Conditions: Hypercholesterolemia
Keywords: Non-statin LMT Low dose statin
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 163
Healthy volunteers: no

Brief summary:
Primary Objective:

To demonstrate the reduction of low-density lipoprotein cholesterol (LDL-C) by alirocumab administration as add-on therapy to non-statin lipid modifying therapy (LMT) including diet therapy alone or the lowest strength of statin in comparison with placebo after 12 weeks of treatment in participants with hypercholesterolemia.

Secondary Objective:

* To evaluate the effect of two treatment regimens of alirocumab on other lipid parameters: 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), triglyceride (TG), and apolipoprotein A-1 (Apo A-1).
* To evaluate the safety and tolerability of alirocumab administration.
* To evaluate the development of anti-alirocumab antibodies.
* To evaluate the pharmacokinetic and pharmacodynamic profiles of alirocumab administration.
* To evaluate the long-term safety in participants receiving open-label alirocumab administration.

Detailed description:
The duration of study per participant was approximately 71 weeks consisting of a run-in period (4 weeks), a screening period (3 weeks), a double-blind treatment period (12 weeks), and an open-label treatment period (52 weeks).

Arms:
arm 1: Double-blind treatment period(DBTP):participants received Alirocumab 150 mg subcutaneous injection every 4 week(Q4W) alternating with placebo(for alirocumab)Q4W added to lowest-strength statin therapy(atorvastatin 5 mg daily),stable non-statin LMT/diet therapy alone for 12weeks. Participants completed DBTP,entered open-label treatment period(OLTP),received alirocumab 150 mg Q4W up to additional 52 weeks. Alirocumab dose up-titrated to 150 mg every 2 weeks(Q2W) at Week 24(OLTP:Week 12),when targeted LDL-C level at Week 20 not achieved as Japan Atherosclerosis Society Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012:1) ≥100 mg/dL(2.59 mmol/L) in heterozygous familial hypercholesterolemia (heFH) participants/non-familial hypercholesterolemia (non-FH)participants with history of documented coronary heart disease;2) ≥120 mg/dL(3.10 mmol/L)in non-FH participants with history of documented diseases/other risk factors as categorized in primary prevention category III) arm 2: In DBTP, participants received Alirocumab 150 mg subcutaneous (SC) injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks. Participants who completed DBTP were entered in OLTP and received alirocumab 150 mg Q4W up to additional 52 weeks. Alirocumab dose up-titrated to 150 mg Q2W at Week 24 (Week 12 of OLTP), when targeted LDL-C levels at Week 20 were not achieved i.e. LDL-C ≥100 mg/dL (2.59 mmol/L) or ≥120 mg/dL (3.10 mmol/L) according to Japan Atherosclerosis Society(JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012. arm 3: In DBTP, participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks. Participants who completed DBTP were entered in OLTP and received alirocumab 150 mg Q4W up to additional 52 weeks. Alirocumab dose up-titrated to 150 mg Q2W at Week 24 (Week 12 of OLTP), when targeted LDL-C levels at Week 20 were not achieved i.e. LDL-C ≥100 mg/dL (2.59 mmol/L) or ≥120 mg/dL (3.10 mmol/L) according to JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012.

Interventions: intervention 1: Alirocumab intervention 2: Placebo intervention 3: Atorvastatin intervention 4: Non-statin Lipid-Modifying Therapy intervention 5: Diet Alone
Intervention descriptions: intervention 1: Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with a disposable auto-injector. intervention 2: Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with a disposable auto-injector. intervention 3: Atorvastatin 5 mg tablet orally. intervention 4: Ezetimibe, Bezafibrate or Fenofibrate at stable dose as background therapy. intervention 5: Stable cholesterol-lowering diet as background therapy.

Protocol document:
Prot_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-002579 VERSION N°11.0 (19-MAR-2015)
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL NO. 3  
COMPOUND: Alirocumab (SAR236553/REGN727)   
A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy 
and Safety of Alirocumab in Patients with Hypercholesterolemia Not Adequately Controlled with 
Non-statin Lipid Modifying Therapy or the Lowest Strength of Statin 
STUDY NUMBER: EFC14305 
STUDY NAME: ODYSSEY NIPPON 
VERSION DATE / STATUS: 26-Apr-2017 / Approved 
Protocol Amendment 3 
Version number: 1 (electronic 1.0) 
Date : 26-Apr-2017 
Amended Clinical Trial Protocol 2 
Version number: 1 (electronic 1.0) 
Date : 15-Mar-2016 
Protocol Amendment 2 
Version number: 1 (electronic 1.0) 
Date : 15-Mar-2016 
Amended Clinical Trial Protocol 1 
Version number: 1 (electronic 1.0) 
Date : 15-Sep-2015 
Protocol Amendment 1 
Version number: 1 (electronic 1.0) 
Date : 15-Sep-2015 
Clinical Trial Protocol 
Version number: 1 (electronic 1.0) 
Date : 03-Jul-2015 
EudraCT  
Not applicable 
IND Number(s) 
Not applicable 
Version Number: 
1  
WHO universal trial number: 
U1111-1170-7697 
Date:
26-Apr-2017
Total number of pages: 
142 
(electronic 3.0)
NCT02584504


AMENDED Clinical Trial Protocol No. 3  
26-Apr-2017 
SAR236553(REGN727)-EFC14305 - 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: 
 
 
 
 
Sanofi K.K. 
Tokyo Opera City Tower, 3-20-2, Nishi 
Shinjuku, Shinjuku-ku, Tokyo 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
 
 
 
(electronic 
 
 
 
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AMENDED Clinical Trial Protocol No. 3  
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Page 3 
CLINICAL TRIAL SUMMARY 
 
COMPOUND: Alirocumab (SAR 
236553/REG727) 
STUDY No: EFC14305 (Odyssey NIPPON) 
TITLE 
A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to 
Evaluate the Efficacy and Safety of Alirocumab in Patients with 
Hypercholesterolemia Not Adequately Controlled with Non-statin Lipid 
Modifying Therapy or the Lowest Strength of Statin 
INVESTIGATOR/TRIAL LOCATION 
Japan, Multi-center 
PHASE OF DEVELOPMENT 
Phase 3 
STUDY OBJECTIVE(S) 
 
Primary Objective 
x 
To demonstrate the reduction of low density lipoprotein cholesterol 
(LDL-C) by alirocumab 150 mg every 4 weeks (Q4W) or 150 mg 
every 2 weeks (Q2W) regimen as add on therapy to non-statin lipid 
modifying therapy (LMT) including diet therapy alone or the lowest 
strength of statin in comparison with placebo after 12 weeks of 
treatment in patients with hypercholesterolemia.  
 
Secondary Objectives 
x 
To evaluate the effect of two treatment regimens of alirocumab on 
other lipid parameters: 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), 
triglyceride (TG), apolipoprotein A-1 (Apo A-1). 
x 
To evaluate the safety and tolerability of alirocumab 150 mg Q4W 
and 150 mg Q2W. 
x 
To evaluate the development of anti- alirocumab antibodies 
x 
To evaluate the pharmacokinetics (PK) and pharmacodynamics 
(PD) profile of alirocumab 150 mg Q4W and 150 mg Q2W. 
x 
To evaluate the long-term safety in patients receiving open-label 
alirocumab 150 mg Q4W and 150 mg Q2W. 
STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled, parallel-group, 
balanced (1:1:1, alirocumab 150 mg Q4W: alirocumab 150 mg Q2W: 
placebo), multi-center phase 3 study. Randomization will be stratified 
according to background statin therapy (Yes/No). “No statin background” will 
be also stratified according to background fibrate/ezetimibe therapy (Yes/No), 
where Yes represents fibrate or ezetimibe, and No represents diet therapy 
alone.  
The study consists of: 
x 
A run-in period of 4 weeks.  Patients will be treated with stable non-
statin LMTs or stable daily atorvastatin 5 mg. Patients who will have 
already been treated with stable non-statin LMTs or stable daily 
atorvastatin 5 mg for at least 4 weeks will be able to skip this period.  
x 
A screening period of up to 3 weeks. 
 
(electronic 
 
 
 
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x 
A double-blind treatment period (DBTP) of 12 weeks. Patients will 
receive double-blind treatment as follows:  
- 
alirocumab 150 mg Q4W alternating with placebo Q4W 
OR 
- 
alirocumab 150 mg Q2W  
OR 
- 
placebo for alirocumab Q2W 
x 
An open-label treatment period (OLTP) of 52 weeks. All patients will 
receive alirocumab 150 mg Q4W from the start of OLTP.  
x 
At Week 24, the up-titration to alirocumab 150 mg Q2W will be 
conducted through Interactive Web Response System (IWRS) only 
under the following circumstances: 
- 
In patients with heFH or in patients with non-FH with 
documented coronary heart disease (CHD), LDL-C is 
100 mg/dL (2.59 mmol/L) at Week 20. 
- 
In patients with non-FH classified as primary prevention 
category III, LDL-C is 120 mg/dL (3.10 mmol/L) at Week 20 
 
The lipid results will be masked from randomization to Week 12 in order to 
keep the double-blind manner of DBTP. No attempts should be made by the 
investigator or patient to routinely have the patient's lipid values 
independently evaluated during DBTP. Lipid values will be communicated to 
the investigators from Week 24. 
 
Patients should be on a stable diet therapy (Japan Atherosclerosis Society 
[JAS] Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 
2012 diet or equivalent) throughout the entire study duration. 
 
Regarding fibrates, only fenofibrate or bezafibrate are allowed during the 
study. 
 
Background LMTs should remain stable (including dose) throughout the entire 
study duration. 
Modification of the background LMT is allowed only under the following 
circumstances: 
x 
Exceptional circumstances per the Investigator's judgment. 
x 
If patient meets the pre-specified TG alert [TG500 mg/dL 
(5.65 mmol/L)], lab alerts will be sent and repeat testing should be 
done as soon as possible. Then diet will have to be reinforced. If 
necessary, LMTs (newly added or dose modifications) might be 
considered based on the best clinical judgement of the 
investigators. 
 
All injections will be conducted by site staffs, patients, or another designated 
person (such as a spouse, relative, etc.) if patients cannot conduct the 
injection. 
x 
Injection training is planned at Week -1 with a placebo for 
alirocumab in cases that injections will be conducted by patients or 
another designated person from Week 0. 
(electronic 
 
 
 
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x 
From Week 0 to Week 10, all injections will be conducted at the 
study site. 
x 
From Week 12, all injections could be conducted by patients or 
another designated person at home if patients agree.  
STUDY POPULATION  
Main selection criteria 
Main Inclusion criteria  
I 01. 
Patients with hypercholesterolemia§ (heFH* or non-FH), receiving 
non statin LMTs** or the lowest strength of statin***. 
 
*     Diagnosis of heFH must be made either by genotyping or by clinical 
criteria before randomization. For those patients not genotyped, the 
clinical diagnosis may be based on JAS Guidelines for Prevention of 
Atherosclerotic Cardiovascular Diseases 2012. If the clinical criteria 
is not met but heFH is strongly suspected by investigators, 
genotyping will be conducted during the screening period after 
signed written informed consent for obtaining genotype information. 
**   Fibrate or ezetimibe, or diet therapy alone. 
***  Defined as atorvastatin 5 mg. 
§ Patients receiving monotherapy with 5 mg daily atorvastatin, fibrate, or 
ezetimibe are allowed to enter the study. It is noted that patients with 
any combined drug therapy, such as atorvastatin + fibrate, atorvastatin 
+ ezetimibe, or fibrate + ezetimibe, are not allowed. Patients with diet 
therapy alone or diet therapy with drug monotherapy (atorvastatin, 
fibrate, or ezetimibe) are allowed to enter the study. 
x 
In patients with heFH, patients with or without a history of 
documented coronary heart disease (CHD). 
x 
In patients with non-FH, patients must have a history of 
documented CHD; otherwise patients have a history of documented 
diseases or other risk factors classified as primary prevention 
category III. 
 
A) Definitions for CHD (includes one or more of the following): 
x 
Myocardial infarction. 
x 
Unstable angina. 
x 
Coronary revascularization procedure (e.g., percutaneous coronary 
intervention [PCI] or coronary artery bypass graft surgery [CABG]). 
x 
Clinically significant CHD diagnosed by invasive or non-invasive 
testing (such as coronary angiography, stress test using treadmill, 
stress echocardiography or nuclear imaging). 
 
B) Definitions for documented diseases or other risk factors 
classified as primary prevention category III: 
x 
Ischemic stroke (excluding cardiogenic cerebro-embolism and/or 
TIA). 
x 
Peripheral arterial disease (PAD). 
x 
Diabetes. 
x 
Chronic kidney disease (CKD): 
x 
Other risk factors. 
(electronic 
 
 
 
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- 
A 10-year fatal CHD risk SCORE 2%. 
- 
A 10-year fatal CHD risk SCORE 0.5% and <2%, and have 
1 or more of the following criteria: 
a) 
Hypo HDL-C (<40 mg/dL). 
b) 
Family history of premature coronary artery disease (first-
degree relative and male: <55 year-old, female: <65 year-old). 
c) 
Impaired glucose tolerance (defined as a fasting blood glucose 
[Fasting blood glucose, FBG] <126mg/dL [<7.0 mmol/L], and a 
two- hour post glucose challenge value: 140-199 mg/dL [7.8-
11.1 mmol/L] [Oral glucose tolerance test, OGTT]). 
 
I 02. 
Hypercholesterolemia (heFH or non-FH) patients with one or more 
following risk factors that can explain why statin is not appropriate or 
why the lowest strength statin dose should not be increased. 
x 
History of side effects caused by statin (Hypersensitivity, elevated 
serum ALT, AST, ȖGT, ALP, and/or LDH levels, statin-induced liver 
dysfunction, abnormal values in CPK, Skeletal muscle-related 
symptoms, etc.)  
x 
CYP3A4 inhibitor (fibrate, immunosuppressant, azole antifungal 
agents or erythromycin) 
x 
Hepatic dysfunction or abnormal liver function (except fatty liver 
and/or confirmed other types of liver disease, history of hepatic 
dysfunction related to other causes) 
x 
Renal Impairment or abnormal renal function (except history of 
renal impairment with defined cause) 
x 
Hypothyroidism 
x 
Impaired glucose tolerance as defined previously or impaired 
fasting glycaemia (FBG 110-125mg/dL [6.1 – 6.9mmol/L]) 
x 
Diabetic nephropathy 
x 
Elderly with BMI<18.5kg/m2 
x 
Other documented factors medically judged by investigators why 
statin is not appropriate or why statin dose cannot be increased 
from the lowest strength for the patients other than the factors 
described above. 
 
I 03. 
Signed written informed consent 
 
Main Exclusion criteria 
x 
LDL-C <100 mg/dL (<2.59 mmol/L) at the screening visit (Week -3) 
in patients with heFH or in patients with non-FH who have a history 
of documented CHD. 
x 
LDL-C <120 mg/dL (<3.10 mmol/L) at the screening visit (Week -3) 
in patients with non-FH patients who have a history of documented 
diseases or other risk factors classified as primary prevention 
category III. 
x 
Not on a stable dose of LMTs (including diet therapy alone) in the 
run-in period or the screening period. 
x 
Use of statins other than atorvastatin 5 mg daily in the run-in period 
(electronic 
 
 
 
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or the screening period. 
x 
Use of fibrates, other than fenofibrate or bezafibrate in the run-in 
period or the screening period. 
x 
Use of nicotinic acid or bile acid-binding sequestrants or probucol or 
EPA (ethyl icosapentate) or red yeast rice products in the run-in 
period or the screening period. 
x 
Fasting serum TG >400 mg/dL (>4.52 mmol/L) at the screening 
period. 
x 
Systolic BP >160 mmHg or diastolic BP >100 mmHg at the run-in 
visit (Week -7) or the screening visit (Week -3) or the randomization 
visit (Week 0). 
Total expected number of patients 
Approximately 159 randomized patients (53:53:53, alirocumab 150 mg Q4W: 
150 mg Q2W: placebo). 
 
 
  
 
 
Expected number of sites 
Investigational medicinal product(s) 
Formulation 
Alirocumab:  
Sterile alirocumab drug product supplied at a concentration of 150 mg/mL in 
histidine, pH 6.0, polysorbate 20, and sucrose with 1 mL volume in an 
autoinjector. 
Placebo: 
Sterile solution consisting of histidine, pH 6.0, polysorbate 20, and sucrose 
with 1 mL volume in an autoinjector. 
Route(s) of administration 
Subcutaneous (SC) injections in the abdomen, thigh or outer area of upper 
arm. 
Dose regimen 
Double-blind treatment period: 
Alirocumab 150 mg Q4W alternating with placebo Q4W 
OR 
 
Alirocumab 150 mg Q2W 
OR 
Placebo for Alirocumab Q2W 
 
Open-label treatment period: 
Alirocumab 150 mg Q4W 
OR 
Alirocumab 150 mg Q4W up to Week 24 followed by alirocumab 150 mg 
Q2W. 
Injection for training 
Placebo for alirocumab 
Non-Investigational product 
Formulation 
 
Route(s) of administration 
x 
Statin (atorvastatin, 5mg daily) 
x 
Cholesterol absorption inhibitor (ezetimibe) 
x 
Fibrate (fenofibrate, bezafibrate, but not other fibrates) 
Oral administration 
(electronic 3.0)


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Dose Regimen 
Dose regimen approved in Japan 
ENDPOINT(S) 
 
Primary Efficacy Endpoint 
x 
The percent change in calculated LDL-C from baseline to Week 12 
in the intent-to-treat (ITT) population, using all LDL-C values 
regardless of adherence to treatment (ITT estimand). 
Key Secondary Efficacy Endpoints  
x 
The percent change in calculated LDL-C from baseline to Week 12 
in the modified ITT (mITT) population, using all LDL-C values during 
the efficacy double-blind treatment period (on-treatment estimand). 
x 
The percent change in calculated LDL-C from baseline to average 
Week 10-12 (ITT and on-treatment estimands). 
x 
The percent change in Apo-B from baseline to Week 12 (ITT and on 
treatment estimands). 
x 
The percent change in non-HDL-C from baseline to Week 12 (ITT 
and on-treatment estimands).  
x 
The percent change in TC from baseline to Week 12 (ITT 
estimand). 
x 
The proportion of patients reaching LDL-C goal at Week 12, i.e., 
calculated LDL-C <100 mg/dL (2.59 mmol/L) for heFH or non-FH 
patients who have a history of documented CHD patients, or LDL-
C<120 mg/dL (3.10 mmol/L) for non-FH patients who have a history 
of documented diseases or other risk factors classified as primary 
prevention category III (ITT and on-treatment estimands). 
x 
The percent change in Lp(a) from baseline to Week 12 (ITT 
estimand). 
x 
The percent change in HDL-C from baseline to Week 12 (ITT 
estimand). 
x 
The percent change in fasting TG from baseline to Week 12 (ITT 
estimand). 
x 
The percent change in and Apo A-1 from baseline to Week 12 (ITT 
estimand).  
 
Other Secondary Efficacy Endpoints 
x 
The proportion of patients with calculated LDL-C <100 mg/dL 
(2.59 mmol/L) at Week 12 (ITT estimand). 
x 
The proportion of patients with calculated LDL-C <120 mg/dL 
(3.10 mmol/L) at Week 12 (ITT estimand). 
x 
The proportion of patients with calculated LDL-C < 70 mg/dL 
(1.81 mmol/L) at Week 12 (ITT estimand). 
x 
The absolute change in LDL-C from baseline to Week 12 (ITT 
estimand). 
x 
The change in Apo-B/Apo A-1 ratio from baseline to Week 12 (ITT 
estimand). 
x 
The proportion of patients with Apo-B <80 mg/dL (0.8 g/L) at Week 
12 (ITT estimand). 
x 
The proportion of patients with non HDL-C <130 mg/dL 
(3.37 mmol/L) at Week 12 (ITT estimand). 
(electronic 
 
 
 
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x 
The proportion of patients achieving at least 50% reduction in LDL-
C at Week 12 (ITT estimand). 
x 
The percent change in TC, Lp(a) from baseline to Week 12 (on 
treatment estimand) 
Safety Endpoints 
x 
Safety parameters (adverse events [including adjudicated 
cardiovascular events], laboratory data, and vital signs) assessed 
throughout the study. 
Other Endpoints 
x 
Anti-alirocumab antibodies assessed throughout the study. 
x 
Proportion of patients who are up-titrated to alirocumab 150 mg 
Q2W during the OLTP.  
Pharmacokinetics and pharmacodynamics: 
x 
Serum alirocumab concentrations. 
x 
Serum total and free PCSK9 concentrations. 
ASSESSMENT SCHEDULE 
Patient assessments in the run-in period: 
On-site visits: Week -7 (run-in visit). 
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 (DBTP): 
On-site visits: Week 0 (randomization visit), Week 2, Week 4, Week 6,
Week 8, Week 10, and Week 12 (end of DBTP). 
Patient assessments during the open-label treatment period (OLTP): 
x 
On-site visits: Week 12 (start of OLTP), Week 20, Week 24, Week 
36, Week 48, and Week 64 (end of OLTP). 
x 
Phone call visits: Week 16, Week 28, Week 32, Week 40, Week 44, 
Week 52, Week 56, and Week 60. 
STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
The study is expected to enroll approximately 159 patients.  
Two pairwise comparisons will be performed (alirocumab 150 mg Q4W 
versus placebo and alirocumab 150 mg Q2W vs placebo). In order to handle 
multiple comparisons Bonferroni adjustment will be used, i.e., the alpha level 
for each comparison is 0.025 to obtain an overall study alpha level of 0.05. 
A sample size of 38 patients in the ITT population (19 in alirocumab group 
and 19 in placebo group) will have 90% power to detect a difference of 30% in 
mean percent change in calculated LDL-C in any pairwise comparison with a 
0.025 two-sided significance level and assuming a common standard 
deviation of 25%. As a result, the total sample size will be 57 patients (19 in 
each of the two alirocumab arms and 19 in the placebo arm). 
The sample size was also considered in order to obtain long-term safety data. 
A sample size of 159 patients (randomization ratio 1:1:1, i.e., 53 in alirocumab 
150 mg Q4W, 53 in alirocumab 150 mg Q2W, and 53 in placebo) will allow 
having long  term open-label safety data. With this sample size, 100 patients 
(electronic 
 
 
 
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are expected to be exposed to alirocumab for a minimum of 12 months 
providing that the proportion of drop out in the entire study duration (from 
randomization to Week 64) is 36%, which is obtained using exponential 
distribution with the same hazard as that of 30% dropout rate within 
12 months. Moreover, with 100 patients treated with alirocumab for at least 
12 months, AEs with a rate 0.03 will be detected with 95% probability. 
Therefore, 159 patients (53 in alirocumab 150 mg Q4W, 53 in alirocumab 
150 mg Q2W,and 53 in placebo) will be needed to evaluate both efficacy and 
safety. 
Analysis populations: 
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 intent to treat (ITT) 
population, defined as the randomized population who has an evaluable 
primary endpoint. The primary efficacy endpoint is evaluable when both 
following conditions are met: 
x 
Availability of at least one value for calculated LDL-C before first 
dose of double-blind investigational medicinal product (IMP) (i.e., 
baseline). 
x 
Availability of at least one value for calculated LDL-C within one of 
the following analysis windows: Week 4, Week 8, Week 10 and 
Week 12. 
The mITT population is defined as the randomized population who took at 
least one dose or part of dose of the double-blind IMP injection and had an 
evaluable primary efficacy endpoint during the efficacy double-blind treatment 
period. The primary efficacy endpoint will be considered evaluable when both 
of the following conditions are met: 
x 
Availability of at least 1 value for calculated LDL-C before the first 
dose of double-blind IMP (i.e., baseline). 
x 
Availability of at least 1 value for calculated LDL-C within one of the 
following analysis window: Week 4, Week 8, Week 10 and Week 12 
during the efficacy double-blind treatment period. 
The efficacy double-blind treatment period will be defined as: 
x 
The time period from the first double-blind IMP injection up to 21 
days after the last double-blind IMP injection (i.e., up to Week 12). 
Patients in the ITT or 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. The safety population will 
be analyzed according to the treatment actually received. 
Primary analysis: 
The primary efficacy endpoints, percent change in calculated LDL-C from 
baseline to Week 12 will be analyzed in the ITT population using mixed-effect 
model with repeated measures (MMRM) approach. All post-baseline data 
available within Week 4, Week 8, Week 10, and Week 12 analysis windows 
will be used (on treatment and off-treatment through Week 12) and missing 
data will be accounted for by the MMRM model.  
The model will include the fixed categorical effects of treatment group 
(electronic 
 
 
 
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(placebo, alirocumab 150 mg Q4W, alirocumab 150 mg Q2W), time point 
(Week 4, Week 8, Week 10, and Week 12), stratification factor of statin 
(Yes/No), treatment-by-time point interaction and statin-by time point 
interaction, as well as the continuous fixed covariates of baseline calculated 
LDL-C value, and baseline value-by-time point interaction.  
This model is used to provide baseline adjusted least square means (LS 
means) estimates at Week 12 for each treatment group with their 
corresponding standard errors. Each alirocumab group will be compared to 
placebo group (at significance level of 2.5%) using appropriate contrasts, and 
the 97.5% confidence interval (CI) of the difference will be provided. 
Subgroup analyses will be performed in order to assess the consistency of 
the treatment effect within stratification factor of statin (Yes/No). 
Analysis of key secondary efficacy endpoints: 
Continuous secondary endpoints anticipated to have a normal distribution 
(i.e., 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 
(i.e., 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. In the 
data dependent case that the logistic regression method is not applicable 
(e.g., the response rate is zero in 1 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. 
Multiplicity adjustment: 
A hierarchical procedure will be used for each pairwise comparison to control 
the type I error and to handle multiple endpoints. If the primary endpoint 
analysis is significant at the 2.5% alpha level, the key secondary efficacy 
endpoints will be tested sequentially at the 0.025 level, using the order 
defined in section “Key secondary efficacy endpoints”. Hierarchical procedure 
for comparisons of alirocumab 150 mg Q4W versus placebo and alirocumab 
150 mg Q2W versus placebo will be processed separately. The other 
secondary efficacy endpoints not included into key secondary endpoints will 
be analyzed for exploratory purpose only. 
No further adjustment will be made for multiple analyses (i.e., first and second 
analyses) described below, since the primary efficacy endpoint and the key 
secondary efficacy endpoints up to Week 12 will have been conducted at the 
time of first analysis only. Analyses conducted in the OLTP are exploratory 
only. 
Safety Analysis: 
Safety analysis (Adverse events [including adjudicated cardiovascular 
events], laboratory, ECG, and vital signs) will be descriptive, based on the 
safety population. The safety analysis will focus on the Treatment Emergent 
Adverse Events (TEAE) period defined as  
x 
TEAE period for DBTP 
- 
The time from the first dose of double-blind IMP to the last 
(electronic 
 
 
 
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Page 12 
dose of double-blind IMP + 70 days (10 weeks) or the first 
dose of open-label IMP injection. 
x 
TEAE period for long-term safety (DBTP and OLTP) 
- 
For 150 Q4W group and 150 Q2W group: 
The time from the first dose of double-blind IMP to the last 
dose of IMP (double-blind or open-label) + 70 days (10 weeks) 
- 
For placebo group:  
The time from the first dose of open-label IMP to the last dose 
of open-label IMP + 70 days (10 weeks) 
Safety analyses will be conducted using data of the DBTP. Besides, safety 
analyses using data of the DBTP and the OLTP (from the first double-blind 
IMP injection for alirocumab 150 mg Q4W group and alirocumab 150 mg 
Q2W group, and from the first open-label IMP injection for placebo group) will 
be conducted to evaluate long-term safety. 
Timing of analyses: 
Two analyses will be conducted: 
x 
First step: Efficacy and safety analyses using data up to 24 weeks 
after randomization (including 12 weeks double-blind) 
The first analysis will be conducted when all patients have been randomized 
and have at least all their data up to Week 24 (including 12 weeks DBTP and 
12 weeks OLTP) collected and validated, and will consist in the final analysis 
of the primary and secondary efficacy endpoints up to Week 12.
 
 The safety analysis will be performed 
on all safety data up to Week 24 collected and validated. 
x 
Second step: Long-term safety and efficacy exploratory analysis  
The second analysis will be conducted at the end of the study with all data 
including the data of the OLTP, and will consist in the final analysis of the 
safety endpoints and exploratory efficacy assessment during the OLTP. 
DURATION OF STUDY PERIOD (per 
patient)  
Approximately 71 weeks (run-in period: 4 weeks, screening: 3 weeks, DBTP: 
12 weeks, OLTP: 52 weeks). 
(electronic 3.0)


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1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
 
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1.2 
STUDY FLOW CHART 
 
Run-in period 
Screening period 
Double-blind treatment period  (DBTP) 
Day (D) / Week (W) / Month (M)  
W-7 
(D-49-to D-22) 
W-3  
(D-21 to D-8) 
W-1 
(D-7) 
W0  
(D1) 
W2 
 (D15) 
W4 
 (D29) 
W6 
 (D43) 
W8 
 (D57) 
W10 
 (D71) 
W12a 
(D85)  
End of DBTP 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Visit Window (Days)k 
 
\ 
±6 
 
±7 
±7 
±7 
±7 
±3 
±3 
Design: 
 
 
 
 
 
 
 
 
 
 
On-site visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Phone call visit 
 
 
 
 
 
 
 
 
 
 
Informed consent/ Patient demography 
X 
 Xb 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
X 
 
X 
 
 
 
 
 
 
Medical / family / surgical history, 
alcohol habits, smoking habits 
X 
X 
 
 
 
 
 
 
 
 
Prior medication history 
X 
X 
 
 
 
 
 
 
 
 
Physical examination  
X 
X 
 
X 
 
 
 
 
 
X 
Body weight 
 
X 
 
X 
 
 
 
 
 
X 
Measured height 
 
X 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
 
 
IWRS contact 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IMP dispensation 
 
 
 
X 
X 
X 
X 
X 
X 
 
Injection training 
 
 
  Xc 
 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
IMP administration  
 
 
 
X 
X 
X 
X 
X 
X 
 
Review of diet 
X 
X 
 
X 
 
 
 
 
 
X 
Compliance check of IMP and NIMP  
 
 
 
X 
X 
X 
X 
X 
X 
 
Concomitant medication 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
(electronic 
 
 
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Run-in period 
Screening period 
Double-blind treatment period  (DBTP) 
Day (D) / Week (W) / Month (M)  
W-7 
(D-49-to D-22) 
W-3  
(D-21 to D-8) 
W-1 
(D-7) 
W0  
(D1) 
W2 
 (D15) 
W4 
 (D29) 
W6 
 (D43) 
W8 
 (D57) 
W10 
 (D71) 
W12a 
(D85)  
End of DBTP 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Visit Window (Days)k 
 
\ 
±6 
 
±7 
±7 
±7 
±7 
±3 
±3 
Vital signs: 
 
 
 
 
 
 
 
 
 
 
Heart rate, blood pressure 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety: 
 
 
 
 
 
 
 
 
 
 
AE / SAE recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
 
X 
 
 
 
 
 
 
 
X 
Laboratory Testing - Efficacy 
 
 
 
 
 
 
 
 
 
 
TC, calculated LDL-C, HDL-C, TG, 
non-HDL-C 
 
X 
 
X 
 
X 
 
X 
X 
X 
Apo-B, Apo A-1, Apo-B/Apo A-1 ratio, 
Lp(a) 
 
 
 
X 
 
 
 
X 
X 
X 
Laboratory Testing - Safety 
 
 
 
 
 
 
 
 
 
 
Hematology and chemistryd 
 
X 
 
X 
 
 
 
 
 
X 
Creatine phosphokinase (CPK) 
 
X 
 
X 
 
 
 
 
 
X 
Liver panele 
 
X 
 
X 
 
X 
 
X 
 
X 
Hepatitis B surface antigen 
 
X 
 
 
 
 
 
 
 
 
Hepatitis C antibodyf 
 
X 
 
 
 
 
 
 
 
 
Serum pregnancy testg 
 
X 
 
 
 
 
 
 
 
 
Urine pregnancy testg 
 
 
 
X 
 
 
 
 
 
X 
Urinalysis (dipstick and microscopy)h  
 
X 
 
X 
 
 
 
 
 
X 
Laboratory Testing - Other 
 
 
 
 
 
 
 
 
 
 
HbA1c 
 
X 
 
 
 
 
 
 
 
X 
Thyroid-stimulating hormone (TSH) 
 
X 
 
 
 
 
 
 
 
 
Anti-alirocumab antibodiesi 
 
 
 
X 
 
X 
 
 
 
X 
(electronic 
 
 
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Run-in period 
Screening period 
Double-blind treatment period  (DBTP) 
Day (D) / Week (W) / Month (M)  
W-7 
(D-49-to D-22) 
W-3  
(D-21 to D-8) 
W-1 
(D-7) 
W0  
(D1) 
W2 
 (D15) 
W4 
 (D29) 
W6 
 (D43) 
W8 
 (D57) 
W10 
 (D71) 
W12a 
(D85)  
End of DBTP 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Visit Window (Days)k 
 
\ 
±6 
 
±7 
±7 
±7 
±7 
±3 
±3 
Serum alirocumab concentrationi 
 
 
 
X 
 
X 
 
X 
X 
X 
  
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
a Patients who prematurely discontinue study treatment (regardless of reason) will have an unscheduled visit with assessments originally planned at the end of study visit (Week 64, it should take place within 5 days 
of treatment discontinuation, if possible). The patients will also continue the study and assessments originally planned until the end of DBTP visit (Week 12, V10), and they will be followed up until recovery or 
stabilization of any AE to be followed up as specified in this protocol. If patients prematurely discontinue the study treatment and deny the study continuation, the patients will have an unscheduled visit with 
assessments originally planned at the end of study visit (Week 64, it should take place within 5 days of treatment discontinuation, if possible) and also the patients will be followed up until recovery or stabilization 
of any AE to be followed up as specified in this protocol. 
b Informed consent and patient demography will be obtained at Week -3 for the patients who start the study from the Screening period. 
c In case injection is conducted by patients, Injection training at screening period visit Week -1 is performed with placebo. Investigators will have the option of providing a second injection training prior to 
randomization visit for patients who require additional injection training. 
d Hematology includes: complete blood cell count (CBC) including hematocrit, red blood cell distribution width (RDW), reticulocyte count, hemoglobin, 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, eGFR, uric acid, lactate dehydrogenase (LDH), total protein, albumin, 
haptoglobin and ȖGT. (Reticulocyte count and haptoglobin are measured only when hemoglobin is decrease with 1.5g/dL from the baseline). 
e Liver panel: ALT, AST, alkaline phosphatase (ALP), and total bilirubin. 
f 
If positive, then confirmed by Hepatitis C Virus (HCV) polymerase chain reaction (PCR). 
g Women of child bearing potential (WOCBP) only. 
h Urinalysis will be performed at the Central Laboratory. Dipstick will be assessed for pH, specific gravity, and for the presence of blood, protein, glucose, ketones, nitrites, leukocyte esterase, urobilinogen, bilirubin 
and microscopic examination. 
i 
Blood samples for anti-alirocumab antibodies and alirocumab concentration have to be taken before the IMP administration. Total and free PCSK9 concentrations will be measured from the same PK sample.   
j 
. 
k In the event an injection is delayed by more than 7 days or is completely missed, the patient should return to the original schedule of the IMP administration without administering the delayed injection. If the delay 
is less than or equal to 7 days from the missed date, the patient should administer the delayed injection and then resume the original dosing schedule of the IMP administration. At least 7 days must be needed 
between the IMP injections. 
(electronic 3.0)


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Open Label Treatment Period 
(OLTP) 
Day (D) / Week (W) / Month (M)  
W12  
(D85)  
Start of 
OLTP 
W16 
(D113) 
 
W20 
(D141) 
W24  
(D169)  
W28 
(D197) 
W32 
(D225) 
W36 
(D253) 
W40 
(D281) 
 W44 
(D309) 
 
 
W48 
(D337) 
W52 
(D365) 
W56 
(D393) 
W60 
(D421) 
W64a 
(D449) 
End of 
OLTP 
Visit Number 
10 
11 
12 
13 
14,15 
16 
17,18 
19 
20,21,22 
23 
Visit Window (Days)l 
±3 
±7 
±7 
±3 
±7 
±3 
±7 
±3 
±7 
±5 
Design: 
 
 
 
 
 
 
 
 
 
 
On-site visit 
X 
 
X 
X 
 
X 
 
X 
 
X 
Phone call visit 
 
X 
 
 
X 
 
X 
 
X 
 
Physical examination  
X 
 
 
X 
 
X 
 
X 
 
X 
Body weight 
X 
 
 
X 
 
X 
 
 
 
X 
IWRS contact 
X 
 
 
X 
 
X 
 
 
X 
 
X 
IMP dispensation 
X 
 
 
X 
 
X 
 
     X 
 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
IMP administration  
X 
X 
X 
Xm 
X 
X 
X 
X 
Xa 
 
Compliance check of IMP  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xk 
Review of dietn 
X 
 
 
X 
 
X 
 
X 
 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs: 
 
 
 
 
 
 
 
 
 
 
Heart rate, blood pressure 
X 
 
X 
X 
 
X 
 
X 
 
X 
Safety: 
 
 
 
 
 
 
 
 
 
 
AE / SAE recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
X 
 
 
 
 
 
X 
Laboratory Testing - Efficacy 
 
 
 
 
 
 
 
 
 
 
TC,calculated LDL-C, HDL-C, TG, non-HDL-C 
Xc 
 
Xc 
X 
 
X 
 
X 
 
X 
Apo-B, Apo A-1, Apo-B/Apo A-1 ratio, Lp(a) 
X 
 
 
      X 
 
X 
 
 
 
X 
(electronic 
 
 
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Open Label Treatment Period 
(OLTP) 
Day (D) / Week (W) / Month (M)  
W12  
(D85)  
Start of 
OLTP 
W16 
(D113) 
 
W20 
(D141) 
W24  
(D169)  
W28 
(D197) 
W32 
(D225) 
W36 
(D253) 
W40 
(D281) 
 W44 
(D309) 
 
 
W48 
(D337) 
W52 
(D365) 
W56 
(D393) 
W60 
(D421) 
W64a 
(D449) 
End of 
OLTP 
Visit Number 
10 
11 
12 
13 
14,15 
16 
17,18 
19 
20,21,22 
23 
Visit Window (Days)l 
±3 
±7 
±7 
±3 
±7 
±3 
±7 
±3 
±7 
±5 
Laboratory Testing - Safety 
 
 
 
 
 
 
 
 
 
 
Hematology and chemistryd 
X 
 
 
X 
 
X 
 
X 
 
X 
CPK 
X 
 
 
X 
 
X 
 
X 
 
X 
Liver panele 
X 
 
 
X 
 
X 
 
X 
 
X 
Hepatitis C antibodyf 
 
 
 
 
 
 
 
 
 
X 
Urine pregnancy test g 
X 
 
 
X 
 
X 
 
X 
 
X 
Urinalysis (dipstick and microscopy)h 
X 
 
 
X 
 
 
 
 
 
X 
Laboratory Testing - Other 
 
 
 
 
 
 
 
 
 
 
HbA1c 
X 
 
 
X 
 
X 
 
X 
 
X 
Anti-alirocumab antibodiesi 
X 
 
 
X 
 
X 
 
X 
 
Xj 
(electronic 
 
 
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a Patients, who prematurely discontinue study treatment (regardless of the reasons) during OLTP, will have an unscheduled visit with assessments originally planned at the end of study visit (Week 64, it should take 
place within 5 days of treatment discontinuation, if possible). The patient will be followed up until recovery or stabilization of any AE to be followed up as specified in this protocol. 
b The last IMP administration for the patients with up-titration to alirocumab 150 mg Q2W will be done at Week 62. 
c Lipid values at Week 12 (Visit 10) will be blinded in order to keep the double-blind manner of DBTP. Lipid values will be communicated to investigators from Week 24 (Visit 13). 
d Hematology includes: CBC including hematocrit, RDW, reticulocyte count, hemoglobin, 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, eGFR, uric acid, LDH, total protein, albumin, haptoglobin and ȖGT (Reticulocyte count and haptoglobin are measured only when 
hemoglobin is decrease with 1.5g/dL from the baseline).   
e Liver panel: ALT, AST, ALP, and total bilirubin. 
f 
If positive, then confirmed by HCV polymerase chain reaction. 
g WOCBP only.   
h Urinalysis will be performed at the Central Laboratory. Dipstick will be assessed for pH, specific gravity, and for the presence of blood, protein, glucose, ketones, nitrites, leukocyte esterase, urobilinogen and 
bilirubin. 
i 
Blood samples for anti-alirocumab antibodies have to be taken before the IMP administration. 
j 
 
k Compliance check of IMP at Week 64 will be done only for the patients with up-titration to alirocumab 150 mg Q2W in order to check the compliance of IMP administration at Week 62. 
l 
In the event an injection is delayed by more than 7 days or is completely missed, the patient should return to the original schedule of the IMP administration without administering the delayed injection. If the delay 
is less than or equal to 7 days from the missed date, the patient should administer the delayed injection and then resume the original dosing schedule of the IMP administration. At least 7 days must be needed 
between the IMP injections. 
m At  week 24, the up-titration to alirocumab 150 mg Q2W will be conducted through Interactive Web Response System (IWRS) based on LDL-C values at Week 20 (Refer Section 6.1) 
n Patients should be on a diet following Japan Atherosclerosis Society Guideline or equivalent. 
 
(electronic 3.0)


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2 
TABLE OF CONTENTS 
1 
FLOW CHARTS.............................................................................................................................13 
1.1 
GRAPHICAL STUDY DESIGN ......................................................................................................13 
1.2 
STUDY FLOW CHART ..................................................................................................................14 
2 
TABLE OF CONTENTS ................................................................................................................20 
3 
LIST OF ABBREVIATIONS ..........................................................................................................26 
4 
INTRODUCTION AND RATIONALE.............................................................................................29 
5 
STUDY OBJECTIVES ...................................................................................................................38 
5.1 
PRIMARY.......................................................................................................................................38 
5.2 
SECONDARY ................................................................................................................................38 
6 
STUDY DESIGN ............................................................................................................................39 
6.1 
DESCRIPTION OF THE PROTOCOL...........................................................................................39 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................41 
6.2.1 
Duration of study participation for each patient .............................................................................41 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................41 
6.3 
TWO-STEP ANALYSIS .................................................................................................................41 
6.4 
STUDY COMMITTEES..................................................................................................................42 
7 
SELECTION OF PATIENTS..........................................................................................................43 
7.1 
INCLUSION CRITERIA..................................................................................................................43 
7.2 
EXCLUSION CRITERIA ................................................................................................................45 
7.2.1 
Exclusion criteria related to study methodology ............................................................................45 
7.2.2 
Exclusion criteria related to the active comparator and/or mandatory background therapies.......48 
7.2.3 
Exclusion criteria related to the current knowledge of Sanofi compound......................................48 
7.2.4 
Additional exclusion criteria during or at the end of screening or run-in phase before 
randomization.................................................................................................................................49 
8 
STUDY TREATMENTS .................................................................................................................50 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) ..........................................................................50 
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8.1.1 
Route and method of administration..............................................................................................50 
8.1.2 
Timing of administration.................................................................................................................51 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) ..................................................................52 
8.3 
BLINDING PROCEDURES............................................................................................................52 
8.3.1 
Methods of blinding........................................................................................................................52 
8.3.1.1 
Lipid parameters ............................................................................................................................53 
8.3.1.2 
Anti-alirocumab antibodies.............................................................................................................53 
8.3.1.3 
Pharmacokinetics measurements, total and free PCSK9 concentrations .....................................54 
8.3.1.4 
Committee......................................................................................................................................54 
8.3.2 
Randomization code breaking during the study.............................................................................54 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................55 
8.5 
PACKAGING AND LABELING ......................................................................................................55 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................56 
8.7 
RESPONSIBILITIES ......................................................................................................................56 
8.7.1 
Treatment accountability and compliance......................................................................................57 
8.7.2 
Return and/or destruction of treatments ........................................................................................57 
8.8 
CONCOMITANT MEDICATION.....................................................................................................57 
8.8.1 
Management of background lipid modifying therapy .....................................................................58 
8.8.2 
Contraception.................................................................................................................................58 
8.8.3 
Prohibited concomitant medications ..............................................................................................58 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................59 
9.1 
EFFICACY ENDPOINT..................................................................................................................59 
9.1.1 
Primary efficacy endpoint...............................................................................................................59 
9.1.2 
Secondary endpoints .....................................................................................................................59 
9.1.2.1 
Key secondary efficacy endpoints .................................................................................................59 
9.1.2.2 
Other Secondary Efficacy Endpoints .............................................................................................60 
9.1.3 
Efficacy assessment method .........................................................................................................60 
9.1.3.1 
Lipid parameters ............................................................................................................................60 
9.2 
SAFETY ENDPOINTS ...................................................................................................................61 
9.2.1 
Adverse events ..............................................................................................................................61 
9.2.2 
Laboratory safety variables,...........................................................................................................63 
9.2.3 
Vital signs.......................................................................................................................................63 
9.2.4 
Electrocardiogram variables ..........................................................................................................63 
9.3 
OTHER ENDPOINTS.....................................................................................................................63 
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9.3.1 
Anti-alirocumab antibodies assessments.......................................................................................63 
9.3.1.1 
Sampling time ................................................................................................................................63 
9.3.1.2 
Sample procedure..........................................................................................................................64 
9.3.1.3 
Bioanalytical method......................................................................................................................64 
9.3.2 
Hemoglobin A1c (HbA1c) .................................................................................................................64 
9.3.3 
Pharmacokinetics...........................................................................................................................64 
9.3.3.1 
Sampling time ................................................................................................................................64 
9.3.3.2 
Pharmacokinetics handling procedure...........................................................................................65 
9.3.3.3 
Bioanalytical method......................................................................................................................65 
9.3.4 
Pharmacogenetic assessment.......................................................................................................65 
9.3.4.1 
Optional stored DNA sample .........................................................................................................66 
9.3.5 
Proportion of patients who are up-titration to alirocumab 150 mg Q2W........................................67 
9.4 
FUTURE USE OF SAMPLES ........................................................................................................67 
9.5 
APPROPRIATENESS OF MEASUREMENTS ..............................................................................67 
9.6 
ASSESSMENT SCHEDULE..........................................................................................................67 
10 
STUDY PROCEDURES ................................................................................................................69 
10.1 
VISIT SCHEDULE..........................................................................................................................72 
10.1.1 
Run-in period..................................................................................................................................72 
10.1.2 
Screening period............................................................................................................................73 
10.1.3 
Double-blind treatment period (Study Site Visits)..........................................................................75 
10.1.3.1 Randomization visit (Visit 4 / Week 0 /Day 1)................................................................................75 
10.1.3.2 Visit 5 / Week 2 (Day 15 ± 7) .........................................................................................................77 
10.1.3.3 Visit 6 / Week 4 (Day 29 ± 7) .........................................................................................................77 
10.1.3.4 Visit 7 / Week 6 (Day 43 ± 7) .........................................................................................................78 
10.1.3.5 Visits 8 / Week 8 (Day 57 ± 7) .......................................................................................................78 
10.1.3.6 Visit 9 / Week 10 (Day 71 ± 3) .......................................................................................................79 
10.1.3.7 Visit 10 / Week 12 (Day 85 ± 3): End of DBTP and Start of OLTP................................................80 
10.1.4 
Open-label treatment period (Study Site Visits or Phone Call Visits)............................................81 
10.1.4.1 Visit 10 / Week 12 (Day 85 ± 3): End of DBTP and Start of OLTP................................................81 
10.1.4.2 Visit 11 / Week 16 (Day 113 ± 7) ...................................................................................................82 
10.1.4.3 Visit 12 / Week 20 (Day 141 ± 7) ...................................................................................................82 
10.1.4.4 Visit 13 / Week 24 (Day 169 ± 3) ...................................................................................................83 
10.1.4.5 Visits 14 and 15 / Weeks 28 (Day 197 ± 7) and 32 (Day 225 ± 7) ................................................85 
10.1.4.6 Visit 16 / Week 36 (Day 253 ± 3) ...................................................................................................85 
10.1.4.7 Visits 17 and 18 / Weeks 40 (Day 281 ± 7) and Week 44 (Day 309 ± 7) ......................................86 
10.1.4.8 Visit 19 / Week 48 (Day 337 ± 3) ...................................................................................................86 
10.1.4.9 Visits 20, 21, and 22 / Weeks 52 (Day 365 ± 7), Week 56 (Day 393 ± 7), and Week 60 
(Day 421 ± 7) .................................................................................................................................87 
10.1.4.10 Visit 23 / Week 64 (Day 449 ± 5) / End of OLTP ...........................................................................88 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................89 
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10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................90 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) ...........................90 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) ...........................90 
10.3.3 
List of criteria for permanent treatment discontinuation.................................................................90 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................91 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................91 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................92 
10.4.1 
Definitions of adverse events.........................................................................................................92 
10.4.1.1 Adverse event ................................................................................................................................92 
10.4.1.2 Serious adverse event ...................................................................................................................92 
10.4.1.3 Adverse event of special interest (AESI) .......................................................................................93 
10.4.2 
General guidelines for reporting adverse events ...........................................................................93 
10.4.3 
Instructions for reporting serious adverse events ..........................................................................94 
10.4.4 
Guideline for reporting adverse events of special interest.............................................................95 
10.4.4.1 Reporting of adverse events of special interest (AESI) with immediate notification......................95 
10.4.4.2 Reporting of adverse events of special interest without immediate notification ............................96 
10.4.5 
Guidelines for management of specific laboratory abnormalities ..................................................97 
10.4.5.1 Hemoglobin decrease ....................................................................................................................97 
10.4.6 
Summary of adverse event reporting instructions .........................................................................98 
10.5 
OBLIGATIONS OF THE SPONSOR .............................................................................................98 
10.6 
SAFETY INSTRUCTIONS .............................................................................................................99 
10.6.1 
Local tolerability (Local Injection Site Reactions) ..........................................................................99 
10.6.2 
Allergic adverse events..................................................................................................................99 
10.6.2.1 Allergic adverse events with cutaneous involvement ....................................................................99 
10.6.2.2 Acute allergic reactions of IMP injection ......................................................................................100 
10.6.3 
Cardiovascular events and all deaths..........................................................................................100 
10.6.4 
Laboratory alert related to two consecutive calculated LDL-C <25 mg/dL (0.65 mmol/L)...........101 
10.7 
ADVERSE EVENTS MONITORING............................................................................................102 
11 
STATISTICAL CONSIDERATIONS............................................................................................103 
11.1 
DETERMINATION OF SAMPLE SIZE.........................................................................................103 
11.2 
DISPOSITION OF PATIENTS .....................................................................................................103 
11.3 
ANALYSIS POPULATIONS.........................................................................................................104 
11.3.1 
Efficacy populations .....................................................................................................................104 
11.3.1.1 Intent–to-treat (ITT) population ....................................................................................................104 
11.3.1.2 Modified intent-to-treat (mITT) population....................................................................................104 
11.3.2 
Safety population .........................................................................................................................105 
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11.3.3 
Other analysis population ............................................................................................................105 
11.4 
STATISTICAL METHODS ...........................................................................................................105 
11.4.1 
Extent of study treatment exposure and compliance...................................................................105 
11.4.1.1 Extent of investigational medicinal product exposure..................................................................106 
11.4.1.2 Compliance ..................................................................................................................................106 
11.4.2 
Analyses of efficacy endpoints.....................................................................................................106 
11.4.2.1 Analysis of primary efficacy endpoint(s) ......................................................................................106 
11.4.2.2 Analyses of secondary efficacy endpoints...................................................................................107 
11.4.2.3 Multiplicity considerations ............................................................................................................108 
11.4.3 
Analyses of safety data................................................................................................................109 
11.4.3.1 Adverse events ............................................................................................................................110 
11.4.3.2 Laboratory data and vital signs....................................................................................................111 
11.4.3.3 Analyses of other endpoints.........................................................................................................111 
11.4.4 
Analyses of pharmacokinetic and pharmacodynamic variables ..................................................112 
11.5 
TIMING OF ANALYSES ..............................................................................................................112 
11.5.1 
First step: Efficacy and safety analyses using data up to 24 weeks after randomization 
(including 12 weeks double-blind)................................................................................................112 
11.5.2 
Second step: Long-term safety and efficacy exploratory analysis...............................................112 
12 
ETHICAL AND REGULATORY CONSIDERATIONS.................................................................113 
12.1 
ETHICAL AND REGULATORY STANDARDS ............................................................................113 
12.2 
INFORMED CONSENT ...............................................................................................................113 
12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) ............114 
13 
STUDY MONITORING.................................................................................................................115 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).....................................................................115 
13.2 
RESPONSIBILITIES OF THE SPONSOR...................................................................................115 
13.3 
SOURCE DOCUMENT REQUIREMENTS..................................................................................116 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST....................................................................................................................................116 
13.5 
USE OF COMPUTERIZED SYSTEMS........................................................................................116 
14 
ADDITIONAL REQUIREMENTS.................................................................................................117 
14.1 
CURRICULUM VITAE..................................................................................................................117 
14.2 
RECORD RETENTION IN STUDY SITES ..................................................................................117 
14.3 
CONFIDENTIALITY .....................................................................................................................117 
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14.4 
PROPERTY RIGHTS...................................................................................................................118 
14.5 
DATA PROTECTION...................................................................................................................118 
14.6 
INSURANCE COMPENSATION..................................................................................................118 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ...............................119 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE..........................................................................................................................................119 
14.8.1 
By the Sponsor.............................................................................................................................119 
14.8.2 
By the Investigator .......................................................................................................................120 
14.9 
CLINICAL TRIAL RESULTS ........................................................................................................120 
14.10 
PUBLICATIONS AND COMMUNICATIONS ...............................................................................120 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................121 
16 
BIBLIOGRAPHIC REFERENCES...............................................................................................122 
17 
APPENDICES..............................................................................................................................126 
APPENDIX A. DIAGNOSTIC CRITERIA FOR THE CLINICAL DIAGNOSIS OF HETEROZYGOUS 
FAMILIAL HYPERCHOLESTEROLEMIA (HEFH) [JAPAN ATHEROSCLEROSIS 
SOCIETY (JAS) GUIDELINES FOR PREVENTION OF ATHEROSCLEROTIC 
CARDIOVASCULAR DISEASES 2012].......................................................................................127 
APPENDIX B. SUMMARY OF DIET FOR PREVENTION OF ATHEROSCLEROTIC 
CARDIOVASCULAR DISEASE (JAS GUIDELINES FOR PREVENTION OF 
ATHEROSCLEROTIC CARDIOVASCULAR DISEASE 2012)....................................................128 
APPENDIX C. THE STAGES OF HEART FAILURE – NYHA CLASSIFICATION .....................................129 
APPENDIX D. SUMMARY OF ADVERSE EVENT REPORTING INSTRUCTIONS ..................................130 
APPENDIX E. GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI....................................................................................................132 
APPENDIX F. GUIDELINES FOR HEMOGLOBIN (HB) DECREASE 1.5 G/DL ......................................137 
APPENDIX G. DNA STORAGE SAMPLES ................................................................................................138 
APPENDIX H. ASSESSMENT OF LOCAL INJECTION SITE REACTIONS..............................................140 
APPENDIX I. MONITORING PLAN FOR CALCULATED LDL-C <25 MG/DL (0.65 MMOL/L) ..................141 
 
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3 
LIST OF ABBREVIATIONS 
 
AE: 
Adverse event 
AESI: 
Adverse event of special interest 
ALT: 
Alanine transaminase 
Apo: 
Apolipoprotein 
AST: 
Aspartate aminotranferase 
AUC: 
Area under the curve 
BMI: 
Body Mass Index 
BP: 
Blood pressure 
CABG: 
Coronary artery bypass graft surgery 
CBC: 
Complete blood cell count 
CEC: 
Clinical events committee 
CHD: 
Coronary heart disease 
CI: 
Confidence interval 
CKD: 
Chronic kidney disease 
CPK: 
Creatine phosphokinase 
CRF: 
Case report form 
CSR: 
Clinical study report 
CV: 
Cardiovascular 
CVD: 
Cardiovascular disease 
DBTP: 
Double-blined treatment period 
DMC: 
Data monitoring committee 
DNA: 
Deoxynucleic acid 
DRF: 
Discrepancy resolution form 
ECG: 
Electrocardiogram 
e-CRF: 
Electric case report form 
eGFR: 
Estimated glomelular filtration rate 
ELISA: 
Enzyme-linked immunosolbent assay 
EPA: 
Ethyl icosapentate 
FBG: 
Fasting blood glucose 
FH: 
Familial hypercholesterolemia 
GCP: 
Good clinical practice 
GT: 
Glutamyl transferase 
Hb: 
hemoglobin 
HbA1c: 
Hemoglobin A1c 
hCG: 
Human chorionic gonadotropin 
HCV: 
Hepatitis C virus 
HDL-C: 
High-density lipoprotein cholesterol 
heFH: 
Heterozygous FH 
HIV: 
Human immunodeficiency virus 
HLGT: 
High level group term 
HLT: 
High level term 
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HR: 
Heart rate 
IB: 
Investigator's brochure 
ICF: 
Informed consent form 
ICH: 
International conference on harmonisation of technical requirement for 
registration of pharmaceuticals for human use 
IEC: 
Independent ethics committee 
IMP: 
Investigational medicinal product 
IRB: 
Institutional review board 
ITT: 
Intent-to-treat 
IVRS: 
Interactive voice response system 
IWRS: 
Interactive web response system 
JAS: 
Japan Athrosclerosis Society 
LDH: 
Lactate dehydrogenase 
LDL-C: 
Low-density lipoprotein cholesterol 
LDL-R: 
Low-density lipoprotein-receptor 
LLN: 
Lower limit of normal range 
LLQ: 
Lower limit of quantification 
LLT: 
Lowest level term 
LMT: 
Lipoprotein modifying therapy 
LOCF: 
Last observation carried forward 
Lp(a): 
Lipoprotein (a) 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MI: 
Myocardial infarction 
MMRM: 
Mixed-effect model with repeated measures 
NIMP: 
Non-investigational medicinal product 
NYHA: 
New York Heart Association 
OGTT: 
Oral glucose tolerant test 
OLTP: 
Open-label treatment period 
PAD: 
Peripheral arterial disease 
PCI: 
Percutaneous coronary itervention 
PCR: 
Polymerase chain reaction 
PCSA: 
Potentially clinically significant abnormality 
PCSK9: 
Proprotein convertase subtilisin kexin type 9 
PD: 
Pharmacodynamics 
PK: 
Pharmacokinetics 
PT: 
Preferred term 
Q2W: 
Every 2 weeks 
Q4W: 
Every 4 weeks 
RDW: 
Red blood cell distribution width 
SAE: 
Serious adverse event 
SAP: 
Statistical analysis plan 
SC: 
Subcutaneous 
SE: 
Standard error 
SNP: 
Single nucleotide polymorphism 
SOC: 
System organ class 
TC: 
Total cholesterol 
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TEAE: 
Treatment emergent adverse event 
TG: 
Triglyceride 
TIA: 
Transient ischemic attack 
TSH: 
Thyroid-stimulating hormone 
ULN: 
Upper limit of normal range 
WOCBP: 
Woman of childbearing potential 
 
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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 Investigator’s Brochure (IB).  
Alirocumab is also referred to as SAR236553 or REGN727. However, for this study protocol 
(EFC14305), it will be referred to as alirocumab. 
Background on patient populations: 
This study will include patients with hypercholesterolemia (heterozygous familial 
hypercholesterolemia [heFH] or nonfamilial hypercholesterolemia [non-FH]). 
Hypercholesterolemia, particularly an increase in low-density lipoprotein cholesterol (LDL-C) 
levels, constitutes a major risk for the development of atherosclerosis and coronary heart disease 
(CHD) (1), the leading cause of death and disability in the Western world (2) and Japan (3). The 
LDL-C is identified as the primary target of cholesterol lowering therapy (4) and is accepted as a 
valid surrogate endpoint (5)(6). 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% (7). Recent data suggest that the lower the LDL-C level, the greater the benefit 
in patients at high cardiovascular risk (7)(8)(9)(10)(11). 
In the Japan Atherosclerosis Society (JAS) Guidelines (12), drug therapy in parallel with life style 
modification (e.g., diet and exercise) is required for dyslipidemia patients who are categorized in 
secondary prevention (non-familial hypercholesterolemia [FH] with history of documented CHD). 
The treatment goal for LDL-C in patients categorized in the secondary prevention is set as 
<100 mg/dL. Since heFH is high risk disease which is highly developing the CHD, the heFH can 
be considered as equivalent as the secondary prevention. The treatment goal for LDL-C in heFH 
is set as <100 mg/dL as well. When the goal cannot be achieved in many heFH cases since the 
LDL-C level is relatively high, 50% reduction of LDL-C from baseline can be adopted for the 
alternative goal (13). For the patients who meet the primary prevention category III, they initiate 
the treatment with life style modification, but the drug therapy is considered from the early stage 
of treatment. The treatment goal for LDL-C is established as <120 mg/dL. 
Current LDL-C-lowering medications include statins, cholesterol absorption inhibitors (i.e. 
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. Since 
hypercholesterolemia is largely asymptomatic, side effects of pharmacologic agents used to 
manage it can undermine patient compliance. In several cohort studies, the reported rate of 
adherence to statin therapy at 1 year ranged from 26% to 85%, with a rapid decline in adherence 
rates typically observed within the first few months (14). While statins are proven to be well 
tolerated agents there is a subset of patients who are intolerant to statin therapy and/or who suffer 
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from side effects. The recently published survey, “Understanding Statin Use in America and Gaps 
in Education (USAGE)” assessed the attitudes, beliefs, practices, and behavior of current and 
former statin users (15). Muscle-related side effects were reported by 60% and 25% of former and 
current users, respectively, and the primary reason for discontinuation was side effects (62%). The 
incidence of severe myopathy is low, occurring in less than 0.1% of patients receiving statin 
monotherapy. Conversely, mild symptoms are far more frequent, in outpatients on statins 
complaining of muscle pain. However, due to a lack of consensus on the definition of muscle 
symptoms in statin-intolerant patients and a lack of agreed upon definition of statin intolerance, 
the true prevalence of statin intolerance is unknown (16). The majority of adverse effects reported 
to be associated with statins are musculoskeletal, hepatic, gastrointestinal, and psychiatric. The 
most prevalent adverse events are musculoskeletal in nature, and the spectrum of statin-associated 
myotoxicity ranges from the more common but less severe myalgia (5% to 10%) to the less 
common but more severe myopathy (0.1%) and its potentially fatal complication, rhabdomyolysis 
(0.01%). A retrospective cohort study in Japan representing a cohort of 35903 adult statin users 
suggested that statin use is generally well tolerated and safe, however, the risk of muscle toxicity 
related to the use of interacting drugs requires further exploration (17). 
Three doses of atorvastatin (5, 10, 20 mg) caused statistically significant reductions from baseline 
in LDL-C (36%, 38%, and 50%, respectively) in Japan Cholesterol Lowering Atorvastatin Study 
(18). Although the starting dose of atorvastatin from package insert is 10 mg in Japan, there still 
are many patients receiving the lower dose, e.g., atorvastatin 5mg based on the results of the 
market research indicating that the doses of 10 mg, 5 mg and 20 mg of atorvastatin are used in 
55%, 42% and 2% of patients, respectively. One of the reasons is likely due to physicians’ 
concerns regarding potential intolerance to the higher dose statin.  
Fibrates or ezetimibe is one of treatment option for the hypercholesterolemic patients (19)(20). 
8% and 4% of Japanese hypercholesterolemic patients are on fibrates and ezetimibe without statin, 
respectively (©2014 IMS Health. All rights reserved. Source: Calculated based on IMS Data NPA 
Oct–Dec 2013. Reprinted with permission). The LDL-C goal attainment may be lower given the 
mild to moderate effect of fibrate or ezetimibe on LDL-C lowering into consideration. 
Additionally the choice of lipid lowering therapy is limited because combination of fibrates and 
statins may increase the risk of rhabdomyolysis, and thus the combination is primarily 
contraindicated in Japan (20). Therefore, alternative treatment approach is deemed necessary in 
patients who are not adequately controlled with non-statin lipoprotein modifying therapies 
(LMTs) or the lowest strength of statin (e.g., atorvastatin 5 mg daily). 
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. The PCSK9 is involved in regulating the levels of 
the low-density lipoprotein receptor (LDL-R) protein (21)(22). Once PCSK9 is secreted into 
plasma it directly binds to the LDL-R and promotes its intracellular 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 (23)(24). In humans, PCSK9 mutations have been identified: the gain of 
function mutations are rare and cause an autosomal dominant form of severe 
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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 (25)(26). One 
report from the Japanese population found the individual heterozygous for W428X mutation of 
PCSK9 had 70.4 mg/dL of plasma LDL-C, corresponding to a 44% decrease from the average 
LDL-C level in the untreated population (126.8 mg/dL). This observation is consistent with the 
finding that the two African-American nonsense mutations were associated with a 40% reduction 
in plasma LDL-C levels (27). 
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 (28). 
 
Summary of main clinical studies with Alirocumab: 
Japanese Phase 1 study (TDU12190) 
The TDU12190 study investigated the safety, tolerability and pharmacokinetics/ 
pharmacodynamics (PK/PD) profile of a single ascending dose of subcutaneous (SC) alirocumab 
in Japanese healthy male volunteers with a LDL-C >100 mg/dL (>2.59 mmol/L) and for whom 
statin therapy was not indicated. A total of 32 subjects were enrolled at a single study site. 
Subjects in each dose cohort (100, 150, 250, or 300 mg) were randomized to receive a single dose 
of alirocumab (n = 6) or placebo (n = 2). The total observation period was 15 weeks (up to Day 
106). All doses were well-tolerated. Very few treatment emergent adverse events (TEAEs) were 
reported with no evidence of dose relationship (1/8 subjects [12.5%] in placebo, and 1/6 subjects 
[16.7%] in 250 mg dose group). None of the TEAEs was reported in other treatment groups 
except 250 mg dose group. All TEAEs were unrelated to the treatment administered and of mild 
intensity, and no injection site reactions were reported. The administration of alirocumab 
significantly induced rapid and substantial reductions from baseline in LDL-C, approximately 40 
to 60%. Regarding the PK profile, when comparing the lowest dose (100 mg) with the highest 
dose (300 mg), the exposure increased with estimates of 3.88 (90% CI = 2.90 to 5.20) for Cmax 
and 5.55 (90% CI = 4.08 to 7.56) for area under the curve (AUC). When comparing the exposure 
of the 100 and 150 mg dose groups, point estimates of 0.87 for Cmax (90% CI = 0.65 to 1.17) and 
1.09 for AUC (90% CI = 0.80 to 1.48) were calculated. Geometric means of t1/2 ranged between 
5.92 and 7.49 days. The PK of alirocumab in Caucasian subjects and in Japanese subjects was not 
dose proportional, the extent of the supra-dose proportionality being approximately similar 
between these 2 populations. 
Oversea Phase 1 study of particular interest for the EFC 14305 study:  
Data from study PKD12910 suggests a limited impact of background therapy with ezetimibe or 
fenofibrate on the duration of action of alirocumab (29). This study assessed PK and PD 
parameters in 72 healthy subjects receiving 150 mg alirocumab every 4 weeks (Q4W) in 
combination with ezetimibe, fenofibrate, or placebo ezetimibe for 120 days. Administration of 
alirocumab 150 mg Q4W either alone or on top of ezetimibe (10 mg/day) or fenofibrate 
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(160 mg/day) produced a decline in LDL-C reaching -47.4%, -56.6% and -54.3% in the 
alirocumab alone, ezetimibe and fenofibrate groups respectively 2 weeks after the 3rd 
administration of alirocumab, in comparison to pre-alirocumab baseline value. At 4 weeks after 
this 3rd administration, the reduction was of 47.0%, 49.6% and 43.1% in the alirocumab alone, 
ezetimibe and fenofibrate groups respectively. This suggests maintenance of the effect when 
alirocumab was administered alone, whereas a small change from the maximum effect was seen 
between 2 and 4 weeks post dose in both combination arms. Overall these data suggest that the 
alirocumab 150 mg Q4W can provide persistent and efficacious reductions in LDL-C over a 4-
week dosing interval in patients as monotherapy or in patients receiving non-statin LMTs. 
Phase 2 studies 
Four Phase 2 studies (DFI11565, R727-CL-1003, DFI11566 and DFI12361 performed in 
Japanese patients) have been conducted in patients receiving a statin (with or without ezetimibe) 
as background therapy. Overall, a total of 349 (75 with DFI12361) patients were exposed to at 
least one dose of alirocumab in the 4 phase 2 studies. Generally, the efficacy and safety results in 
Japanese were similar with the results of overseas 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 Q2W group, with a mean decrease from baseline of up 
to 72.4%. (the least square [LS] mean difference versus placebo of -67.3% in DFI11565, -69.1% 
in DFI12361, -57.2% in R727-CL-1003; all p <0.0001) (30). 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 Q4W; however, 
the treatment effect was not fully maintained over a 4-week period (i.e., 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 study, 
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 
total cholesterol (TC), Apolipoprotein-B (Apo-B), non-high density lipoprotein cholesterol (non-
HDL-C) and Apolipoprotein-B / Apolipoprotein-A-1 (Apo-B/ApoA-1) ratio. A favorable trend 
was also observed for HDL-C, ApoA-1, triglyceride (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 DFI 
11566, 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 
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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 
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 (31). 
Selection of dose/ dose regimen for overseas Phase 3 studies and Japanese EFC 13672 Study: 
Based on the results of the dose finding studies carried out with statin as background therapy, the 
Q2W dosing regimen is appropriate to maintain constant LDL-C lowering throughout the 
interdosing interval in statin-treated patients, with the maximum efficacy at 12 weeks provided by 
the 150 mg Q2W dosing. A 75 mg Q2W dose was developed for patients who may not need the 
magnitude of effect observed with the 150 mg Q2W to achieve the target LDL-C goal, with up 
titration to 150 mg Q2W in patients not achieving their LDL-C goal. This represents an alternative 
dosing regimen in patients not achieving their LDL-C goal with 75 mg Q2W. 
The same dose regimen with the initial dose of 75 mg is also being tested in a Japanese Phase 3 
study (EFC 13672) given the existing data from Japanese and overseas studies and simulation that 
were done, LDL-C reduction is expected to be similar in Japanese and Caucasian. 
Oversea 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 heFH patients, patients with a 
range of cardiovascular (CV) 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 LMTs 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.   
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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 
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 adverse events (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 
transaminase (ALT) increase and hepatic disorders, adjudicated CV events, diabetes mellitus, and 
ophthalmologic disorders.  
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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 (ADRs). 
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 (32). 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. 
Further details on alirocumab are provided in the Investigator’s Brochure.  
 
Rationale for selection of doses / dose regimens in this study: 
This study will explore the alirocumab 150 mg Q4W regimen, which represents a potentially 
viable alternative to a Q2W regimen for some patients.  
Statins increases the activity of nuclear translocation of sterol regulatory element-binding 
protein 2 (SREBP-2), a transcription factor that activates both the LDL-R and PCSK9 genes. It is 
proposed that a statin-stimulated increased production of PCSK9 may affect the duration of action 
of alirocumab in the setting of Q4W dosing, because higher rates of PCSK9 production may result 
in greater target-mediated clearance of the antibody (33). Compared to statins, fibrates and 
ezetimibe appear to have less effect on PCSK9 levels (34), and a Q4W dosing regimen is 
expected to maintain sufficient LDL-C lowering throughout the interdosing interval in patients not 
receiving a statin but receiving these lipid-lowering therapies as well as for alirocumab 
monotherapy. The addition of a PCSK9 inhibitor to fibrate therapy may achieve beneficial 
cholesterol lowering along with the other desirable effects of fibrates (e.g., TG reduction) (35).  
For patients receiving alirocumab in monotherapy, phase 1 data consistently suggested that the 
dose of 150 mg given Q4W should also maintain sufficient LDL-C lowering throughout the 
interdosing interval; similar profile was observed with a background therapy of ezetimibe or 
fenofibrate, without statin from PKD12910 study.  
 
 
 
 
  
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Rationale for protocol design:  
The objective of the present study is to assess the efficacy and safety of alirocumab 150 mg Q4W 
as a potential starting and treatment dose in patients treated with non-statin LMTs or the lowest 
strength of statin. This population that is not at LDL-C goal on LMT (non-statin LMTs including 
diet therapy alone or the lowest strength of statin) with the documented reasons why statin is not 
appropriate or why statin dose cannot be increased for the patients, represents a group with an 
identified unmet medical need that can be addressed by adding alirocumab to their LDL-C 
lowering therapies. This will complement the current program, and help provide well-documented 
dosing recommendations. 
To confirm dose appropriateness of 150 mg Q4W as a starting dose, 150 mg Q2W is also 
evaluated with the comparison of placebo and compared the dose response with 150 mg Q4W. 
Showing higher efficacy in 150 mg Q2W than 150 mg Q4W would lead to justify the dose up 
titration for patients who do not reach LDL-C treatment goal.  
This study will be conducted in 2 patient populations concurrently: patients who are on 
concomitant atorvastatin 5 mg and patients who are on non-statin LMTs including diet therapy 
alone. The stratification will be done at randomization according to background statin treatment: 
(Yes/No). “No statin background” will be also stratified according to background 
fibrate/ezetimibe therapy: (Yes/No). 
To demonstrate superiority of 150 mg Q4W or 150 mg Q2W over placebo with a 90% statistical 
power under an alpha level of 2.5% for each comparison (to obtain an overall study alpha level of  
5%), 38 patients (19 in each arm) will be required assuming a difference of 30% in mean percent 
change in LDL-C between 150 mg Q4W and placebo, between 150 mg Q2W and placebo, and a 
common standard deviation of 25%, by using Bonferroni adjustment for two paired comparisons 
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between alirocumab groups (150 mg Q4W, 150 mg Q2W) and placebo. However, requirements 
for the long-term safety evaluation should also be considered in this study (36). In order to obtain 
>100 patients with 52 weeks exposure of alirocumab, 159 patients will be needed. 
In this study of patients maintaining their background therapy of non-statin LMTs including diet 
therapy alone or the lowest strength of statin, who do not/cannot receive a standard dose of statin, 
the choice of placebo as control over the double-blind treatment period appears appropriate for the 
objectives of this study, since it will provide the most robust assessment of efficacy and safety of 
150 mg Q4W and 150 mg Q2W. 
The primary efficacy parameter will be assessed at week 12 that is considered sufficient to 
provide efficacy and safety information of 150 mg Q4W and 150 mg Q2W on LDL-C levels in 
this study. This treatment duration should also provide a sufficient duration of “exposure” to 
appreciate tolerability and safety profiles of alirocumab in the context of a therapeutic exploratory 
study. The effect of alirocumab on other lipid parameters (e.g., Apo-B, non-HDL-C, TC levels) 
will also be assessed at Week 12 in this study. To obtain additional safety data with this Q4W 
dosing, patients may participate in an open-label treatment period from Week 12 to Week 64. 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
To demonstrate the reduction of low density lipoprotein cholesterol (LDL-C) by alirocumab 
150 mg every 4 weeks (Q4W) or 150 mg every 2 weeks (Q2W) regimen as add-on therapy to 
non-statin lipid modifying therapy (LMT) including diet therapy alone or the lowest strength of 
statin in comparison with placebo after 12 weeks of treatment in patients with 
hypercholesterolemia. 
5.2 
SECONDARY 
The secondary objectives are: 
x To evaluate the effect of two treatment regimens of alirocumab on other lipid parameters: 
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), 
triglyceride (TG), apolipoprotein A-1 (Apo A-1). 
x To evaluate the safety and tolerability of alirocumab 150 mg Q4W and 150 mg Q2W. 
x To evaluate the development of anti-alirocumab antibodies 
x To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) profiles of 
alirocumab 150 mg Q4W and 150 mg Q2W. 
x To evaluate the long-term safety in patients receiving open-label alirocumab 150 mg Q4W 
and 150 mg Q2W. 
 
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6 
STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled, parallel-group, balanced (1:1:1, 
alirocumab 150 mg Q4W: alirocumab 150 mg Q2W: placebo, subcutaneous injection), multi-
center phase 3 study. Randomization will be stratified according to background statin therapy 
(Yes/No). “No statin background” will be also stratified according to background 
fibrate/ezetimibe therapy (Yes/No), where ‘Yes’ represents fibrate or ezetimibe, and ‘No’ 
represents diet therapy alone.   
Approximately 159 subjects (53 subjects per treatment arm) will be recruited and randomized 
  
6.1 
DESCRIPTION OF THE PROTOCOL 
 
The study consists of 4 periods: run-in, screening, double-blind treatment, and open-label 
treatment 
x A run-in period of 4 weeks. Patients will be treated with stable non-statin LMTs, stable 
daily atorvastatin 5mg, or stable diet therapy. Patients who will have already been treated 
with stable non-statin LMTs, stable diet therapy alone, or stable daily atorvastatin 5mg for 
at least 4 weeks will be able skip this period. 
x A screening period of up to 3 weeks. The patients and designated person (such as spouse, 
relative, etc.) will be trained for self-injection / injection with a placebo for alirocumab 
when it is necessary.  
x A double-blind treatment period (DBTP) of 12 weeks. Patients will receive double-
blind treatment as follows, 
- 
Alirocumab 150 mg every 4 weeks (Q4W) alternating with placebo Q4W  
OR 
- 
Alirocumab 150 mg every 2 weeks (Q2W) 
OR 
- 
Placebo for alirocumab Q2W   
 
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 
generally prohibited after randomization of the patient, except for the safety of the patient 
as per Investigator’s judgment.  Lipid values obtained during the DBTP will not be 
communicated to investigator and sponsor to maintain the blind.  
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During the double-blind treatment period, patients should continue taking their therapies 
(daily 5mg atorvastatin, non-statin LMTs with ezetimibe, feno- or beza-fibrate, and/or diet 
therapy). Other LMTs red yeast rice, fibrate (other than feno- or beza-fibrate), ethyl 
icosapentate (EPA), and niacin and bile acid sequestrants are not allowed.  
Permitted atorvastatin at a dose of 5mg daily, non-statin LMTs, or diet therapy should 
remain stable (including dose) from screening through the end of double-blind treatment 
visit (Week 12) barring exceptional circumstances: 
- 
Exceptional circumstances per the investigator’s judgement.  
- 
If patient meets the pre-specified TG alert (TG 500 mg/dL [5.65mmol/L]), lab alert 
will be sent and repeat testing should be done as soon as possible. Then diet will have 
to be reinforced. If necessary LMTs (newly added or dose modifications) might be 
considered based on the best clinical judgement of the investigators.    
- 
If patient meets the pre-specified low LDL alert (2 consecutive calculated LDL-C 
<25 mg/dL (0.65 mmol/L), the sites may receive the alert (See Section 10.6.4).  
It is noted that the reasons of any adjustment should be documented and recorded in the 
electric case report form (e-CRF). 
The lipid results will be masked from specimens obtained after randomization to Week 12 
in order to keep the double-blind manner of DBTP. No attempts should be made by the 
investigator or patient to routinely have the patient’s lipid values independently evaluated 
after randomization.  
x An open-label treatment period (OLTP) of 52 weeks. All patients will receive 
alirocumab 150mg Q4W from the start of OLTP. Lipid values until Week 20 will not be 
opened and the values will be communicated to the investigator from Week 24.  
At Week 24, the up-titration to alirocumab 150mg Q2W will be automatically conducted 
through Interactive Web Response System (IWRS) under the following circumstances: 
- 
In patients with heFH or in patients with non-FH with documented coronary heart 
disease (CHD), LDL-C is 100 mg/dL (2.59mmol/L) at Week 20. 
- 
In patients with non-FH classified as primary prevention category III, LDL-C is 
120 mg/dL (3.10 mmol/L) at Week 20. 
 
During the OLTP, permitted atorvastatin at a dose of 5mg daily, non-statin LMTs, or diet 
therapy also should remain stable (including dose) similar to the DBTP barring 
exceptional circumstances:. 
- 
Exceptional circumstances per the investigator’s judgement.  
- 
If patient meets the pre-specified TG alert (TG 500 mg/dL [5.65mmol/L]), lab alert 
will be sent and repeat testing should be done as soon as possible. Then diet will have 
to be reinforced. If necessary, LMTs (newly added or dose modifications) might be 
considered based on the best clinical judgement of the investigators.    
 
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All investigational medicinal product (IMP) injections will be conducted by site staff, patients, or 
another designated person (such as spouse, relative, etc.) if patients cannot conduct the injection.  
x Injection training is planned at Week -1 with a placebo for alirocumab in case that the 
injections will be conducted by patients or another designated person from Week 0.  
x From Week 0 to Week 10, all IMP injections will be conducted at the study site by site 
staff or patients/designated person under direct supervision of the site staff.  
From Week 12, all IMP injections could be conducted by patients or the designated persons at 
home if patients agree. Otherwise, the IMP injections will be conducted by the site staff at “IMP 
injection site visits” (See Section 10.1.4.2 for detailed procedures). 
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
The study duration includes a run-in period of 4 weeks, a screening period of up to 3 weeks, a 12-
week DBTP for efficacy, and 52-week OLTP for efficacy and safety assessment. 
Thus, the study duration per patient is approximately 71 weeks (i.e., 18 months maximum)  
(up to 4 weeks of run-in period + up to 3 weeks screening + 12 weeks double-blind treatment + 
52 weeks open-label treatment). 
Patients, who experience ongoing SAEs or adverse events of special interest (AESI), at the 
prespecified study end date, should be followed until resolution, stabilization, or death and related 
data will be collected. 
6.2.2 Determination of end of clinical trial (all patients) 
The end of the study per patient is the last protocol planned visit or the resolution/stabilization of 
all SAEs, and AESI, whichever comes last. 
6.3 
TWO-STEP ANALYSIS 
The analyses will be conducted in two steps. The first analysis will be conducted as soon as all 
patients have been randomized and have at least all their data up to Week 24 (including 12 weeks 
DBTP and 12 weeks OLTP) collected and validated, and will consist in the final analysis of the 
primary efficacy endpoint and the secondary efficacy endpoints up to Week 12. The safety 
analysis will be performed on all safety data up to Week 24 collected and validated. The second 
analysis will be conducted at the end of the study with all data including the data of the OLTP, 
and will consist in the final analysis of the safety endpoints and exploratory efficacy assessment 
during the OLTP.   
For further detail, see Section 11.5, “Timing of analyses”. 
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6.4 
STUDY COMMITTEES 
Data Monitoring Committee (DMC): 
An independent DMC, composed of members independent of 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 (e.g., 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. 
Additionally, the DMC will be charged with reviewing the safety of patients with 2 consecutive 
LDL-C <25 mg/dL (0.65 mmol/L) and more particularly, will review adverse events (AEs) 
potentially associated with LDL-C <25 mg/dL (0.65 mmol/L) in conjunction with the Independent 
Physician (see Section 10.6.4 and Appendix I). 
 
Clinical Events Committee (CEC):  
The clinical events committee (CEC) is composed of experts in the field of CVDs, independent 
from the Sponsor and the Investigators. This committee will be responsible for defining, 
validating and classifying, in a blinded fashion, pre-specified CV events and all deaths. 
Classification of events will be as follows: CHD death, non-fatal myocardial infarction (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] or coronary artery bypass graft [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 
Patients meeting all of the following criteria will be considered for enrollment into the study: 
I 01. Patients with hypercholesterolemia§ (heFH* or non-FH) receiving non-statin LMTs**, or 
the lowest strength of statin***.  
* Diagnosis of heFH must be made either by genotyping or by clinical criteria before 
randomization. For those patients not genotyped, the clinical diagnosis may be based on 
JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012. If the 
clinical criteria are not met but heFH is strongly suspected by Investigator, genotyping will 
be conducted during the screening period after signed written informed consent for 
obtaining genotype information. 
** Fibrate or ezetimibe, or diet therapy alone. 
*** Defined as atorvastatin 5 mg. 
§Patients receiving monotherapy with 5mg daily atorvastatin, fibrate, or ezetimibe are 
allowed to enter the study. It is noted that patients with any combined drug therapy, such 
as atorvastatin + fibrate, atorvastatin + ezetimibe, or fibrate + ezetimibe, are not allowed. 
Patients with diet therapy alone or diet therapy with drug monotherapy (atorvastatin, 
fibrate, or ezetimibe) are allowed to enter the study. 
x In patients with heFH, patients with or without a history of documented CHD. 
x In patients with non-FH, patients must have a history of documented CHD; otherwise 
patients have a history of documented diseases or other risk factors classified as primary 
prevention category III 
 
A) Definitions for CHD (includes one or more of the following):  
x Myocardial infarction 
x Unstable angina 
x Coronary revascularization procedure (e.g., percutaneous coronary intervention [PCI] or 
coronary artery bypass graft surgery [CABG]) 
x Clinically significant CHD diagnosed by invasive or non-invasive testing (such as 
coronary angiography, stress test using treadmill, stress echocardiography or nuclear 
imaging) 
 
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B) Definitions for documented diseases or other risk factors classified as primary 
prevention category III: 
1. Ischemic stroke (excluding cardiogenic cerebro-embolism and/or transient ischemic attack 
[TIA]):  
- 
Documented previous ischemic stroke with a focal ischemic neurological deficit that 
persisted more than 24 hours, considered as being of atherothrombotic origin. 
- 
Computed tomography (CT) or magnetic resonance imaging (MRI) must have been 
performed to rule out hemorrhage and non-ischemic neurological disease. 
2. 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 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 
3. Diabetes:  
- 
Type 1 or type 2 diabetes mellitus with or without target organ damage (i.e., 
retinopathy, nephropathy, and/or micro-albuminuria). 
4. Chronic kidney disease (CKD): 
- 
Documented moderate CKD as defined by 30 estimated glomerular filtration rate 
(eGFR) <60 mL/min/1.73 m2 for 3 months or more, including the screening visit. 
5. Other risk factors 
- 
10-year fatal CHD risk SCORE 2% (JAS Guidelines for Prevention of 
Atherosclerotic Cardiovascular Diseases 2012). 
- 
10-year fatal CHD risk SCORE 0.5% and <2%, and have one or more of the 
following criteria (JAS Guidelines for Prevention of Atherosclerotic Cardiovascular 
Diseases 2012). 
a) Hypo HDL-C (<40 mg/dL). 
b) Family history of premature coronary artery disease (first-degree relative and male: 
<55 year-old, female: <65 year-old).  
c) Impaired glucose tolerance (defined as a fasting blood glucose [FBG] <126 mg/dL 
[<7.0 mmol/L], and a two- hour post glucose challenge value: 140-199 mg/dL [7.8-
11.1 mmol/L] [Oral glucose tolerance test, OGTT]). 
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I 02. Hypercholesterolemia patients (heFH or non-FH) with one or more following factors for a 
history or risk of statin tolerability why statin is not appropriate or why statin dose cannot 
be increased from the lowest strength for the patients. 
- 
History of side effects caused by statin (Hypersensitivity, elevated serum ALT, 
aspartate aminotransferase [AST], Ȗ-glutamyl transferase [ȖGT], alkaline phosphatase 
[ALP] and/or lactate dehydrogenase [LDH) levels, statin-induced liver dysfunction, 
abnormal values in creatine phosphokinase [CPK], Skeletal muscle-related symptoms, 
etc.).  
- 
CYP3A4 inhibitor (fibrate, immunosuppressant, azole antifungal agents or 
erythromycin). 
- 
Hepatic dysfunction or abnormal liver function (except fatty liver and confirmed other 
types of liver disease, history of hepatic dysfunction related to other causes). 
- 
Renal impairment or abnormal renal function (except history of renal impairment with 
defined cause). 
- 
Hypothyroidism. 
- 
Impaired glucose tolerance as defined previously or impaired fasting glycaemia (FBG 
110 - 125 mg/dL [6.1 - 6.9 mmol/L]). 
- 
Diabetic nephropathy 
- 
Elderly with body mass index (BMI) <18.5 kg/m2 
- 
Other documented factors medically judged by investigators why statin is not 
appropriate or why statin dose cannot be increased from the lowest strength for the 
patients than the factors described above. 
I 03. 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 4 subsections:  
7.2.1 Exclusion criteria related to study methodology 
E 01. LDL-C <100 mg/dL (<2.59 mmol/L) at the screening visit (Week -3) in patients with 
heFH or in patients with non-FH who have a history of documented CHD as described in 
Section 7.1 
E 02. LDL-C <120 mg/dL (<3.10 mmol/L) at the screening visit (Week -3) in patients with non-
FH patients who have a history of documented diseases or other risk factors as categorized 
in primary prevention category III as described in Section 7.1 
E 03. Not on a stable dose of LMTs (including diet therapy alone) in the run-in period or the 
screening period.  
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E 04. Use of statins other than atorvastatin 5 mg daily in the run-in period or the screening 
period. 
E 05. Use of fibrates, other than fenofibrate or bezafibrate in the run-in period or the screening 
period. 
E 06. Use of nicotinic acid or bile acid-binding sequestrants or probucol or EPA or red yeast rice 
products in the run-in period or the screening period. 
E 07. Use of nutraceutical products or over-the-counter therapies that may affect lipids which 
have not been at a stable dose / amount in the run-in period or the screening period. 
E 08. Patient who has received plasmapheresis treatment within 4 weeks prior to the screening 
visit (Week -3), or has plans to receive during the study.  
E 09. History of a MI, unstable angina leading to hospitalization, CABG, PCI, uncontrolled 
cardiac arrhythmia, stroke, transient ischemic attack, carotid revascularization, 
endovascular procedure or surgical intervention for peripheral vascular disease within 
3 months prior to the run-in visit (Week -7) or the screening visit (Week -3). 
E 10. Planned to undergo scheduled PCI, CABG, carotid or peripheral revascularization during 
the study. 
E 11. Systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg at the run-in 
visit (Week -7), the screening visit (Week -3), or randomization visit (Week 0). 
E 12. History of New York Heart Association (NYHA) Class III or IV heart failure within the 
12 months prior to the run-in visit (Week -7) or the screening visit (Week -3). 
E 13. Known history of hemorrhagic stroke. 
E 14. Age <20 years at the run-in visit (Week -7) or the screening visit (Week -3). 
E 15. Patients not previously instructed on a cholesterol-lowering diet prior to the screening visit 
(Week -3). 
E 16. Poorly controlled diabetes (hemoglobin A1c [HbA1c] >9%) at the screening visit (Week -3). 
E 17. Presence of any clinically significant uncontrolled endocrine disease known to influence 
serum lipids or lipoproteins. 
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 the screening and randomization visits, and 
TSH level is within ±10% of normal range of the Central Laboratory at the run-in visit  
(Week -7) or  the screening visit (Week -3). 
E 18. History of bariatric surgery within 12 months prior to run-in visit (Week -7) or the 
screening visit (Week -3). 
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E 19. Unstable weight defined by a variation >5 kg within 2 months prior to run-in visit  
(Week -7) or the screening visit (Week -3). 
E 20. Known history of homozygous familial hypercholesterolemia. 
E 21. Known history of loss of function of PCSK9 (i.e., genetic mutation or sequence variation). 
E 22. Use of systemic corticosteroids, unless used as replacement therapy for pituitary/adrenal 
disease with a stable regimen for at least 6 weeks prior to the randomization visit (Week 
0). 
Note: Topical, intra-articular, nasal, inhaled and ophthalmic steroid therapies are not 
considered as 'systemic' and are allowed. 
E 23. Use of continuous estrogen or testosterone hormone replacement therapy unless the 
regimen has been stable in the past 6 weeks prior to the run-in (Week -7) or the screening 
visit (Week -3) and no plans to change the regimen during the study. 
E 24. History of cancer within the past 5 years prior to the run-in visit (Week -7) or the screening 
visit (Week -3), except for adequately treated basal cell skin carcinoma, squamous cell 
skin carcinoma or in situ cervical cancer. 
E 25. Known history of a positive human immunodeficiency virus (HIV) test 
E 26. 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 27. 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 28. Conditions/situations such as: 
x Any clinically significant abnormality identified at the time of run-in (Week -7) or 
screening (Week -3) that in the judgment of the Investigator or any sub-Investigator would 
preclude safe completion of the study or constrain endpoints assessment such as major 
systemic diseases, patients with short life expectancy. 
x Considered by the Investigator or any sub-Investigator as inappropriate for this study for 
any reason, e.g.: 
- 
Deemed unable to meet specific protocol requirements, such as scheduled visits. 
- 
Deemed unable to administer or tolerate long-term injections as per the patient or the 
investigator. 
- 
Investigator or any sub-investigator, pharmacist, study coordinator, other study staff or 
relative thereof directly involved in the conduct of the protocol, etc. 
- 
Presence of any other conditions (e.g., geographic, social) actual or anticipated, that 
the investigator feels would restrict or limit the patient’s participation for the duration 
of the study. 
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E 29. Laboratory findings during the screening period (not including randomization Week 0 
labs):  
x Positive test for Hepatitis B surface antigen  
x Positive test for Hepatitis C antibody (if positive, then confirmed by Hepatitis C Virus 
[HCV] polymerase chain reaction [PCR]).  
x Positive serum beta-human chorionic gonadotropin (hCG) or urine pregnancy test 
(including Week 0) in women of childbearing potential 
x Fasting TG >400 mg/dL (>4.52 mmol/L) (1 repeat lab is allowed) 
x Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 according to 4-variable 
Modification of diet in renal disease (MDRD) Study equation (Calculated by central lab) 
x ALT or AST >3 x upper limit of normal range (ULN) (1 repeat lab is allowed) 
x CPK >3 x ULN (1 repeat lab is allowed) 
x Thyroid stimulating hormone (TSH) <lower limit of normal range (LLN) or >ULN 
(1 repeat lab is allowed. For patients with thyroid replacement therapy, refer to E 17.). 
7.2.2 Exclusion criteria related to the active comparator and/or mandatory background 
therapies  
E 30. All contraindications to the background therapies or warning/precaution of use (when 
appropriate) as displayed in the respective the Japanese Product labeling. 
7.2.3 Exclusion criteria related to the current knowledge of Sanofi compound  
E 31. Known hypersensitivity to monoclonal antibody or any component of the drug product. 
E 32. Pregnant or breastfeeding woman. 
E 33. 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, 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 birth control according to the "Note for 
guidance on non-clinical safety studies for the conduct of human clinical trials and marketing 
authorization for pharmaceuticals (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. International Conference on Harmonisation (ICH). 2009 June: 1-25). 
Postmenopausal women must be amenorrheic for at least 12 months. 
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7.2.4 Additional exclusion criteria during or at the end of screening or run-in phase 
before randomization 
E 34. Patient who has withdrawn consent before enrollment/randomization (starting from signed 
informed consent form). 
E 35. Despite screening of the patient, enrolment/randomization is stopped at the study level. 
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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
Sterile alirocumab drug product will be supplied at a concentration of 150 mg/mL in histidine, 
pH 6.0, polysorbate 20 and sucrose with 1 mL volume in an autoinjector. 
Sterile placebo for alirocumab will be prepared in the same formulation as alirocumab without the 
addition of protein as 1 mL volume in an autoinjector. 
Alirocumab 150 mg and placebo for alirocumab will be indistinguishable from each other. 
8.1.1 Route and method of administration 
The investigational medicinal product (IMP) will be administered subcutaneously in the abdomen, 
thigh or outer area of upper arm by site staff, the patient or by another designated person (such as 
a spouse, relative, etc.). The injection site will be rotated among the abdomen, thigh, and outer 
area of upper arm to minimize local site reaction by the IMP injection.   
A manual for IMP administration (injection instruction manual) will be provided to the study sites 
containing detailed instructions on use. It is recommended that the IMP injections should be 
rotated within anatomical areas (e.g., right thigh then left thigh or right abdomen then left 
abdomen). Patients also have the option to inject the IMP in different anatomical area (e.g., thigh, 
abdomen, and then outer area of upper arm). It is noted that the injection in the upper arms could 
be done only by a trained person (spouse, relative, etc.) or health care professional but not the 
patient themselves. If another concomitant drug is being injected at the same site planned for the 
IMP injection, then the IMP injection should be conducted in an alternate location. The used 
autoinjector will be discarded in a sharps container which will be provided to patients. 
Investigators or Pharmacists (and patients who plan self-administration of the IMP) will be asked 
to store the IMP in a refrigerator. Prior to administration, the IMP should be set outside in a safe 
location at room temperature for approximately 30 to 40 minutes. The IMP must be administered 
within 4 hours of removal from the refrigerator. 
Instructions for IMP administration as outlined above should be provided to the patient and/or 
other designated person (such as a spouse, relative, etc.) who will administer the IMP at training 
and as needed during the course of the study. Close supervision and feedback should be given at 
the injection training visit, the randomization visit and the other visits as needed. Anyone that 
plans to administer the IMP must be trained by the site staff. 
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8.1.2 Timing of administration 
Screening period (from Week -3 to Week 0): Training Injection 
During the screening period, a training injection is planned on Week -1 with a placebo for 
alirocumab. If needed, a second training injection is authorized before the randomization visit. It 
is noted that further training with the scheduled double-blind / open-label IMP can be done at any 
time during the study as necessary. 
Double-blind treatment period (from Week 0 to Week 12): 
During the double-blind treatment period, patients will be randomized to receive: 
x Alirocumab 150mg Q4W alternating with placebo for alirocumab Q4W 
OR 
x Alirocumab 150 mg Q2W 
OR 
x Placebo for alirocumab Q2W. 
Alirocumab will be administered at Week 0, Week2, Week 4, Week 6, Week 8, and Week 10 
(Q2W), or at Week 0, Week 4, and Week 8 with alternating placebo for alirocumab administration 
at Week 2, Week 6, and Week 10 (Q4W). The first IMP administration at Week 0 will start as 
soon as possible after the call for randomization using the treatment kit number provided by the 
IWRS. Patients will be monitored at the study site for at least 30 minutes after the first IMP 
administration. 
All IMP injections will be conducted at the study site under direct site staff supervision after all 
study assessments have been performed and all laboratory samples have been collected. 
Open-label treatment period (from Week 12 to Week 64): 
All patients will receive alirocumab 150 mg Q4W from the beginning of the OLTP (Week 12). At 
the beginning of the OLTP, all patients will be monitored at the study site for at least 30 minutes 
after the first IMP administration. 
At Week 24, the up-titration to alirocumab 150 mg Q2W will be conducted through interactive 
Web Response System (IWRS) under the following circumstances: 
x In patients with heFH or in patients with non-FH with documented CHD, LDL-C is 
100 mg/dL (2.59 mmol/L) at Week 20. 
x In patients with non-FH classified as primary prevention category III, LDL-C is 
120 mg/dL (3.10 mmol/L) at Week 20. 
In patients with alirocumab 150 mg Q4W, the last injection will be conducted at Week 60. In 
patients with up-titrated alirocumab 150 mg Q2W, the last injection will be conducted at Week 62. 
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All IMP injections can be conducted home if patients are able to perform (See Section 10.1.4 and 
Section 10.1.4.4). 
Throughout the entire study duration: 
When IMP injection is delayed more than 7 days from the scheduled injection time, or is 
completely missed, the patient should return to the original schedule of the IMP administration 
without administering the delayed injection. If the delay is less than or equal to 7 days from the 
missed date, the patient should administer the delayed injection and then resume the original 
dosing schedule of the IMP administration. At least 7 days must be needed between the IMP 
injections. 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) 
The following classes of drugs are identified as non-investigational medicinal products (NIMPs) 
because the medication is either background therapy or a potential medication: 
x Statin (atorvastatin, 5mg daily) 
x Cholesterol absorption inhibitor (ezetimibe) 
x Fibrate (fenofibrate, bezafibrate, but not other fibrates) 
For NIMP not provided by the Sponsor, tracking and reconciliation has to be achieved by the 
Investigator according to the system proposed by the Sponsor. 
Please see Section 8.8 for further information. 
8.3 
BLINDING PROCEDURES 
8.3.1 Methods of blinding 
Alirocumab and placebo for alirocumab will be provided in identically matched autoinjector 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, patients, Investigators, and study site personnel will 
remain blinded to the study treatment and will not have access to the randomization (treatment 
codes) except under circumstances described in Section 8.3.2 (suspected unexpected adverse drug 
reaction unblinded by the Sponsor).  
During the double-blind study period, neither the Investigator nor the Sponsor will have access to 
the individual data for the primary efficacy parameter obtained after the baseline visit in each 
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patient. However, the study team may review the data for the primary efficacy parameter in 
descriptive statistics with the name of the IMP treatment masked during data review meeting. The 
descriptive statistics for use in any data review meeting will be generated by an independent 
statistician/programmer, who will not be involved in the study operation and execution.  
8.3.1.1 Lipid parameters 
Lipid parameter values from blood samples obtained after the randomization visit (from Week 0 
to Week 20), 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 the randomization visit (from Week 
0 to Week 20) and will not be able to deduce the treatment group of patients based on LDL-C 
level attained during the double-blind treatment period. 
Lipid parameter values from blood samples obtained from Week 24 to Week 64 will be 
communicated to the sites and the Sponsor’s operational team from Week 24. 
During the DBTP, patients who achieve 2 consecutive calculated LDL-C <25 mg/dL (0.65 
mmol/L) will be monitored according to process outlined in Section 10.6.4 and Appendix I. In 
order to maintain the integrity of the blind as much as possible with this monitoring process, 
following process will be undertaken: 
x Specific steps will be in place to ensure the Central Lab work and communication with the 
independent external physician(s) (also known as independent physician), who is 
responsible for closely monitoring patients with 2 consecutive calculated LDL-C <25 
mg/dL (0.65 mmol/L), will be in strict confidence.  
x The independent physician(s) and DMC member (who is also responsible for this specific 
monitoring) will work independently from the clinical team and the sites. Communication 
with such groups will take place via specific process and only when needed.  
x The actual LDL-C levels will not be reported to the sites receiving alerts related to 2 
consecutive calculated LDL-C <25 mg/dL (0.65 mmol/L). 
x In order to maintain the integrity of the blind, study sites may receive true alerts or sham 
alerts. A sham alert is the alert that patient does not meet criteria of the low LDL-C alert, 
which is 2 consecutive calculated LDL-C <25 mg/dL (0.65 mmol/L). Sham alerts for 2 
consecutive calculated LDL-C <25 mg/dL (0.65 mmol/L) will be applied to randomly 
selected placebo patients in any site, who do not meet the criterial for an alert related to 2 
consecutive calculated LDL-C <25 mg/dL (0.65 mmol/L). Study staff and the monitoring 
team will know the alert has occurred, but will not know if it is sham or a true alert.   
8.3.1.2 Anti-alirocumab antibodies 
Patients’ anti-alirocumab antibody results will not be communicated to the sites. 
The sponsor’s operational team will not have access to anti-alirocumab antibodies associated with 
patient identification until the database lock will be completed. 
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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. 
 
 
8.3.1.3 Pharmacokinetics measurements, total and free PCSK9 concentrations 
At the assay institutions charged for PK measurements, total and free PCSK9 concentrations, 
samples will be analyzed prior to the database lock leading to unblinding of responsible 
bioanalysts. Bioanalysts are excluded from the operation’s team and a process will be set up to 
prevent any potential unblinding. 
8.3.1.4 Committee 
The DMC will receive confidential reports blinded by treatment group or unblinded (if necessary) 
from an independent statistician for review (Section 6.4). 
The CEC will review and adjudicate their respective events in a blinded manner (Section 6.4).  
A charter and an adjudication operational manual will specify the procedures, criteria, and 
classification used for adjudication of these events. 
8.3.2 Randomization code breaking during the study 
In case of an adverse event (AE), the code should only be broken in circumstances when 
knowledge of the IMP is required for treating the patient. If possible, a contact should be initiated 
with the Monitoring Team/Medical Monitor before breaking the code.  
Code breaking can be performed at any time by using the proper module of the interactive voice 
response system (IVRS) / interactive web response system (IWRS) and/or by calling any other 
phone number provided by the Sponsor for that purpose.  If the blind is broken, the Investigator 
should document the date, time of day, and reason for code breaking, and report this information 
on the appropriate page of the 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 or to any staff members until database closure. Furthermore, when completing forms 
(e.g., AE, SAE), the study treatment should not be disclosed on the forms. 
The code breaking can also be performed by contacting the “24-hour alert system”, but this 
system should only be used in very exceptional cases (i.e., unavailability of a centralized 
treatment allocation system or inability to contact investigator and/or site staff). 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). A patient card, including 
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the relevant “24-hour alert system” telephone number will be provided to every patient who will 
participate in the study. 
If the code is broken, the patient must be withdrawn from IMP administration but must be 
followed until the end of the study.  
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP 
The randomized list of treatment kit numbers will be generated centrally by Sanofi. The IMP 
(alirocumab 150 mg kit or placebo kit) will be packaged in accordance with this list. 
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 IWRS. Then, the 
IWRS will generate the patient randomization list according to which treatment kits will be 
allocated to the patients. 
Before randomizing a patient, the Investigator or designee will have to contact the IWRS. 
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. 
During the DBTP, patients will be randomized to receive alirocumab 150mg Q4W, alirocumab 
150 mg Q2W, or placebo at a ratio of 1:1:1 with permuted-block randomization. Randomization 
will be stratified according to the statin therapy (Yes/No). “No statin background” will be also 
stratified according to background fibrate/ezetimibe therapy (Yes/No), where ‘Yes’ represents 
fibrate or ezetimibe, and ‘No’ represents diet therapy alone. 
During the OLTP, all patients will receive alirocumab 150 mg Q4W from the beginning of the 
OLTP (Week 12). 
At Week 24, the up-titration to alirocumab 150 mg Q2W will be conducted based on LDL-C level 
at Week 20 following the up-titration rules (see Section 6.1). 
The treatment kit numbers will be allocated using the IWRS on randomization visit (Day 1, 
Week 0), and then at Week 2, Week 4, Week 6, Week 8, Week 10,Week 12, Week 24, Week 36, 
and Week 48 as re-supply visits, and at unscheduled visits if necessary. 
8.5 
PACKAGING AND LABELING 
Packaging is in accordance with the administration schedule. The content of the labeling is in 
accordance with the local regulatory specifications and requirements. 
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For the DBTP, each double-blind treatment kit containing a single autoinjector, either alirocumab 
or placebo, will be prepared.  
In order to protect the blind, all double-blind treatment kit boxes will have the same look and feel, 
and therefore will be labeled with a double-blind label.  
For the OLTP, each open-label treatment kit containing 4 autoinjectors of alirocumab/kit (wallet) 
labeled with an open-label way will be prepared. 
In addition to the double-blind and open-label treatment kits, training kits containing 1 placebo 
autoinjector per kit 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 needed a second training injection is authorized at least one day before the 
randomization visit.  
Written details of packaging and labeling of the IMP will be provided as a pharmacy manual. 
8.6 
STORAGE CONDITIONS AND SHELF LIFE 
Investigators or other authorized persons (e.g., pharmacists) are responsible for storing the IMP in 
a secure and safe place in accordance with local regulations, labeling specifications, policies, and 
procedures.  
Control of IMP storage conditions, especially control of temperature (e.g., 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. 
The IMP (alirocumab or placebo) has to 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 once a day during 
business days and recorded on a log sheet. Investigators or other authorized persons (e.g., 
pharmacists) must maintain the records documenting that all received IMPs are stored under 
adequately controlled conditions.   
8.7 
RESPONSIBILITIES 
The Investigators, the pharmacists, or other persons, who are 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 IMPs will be dispensed in accordance with the Investigator's prescription 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 the Investigator will 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. 
8.7.1 Treatment accountability and compliance 
Measures taken to ensure and document IMP compliance and accountability are described below: 
x The Investigator or designee will obtain the treatment kit number(s) via IVRS / IWRS and 
he/she will dispense the treatment kit(s) to the patient. 
x The Investigator, the pharmacist or designee will complete the corresponding treatment 
log form. 
x The Investigator / study coordinator will enter data in the appropriate electronic case 
report form (e-CRF) pages, according to data recorded in the treatment log form. 
x The monitor will check the data consistency between e-CRF pages, treatment log forms, 
and returned unused autoinjectors of corresponding kits. 
8.7.2 Return and/or destruction of treatments 
Unused treatments kits will be retrieved by the Sponsor. A detailed treatment log of the retrieved 
IMP will be established with the Investigator (or the pharmacist) and countersigned by the 
Investigator and the monitoring team. The Investigator will not destroy the unused IMP unless the 
Sponsor provides written authorization.  
“Partially-used and/or used IMP will be destroyed on site according to the standard practices of 
the site.” 
8.8 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment received by the patient concomitantly to the study 
(until Week 64 [Visit 23]). 
Concomitant medications should be kept to a minimum during the study. However, if these are 
considered necessity 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 LMT, including statin, study sites must follow the national product label of the 
safety monitoring and management of patients.  
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Nutraceutical products or over-the-counter therapies that may affect lipids are allowed only if they 
have been used at a stable dose at run-in visit, and maintained during the first 12 weeks of the 
DBTP. After the Week 12 visit, modification to these nutraceutical products or over-the-counter 
therapies may be allowed but in general should be avoided unless these products are required for 
medical reasons. 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, or 
psyllium.  
8.8.1 Management of background lipid modifying therapy 
Patients must have been on stable 5mg of daily dose of atorvastatin, other LMTs, or diet therapy 
for at least 4 weeks before the screening visit (Week -3). 
During the DBTP, the patients must stay on these stable daily doses of statin, non-statin LMTs, or 
diet therapy. Lipid profile values from samples obtained after randomization will be blinded until 
Week 24. During the OLTP after Week 24, the background LMT might be modified under the 
situations which overriding concerns warrant such changes, as per the Investigator’s judgment. 
8.8.2 Contraception 
Women of childbearing potential, who are the study participants or the partner of the male 
participant, must take an effective contraceptive method throughout the study treatment, and for 
10 weeks after the last IMP injection. 
8.8.3 Prohibited concomitant medications 
Forbidden concomitant medications from the run-in visit or initial screening visit until Week 64 
(Visit 23) include the following: 
x Statin except atorvastatin 5mg. 
x Bile acid-binding sequestrants (colestimide, cholestyramine). 
x Nicotinic acid (niceritrol, nicomol, tocopherol nicotinate). 
x Fibrates, other than fenofibrate or bezafibrate. 
x Probucol. 
x EPA (ethyl icosapentate) 
x Red yeast rice products 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
EFFICACY ENDPOINT 
9.1.1 Primary efficacy endpoint 
The primary efficacy endpoint is the percentage change in calculated LDL-C from baseline to 
Week 12 in the intent-to-treat (ITT) population, using all LDL-C values regardless of adherence 
to treatment (ITT estimand). It is defined as: 100 x (calculated LDL-C value at Week 12 - 
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 injection. For patients randomized and not treated, the baseline value is defined 
as the last available value obtained up to randomization. 
The calculated LDL-C at Week 12 will be the LDL-C level obtained within the Week 12 analysis 
window.  
All calculated LDL-C values (scheduled or unscheduled, fasting or not fasting) may be used in the 
analysis if appropriate according to above definition and analysis window used to allocate a time 
point to a measurement. The analysis window will be defined in the statistical analysis plan 
(SAP). 
9.1.2 Secondary endpoints 
9.1.2.1 Key secondary efficacy endpoints 
The key secondary efficacy will be considered in the following order: 
1. The percentage changes in calculated LDL-C from baseline to Week 12 in the modified 
ITT (mITT) population, using all LDL-C values during the efficacy double-blind treatment 
period (as are defined in Section 11.3.1.2) (on-treatment estimand). 
2. The percentage change in calculated LDL-C from baseline to average Week 10-12 (ITT 
estimand). 
3. The percentage change in calculated LDL-C from baseline to average Week 10-12 (on-
treatment estimand). 
4. The percentage change in Apo-B from baseline to Week 12 (ITT estimand). 
5. The percentage change in Apo-B from baseline to Week 12 (on-treatment estimand). 
6. The percentage change in non-HDL-C from baseline to Week 12 (ITT estimand). 
7. The percentage change in non-HDL-C from baseline to Week 12 (on-treatment estimand). 
8. The percentage change in TC from baseline to Week 12 (ITT estimand). 
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9. The proportion of patients reaching LDL-C goal at Week 12, i.e., calculated LDL-C 
<100 mg/dL (2.59 mmol/L) for heFH or non-FH patients who have a history of 
documented CHD patients, or LDL-C <120 mg/dL (3.10 mmol/L) for non-FH patients 
who have a history of documented diseases or other risk factors classified as primary 
prevention category III (ITT estimand). 
10. The proportion of patients reaching LDL-C goal at Week 12, i.e., calculated LDL-C 
<100 mg/dL (2.59 mmol/L) for heFH or non-FH patients who have a history of 
documented CHD patients, or LDL-C <120 mg/dL (3.10 mmol/L) for non-FH patients 
who have a history of documented diseases or other risk factors classified as primary 
prevention category III (on-treatment estimand). 
11. The percentage change in Lp(a) from baseline to Week 12 (ITT estimand). 
12. The percentage change in HDL-C from baseline to Week 12 (ITT estimand). 
13. The percentage change in fasting TG from baseline to Week 12 (ITT estimand). 
14. The percentage change in Apo A-1 from baseline to Week 12 (ITT estimand).  
9.1.2.2 Other Secondary Efficacy Endpoints 
x The proportion of patients with calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 12 
(ITT estimand). 
x The proportion of patients with calculated LDL-C <120 mg/dL (3.10 mmol/L) at Week 12 
(ITT estimand). 
x The proportion of patients with calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 12 
(ITT estimand). 
x The absolute change in LDL-C from baseline to Week 12 (ITT estimand). 
x The change in Apo-B/Apo A-1 ratio from baseline to Week 12 (ITT estimand). 
x The proportion of patients with Apo-B <80 mg/dL (0.8 g/L) at Week 12 (ITT estimand). 
x The proportion of patients with non HDL-C <130 mg/dL (3.37 mmol/L) at Week 12 (ITT 
estimand). 
x The proportion of patients achieving at least 50% reduction in LDL-C at Week 12 (ITT 
estimand). 
x The percentage change in TC, Lp(a) from baseline to Week 12 (on treatment estimand) 
9.1.3 Efficacy assessment method 
9.1.3.1 Lipid parameters 
The TC, 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. The LDL-C will be calculated using the Friedwald 
formula (37). If TG values exceed 400 mg/dL (4.52 mmol/L), then the Central Laboratory will 
reflexively measure (via the beta quantification method) the LDL-C rather than calculating the 
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LDL-C levels. Non-HDL-C will be calculated by subtracting HDL-C from the TC. Ratio Apo-
B/Apo A-1 will be calculated. Detailed procedures of sample preparation, storage, and shipment 
will be described in the specific laboratory manual which will be provided to study sites.  
Efficacy endpoints will not be considered as AEs, such as those involving abnormalities in lipid 
levels, unless meeting the criteria in Section 10.4.1. 
9.2 
SAFETY ENDPOINTS 
x Safety parameters (adverse events [including adjudicated cardiovascular events], 
laboratory data, and vital signs) assessed throughout the study. 
 
Observation period 
The observation of safety data will be as follows: 
x 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. 
x DOUBLE-BLIND TEAE period: The double-blind TEAE observation period is defined 
as the time from the first dose of double-blind IMP to the last dose of double-blind IMP 
administration + 70 days (10 weeks) or the first administration in the OLTP, whichever 
comes first.  
x OPEN-LABEL TEAE period: The open-label TEAE observation period is defined as the 
time form the first dose of open-label IMP injection to the last dose of open-label IMP 
injection + 70 days (10 weeks).  
x 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 ). 
Note: Double-blind and open-label TEAE periods will be defined for the long-term safety at 
the time of the first analysis.  
x TEAE observation period for long-term safety of alirocumab (DBTP and OLTP):  
- 
For 150 mg Q4W group and 150 mg Q2W group: The time from the first dose of 
double-blind IMP injection to the last dose of IMP injection (double-blind or open-
label) + 70 days (10 weeks). 
- 
For placebo group: The time from the first dose of open-label IMP injection to the last 
dose of open-label IMP injection + 70 days (10 weeks).  
9.2.1 Adverse events 
x All AEs diagnosed by the Investigator, irrespective of the result of the adjudication for CV 
events, will be reported and described. 
x 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 
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Organ Class (SOC)" using the version of MedDRA (Medical Dictionary for Regulatory 
Activities) currently in effect at Sanofi at the time of the considered database lock. 
x AEs of special interest (AESI) include events such as the following: 
- 
General allergic events (please refer to Section 10.4.4.1 and Section 10.6.2) 
- 
Local injection site reactions (using special e-CRF pages) (please refer to Section 
10.4.4.2 and Section 10.6). 
- 
Hemolytic anemia (using special e-CRF pages, see Section 10.4.4.1, Appendix D). 
- 
Neurologic (including neurocognitive) adverse events (please refer to Section 10.4.4.1 
and Appendix D). 
- 
Ophthalmologic adverse events (using special e-CRF pages, see Section 10.4.4.1 and 
Appendix D). 
- 
Skeletal muscle-related adverse events (using special e-CRF pages, see Section 
10.4.4.2). 
- 
Asymptomatic or symptomatic overdose with IMP (see Section 10.4.4.1, Section 
10.4.4.2, and Appendix D). 
- 
Pregnancy of female patient (including male patient’s partner) (see Section 10.4.4.1 
and Appendix D).  
- 
ALT increase (see Section 10.4.4 and Section 10.4.5). 
 
Refer to Section 10.4 and Section 10.6 for details. 
 
Adjudicated CV events include all CV AEs and CV procedures positively adjudicated (see 
Section 10.6.3) occurring from randomization until end of the study. The adjudication categories 
are the following: 
x CHD death. 
x Non-fatal MI. 
x Fatal and non-fatal ischemic and/or hemorrhagic stroke. 
x Unstable angina requiring hospitalization. 
x Congestive heart failure requiring hospitalization. 
x Ischemia-driven coronary revascularization procedure.  
 
In addition, the classification of all deaths will occur. 
Adverse event observation period: 
x The AE observations are per the observation periods defined above.  
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Death observations period: 
x 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 6.2.2). 
9.2.2 Laboratory safety variables,  
The clinical laboratory data consist of urinalysis, hematology (red blood cell count, hemoglobin, 
red blood cell distribution width [RDW], reticulocyte count, hematocrit, platelets, white blood cell 
count with differential blood count), standard chemistry (glucose, sodium, potassium, chloride, 
bicarbonate, calcium, phosphorous, urea nitrogen, creatinine, eGFR, uric acid, total protein, 
albumin, and Ȗ-GT, haptoglobin, LDH), Hepatitis C antibody, liver panel (ALT, AST, 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).  
Clinical laboratory values will be analyzed after conversion into standard international units. 
International units will be used in all listings and tables. 
9.2.3 Vital signs 
x Vital signs include heart rate (HR), and systolic / diastolic blood pressure (BP) in sitting 
position. 
9.2.4 Electrocardiogram variables 
x Electrocardiogram (ECG) data will be assessed by the Investigator based on the automatic 
device reading. 
9.3 
OTHER ENDPOINTS 
9.3.1 Anti-alirocumab antibodies assessments 
Anti-alirocumab antibodies include the antibody status (positive / negative) and antibody titers. In 
patients with antibody positive status, neutralizing antibody status will be also included. The anti-
alirocumab antibodies will be assessed throughout the study.  
9.3.1.1 Sampling time 
Serum samples for anti-alirocumab antibodies determination will be drawn periodically 
throughout the study as per schedule noted in the study flowchart of Section 1. All scheduled 
samples will be obtained before IMP injection (pre-dose). 
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9.3.1.2 Sample procedure 
Detailed procedure of sample preparation, storage, and shipment will be described in the specific 
laboratory manual which will be provided to study sites. Five (5) mL blood volume is to be 
collected for each anti-alirocumab antibodies samples. 
9.3.1.3 Bioanalytical method 
 
 
 
 
 
 
  
 
 
 
9.3.2 Hemoglobin A1c (HbA1c) 
The absolute change in HbA1c (%) will be assessed from baseline (Week -3)  to Week 12, Week 
24 (Visit 13), Week 36, Week 48, and Week 64 (Visit 23, end of OLTP).  
9.3.3 Pharmacokinetics 
Pharmacokinetic variable include total serum alirocumab concentration. Total and free PCSK9 
concentration will be measured from the same PK sample.  
9.3.3.1 Sampling time 
Serum sample for total alirocumab concentration will be collected before IMP (pre-dose) at 
Week 0 (randomization visit) and then at several visits until the end of the OLTP period, as per 
the study flow chart (see Section 1.1). 
Exact date and time of last IMP administration and PK sampling are to be recorded. 
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9.3.3.2 Pharmacokinetics handling 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 
 
 
 
 
9.3.4 Pharmacogenetic assessment 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
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9.3.4.1 Optional stored DNA sample 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.3.5 Proportion of patients who are up-titration to alirocumab 150 mg Q2W 
Proportion of patients who are up-titrated to alirocumab 150 mg Q2W during the OLTP will be 
calculated. 
9.4 
FUTURE USE OF SAMPLES 
 
 
 
 
  
 
  
 
 
 
9.5 
APPROPRIATENESS OF MEASUREMENTS 
The efficacy and safe assessments used in the study are standard for the evaluation of patients 
with hypercholesterolemia (please refer to Section 4 for details). 
9.6 
ASSESSMENT SCHEDULE 
The assessment schedule will be as follows: 
 
x Patient assessments in the run-in period:  
- 
On-site visits: Week -7 (run-in visit) 
x Patients assessments in the screening period:  
- 
On-site visits: Week -3 (screening visit). Week -1 (Injection training visit) 
x Patient assessments in the DBTP: 
- 
On-site visits: Week 0 (randomization visit), Week 2, Week 4, Week 6, Week 8, 
Week 10, and Week 12 (end of DBTP) 
x Patients assessment during the OLTP: 
- 
On-site visits: Week 12 (Start of OLTP), Week 20, Week 24, Week 36, and Week 48. 
- 
Phone call visits: Week 16, Week 28, Week 32, Week 40, Week 44, Week 52, 
Week 56, and Week 60.  
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- 
On-site visits: Week 64 (end of the OLTP) 
Note: Patients who will be up-titrated to alirocumab 150 mg Q2W from Week 24 and/or patients 
who prefer on-site IMP injection during OLTP will have additional on-site visits during the 
OLPT (see Section 10.1.4  and Section 10.1.4.4). 
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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 Week 10, Week 12, Week 24, Week 36, and 
Week 48 are ± 3 days, at Week 64 is ± 5 days, and for all other site visits it is ± 7 days for the 
study period.  
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 sampling: 
The blood sampling for determination of lipid parameters (i.e., total-C, LDL-C, HDL-C, TG, non-
HDL-C, Apo-B, Apo A-1, ratio Apo-B/Apo A-1, Lp[a]) should be performed in the morning, in 
fasting condition (i.e., overnight, at least 10 to 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 a 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 patients 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 and 
forwarded to the central laboratory.  
x Hematology, 
x Chemistry, 
x Lipid panel 1: TC, calculated LDL-C, HDL-C, TG, non-HDL-C 
x Lipid panel 2: Apo-B, Apo A-1, Apo-B/Apo A-1ratio, and Lp(a) 
x Liver panel: in case of total bilirubin values above the normal range, differentiation into 
conjugated and non-conjugated bilirubin will occur automatically,  
x Creatine Phosphokinase (CPK), 
x Hepatitis B surface antigen, 
x Hepatitis C antibody: positive tests will be confirmed with reflexive testing, 
x Serum pregnancy test 
x Urine pregnancy test. 
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Urine samplings:  
x Urinalysis – dipstick will performed at the Central Laboratory and will assess for pH, 
specific gravity, and for the presence of blood, protein, glucose, ketones, nitrites, 
leukocyte esterase, urobilinogen, and bilirubin. The standard microscopic assessment will 
be conducted.  
Notes: Any clinically relevant abnormal laboratory value should be immediately rechecked 
(whenever possible using the central laboratory) 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 10.4.4.1.  
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix E, and Appendix F, and should be followed by Investigators. 
 
Other endpoint assessment methods: 
All other blood parameters will also be measured by a Central Laboratory 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 by a Central Laboratory, 
periodically throughout the study as per the schedule in Section 1.2. 
Pharmacokinetic samples (alirocumab concentration):  
Serum samples for assessment of alirocumab concentration will be obtained periodically 
throughout double-blind trial period as per schedule note in study flowchart of Section 1.2. 
Blood sample will be collected before IMP injection for Week 0 (Visit 4), Week 4 (Visit 6), 
Week 8 (Visit 8), Week 10 (Visit 9), and Week 12 (Visit 10).  
Note: It has to be made certain of blood sample collection before the IMP injection. 
Serum Samples for anti-alirocumab antibody concentration:  
Serum samples for assessment of anti-alirocumab antibody concentration will be obtained 
periodically throughout the study as per schedule note in study flowchart of Section 1.2. 
Blood sample will be collected before IMP injection for Week 0 (Visit 4), Week 4 (Visit 6), 
Week 12 (Visit 10), Week 24 (Visit 13), Week 36 (Visit 16), Week 48 (Visit 19), and Week 64 
(Visit 23). 
Note: It has to be made certain of blood sample collection before the IMP injection. 
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Physical examination: 
A general physical examination should be performed at the time points indicated in the study 
schedule flowchart of 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 judgement.  
Blood pressure / heart rate:  
Blood pressure (BP) 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 comfortable in sitting position for at least 5 minutes). The BP measurement will 
be repeated 3 times. The obtained BP values are averaged and recorded in the e-CRF; both 
systolic and diastolic BP should be recorded. At the first screening visit, BP should be measured 
in both arms. The arm with the highest diastolic BP will be determined at this visit, and BP should 
be measured on this arm throughout the study. This highest BP value will be recorded in the 
e-CRF.   
The heart rate (HR) will also be measured at the time of the measurement of BP.  
Note: in case of high BP values at run-in or screening the Investigator is responsible for the 
optimization of the patient’s treatment to achieve BP targets as defined by local guidelines 
(Japanese Society of Hypertension) or the Seventh Report of the Joint National Committee on 
Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7).  
Electrocardiogram: 
The 12-lead electrocardiogram (ECG) should be performed after at least 10 minutes rest and in 
the supine position.  
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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 
10.4.2 (General guidelines for reporting adverse events). 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 mandatory. Self-reported weights are not acceptable; 
patients must not read the scales themselves. Height needs to be measured and self-reported 
heights are not acceptable.  
10.1 
VISIT SCHEDULE 
10.1.1 Run-in period 
Following the screening for inclusion / exclusion criteria as noted in Section 7, patients not at 
stable doses of atorvastatin or other statins, unstable non-statin LMTs, or unstable diet therapy 
alone are enrolled (Week -7 / Visit 1). Stabilization of daily 5mg atorvastatin dosing, non-statin 
LMTs, or diet therapy will be carried out as necessary.  
x On site visit 
x Complete informed consent – the patients 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.  
Note: All AEs and SAEs will be collected from the time of informed consent signature and 
throughout the study until Week 64 (Visit 23). 
x Obtain patient demography – age, gender, and race. 
x Assess inclusion / exclusion criteria 
x Obtain medical history (including menopausal status), surgical history, alcohol habits, and 
smoking habits. 
x Obtain family medical history (including risk factors relating to premature CHD [before 
55 years of age in a male and 65 years in a female first degree relative], allergy and type-2 
diabetes).  
x Document prior medication history within the previous 8 weeks, especially for lipid 
modifying therapies (including statin) and nutraceutical products that may affect lipids 
(e.g., omega-3 fatty acids, plant stanols such as found in Benecol, flax seed oil, psyllium).  
x Perform physical examination 
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x Contact IVRS/IWRS for notification of entering the run-in period. 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 (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).  
x Review patient’s diet. Patient should be on a diet following Japan Atherosclerosis Society 
Guideline or equivalent (see Section 17, Appendix B). 
x Record concomitant medication. 
x Measure vital signs including HR and BP. 
x Collect AEs/SAEs information from this point onward.  
x An appointment will be given for the next visit.  
x Provide instruction on diet. 
10.1.2 Screening period 
Only patients with stable 5 mg daily atorvastatin, non-statin LMTs, or diet therapy alone, 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 (Week 0). The first screening visit (Week -3) can take 
place from 8 to 21 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). 
Screening Visit (Visit 2 / Week -3 / Day -21 up to Day -8): 
x On-site visit. 
Complete informed consent if the patients skip the run-in period and directly enter the 
screening period. The patients 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.  
Note: All AEs and SAEs will be collected from the time of informed consent signature and 
throughout the study until Week 64 (Visit 23). 
x Obtain patient demography - age, gender, and race of the patient can skip the run-in period. 
x Assess inclusion / exclusion criteria. 
x Obtain medical history (including menopausal status), surgical history, alcohol habits, and 
smoking habits.  
x Obtain family medical history (including risk factors relating to premature CHD [before 
55 years of age in a male and 65 years in a female first degree relative], allergy and type-2 
diabetes).  
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x Document prior medication history within the previous 12 weeks, especially for lipid 
modifying therapy (including statin) and nutraceutical products that may affect lipids (e.g., 
omega-3 fatty acids, plant stanols such as found in Benecol, flax seed oil, psyllium).  
x Perform physical examination 
x Measurement of body weight and body height. 
x 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 (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).  
Review patient’s diet. Patient should be on a diet following Japan Atherosclerosis Society 
Guideline or equivalent (see Section 17, Appendix B). 
x Record concomitant medication. 
x Collect AEs/SAEs information. 
x Measure vital signs including HR and BP.  
x Perform 12-lead ECG recording 
x Obtain fasting blood sample for: 
- 
Lipids: total-C, measured and/or calculated LDL-C, HDL-C, TG, non-HDL-C. 
- 
Hematology: CBC including hematocrit, RDW, reticulocyte count, hemoglobin, red 
blood cell count, white blood cell count with differential count and platelets.  
- 
Chemistry: glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
urea nitrogen, creatinine, eGFR, uric acid, LDH, total protein, albumin, haptoglobin 
and Ȗ-GT.  
- 
CPK. 
- 
Liver panel (ALT, AST, ALP, and total bilirubin). 
- 
Hepatitis B surface antigen and hepatitis C antibody tests. 
- 
Serum pregnancy test (women of childbearing potential only). 
- 
HbA1c. 
- 
TSH. 
x Urinalysis (dipstick including pH, specific gravity, the presence of blood, protein, glucose, 
ketones, nitrites, leukocyte esterase, urobilinogen, and bilirubin, and microscopic 
examination). 
Note: All patients will be qualified for randomization based on the laboratory results 
LDL-C value obtained at this visit.  
x An appointment will be given for the next visit (Week -1).  
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x Provide instruction on diet. 
x If it is planned to have another designated person administer the injections to the patient 
during the study, then the person also should be present at the next visit (injection training 
visit at Week -1). 
Injection training visit at Screening (Visit 3 / Week -1 / Day -7 ± 6): 
Note: Injection training will be carried out if patient prefers self-IMP injection.  
x On-site visit 
x IVRS/IWRS contact for allocation of a batch number for training kit. 
x Record batch number allocated in e-CRF. 
x 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, relatives, etc.) at the study site under direct supervision of site staff with 
appropriate feedback.  
x Measure vital signs including HR and BP.  
x Collect AEs / SAEs information. 
x If patient will undergo the second optional injection training with alirocumab placebo, 
then the following steps are required. However, if patient does not need a second optional 
training injection with alirocumab placebo then do not perform these steps: 
- 
Re-contact IVRS / IWRS for allocation of a second new batch number for a second 
training kit.  
- 
Record and dispense the second batch number allocated in e-CRF.  
- 
Dispense the second placebo training injection to the patient for self-administration. 
Note: Further training with the scheduled double-blind / open-label IMP can be done at any 
time during the study as necessary. The required process for the training is described above.   
x An appointment will be given for the next visit (Week -1 or 0). 
x Remind patient to be in fasting conditions (i.e., overnight, at least 10 to 12 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.  
10.1.3 Double-blind treatment period (Study Site Visits) 
10.1.3.1 Randomization visit (Visit 4 / Week 0 /Day 1) 
Note: Blood sample should be collected before IMP administration. 
x On-site visit 
x Assess Inclusion / Exclusion Criteria. 
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x Perform physical examination. 
x Measure body weight. 
x 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 a 7-digit treatment kit number 
according to the randomization list for the alirocumab injection. Investigator 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 first double-blind IMP injection 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.  
- 
The patients should be observed for at least 30 minutes after the IMP injection.  
- 
In case of self-IMP injection, close supervision, feedback and further training to be 
provided for IMP administration when necessary. 
x Review patient’s diet. Patient should be on a diet recommended by the Japan 
Atherosclerosis Society Guideline or equivalent.  
x Record concomitant medication. 
x Measure vital signs including HR and BP.  
x Collect AEs / SAEs information. 
x Obtain fasting blood sample for: 
- 
Lipids: total-C, measured and/or calculated LDL-C, HDL-C, TG, non-HDL-C, Apo-B, 
Apo A-1, Apo-B / Apo A-1 ratio, and Lp(a).  
- 
Hematology: CBC including hematocrit, RDW, reticulocyte count, hemoglobin, red 
blood cell count, white blood cell count with differential count and platelets.  
- 
Chemistry: glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
urea nitrogen, creatinine, eGFR, uric acid, LDH, total protein, albumin, haptoglobin 
and Ȗ-GT.  
- 
CPK. 
- 
Liver panel (ALT, AST, ALP, and total bilirubin).  
x Urinalysis (dipstick and microscopy). 
x Urine pregnancy test (WOCBP). 
x Anti-alirocumab antibodies. 
x Serum alirocumab concentration (PK). 
x 
 
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x 
 
 
 
x 
 
x Reminders: 
- 
An appointment will be given for the next study site visit (Week2).  
Note: If patients (and/or their designated persons [such as a spouse, relative, etc.]), who 
prefer self-IMP administration and their self-IMP injection capabilities are accepted by the 
site Investigators based on the Injection training session(s) during the Screening visit 
(Week -1), patients will administer the IMP by themselves during the course of study. The 
self-IMP administration will be carried out during the DBTP under direct supervision of 
Investigators and the site staff so that both of patient and the site Investigator can confirm 
the self-IMP administration capability of the patient before the OLTP will start.  
10.1.3.2 Visit 5 / Week 2 (Day 15 ± 7) 
Note: No blood sampling is scheduled. 
x On-site visit 
x IVRS/IWRS contact for allocation of a treatment kit according to the randomization list.  
x IMP administration and compliance check, and 30 minutes observation after the IMP 
administration. 
x Record concomitant medication. 
x Measure vital signs including HR and BP. 
x Collect AEs/SAEs information. 
x Reminders: 
- 
An appointment will be given for the next study site visit (Week 4). 
- 
Remind patient to be in fasting conditions (i.e., 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. 
10.1.3.3 Visit 6 / Week 4 (Day 29 ± 7) 
Note: Blood sample should be collected before IMP administration. 
x On-site visit 
x IVRS/IWRS contact for allocation of a treatment kit according to the randomization list.  
x IMP administration and compliance check, and 30 minutes observation after the IMP 
administration. 
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x Record concomitant medication. 
x Measure vital signs including HR and BP. 
x Collect AEs / SAEs information. 
x Obtain fasting blood sample for: 
- 
Lipids: total-C, measured and/or calculated LDL-C, HDL-C, TG, and non-HDL-C. 
- 
Liver panel (ALT, AST, ALP, and total bilirubin). 
x Anti-alirocumab antibodies. 
x Serum alirocumab concentration (PK). 
x Reminders: 
- 
An appointment will be given for the next study site visit (Week 6). 
 
10.1.3.4 Visit 7 / Week 6 (Day 43 ± 7)  
Note: No blood sampling is scheduled. 
x On-site visit 
x IVRS/IWRS contact for allocation of a treatment kit according to the randomization list.  
x IMP administration and compliance check, and 30 minutes observation after the IMP 
administration. 
x Record concomitant medication. 
x Measure vital signs including HR and BP.  
x Collect AEs / SAEs information. 
x Reminders: 
- 
An appointment will be given for the next study site visit (Week 8). 
- 
Remind patient to be fasting conditions (i.e., 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.  
10.1.3.5 Visits 8 / Week 8 (Day 57 ± 7) 
Note: Blood sample should be collected before IMP administration. 
x On-site visit 
x IVRS/IWRS contact for allocation of a treatment kit according to the randomization list.  
x IMP administration and compliance check, and 30 minutes observation after the IMP 
administration. 
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x Record concomitant medication. 
x Measure vital signs including HR and BP. 
x Collect AEs / SAEs information. 
x Obtain fasting blood sample for: 
- 
Lipids: total-C, measured and/or calculated LDL-C, HDL-C, TG, non-HDL-C, Apo-B, 
Apo A-1, Apo-B / Apo A-1ratio, and Lp(a). 
- 
Liver panel (ALT, AST, ALP, and total bilirubin). 
x Serum alirocumab concentration (PK). 
x Reminders: 
- 
An appointment will be given for the next study site visit (Week 10). 
- 
Remind patient to be fasting conditions (i.e., 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. 
10.1.3.6 Visit 9 / Week 10 (Day 71 ± 3) 
Note: Blood sample should be collected before IMP administration. 
x On-site visit. 
x IVRS/IWRS contact for allocation of a treatment kit according to the randomization list.  
x IMP administration and compliance check, and 30 minutes observation after the IMP 
administration. 
x Record concomitant medication. 
x Measure vital signs including HR and BP. 
x Collect AEs / SAEs information. 
x Obtain fasting blood sample for: 
- 
Lipids: total-C, measured and/or calculated LDL-C, HDL-C, TG, non-HDL-C, Apo-B, 
Apo A-1, Apo-B / Apo A-1 ratio, and Lp(a). 
x Serum alirocumab concentration (PK). 
x Reminders: 
- 
An appointment will be given for the next study site visit. 
- 
Remind patient to be fasting conditions (i.e., 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. 
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10.1.3.7 Visit 10 / Week 12 (Day 85 ± 3): End of DBTP and Start of OLTP 
Note: Blood sample should be collected before IMP administration. 
x On-site visit. 
x Perform physical examination. 
x Measure body weight. 
x IVRS / IWRS contact for allocation of a treatment kit according to the randomization list.  
x Review patient’s diet. Patient should be on a diet recommended by the Japan 
Atherosclerosis Society Guideline or equivalent.  
x IMP administration and compliance check, and 30 minutes observation after the IMP 
administration. 
x Record concomitant medication. 
x Measure vital signs including HR and BP.  
x Collect AEs/SAEs information. 
x Record 12-lead ECG. 
x Obtain fasting blood sample for: 
- 
Lipids: total-C, measured and/or calculated LDL-C, HDL-C, TG, non-HDL-C, Apo-B, 
Apo A-1, Apo-B / Apo A-1 ratio, and Lp(a).  
- 
Hematology: complete blood cell count (CBC) including hematocrit, red blood cell 
distribution width (RDW), reticulocyte count, hemoglobin, red blood cell count, white 
blood cell count with differential count and platelets. (Reticulocyte count and 
haptoglobin are measured only when hemoglobin is decrease with 1.5g/dL from the 
baseline). 
- 
Chemistry: glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
urea nitrogen, creatinine, eGFR, uric acid, lactate dehydrogenase (LDH), total protein, 
albumin, haptoglobin and Ȗ-GT.  
- 
CPK. 
- 
Liver panel (ALT, AST, ALP, and total bilirubin).  
x Urinalysis (dipstick and microscopy). 
x Urine pregnancy test (WOCBP). 
x HbA1c 
x Anti-alirocumab antibodies. 
x Serum alirocumab concentration (PK). 
x 
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10.1.4 Open-label treatment period (Study Site Visits or Phone Call Visits) 
10.1.4.1 Visit 10 / Week 12 (Day 85 ± 3): End of DBTP and Start of OLTP 
Note: The OLPT starts from this visit and it is also the last visit of the DBTP. Blood sample 
should be collected before the IMP administration. The patient who performs self-IMP 
administration during the DBTP will continue the self-IMP administration at his/her home 
during the OLTP. Site staff has to carefully monitor the IMP administration compliance and 
AEs and SAEs collection through phone-visit call. 
x On-site visit. 
x Perform physical examination. 
x Measure body weight. 
x IVRS / IWRS contact for allocation of a treatment kit and the IMP will be supplied before 
Week 24 scheduled visit. 
Note: All patients will be treated with alirocumab 150 mg Q4W from this time point.  
x IMP administration and compliance check, and 30 minutes observation after the IMP 
administration. 
x Review patient’s diet. Patient should be on a diet recommended by the Japan 
Atherosclerosis Society Guideline or equivalent.   
x Record concomitant medication. 
x Measure vital signs including HR and BP.  
x Collect AEs / SAEs information. 
x Record 12-lead ECG. 
x Obtain fasting blood sample for: 
- 
Lipids: total-C, measured and/or calculated LDL-C, HDL-C, TG, non-HDL-C, Apo-B, 
Apo A-1, Apo-B / Apo A-1 ratio, and Lp(a).  
- 
Hematology: CBC including hematocrit, RDW, reticulocyte count, hemoglobin, red 
blood cell count, white blood cell count with differential count and platelets. 
(Reticulocyte count and haptoglobin are measured only when hemoglobin is decrease 
with 1.5g/dL from the baseline). 
- 
Chemistry: glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
urea nitrogen, creatinine, eGFR, uric acid, LDH, total protein, albumin, haptoglobin 
and Ȗ-GT.  
- 
CPK. 
- 
Liver panel (ALT, AST, ALP, and total bilirubin).  
x Urinalysis (dipstick and microscopy). 
x Urine pregnancy test (WOCBP). 
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x HbA1c 
x Anti-alirocumab antibodies. 
x Reminders: 
- 
An appointment will be given for the next study site visit (Week 16). 
10.1.4.2 Visit 11 / Week 16 (Day 113 ± 7)  
x Phone call visit (or IMP injection site visit). 
Note: If the patient decides not to have self-IMP administration at his/her home, the patient 
can visit the site as the “IMP injection site visit” for IMP administration, and the site staff 
or the patient under direct site staff supervision can administer the IMP. 
x IMP administration and compliance check, and 30 minutes observation after the IMP 
administration. 
x Record concomitant medication. 
x Collect AEs / SAEs information. 
x Reminders: 
- 
An appointment will be given for the next study site visit (Week 20). 
- 
Remind patient to be fasting conditions (i.e., overnight, at least 10 to 12 hours fast and 
refrain from smoking) for the Week 20 scheduled study site visit. Also alcohol 
consumption within 48 hours and intense physical exercise within 24 hours preceding 
the next study site visit are discouraged. 
10.1.4.3 Visit 12 / Week 20 (Day 141 ± 7) 
Note: Blood sample should be collected before IMP administration. 
x On-site visit. 
x IMP administration and compliance check, and 30 minutes observation after the IMP 
administration. 
x Record concomitant medication. 
x Measure vital signs including HR and BP. 
x Collect AEs/SAEs collection. 
x Obtain fasting blood sample for: 
- 
Lipids: total-C, measured and/or calculated LDL-C, HDL-C, TG, and non-HDL-C.  
x Reminders: 
- 
An appointment will be given for the next study site visit (Week 24). 
- 
Remind patient to be fasting conditions (i.e., overnight, at least 10 to 12 hours fast and 
refrain from smoking) for the Week 24 scheduled study site visit. Also alcohol 
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consumption within 48 hours and intense physical exercise within 24 hours preceding 
the next study site visit are discouraged. 
10.1.4.4 Visit 13 / Week 24 (Day 169 ± 3) 
Note: Blood sample should be collected before IMP administration. 
x On-site visit. 
x Perform physical examination. 
x Measure body weight. 
x IVRS/IWRS contact for allocation of a treatment kit and the IMP will be supplied before 
Week 36 scheduled study visit. 
Note: Up-titration to the Q2W 150 mg alirocumab treatment will be automatically 
conducted based on the result of serum LDL-C level of Week 20 (see Section 6.1 for details).  
x IMP administration and compliance check, and 30 minutes observation after the IMP 
administration. 
x Review patient’s diet. Patient should be on a diet recommended by the Japan 
Atherosclerosis Society Guideline or equivalent.   
x Record concomitant medication. 
x Measure vital signs including HR and BP.  
x Collect AEs / SAEs information. 
x Record 12-lead ECG. 
x Obtain fasting blood sample for: 
- 
Lipids: total-C, measured and / or calculated LDL-C, HDL-C, TG, non-HDL-C, Apo-
B, Apo A-1, Apo-B / Apo A-1 ratio, and Lp(a).  
- 
Hematology: CBC including hematocrit, RDW, reticulocyte count, hemoglobin, red 
blood cell count, white blood cell count with differential count and platelets. 
(Reticulocyte count and haptoglobin are measured only when hemoglobin is decrease 
with 1.5g/dL from the baseline). 
- 
Chemistry: glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
urea nitrogen, creatinine, eGFR, uric acid, LDH, total protein, albumin, haptoglobin 
and Ȗ-GT.  
- 
CPK. 
- 
Liver panel (ALT, AST, ALP, and total bilirubin).  
x Urinalysis (dipstick and microscopy). 
x Urine pregnancy test (WOCBP). 
x HbA1c 
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x Anti-alirocumab antibodies. 
x Reminders: 
- 
An appointment will be given for the next scheduled study site visit (and/or IMP 
administration site visits). 
 
Instruction of IMP administration in patients receiving Alirocumab 150 mg Q2W up-
titration. 
Patients, who receive up-titrated alirocumab 150 mg Q2W, can select self-IMP injection at their 
home / self-IMP injection at study site on scheduled site visits, site staff IMP injection at study 
site on scheduled site visits and IMP-injection site visits, or mixture of both if necessary. The 
alirocumab 150 mg Q2W administration will be performed on following timing after Week 24: 
x Week 26 (Q2W only) 
x Week 28 (Q2W and Q4W, Phone call / IMP injection site visit,) 
x Week 30 (Q2W only) 
x Week 32 (Q2W and Q4W, Phone call / IMP injection site visit) 
x Week 34 (Q2W only) 
x Week 36 (Q2W and Q4W, Scheduled site visit) 
x Week 38 (Q2W only) 
x Week 40 (Q2W and Q4W, Phone call / IMP injection site visit) 
x Week 42 (Q2W only) 
x Week 44 (Q2W and Q4W, Phone call / IMP injection site visit) 
x Week 46 (Q2W only) 
x Week 48 (Q2W and Q4W, Scheduled site visit) 
x Week 50 (Q2W only) 
x Week 52 (Q2W and Q4W, Phone call / IMP injection site visit) 
x Week 54 (Q2W only) 
x Week 56 (Q2W and Q4W, Phone call / IMP injection site visit) 
x Week 58 (Q2W only)  
x Week 60 (Q2W and Q4W, Phone call / IMP injection site visit) 
and 
x Week 62 (Q2W only) 
 
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Note: When the patients prefer self-IMP administration at their home, site staff has to make 
phone call visits on each IMP administration day to carry out IMP administration 
compliance check, 30 minutes post-IMP administration observation, and collection of 
AEs/SAEs information. If patients prefer IMP-administration at study sites, the site staff has 
to carry out IMP compliance check, 30 minutes post-IMP administration observation, and 
AEs/SAEs information collection after the IMP administration.      
10.1.4.5 Visits 14 and 15 / Weeks 28 (Day 197 ± 7) and 32 (Day 225 ± 7) 
x Phone call visit (or IMP injection site visits) 
x IMP administration and compliance check, and 30 minutes observation after the IMP 
administration. 
x Record concomitant medication. 
x Collect AEs/SAEs collection. 
x Reminders: 
- 
An appointment will be given for the next scheduled study site visit (and/or IMP 
administration site visits). 
- 
Remind patients to be fasting conditions (i.e., overnight, at least 10 to 12 hours fast 
and refrain from smoking) for the Week 36 study site visit. Also alcohol consumption 
within 48 hours and intense physical exercise within 24 hours preceding the next study 
site visit are discouraged. 
10.1.4.6 Visit 16 / Week 36 (Day 253 ± 3) 
Note: Blood sample should be collected before IMP administration. 
x On-site visit. 
x Perform physical examination. 
x Measure body weight. 
x IVRS / IWRS contact for allocation of a treatment kit and the IMP will be supplied before 
next scheduled visit (Week 48). 
x IMP administration and compliance check, and 30 minutes observation after the IMP 
administration. 
x Review patient’s diet. Patient should be on a diet recommended by the Japan 
Atherosclerosis Society Guideline or equivalent. 
x Record concomitant medication. 
x Measure vital signs including HR and BP.  
x Collect AEs / SAEs information. 
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x Obtain fasting blood sample for: 
- 
Lipids: total-C, measured and/or calculated LDL-C, HDL-C, TG, non-HDL-C, Apo-B, 
Apo A-1, Apo-B / Apo A-1 ratio, and Lp(a).  
- 
Hematology: CBC including hematocrit, RDW, reticulocyte count, hemoglobin, red 
blood cell count, white blood cell count with differential count and platelets. 
(Reticulocyte count and haptoglobin are measured only when hemoglobin is decrease 
with 1.5g/dL from the baseline). 
- 
Chemistry: glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
urea nitrogen, creatinine, eGFR, uric acid, LDH, total protein, albumin, haptoglobin 
and Ȗ-GT.  
- 
CPK. 
- 
Liver panel (ALT, AST, ALP, and total bilirubin).  
x Urine pregnancy test (WOCBP). 
x HbA1c 
x Anti-alirocumab antibodies. 
x Reminders: 
- 
An appointment will be given for the next study site visit (scheduled visit and/or IMP 
administration site visits). 
10.1.4.7 Visits 17 and 18 / Weeks 40 (Day 281 ± 7) and Week 44 (Day 309 ± 7) 
x Phone call visit (or IMP injection site visits). 
x IMP administration and compliance check, and 30 minutes observation after the IMP 
administration. 
x Record concomitant medication. 
x Collect AEs / SAEs information. 
x Reminders: 
- 
An appointment will be given for the next scheduled study site visit (and/or un-
scheduled site visits only for the IMP injection). 
- 
Remind patients to be fasting conditions (i.e., overnight, at least 10 to 12 hours fast 
and refrain from smoking) for the Week 48 study site visit. Also alcohol consumption 
within 48 hours and intense physical exercise within 24 hours preceding the next study 
site visit are discouraged. 
10.1.4.8 Visit 19 / Week 48 (Day 337 ± 3) 
Note: Blood sample should be collected before IMP administration. 
x On-site visit. 
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x Perform physical examination. 
x IVRS / IWRS contact for allocation of a treatment kit and the IMP will be supplied until 
the final administration (until Week 60 for Q4W, or until Week 62 for up-titrated Q2W). 
x IMP administration and compliance check, and 30 minutes observation after the IMP 
administration. 
x Review patient’s diet. Patient should be on a diet recommended by the Japan 
Atherosclerosis Society Guideline or equivalent.  
x Record concomitant medication. 
x Measure vital signs including HR and BP.  
x Collect AEs / SAEs information. 
x Obtain fasting blood sample for: 
- 
Lipids: total-C, measured and/or calculated LDL-C, HDL-C, TG, and non-HDL-C.  
- 
Hematology: CBC including hematocrit, RDW, reticulocyte count, hemoglobin, red 
blood cell count, white blood cell count with differential count and platelets. 
- 
Chemistry: glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
urea nitrogen, creatinine, eGFR, uric acid, LDH, total protein, albumin, haptoglobin 
and Ȗ-GT. (Reticulocyte count and haptoglobin are measured only when hemoglobin is 
decrease with 1.5g/dL from the baseline).  
- 
CPK. 
- 
Liver panel (ALT, AST, ALP, and total bilirubin).  
x Urine pregnancy test (WOCBP). 
x HbA1c 
x Anti-alirocumab antibodies. 
x Reminders: 
- 
An appointment will be given for the next study site visit (scheduled visit and/or un-
scheduled site visits only for IMP administration). 
10.1.4.9 Visits 20, 21, and 22 / Weeks 52 (Day 365 ± 7), Week 56 (Day 393 ± 7), and Week 60 
(Day 421 ± 7) 
x Phone call visit (or IMP injection site visit). 
x IMP administration and compliance check, and 30 minutes observation after the IMP 
administration.  
Note: The last IMP administration of patients with Q4W will be on Week 60, and the last 
IMP administration of patients with up-titrated Q2W will be on Week 62. 
x Record concomitant medication. 
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x Collect AEs / SAEs information. 
x Reminders: 
- 
An appointment will be given for the next scheduled study site visit (and/or IMP 
injection site visits). 
- 
Remind patients to be fasting conditions (i.e., overnight, at least 10 to 12 hours fast 
and refrain from smoking) for the Week 64 study site visit. Also alcohol consumption 
within 48 hours and intense physical exercise within 24 hours preceding the next study 
site visit are discouraged. 
10.1.4.10 
Visit 23 / Week 64 (Day 449 ± 5) / End of OLTP 
Note: Blood sample should be collected before IMP administration. 
x On-site visit 
x Perform physical examination. 
x Measure body weight. 
x IVRS / IWRS contact to document the end of the treatment for all patients.  
x Review patient's diet. Patient should be on a diet recommended by the Japan 
Atherosclerosis Society Guideline or equivalent.  
x Record concomitant medication. 
x Measure vital signs including HR and BP.  
x Collect AEs / SAEs information. 
x Record 12-lead ECG. 
x Obtain fasting blood sample for: 
- 
Lipids: total-C, measured and/or calculated LDL-C, HDL-C, TG, non-HDL-C, Apo-B, 
Apo A-1, Apo-B / Apo A-1 ratio, and Lp(a). 
- 
Hematology: CBC including hematocrit, RDW, reticulocyte count, hemoglobin, red 
blood cell count, white blood cell count with differential count and platelets. 
(Reticulocyte count and haptoglobin are measured only when hemoglobin is decrease 
with 1.5g/dL from the baseline). 
- 
Chemistry: glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
urea nitrogen, creatinine, eGFR, uric acid, LDH, total protein, albumin, haptoglobin 
and Ȗ-GT.  
- 
CPK. 
- 
Liver panel (ALT, AST, ALP, and total bilirubin).  
- 
Hepatitis C antibody tests. 
x Urinalysis (dipstick and microscopy). 
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x Urine pregnancy test (WOCBP). 
x HbA1c 
x Anti-alirocumab antibodies. 
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: 
x Agreement, date, and signature of informed consent mentioning the study identification. 
x Patient identification, last participation in a clinical trial, medical history, associated 
disease, and data related to the studied pathology. 
x Contraception methods for women of childbearing potential. 
x Previous and concomitant medication (including the LMT). 
x Study identification. 
x Treatment number, dates of administration. 
x Dates of visit and assessments including the examination report.  
x Vital signs, height, body weight. 
x Faxed Central Laboratory reports (dated and signed by the Principal Investigator or sub-
Investigator). 
x IWRS confirmation report (screening, screen failure, randomization, treatment reallocation, 
discontinuation, end of DBTP, end of study, unblinding if applicable).  
x ECG records signed and dated. 
x 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.  
x Date of premature study discontinuation (if any) and reasons. 
 
Source documentation may be found in the followings: 
x Patient’s identity 
x Medical history 
x Hospital records 
x Nursing notes 
x Physician’s notes 
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x Laboratory reports 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION  
The IMP administration should be continued whenever possible. In case the IMP administration is 
interrupted, it should be determined whether the interruption is temporarily; permanent IMP 
discontinuation should be the last resort. Any IMP discontinuation should be fully documented in 
the CRF. In any case, the patient should remain in the study as long as possible. 
10.3.1 Temporary treatment discontinuation with investigational medicinal product(s) 
Temporary treatment discontinuation may be considered by the Investigator because of suspected 
AEs. Reinitiation 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(s) 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 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 that are not administered to 
the patient as descried 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 IMP at any time.  
10.3.3 List of criteria for permanent treatment discontinuation 
The patients may withdraw from treatment with the IMP if they decide to do so, at any time and 
irrespective of the reason, or this may be the Investigator’s decision. Patient withdrawal from the 
study treatment or study should be avoided as much as possible. All efforts should be made to 
document the reasons for treatment discontinuation and this should be documented in the e-CRF. 
Patients should discontinue the IMP administration for the following reasons:  
x Pregnancy, intention for pregnancy, or no longer with effective contraceptive method of 
birth control (in treated female patients). 
x Acute injection reaction of clinical concern. 
x SAE (or non-serious but severe in intensity) of hypersensitivity reaction considered related 
to IMP.  
x At patient’s request. 
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x If, in the Investigator’s opinion, continuation with the administration of the IMP would be 
detrimental to the patient’s well-being. 
x Intercurrent condition that requires discontinuation of the IMP (e.g., laboratory 
abnormalities, please refer to decision tree Appendix F).  
x At the specific request of the Sponsor. 
x Any code breaking requested by the Investigator. 
x Patient receives double-blind treatment prior to randomization. 
10.3.4 Handling of patients after permanent treatment discontinuation 
x During DBTP: Patients who prematurely discontinue study treatment (regardless of 
reason) will have an unscheduled visit with assessments originally planned at the end of 
study visit (Week 64, it should take place within 5 days of treatment discontinuation, if 
possible). The patients will also continue the study and assessments originally planned 
until the end of DBTP visit (Week 12, V10), and will be followed up until recovery or 
stabilization of any AE to be followed up as specified in this protocol. If patients 
prematurely discontinue the study treatment and deny the study continuation, the patients 
will have an unscheduled visit with assessments originally planned at the end of study visit 
(Week 64, it should take place within 5 days of treatment discontinuation, if possible) and 
also the patients will be followed up until recovery or stabilization of any AE to be 
followed up as specified in this protocol. 
x During OLTP: Patients, who prematurely discontinue study treatment (regardless of the 
reasons) during OLTP, will have an unscheduled visit with assessments originally planned 
at the end of study visit (Week 64, it should take place within 5 days of treatment 
discontinuation, if possible). The patient, at a minimum, will be followed up until recovery 
or stabilization of any AE to be followed up as specified in this protocol. 
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. IWRS should be notified when a patient prematurely discontinues the study treatment.  
For patients randomized and not treated, all efforts should be done to perform Week 12 visits in 
order to collect the lipid data. 
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. If possible, the patients should be assessed using the 
procedure 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 reasons for) when considered as confirmed.   
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For patients who fail to return to the site, the Investigator should make the best effort to re-contact 
the patient (e.g., 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 (e.g., number of 
times and dates of attempted telephone contact, receipt for sending a registered letter).  
The statistical analysis plan (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  
10.4.1.1 Adverse event 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
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 (SAE) is any untoward medical occurrence that at any dose: 
x Results in death, or 
x 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. 
x Requires inpatient hospitalization or prolongation of existing hospitalization, or 
x Results in persistent or significant disability/incapacity, or 
x Is a congenital anomaly/birth defect. 
x 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 
medical or surgical intervention (i.e., specific measures or corrective treatment) to prevent one of 
the other outcomes listed in the definition above. 
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Note: The following list of medically important events is intended to serve as a guideline for 
determining which condition has to be considered as a medically important event. The list is 
not intended to be exhaustive: 
x Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm  
- 
Blood dyscrasias (i.e., agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc.),  
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc.). 
x Development of drug dependence or drug abuse. 
x ALT >3 x ULN + total bilirubin >2 x ULN or asymptomatic ALT increase >10 x ULN. 
x Suicide attempt or any event suggestive of suicidality. 
x Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling). 
x Bullous cutaneous eruptions. 
x Cancers diagnosed during the study or aggravated during the study. 
x Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study. 
10.4.1.3 Adverse event of special interest (AESI) 
An adverse event of special interest (AESI) is an AE (serious or non-serious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them. The AESIs may be added or 
removed during the study by protocol amendment.  
10.4.2 General guidelines for reporting adverse events 
All AEs, regardless of seriousness or relationship to IMP / NIMP, spanning from the signature of 
the informed consent form until the end of the study as defined by the protocol for that patient, are 
to be recorded on the corresponding page(s) or screen(s) of the 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 or by 
the study procedure(s).  
The Investigator should take appropriate measures to follow all AEs until clinical recovery is 
complete and laboratory results have returned to normal, or until progression has been stabilized, 
in order to ensure the safety of the patients or until death. This may imply that observations will 
continue beyond the last planned visit per protocol, and that additional investigations may be 
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requested by the monitoring team up to as noticed by the Sponsor. When treatment is prematurely 
discontinued, the patient’s observations will continue until the end of the study as defined by the 
protocol for that patient.   
Laboratory, vital signs, or ECG abnormalities are to be recorded as AEs only if: 
x Symptomatic and/or,  
x Requiring either corrective treatment or consultation, and/or. 
x Leading to IMP discontinuation or modification of dosing, and/or, 
x Fulfilling a seriousness criterion, and/or 
x Defined as an AESI with immediate notification. 
See Section 17, Appendix D for summary of AE reporting guidelines. 
10.4.3 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator must immediately: 
x ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the e-CRF; the system will automatically send a notification to the Sponsor after approval 
of the Investigator within the e-CRF or after standard delay.   
x SEND (within 24 hours, preferably by fax or e-mail) the signed and dated corresponding 
page(s) from the CRF to the Sponsor’s name, fax number and e-mail address appear in the 
clinical trial protocol. Care must 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 a 
source document provided to the Sponsor. For laboratory result, include the laboratory 
normal range.  
x All further data updates should be recorded in the e-CRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc.) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of acknowledge. In addition, every effort must be made to further 
document any SAE that is fatal or life threatening within a week (7 days) following the 
initial notification.  
x A back-up plan will be used (using paper flow) when the e-CRF system does not work.  
Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the Sponsor.  
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10.4.4 Guideline for reporting adverse events of special interest 
10.4.4.1 Reporting of adverse events of special interest (AESI) with immediate notification 
For AESI, the Sponsor must be informed immediately (i.e., within 24 hours), as per SAEs 
notification described in Section 10.4.3, even it not fulfilling a seriousness criterion, using the 
corresponding screens in the e-CRF.  
x 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 other 
physician(s) for further evaluation of hypersensitivity/allergy, as per the Investigator’s 
medical judgement or as per Section 10.6.2., should be reported as an AESI with 
immediate notification.  
- 
All general allergic events, and all injection site reactions having an allergic 
component or deemed to be allergic, require completion of the specific e-CRF screen 
(see Section 10.6.2), regardless of requirements for immediate reporting.  
x Hemolytic anemia (See Appendix F) 
- 
If there is a decrease in hemoglobin and reflexive testing as per Section 17, Appendix 
F suggesting hemolysis, then report this as AESI with immediate notification. Special 
e-CRF screen will need to be completed.  
x Pregnancy 
- 
Pregnancy occurring in a female patient or the partner of a male patient included in the 
clinical trial. Pregnancy will be recorded as an AESI with immediate notification in all 
cases. It will be qualified as an SAE only if it fulfills the SAE criteria.   
- 
In the event of pregnancy of a female patient included in the clinical trial, IMP should 
be discontinued.  
- 
The follow-up of the pregnancy will be mandatory until the outcome has been 
determined.  
x Symptomatic Overdose with IMP/NIMP 
- 
An overdose (accidental or intentional) with the IMP/NIMP is an event suspected by 
the Investigator or spontaneously notified by the patient (not based on systematic 
injection counts). 
- 
An overdose with the IMP/NIMP is defined as at least twice of the intended dose 
within the intended therapeutic interval (e.g., 2 or more injections from the double-
blind treatment kit are administered in <7 calendar days).  
- 
The symptomatic overdose events should be reported using the corresponding screens 
in the e-CRF using the Term “symptomatic overdose (accidental or intentional)”. The 
circumstances of the overdose should be clearly specified in the verbatim and 
symptoms, if any, entered on separate AE forms.  
- 
The patient should be monitored and appropriate symptomatic treatment instituted. 
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x Neurological (and Neurocognitive) Events:  
- 
Neurologic (and Neurocognitive) Events that require additional examinations / 
procedures and/or referral to a specialist should be reported as an AESI with 
immediate notification (see Section 17, Appendix D).  
x Ophthalmologic Events: 
- 
Ophthalmologic Events that require additional examinations/procedures and/or referral 
to a specialist should be reported as an AESI with immediate notification.  
10.4.4.2 Reporting of adverse events of special interest without immediate notification 
For these AEs, the Sponsor does not have to be informed immediately, unless meeting seriousness 
criterion.  
x ALT 3 ULN (if baseline ALT <ULN) or ALT 2 times the baseline value (if baseline 
ALT ULN) (Please refer Section 17, Appendix E, Increase in ALT). 
x Asymptomatic overdose with IMP/NIMP. 
- 
An overdose (accidental or intentional) with the IMP/NIMP is an event suspected by 
the Investigator or spontaneously notified by the patient (not based on systematic 
injection counts). 
- 
An overdose with the IMP/NIMP is defined as at least twice of the intended dose 
within the intended therapeutic interval (e.g., 2 or more injections from the double-
blind treatment kit are administered in <7 calendar days).  
- 
Asymptomatic overdose events should be reported using the corresponding screens in 
the e-CRF using the Term “asymptomatic overdose (accidental or intentional)”. The 
circumstances (i.e., accidental or intentional) and the lack of symptoms (i.e., 
asymptomatic) should be clearly specified in the verbatim.   
- 
The patient should be monitored if necessary. 
Local injection site reaction (See Section 10.6.1) 
- 
Local injection site reactions that are considered as non-allergic events should be 
further characterized by evaluation of the related symptoms comprising injection site 
reactions such as but not limited to redness, pain, etc. (See Section 17, Appendix H). 
Special e-CRF screens will need to be completed. If such AEs do not occur, then do 
not report the individual components of the reaction but rather the term “local injection 
site reactions”, the individual components being described in the specific e-CRF 
screen. 
x General allergic reactions or local injection site reactions deemed to be allergic or with 
allergic component not referred for consultation with another physician. 
- 
All allergic events will need to have allergy specific e-CRF screens completed (see 
Section 10.6.2), regardless of requirements for immediate reporting.  
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x Skeletal muscle-related events:  
- 
Any AEs related to skeletal muscle abnormalities, including myalgia, muscle spasms 
and stiffness, musculoskeletal discomfort and stiffness, back pain, muscular weakness, 
and muscle fatigue.  
x Neurological (and Neurocognitive) events: 
- 
Any AEs related to neurologic (and neurocognitive) abnormalities with the exception 
of those requiring additional examinations/procedures and/or referral to a specialist 
(see Section 10.4.4.1).  
x Ophthalmologic events: 
- 
Any AEs related to ophthalmologic abnormalities with the exception of those requiring 
additional examinations/procedures and/or referral to a specialist should be reported 
10.4.5 Guidelines for management of specific laboratory abnormalities 
Laboratory abnormalities with pre-specified monitoring should be monitored, documented, and 
managed according to the flowchart shown in Section 17, Appendix E and Appendix F.  
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices:  
x Neutropenia. 
x Thrombocytopenia. 
x Increase in ALT. 
x Acute renal insufficiency. 
x Increase in CPK and suspicion of rhabdomyolysis.  
Decrease in hemoglobin (defined as 1.5 g/dL) (see Section 10.4.5.1, Hemoglobin decrease). 
10.4.5.1 Hemoglobin decrease 
See Section 17, Appendix F.  
At the first post-randomization occurrence of a hemoglobin (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 hemoglobin and reticulocyte decrease has been detected. The Central Lab will then 
provide the results of the reticulocyte count, haptoglobin, LDH, and indirect bilirubin (reflexively 
measured only if the total bilirubin >ULN) to the Investigator. 
x If the following patterns of abnormalities are noted: 
- 
Reticulocyte count >Central Lab’s upper limit of the reference range (also referred to 
as ULN)  
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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.  
x If the results are normal or the pattern of abnormality is something other than that 
described above, then Investigator should exercise his/her medical judgement in the 
interpretation of the results, necessity of workup of the decrease in hemoglobin or referral 
to a hematologist.  
x If as second hemoglobin measurement demonstrating a further decrease 1g/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.  
10.4.6 Summary of adverse event reporting instructions 
Section 17 Appendix D shows the summary of the reporting instructions of adverse events 
described above. 
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 committees (IECs) / institutional 
review boards (IRBs) 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 IB.  
Any other AE not listed as an expected event in the IB will be considered as unexpected. 
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. 
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The Sponsor will report all safety observations made during the conduct of the trial in the CSR.  
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 judgement. See Section 17, Appendix 
H for further information.  
AEs that are obviously not of allergic origin (e.g., 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 and General Allergic Reaction 
Complementary Form should be completed.   
10.6.2 Allergic adverse events 
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 dubious 
significance. These reactions would not be considered to be allergic reactions. Adverse events that 
may constitute an allergic reaction (e.g., 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, etc.) should be considered to be reported on the General Allergic Reaction and/or Local 
Injection Site Reaction Complementary Form.  
Adverse events that are obviously not of allergic origin (e.g., local injection site reactions related 
to mechanics of injection) should only be recorded on the Local Injection Site Reaction 
Complementary Form. However, injection site reactions that progress/expand/worsen/etc. should 
be evaluated as recommended in Section 10.6.2.1 and the 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 or injection site reactions 
which progress/expand/worse/etc., should be evaluated by dermatologist as soon as possible, and 
preferably within one week of the study 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 
hematology, chemistry, Liver panel, PK, and anti-alirocumab antibodies should be obtained. If 
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possible, the investigator will take pictures of the skin lesions in order to provide the patient with 
the abnormal skin images for the dermatologist’s visit. If the photographs of skin lesions are 
obtained, then the photocopies should be kept as source documents with may later be collected by 
the Sponsor. The Investigator will provide 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; 1) a detailed description of the rash 
(such as the morphology [lesion type], shape of individual lesions, arrangement of multiple 
lesions [e.g., scattered, grouped, linear, etc.], distribution, color, consistency, presence of pruritus 
or pain, and other clinical signs): 2) Findings of the skin biopsy (including histopathology and 
immunofluorescence) if it was deemed necessary as per the dermatologist’s or Investigator’s 
medical judgement; and 3) 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 
Sponsor within 24 hours.  
10.6.2.2 Acute allergic reactions of IMP injection 
See also Section 10.4. 
Acute allergic reactions of IMP injection (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 (e.g., antihistamines, bronchodilators, saline, corticosteroids, 
acetaminophen, and epinephrine) must be available for immediate use for the injections at the 
study site.  
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 AE is 
observed. Patients are to remain at the study 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 and all deaths 
The following suspected or confirmed CV events that occur from randomization until end of the 
study should have a corresponding specific e-CRF page +/- adjudication package prepared (as per 
the study site manual) and will be submitted to the CEC: 
x Myocardial infarction. 
x Congestive heart failure requiring hospitalization. 
x Cerebrovascular events (e.g., stroke, transient ischemic attack, intracranial hemorrhage, 
ischemia or bleeding of spine or retina).  
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x Unstable angina requiring an emergency room visit or requiring / prolonging 
hospitalization. 
x All coronary revascularization procedures (e.g., PCI and CABG). 
x All deaths (including CHD death). 
All suspected or confirmed CV 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 (e.g., unstable angina leading to PCI should be reported as ‘unstable angina’ 
instead of ’PCI’).  
10.6.4 Laboratory alert related to two consecutive calculated LDL-C <25 mg/dL 
(0.65 mmol/L) 
The process described in this section and Appendix I includes specific assessment and monitoring 
in all patients, who achieve two consecutive calculated LDL-C values <25 mg/dL (0.65 mmol/L) 
(any time after randomization). The safety and benefit below this level has not yet been 
established. An independent external academic physician(s) (also known as independent 
physician) and a dedicated DMC member will be the coordinators of this specific monitoring.  
Please see Appendix I for an outline of the process. 
Sites may receive an alert related to 2 consecutive calculated LDL-C <25 mg/dL (0.65 mmol/L) 
during the study. These alerts may pertain to true alerts or sham alerts. A sham alert is one in 
which the patients does not meet the criteria related to 2 consecutive calculated LDL-C <25 
mg/dL (0.65 mmol/L) (see Appendix I for criteria for an alert). Sham alert are necessary in order 
to maintain the integrity of the blind (See Section 8.3.1.1).  
Once an alert is received, the Investigator should follow the recommended steps as outlined 
below: 
x Call the patient as soon as possible to inquire about interval occurrence of AEs. 
x Decide whether the patient should be requested to rapidly have an unscheduled site visit, 
or assessment could be done at the next scheduled visit.  
x At the site visit, plan for the following, based on Investigator’s medical judgment: 
- 
Assess the need for conducting clinical investigations, arranging specialist 
consultation(s) as needed, and any relevant additional work-up.  
- 
Assess the need for study treatment temporary or permanent discontinuation, or 
continuation. 
- 
Regardless of action taken regarding study treatment, the patient should continue the 
study as per Section 10.3. 
  
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10.7 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final CSR.  
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11 
STATISTICAL CONSIDERATIONS 
11.1 
DETERMINATION OF SAMPLE SIZE 
 
The study is expected to enroll approximately 159 patients. 
 
Two pairwise comparisons will be performed (alirocumab 150 mg Q4W versus placebo and 
alirocumab 150 mg Q2W vs. placebo). In order to handle multiple comparisons Bonferroni 
adjustment will be used, i.e., the alpha level for each comparison is 0.025 to obtain an overall 
study alpha level of 0.05. 
 
A sample size of 38 patients in the ITT population (19 in alirocumab group and 19 in placebo 
group) will have 90% power to detect a difference of 30% in mean percentage change in 
calculated LDL-C in any pairwise comparison with a 0.025 two-sided significance level and 
assuming a common standard deviation of 25%. 
 As a result, the total sample size 
needed for efficacy will be 57 patients (19 in each of the two alirocumab arms and 19 in the 
placebo arm). 
 
 
The sample size is also considered in order to obtain long-term safety data. A sample size of 
159 patients (randomization ratio 1: 1: 1, i.e., 53 in alirocumab 150 mg Q4W, 53 in alirocumab 
150 mg Q2W, and 53 in placebo) will allow having long-term open-label safety data.  With this 
sample size, 100 patients are expected to be exposed to alirocumab for a minimum of 12 months 
providing that the proportion of drop out in the entire study duration (from randomization to 
Week 64) is 36%, which is obtained using exponential distribution with the same hazard as that of 
30% dropout rate within 12 months. Moreover, with 100 patients treated with alirocumab for at 
least 12 months, AEs with a rate 0.03 will be detected with 95% probability.  
 
Therefore, 159 patients (53 in alirocumab 150 mg Q4W, 53 in alirocumab 150 mg Q2W, and 53 
in placebo) will be needed to evaluate both efficacy and safety.  
 
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 patients, with a treatment kit number allocated and recorded in 
IWRS database, and regardless of whether the treatment kit was used or not.  
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Patients treated without being randomized or treated with a double-blind or open-label treatment 
kit before the randomization will not be considered as randomized and will not be included in any 
analysis population.   
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. 
11.3 
ANALYSIS POPULATIONS 
Randomized population includes any patients who have been allocated to a randomized treatment 
regardless of whether the treatment kit was used or not. 
11.3.1 Efficacy populations 
The primary efficacy analysis population will be the intent-to-treat (ITT population, as defined 
below.  
11.3.1.1 Intent–to-treat (ITT) population 
The ITT population is defined as the randomized population who has an evaluable primary 
endpoint. The primary efficacy endpoint is evaluable when both of the following conditions are 
met:  
x Availability of at least 1 value for calculated LDL-C before the first dose of double-blind 
IMP (i.e., baseline).  
x Availability of at least 1 value for calculated LDL-C within one of the following analysis 
windows: Week 4, Week 8, Week 10, and Week 12. 
Patients in the ITT population will be analyzed according to the treatment group allocated by 
randomization.  
11.3.1.2 Modified intent-to-treat (mITT) population 
The mITT population is defined as the randomized population who took at least one dose or part 
of dose of the double-blind IMP injection and has an evaluable primary efficacy endpoint during 
the efficacy double-blind treatment period. The primary efficacy endpoint will be considered 
evaluable when both of the following conditions are met: 
x Availability of at least 1 value for calculated LDL-C before the first dose of double-blind 
IMP (i.e., baseline). 
x Availability of at least 1 value for calculated LDL-C within one of the following analysis 
window: Week 4, Week 8, Week 10, and Week 12 during the efficacy double-blind 
treatment period.  
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The efficacy double-blind treatment period will be defined as:  
x The time period from the first double-blind IMP injection up to 21 days after the last 
double-blind IMP injection (i.e., up to Week 12).  
Patients in the mITT population will be analyzed according to the treatment group allocated by 
randomization.  
11.3.2  Safety population 
The safety population consists of the randomized population who actually received at least one 
dose or partial dose of IMP. The safety population will be analyzed according to the treatment 
actually received. 
In addition:  
x Non-randomized but treated patients will not be part of the safety population, but their 
safety data will be presented separately.  
x Randomized patients for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized. 
x For patients receiving IMP from more than one treatment group during the trial, the 
treatment group allocation for as-treated analysis will be the one to which the patient was 
treated with the longest duration.  
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 
post first double-blind IMP injection.   
The PK analysis will be performed on all treated patients (safety population) with at least one 
evaluable blood sample for PK post the first double-blind IMP injection.  
 
11.4 
STATISTICAL METHODS 
Statistical methods are briefly described here and will be detailed in the SAP of the study.  
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. 
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11.4.1.1 Extent of investigational medicinal product exposure 
The total exposure will be assessed by: 
x Duration of IMP 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.   
x The number (n) and percentage (%) of patients with an up-titration from alirocumab 150 
mg Q4W to alirocumab 150 mg Q2W.  
11.4.1.2 Compliance  
Compliance will be assessed using the injection frequency defined for each patient as the average 
number of days between 2 injections, that is: (last injection date - first injection date) / (number of 
injections - 1) and will be summarized descriptively (N, Mean, SD, Median, Min and Max).  
11.4.2 Analyses of efficacy endpoints 
The analysis of the primary efficacy endpoint and the secondary efficacy endpoints up to Week 12 
will have been conducted at the time of first analysis only.
 
 
11.4.2.1 Analysis of primary efficacy endpoint(s) 
See also Section 9.1.1. 
The primary efficacy endpoints, percentage change in calculated LDL-C from baseline to 
Week 12 will be analyzed in the ITT population using mixed-effect model with repeated measures 
(MMRM) approach. All post-baseline data available within Week 4, Week 8, Week 10, and 
Week 12 analysis windows will be used (on-treatment and off-treatment through Week 12) and 
missing data will be accounted for by the MMRM model. 
The model will include the fixed categorical effects of treatment group (placebo, alirocumab 
150 mg Q4W, and alirocumab 150 mg Q2W), time point (Week 4, Week 8, Week 10, and Week 
12), stratification factor of statin (Yes/No), treatment-by-time point interaction and statin-by-time 
point interaction, as well as the continuous fixed covariates of baseline calculated LDL-C value, 
and baseline value-by-time point interaction.  
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 least-squares 
means (LS means) estimates at Week 12 for each treatment group with their corresponding 
standard errors (SEs). Let μ0 and μ1 be the population means of the percentage change from the 
baseline in calculated LDL-C at Week 12 under placebo and alirocumab, respectively. The 
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hypothesis that will be tested is “H0: μ0 = μ1” versus H1: “μ0 z  μ1”. Each alirocumab arm will be 
compared to placebo group (at significance level of 2.5%) using appropriate contrasts, and the 
97.5% confidence interval (CI) of the difference will be provided. 
  
Subgroup analyses will be performed in order to assess the consistency of the treatment effect 
within stratification factor of statin (Yes/No). 
11.4.2.2 Analyses of secondary efficacy endpoints  
See also Section 9.1.2. 
For the key secondary efficacy endpoints (defined in Section 9.1.2.1) and the other secondary 
efficacy endpoints (described in Section 9.1.2.2), 
and analyses will be 
performed in the ITT population or mITT population, depending on the specified estimand.  
 
 
 
 
 
 
 
  
A hierarchical procedure will be used for each pairwise comparison to control the type I error and 
to handle for multiple endpoints. If the primary endpoint analysis is significant at the 2.5% alpha 
level, the key secondary endpoints will be tested sequentially at the 0.025 level, using the order 
defined in Section 9.1.2.1. Comparisons of alirocumab 150 mg Q2W versus placebo, and 
alirocumab 150 mg Q4W versus placebo will be processed in parallel.   
 
Continuous endpoints anticipated to have a normal distribution  
 
Continuous secondary endpoints anticipated to have a normal distribution [i.e., 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.  
 
The percentage change in calculated LDL-C from baseline to averaged Week 10 - 12 will be 
analyzed using an appropriate contrast statement (assigning a weight of 0.5 for the two time 
points) from the MMRM model.   
 
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Continuous endpoints anticipated to have non-normal distribution 
 
Continuous secondary endpoints anticipated to have a non-normal distribution [i.e., Lp(a) and 
TG] will be analyzed using multiple imputation approach for handling of missing values followed 
by robust regression model(38) (i.e., ROBUSTREG SAS procedure with M-estimation option) 
with treatment group and stratification factor of statin 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 a 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 
each alirocumab group and placebo group will be provided with the SE, 97.5% confidence 
interval and p-value. 
 
Binary endpoints 
 
Binary secondary endpoints will be analyzed using multiple imputation approach for handling of 
missing values followed by logistic regression. In the data dependent case that the logistic 
regression method is not applicable (e.g., the response rate is zero in 1 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 between each alirocumab group and 
placebo group.   
 
Comparison of alirocumab 150 mg Q4W vs. alirocumab 150 mg Q2W 
 
For a descriptive purpose, the difference of percentage change of calculated LDL-C between 
baseline and Week 12, and between the two alirocumab arms Q4W and Q2W will also be derived, 
with a 95% CI. 
11.4.2.3 Multiplicity considerations 
The multiplicity appears in two kinds in this study, due to the presence of the 2 arms of 
alirocumab 150 mg Q4W and 150 mg Q2W that are compared with placebo, and due to the 
multiple key secondary efficacy endpoints.  
The overall type I error will be controlled at 0.05 by performing each pairwise test (alirocumab 
150 mg Q4W vs. placebo, and alirocumab 150 mg Q2W vs. placebo) for the main efficacy 
endpoint at the 0.025 level.  
Then, a hierarchical procedure will be used for each pairwise comparison to control the type I 
error and to handle multiple endpoints. If the primary endpoint analysis is significant at the 2.5% 
alpha level, the key secondary efficacy endpoints will be tested sequentially at the 0.025 level, 
using the order defined in Section 9.1.2.1.  Hierarchical procedure for comparisons of alirocumab 
150 mg Q4W versus placebo, and alirocumab 150 mg Q2W versus placebo will be processed 
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No further adjustments will be made for other secondary endpoints for which p-values will be 
provided for descriptive purpose only (no claim).  
In addition, no further adjustment will be made for multiple analyses (i.e., first and second 
analyses), since the primary efficacy endpoint and the key secondary efficacy endpoints up to 
Week 12 will have been conducted at the time of first analysis only.
 
  
11.4.3 Analyses of safety data  
See also Section 9.2. 
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 rule:  
x The baseline value is defined generally as the last available value before the first double-
blind IMP injection. For analyses of changes from baseline for laboratory and vital signs 
parameters, baseline of the last available value before double-blind or open-label IMP 
injection may be considered.  
 
Safety analyses will be conducted using data of the DBTP. Besides, safety analyses using data of 
the DBTP and the OLTP (from the first double-blind IMP injection for alirocumab 150 mg Q4W 
group and alirocumab 150 mg Q2W group, and from the first open-label IMP injection for 
placebo group) will be conducted to evaluate long-term safety.  
 
The following definitions will be applied to laboratory parameters and vital signs:  
x 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. 
x The PCSA criteria will determine which patients had at least 1 PCSA during the TEAE 
period, taking into account all evaluations performed during the TEAE period, including 
unscheduled or repeated evaluations. The number of all such patients will be the 
numerator for the PCSA percentage.  
 
Adverse events (AE) definition:  
x Pre-treatment AEs are AEs that develop, worsen, or become serious during the PRE-
TREATMENT period. 
x Treatment-emergent AEs (TEAEs) are AEs that develop, worsen, or become serious 
during TEAE period.   
x Post-treatment AEs are AEs that develop, worsen, or become serious during the POST-
TREATMENT period. 
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Drug-induced liver injury: 
Liver function tests, namely ALT, AST, ALP, 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 will be 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 
preferred terms will be based on standardized MedDRA query (SMQ) Hepatic disorder.  
11.4.3.1 Adverse events  
See also Section 9.2.1. 
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), all treatment 
emerged SAEs, and all TEAEs leading to permanent treatment discontinuation.  
If any clinically significant signal is detected and requires further characterization, or AE of 
clinical interest, exploration of time to onset will be performed for these selected TEAEs.  
Death: 
The following deaths summaries will be generated: 
x Number (%) of patients who died by the study period (TEAE, on-study, post-study) 
summarized on the safety population by treatment received. 
x Death in non-randomized patients, or randomized and not treated patients.   
x 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 CV 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.  
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11.4.3.2 Laboratory data and vital signs  
See also Section 9.2.2 and Section 9.2.3. 
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 time point, 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: 
x Normal / missing. 
x 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.  
11.4.3.3 Analyses of other endpoints  
See also Section 9.3. 
All analyses for other endpoints will be performed on the Safety population unless otherwise 
specified. The baseline value is defined as the last available value before the first double-blind 
IMP. 
The number and percentage of patients with 2 consecutive calculated LDL-C <25 mg/dL 
 will be provided by treatment group. 
 
 
The antibody status (positive / negative), antibody titers, and neutralizing antibody status will be 
summarized by treatment group and time point using descriptive statistics.
 
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11.4.4 Analyses of pharmacokinetic and pharmacodynamic variables  
See also Section 9.3.3. 
Serum total alirocumab concentrations, total and free PCSK9 concentrations will be summarized 
by treatment group and time point using descriptive statistics. Serum concentration time profiles 
will be provided by treatment group. 
 
 
Further details will be provided in SAP. 
11.5 
TIMING OF ANALYSES 
The analysis will be conducted in two steps. In Japan, data up to 24 weeks are required for the 
drug application.  
11.5.1 First step: Efficacy and safety analyses using data up to 24 weeks after 
randomization (including 12 weeks double-blind).  
The first analysis will be conducted when all patients have been randomized and have at least all 
their data up to Week 24 (including 12 weeks DBTP and 12 weeks OLTP) collected and validated, 
and will consist in the final analysis of the primary and secondary efficacy endpoints up to 
Week 12 (Section 9.1).
 The safety analysis will be performed on all safety 
data up to Week 24 collected and validated. 
The results of the first analysis will not be used to change the conduct of the ongoing study in any 
aspect. Since primary and key secondary efficacy endpoints analysis up to Week 12 will have 
been analyzed concluded in all patients at the time of this first analysis, the significance level will 
be 0.025 for each comparison between the alirocumab group and placebo group. 
11.5.2 Second step: Long-term safety and efficacy exploratory analysis 
The second analysis will be conducted at the end of the study with all data including the data of 
the OLTP, and will consist in the final analysis of the safety endpoints and exploratory efficacy 
assessment during the OLTP. 
 
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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 sub-Investigator, 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 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.  
If genotyping is conducted, patient’s consent for genotyping is required and signed written 
informed consent for genotyping must be obtained prior to genotyping.  
The ICF and the optional written ICF for pharmacogenetics 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.  
Prior to collection of blood for pharmacogenetics, the optional 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 person who conducted the informed consent discussion. A copy 
of the signed and dated written optional ICF will be provided to the subject.  
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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 Ethics Committee (IRB / IEC), and is required to forward to the 
respective other party  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, informed consent form, Investigator’s Brochure, Investigator’s 
curriculum vitae [CV], 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 
Investigator’s Brochure 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(s) and delegated Investigator staff undertake(s) to perform the Clinical Trial in 
accordance with this Clinical Trial Protocol, ICH guidelines for GCP and the applicable 
regulatory requirements. 
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 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 sub-
Investigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All sub-Investigators shall be appointed and listed in a timely manner. The sub-
Investigators 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 health 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 CRFs. Thus, the main 
duty of the monitoring team is helping the Investigator and the Sponsor to 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. 
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13.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH guidelines for GCP, the monitoring team must check the CRF entries 
against the source documents, except for the pre-identified source data directly recorded in the 
CRF. The ICF will include a statement by which the patient allows the Sponsor’s duly authorized 
personnel, the Ethics Committee (IRB / IEC), and the regulatory authorities to have direct access 
to original medical records which support the data on the CRFs (e.g., patient's medical file, 
appointment books, original laboratory records, etc.). 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 (CRFS) AND ADDITIONAL 
REQUEST 
It is the responsibility of the Investigator to maintain adequate and accurate 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 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 when available in the e-CRF 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 system used for the study is provided in a separate document 
which is maintained as the Sponsor and Investigator study files.  
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14 
ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
The latest copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and sub-Investigator will be 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 
 
 
 
 
 
 
 
 
 
 
 
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14.4 
PROPERTY RIGHTS 
 
 
 
 
 
 
 
 
 
 
 
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 issues / 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  
Premature discontinuation of the study is decided by the Sponsor in the following case: 
x If the information on the product leads to doubt as to the benefit/risk ratio. 
Premature close-out of a site is decided by the Sponsor in the following cases: 
x If the Investigator has received all IMP, means and information necessary to perform the 
clinical trial from the Sponsor and has not included any patient after a reasonable period of 
time mutually agreed upon. 
x In the event of breach by the Investigator of a fundamental obligation under this agreement, 
including but not limited to breach of the clinical trial protocol, breach of the applicable 
laws and regulations, or breach of the ICH guidelines on GCP. 
x If 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 must notify 30 days in advance the Sponsor of his/her decision to prematurely 
close-out her/his site and give the reason in writing.  
In all cases (decided by the Sponsor or by the Investigator), the appropriate Ethics Committee(s) 
(IRB / IEC) and Health Authorities should be informed according to applicable regulatory 
requirements.  
14.9 
CLINICAL TRIAL RESULTS 
The Sponsor will be responsible for preparing a CSR and to provide a summary of study results to 
the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made parts 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 informed consent form. The 
Investigator must receive an IRB / IEC approval/favorable opinion concerning the revised 
informed consent form prior to implementation of the change and patient signature should be re-
collected if necessary. 
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16 
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low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis 
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management of familial hypercholesterolemia. J Atheroscler Thromb. 2012;19(12):1043-60. 
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simvastatin among patients with and without prior cardiovascular disease: a US managed care 
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prevention, and management of statin adverse effects and intolerance: proceedings of a 
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associated muscle toxicity in Japan: a cohort study conducted using claims database and 
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Atorvastatin Study (J-CLAS) Group. Am J Cardiol. 1997;79(9):1248-52. 
19. Fenofibrate, bezafibrate Package insert in Japan. 
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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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25. 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. 
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and protection against coronary heart disease. N Engl J Med. 2006;354(12):34-42. 
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variants in PCSK9 in the Japanese population: Rare genetic variants in PCSK9 might 
collectively contribute to plasma LDL cholesterol levels in the general population. 
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28. 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. 
29. Rey J, Poitiers F, Paehler T, Brunet A, Pinquier JL, Hanotin C, et al. Randomized, Partial 
Blind Study of the Pharmacodynamics, Pharmacokinetics and Safety of Multiple 
Subcutaneous Doses of Alirocumab, a Fully Human Monoclonal Antibody to Proprotein 
Convertase Subtilisin/Kexin Type 9, Administered Every 4 Weeks Alone or in Combination 
with Ezetimibe or Fenofibrate in Healthy Subjects. poster ACC 2014 March 29-31, 
Washington, DC, USA. 
30. 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. 
31. Alirocumab CIB Ed. 8 (May 2015) 
32. 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. 
33. Stein EA, Mellis S, Yancopoulos GD, Stahl N, Logan D, Smith WB, et al. Effect of a 
Monoclonal Antibody to PCSK9 on LDL Cholesterol. N. Engl J Med. 2012;366:1108-18. 
34. Berthold HK, Seidah NG, Benjannet S, Gouni-Berthold I. Evidence from a randomized trial 
that simvastatin, but not ezetimibe, upregulates circulating PCSK9 levels. PLoS One. 
2013;8(3):e60095. 
35. Noguchi T, Kobayashi J, Yagi K, Nohara A, Yamaaki N, Sugihara M, et al. Comparison of 
effects of bezafibrate and fenofibrate on circulating proprotein convertase subtilisin/kexin type 
9 and adipocytokine levels in dyslipidemic subjects with impaired  glucose tolerance or type 2 
diabetes mellitus: results from a crossover study. Atherosclerosis. 2011; 217(1):165-70. 
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37. Friedewald WT, Levy R I, Fredrickson DS. Estimation of the concentration of Low-Density
Lipoprotein Cholesterol in Plasma, without use of the preparative ultracentrifuge. Clinical
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SAP_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-002643 VERSION 5.0 (27-JUL-2015) 
Page 1
STATISTICIAN:
DATE OF ISSUE: 17-Jun-2016 
Total number of pages: 
68 
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STATISTICAL ANALYSIS PLAN 
A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to 
Evaluate the Efficacy and Safety of Alirocumab in Patients with 
Hypercholesterolemia Not Adequately Controlled with Non-statin Lipid Modifying 
Therapy or the Lowest Strength of Statin  
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Statistical Analysis Plan  
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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...................................................................................................................................8 
1.2.1 
Primary objectives............................................................................................................................8 
1.2.2 
Secondary objectives .......................................................................................................................8 
1.3 
DETERMINATION OF SAMPLE SIZE.............................................................................................8 
1.4 
STUDY PLAN...................................................................................................................................9 
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...................................................................................................12 
2.1.3 
Efficacy endpoints ..........................................................................................................................13 
2.1.3.1 
Primary efficacy endpoint...............................................................................................................14 
2.1.3.2 
Secondary efficacy endpoints ........................................................................................................14 
2.1.4 
Safety endpoints.............................................................................................................................15 
2.1.4.1 
Adverse events variables ...............................................................................................................17 
2.1.4.2 
Deaths............................................................................................................................................20 
2.1.4.3 
Laboratory safety variables ............................................................................................................20 
2.1.4.4 
Vital signs variables........................................................................................................................21 
2.1.4.5 
Electrocardiogram variables...........................................................................................................22 
2.1.5 
Other endpoints..............................................................................................................................22 
2.1.6 
Anti-alirocumab antibodies variables .............................................................................................22 
2.1.7 
Pharmacokinetic variables .............................................................................................................23 
2.1.8 
Pharmacodynamic/genomics endpoints ........................................................................................24 
2.1.9 
Quality-of-life endpoints..................................................................................................................24 
2.1.10 
Health economic endpoints............................................................................................................24 
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2.2 
DISPOSITION OF PATIENTS .......................................................................................................24 
2.2.1 
Randomization and drug dispensing irregularities .........................................................................27 
2.3 
ANALYSIS POPULATIONS ...........................................................................................................27 
2.3.1 
Efficacy populations .......................................................................................................................28 
2.3.1.1 
Intent–to-treat population ...............................................................................................................28 
2.3.1.2 
Modified intent-to-treat population..................................................................................................28 
2.3.2 
Safety population............................................................................................................................28 
2.3.3 
Anti-alirocumab antibody population ..............................................................................................29 
2.3.4 
Pharmacokinetics population .........................................................................................................29 
2.3.5 
Open-label treatment population....................................................................................................29 
2.3.6 
Alirocumab safety population .........................................................................................................29 
2.4 
STATISTICAL METHODS .............................................................................................................29 
2.4.1 
Demographics and baseline characteristics ..................................................................................29 
2.4.2 
Prior, concomitant, or post-treatment medications ........................................................................30 
2.4.3 
Extent of investigational medicinal product exposure and compliance..........................................31 
2.4.3.1 
Extent of investigational medicinal product exposure ....................................................................31 
2.4.3.2 
Compliance ....................................................................................................................................33 
2.4.4 
Analyses of efficacy endpoints.......................................................................................................34 
2.4.4.1 
Analysis of primary efficacy endpoint(s).........................................................................................34 
2.4.4.2 
Analyses of secondary efficacy endpoints .....................................................................................37 
2.4.4.3 
Multiplicity issues............................................................................................................................40 
2.4.4.4 
Additional efficacy analysis ............................................................................................................41 
2.4.5 
Analyses of safety data ..................................................................................................................41 
2.4.5.1 
Analyses of adverse events ...........................................................................................................42 
2.4.5.2 
Deaths............................................................................................................................................45 
2.4.5.3 
Analyses of laboratory variables ....................................................................................................46 
2.4.5.4 
Analyses of vital sign variables ......................................................................................................48 
2.4.5.5 
Analyses of electrocardiogram variables .......................................................................................49 
2.4.6 
Analyses of other endpoints...........................................................................................................49 
2.4.7 
Analyses of anti-alirocumab antibodies variables ..........................................................................50 
2.4.8 
Analyses of pharmacokinetic and pharmacodynamic variables ....................................................50 
2.5 
DATA HANDLING CONVENTIONS...............................................................................................51 
2.5.1 
General conventions ......................................................................................................................51 
2.5.2 
Data handling conventions for secondary efficacy variables..........................................................52 
2.5.3 
Missing data ...................................................................................................................................52 
2.5.4 
Windows for time points.................................................................................................................54 
2.5.4.1 
Time points for efficacy data, laboratory safety data, ADA, and PK ..............................................54 
2.5.4.2 
Time points for vital signs...............................................................................................................55 
2.5.5 
Unscheduled visits .........................................................................................................................56 
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2.5.6 
Pooling of centers for statistical analyses ......................................................................................56 
3 
TWO-STEP ANALYSIS .................................................................................................................57 
4 
DATABASE LOCK ........................................................................................................................59 
5 
SOFTWARE DOCUMENTATION..................................................................................................60 
6 
REFERENCES...............................................................................................................................61 
7 
LIST OF APPENDICES .................................................................................................................62 
APPENDIX A POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA .......................63 
APPENDIX B SUMMARY OF STATISTICAL ANALYSES .........................................................................68 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Ab: 
antibody 
ADA: 
Anti-alirocumab antibody 
AE: 
adverse event 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
ANOVA: 
analysis of variance 
Apo A-1: 
apolipoprotein A-1 
Apo-B: 
apolipoprotein B 
AST: 
aspartate aminotransferase 
BMI: 
body mass index 
CEC: 
Clinical Events Committee 
CHD: 
coronary heart disease, coronary heart disease 
CI: 
confidence interval 
CKD: 
chronic kidney disease 
CMQ: 
company MedDRA query 
DBP: 
diastolic blood pressure 
DBTP: 
double-blind treatment period 
ECG: 
electrocardiogram 
e-CRF: 
electronic case report form 
eDISH: 
evaluation of drug-induced serious hepatotoxicity 
EPA: 
ethyl icosapentate 
GFR: 
glomerular filtration rate 
GGT: 
gamma glutamyl transferarses 
HbA1c: 
glycated hemoglobin A1c 
HCV: 
hepatitis C virus 
HCV RNA: 
hepatitis C virus ribonucleic acid 
HDL-C: 
high density lipoprotein cholesterol 
heFH: 
heterozygous familial hypercholesterolemia 
HR: 
heart rate 
IRT: 
Interactive Response Technology 
ITT: 
intent-to-treat 
IWRS: 
Interactive Web Response System 
LDH: 
lactate dehydrogenase 
LDL-C: 
low-density lipoprotein cholesterol 
LLN: 
lower limit of normal range 
LLOQ: 
lower limit of quantification 
Lp(a): 
lipoprotein (a) 
MCMC: 
Markov chain Monte Carlo 
MDRD: 
modification of diet in renal disease 
MedDRA: 
Medical Dictionary for Regulatory Activities 
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mITT: 
modified intent-to-treat 
MMRM: 
mixed-effect model with repeated measures 
niacin: 
nicotinic acid and derivatives 
non HDL-C: 
non-high-density lipoprotein cholesterol 
non-FH: 
non-familial hypercholesterolemia 
OLTP: 
open-label treatment period 
PCSA: 
potentially clinically significant abnormality 
PCSK9: 
proprotein convertase subtilisin/kexin type 9 
PD: 
pharmacodynamics 
PK: 
pharmacokinetics 
Q1: 
first quartile 
Q2W: 
every 2 weeks 
Q3: 
third quartile 
Q4W: 
every 4 weeks 
RDW: 
red blood cell distribution width 
RNA: 
ribonucleic acid 
SBP: 
systolic blood pressure 
SD: 
standard deviation 
SE: 
standard error 
SMQ: 
standardized MedDRA query 
TC: 
total cholesterol 
TEAE: 
treatment-emergent adverse event 
TG: 
triglyceride 
ULN: 
upper limit of normal range 
ULOQ: 
upper limit of quantification 
US: 
United States of America  
 
(electronic 
 
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1 
OVERVIEW AND INVESTIGATIONAL PLAN   
1.1 
STUDY DESIGN AND RANDOMIZATION 
This is a randomized, double-blind, placebo-controlled, parallel-group, balanced (1:1:1, 
Alirocumab 150 mg every 4 weeks (Q4W): Alirocumab 150 mg every 2 weeks (Q2W): Placebo  
Q2W, subcutaneous injection), multi-center phase 3 study to evaluate the efficacy and safety of 
alirocumab in patients with hypercholesterolemia not adequately controlled with non-statin lipid 
modifying therapy (LMT) or the lowest strength of statin. 
After a screening phase of up to 3 weeks, patients will be centrally randomized (using permuted 
block randomization schedule) via Interactive Response Technology (IRT) in a 1:1:1 ratio to 1 of 
the 3 treatment groups. Randomization will be stratified according to background statin therapy 
(Yes/No). “No statin background” will be also stratified according to background 
fibrate/ezetimibe therapy (Yes/No), where ‘Yes’ represents fibrate or ezetimibe, and ‘No’ 
represents diet therapy alone. 
The study consists of 5 periods: run-in, screening, double-blind treatment period (DBTP), open-
label treatment period (OLTP), and follow-up.  
x 
A run-in period of 4 weeks. Patients will be treated by stable non-statin LMTs or stable 
daily atorvastatin 5 mg. Patients who will have already been treated by stable non-statin 
LMTs or stable daily atorvastatin 5 mg for at least 4 weeks will be able to skip this period. 
x 
A screening period of up to 3 weeks. 
x 
A DBTP of 12 weeks. Patients will receive double-blind treatment as follows, 
- 
Alirocumab 150 mg Q4W alternating with placebo Q4W OR 
- 
Alirocumab 150 mg Q2W OR 
- 
Placebo for alirocumab Q2W 
x 
An OLTP of 52 weeks. All patients will receive alirocumab 150 mg Q4W from the start of 
OLTP. At Week 24, the up-titration to alirocumab 150 mg Q2W will be conducted through 
IRT only under the following circumstances: 
- 
In patients with heterozygous familial hypercholesterolemia (heFH) or in patients with 
non-familial hypercholesterolemia (non-FH) with documented coronary heart disease 
(CHD), low-density lipoprotein cholesterol (LDL-C) is 100 mg/dL (2.59 mmol/L) at 
Week 20. 
- 
In patients with non-FH classified as primary prevention category III, LDL-C is 
120 mg/dL (3.10 mmol/L) at Week 20. 
x 
A follow-up period of 8 weeks. 
Approximately 159 subjects (53 subjects per treatment group) will be recruited and randomized 
 
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1.2 
OBJECTIVES 
1.2.1 Primary objectives 
The primary objective of this study is to demonstrate the reduction of LDL-C by alirocumab 
150 mg Q4W or alirocumab 150 mg Q2W regimen as add on therapy to non-statin LMT including 
diet therapy alone or the lowest strength of statin in comparison with placebo after 12 weeks of 
treatment in patients with hypercholesterolemia. 
1.2.2 Secondary objectives 
The secondary objectives are: 
x 
To evaluate the effect of two treatment regimens of alirocumab on other lipid parameters: 
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), 
triglyceride (TG), apolipoprotein A-1 (Apo A-1). 
x 
To evaluate the safety and tolerability of alirocumab 150 mg Q4W and 150 mg Q2W. 
x 
To evaluate the development of anti-alirocumab antibodies 
x 
To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) profiles of 
alirocumab 150 mg Q4W and 150 mg Q2W. 
x 
To evaluate the long-term safety in patients receiving open-label alirocumab 150 mg Q4W 
and 150 mg Q2W. 
1.3 
DETERMINATION OF SAMPLE SIZE 
The study is expected to enroll approximately 159 patients. 
Two pairwise comparisons will be performed (Alirocumab 150 mg Q4W versus Placebo Q2W 
and Alirocumab 150 mg Q2W vs. Placebo Q2W). In order to handle multiple comparisons 
Bonferroni adjustment will be used, i.e., the alpha level for each comparison is 0.025 to obtain an 
overall study alpha level of 0.05. 
A sample size of 38 patients in the ITT population (19 in alirocumab group and 19 in placebo 
group) will have 90% power to detect a difference of 30% in mean percentage change in 
calculated LDL-C in any pairwise comparison with a 0.025 two-sided significance level and 
assuming a common standard deviation of 25%.
As a result, the total sample size 
needed for efficacy will be 57 patients (19 in each of the two alirocumab arms and 19 in the 
placebo arm). 
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The sample size is also considered in order to obtain long-term safety data. A sample size of 159 
patients (randomization ratio 1: 1: 1, i.e., 53 in Alirocumab 150 mg Q4W, 53 in Alirocumab 
150 mg Q2W, and 53 in Placebo Q2W) will allow having long-term open-label safety data.  With 
this sample size, 100 patients are expected to be exposed to alirocumab for a minimum of 12 
months providing that the proportion of drop out in the entire study duration (from randomization 
to Week 64) is 36%, which is obtained using exponential distribution with the same hazard as that 
of 30% dropout rate within 12 months. Moreover, with 100 patients treated with alirocumab for at 
least 12 months, AEs with a rate 0.03 will be detected with 95% probability.  
Therefore, 159 patients (53 in Alirocumab 150 mg Q4W, 53 in Alirocumab 150 mg Q2W, and 53 
in Placebo Q2W) will be needed to evaluate both efficacy and safety. 
1.4 
STUDY PLAN 
 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
Not applicable. 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
Not applicable. 
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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) injection. For patients randomized and 
not treated, the baseline value is defined as the last available value obtained up to randomization. 
All baseline efficacy and safety parameters (apart from those listed below) are presented along 
with the on-treatment summary statistics in the efficacy and safety sections (Section 2.4.4 and 
Section 2.4.5). 
Demographic characteristics 
Demographic variables are gender (Male, Female), race (Asian), age in years (quantitative and 
qualitative variable: <65, 65 to <75, and 75 years; and <65, and 65 years). 
Medical history 
Medical history of special interest includes:  
x 
Coronary heart disease (CHD) 
- 
Myocardial infarction 
- 
Unstable angina 
- 
Coronary revascularization procedures 
- 
Other clinically significant CHD 
x 
Risk factors as categorized in primary prevention category III 
- 
Ischemic stroke 
- 
Peripheral arterial disease 
- 
Diabetes 
 
 
- Type 1 diabetes 
 
 
- Type 2 diabetes 
- 
Chronic kidney disease 
- 
Other risk factors 
 
 
- 10-year fatal CHD risk score2% 
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- 10-year fatal CHD risk score0.5% and <2% 
 
 
 
- Hypo HDL cholesterolemia 
 
 
 
- Family history of premature coronary artery disease 
 
 
 
- Impaired glucose tolerance 
x 
Cardiovascular history and risk factors includes “Coronary heart disease (CHD)” and Risk 
factors as categorized in primary prevention category III” listed above”. 
All medical history information pre-listed or not in the electronic case report form (e-CRF), will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA), currently in effect at 
Sanofi at the time of database lock for the first step analysis (Timing of first step analysis is 
described  in Section 3 ). 
Efficacy and safety analysis performed according to “diabetes status at baseline” reported in the 
Medical history by the investigator will be done using a company MedDRA query (CMQ), based 
on the HLGT "Diabetes Complications", HLT "Diabetes Mellitus" and HLT "Carbohydrate 
tolerance analyses (incl diabetes)" excluding PT "Blood glucose decreased", and using PT 
"hyperglycemia".  
Disease characteristics at baseline 
Specific disease characteristics include: 
x 
Type of hypercholesterolemia:  
- 
Heterozygous familial hypercholesterolemia (heFH) 
- 
Non-familial hypercholesterolemia (non-FH) 
- 
Secondary prevention in non-FH 
- 
Primary prevention category III in non-FH 
x 
For heFH patients: 
- 
Time from diagnosis of heFH (years); 
- 
Diagnosis made by genotyping (Yes, No); 
x 
For non-FH patients: 
- 
Time from diagnosis of hypercholesterolemia (years); 
- 
Fredrickson classification of hyperlipoproteinemia (IIa, IIb, IV); 
x 
 
x 
Reason why statin is not appropriate or why statin dose cannot be increased from the 
lowest strength for the patients 
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x 
Background LMT at randomization, as reported in the dedicated prior and concomitant 
medications e-CRF pages : 
- 
Statin by statin name and dose 
- 
Any LMT other than statins 
- 
Ezetimibe 
- 
Fibrate 
- 
Fenofibrate  
- 
Bezafibrate 
- 
Others 
- 
Diet alone (defined as patients not taking any Fibrate, Ezetimibe nor Statins) 
Other baseline characteristics 
Other baseline characteristics include body mass index (BMI) in kg/m² (quantitative and 
qualitative variable: <25, 25), smoking status, alcohol habits, randomization strata (as defined in 
Section 1.1) as per IRT. 
Glycated hemoglobin A1c (HbA1c) (quantitative and qualitative variable: <5.7, 5.7 to <6.5, 
6.5%), eGFR (quantitative and qualitative variable: <15 , 15 to < 30 , 30 to < 60 , 60 to <90, 
90 mL/min/1.73m2), 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): 
x 
Calculated LDL-C:  <100,  100 to <130, 130 to <160, 160 to <190, 190 mg/dL (ie, 
<2.59, 2.59 to <3.37, 3.37 to <4.14, 4.14 to <4.91, 4.91 mmol/L); 
x 
HDL-C:  <40, 40 mg/dL (ie, <1.04, 1.04 mmol/L); 
x 
Fasting TGs:  <150, 150 to <200, 200 mg/dL (ie, <1.7, 1.7 to <2.3, 2.3 mmol/L), 
category 150 mg/dL (mixed dyslipidemia) will be also displayed; 
x 
Lp(a): <30, 30 to <50, 50 mg/dL (ie, <0.3, 0.3 to <0.5, 0.5 g/L), category 30 mg/dL 
will be also displayed; 
Any technical details related to computation, dates, and imputation for missing data are described 
in Section 2.5. 
2.1.2 Prior or concomitant medications 
All medications taken within 12 weeks prior to run-in visit (Week -7) or screening visit (Week -3) 
and until the end of the study,
 
 
 
 
 
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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 lock for the first step analysis. 
x 
Prior medications are those the patient used within 12 weeks prior to run-in visit or 
screening visit and prior to first double-blind IMP injection. Prior medications can be 
discontinued before first injection or can be ongoing during treatment period.  
x 
Double-blind concomitant medications are any treatments received by the patient 
concomitantly with the IMP, from the first double-blind IMP injection to the last double-
blind IMP injection +70 days for patient not entering into the OLTP. For patients entering 
into the OLTP, concomitant medications will be truncated at the day before first open-label 
IMP injection. A given medication can be classified both as a prior medication and as a 
concomitant medication. Double-blind concomitant medications do not include 
medications started during the post-treatment period or OLTP (as defined in the 
observation period in Section 2.1.4). 
x 
Post-treatment double-blind medications are those the patient took in the period starting 
from 71 days after the last double-blind IMP injection and ending when the patient 
terminates the study. 
x 
Open-label concomitant medications are defined as any treatments received by the patient 
concomitantly with the open-label IMP, from the first open-label IMP injection to the last 
open-label IMP injection +70 days. 
x 
Post-treatment open-label medications are those the patient took in the period starting from 
71 days after the last open-label 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, Total-C, calculated LDL-C, HDL-C, fasting TGs, 
non-HDL-C, Apo B, Apo A-1, ratio Apo B/Apo A-1, Lp(a)). 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 values will be provided by the Central Laboratory only if 
corresponding TG values exceed 400 mg/dL (4.52 mmol/L), and will not be used for the analysis 
of calculated LDL-C endpoints. 
Unless otherwise 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 (except TG), will be assigned to analysis windows 
(electronic 
 
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defined in Section 2.5.4, Table 2 in order to provide an assessment for Week 4 to Week 64 time 
points.  
For 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 12) 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 
injection. For patients randomized and not treated, the baseline value is defined as the last 
available value obtained up to the date and time of randomization. 
2.1.3.1 Primary efficacy endpoint 
The primary efficacy endpoint is the percent change in calculated LDL-C from baseline to 
Week 12 in the intent-to-treat (ITT) population (defined in Section 2.3.1.1), using all LDL-C 
values regardless of adherence to treatment (ITT estimand). It is defined as: 100 x (calculated 
LDL-C value at Week 12 - calculated LDL-C value at baseline) / calculated LDL-C value at 
baseline. 
2.1.3.2 Secondary efficacy endpoints 
2.1.3.2.1 Key secondary efficacy endpoints 
The key secondary efficacy will be considered in the following order: 
The percentage changes in calculated LDL-C from baseline to Week 12 in the modified ITT 
(mITT) population (defined in Section 2.3.1.2), using all LDL-C values during the efficacy 
double-blind treatment period (on-treatment estimand). 
1. The percentage change in calculated LDL-C from baseline to average Week 10-12 (ITT 
estimand). 
2. The percentage change in calculated LDL-C from baseline to average Week 10-12 (on-
treatment estimand). 
3. The percentage change in Apo-B from baseline to Week 12 (ITT estimand). 
4. The percentage change in Apo-B from baseline to Week 12 (on-treatment estimand). 
5. The percentage change in non-HDL-C from baseline to Week 12 (ITT estimand). 
6. The percentage change in non-HDL-C from baseline to Week 12 (on-treatment estimand). 
7. The percentage change in TC from baseline to Week 12 (ITT estimand). 
8. The proportion of patients reaching LDL-C goal at Week 12, i.e., calculated LDL-C 
<100 mg/dL (2.59 mmol/L) for heFH or non-FH patients who have a history of 
documented CHD patients, or LDL-C <120 mg/dL (3.10 mmol/L) for non-FH patients 
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who have a history of documented diseases or other risk factors classified as primary 
prevention category III (ITT estimand). 
9. The proportion of patients reaching LDL-C goal at Week 12, i.e., calculated LDL-C 
<100 mg/dL (2.59 mmol/L) for heFH or non-FH patients who have a history of 
documented CHD patients, or LDL-C <120 mg/dL (3.10 mmol/L) for non-FH patients 
who have a history of documented diseases or other risk factors classified as primary 
prevention category III (on-treatment estimand). 
10. The percentage change in Lp(a) from baseline to Week 12 (ITT estimand). 
11. The percentage change in HDL-C from baseline to Week 12 (ITT estimand). 
12. The percentage change in fasting TG from baseline to Week 12 (ITT estimand). 
13. The percentage change in Apo A-1 from baseline to Week 12 (ITT estimand). 
2.1.3.2.2 Other Secondary Efficacy Endpoints 
x 
The proportion of patients with calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 12 
(ITT estimand). 
x 
The proportion of patients with calculated LDL-C <120 mg/dL (3.10 mmol/L) at Week 12 
(ITT estimand). 
x 
The proportion of patients with calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 12 
(ITT estimand). 
x 
The absolute change in calculated LDL-C from baseline to Week 12 (ITT estimand). 
x 
The change in Apo-B/Apo A-1 ratio from baseline to Week 12 (ITT estimand). 
x 
The proportion of patients with Apo-B <80 mg/dL (0.8 g/L) at Week 12 (ITT estimand). 
x 
The proportion of patients with non HDL-C <130 mg/dL (3.37 mmol/L) at Week 12 (ITT 
estimand). 
x 
The proportion of patients achieving at least 50% reduction in LDL-C at Week 12 (ITT 
estimand). 
x 
The percentage change in TC, Lp(a) from baseline to Week 12 (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, vital signs, and electrocardiogram (ECG). 
Observation period  
The observation period starts from the time when the patient gives informed consent and will be 
divided into following periods: 
x 
The PRE-TREATMENT period is defined from the signed informed consent up to the first 
dose of double-blind IMP injection. 
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x 
The double-blind treatment-emergent adverse event (TEAE) period is defined as the time 
from the first dose of double-blind IMP injection to the last dose of double-blind IMP 
injection + 70 days (10 weeks) for patients not entering into the OLTP. For patients 
entering into the OLTP, the TEAE period will be truncated at the day before the first open-
label IMP injection.  
The double-blind TEAE period will include: 
- 
The double-blind TREATMENT period: defined as the time from the first double-
blind IMP injection up to the day of last double-blind IMP injection (active or placebo 
depending on the Q2W or Q4W dosing regimen) + 21 days. The treatment period will 
end approximately 35 days after last active injection for most of the patients 
randomized in the alirocumab 150 mg Q4W arm since last planned injection at Week 
10 is a placebo injection. 35 days is considered appropriate since the effect of 
alirocumab 150 mg Q4W is expected to be maintained during the 4-week dosing 
interval. 
- 
The double-blind RESIDUAL TREATMENT period: defined as the time from the day 
of last dose of double-blind IMP injection +22 days up to the day of last dose of 
double-blind IMP injection +70 days (10 weeks) for patients not entering into the 
OLTP. For patients entering into the OLTP, the RESIDUAL TREATMENT period 
will be truncated at the day before the first open-label IMP injection. 
x 
The double-blind POST-TREATMENT period: defined as the time starting the day after 
the end of the double-blind TEAE period (i.e., 71 days after the day of last dose of double-
blind IMP injection) for patients not entering into the OLTP.  
x 
The open-label TEAE period is defined as the time form the first dose of open-label IMP 
injection to the last dose of open-label IMP injection + 70 days (10 weeks). 
The open-label TEAE period will include: 
- 
The open-label TREATMENT period defined as the time from the first dose of open-
label IMP injection up to the day of last dose of open-label IMP injection + 21 days. 
- 
The open-label RESIDUAL TREATMENT period: defined as the time from the day of 
last dose of open-label IMP injection +22 days up to the day of last dose of open-label 
IMP injection +70 days (10 weeks). 
x 
The open-label POST-TREATMENT period: defined as the time starting the day after the 
end of the open-label TEAE period (i.e., 71 days after the day of last dose of open-label 
IMP injection). 
Observation periods below will be analyzed at the first step analysis only. 
x 
The alirocumab exposed TEAE period is defined as follows : 
- 
For alirocumab 150 mg Q4W group and alirocumab 150 mg Q2W group: The time 
from the first dose of double-blind IMP injection to the last dose of IMP injection 
(double-blind or open-label) + 70 days (10 weeks). 
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- 
For placebo Q2W group: The time from the first dose of open-label IMP injection to 
the last dose of open-label IMP injection + 70 days (10 weeks).  
The alirocumab exposed TEAE period will include: 
- 
The alirocumab exposed TREATMENT period: defined below:  
- 
For alirocumab 150 mg Q4W group and alirocumab 150 mg Q2W group: The time 
from the first dose of double-blind IMP injection to the last dose of IMP injection 
(double-blind or open-label) + 21 days. 
- 
For placebo Q2W group: The time from the first dose of open-label IMP injection 
to the last dose of open-label IMP injection + 21 days. 
- 
The alirocumab exposed RESIDUAL TREATMENT period: defined below:  
- 
For alirocumab 150 mg Q4W group and alirocumab 150 mg Q2W group: The time 
from the day of last dose of IMP injection(double-blind or open-label) +22 days up 
to the day of last dose of IMP injection(double-blind or open-label) +70 days 
(10 weeks). 
- 
For placebo Q2W group: The time from the day of last dose of open-label IMP 
injection +22 days up to the day of last dose of open-label IMP injection +70 days 
(10 weeks). 
The double-blind on-study observation period is defined as the time from the day of first dose of 
double-blind IMP injection until the last protocol planned double-blind visit of the patient. The 
last protocol planned double-blind visit is defined as the follow-up visit if done, or a maximum of 
20 weeks after the randomization of the patient, for patients not proceeding into OLTP. For 
patients proceeding into OLTP, the last protocol planned double-blind visit is defined as the end 
of double-blind treatment period visit (Week 12).  
The open-label on-study observation period is defined as the time from the first open-label IMP 
injection until the last protocol planned open-label visit of the patient.  
The alirocumab exposed on-study observation period is defined below: 
x 
For alirocumab 150 mg Q4W group and alirocumab 150 mg Q2W group: The time from 
the day of first dose of double-blind IMP injection until the last protocol planned double-
blind visit for patients not entering into the OLTP or the last protocol planned open-label 
visit for patients entering into the OLTP.  
x 
For placebo Q2W group: The time from the first open-label IMP injection until the last 
protocol planned open-label visit of the patient. 
2.1.4.1 Adverse events variables 
AEs (including SAEs and AESI) are recorded from the time of signed informed consent until the 
end of the study. All AEs diagnosed by the Investigator, irrespective of the result of the 
adjudication for CV events, will be reported and described. 
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All AEs will be coded to a lower-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 Medical Dictionary for Regulatory Activities (MedDRA) currently in effect at Sanofi at 
the time of the database lock for the first step analysis. 
Adverse event observation period  
x 
Pre-treatment AEs are AEs that developed or worsened or became serious during the pre-
treatment period. 
x 
Double-blind TEAEs are AEs that developed or worsened or became serious during the 
double-blind TEAE period.  
x 
Double-blind post-treatment AEs are AEs that developed or worsened or became serious 
during the double-blind post-treatment period. 
x 
Open-label TEAEs are AEs developed or worsened or became serious during the open-
label TEAE period. 
x 
Open-label post-treatment AEs are AEs that developed or worsened or became serious 
during the open-label post-treatment period. 
x 
Alirocumab exposed TEAEs are AEs developed or worsened or became serious during the 
alirocumab exposed TEAE period. 
AESI include the following AEs: 
AESIs are AEs (serious or non-serious) that need to be monitored, documented, and managed in a 
pre-specified manner described in the protocol. In this study, AESIs are the following (their 
complete descriptions are provided in the protocol): 
x 
Local injection site reactions, selected using e-CRF specific tick box on the AE page; 
x 
Allergic events: 
- 
General allergic events will be tabulated. Events will be selected using standardized 
MedDRA query (SMQ) “hypersensitivity” (broad and narrow) excluding the following 
preferred terms linked to local injection site reactions (“infusion site dermatitis”, 
“infusion site hypersensitivity”, “infusion site rash”, “infusion site urticaria”, “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") 
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x 
ALT 3 ULN (if baseline ALT <ULN) or ALT 2 times the baseline value (if baseline 
ALT ULN), selected using laboratory data; 
x 
Hemolytic anemia, selected using e-CRF specific tick box on the AE page and confirmed 
final diagnosis provided in the AE complementary form; 
x 
Neurologic events selected using SMQs “demyelination” (broad and narrow), “peripheral 
neuropathy” (broad and narrow), and “Guillain-Barre syndrome” (broad and narrow) 
excluding the following preferred terms “acute respiratory distress syndrome”, “asthenia”, 
“respiratory arrest” and “respiratory failure”; 
x 
Neurocognitive events, selected using a company MedDRA query (CMQ), based on the 
following 5 HLGTs: “deliria (including confusion)”, “cognitive and attention disorders and 
disturbances”, “dementia and amnestic conditions”, “disturbances in thinking and 
perception”, and “mental impairment disorders” 
x 
Ophthalmologic events selected using SMQs “optic nerve disorders” (broad and narrow), 
“retinal disorders” (narrow), and “corneal disorders” (narrow); 
x 
Overdose with IMP (symptomatic or asymptomatic).The selection is based on the 
preferred terms “Accidental overdose” and “Intentional overdose” and the tick box 
“Overdose with IMP auto-injectors” in the AE complementary e-CRF form; 
x 
Overdose with NIMP (symptomatic or asymptomatic). The selection is based on the 
preferred terms “Accidental overdose” and “Intentional overdose” and the tick box “Other 
medications” in the AE complementary e-CRF form 
x 
Pregnancy of female patient/subject (including male subject’s partner) selected using 
appropriate MedDRA codes. 
x 
 
 
In addition the following grouping of events will be provided: 
x 
Hepatic disorder events using SMQ “Hepatic disorder” 
x 
Diabetes mellitus or diabetic complications using HLGT “diabetes complications” 
(including PTs pertaining to the secondary SOC included in the HLGT), HLT “diabetes 
mellitus”, and HLT “carbohydrate tolerance analyses (incl diabetes)” excluding PTs 
“blood glucose decreased” and “Glycosylated haemoglobin decreased” and including the 
PTs “hyperglycaemia”, “Hyperglycaemic unconsciousness” and “Hyperglycaemic seizure” 
from the HLT "Hyperglyceamic conditions NEC". 
x 
Cataract using HLT “Cataract conditions” 
 
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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 and CV procedures positively adjudicated as defined 
in the CEC charter. The following categories will be described: 
x 
CHD death 
x 
Non-fatal MI, 
x 
Fatal and non-fatal ischemic stroke, 
x 
Unstable angina requiring hospitalization, 
x 
Congestive heart failure requiring hospitalization, 
x 
Ischemia driven coronary revascularization procedure. 
2.1.4.2 Deaths 
The deaths observation period are per the observation periods defined above.  
x 
Death on-study during DBTP: deaths occurring during the double-blind on-study 
observation period, 
x 
Death on-treatment during DBTP:  deaths occurring during the double-blind TEAE period, 
x 
Death on-study during OLTP:  deaths occurring during the open-label on-study 
observation period, 
x 
Death on-treatment during OLTP:  deaths occurring during the open-label TEAE period, 
x 
Death post-study:  deaths occurring after the last planned protocol visit. 
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. International units will be used in all listings and tables. Clinical laboratory values 
converted into conventional (US) units will be also available in the database. Analyses can be 
provided upon request. 
Unless otherwise specified below, blood samples for clinical laboratories were to be collected 
during: 
x 
Screening period at Visit 2 (Week -3) 
x 
DBTP at Visit 4 (Week 0), Visit 10 (Week 12) /or permanent treatment discontinuation 
x 
OLTP at Visit 13 (Week 24), Visit 16 (Week 36), Visit 19 (Week 48), and Visit 23 (Week 
64) /or permanent treatment discontinuation 
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x 
Follow-up period (Visit 24 [Week 72]) in case of abnormality at Visit 23 (Week 64). 
The laboratory parameters (excluding those considered as efficacy parameters) will be classified 
as follows: 
x 
Hematology: 
- 
Red blood cells and platelets:  
red blood cell count, hemoglobin, red blood cell distribution width (RDW), 
reticulocyte count, hematocrit, platelets, haptoglobin; 
- 
White blood cells:  
white blood cell count, neutrophils, lymphocytes, monocytes, basophils, eosinophils. 
x 
Clinical chemistry: 
- 
Metabolism: glucose, total protein, albumin, creatine phosphokinase; 
- 
Electrolytes: sodium, potassium, chloride, bicarbonate, calcium, phosphorus; 
- 
Renal function: creatinine, glomerular filtration rate (eGFR), urea nitrogen, blood uric 
acid; 
- 
Liver function (also measured during DBTP at Week 4 and Week 8, 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. 
x 
Hepatitis screen: 
anti-hepatitis-C antibody (at Week -3 and Week 64/or permanent treatment 
discontinuation). 
Technical formulas are described in Section 2.5.1. 
2.1.4.4 Vital signs variables 
Vital signs include Body weight, heart rate (HR), systolic and diastolic blood pressure (SBP and 
DBP) in sitting position. 
Body weight was to be measured during: 
x 
Screening period at Week -3 
x 
DBTP at Week 0, Week 12/or permanent treatment discontinuation 
x 
OLTP at Week 24, Week 36, Week 64/or permanent treatment discontinuation 
x 
Follow-up period (Week 72). 
HR and blood pressure were to be measured during: 
x 
Run-in and Screening period at Week -7, Week -3, Week -1 
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x 
DBTP at Week 0, Week2, Week 4, Week 6, Week 8, Week 10, Week 12/or permanent 
treatment discontinuation 
x 
OLTP at Week 20, Week 24, Week 36, Week48, Week 64/or permanent treatment 
discontinuation  
x 
Follow-up period (Week 72). 
Vital signs will be described following time windows as defined in Section 2.5.4, Table 4. 
2.1.4.5 Electrocardiogram variables 
The ECG parameters will be recorded automatically by the device at the Investigator site during: 
x 
Screening period at Week -3 
x 
DBTP at Week 12/or permanent treatment discontinuation 
x 
OLTP at Week 24, and Week 64/or permanent treatment discontinuation. 
ECG assessments will be described as normal or abnormal. 
2.1.5 Other endpoints 
Other assessment endpoints listed below are defined using same definitions and rules as for 
calculated LDL-C, when applicable (see Section 2.1.3.1). 
x 
The absolute change in HbA1c (%) from baseline (Week -3) to Week 12 (DBTP), 
Week 24 (OLTP), Week 36 (OLTP), Week 48 (OLTP), and Week 64 (OLTP): 
PCSA criteria for HbA1c will be also used (see Appendix A). 
x 
The proportion of patients with 2 consecutives results, spaced out by at least 21 days, of 
calculated LDL-C <25 mg/dL (<0.65 mmol/L) 
during each treatment period (double-blind and open-label) and the time 
to the first calculated LDL-C <25 mg/dL 
 for 
these patients within the relevant treatment period. 
x 
Proportion of patients who are up-titrated to alirocumab 150 mg Q2W during the OLTP. 
2.1.6 Anti-alirocumab antibodies variables 
Anti-alirocumab antibodies (ADA) are assessed: 
x 
At baseline (before the first IMP injection) 
x 
During DBTP at Week 4, Week 12 
x 
During OLTP at Week 24, Week 36, Week 48 and Week 64/or permanent treatment 
discontinuation  
x 
During follow-up (Week 72).  
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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 72. 
The following variables will be described: 
x 
ADA response (Positive or Negative).  
For ADA positive: 
- 
Titer levels;  
- 
Neutralizing status (Positive or Negative). 
x 
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 (for DBTP: up to follow-up visit for patients not proceeding into 
OLTP, up to first open-label IMP injection for patients proceeding into OLTP, 
  
or  
2) Patients with a positive ADA response at baseline and at least a 4-fold increase in titer 
in the post-baseline period (for DBTP: up to follow-up visit for patients not proceeding 
into OLTP, up to first open-label IMP injection for patients proceeding into OLTP
 
 
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. 
2.1.7 Pharmacokinetic variables 
Concentrations of total alirocumab, total and free PCSK9 in serum are assessed at baseline 
(Week 0), Week 4, Week 8, Week 10, and Week 12. 
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Pharmacokinetic variable is the total alirocumab concentration at each time point. Depending on 
the timing of the sample versus the previous injection, Ctrough, Cmax and Cfollow-up will be defined as 
follows: 
 
   
 
 
 
 
 
 
 
 
 
Alirocumab concentration and total and free PCSK9 concentration will be described following 
time windows as defined in Section 2.5.4, Table 3. 
2.1.8 Pharmacodynamic/genomics endpoints 
2.1.9 Quality-of-life endpoints 
 
2.1.10 Health economic endpoints 
 
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 patient who met the inclusion criteria and signed the 
informed consent.  
Randomized patients consist of all patients, with a treatment kit number allocated and recorded in 
IRT database, and regardless of whether the treatment kit was used or not. Patients treated without 
being randomized or treated with a double-blind or open-label treatment kit before the 
randomization will not be considered as randomized and will not be included in any analysis 
population. 
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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: 
The following categories will be displayed for first and second step analysis: 
x 
Screened patients 
x 
Screen failure patients and reasons for screen failure 
x 
Non-randomized but treated patients, if any 
x 
Randomized patients 
x 
Randomized but not treated patients and reason for not being treated 
x 
Randomized and treated patients 
x 
Patients who completed the double-blind study treatment period (at least 10 weeks of 
exposure with double-blind treatment and Week 12 visit performed )  
x 
Patients who did not complete the double-blind study treatment period (as per definition 
above) 
x 
Main reason for permanent double-blind treatment discontinuation (as per eCRF end-of-
treatment form)  
 
 
 
  
 
 
 
 
 
 
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.  
 
 
 
 
 
 
 
 
 
 
 
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Reasons for treatment discontinuation will be supplied in tables giving numbers and percentages 
by treatment group. 
 
 
 
 
 
 
 
 
 
 
 
 
All major deviations potentially impacting efficacy analyses, randomization and drug-dispensing 
irregularities, and other important deviations will be summarized in tables giving numbers and 
percentages of deviations by treatment group. These deviations are listed in the data review and 
surveillance plan. 
Additionally, the following populations will be summarized by treatment group:  
x 
Randomized population.  
x 
Efficacy population: ITT and mITT populations  
x 
Safety population 
x 
Pharmacokinetics population 
x 
Anti-alirocumab antibody population 
x 
Open-label treatment population 
x 
Alirocumab safety population 
Definitions of the study populations above are provided in Section 2.3 
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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.  
All randomization and drug-dispensing irregularities will be documented in the clinical study 
report. These irregularities will be summarized by treatment group on the randomized population. 
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 dispensed without IVRS transaction 
Kit dispensed erroneously  
Kit not available 
Patient randomized twice 
Stratification error 
2.3 
ANALYSIS POPULATIONS 
Patients treated without being randomized or treated with a double-blind or open-label treatment 
kit before the randomization will not be considered as randomized and will not be included in any 
analysis population. The safety experience of patients treated and not randomized will be reported 
separately. 
Randomized population: includes all randomized patients as defined in Section 2.2. 
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. 
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2.3.1 Efficacy populations 
The primary efficacy analysis population will be the Intent-to-treat (ITT) population. 
2.3.1.1 Intent–to-treat population 
The ITT population is defined as the randomized population who has an evaluable primary 
endpoint. The primary efficacy endpoint is evaluable when both of the following conditions are 
met:  
x 
Availability of at least 1 value for calculated LDL-C before the first dose of double-blind 
IMP (i.e., baseline).  
x 
Availability of at least 1 value for calculated LDL-C within one of the following analysis 
windows: Week 4, Week 8, Week 10, and Week 12. 
Patients in the ITT population will be analyzed according to the treatment group allocated by 
randomization.  
2.3.1.2 Modified intent-to-treat population 
The modified intent-to-treat (mITT population is defined as the randomized population who took 
at least one dose or part of dose of the double-blind IMP injection and has an evaluable primary 
efficacy endpoint during the efficacy double-blind treatment period. The primary efficacy endpoint 
will be considered evaluable when both of the following conditions are met: 
x 
Availability of at least 1 value for calculated LDL-C before the first dose of double-blind 
IMP (i.e., baseline). 
x 
Availability of at least 1 value for calculated LDL-C within one of the following analysis 
window: Week 4, Week 8, Week 10, and Week 12 during the efficacy double-blind 
treatment period.  
The efficacy double-blind treatment period will be defined as:  
x 
The time period from the first double-blind IMP injection up to 21 days after the last 
double-blind IMP injection (i.e., up to Week 12).  
Patients in the mITT population will be analyzed according to the treatment group allocated by 
randomization.  
2.3.2 Safety population 
The Safety population considered for the safety analyses will be the randomized patients who 
actually received at least one dose or partial dose of the double-blind IMP injection. Patients will 
be analyzed according to the treatment actually received (i.e. as-treated treatment group, 
Alirocumab 150mg Q4W, Alirocumab 150mg Q2W or Placebo Q2W).  
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In addition:  
x 
Non-randomized but treated patients will not be part of the safety population, but their 
safety data will be presented separately.  
x 
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 double-blind IMP injection from more than one treatment group during the 
trial (cases reported as protocol deviation), the treatment group allocation for as-treated analysis 
will be the one to which the patient received the highest number of injections. In case of the same 
number of injections of each treatment is received, the as-treated treatment group will be the as-
randomized group. 
2.3.3 Anti-alirocumab antibody population 
The anti-alirocumab antibody analysis will be performed on all randomized and treated patients 
(safety population) with an available ADA sample at Week 0 (baseline) and at least 1 available 
ADA sample post first double-blind IMP injection and up to follow-up visit for patients not 
proceeding into OLTP, up to first open-label IMP injection for patients proceeding into OLTP.  
2.3.4 Pharmacokinetics population 
The PK analysis will be performed on all randomized and treated patients (safety population) with 
at least one evaluable PK sample post the first double-blind IMP injection.  
2.3.5 Open-label treatment population 
The open-label treatment population considered for all analyses in the open-label treatment period 
will be all randomized patients who received at least one dose or part of dose of open-label IMP. 
2.3.6 Alirocumab safety population 
The alirocumab safety population considered for the safety analyses combining exposure of 
alirocumab during DBTP and OLTP will be the randomized patients who actually received at least 
one dose or partial dose of alirocumab IMP (double-blind or open-label). 
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 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) 
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and third quartile (Q3) will be also provided for baseline lipid parameters, HbA1c and eGFR. 
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 as-randomized 
treatment group. Similar analyses will be done on the ITT population, safety population, OLT 
population, and alirocumab safety population
 
 
 
 
 
 
 
 
 
 
 
The reason why statin is not appropriate or why statin dose cannot be increased from the lowest 
strength for the patients will be descriptively summarized using the number and percentage of 
patients by each treatment group. The reason specified in eCRF will be listed for the patient with 
“other reason”.  
 
 
 
 
 
2.4.2 Prior, concomitant, or post-treatment medications 
The prior, concomitant and post-treatment medications will be presented during DBTP for the 
safety population.  
Medications will be summarized by treatment group according to the WHO-DD dictionary, 
considering the first digit of the anatomical therapeutic chemical (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 in several 
categories for the same medication.  
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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 across 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 therapeutic class based on the incidence in the Alirocumab 150mg Q4W 
group. In case of equal frequency across anatomic or therapeutic categories, alphabetical order will 
be used.  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
All concomitant and post-treatment medications recorded during the OLTP will be summarized in 
the OLT population. 
2.4.3 Extent of investigational medicinal product exposure and compliance  
The extent of IMP exposure and compliance will be assessed and summarized for the safety 
population (using as-treated treatment group), OLT population and alirocumab safety population 
(for first step analysis only). 
2.4.3.1 Extent of investigational medicinal product exposure 
Injection (alirocumab or placebo) 
Double-blind IMP injections are those administered from randomization to completion or 
discontinuation of the double-blind study treatment. These injections contain: 
x 
placebo Q2W for patients randomized in the Placebo Q2W group, 
x 
placebo Q4W (to maintain the blind) or 150 mg Q4W of alirocumab for patients 
randomized in the Alirocumab 150 mg Q4W group. 
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x 
150 mg Q2W of alirocumab for patients randomized in the Alirocumab 150 mg Q2W 
group. 
The total exposure during the DBTP will be assessed using descriptive statistics for: 
x 
Duration of double-blind IMP injection exposure in weeks defined as: (date of last dose of 
double-blind IMP injection +14 – date of first dose of double-blind IMP injection) / 7, 
regardless of 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; 
x 
The total number of double-blind IMP injections by patient. 
Duration of double-blind IMP injection exposure will be summarized using number, mean, SD, 
median, minimum and maximum. In addition, it will be summarized according to the following 
categories: 1 day and <4 weeks, 4 weeks and <8 weeks, 8 weeks and <10 weeks, 10 weeks. 
The total exposure during the OLTP will be assessed using descriptive statistics for: 
x 
Duration of open-label IMP injection exposure in weeks defined as: (date of last dose of 
open-label IMP injection +14 – date of first dose of open-label IMP injection) / 7, 
regardless of intermittent discontinuations (see Section 2.5.3 for calculation in case of 
missing or incomplete data). Non-integer values will be rounded to one decimal place; 
x 
The total number of open-label IMP injections by patient. 
Duration of open-label IMP injection exposure will be summarized using number, mean, SD, 
median, minimum and maximum. In addition, it will be summarized according to the following 
categories: 1day and <12 weeks, 12 weeks and <24 weeks, 24 weeks and <36 weeks, 
36 weeks and <48 weeks, 48 weeks. 
The total exposure during alirocumab exposed period (defined in Section 2.4.5) for first step 
analysis only will be assessed using descriptive statistics for: 
x 
Duration of alirocumab IMP injection exposure in weeks defined as: 
- 
For Alirocumab 150 mg Q4W group and Alirocumab 150 mg Q2W group: (date of last 
dose of IMP injection (double-blind or open-label) +14 – date of first dose of double-
blind IMP injection) / 7, regardless of intermittent discontinuations (see Section 2.5.3 
for calculation in case of missing or incomplete data). Non-integer values will be 
rounded to one decimal place; 
- 
For Placebo Q2W group: (date of last dose of open-label IMP injection +14 – date of 
first dose of open-label IMP injection) / 7, regardless of intermittent discontinuations 
(see Section 2.5.3 for calculation in case of missing or incomplete data). Non-integer 
values will be rounded to one decimal place; 
x 
The total number of alirocumab IMP injections by patient. 
Duration of alirocumab IMP injection exposure will be summarized using number, mean, SD, 
median, minimum and maximum. In addition, it will be summarized according to the following 
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categories: 1day and <12 weeks, 12 weeks and <24 weeks, 24 weeks and <36 weeks, 
36 weeks and <48 weeks, 48 weeks and <60 weeks, 60 weeks. 
Titration 
For the OLTP, the number and percentage of patients with an up-titration at Week 24 will be 
described. Patients with an up-titration are defined as up-titrated patients according to IRT Week 
24 transaction with at least 1 injection of alirocumab 150 mg Q2W afterwards. 
2.4.3.2 Compliance  
Compliance for the DBTP will be assessed using the following parameters: 
x 
The mean injection frequency of IMP double-blind injections will be defined for each 
patient as the average number of days between 2 consecutive double-blind injections, that 
is: (last double-blind injection date – first double-blind injection date)/(number of double-
blind injections -1) for patients receiving at least 2 injections. 
x 
The overall compliance for double-blind 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): 
x 
The % days with under-planned dosing 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. 
x 
The % days with above-planned dosing will be defined for each patient as the number of 
days with more than one 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 dosing. 
For the OLTP, only mean injection frequency will be assessed for compliance.  
x 
The mean injection frequency of IMP open-label injections will be defined for each patient 
as the average number of days between 2 consecutive open-label injections, that is: (last 
open-label injection date – first open-label injection date)/(number of open-label injections 
-1) for patients receiving at least 2 injections. 
These parameters will be summarized descriptively (N, Mean, SD, Median, Minimum and 
Maximum). 
The percentage of patients whose overall compliance for injections is <80% will be also 
summarized as well as numbers and percentages of patients with 0%, >0% and 5%, >5% and 
10%, >10% and 20%, and >20% days with above-planned dosing and numbers and percentages 
of patients with 0%, >0% and 5%, >5% and 10%, >10% and 20%, and >20% days 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 the AE analysis (see Section 2.1.4.1). 
The mean injection frequency of IMP open-label injections (until and after Week 24 separately) 
will be summarized according to the up-titration status. 
2.4.4 Analyses of efficacy endpoints 
For statistics where international and conventional units do not impact the results (e.g. means and 
least square (LS) means for percent changes from baseline, p-values for both percent and absolute 
changes from baseline, rates of patients below a threshold), derivations will be done and statistical 
models will be run using conventional units. For other statistics (e.g. descriptive statistics at 
baseline
derivations will be done with both 
international and conventional units. 
Statistical analyses for the primary and secondary efficacy endpoints will be conducted in the 
DBTP.
 
 
2.4.4.1 Analysis of primary efficacy endpoint(s) 
2.4.4.1.1 Primary efficacy analysis 
In the primary analysis, stratification factor of statin will be considered as covariate. Consistency 
of treatment effects between the randomization strata will be evaluated. In case there is 
heterogeneity of treatment effects at Week 24, particularly treatment group-by-stratification factor 
of statin interaction, then analysis by the strata will be performed as secondary. 
The percent change from baseline in calculated LDL-C at Week 12 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 to Week 12 analysis windows 
will be used and missing data are accounted for by the MMRM model. The model will include the 
fixed categorical effects of treatment group (Placebo Q2W, Alirocumab 150 mg Q4W and 
Alirocumab 150 mg Q2W), stratification factor of statin (Yes/No) as per IRT, time point (Week 4, 
Week 8, Week 10, Week 12), treatment-by-time point interaction, and statin-by-time point 
interaction, as well as, the continuous fixed covariates of baseline LDL-C value and baseline 
value-by-time point interaction.  
This model will be run using SAS Mixed procedure with an unstructured correlation matrix to 
model the within-patient errors. Parameters will be estimated using restricted maximum likelihood 
method with the Newton-Raphson algorithm. Denominator degrees of freedom will be estimated 
using Satterthwaite’s approximation. This model will provide baseline adjusted least-squares 
means estimates at Week 12 for each treatment groups with their corresponding standard errors 
(SEs). To compare each alirocumab group to the Placebo Q2W group, an appropriate contrast 
statement will be used to test the differences of these estimates, at the 2-sided 0.025 level.  
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Within group least-squares means and standard errors will be provided, using weights equal to the 
observed proportion of patients in strata variable levels in the study population (i.e. “population 
weight”) rather than equal weights. Population weights are considered more appropriate than 
equal coefficients due to unbalances observed in the study population between levels of the 
randomization stratification factors. 
Let μ0 and μ1 be the population means of the percent change from baseline in calculated LDL-C at 
Week 12 under Placebo Q2W group and each alirocumab group, respectively. The hypothesis that 
will be tested is “H0: μ0 = μ1” versus H1: “μ0 z  μ1”. 
Alirocumab group will be compared to placebo using an appropriate contrast tested at the two-
sided 0.05 level, with corresponding least squares estimate of the mean difference between groups, 
SE and 97.5% CI. 
In addition, the difference between the two alirocumab arms Q4W and Q2W will also be provided, 
with a 95% CI using an appropriate contrast from the same MMRM model. 
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: 
x 
Treatment group * baseline calculated LDL-C 
x 
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 placebo at Week 12 and the corresponding 97.5% 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: 
x 
Normality of studentized residuals, presented graphically using histogram and QQ-plot; 
x 
Plot of studentized residuals versus predicted values; 
x 
Distribution of studentized residuals, presented graphically using boxplots, within each 
category of the fixed categorical effects of the MMRM: 
- 
Treatment group (Placebo Q2W, Alirocumab 150 mg Q4W and Alirocumab 150 mg 
Q2W); 
- 
Time point (Week 4, Week 8, Week 10, Week 12); 
- 
Treatment group-by-time point interaction;  
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- 
Stratification factor of statin (Yes/No); 
- 
Stratification factor of statin - 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 (i.e. 
the stratum recorded in IRT differs from the actual one), the MMRM model will be re-run 
including the actual stratum as per the eCRF instead of the stratum recorded in IRT. 
2.4.4.1.4 Subgroup analyses 
To assess the homogeneity of the treatment effect across various subgroups, treatment 
group-by-subgroup factor, time point-by-subgroup factor and treatment group-by time point-by 
subgroup factor interaction terms and a subgroup factor term will be added in the primary MMRM 
model. LS means difference versus placebo at Week 12 will be provided, as well as the 
corresponding SE and 97.5% CI, within each subgroup. The significance level of the treatment 
group-by-subgroup factor interaction term at Week 12 will be also provided for each factor for 
descriptive purpose. Forest plots will be provided. In order to handle unbalances between 
randomization stratification factors levels, population weights will be used as for the primary 
analysis model. 
Only subgroups with a sufficient number of patients in each level and treatment groups will be 
evaluated. 
Subgroups of interest are: 
x 
BMI (<25 kg/m2, 25 kg/m2); 
x 
Gender (Female, Male); 
x 
Age (<65 years, 65 years); 
x 
Stratification factor of statin as per IRT (Yes, No) 
x 
Randomization strata as per IRT (statin, non-statin LMT, diet alone) : for this specific 
subgroup factor, the MMRM model will include this randomization strata instead of 
stratification factor of statin as per IRT, 
x 
Randomization strata as per LMT (statin, Ezetimibe, Fibrate, diet alone) : for this specific 
subgroup factor, the MMRM model will include this randomization strata instead of 
stratification factor of statin as per IRT, 
x 
heFH population (Yes, No) 
x 
Prior history of MI or ischemic stroke (Yes, No); 
x 
Diabetes status at baseline (Yes, No), which is defined in Section 2.1; 
x 
Chronic kidney disease (CKD) (Yes, No); 
x 
Prior history of side effects caused by statin (Yes, No) 
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x 
Baseline calculated LDL-C (<130, 130 to <160, 160 mg/dL) (ie, <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, stratification factor of statin, baseline LDL-C category, time point, and 
the interactions treatment group-by-time point, stratification factor of statin-by-time point, 
baseline calculated LDL-C category-by-time point, treatment group-by-baseline calculated 
LDL-C category, and treatment group-by-baseline calculated LDL-C category-by-time 
point; 
x 
Baseline HDL-C (<40 mg/dL (<1.04 mmol/L), 40 mg/dL (1.04 mmol/L)), 
x 
Baseline fasting TG (<150 mg/dL (<1.7 mmol/L), 150 mg/dL (1.7 mmol/L) ie, mixed 
dyslipidemia); 
x 
Baseline Lp(a) (<30,  30 to <50, 50 mg/dL) (ie, <0.3,  0.3 to <0.5, 0.5  g/L)); 
x 
Baseline total PCSK9 level (below the median, at or above the median); 
x 
Baseline free PCSK9 level (below the median, at or above the median). 
2.4.4.2 Analyses of secondary efficacy endpoints 
Method for controlling the overall type-I error rate when testing the key secondary efficacy 
endpoints is described in Section 2.4.4.3. 
For key secondary efficacy endpoints and other secondary efficacy endpoints (described in Section 
2.1.3.2), descriptive summaries and analyses will be performed in the ITT population or mITT 
population depending on the estimand. 
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 
calculated LDL-C <100mg/dL). 
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, stratification factor of 
statin as per IRT, planned time points up to Week 12, treatment-by-time point interaction and 
stratification factor of statin-by-time point interaction, as well as the continuous fixed covariates 
of corresponding baseline value and baseline value-by-time point interaction.  
The percentage change in calculated LDL-C from baseline to averaged Week 10 - 12 will be 
analyzed using an appropriate contrast statement (assigning a weight of 0.5 for the two time 
points) from the MMRM model. 
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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 
described below in detail for handling of missing values, followed by the testing of treatment 
groups using a robust regression model (1). Missing data will be imputed 100 times to generate 
100 complete data sets, using the MI SAS procedure. The percent change from baseline at time 
point of interest will be then derived from observed and imputed lipid values at this time point. 
The 100 complete data sets will be then analyzed using a robust regression model with endpoint of 
interest as response variable using M-estimation (using SAS ROBUSTREG procedure) with 
treatment group, stratification factor of statin as per IRT, and corresponding baseline value(s) as 
effects. Then the MIANALYZE procedure will be used to generate valid statistical inferences by 
combining results from the 100 analyses using Rubin’s formulae. Combined means estimates for 
both treatment groups, as well as the differences of these estimates, with their corresponding SEs, 
97.5% CIs and p-value will be provided. 
Multiple imputation model 
Since in general the missing pattern is anticipated to be non-monotone, a two-step approach will 
be used:  
x 
Step 1: The MCMC (Markov chain Monte Carlo)  method will be used in conjunction with 
the IMPUTE=MONOTONE option to create an imputed data set with a monotone missing 
pattern;  
x 
Step 2: Using the monotone data set from step 1, missing data will be imputed using the 
regression method.  
 
  
 
   
 
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, since the distribution 
is assumed non-normal. 
Non continuous variables included in the imputer’s model (ie, treatment group, randomization 
strata and gender) are not expected to be missing. 
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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 (see Section 2.4.4.2.2 for details about 
multiple imputation). In the imputations, log-transform process planned in Section 2.4.4.2.2 will 
not be done for the lipid parameter assuming normal distribution. 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 stratification factor of statin 
(as per IRT, as defined in Section 1.4). Combined estimates of odds ratio versus placebo, 97.5% 
CI, and p-value will be obtained through the SAS MIANALYZE procedure. 
In the data dependent case such logistic regression is not applicable (eg, the response rate is zero 
in 1 treatment arm and thus the maximum likelihood estimate may not exist), the last observation 
carried forward (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 for the endpoints at Week12 will consist of using the last value obtained up to 
the Week 12 analysis window to impute the missing Week 12 value. 
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
 
 
2.4.4.2.4 Sensitivity analyses of key secondary endpoints 
 
 
2.4.4.2.5 Analyses of key secondary endpoints by subgroups 
The endpoint “percent change in fasting TG from baseline to Week 12” will be analyzed 
according to the following subgroups: 
Baseline fasting TG (<150 mg/dL (<1.7 mmol/L), 150 mg/dL (1.7 mmol/L)) ie, mixed 
dyslipidemia) 
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2.4.4.2.6 Summary of results per time point 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
2.4.4.3 Multiplicity issues 
The multiplicity appears in two kinds in this study, due to the presence of the 2 arms of 
alirocumab 150 mg Q4W and 150 mg Q2W that are compared with placebo, and due to the 
multiple key secondary efficacy endpoints.  
The overall type I error will be controlled at 0.05 by performing each pairwise test (alirocumab 
150 mg Q4W vs. placebo, and alirocumab 150 mg Q2W vs. placebo) for the main efficacy 
endpoint at the 0.025 level.  
Then, a hierarchical procedure will be used for each pairwise comparison to control the type I 
error and to handle multiple endpoints. If the primary endpoint analysis is significant at the 2.5% 
alpha level, the key secondary efficacy endpoints will be tested sequentially at the 0.025 level, 
using the order defined in Section 2.1.3.2.1. Hierarchical procedure for comparisons of alirocumab 
150 mg Q4W versus placebo, and alirocumab 150 mg Q2W versus placebo will be processed 
separately.  
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No further adjustments will be made for other secondary endpoints for which p-values will be 
provided for descriptive purpose only (no claim).  
In addition, no further adjustment will be made for multiple analyses (i.e., first and second 
analyses), since the primary efficacy endpoint and the key secondary efficacy endpoints will all 
have been conducted at the time of first analysis.
 
2.4.4.4 Additional efficacy analysis 
 
Not applicable 
2.4.5 Analyses of safety data 
Safety analyses will be conducted using data of the DBTP and OLTP. The summary of safety 
results will be presented separately for the DBTP on the safety population and OLTP on the OLT 
population. Besides, safety analyses performed on the alirocumab exposed period (see Section 
2.1.4) will be conducted on the alirocumab safety population to evaluate long-term safety at the 
first step analysis.  
The analyses performed on the DBTP will be presented by treatment group while the analyses 
performed on the OLTP or the alirocumab exposed period will be presented by overall patients. 
No formal inferential testing will be performed. Summaries will be descriptive in nature. All 
summaries of safety results described below will be presented for each observation period 
respectively, unless otherwise noted. 
General common rules 
All safety analyses will be performed using the following common rules: 
x 
Safety data in patients who do not belong to the safety population (eg, exposed but not 
randomized) will be listed separately 
x 
The baseline value for both double-blind and open-label treatment period is defined as the 
last available value before the first double-blind IMP injection, except otherwise specified.  
x 
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, vital signs, and ECG (PCSA defined in the document “Analysis and 
reporting safety data from clinical trials through the Clinical Study Report (CSR) (Version 
Number: 3.0)” [Appendix A])  
Considering that the threshold defined in the PCSA list for monocytes and basophils can 
be below the ULN, the following PCSA criterion will be used for the PCSA analysis of 
monocytes and basophils: 
- 
PCSA criterion for monocytes: >0.7 Giga/L or > ULN (if ULN 0.7 Giga/L); 
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-
PCSA criterion for basophils: >0.1 Giga/L or > ULN (if ULN 0.1 Giga/L).
x
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.
x
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.
x
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 64 time points.
x
In both the DBTP and the OLTP, 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 of each observation period (see Section 2.1.4). The worst on-treatment value is
defined as the nadir and /or the peak value during the treatment period of each observation
period according to the direction (minimum or maximum) of the abnormality as defined in
PCSA list.
Analyses performed according to diabetes status will be done using the CMQ definition 
(regardless of the ongoing status) (Section 2.1.1). 
2.4.5.1 Analyses of adverse events 
Generalities 
The primary focus of AE reporting will be on TEAEs, presented in each observation period. Pre-
treatment and post-treatment AEs will be described separately.  
If an AE date/time of onset (occurrence, worsening, or becoming serious) is incomplete, an 
imputation algorithm will be used to classify the AE as pre-treatment, treatment-emergent, or 
post-treatment. The algorithm for imputing date/time of onset will be conservative and will 
classify an AE as treatment-emergent unless there is definitive information to determine it is pre-
treatment or post-treatment. Details on classification of AEs with missing or partial onset dates are 
provided in Section 2.5.3. 
AE incidence tables will present, the number (n) and percentage (%) of patients experiencing an 
AE by SOC, HLGT (when applicable), HLT (when applicable), and PT. Multiple occurrences of 
the same event in the same patient will be counted only once in the tables within a treatment phase. 
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 AEs within the observation 
period (pre-treatment, TEAE, and post-treatment). For that purpose, the table of all TEAEs 
presented by SOC and PT sorted by the internationally agreed SOC order and decreasing 
frequency of PTs within SOCs (in the alirocumab 150mg Q4W group) will define the presentation 
order for all other tables by SOC and PT, unless otherwise specified. The tables of AEs by SOC, 
HLGT, HLT and PT will be sorted by the SOC internationally agreed order and the other levels 
(HLGT, HLT, PT) will be presented in alphabetical order, unless otherwise specified 
Analysis of all treatment-emergent adverse events 
The following TEAEs summaries will be generated. 
x 
Overview of TEAEs, summarizing number (%) of patients with any 
- 
TEAE; 
- 
Serious TEAE; 
- 
TEAE leading to death; 
- 
TEAE leading to permanent treatment discontinuation. 
x 
All TEAEs by primary SOC, HLGT, HLT, and PT; 
x 
Number (%) of patients experiencing common TEAE(s) presented by primary SOC, HLT 
and PT (HLT incidence 2 % in any treatment group), sorted by SOC internationally 
agreed order and by alphabetic order for the other levels (HLT and PT); 
x 
All TEAEs by primary SOC and PT, sorted by the internationally agreed SOC order and by 
decreasing incidence of PTs within each SOC (in the alirocumab 150 mg Q4W group).  
This sorting order will be applied to all other tables by SOC and PT of TEAEs, unless 
otherwise specified; 
x 
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; 
x 
All TEAEs by maximal intensity (ie, mild, moderate or severe), presented by primary SOC 
and PT, sorted by the sorting order defined above; 
Analysis of all treatment emergent serious adverse event(s) 
x 
All serious TEAEs by primary SOC, HLGT, HLT, and PT; 
x 
All serious TEAEs by treatment group regardless of relationship in one column and, in the 
same table a second column with TEAEs related to alirocumab according to investigator’s 
opinion, by primary SOC, HLGT, HLT, and PT; 
Analysis of all TEAE(s) leading to treatment discontinuation 
x 
All TEAEs leading to treatment discontinuation, by primary SOC, HLGT, HLT, and PT 
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Analysis of groupings of adverse events including selected adverse events of special interest 
x 
All grouping of TEAEs including adverse events of special interest as listed in Section 
2.1.4.1(except Pregnancy and overdose with NIMP) 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 150 mg Q4W group). 
x 
 
 
x 
Analyses of grouping of AEs for diabetes (Section 2.1.4.1) will be performed overall and 
according to the diabetic status at baseline (Section 2.1.1). 
In addition, the following variables will be tabulated for the local injection site reactions TEAEs: 
x 
Intensity of the event (mild, moderate, severe); 
x 
Number of events divided by the number of double-blind IMP injections received (number 
of open-label IMP injections for analysis in OLTP, number of alirocumab IMP injections 
for analysis in alirocumab exposed period); 
x 
Time from first double-blind IMP injection to first injection site reaction (time from first 
open-label IMP injection for analysis in OLTP, from first alircumab injection for analysis 
in alirocumab exposed period); 
x 
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.  
Analysis of pre-treatment and post-treatment adverse events  
x 
All pre-treatment AEs by primary SOC and PT, sorted by the internationally agreed SOC 
order and decreasing incidence of PTs (in the alirocumab 150mg Q4W group) within each 
SOC; 
x 
All pre-treatment AEs leading to treatment discontinuation by primary SOC and PT, sorted 
by the sorting order defined above; 
x 
All post-treatment AEs by primary SOC and PT, sorted by the internationally agreed SOC 
order and decreasing incidence of PTs (in the alirocumab 150mg Q4W group) within each 
SOC; 
x 
All post-treatment SAEs by primary SOC and PT, sorted by the sorting order defined 
above; 
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Subgroup of patients with 2 consecutive LDL-C <25 mg/dL 
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 
(as defined in Section 2.1.5) . 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 will be 
considered. 
 
 
 
 
 
 
 
 
 
 
 
 
2.4.5.2 Deaths 
The following summaries of deaths will be generated for the DBTP and the OLTP. 
x 
Number (%) of patients who died by period (on-study, on-treatment, post-study) and 
reasons for death as adjudicated by the CEC;  
x 
Deaths in nonrandomized patients or randomized but not treated patients 
x 
TEAEs leading to death (death as an outcome on the AE as reported by the Investigator) by 
primary SOC, HLGT, HLT, and PT sorted by internationally agreed SOC order, with 
HLGT, HLT, and PT presented in alphabetical order within each SOC. TEAE leading to 
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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, Q1, Q3, SD, 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 value of the treatment period, last 
on-treatment and 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), as well as ALT increase as defined as 
AESI and hemoglobin decrease from baseline 15g/L (see Section 2.1.4.1), at any time during the 
TEAE period will be summarized by biological function and treatment group irrespective of the 
baseline level and/or baseline level and/or according to the following baseline status categories:  
x 
Normal/missing 
x 
Abnormal according to PCSA criterion or criteria 
Glucose (quantitative summary and PCSA) will also be analyzed, overall and according to the 
diabetes status at baseline defined in Section 2.1.1. 
CPK (PCSA) will also be analyzed, overall and according to prior history of side effects caused by 
statin. 
For parameters for which no PCSA criteria are defined, similar table(s) using the normal range 
will be provided. 
Hepatitis C 
Analysis of hepatitis C will be done for patients below according to analysis period.  
x 
DBTP (Hepatitis C planned to be tested for patients who prematurely discontinue study 
treatment during DBTP) in safety population.  
x 
Alirocumab exposed period (at first step analysis only) (Hepatitis C planned to be tested 
for patients who prematurely discontinue study treatment during alirocumab exposed 
period) in alirocumab safety population.  
x 
OLTP: in OLT population. 
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 
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positive antibody (Ab) 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 test result 
Negative 
Positive 
Reflexive test a – 
hepatitis C RNA test 
Not available or HCV 
RNA not detected 
HCV RNA 
detected 
HCV RNA not 
detected b  
HCV RNA 
detected 
Not available  
Hepatitis C status - 
label 
Negative 
Positive RNA 
Negative b 
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: 
x 
“Positive RNA” status if at least one post-baseline positive RNA is detected, regardless of 
status of the patient at the end of treatment. 
x 
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.  
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, ALP, and total bilirubin, are used to assess possible 
drug-induced liver toxicity.  The proportion of patients with PCSA values or ALT increase as 
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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). 
Analysis of clinical laboratory variables in the open-label treatment period 
For OLTP, summary tables as described for the DBTP above will be used with the following 
exception: 
x 
Analyses by visit (unless data warrants further investigation) 
Analysis of clinical laboratory variables in the alirocumab exposed period (first step anlaysis 
only) 
For alirocumab exposed period, summary tables as described for the DBTP above will be used 
with the following exception: 
x 
Analyses by visit (unless data warrants further investigation) 
2.4.5.4 Analyses of vital sign variables 
The summary statistics (including number, mean, median, Q1, Q3, SD, minimum and maximum) 
of all vital signs variables (central laboratory values and changes from baseline) will be calculated 
for each visit or study assessment (baseline, each post-baseline  value of the treatment period, 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 TEAE period will be summarized by treatment 
group.  
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Analysis of vital signs variables in the open-label treatment period 
For OLTP, summary tables as described for the DBTP above will be used with the following 
exception: 
x 
Analysis by visit (unless data warrants further investigation) 
Analysis of vital signs variables in the alirocumab exposed period (first step analysis only) 
For alirocumab exposed period, summary tables as described for the DBTP above will be used 
with the following exception: 
x 
Analyses by visit (unless data warrants further investigation) 
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: 
x 
Normal/missing; 
x 
Abnormal. 
2.4.6 Analyses of other 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 
64 time points. 
HbA1c parameters will be summarized by analysis visit using number of available data, mean, SD, 
median, minimum, and maximum for each treatment group during the DBTP and OLTP. For 
HbA1c in DBTP, summary will be also provided according to the diabetes status at baseline 
defined in Section 2.1.1. The time profile of each parameter will be also plotted by treatment 
group with the means and the corresponding SEs for HbA1c in DBTP. The incidence of PCSA at 
any time during the double-blind TEAE period will be also summarized on safety population by 
treatment group using descriptive statistics. PCSA for HbA1c will be also provided according to 
the diabetes status at baseline. The incidence of PCSA at any time during the open-label TEAE 
period (on OLT population) and during alirocumab exposed TEAE period (on alirocumab exposed 
population, at first step analysis only) will be also summarized using descriptive statistics. PCSA 
for HbA1c will be also provided according to the diabetes status at baseline. 
Binary endpoints defined in Section 2.1.5 will be described using count and percentage.
 
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. 
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2.4.7 Analyses of anti-alirocumab antibodies variables 
The summary of ADA variables will be presented separately for the DBTP (on ADA population) 
and 
 
 
 
 
 
 
The following summaries will be performed, taking into account all samples regardless of timing 
in relation to injections but within each study period separately: 
 
 
 
 
 
 
x 
Number (%) of patients with pre-existing ADA and number (%) of patients with treatment-
emergent ADA positive response  
Number (%) of patients with persistent/transient/indeterminate treatment-emergent ADA 
positive response (for alirocumab exposed period and 
; 
x 
Time to onset of treatment-emergent ADA positive response using descriptive 
statistics.beginning from the first IMP administration within the relevant period
 
 
2.4.8 Analyses of pharmacokinetic and pharmacodynamic variables 
Serum total alirocumab concentration (alirocumab concentration, Ctrough 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. 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). 
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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”: 
x 
Intermittent claudication (linked to PAD) TOGETHER WITH ankle-brachial index 0.90 
Or 
x 
Intermittent claudication (linked to PAD) TOGETHER WITH peripheral revascularization 
procedure (angioplasty, stenting) for PAD or peripheral revascularization surgery (arterial 
bypass) for PAD 
Or 
x 
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 (for double-blind and for open-label) 
The date of the last injection in the DBTP is equal to the last date of administration reported on 
injection administration case report form page in DBTP, or missing if the last administration date 
is unknown.  
The date of the last injection in the OLTP is equal to the last date of administration reported on 
injection administration case report form page in OLTP, or missing if the last administration date 
is unknown.  
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Renal function formulas  
estimated Glomerular filtration rate (eGFR) value will be derived using the Modification of the 
Diet in Renal Disease (MDRD) equation: 
175 × (creatinine in μmol/L / 88.4)-1.154 × (age in years)-0.203 (x 0.742 if female, x 1.212 if race is 
"black or african american").  
Lipids variables, 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. 
Pharmacokinetic variables 
Data below the LLOQ are set to zero. 
2.5.2 Data handling conventions for secondary efficacy variables 
See Section 2.1.3. 
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 the time of assessment at Week 0 visit is 
missing then the baseline value is defined as the last available value obtained before or on the day 
of the first double-blind IMP administration. 
Handling of computation of treatment duration and compliance if investigational medicinal 
product first or end of treatment date is missing 
If the last or first injection date is missing, the exposure duration and compliance will be left as 
missing. 
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Handling of safety and efficacy analysis periods and survival analysis if investigational 
medicinal product end of treatment date is missing  
If the last injection date of DBTP or OLTP is missing, then this date is imputed to the earliest 
between: 
x 
the last day of the month and year, when applicable or else the 31st of December of the 
year,  
x 
the date of the end of treatment visit of the period (DBTP: Week 12 visit for patients who 
completed the double-blind study treatment period as per protocol, early end of treatment 
visit for patients who prematurely discontinued the IMP; OLTP: Week 64 visit for patients 
who completed the open-label study treatment period as per protocol, early end of 
treatment visit for patients who prematurely discontinued the IMP) 
x 
and the date of the last contact, 
for the purpose of safety and efficacy analysis period start and/or end.  
The last dose intake should be clearly identified in the case report form and will not be 
approximated by the last returned package date. 
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 posttreatment medication. 
Handling of adverse events with missing or partial date/time of onset 
Missing or partial AE dates and times will be imputed so that if the partial AE date/time 
information does not indicate that the AE started prior to treatment or after the TEAE period, the 
AE will be classified as treatment-emergent. These data imputations are for categorization purpose 
only and will not be used in listings. No imputation is planned for date/time of AE resolution. 
Handling of adverse events when date and time of first investigational medicinal product 
administration is missing 
When the date and time of the first double-blind IMP administration is missing, all adverse events 
that occurred on or after the day of randomization should be considered as treatment-emergent 
adverse events.  The exposure duration should be kept as missing. 
When the time of the first double-blind IMP administration is missing, all AEs that occurred on 
the day of the first double-blind IMP administration will be considered as TEAEs. 
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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 and the adverse event considered as such in the frequency tables of possibly related 
adverse events, but no imputation should be done at the data level. 
Handling of potentially clinically significant abnormalities 
If a patient has a missing baseline value he will be grouped in the category “normal/missing at 
baseline”. 
For PCSAs with 2 conditions, one based on a change from baseline value and the other on a 
threshold value or a normal range, with the first condition being missing, the PCSA will be based 
only on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; 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 
2.5.4.1 Time points for efficacy data, laboratory safety data, ADA, and PK 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
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2.5.4.2 Time points for vital signs 
 
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2.5.5 Unscheduled visits 
For efficacy, safety laboratory data, or 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. 
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 to not 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 
TWO-STEP ANALYSIS 
The analysis will be conducted in 2 steps, although no formal interim analysis for efficacy is 
planned in this study. No multiplicity adjustment for multiple analyses is needed as explained in 
Section 2.4.4.3. 
x 
First step: Efficacy and safety analyses using data up to 24 weeks after randomization 
(including 12 weeks double-blind). 
- 
This analysis will be conducted as soon as all patients have been randomized and have 
at least all their data up to Week 24 (including 12 weeks DBTP and 12 weeks OLTP) 
collected and validated. 
- 
The final analysis of the primary and secondary efficacy endpoints will be performed 
up to Week 12 time point. The results of this analysis will not be used to change the 
conduct of the ongoing study in any aspect. 
- 
 
 
- 
The safety analyses will be performed on all safety data up to the patient’s cut-off date 
defined as the date of Week 24 visit or the date corresponding to 169 days (i.e. 
6 months) after first double-blind IMP injection for patients with no Week 24 visit. 
x 
Second step: Long-term safety and efficacy exploratory analysis 
- 
This analysis will be conducted at the end of the study with all data including the data 
of the OLTP, and will consist in the final analysis of the safety endpoints and 
exploratory efficacy assessment during the OLTP. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4 
DATABASE LOCK 
Two database locks will be done: 
x
First database lock (for first analysis):  will include all available data on all randomized
patients up to date of Week 24 visit for each patient as defined in Section 3. 
x
Final database lock (for second analysis):  will include all data, including follow-up, for all
randomized patients. 
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5 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses will be generated using SAS version 9.4 or higher. 
 
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6 
REFERENCES 
1. 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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