fully maintained over a 4-week period 
(ie, the time interval between the two injections) in all these statin-treated patients. 
The same magnitude of effect was shown for the dose of 150 mg Q2W in the DFI11566, with a 
statistically significant decrease in LDL-C at 8 weeks in the alirocumab 150 mg + atorvastatin 
80 mg group (median reduction of 70.6 %) compared with the placebo + atorvastatin 80 mg group 
(median reduction of 26.9 %). In all three studies, consistent results were seen for TC, 
Apolipoprotein (Apo) B, non-high density lipoprotein cholesterol (non-HDL-C) and Apo B/Apo 
A-1 ratio. A favorable trend was also observed for high density lipoprotein cholesterol (HDL-C), 
Apo A-1, TG and lipoprotein a (Lp[a]). 
Safety results: 
Alirocumab was well tolerated in all completed Phase 2 studies throughout the treatment period 
and for all treatment groups. Injection site reactions were reported in patients including placebo 
treated patients; the reporting of these events was greatest in the R727-CL-1003 study (40.3% in 
alirocumab-treated patients versus 12.6%, 9.3% and 3.3% in DFI11565, DFI12361 and DFI11566, 
respectively); however these events were generally transient. Rare cases of hypersensitivity 
reactions were reported. Among all serious adverse events (SAEs) reported for all alirocumab 
studies, only one case, leucocytoclastic vasculitis (angiitis), was reported as being related to 
alirocumab (DFI11565 study). The patient developed one episode of diarrhea followed on the 
same evening by rash in arms, legs and abdomen 9 days after the first administration of 
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alirocumab 300 mg Q4W. The diagnosis was confirmed by skin biopsy. The patient was 
discontinued from study drug but completed the study. The lesions resolved after a course of 
tapering steroid administration. No particular signal was noted for TEAEs related to 
musculoskeletal or connective tissue disorders as well as no elevations in liver enzymes. For 
detailed information, please refer to the IB (28). 
Phase 3 studies: 
As of 31 December 2014, 12 Phase 3 studies were completed or had the first step analysis 
completed, with 10 evaluating alirocumab administered at Q2W regimen and 2 evaluating 
alirocumab administered at Q4W regimen. These studies evaluated heterozygous FH patients, 
patients with a range of cardiovascular risk but predominately high and very high risk, and 
patients not taking statins including statin intolerant patient. 
Phase 3 studies that evaluated Q2W regimen – efficacy results: 
Ten studies that were completed or had the first step analysis evaluating 75 mg Q2W (with 
possible up-titration to 150 mg Q2W at Week 12) and 150 mg Q2W as initiation dose regimen 
were performed. These studies demonstrated reductions in LDL-C from baseline to Week 24 
ranging from 42.7% to 50.6%, and from 45.7% to 61.0%, respectively. Superiority in LDL-C 
reduction was demonstrated in all placebo-controlled studies with alirocumab administered as 
add-on to a maximally tolerated dose of statin. Superiority in LDL-C reduction was also 
demonstrated in all ezetimibe-controlled studies, with alirocumab being administered as add-on to 
statin, or to lipid modifying therapy (LMT) other than statin, or in monotherapy. 
LDL-C reduction observed at Week 24 was maintained over time in all the studies including those 
up to 78 weeks. In all studies, the LDL-C reduction was observed at the first LDL-C measurement 
following the first alirocumab dose at Week 4. 
Phase 3 studies that evaluated Q4W regimen – efficacy results: 
Two studies EFC13786 and R727-CL-1308 (first-step analysis), have evaluated the 150 mg Q4W 
and 300 mg Q4W, respectively, as initiation dose regimen with a possible up-titration to 150 mg 
Q2W. For both studies, LDL-C reduction was observed at Week 4 was maintained over time up to 
Week 24. As with Q2W dosing, changes in non-HDL-C, Apo B, and Total-C tended to correlate 
with LDL-C. The R727-CL-1308 study included patients with and without concomitant statin. In 
both of these populations, there were statistically significant effects in favor of alirocumab 
300 mg Q4W with possible up-titration to 150 mg Q2W for both co-primary efficacy endpoints 
(percentage change in LDL-C from baseline to Week 24 and to averaged Weeks 21 - 24). For 
LDL-C reduction, the LS mean treatment difference for alirocumab versus placebo at Week 24 
was -52.4% and -58.7% for the non-concomitant statin population and concomitant statin 
population, respectively. The results obtained at Week 12 were consistent with those at Week 24 
for both populations, whereby the Week 12 effect assessed the sole contribution of 300 mg Q4W 
dose regimen. 
The EFC13786 study included a vast majority of statin intolerant patients with many on 
background ezetimibe therapy. At Week 24, statistically significant LS mean treatment difference 
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for alirocumab (150 mg Q4W with possible up-titration to 150 mg Q2W) versus placebo 
of -56.4% was achieved for LDL-C reduction. The results obtained at Week 12 showed 
statistically significant LS mean treatment difference of -44.9%, whereby the Week 12 effect 
assessed the sole contribution of the 150 mg Q4W dose regimen. 
Clinical safety 
In the completed studies, or studies with first-step analysis, 391 patients from Phase 1, and 
4300 patients from Phase 2 and Phase 3 have been exposed to 1 or more doses of alirocumab. As 
of 31 December 2014, there are 4818 subjects / patients estimated to be exposed to alirocumab 
from the blinded phase 3 studies and 1550 patients are exposed to alirocumab in ongoing open 
label studies. 
Phase 2 and Phase 3 safety results: 
Safety data was analyzed from pooled phase 2 and phase 3 studies with a Q2W dosing, which 
included a total of 5234 patients, of which 3340 patients were treated with alirocumab at a dose of 
75 or 150 mg Q2W.  
In the placebo-controlled and ezetimibe-controlled pooled studies, no dose relationship was noted 
for any AEs and these was not evidence of a pattern in the type of AEs observed. The percentages 
of patients who experienced at least 1 TEAE, at least 1 treatment-emergent SAE and any TEAEs 
leading to permanent treatment discontinuation were similar between the alirocumab and control 
groups. 
There was no safety signal observed with neurologic events and neurocognitive disorders, alanine 
aminotransferase (ALT) increase and hepatic disorders, adjudicated CV events, diabetes mellitus, 
and ophthalmologic disorders. The most common adverse reactions in patients treated with 
alirocumab were local injection site reactions (6.2% patients in the alirocumab group versus 4.2% 
in control groups in the global pool). Injection site reactions, influenza and pruritus were 
identified as adverse drug reactions. Rare and sometimes serious allergic adverse reactions (e.g., 
hypersensitivity, eczema nummular, urticaria, and hypersensitivity vasculitis) have been reported 
from clinical studies in patients receiving alirocumab. 
There was no safety signal in patients who had at least 2 consecutive values of LDL-C <25 or 
15 mg/dL (0.65 or 0.39 mmol/L), particularly in regard to neurological or other adverse effects 
that could potentially be related to low LDL-C (29). The analysis of the safety data with Q2W 
dosing did not suggest a safety signal as of 31 December 2014. 
Overall, the safety profile of the alirocumab Q4W dosing regimen was similar to alirocumab 
Q2W regimen, except for the frequency and onset of injection site reactions. The reactions tended 
to occur sooner after the first drug injection, and last longer, in the alirocumab group.  
Selection of the dose: 
Two main doses of alirocumab are evaluated in the ongoing ODYSSEY Phase 3 program: 75 mg 
and 150 mg, to be administered subcutaneously Q2W, based on data from the phase 1 and 
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2 programs. The selection of doses, dosing frequency and up-titration approach is also based on 
the expected LDL-C reduction needed to provide the best benefit in terms of CVD reduction, and 
potential safety considerations regarding low LDL-C values. 
The current and most relevant evidence around the effects of achieved low LDL-C levels comes 
from examinations of large statin trials (30, 31, 32) and patients with PCSK9 loss-of-function 
mutations (33). The patients achieving the lower levels of LDL-C had the lower CV event rates. 
To date, there is no evidence that very low LDL-C levels result in significant adverse health 
effects based on these sources of information, though this conclusion is based on a relatively low 
number of patients with very low LDL-C who have been studied. 
Based on the results of the two dose finding studies, the Q2W dosing regimen best maintained 
constant LDL-C lowering throughout the interdosing interval, with the maximum efficacy at 
12 weeks provided by the 150 mg Q2W dosing. However, for many patients, the magnitude of 
effect observed with the 150 mg Q2W dose may not be needed to achieve the target LDL-C goal, 
and starting with a lower dose may be undertaken. Using a dose response model, 75 mg Q2W has 
been selected: all patients will be initially treated with 75 mg Q2W, and only those patients whose 
LDL-C levels remain equal to or higher than 70 mg/dL after 8 weeks of treatment will be dose 
up-titrated to 150 mg Q2W (at week 12). With this treatment scheme, most patients with primary 
hypercholesterolemia can be expected to achieve their target LDL-C level, with few patients 
reaching a level below 25 mg/dL.  
Rationale for protocol design: 
The objective of the present study is to demonstrate the superiority of alirocumab versus 
ezetimibe in Asia in patients at high cardiovascular risk and who require additional 
pharmacological management since their current maximally tolerated statin therapy failed to 
achieve the LDL-C treatment goal.   
The target population in this study is patients at high cardiovascular risk. The definition of high 
cardiovascular risk is based on existing guidelines (6, 16). In the context of a clinical trial, this 
definition has been focused on objective parameters whenever possible, when guidelines 
definition mentioned conditions that could encompass various levels of severity, such as 
peripheral arterial disease (PAD). Patients with type 2 diabetes without a history of CAD or CVD 
are considered high risk per guidelines, but have a risk for a CV event that is deemed less than 
patients who have had a previous CHD event (34, 35, 36). Thus, stringent criteria, based on 
consultation with the steering committee in ODYSSEY trials, have also been added for diabetes. 
Randomization of patients with DM and 2 or more additional risk factors but without CHD, PAD, 
or stroke will be limited to 25% of the overall randomized population. 
The control arm that has been selected for this study is ezetimibe 10 mg by mouth (PO) daily. 
This will allow for a study comparing the addition of alirocumab to a maximal tolerated dose of 
statin against a treatment option (ie, ezetimibe) which is available in routine clinical practice (37). 
Ezetimibe has been recommended as a possible agent that may be used in combination with statin, 
when LDL-C target levels have not been reached (6, 38). 
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The sample size of 600 patients with treatment duration for 24 weeks is intended to provide 
efficacy and safety experience in Asia patient populations that will ultimately derive potential 
benefit from the drug.  
A treatment difference of 20% on LDL-C reduction with alirocumab versus ezetimibe could be 
expected at 24 weeks of treatment.  This is based on a treatment effect of about 25% to 30% on 
LDL-C reduction with ezetimibe 10 mg when added to ongoing statin therapy (39, 40, 41, 42,43) 
and a treatment effect of about 50% on LDL-C reduction with alirocumab 75 mg Q2W expected, 
based on simulations from the efficacy profile observed in the phase 2 studies. 
 
Preliminary pharmacokinetic (PK) data from Phase 2 studies DFI11565, DFI11566 and R727-CL-
1003, showed that exposure to alirocumab declined during the 8-week follow-up period that 
followed the double-blind treatment period (DBTP), with serum total concentrations of 
alirocumab still detectable, but at very low levels. Therefore to ensure sufficient low, non-
effective serum alirocumab concentrations, patients will continue to be followed during a follow-
up period of 8 weeks (ie, 10 weeks after last dosing). 
Conclusion on the benefit risk assessment with alirocumab 
Based on the clinical data available to date, treatment with alirocumab has demonstrated a 
significant LDL-C lowering effect and was generally well tolerated in a population of patients 
with non-FH or with heterozygous FH. The efficacy on LDL-C was associated with consistent 
results in TC, Apo B, non-HDL-C and Apo B/Apo A-1 ratio and a positive trend for HDL-C, TG 
and Lp(a). There was no evidence that alirocumab adversely affects other CV risk factors, 
eg, body weight, blood pressure (BP), glucose, or C-reactive protein. 
Important identified or potential risks with alirocumab are local injection site reactions, 
immunogenicity and hypersensitivity reactions. Local injection site reactions were reported in 
both alirocumab and placebo treatment groups. Patients are monitored for these AEs in the 
Phase 3 program. A substantial number of patients reached low LDL-C levels (<25 mg/dl 
[0.65 mmol/L]) with no safety signal identified to date. However, further monitoring for potential 
AEs associated with low LDL-C levels will be implemented. Although no particular signal related 
to creatinine phosphokinase (CPK) elevation and associated AEs (eg, myalgia, rhabdomyolysis) 
was detected with the coadministration of alirocumab and statins over a maximum duration of 12 
weeks, monitoring for such AEs will continue for all the Phase 3 studies. An independent Data 
Monitoring Committee (DMC) will meet periodically to review unblinded safety data for all 
Phase 3 studies, including this study. 
 
This specific study is undertaken to demonstrate in Asia in hypercholesterolemic patients with 
established CHD or a CHD risk equivalent and who are not at their LDL-C goal that alirocumab 
75 mg Q2W or 75 mg Q2W/150 mg Q2W as add-on therapy to statin causes a statistically 
significant and clinically meaningful reduction in LDL-C. This population that is not at LDL-C 
goal on optimized statin therapy represents a highest risk group with a well identified medical 
need that may be addressed by adding alirocumab to their statin therapy, in comparison to current 
treatment option, ie, adding ezetimibe. 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
To demonstrate the reduction of LDL-C by alirocumab as add-on therapy to stable maximally 
tolerated daily statin therapy in comparison with ezetimibe 10 mg daily after 24 weeks of 
treatment in Asia in patients with hypercholesterolemia at high CV risk. 
5.2 
SECONDARY 
The secondary objectives are: 
• 
To evaluate the effect of alirocumab 75 mg in comparison with ezetimibe 10 mg on 
LDL-C after 12 weeks of treatment 
• 
To evaluate the effect of alirocumab on other lipid parameters: eg, Apo B, non-HDL-C, 
TC, Lp(a), HDL-C, TG, Apo A-1  
• 
To evaluate the safety and tolerability of alirocumab 
• 
To evaluate the development of anti-alirocumab antibodies 
• 
To evaluate the PK of alirocumab 
 
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6 
STUDY DESIGN 
This is a randomized, double-blind, double-dummy, active-controlled, unbalanced (2:1, 
alirocumab:ezetimibe), parallel-group, multi-national, multi-center study to evaluate the efficacy 
and safety of alirocumab versus ezetimibe in high CV risk in Asia in patients with 
hypercholesterolemia not adequately controlled with their statin therapy. Not adequately 
controlled is defined as an LDL-C ≥70 mg/dL (1.81 mmol/L) at the screening visit (Week -3) in 
patients with a history of documented CVD OR LDL-C ≥100 mg/dL (2.59 mmol/L) at the 
screening visit (Week -3) in patients without a history of documented CVD. Randomization will 
be stratified according to prior history of myocardial infarction (MI) or ischemic stroke [Yes/No], 
and high-intensity statin treatment (Yes defined as atorvastatin 40 to 80 mg daily or rosuvastatin 
20 to 40 mg daily, No for simvastatin whatever the dose daily, atorvastatin below 40 mg daily or 
rosuvastatin below 20 mg daily) and Country. After randomization, patients will receive double-
blind, double-dummy study treatment (either alirocumab or ezetimibe) over a period of 24 weeks 
on top of stable maximally tolerated daily statin therapy. A dose up-titration of alirocumab from 
75 mg to 150 mg depending on Week 8 LDL-C levels may occur at Week 12 for patients 
randomized to alirocumab. Patients will be followed for 8 weeks after the last visit of the DBTP. 
6.1 
DESCRIPTION OF THE PROTOCOL 
The study consists of 3 periods: screening, double-blind treatment, and follow up. 
• 
Screening period – up to 3 weeks in duration including an intermediate visit during which 
the patient (or another designated person such as spouse, relative, etc) will be trained to 
self-inject/inject with placebo for alirocumab. Eligibility assessments will be performed to 
permit the randomization of the patients into the study. Investigators will have the option 
for providing a second training kit of placebo for alirocumab for patients who require 
additional self-injection training prior to randomization visit, eg, the patient or investigator 
may elect to have patient inject at home or at study site. 
• 
Double-blind treatment period – A randomized, double-blind study treatment period of 
24 weeks. The first injection during the double-blind period will be done at the site on the 
day of randomization (Week 0 [D1] -V3) and as soon as possible after the contact with 
interactive voice response system (IVRS)/ interactive web response system (IWRS) for 
randomization into the study. The subsequent injections will be done by the patient (self-
injection) or another designated person (such as spouse, relative, etc) at a patient-preferred 
location (eg, home, study site).  
Patients randomized to alirocumab will receive a dose of 75 mg of the investigational 
medicinal product (IMP) from randomization (V3) up to Week 12 (V6) (ie, Weeks 0, 2, 4, 6, 
8, and 10) + placebo for ezetimibe PO daily.  
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At the Week 12 visit (V6) these patients will, in a blinded manner, either: 
- 
Continue alirocumab 75 mg Q2W from Week 12 onwards until the last injection at 
Week 22 + Placebo for ezetimibe PO daily, if the Week 8 LDL-C is <70 mg/dL 
(1.81 mmol/L)  
OR 
- 
Dose up-titrate to alirocumab 150 mg Q2W from Week 12 onwards until the last 
injection at Week 22), + Placebo for ezetimibe PO daily if the Week 8 LDL-C is 
≥70 mg/dL (1.81 mmol/L). 
NOTE: Lipid values obtained at Week 8 for the purpose of up-titration will not be 
communicated to investigators to maintain the blind. The continuation of the 75 mg dose or 
dose up-titration to the 150 mg dose will occur automatically through IVRS/IWRS process 
without site or patient awareness. 
Patients randomized to ezetimibe will receive placebo for alirocumab SC Q2W until the last 
injection at Week 22 + ezetemibe 10 mg PO daily from randomization (V3) up to Week 24 (V8).  
• 
Follow-up period – A period of 8 weeks after the end of the DBTP.   
The laboratory measurement of lipid parameters will be performed by a central laboratory 
(central lab) during the study.  Local laboratory testing for lipid parameters is prohibited after 
randomization of the patient, except for the safety of the patient as per investigator’s judgment. 
The specific results of the central lab testing for lipid parameters from samples obtained after 
randomization will not be communicated to the sites. However, under some circumstances, the 
central lab will inform sites of TG alert (see Section 10.6.4).  
Statin should be stable (including dose) throughout the whole study duration from screening to the 
follow-up visit barring exceptional circumstances whereby overriding concerns (including but not 
limited to TG alert posted by the central lab) warrant such changes, as per the investigator’s 
judgment.  
Fibrates, other than fenofibrate, are not allowed during the study. 
Patients should be on a stable diet (NCEP-ATP III therapeutic lifestyle changes [TLC] diet or 
equivalent – see Appendix A) throughout the entire study duration from screening. The dietician 
or site staff with appropriate training will review the patient’s diet at the screening visit and 
periodically throughout the study. 
Patients with prespecified CV events (see Section 10.6.3) from randomization until the final 
follow up visit should have an adjudication package prepared and sent to the independent 
Cardiovascular Events Adjudication Committee (CEC). 
Pharmacokinetic variables include total serum alirocumab concentration. Total and free PCSK9 
concentrations will be measured from the same PK sample. 
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At least 110 patients in total from pre-selected sites who consented for PK sampling will have PK 
analysis during the study, in order to have 60 paitents on alirocumab treatment (at least 
30 Chinese and 24 Indian patients). 
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
The study duration includes a screening period of up to 3 weeks, a 24-week DBTP for efficacy 
and safety assessment and an 8-week post-treatment follow-up period for all patients after the last 
visit of the DBTP. 
Thus, the study duration per patient is about 35 weeks (up to 3 weeks screening + 24 weeks 
double-blind treatment + 8 weeks follow-up).  
Patients who experience an ongoing SAEs or an adverse event of special interest (AESI), at the 
pre-specified study end-date, should be followed until resolution, stabilization, or death and 
related data will be collected. 
Patients who have a titer at or above 240 for anti-alirocumab antibody at follow up visit will have 
additional antibody sample(s), at 6 to 12 months after the last dose and thereafter, about every 3 to 
6 months until titer returns below 240. 
The end of the study per patient is the last protocol planned visit, or the resolution/stabilization of 
all SAEs, and AESI, or the resolution of anti-alirocumab (titer below 240), whichever comes last. 
6.2.2 Determination of end of clinical trial (all patients) 
The end of the study is defined as being the last patient last on site visit as scheduled by protocol.   
6.3 
STUDY COMMITTEES 
Data Monitoring Committee:  
An independent DMC, composed of members independent from the Sponsor and the study 
investigators, is implemented in order to monitor patient safety by conducting formal reviews of 
accumulated safety data that will be blinded by treatment group; if requested, the DMC may have 
access to the treatment allocation code or any other requested data for the purposes of a 
risk-benefit assessment (eg, lipid efficacy data). The DMC will provide the Sponsor with 
appropriate recommendations on the conduct of the clinical trial to ensure the protection and 
safety of the patients enrolled in the study. In addition, the DMC will also institute any measures 
that may be required for ensuring the integrity of the study results during the study execution. All 
activities and responsibilities of the DMC are described in the DMC charter. 
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Cardiovascular Events Adjudication Committee:   
The CEC is composed of experts in the field of cardiovascular diseases, independent from the 
Sponsor and the Investigators. This committee will be responsible for defining, validating and 
classifying, in a blinded fashion, pre-specified cardiovascular events and all deaths. Classification 
of events will be as follows: CHD death, non-fatal MI, fatal and non-fatal ischemic stroke, 
unstable angina requiring hospitalization, congestive heart failure requiring hospitalization, and 
ischemia-driven coronary revascularization procedure (percutaneous coronary intervention [PCI], 
coronary artery bypass graft surgery [CABG]). In addition, the classification of the cause of all 
deaths will occur. A charter and an adjudication operational manual will specify the procedures, 
criteria, and classification used for adjudication of these events.   
 
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7 
SELECTION OF PATIENTS 
7.1 
INCLUSION CRITERIA 
I 01. Patients with hypercholesterolemia and established CHD or CHD risk equivalents 
(see below for definitions) who are not adequately controlled with a maximally tolerated 
daily dose of statin* at a stable dose for at least 4 weeks prior to the screening visit 
(Week -3) 
*Definition of maximally tolerated dose (any of the following are acceptable):  
• 
Atorvastatin 40 mg to 80 mg daily  
• 
Rosuvastatin 20 mg to 40 mg daily  
• 
Simvastatin 40 mg daily  
• 
Patients not able to be on any of the above statin doses, should be treated with the dose of 
daily atorvastatin, rosuvastatin or simvastatin which is considered appropriate for the 
patient as per the investigator's judgment or concerns. Some examples of acceptable 
reasons for a patient taking a lower statin dose include, but are not limited to: adverse 
effects on higher doses, advanced age, low body mass index (BMI), local prescribing 
information, concomitant medications, comorbid conditions such as impaired glucose 
tolerance/impaired fasting glucose. The reason(s) will need to be documented in the case 
report form. 
A) Documented history of CHD (includes one or more of the following):  
• 
Acute MI 
• 
Silent MI 
• 
Unstable angina 
• 
Coronary revascularization procedure (eg, PCI, CABG) 
• 
Clinically significant CHD diagnosed by invasive or non-invasive testing (such as 
coronary angiography, stress test using treadmill, stress echocardiography or nuclear 
imaging) 
B) CHD risk equivalents (includes one or more of the following 4 criteria): 
i) Documented peripheral arterial disease (PAD) (one of the following criteria [a, b, or c] 
must be satisfied): 
(a) Current intermittent claudication (muscle discomfort in the lower limb 
produced by exercise that is both reproducible and relieved by rest within 
10 minutes) of presumed atherosclerotic origin TOGETHER WITH 
ankle-brachial index equal to or less than 0.90 in either leg at rest OR  
(b) History of intermittent claudication (muscle discomfort in the lower limb 
produced by exercise that is both reproducible and relieved by rest within 
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10 minutes) TOGETHER WITH endovascular procedure or surgical 
intervention in one or both legs because of atherosclerotic disease OR 
(c) History of critical limb ischemia TOGETHER WITH thrombolysis, 
endovascular procedure or surgical intervention in one or both legs because of 
atherosclerotic disease 
ii) Documented previous ischemic stroke with a focal ischemic neurological deficit that 
persisted more than 24 hours, considered as being of atherothrombotic origin.  CT or 
MRI must have been performed to rule out primary hemorrhage and non-ischemic 
neurological disease. 
iii) Documented chronic kidney disease (CKD) as defined by 
30 ≤eGFR <60 mL/min/1.73 m2 for 3 months or more, including the screening visit 
iv) Known history of diabetes mellitus AND 2 or more additional risk factors (as listed 
below): 
(a) History of hypertension (established on antihypertensive medication) 
(b) Documented history of ankle-brachial index ≤0.90 
(c) Documented history of microalbuminuria or macroalbuminuria (44) OR 
dipstick urinalysis at screening visit (Week -3) with >2 + protein 
(d) Documented history of preproliferative or proliferative retinopathy or laser 
treatment for retinopathy 
(e) Known family history of premature CHD (CHD in father or brother before 
55 years of age; CHD in mother or sister before 65 years of age) 
I 02. Signed written informed consent 
7.2 
EXCLUSION CRITERIA 
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following 3 subsections:  
7.2.1 Exclusion criteria related to study methodology 
E 01. Patients without established CHD or CHD risk equivalents 
E 02. LDL-C <70 mg/dL (<1.81 mmol/L) at the screening visit (Week -3) in patients with an 
history of documented CV disease 
E 03. LDL-C <100 mg/dL (<2.59 mmol/L) at the screening visit (Week -3) in patients without 
history of documented CV disease 
NOTE – CVD is defined as CHD, ischemic stroke or PAD as described in Section 7.1 
E 04. Change in statin dose or dose regimen from screening to randomization 
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E 05. Currently taking a statin that is not atorvastatin, rosuvastatin or simvastatin  
E 06. Atorvastatin, rosuvastatin or simvastatin is not taken daily or not taken at a registered dose 
E 07. Daily dose above atorvastatin 80 mg, rosuvastatin 40 mg or simvastatin 40 mg  
E 08. Use of cholesterol absorption inhibitor (ie, ezetimibe), omega-3 fatty acid 
(at doses ≥1000 mg daily), nicotinic acid, fibrates, bile acid-binding sequestrant, or red 
yeast rice products within the past 4 weeks prior to screening visit (Week -3) or between 
screening and randomization visits 
E 09. Use of nutraceutical products or over-the-counter therapies that may affect lipids which 
have not been at a stable dose/amount for at least 4 weeks prior to the screening visit 
(Week -3) or between screening and randomization visits 
E 10. Patient who has received plasmapheresis treatment within 2 months prior to the screening 
visit (Week -3), or has plans to receive during the study. 
E 11. History of a MI, unstable angina leading to hospitalization, CABG, PCI, uncontrolled 
cardiac arrhythmia, carotid surgery or stenting, stroke, transient ischemic attack, carotid 
revascularization, endovascular procedure or surgical intervention for peripheral vascular 
disease within 3 months prior to the screening visit (Week -3, V1) 
 
E 12. Planned to undergo scheduled PCI, CABG, carotid or peripheral revascularization during 
the study 
E 13. Systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg at screening 
visit or randomization visit 
E 14. History of New York Heart Association (NYHA) Class III or IV heart failure within the 
past 12 months (Appendix B) 
E 15.  Known history of hemorrhagic stroke 
E 16. Age <18 years or legal age of majority at the screening visit (Week -3) whichever is 
greater 
E 17. Patients not previously instructed on a cholesterol-lowering diet prior to the screening visit 
(Week-3) 
E 18. Newly diagnosed (within 3 months prior to randomization visit [Week 0]) or poorly 
controlled (HbA1 c >9% at the screening visit [Week -3]) diabetes 
E 19. Presence of any clinically significant uncontrolled endocrine disease known to influence 
serum lipids or lipoproteins.   
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NOTE: Patients on thyroid replacement therapy can be included if the dosage has been stable for 
at least 12 weeks prior to screening and between screening and randomization visits, and thyroid 
stimulating hormone (TSH) level is within the normal range at the screening visit. 
E 20. History of bariatric surgery within 12 months prior to the screening visit (Week -3) 
E 21. Unstable weight defined by a variation >5 kg within 2 months prior to the screening visit 
(Week -3) 
E 22. Known history of homozygous or heterozygous FH 
E 23. Known history of loss of function of PCSK9 (ie, genetic mutation or sequence variation) 
E 24. Use of systemic corticosteroids, unless used as replacement therapy for pituitary/adrenal 
disease with a stable regimen for at least 6 weeks prior to randomization (Week 0) 
NOTE: Topical, intra-articular, nasal, inhaled and ophthalmic steroid therapies are not considered 
as ‘systemic’ and are allowed 
E 25. Use of continuous estrogen or testosterone hormone replacement therapy unless the 
regimen has been stable in the past 6 weeks prior to the Screening visit (Week -3) and no 
plans to change the regimen during the study 
E 26. History of cancer within the past 5 years, except for adequately treated basal cell skin 
cancer, squamous cell skin cancer or in situ cervical cancer 
E 27. Known history of a positive HIV test 
E 28. Patient who has taken any investigational drugs other than the alirocumab training placebo 
kits within 1 month or 5 half lives, whichever is longer 
E 29. Patient who has been previously treated with at least one dose of alirocumab or any other 
anti-PCSK9 monoclonal antibody in other clinical trials 
E 30. Patient who withdraws consent during the screening period (patient who is not willing to 
continue or fails to return) 
E 31. Conditions/situations such as: 
Any clinically significant abnormality identified at the time of screening that in the 
judgment of the Investigator or any Subinvestigator would preclude safe completion of the 
study or constrain endpoints assessment such as major systemic diseases, patients with 
short life expectancy. 
Considered by the Investigator or any Subinvestigator as inappropriate for this study for 
any reason, eg: 
- 
Deemed unable to meet specific protocol requirements, such as scheduled visits 
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- 
Deemed unable to administer or tolerate long-term injections as per the patient or the 
investigator 
- 
Investigator or any Subinvestigator, pharmacist, study coordinator, other study staff or 
relative thereof directly involved in the conduct of the protocol, etc 
- 
Presence of any other conditions (eg, geographic, social) actual or anticipated, that the 
Investigator feels would restrict or limit the patient’s participation for the duration of the 
study 
E 32. Laboratory findings during the screening period (not including randomization Week 0 
labs):  
- 
Positive test for Hepatitis B surface antigen or Hepatitis C antibody (confirmed by reflexive 
testing) 
- 
Positive serum beta-hCG or urine pregnancy test (including Week 0) in women of 
childbearing potential 
- 
Triglycerides >400 mg/dL (>4.52 mmol/L) (1 repeat lab is allowed) 
- 
eGFR <30 mL/min/1.73 m2  
- 
ALT or AST >3 x ULN (1 repeat lab is allowed) 
- 
CPK >3 x ULN (1 repeat lab is allowed) 
- 
TSH <LLN or >ULN (1 repeat lab is allowed) 
7.2.2 Exclusion criteria related to the active comparator and/or mandatory background 
therapies  
E 33. All contraindications to the ezetimibe or warning/precaution of use (when appropriate) as 
displayed in the respective National Product Labeling  
E 34. All contraindications to the background statins or warning/precaution of use (when 
appropriate) as displayed in the respective National Product Labeling. 
7.2.3 Exclusion criteria related to the current knowledge of alirocumab  
E 35. Known hypersensitivity to monoclonal antibody or any component of the drug products 
E 36. Pregnant or breast-feeding women 
E 37. Women of childbearing potential not protected by highly-effective method(s) of birth 
control and/or who are unwilling or unable to be tested for pregnancy 
NOTE: Women of childbearing potential must have a confirmed negative pregnancy test at 
screening and randomization visits. They must use an effective contraceptive method throughout 
the entire duration of the study treatment, and for 10 weeks after the last intake of IMP (injection 
or capsule, whichever come last), and agree to repeat urine pregnancy test at designated visits. 
The applied methods of contraception have to meet the criteria for a highly effective method of 
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birth control according to the ‘Guidance on nonclinical safety studies for the conduct of human 
clinical trials and marketing authorization for pharmaceuticals’ (45). Postmenopausal women 
must be amenorrheic for at least 12 months.  
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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
Sterile alirocumab drug product will be supplied at a concentration of 75 mg/mL and/or 
150 mg/mL both as 1 mL volume in an auto-injector. 
Sterile placebo for alirocumab will be prepared in the same formulation as alirocumab without the 
addition of protein as 1mL volume in an auto-injector. 
Ezetimibe 10 mg tablets over-encapsulated. 
Match placebo for over-encapsulated ezetimibe tablets. 
NOTE: in order to ensure the continuity of the study treatment without interruption (only in the 
event the manufacturer faces any performance or supply issues of the auto-injector), contingency 
alternatives are: 
• 
in case of disruption of the 150 mg auto-injector only, if the use of 75 mg auto-injectors is 
maintained, patients will need to administer 2 injections as follows: 
- 
2 injections of 75 mg as 1 mL each in an auto-injector for patients receiving the 150 mg 
dose, 
- 
1 injection of 75 mg as 1 mL in an auto-injector plus 1 injection of placebo as 1 mL in an 
auto-injector for patients receiving the 75 mg dose,  
- 
2 placebo injections as 1 mL each in an auto-injector for patients receiving placebo. 
OR 
• 
in case of disruption of either 75 mg or 150 mg or both auto-injectors, patients will be 
switched to the use of prefilled syringes of placebo, 75 mg and 150 mg, with one injection 
of 1 mL for each of these doses. 
Should this occur, the alternative IMP will be maintained until the end of the study. 
8.1.1 Route and method of administration 
A manual for alirocumab IMP administration (injection instruction manual) will be provided to 
patients containing detailed instructions on use. Also, an administration package containing gauze, 
alcohol swabs, Band-aids, etc will be provided to the patients.  
The alirocumab IMP could be administered by self-injection or by another designated person 
(such as a spouse, relative, etc). The used auto-injector will be discarded in a sharps container 
which will be provided to patients. It is recommended that the IMP injections be rotated within an 
anatomical area (eg, right abdomen then left abdomen).  If another concomitant drug is being 
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injected in the abdomen, then the patient should be advised to use a different part of the abdomen 
for administration of the IMP.  
Patients will be asked to store the alirocumab IMP in a refrigerator (DO NOT FREEZE). Prior to 
administration, the IMP should be set outside in a safe location at room temperature for about 30 
to 40 minutes. Thereafter, the IMP should be administered as soon as possible. 
Instructions as outlined above should be provided to the patient (or another designated person 
[such as spouse, relative, etc] who will administer the injections) at training and as needed during 
the course of the study. Close supervision and feedback should be given at the training visit, 
randomization visit, and other visits as needed. Anyone that plans to administer IMP must be 
trained by the study staff.  
8.1.2 Timing of administration 
A training injection is planned on Week -1 (V2) with a placebo for alirocumab.  A second training 
injection with placebo for alirocumab may be administered between Week -1 and randomization 
visit. 
During the double-blind treatment period, alirocumab or placebo for alirocumab will be 
administered SC Q2W, starting at Week 0 continuing up to the last injection (Week 22) 2 weeks 
before the end of the DBTP.  If the injection is scheduled to take place on the same date as the site 
visit, then the IMP should be administered after the blood sampling has been completed.  
Further training with the scheduled double-blind alirocumab IMP can be done between W 0 and 
W 4 and at additional scheduled or unscheduled visits, as per investigator’s judgment. 
Double-blind IMP will start as soon as possible after the call for randomization using the 
treatment kit number provided by the IVRS/IWRS. The first injection after randomization will be 
done at the site by the patient or another designated person (such as spouse, relative, etc) under 
direct site staff supervision.  Patients will be monitored at the investigational site for at least 
30 minutes after this first double-blind injection.  
Alirocumab IMP injection should be administered Q2W SC at approximately the same time of the 
day; however it is acceptable to have a window period of ±3 days. The time of the day is based on 
patient’s preference.  
If by mistake or due to other circumstances an injection is delayed by more than 7 days or 
completely missed, then the patient should return to the original schedule of study treatment 
administration without administering delayed injections. On the other hand, if the delay is less 
than or equal to 7 days from the missed date, then the patient should administer the delayed 
injection and then resume the original schedule of study treatment administration.   
Ezetimibe 10 mg or placebo for ezetimibe capsules will be taken orally once daily at 
approximately the same time of the day, with or without food. Preferably, on the injection days 
the IMP capsule will be administered roughly at the time of injection (either before or shortly 
after). The capsules must be taken until the day before the end-of-treatment visit (early or not), 
and not stopped at the time of the last injection.  
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8.2 
NON-INVESTIGATIONAL MEDICINAL PRODUCT(S) 
The following classes of drugs are identified as non-investigational medicinal products (NIMP) 
because the medication is either a background therapy or a potential rescue medication for 
elevated TG: 
• 
Statins (atorvastatin, rosuvastatin, simvastatin) 
• 
Fenofibrate 
Please see Section 8.9 for further information. 
8.3 
BLINDING PROCEDURES 
8.3.1 Methods of blinding 
Alirocumab and placebo for alirocumab will be provided in identically matched auto injector and 
packaged identically which includes labeling to protect the blind.   
Ezetimibe and placebo for ezetimibe will be provided in identically matched caps and packaged 
identically which includes labeling to protect the blind.   
Each double-blind treatment kit will be labeled with a number, which will be generated by a 
computer program from Sanofi. The treatment kit numbers will be obtained by the investigator at 
the time of patient randomization and subsequent patient visits scheduled via a centralized 
treatment allocation system that will be available 24 hours-a-day, 7 days-a-week. 
In accordance with the double-blind design, study patients, investigators and study site personnel 
will remain blinded to study treatment and will not have access to the randomization (treatment 
codes) except under circumstances described in Section 8.3.2.  
8.3.1.1 Lipid parameters 
Lipid parameter values from blood samples obtained after the randomization visit, run by the 
central lab, will not be communicated to the sites so that they cannot deduce the treatment group 
of their patients based on LDL-C level attained.  The sponsor’s operational team will not have 
access to lipid parameters after randomization and until after the final database lock has occurred.   
8.3.1.2 Anti-alirocumab antibodies 
Patients’ anti-alirocumab antibody results will not be communicated to the sites during the study.   
The sponsor’s operational team will not have access to anti-alirocumab antibodies associated with 
patient identification until after the final database lock has occurred.   
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The lab technicians involved in the determination of patients’ anti-alirocumab antibodies are 
excluded from the operational team and a process will be set up to prevent any potential 
unblinding.  
Patients who have a titer at or above 240 for anti-alirocumab antibody at follow-up visit will have 
additional antibody sample(s), at 6 to 12 months after the last dose and thereafter, about every 3 to 
6 months until titer returns below 240. 
In order to maintain the blind of the study, the requests for sample collection of post-study 
anti-alirocumab antibodies will also be made on patients with titers below 240 at the follow-up 
visit (sham request). 
8.3.1.3 Pharmacokinetics measurements 
At the assay institutions charged for PK measurements, samples will be analyzed prior to data 
base lock leading to unblinding of responsible bioanalysts.  Bioanalysts are excluded from the 
operation’s team and a process is set up to prevent any potential unblinding. 
8.3.1.4 Committees 
The independent CEC will review and adjudicate their respective events in a blinded manner. 
The DMC will receive blinded by treatment group or unblinded (if necessary) confidential reports 
from an independent statistician for review (Section 6.3). 
8.3.2 Randomization code breaking during the study 
In case of an adverse event, the code must be broken by the site only in exceptional circumstances 
when knowledge of the IMP is essential for treating the patient. If possible, a contact should be 
initiated with the Monitoring Team/Medical Monitor before breaking the code. All calls will be 
documented by the Monitoring Team as appropriate to include date and time of the call, name of 
the person contacted within the Monitoring Team, patient ID, documentation of the request, and 
decision for unblinding or not. 
Code breaking can be performed at any time by using the proper module of the centralized 
treatment allocation system and/or by calling any other phone number provided by the Sponsor 
for that purpose. However, it is preferable to contact the Medical Monitor to discuss the case 
before unblinding the case. If the blind is broken, the Investigator should document the date, time 
of day, and reason for code breaking, and report this information (or “relevant information as 
required by”) on the appropriate page of the electronic-Case Record Form (e-CRF).  
Note that when documenting the reason for unblinding, the Investigator must not provide any 
detail regarding the nature of the IMP. The Investigator should not divulge IMP detail to the 
Sponsor’s representative or to any staff members until database closure. Furthermore, when 
completing forms (eg, AEs, SAEs), the study treatment should not be disclosed on the forms. 
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The code-breaking can also be performed by contacting the "24 hour alert system"; but this 
system should be used in very exceptional cases only (ie, unavailability of a centralized treatment 
allocation system or inability to contact Investigator and/or site staff). However, the preferred 
option is to unblind using a centralized treatment allocation system. The Investigators will be 
informed by the clinical monitoring team about the availability of the local code-breaking details 
(through an emergency centralized 24 hour telephone system for use with e-SMS). A patient card, 
including the relevant “24 hour alert system” telephone number will be provided to every patient 
who will participate in the study. 
Unblinding may also be performed by the Sponsor for some SAEs that are both related and 
unexpected in order to conform to regulatory reporting requirements. 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP 
Two randomized lists of treatment kit numbers will be generated centrally by Sanofi. The IMP 
(alirocumab 75 mg, 150 mg, or placebo for alirocumab kits and ezetimibe or placebo for 
ezetimibe kits) will be packaged in accordance with these 2 lists. 
The Trial Supply Operations Manager will provide the randomized list of treatment kit numbers 
and the Study Biostatistician will provide the randomization scheme to the centralized treatment 
allocation system provider. Then, this centralized treatment allocation system provider will 
generate the patient randomization list according to which it will allocate the treatment kits to the 
patients. 
Patients will be randomized to receive either alirocumab or ezetimibe during the double-blind 
study treatment period using a ratio 2:1, with permuted-block randomization. Randomization will 
be stratified according to prior history of MI or ischemic stroke [Yes/No],  statin treatment 
(atorvastatin 40 to 80 mg daily or rosuvastatin 20 to 40 mg daily versus simvastatin whatever the 
dose  daily, atorvastatin below 40 mg daily or rosuvastatin below 20 mg daily) and 
Country/region.   
The treatment kit numbers will be allocated using the centralized treatment allocation system on 
randomization visit (Day 1, Week 0), and then at Week 12, as re-supply visits, and at unscheduled 
visits, if needed.  
For patients in the alirocumab treatment arm, the treatment kit allocated at week 12 will be based 
on their week 8 LDL-C level following the up-titration rules (see Section 6.1). 
Before randomizing a patient, the Investigator or designee will have to contact the centralized 
treatment allocation system.  
A randomized patient is defined as a patient who is registered and assigned with a treatment kit 
number from the centralized treatment allocation system, as documented from its log file. 
A patient cannot be randomized more than once in the study. If a treatment is used without 
contacting the centralized treatment allocation system patient will be considered as not 
randomized and withdrawn from the study. 
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Two types of centralized treatment allocation system will be used, the IVRS and the IWRS 
depending on the choice of the site. 
8.5 
DOSE UP-TITRATION 
During the DBTP, patients randomized to alirocumab will receive a dose of 75 mg of the IMP 
from randomization (V3) up to Week 12 (V6) (ie, Weeks 0, 2, 4, 6, 8, and 10) + placebo for 
ezetimibe PO daily. At the Week 12 visit (V6) these patients will, in a blinded manner, either: 
• 
Continue alirocumab 75 mg Q2W from Week 12 onwards until the last injection at 
Week 22 + Placebo for ezetimibe PO daily, if the Week 8 LDL-C is <70 mg/dL 
(1.81 mmol/L)  
OR 
• 
Dose up-titrate to alirocumab 150 mg Q2W from Week 12 onwards until the last injection 
at Week 22), + Placebo for ezetimibe PO daily if the Week 8 LDL-C is ≥70 mg/dL 
(1.81 mmol/L). 
NOTE: Lipid values obtained at Week 8 for the purpose of up-titration will not be 
communicated to investigators to maintain the blind. The continuation of the 75 mg dose or 
dose up-titration to the 150 mg dose will occur automatically through IVRS/IWRS process 
without site or patient awareness. 
Patients randomized to ezetimibe will receive placebo for alirocumab SC Q2W until the last 
injection at Week 22 + ezetemibe 10 mg PO daily from randomization (V3) up to Week 24 (V8).  
8.6 
PACKAGING AND LABELING 
Packaging is in accordance with the administration schedule. 
For the DBTP, each double-blind alirocumab treatment kit, either alirocumab or placebo for 
alirocumab, will be supplied in kits of ready to use autoinjectors (see Section 8.1). Each kit will be 
prepared to contain 6 auto injectors in a mimic child-resistant package for a 12 week supply of 
alirocumab or placebo (ie, each autoinjector provides 2 weeks of treatment). The content of the 
labeling is in accordance with the local regulatory specifications and requirements. 
In order to protect the blind, all alirocumab double-blind treatment kit boxes will have the same 
look and feel and therefore will be labeled with a double-blind label. 
In addition to the alirocumab double-blind treatment kits, a training kit containing 1 placebo for 
alirocumab auto injector will be prepared for the purpose of instructing patients on injection 
administration which is to be performed prior to randomization at the injection training visit 
(Week -1, V2). If deemed necessary, a second injection training with placebo for alirocumab can 
be performed before the randomization visit using an additional training kit. 
The double-blind ezetimibe kits, either ezetimibe 10 mg or placebo for ezetimibe, will be prepared 
to contain 3 monthly child resistance wallets of 36 capsules in each. 
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In order to protect the blind, all ezetimibe double-blind treatment kit boxes will have the same 
look and feel and therefore will be labeled with a double-blind label. 
8.7 
STORAGE CONDITIONS AND SHELF LIFE 
Alirocumab will be shipped to the sites at 2°C to 8°C on an as-needed basis. 
At sites, the alirocumab IMP kits (alirocumab or placebo for alirocumab) will be stored in a 
refrigerator between +2°C and +8°C (36°- 46°F) by the site. The temperature of the site 
refrigerator should be checked daily and recorded on a log sheet. Based on ongoing real time and 
accelerated stability data, as well as research stability data, alirocumab is stable until the date 
specified on the labels.  
The ezetimibe kits (ezetimibe 10 mg or placebo for ezetimibe) will be stored between +2°C and 
+30°C (36°- 86°F) by the site. The temperature of the site storage room should be checked weekly 
at least and recorded on a log sheet. 
The IMP that will be stored at the investigational site should be kept in an appropriate locked 
room, under the responsibility of the Investigator or designee or other authorized person in 
accordance with the storage conditions indicated on the label. 
Physician or other authorized persons (eg, pharmacists) are responsible for storing the study 
product(s) in a secure and safe place in accordance with local regulations, labeling specifications, 
policies, and procedures.  
Control of study product(s) storage conditions, especially control of temperature (eg, refrigerated 
storage) and information on in-use stability and instructions for handling the Sanofi compound 
should be managed according to the rules provided by the Sponsor. 
After the supply of IMP kits to patients at the study site visits, appropriate provisions will be in 
place for transportation of the alirocumab IMP kits from the study site to the patient’s refrigerator. 
8.8 
RESPONSIBILITIES 
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the Sponsor and in accordance with applicable regulatory requirements. 
All IMP will be dispensed in accordance with the Clinical Trial Protocol and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) should be promptly notified to the 
Sponsor. Some deficiencies may be recorded through a complaint procedure. 
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A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party, allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
8.8.1 Treatment accountability and compliance 
IMP administration data will be recorded by the patients onto a patient’s diary. 
Measures taken to ensure and document IMP compliance and accountability are described below: 
• 
The Investigator or designee will obtain via IVRS/IWRS the treatment kit numbers and 
he/she will dispense the treatment kits to the patient. 
• 
The accountability is to be performed at alirocumab IMP kit re-supply visits only 
(see Section 10.1.2). The used and unused IMP kit(s) should be brought back to such visits 
for accountability purposes. Sharps container will be supplied to each patient for used auto 
injectors. The patients should return it to the site for destruction purpose at the end of 
study participation. 
• 
All ezetimibe kits are returned by the patient at the designated visit. 
• 
The Investigator or designee will complete the corresponding treatment log form from 
patient’s diary. 
• 
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 between e-CRF pages, treatment log forms 
using patient’s diary, and returned unused auto-injectors or capsules of a corresponding 
kit. 
8.8.2 Return and/or destruction of treatments 
It is Sanofi’s responsibility to ensure the destruction of all used or unused alirocumab. All used 
and unused treatments kits will be retrieved by the Sponsor or destroyed on site, depending on 
local requirements. 
A detailed treatment log of the returned and destroyed IMP will be established with the 
Investigator or designee and countersigned by the Investigator and the Monitoring Team. 
The physician will not destroy the used or unused autoinjectors unless Sanofi provides written 
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8.9 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment received by the patient concomitantly to the study 
(from screening visit until follow-up visit).  
Concomitant medications should be kept to a minimum during the study. However, if these are 
considered necessary for the patient’s welfare and are unlikely to interfere with the IMP, they may 
be given at the discretion of the Investigator, with a stable dose (when possible). Besides the 
specific information related to concomitant medications provided in this section, any other 
concomitant medication(s) will be allowed and will have to be recorded in the e-CRF and source 
data.  
For background statins (and any additional LMT as per Section 8.9.1), sites must follow the 
national product label for the safety monitoring and management of patients. 
Nutraceutical products or over-the-counter therapies that may affect lipids are allowed only if they 
have been used at a stable dose for at least 4 weeks prior to screening visit, during the screening 
period and maintained during the 24 weeks of the DBPT. Examples of such nutraceutical products 
or over-the-counter therapies include omega-3 fatty acids at doses <1000 mg, plant stanols such as 
found in Benecol, flax seed oil, and psyllium. 
8.9.1 Management of background lipid modifying therapy / Rescue therapy 
Patients must have been on stable maximally tolerated daily registered doses of statins for at least 
4 weeks before screening visit. 
During the study, the patients should stay on these stable maximally tolerated registered daily 
doses of statins. Lipid profile values from samples obtained after randomization will be blinded. 
Nevertheless, sites will be made aware of TG alert, in order to make decisions on the patient’s 
background LMT.  
From the screening visit (Week -3) until Week 24 of the DBPT, the background LMT should not 
be changed. No dose adjustment, discontinuation or initiation of other statins should take place 
during this time, barring exceptional circumstances whereby overriding concerns (including but 
not limited to TG alert posted by the central lab) warrant such changes, as per the investigator’s 
judgment. 
For a TG alert (see Section 10.6.4) that has been confirmed by repeat testing, the investigator 
should perform investigations, manage the patient, and modify the background LMT as per 
his/her medical judgment. 
In summary, background statin therapy should not be modified from screening to the follow up 
visit. However, up to Week 24, if a confirmed TG alert is reached or if there is an overwhelming 
clinical concern (at the discretion of the investigator) then modification of the background LMT is 
allowed. 
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8.9.2 Contraception 
Women of childbearing potential must take an effective contraceptive method throughout the 
study treatment and for 10 weeks after the last intake of IMP (injection or capsule, whichever 
comes last) (eg, Follow-up visit). 
8.9.3 Prohibited concomitant medications 
Forbidden concomitant medications from the initial screening visit until the randomization visit 
include the following: 
• 
Statins other than atorvastatin, rosuvastatin and simvastatin 
• 
Fibrates  
• 
Cholesterol absorption inhibitor (ie, ezetimibe) 
• 
Omega-3 fatty acid (at doses ≥1000 mg daily)  
• 
Nicotinic acid 
• 
Bile acid-binding sequestrant (such as cholestyramine, colestipol, colesevelam) 
• 
Red yeast rice products 
Forbidden concomitant medications after the randomization visit until the follow up period 
include the following: 
• 
Statins other than atorvastatin, rosuvastatin and simvastatin 
• 
Fibrates (except fenofibrate if patient meets the prespecified TG alert [TG ≥500 mg/dL 
(5.65 mmol/L)]) 
• 
Cholesterol absorption inhibitor (ie, ezetimibe) 
• 
Omega-3 fatty acid (at doses ≥1000 mg daily)  
• 
Bile acid-binding sequestrant (such as cholestyramine, colestipol, colesevelam) 
• 
Red yeast rice products 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
EFFICACY ENDPOINTS 
9.1.1 Primary efficacy endpoint 
The primary efficacy endpoint is the percent change in calculated LDL-C from baseline to 
Week 24, in the intent-to-treat (ITT) population, using all LDL-C values regardless of adherence 
to treatment (ITT estimand). Primary endpoint is defined as:  
100 x (calculated LDL-C value at Week 24 - calculated LDL-C value at baseline) / calculated 
LDL-C value at baseline. 
The baseline calculated LDL-C value will be the last LDL-C level obtained before the first 
double-blind IMP defined as the earliest between the first double-blind injection and the first 
capsule intake. 
The calculated LDL-C at Week 24 will be the LDL-C level obtained within the Week 24 analysis 
window. 
All calculated LDL-C values (scheduled or unscheduled, fasting or not fasting) may be used to 
provide a value for the primary 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 Statistical 
Analysis Plan (SAP).   
9.1.2 Secondary efficacy endpoints 
9.1.2.1 Key secondary efficacy endpoints 
• 
The percent change in calculated LDL-C from baseline to Week 24 in the mITT 
population, using all LDL-C values during the efficacy treatment period as defined in 
Section 11.3.1.2 (on-treatment estimand). 
• 
The percent change in calculated LDL-C from baseline to Week 12 (ITT estimand). 
• 
The percent change in calculated LDL-C from baseline to Week 12 (on-treatment 
estimand).  
• 
The percent change in Apo B from baseline to Week 24 (ITT estimand).  
• 
The percent change in Apo B from baseline to Week 24 (on-treatment estimand).  
• 
The percent change in non-HDL-C from baseline to Week 24 (ITT estimand).  
• 
The percent change in non-HDL-C from baseline to Week 24 (on-treatment estimand).   
• 
The percent change in TC from baseline to Week 24 (ITT estimand). 
• 
The percent change in Apo B from baseline to Week 12 (ITT estimand).  
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• 
The percent change in non-HDL-C from baseline to Week 12 (ITT estimand).  
• 
The percent change in TC from baseline to Week 12 (ITT estimand). 
• 
The proportion of patients reaching calculated LDL-C <70 mg/dL (1.81 mmol/L) at 
Week 24 (ITT estimand). 
• 
The proportion of patients reaching calculated LDL-C <70 mg/dL (1.81 mmol/L) at 
Week 24 (on-treatment estimand). 
• 
The percent change in Lp(a) from baseline to Week 24 (ITT estimand). 
• 
The percent change in HDL-C from baseline to Week 24 (ITT estimand). 
• 
The percent change in fasting TG from baseline to Week 24 (ITT estimand). 
• 
The percent change in Apo A-1 from baseline to Week 24 (ITT estimand). 
• 
The percent change in Lp(a) from baseline to Week 12 (ITT estimand). 
• 
The percent change in HDL-C from baseline to Week 12 (ITT estimand). 
• 
The percent change in fasting TG from baseline to Week 12 (ITT estimand). 
• 
The percent change in Apo A-1 from baseline to Week 12 (ITT estimand). 
9.1.2.2 Other secondary efficacy endpoints 
• 
The proportion of patients with calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 12 
and Week 24 (ITT estimand) 
• 
The proportion of patients reaching calculated  LDL-C <70 mg/dL (1.81 mmol/L) at 
Week 12 (ITT estimand). 
• 
The absolute change in calculated LDL-C (mg/dL and mmol/L) from baseline to Week 12 
and Week 24 (ITT estimand). 
• 
The absolute change in ratio Apo B/Apo A-1 from baseline to Week 12 and Week 24 (ITT 
estimand). 
• 
The proportion of patients with Apo B <80 mg/dL (0.8 g/L) at Week 12 and Week 24 (ITT 
estimand). 
• 
The proportion of patients with non-HDL-C <100 mg/dL (2.59 mmol/L) at Week 12 and 
Week 24 (ITT estimand). 
• 
The proportion of patients with non-HDL-C <130 mg/dL (3.37 mmol/L) at Week 12 and 
Week 24 (ITT estimand). 
• 
The proportion of patients with calculated LDL-C <70 mg/dL (1.81 mmol/L) and/or ≥50% 
reduction in calculated LDL-C (if calculated LDL-C ≥70 mg/dL [1.81 mmol/L]) at 
Week 12 and Week 24 (ITT estimand). 
• 
The proportion of patients with ≥50% reduction in calculated LDL-C at Week 12 and 
Week 24 (ITT estimand). 
• 
The absolute change in ratio TC/HDL-C from baseline to Week 12 and Week 24 (ITT 
estimand). 
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• 
The percent change in TC from baseline to Week 12 and 24 (on-treatment estimand) 
• 
The percent change in Apo B from baseline to Week 12 (on-treatment estimand) 
• 
The percent change in non-HDL-C from baseline to Week 12 (on-treatment estimand) 
• 
The percent change in Lp(a) from baseline to Week 12 and 24 (on-treatment estimand)   
• 
The proportion of patients reaching calculated LDL-C <100 mg/dL (2.59 mmol/L) at 
Week 24 (on-treatment estimand) 
9.1.3 Efficacy assessment method 
9.1.3.1 Lipid parameters 
Total cholesterol, HDL-C, TG, Apo B, Apo A-1, and Lp(a) will be directly measured by the 
Central Laboratory as per the schedule in Section 1.2. LDL-C will be calculated using the 
Friedewald formula (17) at all visits (except Week -1 and Follow Up visit). If TG values exceed 
400 mg/dL (4.52 mmol/L) then the central lab will reflexively measure (via the beta quantification 
method) the LDL-C rather than calculating it. LDL-C will also be measured (via the beta 
quantification method) at Week 0 and Week 24.Non-HDL-C will be calculated by subtracting 
HDL-C from the TC. Apo B/Apo A-1 ratio will be calculated. Detailed procedures of sample 
preparation, storage and shipment will be described in the specific laboratory manual which will 
be provided to sites. Information on the processing, methodology and other relevant information 
will be available in the Reference Laboratory Manual. 
Efficacy endpoints will not be considered as AEs, such as those involving abnormalities in lipid 
levels, unless meeting the criteria in Section 10.4.3. 
9.2 
SAFETY ENDPOINTS 
Observation period 
The observation of safety data will be as follows: 
• 
PRE-TREATMENT period: The PRE-TREATMENT observation period is defined from 
the signed informed consent up to the first dose of double-blind IMP (injection or capsule, 
whichever comes first). 
• 
TEAE period: The TEAE observation period is defined as the time from the first dose of 
double-blind IMP (injection or capsule, whichever comes first) to the last dose of 
double-blind IMP injection + 70 days (10 weeks) as residual effect of treatment is 
expected until 10 weeks after the stop of double-blind IMP. 
• 
POST-TREATMENT period: The POST-TREATMENT observation period is defined as 
the time starting the day after the end of the TEAE period up to the end of the study 
(see definition in Section 6.2.1). 
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9.2.1 Adverse event  
All AEs diagnosed by the investigator, irrespective of the result of the adjudication for CV events, 
will be reported and described. 
All AEs will be coded to a “lowest level term (LTT)”, “preferred term (PT)”, “high level term 
(HLT)”, “high level group term (HLGT)” and associated primary “system organ class (SOC)” 
using the version of medical dictionary for regulatory activities (MedDRA) currently in effect at 
Sanofi at the time of the considered database lock.  
AEs of clinical interest include the following: 
• 
General allergic reactions (using special e-CRF pages, see Section 10.4.5.1, 
Section 10.4.5.2 and Section 10.6.2) 
• 
Local injection site reactions (using special e-CRF pages) (please refer to Section 10.6.1) 
• 
Hemolytic anemia (using special e-CRF pages, see Section 10.4.5.1) 
• 
Neurological (including neurocognitive) AEs (using special e-CRF pages, see  
Section 10.4.5.1, and Section 10.4.5.2) 
• 
Ophtalmologic AEs (using special e-CRF pages, see Section 10.4.5.1 and 
Section 10.4.5.2) 
Adjudicated CV events include all CV AEs positively adjudicated (see Section 10.6.3).  The 
adjudication categories are the following:   
• 
CHD death 
• 
Non-fatal MI 
• 
Fatal and Non-fatal ischemic stroke 
• 
Unstable angina requiring hospitalization 
• 
Congestive heart failure requiring hospitalization 
• 
Ischemia-driven coronary revascularization procedure 
In addition, the classification of all deaths will occur. 
Adverse event observation period 
The AE observations are per the observation periods defined above. 
Death observation period 
The death observations are per the observation period defined above. In addition, “post-study” 
death includes all deaths reported after the end of the study (see definition of end of study period 
per patient in Section 6.2.1). 
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9.2.2 Safety laboratory 
The clinical laboratory data consist of urinalysis, hematology (complete blood cell count [CBC] 
including red blood cell distribution width [RDW] and reticulocyte count, hematocrit, hemoglobin 
[Hb], red blood cell count, white blood cell count with differential blood count and platelet), 
standard chemistry (glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
urea nitrogen, creatinine, uric acid, lactate dehydrogenase [LDH], total protein, albumin and 
gamma glutamyl transferase [γGT]). Hepatitis C antibody, liver panel (ALT, aspartate 
aminotransferase [AST], alkaline phosphatase [ALP], and total bilirubin), and CPK.  
Some additional safety laboratory parameters may be reflexively measured, based on actual data 
(please refer to Section 10.4.5.1).  
Clinical laboratory values will be analyzed after conversion into standard international units. 
Standard international units will be used in all listings and tables. 
9.2.3 Vital signs measurement 
Vital signs include: heart rate (HR), systolic and diastolic BP in sitting position. 
9.3 
OTHER ENDPOINTS 
9.3.1 Anti-alirocumab antibody assessments 
Anti-alirocumab antibodies include the antibody status (positive/negative) and antibody titers. 
9.3.1.1 Sampling time 
Serum samples for anti-alirocumab antibody determination will be drawn periodically throughout 
the study as per schedule noted in the study flowchart of Section 1.2. All scheduled samples will 
be obtained before IMP injection (pre-dose).  
Patients who have a titer at or above 240 for anti-alirocumab antibody at follow-up visit will have 
additional antibody sample(s), at 6 to 12 months after the last dose and thereafter, about every 3 to 
6 months until titer returns below 240. 
In order to maintain the blind of the study, the requests for sample collection of post-study 
anti-alirocumab antibodies will be made on patients with titers below 240 at the follow-up visit.  
The sponsor will notify the sites. 
9.3.1.2 Sampling procedure 
Detailed procedure of sample preparation, storage and shipment will be described in the specific 
laboratory manual which will be provided to sites. Five (5) ml blood volume is to be collected for 
each anti-alirocumab antibody sample. 
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9.3.1.3 Bioanalytical method 
All anti-alirocumab antibody (anti-drug antibody [ADA]) samples will be analyzed by the 
Regeneron Clinical Bioanalysis group. 
Anti-alirocumab antibody samples will be analyzed using a validated non-quantitative, titer-based 
bridging immunoassay. It involves an initial screen, a confirmation assay based on drug 
specificity, and a measurement of the titer of anti-alirocumab antibodies in the sample. 
 
Samples that are positive in the ADA assay will be assessed for neutralizing antibodies using a 
validated, non-quantitative, competitive ligand binding assay 
 
 
 
9.3.2 Glycated hemoglobin A1c  
The absolute change in glycated hemoglobin A1c (HbA1c) (%) from baseline to Week 12 and 
Week 24. 
9.3.3 Pharmacokinetic variables 
Pharmacokinetic variables include total serum alirocumab concentration. Total and free PCSK9 
concentrations will be measured from the same PK sample. 
At least 110 patients in total from pre-selected sites who consented for PK sampling will have PK 
analysis during the study, in order to have 60 paitents on alirocumab treatment (at least 
30 Chinese and 24 Indian patients). 
9.3.3.1 Sampling time 
Serum samples for total alirocumab concentration will be collected before IMP (pre-dose), after 
randomization at Week 0 (randomization visit). Additional samples will be collected before IMP 
(pre-dose) at Week 4, Week 12, Week 16 and Week 24, as per the study flowchart 
(see Section 1.2). 
To collect information on the absorption phase, an optional PK sample will be collected at 5 days 
(±2) after the Week 22 IMP injection or later.   
Randomized patients who agree to have this additional PK sample will be required to provide 
additional consent prior to collection of the PK sample. 
Exact date and time of last IMP administration and PK sampling are to be recorded. 
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9.3.3.2 Sampling procedure 
Detailed procedure of sample preparation, storage and shipment will be described in the specific 
laboratory manual which will be provided to sites. Five (5) ml blood volume is to be collected for 
each PK sample. 
9.3.3.3 Bioanalytical method 
All PK samples will be analyzed by the Regeneron Clinical Bioanalysis Group. 
PK samples will be analyzed for the determination of total alirocumab concentrations (ie, free 
alirocumab and alirocumab present in PCSK9: alirocumab complexes) using a validated 
enzyme-linked immunosorbent assay (ELISA).
 
PK samples can also be analyzed for the determination of the total and free PCSK9 levels using 
validated ELISA. 
9.3.4 Pharmacogenetic Samples 
 
 
  
 
 
 
 
 
 
 
 
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10 
STUDY PROCEDURES 
For all visits after Day 1/Week 0 (randomization visit), a timeframe of a certain number of days 
will be allowed. The window period for visits at Weeks 12 and 24 are ± 3 days, and for all other 
site visits it is ±7 days during the DBTP, and follow-up period. A window period of +3 days is 
allowed for the randomization visit (Day 1/Week 0) and ±7 days for the injection training visit 
during the screening period (Week -1).   
For all visits after Day 1/randomization visit, if one visit date is changed, then the next visit 
should take place according to the original schedule as outlined Section 1.2. 
Blood samplings:  
The blood sampling for determination of lipid parameters (ie, TC, LDL-C, HDL-C, TG, 
non-HDL-C, Apo B, Apo A-1, Apo B/Apo A-1 ratio, Lp[a]) should be performed in the morning, 
in fasting condition (ie, overnight, at least 10-12 hours fast and refrain from smoking) for all site 
visits throughout the study. Alcohol consumption within 48 hours and intense physical exercise 
within 24 hours preceding the blood sampling are discouraged.  
NOTE: if the patient is not in fasting conditions, the blood sample will not be collected and a new 
appointment will be given the day after (or as close as possible to this date) to the patient with 
instruction to be fasted (see above conditions).   
Laboratory tests:  
The laboratory data are collected in accordance with the study schedule in Section 1.2: 
• 
Hematology 
• 
Chemistry  
• 
Liver panel: in case of total bilirubin values above the normal range, differentiation into 
conjugated and non-conjugated bilirubin will occur automatically.   
• 
CPK  
• 
Hepatitis B surface antigen  
• 
Hepatitis C antibody: positive tests will be confirmed with reflexive testing at the end of 
treatment only. 
• 
Serum pregnancy test 
Urine samplings: 
• 
Urinalysis - will assess for pH, specific gravity, and for the presence of blood, protein, 
glucose, ketones, nitrates, leukocyte esterase, uro-bilinogen and bilirubin.  
• 
Urine pregnancy test 
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NOTE: 
Any clinically relevant abnormal laboratory value should be immediately rechecked for 
confirmation before making any decision for the concerned patient. It should be documented as an 
AE/SAE as applicable. Please also refer to Section 10.4.3.  
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix C, Appendix D and Appendix E. 
Other endpoints assessment methods 
All other blood parameters will also be measured during the study (as per the schedule in 
Section 1.2, on blood samples taken preferably in the morning in fasting condition (at least 10 to 
12 hours fast and refrain from smoking). Alcohol consumption within 48 hours and intense 
physical exercise within 24 hours preceding the blood sampling are discouraged. 
• 
Glycemic parameters (HbA1c) and serum glucose will be measured, periodically 
throughout the study as per the schedule in Section 1.2. 
NOTE: in case of high HbA1c values at screening, the investigator is responsible for the 
optimization of the patient’s treatment to achieve HbA1c targets as defined by local guidelines or 
the Standards of Medical Care in Diabetes-2012 by the American Diabetes Association (46,47).  
PK samples  
Serum samples for assessment of alirocumab concentration will be obtained periodically 
throughout the study as per schedule note in study flowchart of Section 1.2. 
Library samples  
Library (plasma and serum) samples should be collected, as permitted by local regulatory policies. 
They will be collected periodically throughout the study as per schedule noted in the study 
flowchart of Section 1.2. The first scheduled sample at randomization visit will be obtained before 
IMP injection (predose).  
Library samples will be coded to maintain patient confidentiality and may be stored for up to 
10 years for exploratory research that may include the study of PCSK9 levels, PCSK9 function, 
effect(s) of PCSK9 inhibition with a monoclonal antibody, lipoprotein sub-fractionation, and 
mechanisms of hyperlipidemia and CV disease (eg lipoprotein–associated phospholipase A2). If 
needed, samples may also be used to identify markers associated with toxicity.  
 
 
Detailed procedure of sample preparation, storage and shipment will be described in the specific 
laboratory manual which will be provided to sites. Library samples will be sent to a central 
laboratory (only for randomized patients) for long-term storage between –70°C to –85°C. 
• 
Plasma samples: 8.5 mL blood volume to be collected as specified in the specific 
laboratory manual   
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• 
Serum samples:  2.5 mL blood volume to be collected as specified in the specific 
laboratory manual 
Physical examination:  
A general physical examination should be performed at the time points indicated in the study 
schedule flowchart in Section 1.2. If a new clinically significant abnormality or worsening from 
baseline is detected after randomization, then an AE should be reported and the patient should be 
considered for further clinical investigations and/or specialist consultation as per the investigator’s 
medical judgment.   
Blood pressure / heart rate:  
Blood pressure should be measured in sitting position under standardized conditions, 
approximately at the same time of the day, on the same arm, with the same apparatus (after the 
patient has rested comfortably in sitting position for at least five minutes). Values are to be 
recorded in the e-CRF; both systolic BP and diastolic BP should be recorded. At the first 
screening visit, BP should be measured in both arms. The arm with the highest diastolic pressure 
will be determined at this visit, and BP should be measured on this arm throughout the study. This 
highest value will be recorded in the e-CRF.   
Heart rate will be measured at the time of the measurement of BP. 
NOTE: in case of high BP values at screening the investigator is responsible for the optimization 
of the patient’s treatment to achieve BP targets as defined by local guidelines or the Seventh 
Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of 
High Blood Pressure (JNC 7) (48).  
Electrocardiogram:  
The 12-lead electrocardiogram (ECG) should be performed after at least 10 minutes rest and in 
the supine position. The electrodes should be positioned at the same place as much as possible, for 
each ECG recording throughout the study. The ECG will be interpreted locally by the 
investigator. Any new and/or clinically significant changes in ECG parameters should be 
immediately rechecked for confirmation before making any decision for the concerned patient. 
Any clinically significant abnormality should be documented as an AE/SAE as applicable. Please 
also refer to Section 10.4.3. Each trace will be analyzed in comparison with the screening 
recorded trace. All ECG traces will be kept as source data. 
Body weight and height 
Body weight should be obtained 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 needs to be measured as self-reported heights are not acceptable. 
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10.1 
VISIT SCHEDULE 
10.1.1 Screening Period 
Only patients who meet the inclusion criteria as noted in Section 7.1 should be screened. The 
screening period will take place up to 3 weeks or 21 days (and as short as possible, upon receipt of 
laboratory eligibility criteria) prior to randomization/Day 1 visit. The first screening visit 
(Week -3) can take place from 21 to 8 days before the randomization visit. If it is planned to have 
another designated person administer the injections to the patient during the study, then this 
person should be present at the injection training visit (Week -1). 
10.1.1.1 Screening Visit (Visit1/Week -3 /Day -21 up to -8) 
• 
Complete informed consent - the patient will receive complete information about the study 
both verbally and in writing. Written informed consent for the study must be obtained 
prior to any study-related investigations 
• 
Assess inclusion/exclusion criteria 
• 
Obtain patient demography – age, gender, race, and ethnicity 
• 
Obtain medical history (including menopausal status), surgical history, alcohol habits, and 
smoking habits 
• 
Obtain family medical history including risk factors related to premature CHD (before 
55 years of age in a male, 65 years in a female first degree relative), allergy and Type 2 
diabetes 
• 
Document prior medication history within the previous 12 weeks, especially for LMT 
(including statin) and nutraceutical products that may affect lipids (eg, omega-3 fatty acids 
at doses <1000 mg, plant stanols such as found in Benecol, flax seed oil, psyllium)   
• 
Record concomitant medication 
• 
Get body weight and height measurements   
• 
Take vital signs including HR and BP 
• 
Contact IVRS/IWRS for notification of screening.  Patient number will be allocated by the 
IVRS/IWRS.  This patient number is composed of a 9-digit number containing the 3-digit 
country code, the 3-digit center code and the 3-digit patient chronological number (the 
3-digit patient chronological number is 001 for the first patient screened in a center, 
002 for the second patient screened in the same center) 
• 
Collect AEs from this point onward:  
All AEs and SAEs will be collected from the time of informed consent signature and 
throughout the study until the post study treatment follow up visit. 
• 
Perform 12-lead ECG 
• 
Urinalysis  
• 
Obtain fasting blood sample for: 
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- 
Lipids: measure or calculation of TC, LDL-C, HDL-C, TG, non-HDL-C 
- 
Hematology: CBC including RDW and reticulocyte count, hematocrit, Hb, red blood 
cell count, white blood cell count with differential blood count and platelet  
- 
Chemistry: glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
urea nitrogen, creatinine, uric acid, LDH, total protein, albumin and γGT 
- 
HbA1c 
- 
TSH 
- 
Liver panel (ALT, AST, ALP, and total bilirubin) 
- 
CPK 
- 
Hepatitis B surface antigen and hepatitis C antibody tests 
- 
Serum pregnancy test (women of child bearing potential [WOCBP] only). 
NOTE: All patients will be qualified for randomization based on the laboratory results 
obtained at this visit.   
• 
An appointment will be given for the next visit. 
• 
If it is planned to have another designated person administer the injections to the patient 
during the study, then this person should also be present at the next visit (injection-training 
visit at Week -1) 
10.1.1.2 Injection-training Visit at Screening (Visit 2/Week -1/Day -7 ± 7) 
• 
Assess inclusion/exclusion criteria 
• 
Collect AEs  
• 
Record concomitant medication  
• 
Take vital signs including HR and BP   
• 
IVRS/IWRS contact for allocation of a batch number for training kit  
• 
Record batch number allocated in e-CRF 
• 
Injection training should be provided as outlined in Section 8.1 
• 
The placebo for alirocumab should be administered by the patient or another designated 
person (such as spouse, relative, etc) at the study site under supervision of site staff with 
appropriate feedback 
• 
If patient will undergo the second optional injection training with placebo for alirocumab, 
then the following steps are needed.  However, if patient does not need a second optional 
training injection with placebo then do not perform these steps: 
- 
Recontact IVRS/IWRS for allocation of a second new batch number for a second 
training kit 
- 
Record the second batch number allocated in e-CRF 
- 
Dispense the second placebo training injection to the patient for self-administration 
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• 
An appointment will be given for the next visit 
• 
Remind patient to be in fasting conditions (ie, overnight, at least 10 to12 hours fast and 
refrain from smoking) for next visit. Also, alcohol consumption within 48 hours and 
intense physical exercise within 24 hours preceding the next visit are discouraged  
10.1.2 Double-Blind Double-Dummy Treatment Period (Study Site Visits) 
10.1.2.1 Randomization Visit (Visit 3/Week 0/Day 1 + 3) 
• 
Assess Inclusion/Exclusion Criteria 
• 
Collect AEs  
• 
Record concomitant medication 
• 
Review patient’s diet.  Patient should be on a NCEP ATP III TLC diet or equivalent. 
• 
Perform physical examination 
• 
Get body weight measurement   
• 
Take vital signs including HR and BP   
• 
 
   
- 
 
  
• 
Present ICF for the optional PK (for a subset of patients), and if patient agrees to 
participate then obtain written consent.   
- 
If patient declines participation in the PK then this has no consequences for 
participation in the study otherwise.   
• 
Urinalysis 
• 
Urine pregnancy test (WOCBP only). 
• 
Obtain fasting blood sample for: 
- 
Lipids: measure and/or calculation of TC, LDL-C, HDL-C, TG, non-HDL-C, Apo B, 
Apo A-1, Apo B/Apo A-1 ratio and Lp(a) 
- 
Library samples 
- 
Hematology: CBC including RDW and reticulocyte count, hematocrit, Hb, red blood 
cell count, white blood cell count with differential blood count and platelet  
- 
Chemistry: glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
urea nitrogen, creatinine, uric acid, LDH, total protein, albumin and γGT 
- 
Liver panel (ALT, AST, ALP, and total bilirubin) 
- 
CPK 
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- 
Anti-alirocumab antibodies (to be performed prior to the IMP injection, after 
randomization) 
- 
Serum alirocumab concentration (PK), for specifically consented patients only (to be 
performed prior to the IMP injection, after randomization)  
- 
 
• 
If the patient is confirmed eligible (and in fasting conditions), the Investigator will start the 
next study procedures: 
- 
IVRS/IWRS contact for randomization and allocation of two 7-digit treatment kit 
numbers according to the randomization list, for the alirocumab injections and the 
ezetimibe capsules. Investigators should never allocate a treatment kit number to a 
patient without contacting IVRS/IWRS. 
• 
Double-blind IMP kits dispensation as per treatment kit numbers provided by IVRS/IWRS 
along with schedule reminder. The patient injection instruction manual and treatment 
administration package should be provided.  The patient diary should be given and 
instructions on its completion should be reviewed. 
• 
The first double-blind IMP injection and the first ezetimibe capsule administration will 
take place at the study site, but only after the collection of the fasting blood samples and 
after the assessment of all evaluations planned at that visit. Close supervision, feedback 
and further training to be provided for IMP administration. The patient should be observed 
for at least 30 minutes after the injection. 
• 
Reminders 
- 
An appointment will be given for the next study site visit. 
- 
Remind patient to be in fasting conditions (ie, overnight, at least 10 to 12 hours fast 
and refrain from smoking) for next study site visit. Also, alcohol consumption within 
48 hours and intense physical exercise within 24 hours preceding the next study site 
visit are discouraged. 
- 
Patient to bring the diary, at the next study site visit. 
- 
Patient to bring used and unused kits at the next study site visit  
10.1.2.2 Visit 4/ Week 4, Visit 5/ Week 8 and Visit 7/Week 16 (Day 29, 57 and 113 ± 7)   
• 
Collect AEs 
• 
Record concomitant medication 
• 
Take vital signs including HR and BP   
• 
Data collection on IMP administration and IMP compliance check by review of diary and 
treatment kit 
• 
Obtain fasting blood sample for: 
- 
Lipids: measure or calculation of TC, LDL-C, HDL-C, TG, non-HDL-C 
NOTE – For Week 8 visit, please ensure that unscheduled fasting blood sample 
through the Central Lab for the lipid parameters are obtained if the lipid lab parameters 
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are not done as per schedule or the lipid labs were drawn but an issue is later 
discovered with the samples which require retesting. 
- 
Liver panel (ALT, AST, ALP, and total bilirubin) 
- 
Anti-alirocumab antibodies (Visit 4/Week 4 only) (to be performed prior to the IMP 
injection) 
- 
Library sample (Visit 4/Week 4 only) 
- 
Serum alirocumab concentration (Visit 4/Week 4 and Visit 7/Week 16 only), for 
specifically consented patients only 
• 
Reminders 
- 
An appointment will be given for the next study site visit. 
- 
Remind patient to be in fasting conditions (ie, overnight, at least 10 to 12 hours fast 
and refrain from smoking) for next study site visit. Also, alcohol consumption within 
48 hours and intense physical exercise within 24 hours preceding the next study site 
visit are discouraged. 
- 
Patient to bring the diary at the next study site visit.   
- 
Patient to bring used and unused kits at the next study site visit  
10.1.2.3 Visit 6/Week 12 (Day 85 ± 3):  
• 
Collect AEs 
• 
Record concomitant medication 
• 
Get body weight measurement 
• 
Take vital signs including HR and BP   
• 
Review patient’s diet. Patient should be on a NCEP-ATPIII TLC diet or equivalent  
• 
Urinalysis  
• 
Urine pregnancy test (WOCBP only). 
• 
Obtain fasting blood sample for: 
- 
Lipids: measure and/or calculation of TC, LDL-C, HDL-C, TG, non-HDL-C, Apo B, 
Apo A-1, Apo B/Apo A-1 ratio and Lp(a) 
- 
Library samples 
- 
Serum alirocumab concentration (PK), for specifically consented patients only 
- 
Hematology: : CBC including RDW and reticulocyte count, hematocrit, Hb, red blood 
cell count, white blood cell count with differential blood count and platelet  
- 
Chemistry: glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
urea nitrogen, creatinine, uric acid, LDH, total protein, albumin and γGT 
- 
HbA1c  
- 
Liver panel (ALT, AST, ALP, and total bilirubin) 
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- 
CPK 
- 
Anti-alirocumab antibodies (to be performed prior to the IMP injection) 
• 
Data collection on IMP administration and IMP compliance check by review of diary and 
treatment kit accountability. 
• 
IVRS/IWRS contact to get treatment kit number for two kits resupply, for the alirocumab 
injections and the ezetimibe capsules. 
• 
Double-blind IMP kits dispensation as per treatment kit numbers provided by IVRS/IWRS 
along with schedule reminder and the treatment administration package should be 
provided.  The patient injection instruction manual and diary may be given, as needed. 
• 
Reminders 
- 
An appointment will be given for the next study site visit. 
- 
Remind patient to be in fasting conditions (ie, overnight, at least 10 to 12 hours fast 
and refrain from smoking) for next study site visit.  Alcohol consumption within 
48 hours and intense physical exercise within 24 hours preceding the next study site 
visit are discouraged. 
- 
Patient to bring the diary at the next study site visit. 
- 
Patient to bring used and unused kits at the next study site visit  
10.1.2.4 Unscheduled PK visit / 5 days (± 2) after Week 22 IMP injection or after (optional) 
• 
Obtain fasting blood sample 5 days (±2 days) after the IMP injection for: 
- 
Serum alirocumab concentration (PK) 
10.1.2.5 Visit 8/Week 24 (Day 169 ± 3): End of treatment visit 
• 
Collect AEs 
• 
Record concomitant medication 
• 
Get body weight measurement   
• 
Take vital signs including HR and BP 
• 
Review patient’s diet. Patient should be on a NECP-ATP III TLC diet or equivalent  
• 
Perform 12-lead ECG  
• 
Perform physical examination 
• 
IVRS/IWRS contact to document the end of treatment 
• 
Data collection on IMP administration and IMP compliance check by review of diary and 
treatment kit accountability. 
• 
Urinalysis  
• 
Urine pregnancy test (WOCBP only). 
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• 
Obtain fasting blood sample for: 
- 
Anti-alirocumab antibodies (to be performed prior to the IMP injection). 
- 
Lipids: measure and/or calculation of TC, LDL-C, HDL-C, TG, non-HDL-C, Apo B, 
Apo A-1, Apo B/Apo A-1 ratio and Lp(a) 
- 
Library samples 
- 
Hematology: CBC including RDW and reticulocyte count, hematocrit, Hb, red blood 
cell count, white blood cell count with differential blood count and platelet  
- 
Chemistry: glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
urea nitrogen, creatinine, uric acid, LDH, total protein, albumin and γGT 
- 
Hepatitis C Antibody Test (with automatic confirmatory testing if positive) 
- 
HbA1c 
- 
Liver panel (ALT, AST, ALP, and total bilirubin) 
- 
CPK 
- 
Serum alirocumab concentration (PK) 
• 
Reminders 
- 
An appointment will be given for the next study site visit. 
- 
Remind patient to be in fasting conditions (ie, overnight, at least 10-12 hours fast and 
refrain from smoking) for next study site visit, if needed. Also, alcohol consumption 
within 48 hours and intense physical exercise within 24 hours preceding the next study 
site visit are discouraged. 
- 
Sharp-container (containing all used auto-injectors) must be returned at site for 
destruction. 
10.1.3 Follow-Up Period  
10.1.3.1 Follow-Up Visit (Visit 9/ Week 32/ Day 225 ± 7) 
• 
Collect AEs 
• 
Record concomitant medication 
• 
Get body weight measurement   
• 
Take vital signs including HR and BP.   
• 
Perform physical examination (only in case of clinically relevant abnormality at the end of 
treatment visit) 
• 
IVRS/IWRS contact to document the end of study 
• 
Urinalysis (only in case of clinically relevant abnormal value at the end of treatment visit) 
• 
Urine pregnancy test (WOCBP only) 
• 
Obtain fasting blood sample for: 
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- 
Anti-alirocumab antibodies (as per schedule note in study flowchart of Section 1.2) 
- 
Only in case of clinically relevant abnormal values for these parameters at the end of 
treatment visit will the following be obtained at this visit: 
a) Hematology: CBC including RDW and reticulocyte count, hematocrit, Hb, red blood 
cell count, white blood cell count with differential blood count and platelet  
b) Chemistry: glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
urea nitrogen, creatinine, uric acid, LDH, total protein, albumin and γGT 
c) HbA1c 
d) Liver panel (ALT, AST, ALP, and total bilirubin) 
e) CPK 
10.2 
DEFINITION OF SOURCE DATA 
Evaluations that are reported in the e-CRF must be supported by appropriately signed identified 
source documentation related but not limited to the following: 
• 
Agreement, date, and signature of informed consent mentioning the study identification. 
• 
Patient identification, last participation in a clinical trial, medical history, associated 
diseases, and data related to the studied pathology. 
• 
Contraception methods for women of childbearing potential. 
• 
Previous and concomitant medication (including the LMT). 
• 
Study identification. 
• 
Treatment number, dates of administration. 
• 
Dates of visits and assessments including the examination report. 
• 
Vital signs, height, body weight. 
• 
Faxed central lab reports (dated and signed by the Principal Investigator or 
Subinvestigator). 
• 
IVRS/IWRS confirmation fax (screening, screen failure, training kit allocation, 
randomization, treatment reallocation, discontinuation, end of DBTP, end of study, 
unblinding if applicable). 
• 
ECG records signed and dated. 
• 
AEs and follow-up: 
- 
In case of SAE, the site should file in the source document at least copies of the 
hospitalization reports and any relevant examination reports documenting the 
follow-up of the SAE. 
• 
Date of premature study discontinuation (if any) and reason. 
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• 
Patient’s identity. 
• 
Medical history. 
• 
Hospital records. 
• 
Nursing notes. 
• 
Physician’s notes. 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION  
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined if the stop can be made temporarily; permanent IMP discontinuation should be a last 
resort. Any IMP discontinuation should be fully documented in the e-CRF and source notes. In 
any case, the patient should remain in the study as long as possible. 
Pregnancy will lead to definitive treatment discontinuation in all cases.  
10.3.1 Temporary treatment discontinuation with investigational medicinal product(s) 
Temporary treatment discontinuation (also referred to as treatment interruption) may be 
considered by the Investigator because of suspected AEs. Reinitiating of treatment with the IMP 
will be done under close and appropriate clinical and/or laboratory monitoring once the 
Investigator will have considered according to his/her best medical judgment that the 
responsibility of the IMP in the occurrence of the concerned event was unlikely and if the 
selection criteria for the study are still met (refer to Section 7.1 and Section 7.2). 
All treatment interruption duration should be recorded by the Investigator in the appropriate 
e-CRF screens when considered as confirmed. 
Treatment interruption is defined as one or more scheduled injections or one or more capsules that 
are not administered to the patient as decided by the Investigator.    
10.3.2 Permanent treatment discontinuation with investigational medicinal product(s) 
Permanent treatment discontinuation (also referred to as treatment discontinuation) is any 
treatment discontinuation associated with the definitive decision from the Investigator or the 
patient not to re-expose the patient to the IMP at any time. 
Patient withdrawal from the study treatment or study should be avoided as much as possible.  
10.3.3 List of criteria for permanent treatment discontinuation 
The patients may withdraw from treatment if they decide to do so, at any time and irrespective of 
the reason, or this may be the Investigator’s decision. All efforts should be made to document the 
reasons for treatment discontinuation and this should be documented in the e-CRF. 
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Patients should discontinue the IMP for the following reasons: 
• 
Pregnancy, intention for pregnancy, or no longer with effective contraceptive method of 
birth control (females only). 
• 
Acute injection reaction of clinical concern. 
• 
Serious adverse event (or non-serious but severe in intensity) of hypersensitivity reaction 
considered related to IMP. 
• 
At patient request "i.e., withdrawal of the consent for treatment" 
• 
If, in the investigator's opinion, continuation with the administration of the IMP would be 
detrimental to the patient's well-being. 
• 
Intercurrent condition that requires discontinuation of the IMP (eg, laboratory 
abnormalities, please refer to decision tree Appendix D. 
• 
At the specific request of the Sponsor. 
• 
Any code breaking requested by the Investigator. 
• 
Patient receives double-blind treatment prior to randomization  
10.3.4 Handling of patients after permanent treatment discontinuation 
Patients who prematurely discontinue study treatment (regardless of the reason) should still 
continue the study and undergo all visits and procedures as described in Section 1.2 with the 
exception of study treatment administration and its associated procedures. At the time of treatment 
discontinuation, the patient should have, as soon as possible, an unscheduled visit with 
assessments normally planned at end of treatment visit (this should take place within 5 days of 
treatment discontinuation, if possible) and then resume the original study schedule until end of 
study (ie, follow up visit). In particular, in case of early treatment discontinuation before week 24, 
all efforts should be done to perform the week 12 and week 24 visits.  
If after treatment discontinuation, the patient refuses to continue the study, then if possible, the 
patient should undergo an unscheduled visit with assessments normally planned at the end of 
treatment visit (it should take place within 5 days of treatment discontinuation, if possible). The 
patient, at a minimum, should then be followed up for at least 10 weeks from last study treatment 
administration or up to recovery or stabilization of any AE to be followed-up as specified in this 
protocol, whichever comes last.  A final end of study visit can take place with assessments as 
specified in the end of study visit (ie, follow up visit) at 10 weeks after the premature treatment 
discontinuation. 
All definitive discontinuation of study treatment should be recorded by the Investigator in the 
appropriate screens of the e-CRF and in the patient’s medical records when considered as 
confirmed. IVRS/IWRS should be notified when a patient prematurely discontinues study 
treatment. 
For patients randomized and not treated, all efforts should be made to perform the Week 12 and 
Week 24 visits in order to collect the laboratory data and at the least, the lipid parameters. 
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10.3.5 Procedure and consequence for patient withdrawal from study 
The patients may withdraw from the study, before study completion if they decide to do so, at any 
time and irrespective of the reason. Withdrawal of consent for treatment should be distinguished 
from withdrawal of consent for follow-up visits and from withdrawal of consent for non-patient 
contact follow-up, eg, medical records check. Patients requesting withdrawal should be informed 
that withdrawal of consent for follow-up may jeopardize the public health value of the study. If 
possible, the patients should be assessed using the procedures defined above. All study 
withdrawals should be recorded by the Investigator in the appropriate screens of the e-CRF and in 
the patient’s medical records (with, in this medical records, at least date of withdrawal and reason 
for) when considered as confirmed. 
Patients who withdraw should be explicitly asked about the contribution of possible AEs to their 
decision to withdraw consent, and any AE information elicited should be documented. Preferably 
the patient should withdraw consent in writing and, if the patient or the patient’s representative 
refuses or is physically unavailable, the site should document and sign the reason for the patient’s 
failure to withdraw consent in writing. 
For patients who fail to return to the site, the Investigator should make the best effort to re-contact 
the patient (eg, contacting patient’s family or private physician, review available registries or 
health care database), and to determine his/her health status, including at least his/her vital status. 
Attempts to contact such patients must be documented in the patient’s records (eg, times and dates 
of attempted telephone contact, receipt for sending a registered letter). 
The SAP will specify how these patients lost to follow-up for their primary endpoints will be 
considered. 
Patients who have withdrawn from the study cannot be re-randomized (treated) in the study. Their 
inclusion and treatment number must not be reused. 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.4.1 Definitions of adverse events 
Please refer to Appendix C for AE reporting requirements. 
10.4.1.1 Adverse event 
An Adverse Event is any untoward medical occurrence or clinical investigation in a patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. 
10.4.1.2 Serious adverse event 
A Serious Adverse Event is any untoward medical occurrence that at any dose: 
• 
Results in death or; 
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• 
Is life-threatening or; 
Note: The term "life-threatening" in the definition of "serious" refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization or; 
• 
Results in persistent or significant disability/incapacity or; 
• 
Is a congenital anomaly/birth defect; 
• 
Is a medically important event: 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention (ie, specific measures or corrective treatment) to prevent one of the other outcomes 
listed in the definition above. 
NOTE: The following medically important events intend to serve as a guideline for determining 
which condition has to be considered as a medically important event. It is not intended to be 
exhaustive: 
• 
Intensive treatment in an emergency room or at home for: 
- 
allergic bronchospasm,  
- 
blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia…),  
- 
convulsions (seizures, epilepsy, epileptic fit, absence…) 
• 
Development of drug dependency or drug abuse, 
• 
ALT >3 ULN + total bilirubin >2 ULN or asymptomatic ALT increase  >10 ULN, 
• 
Suicide attempt or any event suggestive of suicidality, 
• 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling), 
• 
Bullous cutaneous eruptions, 
• 
Cancers diagnosed during the study or aggravated during the study, 
• 
Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study.  
10.4.2 Adverse event of special interest 
Adverse event of special interest are AEs (serious or non-serious) that need to be monitored, 
documented, and managed in a pre-specified manner described in the protocol. Please see Section 
10.4.5 and Appendix C for additional information.  
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10.4.3 General guidelines for reporting adverse events 
All AEs regardless of seriousness or relationship to IMP, spanning from the signature of the ICF, 
until the end of the study (post-study treatment follow up visit), are to be recorded on the 
corresponding screen(s) included in the e-CRF.  
Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. The 
Investigator should specify the date of onset, intensity, action taken with respect to IMP, 
corrective treatment/therapy given, additional investigations performed, outcome and his/her 
opinion as to whether there is a reasonable possibility that the AE was caused by the IMP. 
Laboratory, vital signs or ECG abnormalities are to be recorded as AEs only if:  
• 
Symptomatic and/or  
• 
Requiring either corrective treatment or consultation, and/or  
• 
Leading to IMP discontinuation or modification of dosing, and/or  
• 
Fulfilling a seriousness criterion, and/or  
• 
Defined as an AE of special interest with immediate notification. 
See Appendix C for a summary of AE reporting guidelines. 
10.4.4 Instructions for reporting serious adverse events 
In the case of occurrence of a SAE, the Investigator must immediately: 
• 
ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the e-CRF; the system will automatically send the notification to the Monitoring Team and 
Pharmacovigilance after approval of the Investigator within the e-CRF or after a standard 
delay.  
• 
SEND (preferably by fax or e-mail) the photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the 
Monitoring Team whose name, fax number and email address appear on the Clinical Trial 
Protocol. Care should be taken to ensure that the patient's identity is protected and the 
patient's identifiers in the Clinical Trial are properly mentioned on any copy of source 
document provided to the Sponsor. For laboratory results, include the laboratory normal 
ranges. 
• 
All further data updates should be recorded in the e-CRF as appropriate, and further 
documentation as well as additional information (for Lab data, concomitant Medication, 
patient status ..) should be sent (by fax or e-mail) to the Monitoring Team within 24 hours 
of knowledge. In addition, any effort should be made to further document each Serious AE 
that is fatal or life threatening within the week (7 days) following initial notification. 
• 
A back-up plan will be used (using paper flow) when the e-CRF system does not work. 
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10.4.5 Guidelines for reporting adverse events of special interest   
10.4.5.1 Reporting of adverse events of special interest (AESI) with immediate notification 
For these AEs, the Sponsor will be informed immediately (ie, within 24 hours), as per SAEs 
notification described in Section 10.4.4, even if not fulfilling a seriousness criterion, using the 
corresponding screens in the e-CRF.  
• 
ALT ≥3 ULN (if baseline ALT <ULN) Or ALT ≥2 times the baseline value (if baseline 
ALT ≥ULN) (Please refer to related flowchart in Appendix D. 
• 
Allergic events 
- 
General allergic drug reactions and/or local injection site reactions deemed to be 
allergic (or have an allergic component) that require consultation with another 
physician for further evaluation of hypersensitivity/allergy, as per the investigator's 
medical judgment or as per Section 10.6.2, should be reported as an AESI with 
immediate notification. These reactions require completion of the specific e-CRF 
screen (see Section 10.6.2) 
- 
General allergic events, and all injection site reactions require completion of the 
specific e-CRF screen (see Section 10.6.2), regardless of requirements for immediate 
reporting. 
• 
Hemolytic anemia (See Section 10.4.6.1 and Appendix E) 
- 
If there is a decrease in Hb and reflexive testing as per Appendix E suggesting 
hemolysis, then report this as an AESI with immediate notification.  Special e-CRF 
screen will need to be completed.     
• 
Pregnancy 
- 
Pregnancy occurring in a female patient enrolled in the clinical trial will be recorded as 
a pre-specified AE with immediate notification and IMP should be discontinued in all 
cases. It will be qualified as an SAE only if it fulfills the SAE criteria. The follow-up 
of the pregnancy will be mandatory until the outcome has been determined. 
- 
Pregnancy occurring in a female partner of a male patient enrolled in the clinical trial, 
if permitted by the female partner and by local regulatory policies, pregnancy will be 
recorded as a pre-specified AE with immediate notification. The pregnancy will be 
qualified as an SAE only if it fulfills the SAE criteria and should be followed-up until 
the outcome has been determined. 
• 
Symptomatic Overdose with IMP 
- 
Alirocumab or placebo for alirocumab: 
f) 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 the intended dose within the intended therapeutic interval (ie, 
2 or more injections from the double-blind treatment kit are administered in 
<7 calendar days); to be reported using the corresponding screens in the e-CRF using 
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the Term ‘Symptomatic OVERDOSE (accidental [or intentional])’. The patient should 
be monitored and appropriate symptomatic treatment instituted. 
g) The circumstances of the overdose should be clearly specified in the verbatim. 
- 
Ezetimibe or placebo for ezetimibe: 
a) An overdose (accidental or intentional) is an event suspected by the Investigator or 
spontaneously notified by the patient (not based on systematic capsule counts) and 
defined as at least twice the intended dose within the intended therapeutic interval (ie, 
2 or more capsules from the double-blind treatment kit are administered within one 
calendar day); 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. 
• 
Neurological (including neurocognitive) Events 
- 
Neurological (including neurocognitive) Events that require additional 
examinations/procedures and/or referral to a specialist should be reported as an AESI 
with immediate notification. 
• 
Ophthalmologic Events  
- 
Ophthalmologic Events that require additional examinations/procedures and/or referral 
to a specialist should be reported as an AESI with immediate notification. 
10.4.5.2 Reporting of adverse events of special interest (AESI) without immediate 
notification  
See Appendix C. 
For these AEs, the Sponsor does not have to be informed immediately, unless meeting seriousness 
criterion. 
• 
Asymptomatic overdose with IMP 
- 
Alirocumab or placebo for alirocumab: 
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 the intended dose within the intended therapeutic interval 
(ie, 2 or more injections from the double-blind treatment kit are administered in 
<7 calendar days); to be reported using the corresponding screens in the e-CRF using 
the Term ‘Asymptomatic OVERDOSE (accidental [or intentional])’. The patient 
should be monitored for any AEs and treated, as needed.  
- 
Ezetimibe or placebo for ezetimibe: 
An overdose (accidental or intentional) is an event suspected by the Investigator or 
spontaneously notified by the patient (not based on systematic capsule counts) and 
defined as at least twice the intended dose within the intended therapeutic interval 
(ie, 2 or more capsules from the double-blind treatment kit are administered within one 
calendar day); to be reported using the corresponding screens in the e-CRF using the 
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Term ‘Asymptomatic OVERDOSE (accidental [or intentional])’. The patient should be 
monitored for any AEs and treated, as needed. 
• 
Local injection site reactions (see Section 10.6.1) 
- 
Local injection site reactions that are considered as non-allergic events and that are 
related to the IMP injection, as opposed to another injectable agent, should be further 
characterized by evaluating the related symptoms that comprise an injection site 
reaction such as but not limited to redness, pain, etc (See Appendix G). Special e-CRF 
screens will need to be completed.  If such an AE were to occur, then do not report the 
individual components of the reaction but rather the term “local injection site 
reaction”, the individual components being described in the specific e-CRF screen.  
• 
Allergic events (local injection site reaction and/or general allergic reaction) not referred 
for consultation with another physician (see Section 10.4.5.1) should be reported as AESI 
without immediate notification 
- 
All allergic events will need to have allergy specific e-CRF screens completed 
(see Section 10.6.2), regardless of requirements for immediate reporting. 
• 
Neurological (including neurocognitive) events 
- 
Any AEs related to neurological (including neurocognitive) abnormalities with the 
exception of those requiring additional examinations/procedures and/or referral to a 
specialist (as mentioned in Section 10.4.5.1) should be reported as AESI without 
immediate notification 
• 
Ophthalmologic events 
- 
Any AEs related to ophthalmologic abnormalities with the exception of those requiring 
additional examinations/procedures and/or referral to a specialist (as mentioned in 
Section 10.4.5.1), should be reported as AESI without immediate notification 
10.4.6 Guidelines for management of specific laboratory abnormalities 
Laboratory abnormalities with pre-specified monitoring should be monitored, documented, and 
managed according to the related flowchart in protocol Appendix C, Appendix D and Appendix E 
• 
Neutropenia 
• 
Thrombocytopenia 
• 
Increase in ALT 
• 
Acute renal insufficiency 
• 
Increase in CPK and suspicion of rhabdomyolysis 
• 
Decrease in Hb (defined as ≥1.5 g/dL)  
10.4.6.1 Hemoglobin decrease 
Please refer to Appendix E. 
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At the first post-randomization occurrence of a Hb measurement decrease by ≥1.5 g/dL as 
compared to the randomization visit Hb measurement, then the Central Lab will reflexively 
measure haptoglobin using specimens already obtained at the same time point for which the Hb 
decrease was detected. In the same time the reticulocyte count, LDH and total bilirubin will be 
measured. The Central Lab will provide the results of the reticulocyte count, haptoglobin, LDH 
and indirect bilirubin (reflexively measured only if the total bilirubin >ULN) to the investigator.   
• 
If the following pattern of abnormalities is noted: 
- 
Reticulocyte count >Central Lab’s upper limit of the reference range (also referred to 
as ULN) AND 
- 
Haptoglobin <Central Lab’s lower limit of the reference range (also referred to as 
LLN) AND 
- 
LDH >ULN AND 
- 
Indirect bilirubin >ULN  (only if the total bilirubin >ULN) 
The patient should be referred to a hematologist. The hematologist should obtain a peripheral 
blood smear and anti-erythrocyte antibodies (direct and indirect) by Coombs test. Further 
investigations are at the discretion of the hematologist.   
• 
If the results are normal or the pattern of abnormality is something other than that 
described above, then the investigator should exercise his/her medical judgment in the 
interpretation of the results, necessity for workup of the decrease in Hb or referral to a 
hematologist.  
If a second Hb measurement demonstrating a further decrease of ≥1 g/dL from the last available 
value is observed, even if the previous work-up was negative, the same investigations can be 
repeated and a hematology consultation can be requested at the discretion of the Investigator or at 
the Sponsor's request. 
10.5 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner all SAEs that are 
both unexpected and at least reasonably related to the IMP (Suspected Unexpected Serious 
Adverse Reaction [SUSAR]), to the Health Authorities, Independent Ethics Committee 
(IEC)/Institutional Review Board (IRB) as appropriate and to the Investigators.    
In addition, the Sponsor will report in an expedited manner all SAEs that are expected and at least 
reasonably related to the IMP to the Authorities, according to local regulations. 
In this study, some AEs are considered related to the underlying condition and thus will not be 
considered unexpected as given in the CIB.  
Any other AE not listed as an expected event in the CIB or in this protocol will be considered as 
unexpected. 
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The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report. 
10.6 
SAFETY INSTRUCTIONS 
10.6.1 Local tolerability (Local Injection Site Reactions) 
In case the Investigator or the patient recognizes any signs of local intolerability, then this should 
be treated and followed up as per the investigator’s medical judgment.  See Section 10.4.5.2 and 
Appendix C for further information. 
10.6.2 Allergic adverse events 
See Section 10.4.5.1 and Section 10.4.5.2. 
Specific e-CRF screens are to be filled in to assess allergic reactions or allergic-like reactions that 
may occur during the clinical studies conducted with alirocumab. 
Sometimes transient injection site reactions, irritant in nature, may occur, requiring no 
intervention and being of uncertain significance. These reactions would not be considered to be 
allergic reactions.  
AEs that may constitute an allergic reaction (eg, generalized itch, nasal itch, swelling at injection 
site, flushing, hives, swelling at lips, eyes, face, tongue, hands, feet, lump in throat, difficulty to 
swallow, hoarseness, change in pitch of voice, incapacity to speak, wheezing, chest tightness, 
stridor) should be considered to be reported on the General Allergic Reaction and/or Local 
Injection Site Reaction Complementary Form. 
AEs that are obviously not of allergic origin (eg, local injection site reactions) should only be 
recorded on the Local Injection Site Reaction Complementary Form.  However, injection site 
reactions which progress/expand/worsen/etc should be evaluated as recommended in 
Section 10.6.2.1 and General Allergic Reaction Complementary form should be completed. 
The IMP should be immediately interrupted (temporarily discontinued) if there is a suspicion of 
an allergic event related to IMP.  See Section 10.3.1 for further information on treatment 
interruption and Section 10.3.3 for criteria for permanent treatment discontinuation. 
10.6.2.1 Allergic adverse events with cutaneous involvement 
AEs with cutaneous involvement which are obviously of allergic origin, general allergic reactions 
or local injection site reactions (with an allergic component) which progress/expand/worsen/etc 
should be evaluated by a dermatologist as soon as possible, and preferably within one week of the 
site first becoming aware of the event. 
The investigator should evaluate the patient for possible etiologies (new medications, etc) and 
extra-cutaneous symptoms and signs.  An unscheduled Central Laboratory assessment for 
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hematology, chemistry, liver panel and ADA should be obtained. If it is possible, the site will take 
pictures of the skin lesions in order to provide the patient with them for the dermatologist’s visit. 
If the photos are obtained, then copies should be kept as source documents which may later be 
collected by the sponsor.  The investigator will provide a summary of the patient's case, reason for 
consultation, and information being requested to the consulting dermatologist.   
A full consultation report should be sent by the dermatologist to the investigator.  The full report 
should contain, at a minimum, the following information; a detailed description of the rash 
(such as the morphology [lesion type], shape of individual lesions, arrangement of multiple 
lesions [eg, scattered, grouped, linear], distribution, color, consistency, presence of pruritus or 
pain, and other clinical signs) and in case a skin biopsy (including histopathology and 
immunofluorescence) was done (if it was deemed necessary as per the dermatologist’s or 
investigator’s medical judgment), the results of this investigation with, if applicable, a specific 
diagnosis of the AE. The investigator will fax the full report and the corrected AE form if 
necessary, to the Monitoring Team Representative within 24 hours.  
10.6.2.2 Acute allergic Injection Reactions  
See Section 10.4.5.2. 
Acute allergic injection reaction (which are considered under the category of general allergic 
reactions) is defined as any AE that occurs during or shortly after injection of the IMP 
(characterized by but not limited to hypotension, bronchoconstriction, urticaria, edema, 
angioedema, nausea, vomiting).  Emergency equipment and medication for the treatment of these 
potential adverse effects (eg, antihistamines, bronchodilators, IV saline, corticosteroids, 
acetaminophen, and epinephrine) must be available for immediate use for the injections at the 
training, and randomization visits. 
Patients will be observed at the investigational site for at least 30 minutes following the injection 
that takes place at the randomization visit. Patients should be treated symptomatically if any AEs 
are observed. Patients are to remain at the site until any acute injection reaction is assessed as 
stable, per the Investigator’s discretion. 
General Allergic Reaction and/or Local Injection Site Reaction Complementary Form will have to 
be completed. 
10.6.3 Cardiovascular events 
The following suspected or confirmed cardiovascular events that occur from randomization until 
the follow-up visit, should have a corresponding specific eCRF pages ± adjudication package 
prepared (as per the site manual) and submitted to the CEC: 
• 
MI 
• 
Cerebrovascular events (eg, stroke, transient ischemic attack, intracranial bleeding, 
ischemia or bleeding of spine or retina) 
• 
Unstable angina requiring an emergency room visit or requiring/prolonging hospitalization 
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• 
Congestive heart failure requiring an emergency room visit or requiring/prolonging 
hospitalization 
• 
All coronary revascularization procedures (eg, PCI, CABG) 
• 
All deaths (including CHD death) 
All suspected or confirmed cardiovascular events should also be reported as SAEs. For coronary 
revascularization procedures, please note that a medical or surgical procedure should not be 
reported as an adverse event, but rather, the reason for the procedure should be reported as the 
adverse event term (eg, unstable angina leading to PCI should be reported as ‘unstable angina’ 
instead of ‘PCI’).  
10.6.4 Laboratory alert related to TG rescue  
The lipid results on blood samples obtained after the randomization visit will not be 
communicated to the investigators. However, sites will be notified if any of the following occur: 
• 
TG alert: 
- 
TG ≥500 mg/dL (5.65 mmol/L) (any time after randomization).    
Repeat testing should be done as soon as possible for the TG alert.  For a confirmed TG alert, 
please refer to the relevant information in Section 8.9.1 for further information.  
10.7 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final clinical study report. 
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11 
STATISTICAL CONSIDERATIONS 
11.1 
DETERMINATION OF SAMPLE SIZE 
A total sample size of 96 patients (64 in alirocumab and 32 in ezetimibe) will have 95% power to 
detect a difference in means percent change in LDL-C of 20% with a 0.05 two-sided significance 
level and assuming a common standard deviation (SD) of 25% and all these 96 patients having an 
evaluable primary endpoint. 
Nevertheless, to meet registration requirement and provide safety documentation in participating 
countries the final total sample size will be 600 with a randomization ratio 2:1 (400 in alirocumab 
and 200 in ezetimibe arms). 
Calculations were made using nQuery Advisor 7.0. 
11.2 
DISPOSITION OF PATIENTS 
Screened patients are defined as any patient who 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 populations.  
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population. The safety experience associated with any later 
randomization will be assessed separately. 
The safety experience of patients treated and not randomized will be reported separately, and 
these patients will not be in the safety population. 
11.3 
ANALYSIS POPULATIONS 
11.3.1 Efficacy populations 
The primary efficacy analysis population will be the ITT population as defined below. 
 
 
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11.3.1.1 Intent–to-treat population 
ITT population: all randomized patients who had an evaluable primary endpoint. The primary 
endpoint is evaluable when the following 2 conditions are met:  
• 
Availability of at least 1 baseline calculated LDL-C value; 
• 
 Availability of at least 1 calculated LDL-C value within one of the analysis windows up 
to Week 24 
Patients in the ITT population will be analyzed according to the treatment group allocated by 
randomization (ie, as-randomized treatment group).  
11.3.1.2 Modified Intent–to-treat (mITT) population 
The mITT population is defined as the all randomized patients who took at least 1 dose or part of 
a dose of study drug (injection or capsule) and have an evaluable primary efficacy endpoint 
during the efficacy treatment period.  The primary efficacy endpoint is considered as evaluable 
when the following 2 conditions are met: 
• 
Availability of  a baseline calculated LDL-C value; 
• 
Availability of at least 1 calculated LDL-C value within one of the analysis windows up to 
Week 24 and during the efficacy treatment period.   
The efficacy treatment period is defined as the time period from the first double-blind IMP 
(injection or capsule, whichever comes first) up to the day of last injection + 21 days or the day of 
last capsule intake date +3 days, whichever comes first. 
Patients in the mITT population will be analyzed according to the treatment group allocated by 
randomization. 
11.3.2 Safety population 
The safety population considered for safety analyses will be the randomized patients who actually 
received at least 1 dose or part of a dose of the double-blind IMP (injection or capsule). Patients 
will be analyzed according to the treatment actually received (alirocumab or ezetimibe). 
In addition:  
• 
Randomized patients for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized. 
• 
For patients receiving study drug from more than 1 treatment group during the trial, the 
treatment group allocation for as-treated analysis will be the one in which the patient was 
treated with the longest duration. 
  
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11.3.3 Other analysis population  
The anti-alirocumab antibody analysis will be performed on all treated patients (safety population) 
with a blood sample on Week 0 (baseline) and at least one evaluable blood sample for antibodies 
after first double-blind IMP injection. 
 
The PK analysis will be performed in a subset of randomized and treated patients who will have at 
least one evaluable blood sample for PK after first double-blind IMP injection. 
 
 
11.4 
STATISTICAL METHODS 
11.4.1 Extent of study treatment exposure and compliance 
The extent of study treatment exposure and compliance will be assessed and summarized by 
actual treatment received within the safety population. 
In order to ensure the continuity of the investigational treatment for the patients without 
interruption (only in case a disruption occurs in the availability of device components or during 
production of the auto injectors), back-up plans may be implemented as described in Section 8.1. 
In that case, exposure to initial device and back-up device will be summarized and impact on 
study results will be assessed. More details will be provided in the SAP, if applicable. 
11.4.1.1 Extent of investigational medicinal product exposure 
The total exposure will be assessed by: 
• 
Duration of IMP injection exposure in weeks defined as: (last dose of double-blind IMP 
injection date – first dose of double-blind IMP injection date + 14 days)/7, regardless of 
unplanned intermittent discontinuations. 
• 
Duration of IMP capsule exposure in weeks defined as: (last capsule intake date – first 
capsule intake date + 1 day)/7, regardless of unplanned intermittent discontinuations. 
• 
The total number of injections by patient. 
The number (n) and percentage (%) of patients with an up-titration in the alirocumab group will 
be described.  
11.4.1.2 Compliance  
Compliance will be assessed using the following parameters: 
• 
The mean injection frequency of IMP double-blind injections will be defined for each 
patient as the average number of days between 2 injections, that is: (last dose date – first 
dose date)/(number of injections -1). 
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• 
The compliance for capsules will be defined as the number of capsules taken / (last 
capsule intake date – first capsule intake date + 1) * 100 during the capsule exposure 
period. 
These parameters will be summarized descriptively (N, Mean, SD, Median, Min and Max). 
11.4.2 Analyses of efficacy endpoints 
11.4.2.1 Analysis of primary efficacy endpoint(s)  
The percent change from baseline in calculated LDL-C at Week 24 as defined in Section 9.1.1 
will be analyzed in the ITT population using a mixed effect model with repeated measures 
(MMRM) approach. All post-baseline data available within Week 4 to Week 24 analysis windows 
will be used and missing data are accounted for by the MMRM model. The model will include the 
fixed categorical effects of treatment group (ezetimibe versus alirocumab), time point (Week 4, 
Week 8, Week 12, Week 16, Week 24), ), randomization strata (prior history of MI or ischemic 
stroke [Yes/No], statin treatment [atorvastatin 40 to 80 mg daily or rosuvastatin 20 to 40 mg daily 
versus simvastatin whatever the daily dose, atorvastatin below 40 mg daily or rosuvastatin below 
20 mg daily], and country), treatment-by-time point interaction and strata-by time point 
interaction, as well as, the continuous fixed covariates of baseline LDL-C value and baseline 
value-by-time point interaction. Model assumptions for normality will be explored prior to the 
analysis testing.  
This model will be run using 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 LS means 
estimates at Week 24 for both treatment groups with their corresponding standard errors (SE) and 
95% confidence intervals (CI). To compare the alirocumab group to the ezetimibe group, an 
appropriate contrast statement will be used to test the differences of these estimates, at the 2-sided 
0.05 level.  
Let µ0 and µ1 be the population means of the percent change from baseline in calculated LDL-C 
at Week 24 under ezetimibe and alirocumab, respectively. The hypothesis that will be tested is 
“H0: µ0 = µ1” versus “H1: µ0 ≠ µ1”. 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). In addition, sensitivity analysis 
will be conducted using measured LDL-C to evaluate the robustness of the results regardless of 
the way to assess LDL-C. Correlation of calculated LDL-C with measured LDL-C will be 
explored graphically as deemed necessary.  
11.4.2.2 Analysis of secondary efficacy endpoint(s) 
Method for controlling the overall type-I error rate when testing the key secondary efficacy 
endpoints is described in Section 11.4.2.3. 
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For key secondary efficacy endpoints (defined in Section 9.1.2.1) and other secondary efficacy 
endpoints (described in Section 9.1.2.2), descriptive summaries and analyses will be performed in 
the ITT population or mITT population depending on the estimand used.   
For descriptive summaries, percent change from baseline in calculated LDL-C, TC, HDL-C, TG, 
and non-HDL-C will be provided at each time point for each treatment group.  All measurements, 
scheduled or unscheduled will be assigned to analysis windows defined in the SAP in order to 
provide an assessment for these time points.  Laboratory assessments other than the ones provided 
by the central laboratory will be excluded.  For TG, measurements on not-fasting patients will be 
excluded.  The time profile of each parameter will be plotted by treatment group with the 
corresponding SE. Similar tables (with either percent change from baseline or absolute change 
from baseline for the ratio) and plots will be provided for other efficacy parameters:  ApoB, 
ApoA-1, ApoB/ApoA-1 ratio, Lp(a).  For TG and Lp(a), summary statistics will include Q1 and 
Q3, and medians (instead of means) by time point will be plotted. 
Multiple types of measurements are planned to be analyzed during differing time points in the 
trial, specifically continuous measurements expected to have a normal distribution 
(example: percent change in calculated LDL-C), continuous measurements expected to have a 
non-normal distribution (example: TG), and binary measurements (example: proportion of 
patients reaching LDL-C <100 mg/dL).  
Continuous endpoints anticipated to have a normal distribution 
Continuous secondary variables defined in Section 9.1.2 anticipated to have a normal distribution 
(ie, lipids other than TG and Lp[a]) will be analyzed using the same MMRM model as for the 
primary endpoint. Specifically, the model will contain fixed categorical effects of treatment 
group, randomization strata, planned time points to Week 24, 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. 
Continuous endpoints anticipated to have a non-normal distribution 
Continuous secondary efficacy variables endpoints defined in Section 9.1.2 anticipated to have a 
non-normal distribution (ie, TG and Lp[a]) will be analyzed using a robust regression model 
(ie, ROBUSTREG SAS procedure with M-estimation option) with treatment group and 
randomization strata as main effect and corresponding baseline value(s) as covariate. Missing 
values will be addressed using a multiple imputation approach, which will be described in the 
SAP.  The variables in the multiple imputation model will at least include the same variables as 
used in the robust regression model.  The treatment group combined means will be provided with 
respective SE estimates. The combined mean difference between the treatment groups will be 
provided with the SE, 95% CI and p-value.  
Binary endpoints 
Binary secondary efficacy variables defined in Section 9.1.2 will be analyzed in using logistic 
regression with treatment group as main effect and corresponding baseline value(s) as covariate, 
stratified by randomization factors. Missing values will be addressed using a multiple imputation 
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approach which will be described in the SAP.  The variables in the multiple imputation model will 
at least include the same variables as used in the logistic regression model. Treatment effects will 
be compared and the combined odds ratio estimate between the treatment groups, with the 
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 one treatment arm and thus the maximum likelihood estimate may not exist), the 
LOCF (Last Observation Carried Forward) approach would be used for handling of missing 
values and a stratified 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 Week 24 time window (or Week 12 as applicable) to impute the missing Week 24 value (or 
Week 12 respectively).  
11.4.2.3 Multiplicity considerations 
In order to handle multiple key secondary endpoints, the overall type-I error will be controlled by 
the use of a sequential inferential approach. Statistical significance of the primary parameter at the 
0.05 alpha level is required before drawing inferential conclusions about first key secondary 
parameter (refer to order of list in Section 9.1.2.1). Inferential conclusions about successive key 
secondary parameters require statistical significance of the prior one. 
This fixed hierarchical approach will ensure a strong control of the overall type-I error rate at the 
0.05 level. 
No further adjustments will be made for other secondary endpoints for which p-values will be 
provided for descriptive purpose. 
11.4.3 Analyses of safety data 
The summary of safety results will be presented by treatment group. No formal inferential testing 
will be performed. Summaries will be descriptive in nature.  
All safety analyses will be performed on the Safety population using the following common rules: 
• 
The baseline value is defined generally as the last available value before double IMP 
(injection or capsule, whichever comes first).   
The following definitions will be applied to laboratory parameters and vital signs. 
• 
The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests and vital signs.  
• 
PCSA criteria will determine which patients had at least 1 PCSA during the TEAE period, 
taking into account all evaluations performed during the TEAE period, including 
unscheduled or repeated evaluations.  The number of all such patients will be the 
numerator for the on-treatment PCSA percentage.   
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• 
Treatment period: the treatment period used for quantitative analysis is defined as the time 
from first dose of double-blind IMP (injection or capsule, whichever comes first) to the 
last dose of double-blind IMP injection + 21 days.  
AE definition: 
• 
Pre-treatment AEs are AEs that developed or worsened or became serious during the 
PRETREATMENT period; 
• 
Treatment-emergent AEs (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 
POSTTREATMENT period. 
Drug induced liver injury  
The 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 PCSA values 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 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 PT 
will be based on standardized MedDRA query (SMQ) Hepatic disorder. Time to liver-related 
treatment discontinuation and time to liver death may also be provided based on hepatic disorder 
SMQ. 
11.4.3.1 Adverse events 
Adverse event incidence tables will present by SOC (sorted by internationally agreed order), 
HLGT, HLT and PT sorted in alphabetical order for each treatment group, the number (n) and 
percentage (%) of patients experiencing an AE.  Multiple occurrences of the same event in the 
same patient will be counted only once in the tables within a treatment phase. The denominator 
for computation of percentages is the safety population within each treatment group. 
Adverse event incidence table will be provided by treatment group for all types of TEAEs: all 
TEAEs, all treatment emergent AESI (defined with a PT or a prespecified grouping), TEAE by 
maximal intensity, all treatment emergent SAEs and all TEAEs leading to permanent treatment 
discontinuation. 
If any clinically significant signal is detected and need further characterization or for AE of 
clinical interest, exploration of time to onset will be performed for these selected TEAEs as 
described below to account for the differential exposure time in all patients. 
Selected TEAEs will be also analyzed using time-to-event approach (Kaplan-Meier 
methodology). Time from the first dose of double-blind IMP injection to the first occurrence of 
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the event will be calculated (only the first event will be counted). Patients without any event will 
be censored at the end of the TEAE period. 
Death: The following deaths summaries will be generated: 
• 
Number (%) of patients who died by study period (TEAE, on-study, 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 CRF page as reported by the 
Investigator) by primary SOC , HLGT, HLT and PT showing number (%) of patients 
sorted by internationally agreed order of SOC and alphabetic order of HLGT, HLT, and 
PT.  
Adjudicated cardiovascular events: 
The number and percentage of patients experiencing a positively adjudicated CV event will be 
presented by treatment group overall and by category of adjudication. 
11.4.3.2 Laboratory and vital signs 
The summary statistics (including mean, median, Q1, Q3, SE, minimum and maximum) of all 
laboratory variables and all vital signs 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 
SE 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 criterion or criteria 
For laboratory parameters for which PCSA criterion 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. 
11.4.4 Analyses 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 double-blind IMP (injection or capsule, whichever 
comes first). 
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The number and percentage of patients with 2 consecutive results, spaced out by at least 21 days, 
of calculated LDL-C <25 mg/dL and calculated LDL-C <15 mg/dL, respectively, will be provided 
by 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. 
HbA1c will be summarized by time points using number of available data, mean, SD, median, 
minimum, and maximum for each treatment group. The time profile of each parameter will be 
also plotted by treatment group with the corresponding SE.  
Further details will be provided in SAP. 
11.4.5 Analyses of pharmacokinetic variables 
Serum total alirocumab concentrations, total and free PCSK9 concentrations if applicable, will be 
summarized by treatment group and visit using descriptive statistics. Serum concentration time 
profiles will be provided by treatment group. Additional plots will be prepared, as deemed 
necessary. Further details will be provided in SAP. 
Serum total alirocumab concentrations might be used for population PK modeling if considered 
necessary. Further details will be provided in Population Analysis Plan and the results of 
population PK modeling will be reported separately from the study report. 
11.4.6 Analyses of pharmacogenomics variables 
 
 
 
11.5 
INTERIM ANALYSIS 
No interim analysis is planned. 
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12 
ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 
ETHICAL AND REGULATORY STANDARDS 
This clinical trial will be conducted by the Sponsor, the Investigator, delegated Investigator staff 
and Subinvestigator, in accordance with the principles laid down by the 18th World Medical 
Assembly (Helsinki, 1964) and all applicable amendments laid down by the World Medical 
Assemblies, and the International Conference on Harmonization (ICH) guidelines for good 
clinical practice (GCP), all applicable laws, rules and regulations. 
This clinical trial will be recorded in a free, publicly accessible, internet-based registry, no later 
than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with Sanofi public disclosure commitments.  
12.2 
INFORMED CONSENT 
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the patient of all 
pertinent aspects of the clinical trial including the written information giving approval/favorable 
opinion by the Ethics Committee (IRB/IEC). All participants should be informed to the fullest 
extent possible about the study, in language and terms they are able to understand. 
Prior to a patient’s participation in the clinical trial, the written ICF should be signed, name filled 
in and personally dated by the patient or by the patient’s legally acceptable representative, and by 
the person who conducted the informed consent discussion. A copy of the signed and dated 
written ICF will be provided to the patient.  
Prior to collection of blood for pharmacokinetics and/or pharmacogenetics, the optional 
pharmacokinetic and/or pharmacogenetic ICF (written) should be signed, name filled in, and 
personally dated by the patient or by the subject’s legally acceptable representative, and by the 
person who conducted the informed consent discussion. A copy of the signed and dated written 
optional informed consent form will be provided to the subject. 
The informed consent form, optional pharmacokinetic and/or pharmacogenetic informed consent 
form used by the Investigator for obtaining the patient's informed consent must be reviewed and 
approved by the Sponsor prior to submission to the appropriate Ethics Committee (IRB/IEC) for 
approval/favorable opinion. 
12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) 
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the appropriate IRB/IEC, and is required to forward to the respective other party 
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a copy of the written and dated approval/favorable opinion signed by the Chairman with  IRB/IEC 
composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, ICF, CIB, Investigator’s curriculum vitae, etc) and the date of the 
review should be clearly stated on the written (IRB/IEC) approval/favorable opinion. 
IMP will not be released at the study site and the Investigator will not start the study before the 
written and dated approval/favorable opinion is received by the Investigator and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the IRB/IEC before implementation, unless the change is necessary to eliminate an 
immediate hazard to the patients, in which case the IRB/IEC should be informed as soon as 
possible. It should also be informed of any event likely to affect the safety of patients or the 
continued conduct of the clinical trial, in particular any change in safety. All updates to the CIB 
will be sent to the IRB/IEC. 
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial.  
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13 
STUDY MONITORING 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the e-CRF, Discrepancy Resolution Form [DRF] or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Subinvestigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Subinvestigators shall be appointed and listed in a timely manner. The 
Subinvestigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR 
The Sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the e-CRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE documentation, IMP allocation, patient 
compliance with the IMP regimen, IMP accountability, concomitant therapy use and quality of 
data. 
13.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH GCP, the monitoring team must check the e-CRF entries against the source 
documents, except for the pre-identified source data directly recorded in the e-CRF. The informed 
consent form will include a statement by which the patient allows the Sponsor’s duly authorized 
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personnel, the Ethics Committee (IRB/IEC), and the regulatory authorities to have direct access to 
original medical records  which support the data on the e-CRFs (eg, patient's medical file, 
appointment books, original laboratory records). These personnel, bound by professional secrecy, 
must maintain the confidentiality of all personal identity or personal medical information 
(according to confidentiality and personal data protection rules). 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS AND ADDITIONAL REQUEST 
It is the responsibility of the Investigator to maintain adequate and accurate e-CRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All e-CRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data. 
Should a correction be made, the corrected information will be entered in the e-CRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the Sponsor as soon as they are entered in the e-CRF. 
The computerized handling of the data by the Sponsor may generate additional requests (DRF) to 
which the Investigator is obliged to respond by confirming or modifying the data questioned. The 
requests with their responses will be managed through the e-CRF. 
13.5 
USE OF COMPUTERIZED SYSTEMS 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor and Investigator study files. 
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14 
ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Subinvestigator will be signed, dated and provided to the Sponsor prior to 
the beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES 
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that 
a longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to 
a mutually agreed upon designee.  
14.3 
CONFIDENTIALITY 
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the e-CRF, the CIB and the results obtained 
during the course of the clinical trial, is confidential, prior to the publication of results. The 
Investigator and any person under his/her authority agree to undertake to keep confidential and 
not to disclose the information to any third party without the prior written approval of the 
Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
Ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The Subinvestigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Subinvestigators of the confidential nature of the clinical trial. 
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The Investigator and the Subinvestigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
14.4 
PROPERTY RIGHTS 
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff/Subinvestigator not to 
mention any information or the Product in any application for a patent or for any other intellectual 
property rights. 
All the results, data, documents and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Subinvestigators shall provide all assistance 
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.5 
DATA PROTECTION 
• 
The patient's personal data, which are included in the Sponsor database shall be treated in 
compliance with all applicable laws and regulations; 
• 
When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 
• 
The Sponsor also collects specific data regarding Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations. 
14.6 
INSURANCE COMPENSATION 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship.  This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IECs/IRBs or regulatory authorities in countries requiring this document.  
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14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES 
For the purpose of ensuring compliance with the clinical trial protocol, GCP and applicable 
regulatory requirements, the Investigator should permit auditing by or on the behalf of the 
Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
14.8.1 By the Sponsor  
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
• 
The information on the product leads to doubt as to the benefit/risk ratio; 
• 
Patient enrollment is unsatisfactory; 
• 
The Investigator has received from the Sponsor all IMP, means and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon; 
• 
Non-compliance of the Investigator or Subinvestigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP; 
• 
The total number of patients are included earlier than expected; 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
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14.8.2 By the Investigator 
The Investigator may terminate his/her participation upon thirty (30) days' prior written notice if 
the study site or the Investigator for any reason becomes unable to perform or complete the 
clinical trial.  
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.9 
CLINICAL TRIAL RESULTS 
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS 
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway or 
planned within twelve (12) months of the completion of this study at all sites, the Investigator 
shall have the right to publish or present independently the results of this study in agreement with 
other Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of 
any such presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication.  In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
90 days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights.  
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes of the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) 
to clinical trial patients, or when the change(s) involves only logistical or administrative aspects of 
the trial. Any change agreed upon will be recorded in writing, the written amendment will be 
signed by the Investigator and by the Sponsor and the signed amendment will be filed with this 
clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In some instances, an amendment may require a change to the ICF. The Investigator must receive 
an IRB/IEC approval/favorable opinion concerning the revised ICF prior to implementation of the 
change and patient signature should be re-collected if necessary. 
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16 
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21. Benjannet S, Rhainds D, Essalmani R, Mayne J, Wickham L, Jin W, et al. NARC-1/PCSK9 
and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) 
receptor and LDL cholesterol. J Biol Chem. 2004;279(47):48865-75. 
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22. Park SW, Moon YA, Horton JD. Post-transcriptional regulation of low density lipoprotein 
receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J Biol Chem. 
2004;279:50630-8. 
23. Rashid S, Curtis DE, Garuti R, Anderson NN, Bashmakov Y, Ho YK, et al. Decreased plasma 
cholesterol and hypersensitivity to statins in mice lacking PCSK9. Proc Natl Acad Sci USA. 
2005;102(15):5374-9. 
24. Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M, et al. Mutations in 
PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34(2):154-6. 
25. Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH. Sequence variations in PCSK9, low LDL, 
and protection against coronary heart disease. N Engl J Med. 2006;354(12):34-42. 
26. Steinberg D, Witztum JL. Inhibition of PCSK9: a powerful weapon for achieving ideal LDL 
cholesterol levels. Proc Natl Acad Sci USA. 2009;106(24):9546-7. 
27. Koren M, Stein E, Roth E, Mckenney JM, Gipe D, Hanotin C, et al. Efficacy, safety and 
tolerability of 150 mg Q2W dose of the anti-PCSK9 mAb, REGN727/SAR236553: Data from 
3 phase 2 studies Eur. Heart J. 2012;33:37. 
28. Alirocumab CIB Ed. 8 (May 2015) 
29. Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, et al. ODYSSEY LONG 
TERM Investigators. Efficacy and Safety of Alirocumab in Reducing Lipids and 
Cardiovascular Events. N Engl J Med. 2015;372(16):1489-99. 
30. Wiviott SD, Cannon CP, Morrow DA, Ray KK, Pfeffer MA, Braunwald E, et al. Can low-
density lipoprotein be too low? The safety and efficacy of achieving very low low-density 
lipoprotein with intensive statin therapy: a PROVE IT-TIMI 22 substudy. J Am Coll Cardiol. 
2005;46(8):1411-6. 
31. LaRosa JC, Grundy SM, Kastelein JJ, Kostis JB, Greten H, Treating to New Targets (TNT) 
Steering Committee and Investigators. Safety and efficacy of Atorvastatin-induced very low-
density lipoprotein cholesterol levels in Patients with coronary heart disease (a post hoc 
analysis of the treating to new targets [TNT] study). Am J Cardiol. 2007;100(5):747-52. 
32. Hsia J, MacFadyen JG, Monyak J, Ridker PM. Cardiovascular event reduction and adverse 
events among subjects attaining low-density lipoprotein cholesterol <50 mg/dl with 
rosuvastatin. The JUPITER trial (Justification for the Use of Statins in Prevention: an 
Intervention Trial Evaluating Rosuvastatin). J Am Coll Cardiol. 2011;57(16):1666-75. 
33. Zhao Z, Tuakli-Wosornu Y, Lagace TA, Kinch L, Grishin NV, Horton JD, et al. Molecular 
characterization of loss-of-function mutations in PCSK9 and identification of a compound 
heterozygote. Am J Hum Genet. 2006;79(3):514-23. 
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34. Bhatt DL, Eagle KA, Ohman EM, Hirsch AT, Goto S, Mahoney EM, et al. Comparative 
determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with 
atherothrombosis. JAMA. 2010;304(12):1350-7. 
35. Krempf M, Parhofer KG, Steg PG, Bhatt DL, Ohman EM, R?ther J, et al. Cardiovascular 
event rates in diabetic and nondiabetic individuals with and without  established 
atherothrombosis (from the REduction of Atherothrombosis for Continued Health [REACH] 
Registry). Am J Cardiol. 2010;105(5):667-71. 
36. Cano JF, Baena-Diez JM, Franch J, Vila J, Tello S, Sala J, et al. Long-term cardiovascular risk 
in type 2 diabetic compared with nondiabetic first acute myocardial infarction patients: a 
population-based cohort study in southern Europe. Diabetes Care. 2010;33(9):2004-9. 
37. Ara R, Tumur I, Pandor A, Duenas A, Williams R, Wilkinson A, et al. Assessment Report 
Guide Ezetimibe for the treatment of hypercholesterolaemia. Technology Assessment Report 
commissioned by the NHS R&D HTA Programme on behalf of the National Institute for 
Health and Clinical Excellence - 08 Dec 2006. 
https://www.nice.org.uk/guidance/ta132/documents/assessment-report-december-20062 (last 
access date 17 Dec 2015) 
38. China expert consensus on clinical usage of cholesterol absorption inhibitor. Chin J Intern 
Med. 2013;52(7):617-620. 
39. Gagne C, Bays HE, Weiss SR, Mata P, Quinto K, Melino M, et al. Efficacy and safety of 
ezetimibe added to ongoing statin therapy for treatment of patients with primary 
hypercholesterolemia. Am J Cardiol. 2002;90(10):1084-91. 
40. Conard SE, Bays HE, Leiter LA, Bird SR, Rubino J, Lowe RS, et al. Efficacy and safety of 
ezetimibe added on to atorvastatin (20 mg) versus uptitration of atorvastatin (to 40 mg) in 
hypercholesterolemic patients at moderately high risk for coronary heart disease. Am J Cardiol. 
2008;102(11):1489-94. 
41. Leiter LA, Bays H, Conard S, Bird S, Rubino J, Hanson ME, et al. Efficacy and safety of 
ezetimibe added on to atorvastatin (40 mg) compared with uptitration of atorvastatin (to 80 mg) 
in hypercholesterolemic patients at high risk of coronary heart disease. Am J Cardiol. 
2008;102(11):1495-501. 
42. Bardini G, Giorda CB, Pontiroli AE, Grazie C, Rotella CM. Ezetimibe + simvastatin versus 
doubling the dose of simvastatin in high cardiovascular risk diabetics: a multicenter, 
randomized trial (the LEAD study). Cardiovascular Diabetology. 2010;9:20 
43. Mikhailidis DP, Sibbring GC, Ballantyne CM, Davies GM, Catapano L. Meta-analysis of the 
cholesterol lowering effect of ezetimibe added to ongoing statin therapy. Curr Med Res Opin. 
2007;23:2009-26. 
44. Nelson RG, Tuttle KR. The new KDOQI TM clinical practice guidelines and clinical practice 
recommendations for diabetes and CKD. Blood Purif. 2007;25:112–114. 
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45. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. M3(R2): Guidance on nonclinical safety studies for the 
conduct of human clinical trials and marketing authorization for pharmaceuticals. ICH.2009:1-
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46. Standards of medical care in diabetes- 2014. Diabetes Care. 2014;37 Suppl 1:S14-80. 
47. Executive summary: Standards of medical care in diabetes- 2014. Diabetes Care. 2014;37 
Suppl 1:S5-13. 
48. Chobanian AV, 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;289(19):2560-72.  
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17 
APPENDICES 
Appendix A. 
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  
* NCEP 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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Appendix B. 
The Stages of Heart Failure – NYHA Classification 
Physicians often assess the stage of heart failure according to the NYHA functional classification 
system.  This system relates symptoms to everyday activities and the patient's quality of life. 
 
Class  
Patient Symptoms  
Class I (Mild)  
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, 
or dyspnea (shortness of breath).  
Class II (Mild)  
Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in 
fatigue, palpitation, or dyspnea.  
Class III 
(Moderate)  
Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes 
fatigue, palpitation, or dyspnea.  
Class IV (Severe)  
Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency at 
rest. If any physical activity is undertaken, discomfort is increased.  
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Appendix C. 
Summary of Adverse Event Reporting Instructions 
 
CASE REPORT FORM 
COMPLETION 
EVENT CATEGORY 
REPORTING 
TIMEFRAME 
SPECIFIC EVENTS IN 
THIS CATEGORY 
AE 
form 
Safety 
Complementary 
Form* 
Other 
specific 
forms 
Adverse Event (non-SAE, 
non-AESI) 
Routine 
Any AE that is not SAE or AESI 
Yes 
No 
No 
Serious Adverse Event 
(non-AESI or AESI) 
Expedited (within 
24 hours) 
Any AE meeting seriousness 
criterion per Section 10.4.1.2  
Yes 
Yes 
No, unless 
applicable 
Asymptomatic overdose with 
IMP 
Yes 
No 
No 
Local injections site reactions  
Yes 
No 
Yes 
Allergy events (except events 
specified in Section 10.4.5.2) 
Yes 
No 
Yes 
Ophthalmologic events (NOT 
requiring additional 
examinations/procedures 
and/or consultation with a 
specialist, as described in 
Section 10.4.5.2) 
Yes 
No 
Yes 
Adverse Event of Special 
Interest (AESI) WITHOUT 
immediate notification 
(non-SAE) 
Routine 
Neurological (including 
neurocognitive) events (NOT 
requiring additional 
examinations/procedures 
and/or consultation with a 
specialist, as described in 
Section 10.4.5.2) 
Yes 
No 
Yes 
Pregnancy of female 
patient/subject (including male 
subject’s partner) 
Yes 
Yes 
Yes 
Symptomatic overdose with 
IMP 
Yes 
Yes 
No 
Increase in ALT as follows: 
- ALT ≥3 ULN (if baseline ALT 
<ULN) Or  
- ALT ≥2 times the baseline 
value (if baseline ALT ≥ULN)  
Please refer to related 
flowchart (per Appendix D) 
Yes 
Yes 
Yes 
Adverse Event of Special 
Interest (AESI) WITH 
immediate notification 
(non-SAE) 
Expedited (within 
24 hours) 
Allergic drug reactions and/or 
local injections site reactions 
deemed to be allergic  as 
Yes 
Yes 
Yes 
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CASE REPORT FORM 
COMPLETION 
EVENT CATEGORY 
REPORTING 
TIMEFRAME 
SPECIFIC EVENTS IN 
THIS CATEGORY 
AE 
form 
Safety 
Complementary 
Form* 
Other 
specific 
forms 
specified in Section 10.4.5.1 
Hemolytic anemia 
Yes 
Yes 
Yes 
Ophthalmologic events 
(requiring additional 
examinations/procedures 
and/or consultation with a 
specialist, as described in 
Section 10.4.5.1) 
Yes 
Yes 
Yes 
Neurological (including 
neurocognitive) events 
(requiring additional 
examinations/procedures 
and/or consultation with a 
specialist, as described in 
Section 10.4.5.1) 
Yes 
Yes 
Yes 
Neutropenia (per Appendix D) 
Yes 
No 
No 
Thrombocytopenia (per 
Appendix D) 
Yes 
No 
No 
Acute renal insufficiency (per 
Appendix D) 
Yes 
No 
No 
Laboratory, vital sign, or 
ECG abnormality (non-
SAE, non-AESI) that is:  
- Symptomatic 
- Requiring corrective 
treatment or consultation 
- Leading to IMP 
discontinuation or dose 
regimen modification  
Routine 
Increase in CPK and suspicion 
of rhabdomyolysis (per 
Appendix D) 
Yes 
No 
No 
Cardiovascular events 
and death from any 
cause 
Expedited (within 
24 hours) 
MI, cerebrovascular events (eg, 
stroke, transient ischemic 
attack, intracranial bleeding, 
ischemia or bleeding of spine 
or retina), unstable angina 
requiring hospitalization, 
congestive heart failure 
requiring hospitalization, 
coronary revascularization 
(PCI, CABG), and an event 
with outcome of fatal (including 
CHD death) 
Yes 
Yes 
Yes 
*Completion of a Safety Complementary Form is required for any AE meeting a seriousness criterion, even if this is not required according to the 
table for a particular type of AE 
 
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Appendix D. 
General Guidance for the follow-up of laboratory abnormalities by 
Sanofi 
NEUTROPENIA
Neutrophils < 1500/mm3
or according to ethnic group
Repeat immediately a full blood count 
if value close to 1500/mm3
In both situations
Note
•
The procedures described in the above flowchart are to be discussed with the patient only in case 
the event occurs. If applicable (according to local regulations) , an additional consent (e.g., for
HIV testing) will only be obtained in the case the event actually occurs.
•
For individuals of African descent, the relevant value of concern is <1000/mm3
Neutropenia are to be recorded as AE only if they are :
•
Symptomatic, and/or
•
Requiring either corrective treatment or consultation, and/or
•
Leading to IMP discontinuation or modification of dosing, and/or
•
Fulfilling a seriousness criterion [in that case, the event (SAE) should be notified within 24 hours to 
the MT], and/or
•
Defined as an Adverse Event of Special Interest (AESI) with immediate notification
Neutrophils < 1500/mm3 confirmed 
with signs of infection
Neutrophils < 1500/mm3 confirmed 
with no signs of infection
1.  DISCONTINUE
Investigational Medicinal 
Product, hospitalization 
should be considered
2.  PERFORM biological 
investigations for infection
1.  DISCONTINUE
Investigational Medicinal 
Product
2.  INVESTIGATE for infection
3.  INFORM the local monitor
4.  INVESTIGATE previous treatments particularly long-term, even a long time ago, 
exposure to toxic agents, e.g., benzene, X- rays, etc.
5. PERFORM and collect the following investigations (results):
•
RBC and platelet counts
•
Serology: EBV, (HIV), mumps, measles, rubella 
6. DECISION for bone marrow aspiration: to be taken in specialized unit
7. FREEZE serum (5mL x 2) on Day 1 (cessation of investigational medicinal product) 
and Day 5 (for further investigations) 
8. MONITOR the leukocyte count 3 times per week for at least one  week, then twice a 
month until it returns to normal
NEUTROPENIA
Neutrophils < 1500/mm3
or according to ethnic group
Repeat immediately a full blood count 
if value close to 1500/mm3
In both situations
Note
•
The procedures described in the above flowchart are to be discussed with the patient only in case 
the event occurs. If applicable (according to local regulations) , an additional consent (e.g., for
HIV testing) will only be obtained in the case the event actually occurs.
•
For individuals of African descent, the relevant value of concern is <1000/mm3
Neutropenia are to be recorded as AE only if they are :
•
Symptomatic, and/or
•
Requiring either corrective treatment or consultation, and/or
•
Leading to IMP discontinuation or modification of dosing, and/or
•
Fulfilling a seriousness criterion [in that case, the event (SAE) should be notified within 24 hours to 
the MT], and/or
•
Defined as an Adverse Event of Special Interest (AESI) with immediate notification
Neutrophils < 1500/mm3 confirmed 
with signs of infection
Neutrophils < 1500/mm3 confirmed 
with no signs of infection
1.  DISCONTINUE
Investigational Medicinal 
Product, hospitalization 
should be considered
2.  PERFORM biological 
investigations for infection
1.  DISCONTINUE
Investigational Medicinal 
Product
2.  INVESTIGATE for infection
3.  INFORM the local monitor
4.  INVESTIGATE previous treatments particularly long-term, even a long time ago, 
exposure to toxic agents, e.g., benzene, X- rays, etc.
5. PERFORM and collect the following investigations (results):
•
RBC and platelet counts
•
Serology: EBV, (HIV), mumps, measles, rubella 
6. DECISION for bone marrow aspiration: to be taken in specialized unit
7. FREEZE serum (5mL x 2) on Day 1 (cessation of investigational medicinal product) 
and Day 5 (for further investigations) 
8. MONITOR the leukocyte count 3 times per week for at least one  week, then twice a 
month until it returns to normal
 
 
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THROMBOCYTOPENIA
Repeat immediately the count (rule out EDTA 
anticoagulant in the sample 
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
HOSPITALIZATION
should be considered
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
INVESTIGATE
for 
bleeding
In both situations
Platelets < 100 000/mm3 (rule out EDTA-induced 
pseudo-thrombocytopenia
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
HOSPITALIZATION
should be considered
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
INVESTIGATE
for 
bleeding
Platelets < 100 000/mm3 confirmed 
with bleeding
Platelets < 100 000/mm3 confirmed 
with no bleeding
3.  INFORM the local monitor
4. 
QUESTION about last intake of quinine (drinks), alcoholism, heparin 
administration 
5. 
PERFORM or collect the following investigations
•
Complete blood count, schizocytes, creatinine 
•
Bleeding time and coagulation test (fibrinogen, PT, aPTT), Fibrin  
Degradation Product
•
Viral serology: EBV, HIV, mumps, measles, rubella
6.
FREEZE serum (5mL x 2) on Day 1 (end of treatment) and Day 5 to test for 
drug-induced antiplatelet antibodies
7. 
DECISION for bone marrow aspiration: to be taken in specialized unit
•
On Day 8 if the Platelets remain < 50 000/mm3
•
On Day 1 in the case of associated anemia and/or leukopenia
8.
MONITOR the platelet count every day for at least one week and then 
regularly until it returns to normal
NOTE:
the procedures described in the above flowchart are to be discussed with the patient only in case
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs
Thrombocytopenia are to be recorded as AE only if they are: 
•
Symptomatic, and/or 
•
Requiring either corrective treatment or consultation, and/or 
•
Leading to IMP discontinuation or modification of dosing, and/or
•
Fulfilling a seriousness criterion [in that case, the event (SAE should be notified within 24 hours
to the MT], and/or
•
Defined as an Adverse Event of Special Interest (AESI) with immediate notification
THROMBOCYTOPENIA
Repeat immediately the count (rule out EDTA 
anticoagulant in the sample 
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
HOSPITALIZATION
should be considered
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
INVESTIGATE
for 
bleeding
In both situations
Platelets < 100 000/mm3 (rule out EDTA-induced 
pseudo-thrombocytopenia
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
HOSPITALIZATION
should be considered
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
INVESTIGATE
for 
bleeding
Platelets < 100 000/mm3 confirmed 
with bleeding
Platelets < 100 000/mm3 confirmed 
with no bleeding
3.  INFORM the local monitor
4. 
QUESTION about last intake of quinine (drinks), alcoholism, heparin 
administration 
5. 
PERFORM or collect the following investigations
•
Complete blood count, schizocytes, creatinine 
•
Bleeding time and coagulation test (fibrinogen, PT, aPTT), Fibrin  
Degradation Product
•
Viral serology: EBV, HIV, mumps, measles, rubella
6.
FREEZE serum (5mL x 2) on Day 1 (end of treatment) and Day 5 to test for 
drug-induced antiplatelet antibodies
7. 
DECISION for bone marrow aspiration: to be taken in specialized unit
•
On Day 8 if the Platelets remain < 50 000/mm3
•
On Day 1 in the case of associated anemia and/or leukopenia
8.
MONITOR the platelet count every day for at least one week and then 
regularly until it returns to normal
NOTE:
the procedures described in the above flowchart are to be discussed with the patient only in case
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs
Thrombocytopenia are to be recorded as AE only if they are: 
•
Symptomatic, and/or 
•
Requiring either corrective treatment or consultation, and/or 
•
Leading to IMP discontinuation or modification of dosing, and/or
•
Fulfilling a seriousness criterion [in that case, the event (SAE should be notified within 24 hours
to the MT], and/or
•
Defined as an Adverse Event of Special Interest (AESI) with immediate notification
 
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ALT > 3 ULN
Monitor LFTs every 72 hours
ALT ≤ 5 ULN
ALT > 3 ULN &
Total Bilirubin > 2 ULN 
Permanent Discontinuation of IMP
ALT > 5 ULN 
In ANY CASE, FOLLOW the instructions listed in the box below: 
1.
INFORM the Site Monitor who will forward the information to the Study Manager
2.
COMPLETE the CRF for «ALT Increase» for any permanent discontinuations due to liver injury (See 
protocol/CRF instructions)
3.
INVESTIGATE specifically for malaise with or without loss of consciousness, dizziness, and/or 
hypotension and/or episode of arrhythmia in the previous 72 hours; rule out muscular injury
4.
PERFORM the following tests:
- LFTs: AST, ALT, alkaline phosphatase, total and conjugated bilirubin and prothrombin time / INR
- CPK, serum creatinine, complete blood count
- Anti-HAV IgM, anti-HBc IgM, (HBV-DNA if clinically indicated), anti-HCV and HCV RNA, anti-
CMV IgM and anti-HEV IgM antibodies
- Depending on the clinical context, check for recent infection with EBV, herpes viruses, and toxoplasma
- Hepatobiliary ultrasonography (or other imaging investigations if needed)
5.    CONSIDER Auto-antibodies: antinuclear, anti-DNA, anti-smooth muscle, anti-LKM
6.
CONSIDER consulting with hepatologist
7.
CONSIDER patient hospitalization if INR>2 (or PT<50%) and/or central nervous system disburbances 
suggesting hepatic encephalopathy
8.
MONITOR LFTs after discontinuation of IMP:
- As closely as possible (or every 48 hours) until stabilization, then every 2 weeks until return to 
normal/baseline or clinical resolution.
9.
FREEZE serum sample (5ml x 2)
10.
In case of SUSPICION of GILBERT Syndrome, a DNA diagnostic test should be done
Note: 
Normalization is defined as < ULN or baseline value if baseline value is >ULN.
As soon as seriousness criterion is met or the event leads to permanent treatment discontinuation, the monitoring 
team should be notified within 24 hours.
*If unable to retest in 72 hours, use original lab results to decide on further monitoring/ discontinuation . 
Check if special CRF should be 
completed per protocol/CRF 
instructions
Confirm ALT > 3 ULN
Retest within 72 hours of initial sample*
IMP administration can be continued as 
long as – under close monitoring –
conditions for permanent 
discontinuation or temporary 
interruption per protocol are not met
 
 
Note: ALT ≥ 3 ULN (if baseline ALT < ULN) or ALT ≥ 2 times the baseline value (if baseline ALT ≥ ULN) 
should be notified within 24 hours to the monitoring team (see Section 10.4.2, Section 10.4.5, and  
Section 11.4.6). In addition, if ALT < 3 ULN meets a seriousness criterion, the event should be notified within 
24 hours to the monitoring team. 
 
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Rapid increase in serum creatinine over 150 µmol/L 
or rapid decrease in creatinine clearance below 
50ml/mn
ACUTE RENAL FAILURE
Can be rapidly reversed:
•
By volume repletion
•
Or relief of urinary tract 
obstruction (according to etiology)
Cannot be rapidly reversed: 
• Occurrence/aggravation of life 
threatening symptoms of ARF: 
anemia, hyperkalemia, 
hyperuricemia, metabolic acidosis, 
cardiac insufficiency, pulmonary 
edema, arrhythmia, DIC, etc.
• And/or predominant elimination of 
Investigational Medicinal Product 
by renal route
1.
Investigational Medicinal 
Product may be continued
2.
MONITOR
serum 
creatinine until return to 
baseline level
1.
INFORM
the local monitor
2.
DISCONTINUE
Investigational Medicinal Product 
administration
3.
HOSPITALIZATION
should be 
considered and seek for nephrologic
advice
4.
PERFORM
the following 
examinations: 
•
BP, HR, hydration status, 
ECG
•
Blood count
•
Liver function tests + CPK
•
Biochemistry, including urea
•
Urinalysis
5.
FREEZE serum (5mL x 2)
6.
MONITOR
renal function until 
return to baseline level (every day 
at the beginning, then every week)
Acute renal failure is to be recorded as AE only if it is : 
•
Symptomatic, and/or 
•
Requiring either corrective treatment or consultation, and/or 
•
Leading to IMP discontinuation or modification of dosing, and/or
•
Fulfilling a seriousness criterion [in that case, the event (SAE ) should be notified 
within 24 hours to the MT], and/or
•
Defined as an Adverse Event of Special Interest (AESI) with immediate notification
Rapid increase in serum creatinine over 150 µmol/L 
or rapid decrease in creatinine clearance below 
50ml/mn
ACUTE RENAL FAILURE
Can be rapidly reversed:
•
By volume repletion
•
Or relief of urinary tract 
obstruction (according to etiology)
Cannot be rapidly reversed: 
• Occurrence/aggravation of life 
threatening symptoms of ARF: 
anemia, hyperkalemia, 
hyperuricemia, metabolic acidosis, 
cardiac insufficiency, pulmonary 
edema, arrhythmia, DIC, etc.
• And/or predominant elimination of 
Investigational Medicinal Product 
by renal route
1.
Investigational Medicinal 
Product may be continued
2.
MONITOR
serum 
creatinine until return to 
baseline level
1.
INFORM
the local monitor
2.
DISCONTINUE
Investigational Medicinal Product 
administration
3.
HOSPITALIZATION
should be 
considered and seek for nephrologic
advice
4.
PERFORM
the following 
examinations: 
•
BP, HR, hydration status, 
ECG
•
Blood count
•
Liver function tests + CPK
•
Biochemistry, including urea
•
Urinalysis
5.
FREEZE serum (5mL x 2)
6.
MONITOR
renal function until 
return to baseline level (every day 
at the beginning, then every week)
Acute renal failure is to be recorded as AE only if it is : 
•
Symptomatic, and/or 
•
Requiring either corrective treatment or consultation, and/or 
•
Leading to IMP discontinuation or modification of dosing, and/or
•
Fulfilling a seriousness criterion [in that case, the event (SAE ) should be notified 
within 24 hours to the MT], and/or
•
Defined as an Adverse Event of Special Interest (AESI) with immediate notification
 
 
 
(electronic 
 
 
 
1.0)


Amended Clinical Trial Protocol 01  
17-Dec-2015 
SAR236553/REGN727-EFC13889 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 114 
SUSPICION OF RHABDOMYOLYSIS
Muscular symptoms (myalgia, pain, 
weakness, dark urines)
Systematic CPK assessment as per 
protocol
Perform CPK
If Increase in CPK (express in ULN)
> 3 ULN
Repeat immediately the count.
If confirmed, inform the local monitor and
INVESTIGATE for the origin:
-
PERFORM:
•
ECG
•
CPK-MB-MM
•
Troponin
•
Creatinine
•
Iono (k+, Ca 2+)
•
Transaminases + Total and conjugated bilirubin
•
Myoglobin (serum and urines)
-
FREEZE: SERUM (5mlx2) for PK
-
INTERVIEW the patient about a recent intensive muscular effort, trauma, convulsions, electrical 
injury, injury or stress to the skeletal muscle, multiple intramuscular injections, recent surgery, 
concomitant medications, consumption of alcohol, morphine, cocaine.
-
SEARCH for alternative causes to cardiac or muscular toxicity, ie: stroke, pulmonary infarction, 
dermatomyositis or polymyositis, convulsions, hypothyroidism, delirium tremens, muscular 
dystrophies.
If either the cardiac origin or the 
rhabdomyolysis is confirmed or if CPK >
10 ULN:
1.
DISCONTINUE Investigational 
Medicinal Product administration
2.
MONITOR CPK every 3 days for the 
first week when once weekly until return 
to normal or for at least 3 month
3.
HOSTITALIZATION should be 
considered
If the cardiac origin or the rhabdomyolysis is 
ruled out and if CPK ≤10 ULN:
MONITOR CPK every 3 days for the first 
week then once weekly until return to normal 
or for at least 3 months
Suspicion of rhabdomyolysis is to be recorded as AE only if it is:
•
Symptomatic, and/or
•
Requiring either corrective treatment or consultation, and/or
•
Leading to IMP discontinuation or modification of dosing, and/or
•
Fulfilling a seriousness criterion [in that case, the event (SAE) should be notified within 24 hours to 
the MT], and/or
•
Defined as an Adverse Event of Special Interest (AESI) with immediate notification
SUSPICION OF RHABDOMYOLYSIS
Muscular symptoms (myalgia, pain, 
weakness, dark urines)
Systematic CPK assessment as per 
protocol
Perform CPK
If Increase in CPK (express in ULN)
> 3 ULN
Repeat immediately the count.
If confirmed, inform the local monitor and
INVESTIGATE for the origin:
-
PERFORM:
•
ECG
•
CPK-MB-MM
•
Troponin
•
Creatinine
•
Iono (k+, Ca 2+)
•
Transaminases + Total and conjugated bilirubin
•
Myoglobin (serum and urines)
-
FREEZE: SERUM (5mlx2) for PK
-
INTERVIEW the patient about a recent intensive muscular effort, trauma, convulsions, electrical 
injury, injury or stress to the skeletal muscle, multiple intramuscular injections, recent surgery, 
concomitant medications, consumption of alcohol, morphine, cocaine.
-
SEARCH for alternative causes to cardiac or muscular toxicity, ie: stroke, pulmonary infarction, 
dermatomyositis or polymyositis, convulsions, hypothyroidism, delirium tremens, muscular 
dystrophies.
If either the cardiac origin or the 
rhabdomyolysis is confirmed or if CPK >
10 ULN:
1.
DISCONTINUE Investigational 
Medicinal Product administration
2.
MONITOR CPK every 3 days for the 
first week when once weekly until return 
to normal or for at least 3 month
3.
HOSTITALIZATION should be 
considered
If the cardiac origin or the rhabdomyolysis is 
ruled out and if CPK ≤10 ULN:
MONITOR CPK every 3 days for the first 
week then once weekly until return to normal 
or for at least 3 months
Suspicion of rhabdomyolysis is to be recorded as AE only if it is:
•
Symptomatic, and/or
•
Requiring either corrective treatment or consultation, and/or
•
Leading to IMP discontinuation or modification of dosing, and/or
•
Fulfilling a seriousness criterion [in that case, the event (SAE) should be notified within 24 hours to 
the MT], and/or
•
Defined as an Adverse Event of Special Interest (AESI) with immediate notification
 
(electronic 
 
 
 
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Amended Clinical Trial Protocol 01  
17-Dec-2015 
SAR236553/REGN727-EFC13889 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 115 
Appendix E. 
Guidelines for hemoglobin (Hb) decrease >=1.5 g/dL 
* First Post randomization visit Hb decrease ≥1.5 g/dL as compared to randomization visit Hb
Central Lab automatically measures reticulocyte count and haptoglobin on specimens already 
obtained at the same time point for which the hemoglobin decrease was detected
Investigator reviews all labs including Hb, total bilirubin, indirect bilirubin (only if the 
total bilirubin >ULN), reticulocyte count, haptoglobin, and LDH
Is the following observed?
Reticulocyte count > ULN and
Haptoglobin < LLN and
LDH > ULN and
Indirect bilirubin > ULN (only if the 
total bilirubin > ULN)
Refer patient to a hematologist.  Ask hematologist to 
obtain the following lab specimens:
x
A peripheral blood smear
x
Anti-erythrocyte antibodies (direct and indirect) by 
Coombs test   
The hematologist conducts further investigations at 
his/her discretion. 
Investigator should exercise 
his/her medical judgment in the 
interpretation of the results, 
necessity for and workup of the 
decrease in hemoglobin or 
referral to a hematologist.
YES
NO
Suspicion of hemolytic anemia is recorded as AE only if: 
• Symptomatic and/or 
• Requiring either corrective treatment or consultation, and/or 
• Leading to IMP discontinuation or modification of dosing, and/or 
• Fulfilling a seriousness criterion 
* If a second hemoglobin measurement demonstrating a further decrease of ≥1 g/dL from the 
last available value is observed, even if the previous work-up was negative, the same 
investigations can be repeated and a hematology consultation can be requested at the 
discretion of the Investigator or at the Sponsor’s request.
* First Post randomization visit Hb decrease ≥1.5 g/dL as compared to randomization visit Hb
Central Lab automatically measures reticulocyte count and haptoglobin on specimens already 
obtained at the same time point for which the hemoglobin decrease was detected
Investigator reviews all labs including Hb, total bilirubin, indirect bilirubin (only if the 
total bilirubin >ULN), reticulocyte count, haptoglobin, and LDH
Is the following observed?
Reticulocyte count > ULN and
Haptoglobin < LLN and
LDH > ULN and
Indirect bilirubin > ULN (only if the 
total bilirubin > ULN)
Refer patient to a hematologist.  Ask hematologist to 
obtain the following lab specimens:
x
A peripheral blood smear
x
Anti-erythrocyte antibodies (direct and indirect) by 
Coombs test   
The hematologist conducts further investigations at 
his/her discretion. 
Investigator should exercise 
his/her medical judgment in the 
interpretation of the results, 
necessity for and workup of the 
decrease in hemoglobin or 
referral to a hematologist.
YES
NO
Suspicion of hemolytic anemia is recorded as AE only if: 
• Symptomatic and/or 
• Requiring either corrective treatment or consultation, and/or 
• Leading to IMP discontinuation or modification of dosing, and/or 
• Fulfilling a seriousness criterion 
* If a second hemoglobin measurement demonstrating a further decrease of ≥1 g/dL from the 
last available value is observed, even if the previous work-up was negative, the same 
investigations can be repeated and a hematology consultation can be requested at the 
discretion of the Investigator or at the Sponsor’s request.
 
 
(electronic 
 
 
 
1.0)


Amended Clinical Trial Protocol 01  
17-Dec-2015 
SAR236553/REGN727-EFC13889 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 116 
Appendix F. 
DNA storage samples  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(electronic 
 
 
1.0)


Amended Clinical Trial Protocol 01  
17-Dec-2015 
SAR236553/REGN727-EFC13889 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 117 
 
 
 
 
 
 
 
 
 
 
 
 
2. 
SHIPMENT CONTACT NAMES AND ADDRESSES 
For Optional DNA Banking Samples: 
Use for Asia-Pacific, including Thailand, Malaysia, and Australia: 
Covance CLS Singapore 
1 International Business Park 
#05-12A/B The Synergy 
Singapore 609917 
Tel: 
 
Fax: 
 
Use for China only: 
Covance CLS Shanghai 
1st Floor, No. 6 Building 
151 Li Bing Rd 
Zhangjiang Hi-Tech Park 
Shanghai 201203 
China 
Tel: 
 
Fax: 
 
 
(electronic 
 
 
 
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Amended Clinical Trial Protocol 01  
17-Dec-2015 
SAR236553/REGN727-EFC13889 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 118 
Appendix G. 
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 
 
(electronic 
 
 
 
1.0)


 
 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy 
HH:mm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EFC13889 Amended Protocol 1
Clinical Approval
18-Dec-2015 07:35 GMT+01
Clinical Approval
18-Dec-2015 13:54 GMT+01
Regulatory Approval
21-Dec-2015 06:43 GMT+01
Clinical Approval
21-Dec-2015 09:09 GMT+01

SAP_000.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-002643 VERSION 6.0 (06-JUL-2016) 
Page 1 
STATISTICAL ANALYSIS PLAN 
A Randomized, Double-Blind, Parallel Group Study to Evaluate the Efficacy and 
Safety of Alirocumab (SAR236553/REGN727) Versus Ezetimibe in Asia in High 
Cardiovascular Risk Patients with Hypercholesterolemia Not Adequately 
Controlled With Their Statin Therapy 
SAR236553/REGN727-EFC13889 
ODYSSEY EAST 
STATISTICIAN: 
  
DATE OF ISSUE: 17-Oct-2017 
Total number of pages: 
64 
(electronic 1.0)
NCT02715726


Statistical Analysis Plan  
17-Oct-2017 
SAR236553/REGN727-EFC13889 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ...................................................................................................................1 
TABLE OF CONTENTS..................................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................................................................5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................7 
1.1 
STUDY DESIGN AND RANDOMIZATION ......................................................................................7 
1.2 
OBJECTIVES...................................................................................................................................7 
1.2.1 
Primary objectives............................................................................................................................7 
1.2.2 
Secondary objectives.......................................................................................................................7 
1.3 
DETERMINATION OF SAMPLE SIZE.............................................................................................8 
1.4 
STUDY PLAN...................................................................................................................................8 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL..................................9 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN .......................9 
2 
STATISTICAL AND ANALYTICAL PROCEDURES ....................................................................10 
2.1 
ANALYSIS ENDPOINTS ...............................................................................................................10 
2.1.1 
Demographic and baseline characteristics ....................................................................................10 
2.1.2 
Prior or concomitant medications...................................................................................................13 
2.1.3 
Efficacy endpoints ............................................................................................................................13 
2.1.3.1 
Primary efficacy endpoint(s) ..........................................................................................................14 
2.1.3.2 
Secondary efficacy endpoint(s)......................................................................................................14 
2.1.4 
Safety endpoints ............................................................................................................................15 
2.1.4.1 
Adverse events variables...............................................................................................................16 
2.1.4.2 
Deaths............................................................................................................................................18 
2.1.4.3 
Laboratory safety variables............................................................................................................18 
2.1.4.4 
Vital signs variables .......................................................................................................................19 
2.1.4.5 
Electrocardiogram variables ..........................................................................................................19 
2.1.5 
Other endpoints..............................................................................................................................19 
2.1.6 
Anti-alirocumab antibodies variables .............................................................................................20 
2.1.7 
Pharmacokinetics variables ...........................................................................................................20 
2.1.8 
Pharmacogenetics endpoints.........................................................................................................21 
2.2 
DISPOSITION OF PATIENTS .......................................................................................................21 
(electronic 
 
 
 
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Statistical Analysis Plan  
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Property of the Sanofi Group - strictly confidential 
Page 3 
2.2.1 
Randomization and drug dispensing irregularities.........................................................................22 
2.3 
ANALYSIS POPULATIONS...........................................................................................................23 
2.3.1 
Efficacy populations .......................................................................................................................23 
2.3.1.1 
Intent–to-treat population ..................................................................................................................23 
2.3.1.2 
Modified intent-to-treat population ...................................................................................................24 
2.3.2 
Safety population ...........................................................................................................................24 
2.3.3 
Anti-alirocumab antibody population..............................................................................................24 
2.3.4 
Pharmacokinetic population...........................................................................................................25 
2.4 
STATISTICAL METHODS .............................................................................................................25 
2.4.1 
Demographics and baseline characteristics ..................................................................................25 
2.4.2 
Prior or concomitant medications...................................................................................................26 
2.4.3 
Extent of investigational medicinal product exposure and compliance .........................................27 
2.4.3.1 
Extent of investigational medicinal product exposure....................................................................27 
2.4.3.2 
Compliance ....................................................................................................................................28 
2.4.4 
Analyses of efficacy endpoints.......................................................................................................29 
2.4.4.1 
Analysis of primary efficacy endpoint(s) ........................................................................................29 
2.4.4.2 
Analyses of secondary efficacy endpoints.....................................................................................33 
2.4.4.3 
Multiplicity issues ...........................................................................................................................35 
2.4.4.4 
Additional efficacy analysis(es)......................................................................................................36 
2.4.5 
Analyses of safety data..................................................................................................................36 
2.4.5.1 
Analyses of adverse events ...........................................................................................................37 
2.4.5.2 
Deaths............................................................................................................................................40 
2.4.5.3 
Analyses of laboratory variables....................................................................................................40 
2.4.5.4 
Analyses of vital sign variables ......................................................................................................42 
2.4.5.5 
Analyses of electrocardiogram variables .......................................................................................43 
2.4.6 
Analyses of other endpoints...........................................................................................................43 
2.4.7 
Analyses of anti-alirocumab antibodies variables..........................................................................43 
2.4.8 
Analyses of pharmacokinetics variables........................................................................................44 
2.5 
DATA HANDLING CONVENTIONS ..............................................................................................44 
2.5.1 
General conventions ......................................................................................................................44 
2.5.2 
Data handling conventions for secondary efficacy variables.........................................................45 
2.5.3 
Missing data...................................................................................................................................45 
2.5.4 
Windows for time points.................................................................................................................47 
2.5.5 
Unscheduled visits .........................................................................................................................47 
2.5.6 
Pooling of centers for statistical analyses......................................................................................48 
3 
INTERIM ANALYSIS .....................................................................................................................49 
4 
DATABASE LOCK........................................................................................................................50 
5 
SOFTWARE DOCUMENTATION .................................................................................................51 
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Statistical Analysis Plan  
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Property of the Sanofi Group - strictly confidential 
Page 4 
6 
REFERENCES...............................................................................................................................52 
7 
LIST OF APPENDICES.................................................................................................................53 
APPENDIX A 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA ......................54 
APPENDIX B 
DETAILED STATISTICAL METHODOLOGY FOR PATTERN MIXTURE MODEL............59 
APPENDIX C LIST OF MEDDRA TERMS FOR CMQS ............................................................................61 
APPENDIX D AS TREATED TREATMENT GROUP DEFINITION ...........................................................64 
(electronic 
 
 
 
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Statistical Analysis Plan  
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Property of the Sanofi Group - strictly confidential 
Page 5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Ab: 
antibody 
ADA: 
anti-drug antibody 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotrasferase 
ANCOVA: 
analysis of covariance 
ANOVA: 
analysis of variance 
Apo: 
apolipoprotein 
AST: 
aspartate aminotransferase 
ATC: 
anatomic therapeutic category 
CEC: 
clinical events classification 
CHD: 
coronary heart disease 
CI: 
confidence interval 
CKD: 
chronic kidney disease 
CV: 
cardiovascular 
CVD: 
cardiovascular disease 
ECG: 
electrocardiogram 
e-CRF: 
electronic case record form 
eDISH: 
evaluation of drug-induced serious hepatotoxicity 
EZE: 
ezetimibe 
GGT: 
glutamyl transferase 
HbA1c: 
glycated hemoglobin A1c 
HCV: 
hepatitis C virus 
HDL-C: 
high density lipoprotein cholesterol 
HLGT: 
high level group term 
HLT: 
high level term 
IMP: 
investigational medicinal product 
ITT: 
intent to treat, intent-to-treat 
IVRS: 
interactive voice response system 
IWRS: 
interactive web response system 
LDH: 
lactate dehydrogenase 
LDL-C: 
low density lipoprotein cholesterol 
LLOQ: 
lower limit of quantification 
LLT: 
lowest level term 
LMT: 
lipid modifying therapy 
LS: 
least square 
MAR: 
missing at random 
MCMC: 
Markov Chain Monte Carlo 
MedDRA: 
medical dictionary for regulatory activities 
MI: 
myocardial infarction 
(electronic 
 
 
 
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Statistical Analysis Plan  
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Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 6 
MMRM: 
mixed effect model with repeated measures 
NMAR: 
not missing at random 
PAD: 
peripheral arterial disease, peripheral arterial disease 
PCSA: 
potentially clinical significant abnormality 
PK: 
pharmacokinetics 
PT: 
preferred term 
Q1: 
first quartile 
Q2W: 
every 2 weeks 
Q3: 
third quartile 
QQ: 
quantile quantile 
RDW: 
red blood cell distribution width 
SAEs: 
serious adverse events 
SD: 
standard deviation 
SOC: 
system organ class 
TC: 
total cholesterol 
TG: 
triglycerides 
ULN: 
upper limit of normal range 
ULOQ: 
upper limit of quantification 
WHO-DD: 
World Health Organization-Drug Dictionary 
 
 
 
(electronic 
 
 
 
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Statistical Analysis Plan  
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Property of the Sanofi Group - strictly confidential 
Page 7 
1 
OVERVIEW AND INVESTIGATIONAL PLAN   
1.1 
STUDY DESIGN AND RANDOMIZATION 
This is a randomized, double-blind, parallel-group, double dummy, ezetimibe-controlled, 
unbalanced (2:1, alirocumab: ezetimibe), multi-center, multi-national study conducted in China, 
India and Thailand. 
After a screening phase of up to 3 weeks, patients were centrally randomized via interactive voice 
response system (IVRS)/interactive web response system (IWRS) to 1 of the 2 treatment groups 
and treated in a double-blind manner for approximately 24 weeks.  
Randomization was stratified according to: 
• Prior history of myocardial infarction (MI) or ischemic stroke (Yes versus No); 
• High-intensity statin treatment (Yes versus No; Yes defined as atorvastatin 40 to 80 mg 
daily or rosuvastatin 20 to 40 mg daily, No for simvastatin whatever the dose, atorvastatin 
below 40 mg daily or rosuvastatin below 20 mg daily); 
• Country (China, India or Thailand). 
Starting dose of alirocumab was 75 mg every 2 weeks (Q2W). A dose up-titration at Week 12 to 
150 mg Q2W, depending on Week 8 low-density lipoprotein cholesterol (LDL-C) levels, may 
occur for patients randomized to alirocumab group. Patients will be followed for 8 weeks after the 
last visit of the double-blind treatment period. 
Approximately 600 patients (400 in alirocumab and 200 in ezetimibe groups) were to be 
randomized from approximately 69 sites. 
1.2 
OBJECTIVES 
1.2.1 Primary objectives 
The primary objective of this study is to demonstrate the reduction of low-density lipoprotein 
cholesterol (LDL-C) by alirocumab as add-on therapy to stable maximally tolerated daily statin 
therapy in comparison with ezetimibe (EZE) 10 mg daily after 24 weeks of treatment in Asia in 
patients with hypercholesterolemia at high cardiovascular (CV) risk. 
1.2.2 Secondary objectives 
The secondary objectives are:  
• To evaluate the effect of alirocumab 75 mg in comparison with ezetimibe 10 mg on LDL-
C after 12 weeks of treatment. 
(electronic 
 
 
 
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Statistical Analysis Plan  
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Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 8 
•
To evaluate the effect of alirocumab on other lipid parameters: eg, Apolipoprotein B (Apo
B), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC),
lipoprotein a (Lp[a]) ,high-density lipoprotein cholesterol (HDL-C), triglycerides (TG),
and Apo A-1 levels).
•
To evaluate the safety and tolerability of alirocumab.
•
To evaluate the development of anti-alirocumab antibodies.
•
To evaluate the pharmacokinetics (PK) of alirocumab.
1.3 
DETERMINATION OF SAMPLE SIZE 
A total sample size of 96 patients (64 in alirocumab and 32 in ezetimibe arms) will have 95% 
power to detect a difference in mean percent change in LDL-C of 20% with a 0.05 two-sided 
significance level and assuming a common standard deviation (SD) of 25% and all these patients 
having an evaluable primary endpoint. 
Nevertheless, to meet registration requirement and provide safety documentation in participating 
countries the final total sample size will be 600 with a randomization ratio 2:1 (alirocumab: 400, 
ezetimibe: 0).  
1.4 
STUDY PLAN 
The following figure presents the graphical study design: 
Figure 1 - Graphical study design 
* Every effort should be made to ensure that the screening window is as short as possible and ideally within two weeks.
(electronic 1.0)


Statistical Analysis Plan  
17-Oct-2017 
SAR236553/REGN727-EFC13889 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 9 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
There are no major changes to the protocol statistical section. 
The first patient was screened on 27 July 2016(screen-failed). The first patient was randomized on 
11 August 2016. There are no planned interim analyses.  
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
Not applicable. 
(electronic 
 
 
 
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Statistical Analysis Plan  
17-Oct-2017 
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2 
STATISTICAL AND ANALYTICAL PROCEDURES 
2.1 
ANALYSIS ENDPOINTS 
2.1.1 Demographic and baseline characteristics 
The baseline value is defined as the last available value obtained up to the date and time of the 
first double-blind investigational medicinal product (IMP) administration. The first double-blind 
IMP administration is defined as the earliest administration between the first double-blind 
injection date and the first capsule intake. 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 summary statistics in the safety and efficacy sections (Section 2.4.4 and Section 2.4.5). 
Demographic characteristics 
Demographic variables are gender (Male, Female), race (Asian, other), age in years (quantitative 
and qualitative variable: <45, ≥45 to <65, ≥65 to <75, and ≥75 years; and <65, and ≥65 years). 
Medical history 
Medical history of specific interest includes:  
• Coronary heart disease (CHD) 
• CHD risk equivalents 
• Cardiovascular (CV) risk factors other than hypercholesterolemia (hypertension, type 2 
diabetes, type 1 diabetes, family history of premature CHD). Smoking status will be 
summarized separately. 
• Family history of type 2 diabetes 
• Patient’s allergies (described using all pre-printed terms collected in the medical allergic 
history electronic case report form [e-CRF] page). 
The CHD, CHD risk equivalents, and CV risk factors will be based on items or combination of 
items pre-listed in the dedicated medical history e-CRF page (unless otherwise specified). 
CHD and CHD risk equivalents will be detailed as follows: 
CHD (regardless if it is ongoing or not) 
• Acute myocardial infarction  
• Silent myocardial infarction 
• Unstable angina 
• Coronary revascularization procedure 
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• Other clinically significant CHD diagnosed by invasive or non-invasive testing  
CHD risk equivalents 
• Peripheral arterial disease (as defined in Section 2.5.1) 
• Ischemic stroke 
• Moderate chronic kidney disease (as defined in protocol) 
• Known history of diabetes mellitus 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 -3/Week -2) with >2+ protein; 
- 
History of pre-proliferative or proliferative diabetic retinopathy or laser treatment for 
diabetic retinopathy; 
- 
Known family history of premature CHD.  
In addition, patients’ status as primary and secondary cardiovascular disease (CVD) prevention 
will be summarized. 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 peripheral arterial disease (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. 
All medical history information pre-listed or not in the e-CRF, will be coded using the version of 
Medical Dictionary for Regulatory Activities (MedDRA) currently in effect at Sanofi at the time 
of database lock.  
Disease characteristics at baseline   
Specific disease history includes: 
• Lipid modifying therapy history, as reported in the “History of Hyperlipoproteinemia” e-
CRF page: 
- 
Type of lipid-modifying therapy ever taken (statin, fibrates, bile acid sequestrant, 
cholesterol absorption inhibitor, nicotinic acid and derivates, omega 3 fatty acids 
≥1000 mg/day, other); 
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- 
Number of patients taking atorvastatin 40 to 80 mg, rosuvastatin 20 to 40 mg or 
simvastatin 40 mg daily at screening and, for those not taking one of these agents at 
one of the specified doses, reasons for being on a lower dose or for not taking a statin. 
• Background lipid modifying therapy (LMT) at randomization, as reported in the dedicated 
prior and concomitant medications e-CRF pages: 
- 
Number of patients taking high-intensity statin treatment (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, other); 
- 
Any LMT other than statins; 
- 
Any LMT other than nutraceuticals (by chemical class and drug name); 
- 
Nutraceuticals (omega 3 fatty acids (<1000 mg/day), phytosterols, psyllium/plantago, 
policosanol, other nutraceuticals). 
Details (ie, statin names, doses) for patients who had received at least 2 statins the day of 
randomization will be listed.  
Other baseline characteristics 
Other baseline characteristics include body mass index (BMI) in kg/m2 (quantitative and 
qualitative variables: <30, ≥30), smoking status, alcohol habits and randomization strata (as 
defined in Section 1.1) as per IVRS and e-CRF.  
Statin treatment stratum as per e-CRF will be derived using the statin name and dose taken the 
day of the randomization. If a patient takes neither atorvastatin, rosuvastatin nor simvastatin the 
day of randomization, stratum will be equal to the low/moderate dose stratum defined as 
“simvastatin whatever the dose, atorvastatin below 40 mg daily or rosuvastatin below 20 mg 
daily”. In case of combination of statins, stratum will be allocated to the high dose stratum defined 
as “atorvastatin 40 to 80 mg daily or rosuvastatin 20 to 40 mg daily” if at least one of the statins 
taken is in this category. If a patient takes atorvastatin, rosuvastatin or simvastatin the day of 
randomization but the daily dose is missing from the e-CRF, the stratification applied at 
randomization (ie, IVRS strata) will be applied.  
Glycated hemoglobin A1c (HbA1c) (quantitative and qualitative variable: <5.7%, ≥5.7% to 
<6.5%, ≥6.5%),and efficacy lipid parameters (quantitative variables for all efficacy parameters 
and the following qualitative variables) will be also summarized at baseline (definitions in 
Section 2.1.3): 
• calculated LDL-C: <1.81, ≥1.81 to <2.59, ≥2.59 to <3.37, ≥3.37 to <4.14, ≥4.14 to <4.91, 
≥4.91 mmol/L; 
• HDL-C: <1.04, ≥1.04 mmol/L; 
• Fasting TG: <1.7, ≥1.7 to <2.3, ≥2.3 mmol/L, category ≥1.7mmol/L (mixed 
dyslipidaemia) will be also displayed; 
• Lp(a): <0.3, ≥0.3 to <0.5, ≥0.5 g/L, category ≥0.3g/L will be also displayed.  
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Any technical details related to computation, dates, and imputation for missing dates is described 
in Section 2.5.  
2.1.2 Prior or concomitant medications  
All medications taken within 12 weeks prior to screening and until the end of the study, including 
LMTs are to be reported in the case report form pages: 
• Previous and concomitant statin drugs; 
• Previous and concomitant lipid lowering drugs (other than statins); 
• Previous and concomitant medications (other than statin, lipid lowering drugs). 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi at the time of database locks.  
Prior medications are those the patient used within 3 months to screening visit and prior to first 
double-blinded investigational medicinal product (IMP) administration (capsule or injection, 
whichever comes first).  Prior medications can be discontinued before first administration or can 
be ongoing during treatment phase. 
Concomitant medications are any treatments received by the patient concomitantly to the IMPs, 
from first double-blind IMP (capsule or injection, whichever comes first) to the last IMP injection 
+70 days. A given medication can be classified both as a prior medication and as a concomitant 
medication.  Concomitant medications do not include medications started during the post-
treatment period (as defined in the observation period in Section 2.1.4).  
Post-treatment medications are those the patient took in the period starting from 71 days after the 
last IMP injection and ending when the patient terminates the study.  
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5. 
2.1.3 
Efficacy endpoints 
Efficacy parameters include lipid parameters (ie, TC, calculated LDL-C, measured LDL-C, HDL-
C, fasting TG, non-HDL-C, Apo B, Apo A-1, Apo B/Apo A-1 ratio, Lp[a], TC/HDL-C ratio). All 
these parameters are measured or calculated by a Central Laboratory, for both scheduled and 
unscheduled time points. Calculated LDL-C is obtained using the Friedewald formula. Non-HDL-
C is calculated by subtracting HDL-C from the TC. Measured LDL-C is obtained via beta 
quantification method. All measured LDL-C values provided by the Central Laboratory including 
those done in case of TG values exceeding 400mg/dL (4.52mmol/L) will not be used for the 
analysis of calculated LDL-C endpoints. 
Unless other specified, all lipid values (scheduled or unscheduled, fasting or not fasting) may be 
used to provide a value for the primary and secondary efficacy endpoints. All measurements 
scheduled or unscheduled, fasting or not fasting, will be assigned to analysis windows defined in 
Section 2.5.4, Table 2 in order to provide an assessment for Week 4 to Week 24 time points. For 
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TG, only fasting measurements will be used. Measurements with missing fasting status will be 
excluded from the analyses. 
For all time points post-baseline, the value used for the analyses at a given time point (eg, at Week 
24) is the value obtained within the corresponding analysis window. The baseline value is the last 
available measurement obtained up to the date and time of the first double-blind IMP 
administration (capsule or injection, whichever comes first). 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. 
2.1.3.1 Primary efficacy endpoint(s) 
The primary efficacy endpoint is the percent change in calculated LDL-C from baseline to Week 
24 in the ITT population, using all LDL-C values regardless of adherence to treatment (ITT 
estimand). Primary endpoint is defined as: 100 × (calculated LDL-C value at Week 24 – 
calculated LDL-C value at baseline) / calculated LDL-C value at baseline.  
2.1.3.2 Secondary efficacy endpoint(s) 
2.1.3.2.1 Key secondary efficacy endpoints  
The key secondary endpoints are:  
• The percent change in calculated LDL-C from baseline to Week 24 in the mITT 
population, using all LDL-C values during the efficacy treatment period (on-treatment 
estimand); 
• The percent change in calculated LDL-C from baseline to Week 12 (ITT estimand); 
• The percent change in calculated LDL-C from baseline to Week 12 (on-treatment 
estimand); 
• The percent change in Apo B from baseline to Week 24 (ITT estimand); 
• The percent change in Apo B from baseline to Week 24 (on-treatment estimand); 
• The percent change in non-HDL-C from baseline to Week 24 (ITT estimand); 
• The percent change in non-HDL-C from baseline to Week 24 (on-treatment estimand); 
• The percent change in TC from baseline to Week 24 (ITT estimand); 
• The percent change in Apo B from baseline to Week 12 (ITT estimand); 
• The percent change in non-HDL-C from baseline to Week 12 (ITT estimand); 
• The percent change in TC from baseline to Week 12 (ITT estimand); 
• The proportion of patients reaching calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 
24 (ITT estimand); 
• The proportion of patients reaching calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 
24 (on-treatment estimand); 
• The percent change in Lp(a) from baseline to Week 24 (ITT estimand); 
• The percent change in HDL-C from baseline to Week 24 (ITT estimand); 
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• The percent change in fasting TG from baseline to Week 24 (ITT estimand); 
• The percent change in Apo A-1 from baseline to Week 24 (ITT estimand); 
• The percent change in Lp(a) from baseline to Week 12 (ITT estimand); 
• The percent change in HDL-C from baseline to Week 12 (ITT estimand); 
• The percent change in fasting TG from baseline to Week 12 (ITT estimand);  
• The percent change in Apo A-1 from baseline to Week 12 (ITT estimand). 
2.1.3.2.2 Other secondary efficacy endpoints  
• The proportion of patients with calculated LDL-C <100 mg/dL (2.59 mmol/L) at 
Weeks 12 and Week 24 (ITT estimand); 
• The proportion of patients reaching calculated LDL-C <70 mg/dL (1.81 mmol/L) at 
Week 12 (ITT estimand); 
• The absolute change in calculated LDL-C (mg/dL and mmol/L) from baseline to Week 12 
and Week 24 (ITT estimand);  
• The absolute change in Apo B/Apo A-1 ratio from baseline to Week 12 and Week 24 (ITT 
estimand); 
• The proportion of patients with Apo B <80 mg/dL (0.8 g/L) at Week 12 and Week 24 (ITT 
estimand); 
• The proportion of patients with non-HDL-C <100 mg/dL (2.59 mmol/L) at Week 12 and 
Week 24 (ITT estimand); 
• The proportion of patients with non-HDL-C <130 mg/dL (3.37 mmol/L) at Week 12 and 
Week 24 (ITT estimand); 
• The proportion of patients with calculated LDL-C <70 mg/dL (1.81 mmol/L) and/or ≥50% 
reduction in calculated LDL-C (if calculated LDL-C ≥70 mg/dL [1.81 mmol/L]) at 
Week 12 and Week 24 (ITT estimand); 
• The proportion of patients with ≥50% reduction in calculated LDL-C at Week 12 and 
Week 24 (ITT estimand); 
• The absolute change in TC/HDL-C ratio from baseline to Week 12 and Week 24 (ITT 
estimand); 
• The percent change in TC from baseline to Week 12 and 24 (on-treatment estimand); 
• The percent change in Apo B from baseline to Week 12 (on-treatment estimand); 
• The percent change in non-HDL-C from baseline to Week 12 (on-treatment estimand); 
• The percent change in Lp(a) from baseline to Week 12 and 24 (on-treatment 
estimand);The proportion of patients reaching calculated LDL-C <100 mg/dL 
(2.59 mmol/L) at Week 24 (on-treatment estimand). 
2.1.4 Safety endpoints 
The safety analysis will be based on the reported adverse events (AEs) and other safety 
information, such as clinical laboratory data, electrocardiogram (ECG) and vital signs.  
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Observation period  
The period of safety observation starts from the time when the patient gives informed consent and 
is divided into the following periods: 
• The PRE-TREATMENT period: defined as the time from the signed informed consent up 
to the first dose of double-blind IMP; 
• The treatment-emergent adverse event (TEAE) period: defined as the time from the first 
dose of double-blind IMP up to the day of last dose of double-blind IMP injection+70 days 
(10 weeks) as residual effect of alirocumab is possible until 10 weeks after the 
discontinuation of double-blind IMP injection. 
The TEAE period will include: 
- 
The TREATMENT period defined as the time from the first dose of double-blind IMP 
up to the day of last dose of double-blind IMP injection + 21 days, as serum 
concentration of alirocumab is expected to be >10 µg/mL for approximately 21 days 
following administration of 150 mg, and because throughout the previous studies it 
was observed that when alirocumab concentrations declined below this concentration, 
decrease in effect on LDL-C is observed. 
- 
The RESIDUAL TREATMENT defined as the time from the day of last dose of 
double-blind IMP injection + 22days up to the day of last dose of double-blind 
IMPinjection + 70 days (10 weeks). 
• The POST-TREATMENT period: defined as the time starting the day after the end of the 
TEAE period (ie, 71 days after the day of last dose of double-blind IMP injection). 
The on-study observation period is defined as the time from the day of first dose of double-blind 
IMP (capsule or injection, whichever comes first) until the last protocol planned visit of the 
patient. The last protocol planned visit is defined as the follow-up visit if done, or else 32 weeks 
after the randomization of the patient.  
2.1.4.1 Adverse events variables 
Adverse events (including serious adverse events [SAEs], 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, including CV events (irrespective of the result of the adjudication), will be 
reported and described. 
All AEs will be coded to a “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 currently in effect at Sanofi at the time of database lock. 
Adverse event observation period  
Pretreatment adverse events are adverse events that developed or worsened or became serious 
from the signed informed consent date up to first administration of IMP. 
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Treatment-emergent adverse events are adverse events that developed or worsened or became 
serious during the treatment-emergent adverse event period. 
Post-treatment adverse events are adverse events that developed or worsened or became serious 
during the post-treatment period. 
Grouping of adverse events (including adverse event of special interest)  
Adverse events of special interest (AESI) are AEs (serious or non-serious) that need to be 
monitored, documented, and managed in a pre-specified manner described in the protocol. More 
generally, below are the grouping of adverse events that will be analyzed  
• Alanine aminotransferase (ALT) ≥3 upper limit of normal range (ULN) (if baseline 
ALT<ULN) or ALT ≥2 times the baseline value (if baseline ALT ≥ULN), selected using 
laboratory data; 
• Allergic events: 
- 
General allergic events, selected using SMQ “hypersensitivity” (broad and narrow) 
excluding the following preferred terms linked to local injection site reactions 
(“infusion site dermatitis”, “infusion site hypersensitivity”, “infusion site rash”, 
“infusion site urticaria”, “injection site dermatitis”, “injection site hypersensitivity”, 
“injection site rash”, “injection site urticaria”, and “injection site vasculitis”) 
- 
General allergic events and local allergic reactions at IMP injection site will be 
described. This selection will be based on the above selection for general allergic event 
and on the following selection of PT from the symptoms complementary form for local 
injection site reaction: “Injection site dermatitis”, “Injection site hypersensitivity”, 
“Injection site oedema”, “Injection site rash”, “Injection site urticaria”, “Injection site 
eczema”, “Injection site vasculitis”, “Injection site swelling“, “Infusion site 
dermatitis”, “Infusion site hypersensitivity”, “Infusion site oedema”, “Infusion site 
rash”, “Infusion site urticaria”, “Infusion site swelling“. 
• Local injection site reactions, selected using e-CRF specific tick box on the AE page 
• Hemolytic anemia, selected using e-CRF specific tick box on the AE page and confirmed 
final diagnosis provided in the AE complementary form; 
• Neurologic events selected using a CMQ, based on 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 C Table 5 for the list of terms); 
• Neurocognitive events: 
- 
Selected using a CMQ, based on the following 5 HLGTs: “deliria (including 
confusion)”, “cognitive and attention disorders and disturbances”, “dementia and 
amnestic conditions”, “disturbances in thinking and perception”, and “mental 
impairment disorders” 
- 
A second grouping of terms for neurocognitive events was defined based on 
Regulatory Agency request (see Appendix C Table 6 for the list of terms) 
• Ophthalmologic events selected using SMQs; 
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• Cataract using HLT “Cataract conditions” 
• Overdose of IMP (symptomatic or asymptomatic), selected using appropriate 
MedDRAcodes and the tick box “Overdose with IMP” in the adverse event 
complementary e-CRF form 
• Pregnancy of female patient/subject (including male subject’s partner) selected using 
appropriate MedDRA codes; 
• Hepatic disorder events using SMQ “Hepatic disorder”; 
• Diabetes mellitus or diabetic complications selected using HLGT “diabetes complications” 
(including PTs pertaining to the secondary SOC included in the HLGT), HLT “diabetes 
mellitus”, and HLT “carbohydrate tolerance analyses (incl diabetes)” excluding PTs 
“blood glucose decreased” and “Glycosylated haemoglobin decreased” and including the 
PTs “hyperglycaemia”, “Hyperglycaemic unconsciousness” and “Hyperglycaemic 
seizure” from the HLT “Hyperglyceamic conditions NEC"; 
Cardiovascular events 
Suspected CV events that occur from randomization until the follow up visit will be submitted to 
the Clinical Events Committee (CEC) for adjudication. 
Adjudicated CV events include all CV AEs positively adjudicated as defined in the Clinical 
Events Committee charter. The following categories will be described: 
• CHD death; 
• Non-fatal MI; 
• Fatal and non-fatal ischemic stroke; 
• Unstable angina requiring hospitalization; 
• Congestive heart failure requiring hospitalization; 
• Ischemia driven coronary revascularization procedure. 
2.1.4.2 Deaths 
The deaths observation period are per the observation periods defined below.  
• Death on-study:  deaths occurring during the on-study observation period; 
• Death on-treatment:  deaths occurring during the treatment-emergent adverse event period; 
• Death post-study:  deaths occurring after the end of the study.  
2.1.4.3 Laboratory safety variables 
Clinical laboratory data consists of blood analysis, including hematology, clinical chemistry, and 
urinalysis.  Clinical laboratory values after conversion will be analyzed into standard international 
units and will be used in all listings and tables.  
Unless otherwise specified, blood samples for clinical laboratories will be taken at Visit 1 
(Week -3), Visit 3 (Week 0), Visit 6 (Week 12), Visit 8 (Week 24), or early termination, and 
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during the follow-up visit (Visit 9 [Week 32]) in case of abnormality unless otherwise specified.  
The laboratory parameters will be classified as follows:   
• Hematology: 
- 
Red blood cells and platelets: hemoglobin, hematocrit, erythrocytes count, platelets 
count, reticulocyte count, red blood cell distribution width (RDW); 
- 
White blood cells: white blood cell count, neutrophils, lymphocytes, monocytes, 
basophils, eosinophils. 
• Clinical chemistry: 
- 
Metabolism: glucose, total protein, albumin, creatine phosphokinase; 
- 
Electrolytes: sodium, potassium, chloride, calcium, phosphorus, bicarbonate; 
- 
Renal function: creatinine, eGFR, blood urea nitrogen, uric acid; 
- 
Liver function (also measured at Week 4, Week 8, and Week 16, except gamma 
glutamyl transferarses [GGT] and lactate dehydrogenase [LDH]): ALT, aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), GGT, total bilirubin, and in case 
of total bilirubin values above the normal range, must include direct and indirect 
bilirubin, LDH. 
• Hepatitis screen: anti-hepatitis-C antibody (Ab) (at Week -3 and Week 24/or early 
termination). 
Technical formulas are described in Section 2.5.1. 
2.1.4.4 Vital signs variables 
Vital signs include: heart rate (HR), systolic and diastolic blood pressure (SBP and DBP) in sitting 
position.  
2.1.4.5 Electrocardiogram variables 
The ECG parameters were recorded automatically by the device at the Investigator site at 
Week -3/Week -2, Week 24, or early termination. 
2.1.5 Other endpoints 
The assessment endpoint listed below is defined using the same definitions and rules as for 
calculated LDL-C, when applicable (see Section 2.1.3.1). 
• The absolute change in HbA1c (%) from baseline to Week 12 and Week 24. PCSA criteria 
for HbA1c will be used (see Appendix A). 
• The proportion of patients with 2 consecutive results, spaced out by at least 21 days, of 
calculated LDL-C <25 mg/dL (<0.65 mmol/L) (respectively calculated LDL-C 
<15 mg/dL, ie, <0.39 mmol/L) during the treatment period and the time to the first 
calculated LDL-C <25 mg/dL (respectively, calculated LDL-C <15 mg/dL for these 
patients). 
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2.1.6 Anti-alirocumab antibodies variables 
Anti-alirocumab antibodies are assessed at baseline (before the first IMP injection), at Week 4, 
Week 12, Week 24/or early termination and during follow-up (Week 32). Anti-drug antibody 
(ADA ) measurements will be assigned to similar analysis windows as defined for efficacy 
endpoints (Table 2), with an additional analysis window for the ADA follow-up measurement 
performed at Week 32. 
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 (up to 
follow-up visit) or 2) Patients with a positive ADA response at baseline and at least a 4-
fold increase in titer in the post-baseline period (up to follow-up visit). 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. 
In addition, potential ADA samples to be collected after follow-up visit for patients with titer 
>240 at early end of treatment or follow-up visit will be listed. 
2.1.7 Pharmacokinetics variables 
Concentrations of total alirocumab, total and free proprotein convertase subtilisin/kexin type 9 
(PCSK9) concentrations in serum are assessed at baseline (Week 0), Week 4, Week 12, Week 16, 
Week 24, and during the post-treatment follow-up visit (Week 32). To collect information on the 
absorption phase, an optional PK sample can be collected 5 days (±2) after the Week 22 IMP 
injection. 
Pharmacokinetic variable is the total alirocumab concentration at each time point. Depending on 
the timing of the sample versus the previous injection, Ctrough, Ctrough,av, Cmax and CFollow-Up will be 
defined as follows: 
• Cmax: alirocumab concentration sample taken 5 days ±2 days after previous injection; 
• Ctrough: alirocumab concentration sample taken 14 days ±6 days after previous injection 
(may be just prior the next injection): 
- 
Ctrough,av: Alirocumab average trough concentrations (“Ctrough,av”) will be calculated for 
each patient as the mean of “Ctroughs” considered at steady state. The occurrence of 
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steady state will be assessed graphically, by plotting “Ctrough” throughout the study 
visits over all patients. 
• CFollow-up: alirocumab concentration sample taken more than 21 days after last injection and 
no more than 14 weeks after last injection. 
Alirocumab concentration and total and free PCSK9 concentration will be described following 
time windows as defined in Section 2.5.4, Table 2. 
2.1.8 
 
 
2.2 
DISPOSITION OF PATIENTS 
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
Screened patients are defined as any patients who 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. 
For patient study status, the total number of patients in each of the following categories will be 
presented in the clinical study report using a flowchart diagram or summary table: 
• Screened patients; 
• Screen failure patients and reasons for screen failure; 
• Non-randomized but treated patients, if any; 
• Randomized patients; 
• Randomized but not treated patients and reason for not being treated; 
• Randomized and treated patients; 
• Patients who did not complete the study treatment period as per protocol; 
• Patients who discontinued study treatment by main reason for permanent treatment 
discontinuation; 
• Status at last study contact. 
For all categories of patients (except for the screened and nonrandomized categories) percentages 
will be calculated using the number of randomized patients as the denominator divided by the 
number of exposed patients.   
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Reasons for treatment discontinuation will be supplied in tables giving numbers and percentages 
by treatment group.   
The incidence of premature treatment discontinuation (irrespective of the reason) and premature 
treatment discontinuation due to AEs will be presented graphically by treatment group on 
randomized and treated patients (as randomized), using Kaplan-Meier method. 
Patients with insufficient post-treatment follow-up will be described. A patient is considered 
insufficient post-treatment follow-up at the end of the study in following cases: 
• If the patient is not assessed at the post-treatment follow-up visit, or any post-treatment 
visit, unless patient died before; 
• If the post-treatment follow-up visit is less than 9 weeks after the last double-blind IMP 
injection. 
All critical or major deviations potentially impacting efficacy analyses, randomization, and 
drug-dispensing irregularities, and other major or critical deviations will be summarized in tables 
giving numbers and percentages of deviations by treatment group. Additionally, the analysis 
populations will be summarized in a table by number of patients on the randomized population.  
• Randomized population; 
• Efficacy population: intent-to-treat (ITT) population/modified intent-to-treat (mITT) 
population; 
• Safety population; 
• Pharmacokinetics population; 
• Anti-alirocumab antibody population. 
• Definitions of the study population are provided in Section 2.3. 
2.2.1 Randomization and drug dispensing irregularities 
Randomization and drug-dispensing irregularities occur whenever: 
1. A randomization is not in accordance with the protocol-defined randomization method, 
such as a) a patient is randomized based on an incorrect stratum, b) a patient is randomized 
twice. 
 
OR 
2. A patient is dispensed an IMP kit not allocated by the protocol-defined randomization, 
such as a) a patient at any time in the study is dispensed a different treatment kit than as 
randomized (which may or may not contain the correct-as-randomized IMP), or b) a 
nonrandomized patient is treated with IMP reserved for randomized patients. 
Randomization and drug-dispensing irregularities will be monitored throughout the study and 
reviewed on an ongoing basis.  
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All randomization and drug-dispensing irregularities will be documented in the clinical study 
report.  These irregularities will be summarized among randomized patients (number and 
percentages).  Nonrandomized, treated patients will be described separately.  
Randomization and drug-dispensing irregularities to be prospectively identified include but are 
not limited to:  
Randomization and drug allocation irregularities 
Kit dispensation without IRT transaction 
Erroneous kit dispensation 
Kit not available 
Randomization by error 
Patient randomized twice 
Stratification error 
A kit allocated at Day 1 or any unscheduled replacement before Week 12 is administered to the patient after the up-
titration visit (Week 12) 
2.3 
ANALYSIS POPULATIONS 
Patients treated without or before being randomized will not be considered randomized and will 
not be included in any analysis populations. The safety experience of patients treated and not 
randomized will be reported separately. 
The randomized population includes any patient who has been allocated to a randomized 
treatment by IVRS/IWRS regardless of whether the treatment kit was used. 
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population.  The safety experience associated with any later 
randomization will be assessed separately. 
The safety experience of patients treated and not randomized will be reported separately, and 
these patients will not be in the safety population. 
2.3.1 Efficacy populations 
The primary efficacy analysis population will be the ITT population. 
2.3.1.1 
Intent–to-treat population 
The intent-to-treat population is the randomized patients who had an evaluable primary efficacy 
endpoint. The primary efficacy endpoint is evaluable when the following 2 conditions are met: 
• Availability of a baseline calculated LDL-C value; 
• Availability of at least 1 calculated LDL-C value within one of the analysis windows up to 
Week 24. 
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Patients in the ITT population will be analyzed according to the treatment group allocated by 
randomization (ie, as-randomized treatment group). 
2.3.1.2 Modified intent-to-treat population  
The modified intent-to-treat population is defined as all randomized patients who took at least 
1 dose or part of a dose of the double-blind IMP injection and had an evaluable primary efficacy 
endpoint during the efficacy treatment period. The primary efficacy endpoint is evaluable when 
the following 2 conditions are met: 
• Availability of a baseline calculated LDL-C value; 
• Availability of at least 1 calculated LDL-C value during the efficacy treatment period 
within one of the analysis windows up to Week 24. 
The efficacy treatment period is defined as the time period from the first double-blind IMP 
(capsule or injection, whichever comes first) up to the day of last injection +21 days or the day of 
last capsule intake date +3 days, whichever comes first. 
Patients in the mITT population will be analyzed according to the treatment group allocated by 
randomization (ie, as-randomized treatment group). 
2.3.2 Safety population 
The safety population is defined as randomized patients who actually received at least 1 dose or 
part of a dose of the IMP (injection or capsule). Patients will be analyzed according to the 
treatment actually received (ie, as-treated treatment group, alirocumab or ezetimibe). 
In addition: 
• Randomized patients for whom it is unclear whether they took the IMP will be included in 
the safety population as randomized. 
For patients receiving double-blind IMP from both treatments during the trial, the treatment group 
used for as-treated analysis will be the one to which the patient was treated with the highest 
number of injections except in the case where the patient is randomized in the alirocumab group 
but received more placebo injections than alirocumab injections and took more placebo capsules 
than ezetimibe capsules. In that case the as-treated group is defined as alirocumab (see Appendix 
D). In case of the same number of injections of each treatment is received, the as-treated treatment 
group will be the as-randomized group. 
2.3.3 Anti-alirocumab antibody population 
The anti-alirocumab antibody analysis will be performed on all randomized and treated patients 
(safety population) with a blood sample on Week 0 (baseline) and at least one evaluable blood 
sample for antibodies after the first double-blind IMP injection. 
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2.3.4 Pharmacokinetic population 
The PK analysis will be performed on all randomized and treated patients (safety population) with 
at least 1 evaluable PK sample post first double-blind IMP injection. 
2.4 
STATISTICAL METHODS 
2.4.1 Demographics and baseline characteristics 
Parameters described in Section 2.1.1 will be summarized by treatment group and overall 
treatment groups using descriptive statistics.  
Continuous data will be summarized using the number of available data, mean, standard 
deviation (SD), median, minimum, and maximum for each treatment group. First quartile (Q1) 
and third quartile (Q3) will be provided for baseline lipid and HbA1c. Categorical and ordinal 
data will be summarized using the number and percentage of patients in each treatment group.  
Parameters will be summarized on the randomized population analyzed in the treatment group to 
which they were randomized. Similar analyses will be done on the ITT population in the as-
randomized treatment group (respectively safety population in the as-treated treatment group) and 
will be included in the appendices if the size of the ITT population (respectively safety 
population) is different (>10%) from the size of the randomized population for any treatment 
group.  In the randomized population, parameters will also be summarized within each 
randomization stratum as per IVRS. 
All reported patient’s medical and surgical history will be presented by primary SOC and HLT. 
The tables will be sorted by SOC internationally agreed order and decreasing frequency of HLT 
based on the overall incidence across treatment groups. In addition all medical history of specific 
interest (see Section 2.1.1) will be presented by treatment group. 
For the patients with a primary CVD prevention status, the number (%) of patients with the 
following comorbidities/risk factors will be tabulated: 
• Diabetes mellitus with target organ damage (renal damage [microalbuminuria, or 
macroalbuminuria, moderate chronic kidney disease (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 2.1.1); 
• Family history of premature CHD; 
• Hypertension; 
• Moderate CKD. 
In addition, smoking status will be summarized in patients with primary CVD prevention status. 
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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 2.1.1); 
• 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. 
Besides: 
• The number (%) of patients with a secondary prevention status with 1 or more associated 
comorbidity among hypertension, diabetes mellitus, moderate CKD will be tabulated. 
• 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 presented. 
2.4.2 Prior or concomitant medications  
The prior and concomitant medications will be presented for the randomized population.  
Medications will be summarized by treatment group according to the WHO-DD dictionary, 
considering the first digit of the anatomic therapeutic category (ATC) class (anatomic category) 
and the first 3 digits of the ATC class (therapeutic category).  All ATC codes corresponding to a 
medication will be summarized, and patients will be counted once in each ATC category 
(anatomic or therapeutic) linked to the medication. Therefore patients may be counted several 
times for the same medication.  
The table for prior medications will be sorted by decreasing frequency of ATC followed by all 
other therapeutic classes based on the overall incidence across treatment groups.  In case of equal 
frequency regarding ATCs (anatomic or therapeutic categories), alphabetical order will be used. 
The tables for concomitant and post-treatment medications will be sorted by decreasing frequency 
of ATC followed by all other therapeutic classes based on the incidence in the alirocumab group.   
In case of equal frequency regarding ATCs, alphabetical order will be used.  
In addition, concomitant LMTs and CV medications will be summarized by pre-specified 
categories/chemical class and standardized medication name. 
Lipid modifying therapy (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; 
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• Atorvastatin below 40 mg daily or rosuvastatin below 20 mg daily or simvastatin at any 
daily dose; 
• LMT other than statin only; 
• No LMT. 
The LMTs intensity at randomization is defined as: 
• High intensity is atorvastatin 40 to 80 mg daily or rosuvastatin 20 to 40 mg daily; 
• Low intensity is atorvastatin below 40 mg daily or rosuvastatin below 20 mg daily or 
simvastatin at any daily dose. 
2.4.3 Extent of investigational medicinal product exposure and compliance  
The extent of IMP exposure and compliance will be assessed and summarized by actual treatment 
within the safety population (Section 2.3.2). 
2.4.3.1 Extent of investigational medicinal product exposure 
Injection (alirocumab or placebo) 
The extent of IMP exposure will be assessed by the duration of IMP exposure, and actual dose 
information. 
Double-blinded IMP injections are those administered from randomization to completion or 
discontinuation of the study treatment. These injections contain: 
• Placebo for patients randomized in the ezetimibe group; 
• 75 or 150mg of alirocumab for patients randomized in the alirocumab group. 
Total exposure will be assessed using descriptive statistics for:  
• Duration of IMP injection exposure in weeks is defined as: (last dose of double-blind IMP 
injection date – first dose of double-blind IMP injection date + 14 days)/7, regardless of 
unplanned intermittent discontinuations (see Section 2.5.3 for calculation in case of 
missing or incomplete data). Non-integer values will be rounded to 1 decimal place; 
• The total number of injections by patient. 
These parameters will be also analyzed per dose of alirocumab using similar definitions. 
Titration 
The number and percentage of patients with an up-titration in the alirocumab group will be 
described. Patients with an up-titration are defined as up-titrated patients according to 
IVRS/IWRS Week 12 transaction with at least 1 injection of alirocumab 150 mg afterwards. 
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Capsule (ezetimibe or placebo) 
The total exposure of capsule will be assessed by duration in weeks defined as: (last capsule 
intake date – first capsule intake date + 1 day) / 7, regardless of intermittent discontinuations. 
Non-integer values will be rounded to 1 decimal place. 
All quantitative parameters above will be summarized using number, mean, SD, median, 
minimum, and maximum. In addition, the durations of treatment exposure will be summarized 
and presented graphically using bar chart displaying the percentage of patients according to the 
following categories: ≥1 and <4 weeks, ≥4 weeks and <8 weeks, ≥8 weeks and <12 weeks, 
≥12 weeks and <16 weeks, ≥16 weeks and < 22 weeks, and ≥22 weeks. 
2.4.3.2 Compliance  
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol.  No imputation will be made for patients with 
missing or incomplete data.  
Compliance will be assessed using the following parameters: 
Mean injection frequency of IMP double-blind injections, is 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. 
The overall compliance for injections will be defined for each patient as: 100 – (%days with 
under-planned dosing + %days with above-planned dosing). Under-planned and above-planned 
dosing will be defined as follows, considering that injections should be performed every 2 weeks 
(±3 days as per protocol): 
Above-planned dosing percentage will be defined for each patient as the number of days with 
more than 1 injection administered within the 11 days before divided by the duration of IMP 
injection exposure in days. For example if a patient takes a dose 9 days after his/her previous 
injection, then 2 days are counted as days above-planned dose. 
Under-planned dosing percentage will be defined for each patient as the number of days with 
no injection administered within the previous 17 days divided by the duration of IMP injection 
exposure in days. For example if a patient takes a dose 18 days after his/her previous injection, 
then 1 day is counted as a day under-planned dosing.  
These parameters will be summarized descriptively (number, mean, SD, median, minimum, and 
maximum).  
The percentage of patients whose compliance is <80% will be summarized, as well as numbers 
and percentages of patients with 0%, >0 to ≤5%, >5 to ≤10%, >10 to ≤20%, and >20% day with 
above-planned dosing and numbers and percentages of patients with 0%, >0 to ≤5%, >5 to ≤10%, 
>10 to ≤20%, and >20% day with under-planned dosing. 
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According to protocol, cases of overdose are reported in the AE e-CRF pages and will be 
described in AE analysis (see Section 2.1.4.1 and Section 2.4.5.1). 
2.4.4 Analyses of efficacy endpoints 
2.4.4.1   Analysis of primary efficacy endpoint(s) 
2.4.4.1.1 Primary efficacy analysis 
The percent change from baseline in calculated LDL-C at Week 24 as defined in Section 2.1.3.1 
will be analyzed in the ITT population using a mixed effect model with repeated measures 
(MMRM) approach. All post-baseline data available within Week 4 and Week 24 analysis 
windows will be used and missing data are accounted for by the MMRM model. The model will 
include the fixed categorical effects of treatment group (ezetimibe versus alirocumab), 
randomization strata (as per IVRS, as defined in Section 1.1), time point (Week 4, Week 8, 
Week 12, Week 16, and Week 24 as defined in Section 2.5.4), treatment -by-time point 
interaction, strata-by-time point interaction, and the continuous fixed covariates of baseline LDL-
C value and baseline value-by-time point interaction. In case the number of patients is lower than 
10 in a given stratum (eg, MI/Ischemic Stroke = Yes), the corresponding stratum 
(eg, MI/Ischemic stroke) and stratum-by-time point interaction terms will be removed from the 
model. The same will be applied to sensitivity analyses and subgroup analyses. 
This model will be run using 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 LS means 
estimates at Week 24 for both treatment groups with their corresponding standard errors (SEs) and 
95% confidence intervals (CIs). To compare the alirocumab group to the ezetimibe group, an 
appropriate contrast statement will be used to test the differences of these estimates, at the 2-sided 
0.05 level. 
Within group least square (LS) means and SEs will be provided, using weights equal to the 
observed proportion of patients in strata variable levels in the study population (ie, “population 
weight”) rather than equal weights. Population weights are considered more appropriate than 
equal coefficients due to unbalances between levels of the randomization stratification factors 
observed in the study population. 
Let µ0 and µ1 be the population means of the percent change from baseline in calculated LDL-C at 
Week 24 under ezetimibe and alirocumab, respectively. The hypothesis that will be tested is “H0: 
µ0 = µ1” versus “H1: µ0 ≠ µ1”. 
The MMRM model relies on the “missing-at-random” (MAR) assumption. As we can never 
exclude the possibility for a not-missing-at-random (NMAR) missingness mechanism, sensitivity 
analyses to explore the impact of non-ignorable missingness on the primary efficacy analysis will 
be conducted (see pattern mixture model defined in Section 2.4.4.1.4). 
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2.4.4.1.2 Model assumption checks 
Homogeneity of treatment effect across baseline LDL-C levels 
In order to check the homogeneity of treatment effect versus baseline LDL-C, the following 
interaction terms will be added in the primary MMRM model: 
• Treatment group * baseline calculated LDL-C 
• Treatment group * time-point * baseline calculated LDL-C 
Within the framework of this model with interaction terms, a graph presenting the LS means 
difference versus ezetimibe at Week 24 and the corresponding 95% CI will be provided by 
baseline LDL-C value. 
Analysis of residuals: 
The analysis of the residuals of the MMRM will be primarily based on studentized residuals. It 
will include: 
• Normality of studentized residuals, presented graphically using histogram and quantile 
quantile (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 (ezetimibe, alirocumab); 
- 
Time point (Week 4, Week 8, Week 12, Week 16, Week 24); 
- 
Treatment-by-time point interaction; 
- 
Randomization strata; 
- 
Randomization strata-by time point interaction. 
2.4.4.1.3 Sensitivity to randomization strata 
In order to assess the robustness of the primary analysis to randomization stratum mistakes (ie, the 
stratum recorded in IVRS differs from the actual one), the MMRM model will be re-run including 
the actual stratum as per the e-CRF instead of the stratum recorded in IVRS. 
2.4.4.1.4 Sensitivity to handling of missing data 
Sensitivity analyses will be conducted to assess the robustness of primary efficacy analysis with 
regards to handling of missing data (1). 
Visual examination: 
• In order to explore the missing data pattern, post-baseline calculated LDL-C  observations 
(in the ITT population) will be described according to the following groups: 
- 
Calculated LDL-C available at Week 24*(ie, primary efficacy endpoint available); 
- 
Calculated LDL-C available at Week 16* but missing at Week 24 *; 
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- 
Calculated LDL-C available at Week 12* but missing from Week 16*; 
- 
Calculated LDL-C available at Week 8* but missing from Week 12*; 
- 
Calculated LDL-C available at Week 4* but missing from Week 8*; 
- 
Calculated LDL-C missing from Week 4*. 
(*): as defined in Section 2.5.4 
Then, a graph of mean LDL-C calculated levels (respectively percent change from 
baseline in calculated LDL-C) ± SE at baseline, Week 4, Week 8, Week 12, Week 16, and 
Week 24 will be provided by missing data pattern, for each treatment group. 
• In the ITT population, demographic and baseline characteristics will be described within 
the missing data pattern number 1 versus the pooled others. P-values from Fisher exact test 
for categorical data and from asymptotic 1-way ANOVA test for Wilcoxon scores 
(Kruskal-Wallis test) for continuous data will be also provided for descriptive purposes. 
Multiple imputations (under MAR assumption) 
In addition to the MMRM method, the multiple imputation (MI) method will be used to address 
missing values, in the randomized population, followed by the testing of treatment arms using an 
analysis of covariance (ANCOVA) model, with the intent to evaluate the robustness of the 
primary analysis using a different statistical method. The imputation model described in 
Section 2.4.4.2.2 will be used but without log transformation. Missing data from the randomized 
population will be imputed 100 times to generate 100 complete data sets. The percent change 
from baseline at Week 24 will be then derived from observed and imputed LDL-C at this time 
point. The 100 complete data sets will be then analyzed using an ANCOVA model with treatment 
group and randomization strata (as per IVRS, as defined in Section 1.1) as fixed effects, and the 
baseline calculated LDL-C value as continuous covariate, and the MIANALYZE procedure will 
be used to generate valid statistical inferences by combining results from the 100 analyses using 
Rubin’s formulae (1). 
• 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 until 
stable estimates are obtained. 
In addition, for each simulation leading to negative imputed value, another value will be redrawn 
using MINIMUM option of MI SAS procedure (2). 
Pattern mixture model (see Appendix B for more details) 
Multiple imputations will be used with different imputation strategies applied to calculated LDL-
C values missing during the on-treatment period (i.e. within the time period from the first double-
blind IMP injection up to the day of last injection + 21 days) versus calculated LDL-C values 
missing after treatment discontinuation (ie, after the day of last injection + 21 days) based on the 
following assumptions: 
• Patients within 21 days of their last blind IMP injection would continue to show benefit 
from treatment similar to that observed at the scheduled time point. Therefore, calculated 
LDL-C values missing during the on-treatment period (eg, samples obtained out-side the 
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specified window, no blood sample available although visit was performed) should be 
considered “missing-at-random” and imputed based on other on-treatment measurements. 
• Patients who stopped taking their study treatment no longer benefited from it after 
discontinuation, and thus tended to have calculated LDL-C values returning to baseline. 
Therefore, calculated LDL-C values missing more than 21 days after treatment 
discontinuation should be imputed based on patient’s own baseline value. 
Missing calculated LDL-C values will be imputed 100 times to generate 100 complete data sets. 
The percent change from baseline to Week 24 will be derived from observed and imputed LDL-C 
at this time point. The completed data sets will be analyzed using an ANCOVA model with 
treatment group and randomization strata as fixed effects, and the baseline calculated LDL-C 
value as continuous covariate. The results from the 100 analyses will be combined using Rubin’s 
formulae. 
2.4.4.1.5 Sensitivity to the use of calculated versus measured LDL-C measurements 
 
In order to assess the robustness of the primary analysis to the use of calculated versus measured 
LDL-C assessments, an ANCOVA model will be run using measured LDL-C within Week 24 
analysis window. This model will include the treatment group, the baseline value for measured 
LDL-C and the randomization strata. Patients from ITT population with a measured LDL-C at 
baseline and at least 1 measured LDL-C available within Week 24 analysis window will be 
included in the analysis. 
2.4.4.1.6 Subgroup 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 ezetimibe at Week 24 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 24 will also be 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. 
Subgroups of interest are: 
• BMI (<30 kg/m2, ≥30 kg/m2); 
• Gender (Female, Male); 
• Age (<65 years, ≥65 to <75 years, ≥75 years); 
• High intensity statin treatment (atorvastatin 40 to 80 mg daily or rosuvastatin 20 to 40 mg 
daily versus atorvastatin below 40 mg daily, rosuvastatin below 20 mg daily or simvastatin 
whatever the daily dose); 
• Prior history of myocardial infarction (MI) or ischemic stroke (Yes, No); 
• Diabetes (Yes, No); 
• Moderate CKD (Yes, No); 
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• Baseline LDL-C (<2.59, ≥2.59 to <3.37, ≥3.37 to <4.14, ≥4.14 mmol/L): for this specific 
subgroup factor, the MMRM model will include fixed categorical effects for treatment 
group, randomization strata (as per IVRS), baseline LDL-C category, time point, and the 
interactions treatment-by-time point, strata-by-time point, baseline LDL-C category-by-
time point, treatment group-by-baseline LDL-C category, and treatment group-by-baseline 
LDL-C category-by-time point; 
• Baseline HDL-C (<1.04 mmol/L, ≥1.04 mmol/L); 
• Baseline fasting TG (<1.70 mmol/L, ≥1.70 mmol/L, ie, mixed dyslipidemia); 
• Baseline Lp(a) (<0.3, ≥0.3 to <0.5, ≥0.5 g/L); 
If the subgroup factor is a randomization stratification factor, then the IVRS strata will be used.  
2.4.4.2   Analyses of secondary efficacy endpoints 
2.4.4.2.1 Continuous endpoints anticipated to have a normal distribution 
Continuous secondary variables defined in Section 2.1.3.2 anticipated to have a normal 
distribution (ie, lipids other than TG and Lp[a]) will be analyzed using the same MMRM model as 
for the primary endpoint with fixed categorical effects of treatment group, randomization strata 
(as per IVRS), planned time points up to Week 24, treatment-by-time point interaction and  strata-
by-time point interaction, as well as, the continuous fixed covariates of corresponding baseline 
value and baseline value-by-time point interaction. 
2.4.4.2.2 Continuous endpoints anticipated to have a non-normal distribution 
Continuous secondary efficacy variables defined in Section 2.1.3.2 anticipated to have a non-
normal distribution (ie, TG and Lp[a]) will be analyzed using multiple imputation approach for 
handling of missing values. 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 (3) with endpoint of interest as response variable using M-
estimation (using SAS ROBUSTREG procedure) with treatment group, randomization strata (as 
per IVRS, as defined in Section 1.1) and corresponding baseline value(s) as effects to compare 
treatment effects. 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. In case the number of patients is lower than 10 in a given 
stratum (eg, MI/Ischemic Stroke = Yes), the corresponding stratum (eg, MI/Ischemic Stroke) term 
will be removed from the multiple imputation and robust regression models. 
Multiple imputation model 
Since in general the missing pattern is anticipated not to be monotone, a two-step approach will be 
used: 
• Step 1: The Markov Chain Monte Carlo (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 time-points up to Week 24. 
The imputation model for step 2 will include the same variables as in step 1 with the following 
additional variables: 
• The randomization strata; 
• Age, BMI, and gender (age and BMI included as continuous variables). 
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. 
2.4.4.2.3 Binary endpoints 
Binary secondary efficacy endpoints defined in Section 2.1.3.2 will be analyzed using multiple 
imputation approach for handling of missing values as described for non-normally distributed 
endpoints but without log-transformation (see Section 2.4.4.2.2 for details about multiple 
imputation). 
For each simulation leading to negative imputed value, another value will be redrawn using 
MINIMUM option of MI SAS procedure.  
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 treatment group as main effect and corresponding baseline value(s) as covariate, stratified by 
randomization factors (as per IVRS, as defined in Section 1.1). Combined estimates of odds ratio 
versus ezetimibe, 95% CI, and p-value will be obtained through the SAS MIANALYZE 
procedure. 
In case the number of patients is lower than 10 in a given stratum (eg, MI/Ischemic Stroke = Yes), 
the corresponding stratum (eg, MI/Ischemic Stroke) term will be removed from the multiple 
imputation and logistic regression models. 
In the data dependent case when such logistic regression is not applicable (eg, the response rate is 
zero in one treatment arm and thus the maximum likelihood estimate may not exist), the last 
observation carried forward (LOCF) approach would be used for handling of missing values and a 
stratified 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 Week 24 
analysis window (Week 12 respectively) to impute the missing Week 24 value (Week 12 
respectively). 
In case of computing issues with exact logistic regression, the baseline level(s) will be entered in 
the model as a categorical variable(s) using quartiles. In case the model would not converge with 
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stratification variables, an unstratified exact logistic regression will be performed. Exact odds 
ratio versus ezetimibe, 95% CI, and p-value will be provided. 
2.4.4.2.4 Sensitivity analyses of key secondary endpoints 
In order to assess secondary endpoints during the efficacy treatment period, the same statistical 
approach as described above from Section 2.4.4.2.1 to Section 2.4.4.2.3 will be applied during the 
efficacy treatment period in the mITT population (see Section 2.3.1.2). 
2.4.4.2.5 Analyses of key secondary endpoints by subgroups 
The endpoint “the percent change in fasting TG from baseline to Week 24” will be analyzed 
according to the following subgroups: 
• Baseline fasting TG (<150 mg/dL [<1.70 mmol/L], ≥150 mg/dL [≥1.70 mmol/L] ie, mixed 
dyslipidemia). 
2.4.4.2.6 Summary of results per time point 
Central laboratory values, percent change from baseline, and/or when appropriate absolute change 
from baseline, for calculated LDL-C, TC, HDL-C, fasting TG, non HDL-C, and T C/HDL-C ratio 
at Week 4, Week 8, Week 12, Week 16, Week 24 time points, for Lp(a), Apo B, Apo A-1 at Week 
12 and Week 24 time points will be summarized in the ITT population using: 
• 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 including planned time points 
and with raw values, changes from baseline, or percent change from baseline as response 
variable in the model as appropriate. 
• 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 including planned time points and with raw values or percent changes from baseline 
as response variable in the model as appropriate. 
In addition, quantitative descriptive summaries by time point (value at visit and % change from 
baseline) will be presented for all lipids using observed (ie, non-missing) data. In addition binary 
variables for LDL-C will be also described by time point. 
2.4.4.3   Multiplicity issues 
In order to handle multiple key efficacy secondary endpoints, the overall type-I error will be 
controlled by the use of a sequential inferential approach. Statistical significance of the primary 
parameter at the 0.05 alpha level is required before drawing inferential conclusions about first key 
secondary parameter (refer to the order in Section 2.1.3.2.1). Inferential conclusions about 
successive key secondary parameters require statistical significance at the 0.05 alpha level of the 
prior ones. 
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This fixed hierarchical approach will ensure a strong control of the overall type-I error rate at the 
0.05 level. 
No further adjustments will be made for other secondary efficacy endpoints for which p-values 
will be provided for descriptive purpose only. 
2.4.4.4   Additional efficacy analysis(es) 
Not applicable. 
2.4.5 Analyses of safety data 
The summary of safety results will be presented by treatment group. No formal inferential testing 
will be performed. Summaries will be descriptive in nature.  
General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.2, unless 
otherwise specified, using the following common rules: 
• Safety data in patients who do not belong to the safety population (eg, 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 double-blind IMP administration (capsule or injection, whichever comes first), 
except otherwise specified.  
• The potentially clinical significant abnormality (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 A]). In case 
the threshold defined in the PCSA list for a given lab parameter is below the ULN, the 
following PCSA criterion will be used for the PCSA analysis: >PCSA threshold or > ULN 
(if ULN ≥PCSA threshold). 
• PCSA criteria will determine which patients had at least 1 PCSA during the TEAE period, 
taking into account all evaluations performed during TEAE period, including 
nonscheduled or repeated evaluations. 
• The treatment-emergent PCSA denominator by 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 Section 2.5.4, Table 2 in order to provide an assessment for Week 4 to Week 
24 time points. 
• For quantitative safety parameters based on central laboratory/reading measurements, 
descriptive statistics will be used to summarize results and change from baseline values by 
visit and treatment group using analysis windows. Summaries will also include the last on-
treatment value and the worst on-treatment value. The last on-treatment value is defined as 
the last value collected during the treatment period (see Section 2.1.4). The worst on-
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treatment value is defined as the nadir and /or the peak value during the treatment period 
according to the direction (minimum or maximum) of the abnormality as defined in the 
PCSA list. 
• For exploratory purpose, key safety analyses could also be provided according to up-
titration status, ie, according to whether the patients remained on the 75 mg dose or 
whether they were up-titrated to 150 mg. 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 and 
those remaining on 75 mg. 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 
dose 75 mg is proposed for this time period and consequently the early events occurring 
before Week 12 can only be attributed to this dose. 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). 
2.4.5.1   Analyses of adverse events 
Generalities 
The primary focus of adverse event (AE) reporting will be on treatment-emergent adverse events 
(TEAEs).  Pre-treatment and post-treatment adverse events will be described separately.  
If an adverse event date/time of onset (occurrence, worsening, or becoming serious) is incomplete, 
an imputation algorithm will be used to classify the adverse event as pretreatment, treatment-
emergent, or post-treatment.  The algorithm for imputing date/time of onset will be conservative 
and will classify an adverse event as treatment emergent unless there is definitive information to 
determine it is pretreatment or post-treatment.  Details on classification of adverse events with 
missing or partial onset dates are provided in Section 2.5.3. 
Adverse event incidence tables will present by SOC, HLGT, HLT, and PT, sorted in alphabetical 
order for each treatment group, the number (n) and percentage (%) of patients experiencing an 
adverse event.  Multiple occurrences of the same event in the same patient will be counted only 
once in the tables within a treatment phase.  The denominator for computation of percentages is 
the safety population within each treatment group. 
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Sorting within tables ensures the same presentation for the set of all adverse events within the 
observation period (pre-treatment, treatment-emergent, and post-treatment).  For that purpose, the 
table of all treatment-emergent adverse events presented by SOC and PT sorted by the 
internationally agreed SOC order and decreasing frequency of PTs within SOCs will define the 
presentation order for all other tables unless otherwise specified. The tables of AEs by SOC, 
HLGT, HLT, and PT will be sorted by the SOC internationally agreed order and the other levels 
(HLGT, HLT, and PT) will be presented in alphabetical order, unless otherwise specified.   
Analysis of all treatment-emergent adverse events 
The following treatment-emergent adverse event summaries will be generated for the safety 
population. 
• 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, showing number (%) of patients with 
at least 1 TEAE sorted by the SOC internationally agreed order.  The other levels (HLGT, 
HLT, PT) will be presented in alphabetical order; 
• All TEAEs by primary SOC and PT, showing the number (%) of patients with at least 1 
TEAE, sorted by the internationally agreed SOC order and by decreasing incidence of PTs 
within each SOC.  This sorting order will be applied to all other tables, unless otherwise 
specified; 
• 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, sorted by the sorting order defined above; 
• All TEAEs by maximal intensity (ie, mild, moderate, or severe), presented by primary 
SOC and PT, sorted by the sorting order defined above; 
• Kaplan-Meier curves will be provided, when appropriate, for time from first dose of 
double-blind IMP (capsule or injection, whichever comes first) to the first occurrence of 
selected TEAEs. Patients without any event will be censored at the end of the TEAE 
period. Selected TEAEs could be local injection site reactions, general allergic reactions, 
hepatic disorders, diabetes among non-diabetic patients at baseline and TEAE related to 
any clinically significant signal that needs further characterization. 
Analysis of all treatment emergent serious adverse event(s) 
• All TEAEs by primary SOC, HLGT, HLT, and PT, showing the number (%) of patients 
with at least 1 serious TEAE, sorted by the internationally agreed SOC order.  The other 
levels (HLGT, HLT, PT) will be presented in alphabetical order; 
• 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 administration according to 
investigator’s opinion, by primary SOC, HLGT, HLT, and PT. 
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Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
• All TEAEs leading to treatment discontinuation, by primary SOC, HLGT, HLT, and PT. 
Analysis of groupings of adverse event(s) including selected adverse events of special interest 
• All grouping of TEAEs including adverse events of special interest as listed in 
Section 2.1.4.1 will be analyzed using selections defined in Section 2.1.4.1 and will be 
presented by SMQ and PT (when selection is based on SMQs) and by SOC and PT (when 
selection is based on the e-CRF tick box or HLGT/HLT). The summaries will be sorted by 
decreasing incidence of PT within each SOC/SMQ (in the alirocumab group). 
• Analyses of grouping of AEs for diabetes will be performed overall and according to the 
diabetic status at baseline. 
 
In addition, the following variables will be tabulated for the local injection site reactions TEAEs: 
• Intensity of the event (mild, moderate, severe); 
• Number of events divided by the number of double-blind IMP injections received; 
• Time from first double-blind IMP 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. 
 
Besides, description of symptoms and possible etiologies for General Allergic Reaction TEAE 
reported by investigator (using the tick box), will be presented. 
Analysis of cardiovascular events 
Adjudication results of treatment-emergent CV events will be summarized on the safety 
population. 
Analysis of pre-treatment and post-treatment adverse events 
• All pre-treatment AEs by primary SOC and PT, sorted by the internationally agreed SOC 
order and decreasing incidence of PTs (in the alirocumab group) within each SOC; 
• All pre-treatment AEs leading to treatment discontinuation by primary SOC and PT, 
sorted by the sorting order defined above; 
• All post-treatment AEs by primary SOC and PT, sorted by the internationally agreed SOC 
order and decreasing incidence of PTs (in the alirocumab group) within each SOC; 
• All post-treatment SAEs by primary SOC and PT, sorted by the sorting order defined 
above. 
Subgroup of patients with 2 consecutive LDL-C <25 mg/dL (<0.65 mmol/L) 
If applicable, similar summaries of TEAEs as those described above will be also provided on the 
safety subgroup population of patients with 2 consecutive results of calculated LDL-C <25 mg/dL 
(<0.65 mmol/L, as defined in Section 2.1.5) in both treatment groups. Only TEAE for which it 
will be confirmed or unclear that they occurred, worsened or became serious the day or after the 
first level of LDL-C <25 mg/dL (<0.65 mmol/L) will be considered. 
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2.4.5.2 Deaths 
The following summaries of deaths will be generated for the safety population. 
• Number (%) of patients from the safety population who died by study period (on-study, 
on-treatment, post-study) and reasons for death as adjudicated by the clinical events 
classification (CEC); 
• Deaths in nonrandomized patients or randomized but not treated patients; 
• TEAEs leading to death (death as an outcome on the adverse event case report form page 
as reported by the Investigator) by primary SOC , HLGT, HLT, and PT showing number 
(%) of patients sorted by internationally agreed SOC order, with HLGT, HLT, and PT 
presented in alphabetical order within each SOC. TEAE leading to death are TEAE that 
led to death regardless of timing of death in relation to IMP injection (ie, death occurring 
in the TEAE period or during the post-treatment period). 
2.4.5.3 Analyses of laboratory variables  
The summary statistics (including number, mean, median, first quartile (Q1), third quartile 
(Q3), standard deviation, minimum and maximum) of all laboratory variables (central laboratory 
values and changes from baseline) will be calculated for each visit or study assessment (baseline, 
each post-baseline time point, last on-treatment, worst on-treatment value) by treatment group. In 
addition, for some parameters of interest, mean changes from baseline with the corresponding SE 
could be plotted over time (at same time points) in each treatment group. This section will be 
organized by biological function as specified in Section 2.1.4.3. For glucose, only fasting samples 
will be summarized.   
The incidence of PCSAs (list provided in Appendix A), at any time during the TEAE period will 
be summarized by biological function and treatment group whatever the baseline level and/or 
according to the following baseline status categories:  
• Normal/missing; 
• Abnormal according to PCSA criterion or criteria. 
Glucose (quantitative summary and PCSA) will also be analyzed, overall and according to the 
diabetic status at baseline. 
For parameters for which no PCSA criteria are defined, similar table(s) using the normal range 
will be provided. 
If any clinically significant signal is detected and need further characterization, exploration of 
time to onset will be performed for selected PCSAs assessed during the TEAE period as described 
below to account for the differential exposure time in all patients. 
Kaplan-Meier curves during TEAE period will be also provided using the midpoint of the time 
interval between the first assessment with PCSA and the previous assessment. Only the first event 
(PCSA) will be counted. Patients without any event will be censored at the last assessment 
performed during the TEAE period. 
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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 ribonucleic acid” (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 to hepatitis C virus (HCV) for a patient will be defined as follows for all 
evaluations (baseline and post-baseline). 
Table 1 - Definition of the patient status regarding hepatitis C virus 
Hepatitis C Antibody (Ab) 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 the 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” status if at least one 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 one 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 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. 
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For the description of the positive hepatitis C virus test during the TEAE period, all above rules 
applied by replacing post-baseline by TEAE period. 
Drug-induced liver injury 
The liver function tests, namely AST, ALT, alkaline phosphatase (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 in AESI section (see Section 2.1.4.1) 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 (ie, 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 2.4.5.1). 
2.4.5.4 Analyses of vital sign variables 
The summary statistics (including number, mean, median, Q1, Q3, standard deviation, minimum 
and maximum) of all vital signs variables in sitting position (central laboratory values and 
changes from baseline) will be calculated for each visit or study assessment (baseline, each post-
baseline time point, last on-treatment, worst on-treatment value, and follow-up visit ) by treatment 
group. In addition for some parameters of interest; mean changes from baseline with the 
corresponding SE could be plotted over time (at same time points) in each treatment group. 
Vital signs without position filled in will only be used for the PCSA analysis described below. 
The incidence of PCSAs at any time during the treatment-emergent adverse event period will be 
summarized by treatment group irrespective of the baseline level and/or according to the 
following baseline status categories:  
• Normal/missing; 
• Abnormal according to PCSA criterion or criteria. 
If any clinically significant signal is detected and needs further characterization, exploration of 
time to onset will be performed for selected PCSAs assessed during the TEAE period as described 
below to account for the differential exposure time in all patients. 
Kaplan-Meier curves during TEAE period will be also provided using the midpoint of the time 
interval between the first assessment with PCSA and the previous assessment. Only the first event 
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(PCSA) will be counted. Patients without any event will be censored at the last assessment 
performed during the TEAE period. 
2.4.5.5 Analyses of electrocardiogram variables 
The count and percentage of patients with at least 1 abnormal ECG will be summarized by 
treatment group during TEAE period according to the following baseline status categories: 
• Normal/missing; 
• Abnormal. 
2.4.6 Analyses of other endpoints 
All analyses for other endpoints will be performed on the Safety population. All measurements, 
scheduled or unscheduled, fasting or not fasting, will be assigned to analysis windows defined in 
Section 2.5.4, Table 2 in order to provide an assessment for Week 4 to Week 24 time points. 
HbA1c parameter will be summarized by analysis visit using number of available data, mean, SD, 
median, minimum, and maximum for each treatment group during the treatment period. Summary 
will also be provided according to the diabetes mellitus status at baseline. The time profile will 
also be plotted by treatment group with the means and the corresponding SEs. The incidence of 
PCSA at any time during the TEAE period will also be summarized by treatment group using 
descriptive statistics, overall and according to diabetes mellitus status at baseline. 
Binary endpoints defined in Section 2.1.5 will be described using count and percentage. Kaplan-
Meier curves will be provided for the “Time to” variables. Patient without event will be censored 
at the end of the treatment period. For the analysis of the time to the first of the 2 consecutive 
LDL-C, patients without post-baseline LDL-C result or with only 1 post-baseline LDL-C result 
will not be included. 
2.4.7 Analyses of anti-alirocumab antibodies variables 
The following summaries will be performed on the ADA population, taking into account all 
samples regardless of timing relative to the injections: 
• ADA results (negative or positive) by time point and by treatment group and also 
according to up-titration status; 
• Neutralizing status (negative or positive) by time point for positive ADA and by treatment 
group and also according to up-titration status; 
• ADA titers using descriptive statistics (median, minimum and maximum) for positive 
ADA by time point and by treatment group and also according to up-titration status; 
• Number (%) of patients with pre-existing ADA and number (%) of patients with 
treatment-emergent ADA positive response by treatment group, overall and according to 
up-titration status; 
• Number (%) of patients with persistent/transient/indeterminate treatment-emergent ADA 
positive response by treatment group, overall and according to up-titration status; 
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• Time to onset of treatment-emergent ADA positive response using descriptive statistics by 
treatment group, overall and according to up-titration status. 
Correlations between ADA parameters (eg, titers, treatment-emergent ADA positive status, 
neutralizing status) and safety and/or efficacy endpoints will be also explored (eg, scatter plot). 
2.4.8 Analyses of pharmacokinetics variables 
Concentrations of total alirocumab in serum (Ctrough, Cmax and CFollow-up), free and total PCSK9 
concentrations will be summarized on the PK population by treatment group and visit using 
descriptive statistics. Ctrough,av will be summarized on the PK population by treatment group using 
descriptive statistics. These summaries will be also provided by dose in the alirocumab group to 
explore the impact of up-titration on concentrations (Ctrough, Cmax and CFollow-up). Descriptive 
statistics could be provided by specific sub-groups (eg, gender, BMI, age), as needed. 
Time profiles for Ctrough concentration, total and free PCSK9 will be also provided by treatment 
group using graphs (mean ± SE or Median, as appropriate). 
Additional plots will be prepared, as deemed necessary (eg, to explore the relationship with some 
safety or efficacy endpoints of interest). 
Concentrations of total alirocumab in serum and PCSK9 levels might be used for population PK 
modeling if considered necessary and the results of population PK modeling will be reported 
separately from the study report. 
2.5 
DATA HANDLING CONVENTIONS 
2.5.1 General conventions 
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. 
Medical History 
“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 
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• 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. 
Date of last dose of IMP 
The date of 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. 
Lipid variable, laboratory safety variables 
For data below the lower limit of quantification (LLOQ)/limit of linearity, half of the lower limit 
value (ie, LLOQ/2) will be used for quantitative analyses. For data above the upper limit of 
quantification (ULOQ)/limit of linearity, the upper limit value (ie, ULOQ) will be used for 
quantitative analyses. 
2.5.2 Data handling conventions for secondary efficacy variables 
See Section 2.4.4.2 Analysis of secondary endpoints. 
2.5.3 Missing data 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified.  When relevant, the number of patients with missing data 
is presented. 
Handling of baseline definition if time of first double-blind administration or time of 
assessment at Week 0 visit is missing 
If the time of the first double-blind administration or time 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 double-blind IMP administration. 
Handling of computation of treatment duration and compliance if investigational medicinal 
product end of treatment date is missing  
If the last or first injection date (capsule administration respectively) is missing, the injection 
(capsule respectively) exposure duration and compliance will be left as missing.  
Handling of safety and efficacy analysis periods and survival analysis if investigational 
medicinal product end of treatment date is missing 
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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 24 visit for completer, early end of treatment 
visit for patients who prematurely discontinued the IMP); 
• And the date of the last contact; 
in order to determine the end of the safety and efficacy analysis periods. 
If the last capsule intake date is missing, the last known capsule intake date is used to define the 
end of the efficacy treatment period. 
Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed.  If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior, concomitant, and post-treatment medication. 
Handling of adverse events with missing or partial date/time of onset, worsening, seriousness 
Missing or partial AE onset dates and times will be imputed so that if the partial AE onset 
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.  No imputation of AE end dates/times 
will be performed.  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 investigational medicinal product 
administration is missing 
When the date and time of the first IMP administration (capsule or injection, whichever comes 
first) is missing, all AEs that occurred on or after the day of randomization should be considered 
as treatment-emergent adverse events.   
Handling of missing assessment of relationship of adverse events to investigational medicinal 
product  
If the assessment of the relationship to IMP is missing, then the relationship to IMP 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 he will be grouped in the category “normal/missing at 
baseline.” 
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For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, 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; eg, 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.   
2.5.4 Windows for time points 
Data analyzed by time point (including efficacy, laboratory safety data, vital signs, and ADA) will 
be summarized using the analysis windows given in Table 2. These analysis windows will be 
applicable for all analyses, and they are defined to provide more homogeneous data for time 
point-specific analyses.  
Table 2 - Analysis windows definition 
Time point 
Targeted study day 
Analysis window in study days 
Week 4 
29 
15 to 42 
Week 8 
57 
43 to 70 
Week 12 
85 
71 to minimum (98; study day corresponding to the first 
injection with  IMP from kit allocated at up-titration IVRS 
contact) 
Week 16 
113 
99 to 126 
Week 24 
169 
155 to 182 
Follow-upa 
Last double-blind IMP injection + 10 weeks 
Last double-blind IMP injection +10 weeks ± 4weeks 
Study days are calculated from the day of first double-blind IMP (capsule or injection, whichever comes first), the day of first double-blind IMP 
being Day 1. For randomized but not treated patients, Day 1 is the day of randomization.  
a Only for ADA and vital signs. 
If multiple valid values of a variable exist within an analysis window, the nearest one 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 the same day, the first value of the 
day will be selected when time is available, or the scheduled visit will be selected. 
2.5.5 Unscheduled visits 
For efficacy, safety laboratory data, and vital signs, 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/PCSA.  
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2.5.6 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 
is already controlled. Therefore, the center will not be added as factor in the primary analysis 
model. 
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3 
INTERIM ANALYSIS 
No interim analysis is planned. 
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4 
DATABASE LOCK 
The database is planned to be locked at 4 weeks after last patient last visit. 
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5 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses will be generated using SAS version 9.2 or higher. 
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6 
REFERENCES 
1. 
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;367(14):1355-
60. 
2. 
SAS Institute Inc. 2009. SAS/STAT® 9.2 User’s Guide. 2nd Ed. Cary, NC: SAS Institute 
Inc. 
3. 
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. 
 
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7 
LIST OF APPENDICES 
 
Appendix A: 
Potentially clinically significant abnormalities (PCSA) criteria 
Appendix B: 
Detailed statistical methodology for pattern mixture model   
Appendix C 
List of MedDRA terms for CMQs 
Appendix D 
As treated treatment group definition 
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Appendix A 
Potentially clinically significant abnormalities criteria  
 
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. 
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Parameter 
PCSA 
Comments 
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. 
CLcr (mL/min) 
(Estimated creatinine clearance 
based on the Cokcroft-Gault 
equation)  
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
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 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - <60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with 
impaired renal function-study 
design, data analysis, and impact 
on dosing and labeling 
Creatinine 
≥150 µmol/L (Adults) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
 
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. 
Total Cholesterol 
≥7.74 mmol/L  
Threshold for therapeutic 
intervention. 
Triglycerides 
≥4.6 mmol/L 
Threshold for therapeutic 
intervention. 
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. 
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Parameter 
PCSA 
Comments 
ECG 
Ref.: ICH E14 guidance (2005) 
and E14 Q&A (2012), and 
Cardiac Safety Research 
Consortium White Paper on PR 
and QRS (Nada et al. Am Heart J. 
2013; 165(4) : 489-500) 
HR 
<50 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
<40 bpm 
<40 bpm and decrease from baseline ≥20 bpm 
<30 bpm 
<30 bpm and decrease from baseline ≥20 bpm 
 
>90 bpm 
>90 bpm and increase from baseline ≥20bpm 
>100 bpm  
>100 bpm and increase from baseline ≥20bpm 
>120 bpm  
>120 bpm and increase from baseline ≥20 bpm 
Categories are cumulative 
 
 
 
 
 
 
Categories are cumulative 
 
PR 
>200 ms 
>200 ms and increase from baseline ≥25% 
> 220 ms 
>220 ms and increase from baseline ≥25% 
> 240 ms 
> 240 ms and increase from baseline ≥25% 
Categories are cumulative 
 
QRS 
>110 ms 
>110 msec and increase from baseline ≥25% 
>120 ms 
>120 ms and increase from baseline ≥25% 
Categories are cumulative 
QT 
>500 ms 
 
QTc 
 
Absolute values (ms) 
 
 
>450 ms 
>480 ms 
>500 ms 
 
Increase from baseline 
Increase from baseline ]30-60] ms 
Increase from baseline >60 ms 
To be applied to any kind of QT 
correction formula.  
Absolute values categories are 
cumulative 
 
QTc >480 ms and ∆QTc>60 ms 
are the 2 PCSA categories to be 
identified in individual 
subjects/patients listings. 
 
 
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Appendix B 
Detailed statistical methodology for pattern mixture model 
As a sensitivity analysis of the primary efficacy endpoint (i.e. percent change from baseline to 
Week 24 in calculated LDL-C), a pattern-mixture model approach will be used, with a different 
imputation strategy applied for missing calculated LDL-C values during the on-treatment period 
(ie, within the time period from the first double-blind IMP injection up to the day of the last 
injection +21 days) and missing calculated LDL-C values after treatment discontinuation (ie, after 
the day of last injection +21 days) based on the following assumptions: 
• Patients within 21 days of their last IMP injection would continue to show benefit from 
treatment similar to that observed at the scheduled time point. Therefore, calculated LDL-
C values missing during the on-treatment period will be considered “Missing At Random” 
and imputed using a model estimated using all samples collected on treatment. 
• Patients who stopped taking their study treatment no longer benefited from it in the future, 
and thus tended to have calculated LDL-C values returning to baseline. Thus calculated 
LDL-C values missing after treatment discontinuation will be imputed based on patient’s 
own baseline value. 
The assumptions for this approach are based on the following considerations: 
• Missing values during the on-treatment period are mostly consecutive to: 
- 
Visits performed outside of the pre-specified time-window 
- 
No blood sample available although visit was done 
- 
Calculated LDL-C not measurable due to technical reasons 
In addition, these missing data are often intermittent, i.e. followed by calculated LDL-C 
values collected at subsequent visits. It is therefore considered reasonable to assume that 
these missing data were “At Random”. 
• Phase 2 studies DFI11565 and R727-CL-1003 included a prospective assessment of 
calculated LDL-C during the follow-up period after a 12-week treatment period. These 
studies showed that after treatment discontinuation, the average calculated LDL-C 
returned to baseline level within 4 weeks after ceasing alirocumab treatment. 
Missing calculated LDL-C values will be imputed 100 times to generate 100 complete data sets. 
The percent change from baseline to Week 24 will be derived from observed and imputed LDL-C 
at this time point. The completed data sets will be analyzed using an analysis of covariance model 
with treatment group and randomization strata as fixed effects, and the baseline calculated LDL-C 
value as continuous covariate. The results from the 100 analyses will be combined using Rubin’s 
formulae. 
Imputation of missing data during the on-treatment period 
Missing calculated LDL-C values during the on-treatment period will be imputed from other 
ontreatment measurements assuming Missing At Random, using SAS MI procedure. 
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Only calculated LDL-C values collected during the on-treatment period will be included in the 
imputation model. This way, missing calculated LDL-C values during the on-treatment period 
will be imputed based solely on observed on-treatment calculated LDL-C values. 
The imputation model will include the treatment arm, baseline calculated LDL-C value and all 
calculated LDL-C values at pre-specified visits. Since the pattern of missing data is necessarily 
non-monotone, a Monte-Carlo Markov Chain (MCMC) method is used. A minimum value of 0 
will be specified in order to avoid negative imputed LDL-C values. 
A sample SAS code is provided below: 
proc mi data=DATAIN out=DATAOUT nimpute=100 minimum=0; 
var ARM LDL_BASE LDL_W4 LDL_W8 LDL_W12 LDL_W16 LDL_W24; 
run; 
As stated above, the input dataset DATAIN will include only calculated LDL-C values collected 
during the on-treatment period. Any calculated LDL-C values collected during the post-treatment 
period will be excluded from the input dataset. In practice, the MI procedure generates imputed 
values for all missing values (whether on-treatment or post-treatment), but only imputed values 
during the-on-treatment period will be kept in the final datasets that will be analyzed using 
ANCOVA. Imputed values during the post-treatment period will be discarded and replaced by 
imputed values described in the next paragraph. 
Imputation of missing data after treatment discontinuation 
Missing calculated LDL-C values during the post-treatment period will be imputed 
assumingLDL-C values would on average return to baseline values. 
For each patient, missing post-treatment calculated LDL-C values will be imputed 100 times, 
using a random draw from a normal distribution, with mean equal to patient’s own baseline value 
and variance equal to the conditional variance at the specific time-point, given the baseline value. 
Let Y0 and Y1 denote the LDL-C at baseline and at the specific time-point respectively. Since Y0 
and Y1 are assumed to have a bivariate normal distribution, the conditional variance of Y1 given 
Y0 is: 
 
Where 
 denotes the variance of Y1 and ρ the coefficient of correlation between Y0 and Y1. 
The conditional variance will be estimated from observed data within the same treatment arm at 
the specific time-point. 
During the random generation process, a minimum value of 0 will also be applied in order to 
avoid negative imputed LDL-C values. 
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Appendix C 
List of MedDRA terms for CMQs 
Table 3 - 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 
 
Table 4 – CMQ “Impaired Glucose Control” 
MedDRA Term Label 
Preferred Term Code 
Glucose tolerance impaired 
10018429 
Insulin resistance 
10022489 
Insulin resistance syndrome 
10022490 
Impaired fasting glucose 
10056997 
 
Table 5 – Selected PTs from SMQ “Optic nerve disorders” including in the CMQ for neurologic 
events 
MedDRA Term Label 
Preferred Term Code 
Benign neoplasm of optic nerve 
10057424 
Optic atrophy 
10030910 
Optic discs blurred  
10030923 
Optic nerve disorder 
10061322 
Optic nerve injury 
10030938 
Optic nerve neoplasm 
10053645 
Optic nerve operation 
10053272 
Optic neuropathy 
10061323 
Papillitis 
10033708 
Pseudopapilloedema 
10037141 
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MedDRA Term Label 
Preferred Term Code 
Subacute myelo-opticoneuropathy 
10058009 
Toxic optic neuropathy 
10044245 
Visual evoked potentials abnormal 
10047549 
Amaurosis fugax 
10001903 
Blindness 
10005169 
Blindness unilateral 
10005186 
Colour blindness acquired 
10010051 
Colour vision tests abnormal 
10010056 
Cranial nerve injury 
10061094 
Delayed myelination 
10076456 
Fundoscopy abnormal 
10017520 
Hemianopia 
10019452 
Hemianopia heteronymous 
10019455 
Hemianopia homonymous 
10019456 
Loss of visual contrast sensitivity 
10064133 
Neuro-ophthalmological test abnormal 
10029256 
Night blindness 
10029404 
Ophthalmological examination abnormal 
10056836 
Optic pathway injury 
10030949 
Optical coherence tomography abnormal 
10073561 
Quadranopia 
10075427 
Visual acuity reduced 
10047531 
Visual acuity reduced transiently 
10047532 
Visual acuity tests abnormal 
10047534 
Visual field defect 
10047555 
Visual field tests abnormal 
10047567 
Visual impairment  
10047571 
Visual pathway disorder 
10061411 
 
Table 6 – CMQ “Neurocognitive disorders – FDA’s recommendation” 
MedDRA level 
MedDRA Code 
MedDRA Term Label 
PTCD 
10001949 
Amnesia 
PTCD 
10061423 
Amnestic disorder 
PTCD 
10002711 
Anterograde Amnesia 
PTCD 
10066842 
Behavioural and Psychiatric Symptoms of Dementia 
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MedDRA level 
MedDRA Code 
MedDRA Term Label 
PTCD 
10008398 
Change in sustained attention 
LLTCD 
10009843 
Cognitive Deterioration 
PTCD 
10057668 
Cognitive Disorder 
LLTCD 
10010300 
Confusion 
LLTCD 
10048321 
Confusion Aggravated 
PTCD 
10010305 
Confusional State 
PTCD 
10012218 
Delirium 
PTCD 
10012267 
Dementia 
PTCD 
10012271 
Dementia Alzheimer's type 
LLTCD 
10012290 
Dementia Nos 
LLTCD 
10012291 
Dementia Nos Aggravated 
LLTCD 
10012292 
Dementia of the Alzheimer's type NOS 
PTCD 
10067889 
Dementia with Lewy Bodies 
PTCD 
10013395 
Disorientation 
PTCD 
10013496 
Disturbance in attention 
PTCD 
10070246 
Executive dysfunction 
PTCD 
10068968 
Frontotemporal Dementia 
LLTCD 
10058669 
Global Amnesia 
PTCD 
10021402 
Illogical Thinking 
PTCD 
10071176 
Impaired reasoning 
PTCD 
10021630 
Incoherent 
PTCD 
10023236 
Judgement impaired 
PTCD 
10027175 
Memory Impairment 
PTCD 
10027374 
Mental Impairment 
LLTCD 
10027376 
Mental Impairment Nos 
LLTCD 
10048345 
Mental State Abnormal Aggravated 
PTCD 
10048294 
Mental Status Changes 
PTCD 
10065424 
Mini Mental Status Examination Abnormal 
PTCD 
10036631 
Presenile Dementia 
PTCD 
10038965 
Retrograde Amnesia 
PTCD 
10039966 
Senile Dementia 
LLTCD 
10039967 
Senile Dementia Nos 
LLTCD 
10040602 
Short-term Memory Loss 
PTCD 
10043431 
Thinking Abnormal 
LLTCD 
10043438 
Thinking Slowed 
PTCD 
10044380 
Transient Global Amnesia 
PTCD 
10057678 
Vascular Dementia 
 
(electronic 
 
 
 
1.0)


Statistical Analysis Plan  
17-Oct-2017 
SAR236553/REGN727-EFC13889 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 64 
Appendix D 
As treated treatment group definition 
Randomized 
Treatment 
group 
Kit 
Type 
Allocated 
kit 
decode 
Actual kit 
As treated 
group 
ALIROCUMAB 
Injection 
Capsule 
Alirocumab 
Placebo 
Placebo injections > alirocumab injections 
Placebo, or more placebo capsules taken than ezetimibe 
capsules 
ALIROCUMAB 
ALIROCUMAB 
Injection 
Capsule 
Alirocumab 
Placebo 
alirocumab, or alirocumab 3 injections > Placebo injections 
More ezetimibe capsules taken than Placebo capsules 
ALIROCUMAB 
ALIROCUMAB 
Injection 
Capsule 
Alirocumab 
Placebo 
Placebo injections > alirocumab injections 
More ezetimibe capsules taken than Placebo capsules 
EZETIMIBE 
ALIROCUMAB 
Injection 
Capsule 
Alirocumab 
Placebo 
alirocumab, or alirocumab injections > Placebo injections 
Placebo, or more placebo capsules taken than ezetimibe 
capsules 
ALIROCUMAB 
EZETIMIBE 
Injection 
Capsule 
Placebo 
EZETIMIBE 
alirocumab injections > Placebo injections 
ezetimibe, or more ezetimibe capsules taken than Placebo 
capsules 
ALIROCUMAB 
EZETIMIBE 
Injection 
Capsule 
Placebo 
EZETIMIBE 
Placebo, or placebo injections > alirocumab injections 
More Placebo capsules taken than ezetimibe capsules 
EZETIMIBE 
EZETIMIBE 
Injection 
Capsule 
Placebo 
EZETIMIBE 
alirocumab injections > Placebo injections 
More Placebo capsules taken than ezetimibe capsules 
ALIROCUMAB 
EZETIMIBE 
Injection 
Capsule 
Placebo 
EZETIMIBE 
Placebo, or placebo injections > alirocumab injections 
ezetimibe, more ezetimibe capsules taken than Placebo 
capsules 
EZETIMIBE 
 
(electronic 
 
 
 
1.0)


 
 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EFC13889 16.1.9 Statistical analysis plan
Clinical Approval
02-Nov-2017 08:37 GMT+0100
Clinical Approval
01-Dec-2017 15:04 GMT+0100