A Multi-country, Multicenter, Single-arm, Open-label Study to Document the Safety, Tolerability and Effect of Alirocumab on Atherogenic Lipoproteins in High Cardio-vascular Risk Patients With Severe Hypercholesterolemia Not Adequately Controlled With Conventional Lipid-modifying Therapies
Phase: PHASE3
Conditions: Hypercholesterolemia
Sponsor: Sanofi

According to template: QSD-003152 VERSION N°2.0 (28-JUN-2013) 
Page 1
AMENDED CLINICAL TRIAL PROTOCOL 01 
COMPOUND: alirocumab 
A Multi-Country, Multicenter, Single-Arm, Open-Label Study to Document the 
Safety, Tolerability and Effect of Alirocumab on atherogenic lipoproteins in High 
Cardio-Vascular Risk Patients With Severe Hypercholesterolemia Not Adequately 
Controlled With Conventional Lipid-Modifying Therapies  
STUDY NUMBER: LPS14245  
STUDY NAME: ODYSSEY APPRISE 
VERSION DATE / STATUS: 01-Mar-2016 / Approved 
CLINICAL STUDY DIRECTOR: 
 
Protocol Amendment 5 
Version number: 1 (electronic 2.0) 
Date: 01-Mar-2016 
Amended Clinical Trial Protocol 1 (DK) 
Version number: 1 (electronic 1.0) 
Date: 30-Jul-2015 
Protocol Amendment 4 (DK) 
Version number: 1 (electronic 1.0) 
Date: 30-Jul-2015 
Amended Clinical Trial Protocol 1 (DE) 
Version number: 1 (electronic 1.0) 
Date: 14-Jul-2015 
Protocol Amendment 3 (DE) 
Version number: 1 (electronic 2.0) 
Date: 14-Jul-2015 
Amended Clinical Trial Protocol 1 (FR) 
Version number: 1 (electronic 1.0) 
Date: 21-May-2015 
Protocol Amendment 2 (FR) 
Version number: 1 (electronic 1.0) 
Date: 21-May-2015 
Amended Clinical Trial Protocol 1 (BE) 
Version number: 1 (electronic 1.0) 
Date: 21-May-2015 
Protocol Amendment 1 (BE) 
Version number: 1 (electronic 1.0) 
Date: 21-May-2015 
Clinical Trial Protocol 
Version number: 1 (electronic 3.0) 
Date: 19-Mar-2015 
EudraCT: 
2015-000620-28 
IND number: 
- 
(electronic 2.0)
NCT02476006
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 

Amended Clinical Trial Protocol 01  
01-Mar-2016 
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Page 2 
NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
  
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
  
Company: 
Address: 
 
 
 
 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
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Amended Clinical Trial Protocol 01  
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Property of the Sanofi Group- strictly confidential 
Page 3 
CLINICAL TRIAL SUMMARY 
COMPOUND: alirocumab 
STUDY No: LPS14245 
TITLE 
A Multi-Country, Multicenter, Single-Arm, Open-Label Study to Document the 
Safety, Tolerability and Effect of Alirocumab on atherogenic lipoproteins in High 
Cardio-Vascular Risk Patients With Severe Hypercholesterolemia Not Adequately 
Controlled With Conventional Lipid-Modifying Therapies. 
INVESTIGATOR/TRIAL LOCATION Europe & Canada. 
PHASE OF DEVELOPMENT 
Phase IIIb. 
STUDY OBJECTIVE(S) 
Primary objective 
• 
To provide patients with severe hypercholesterolemia at risk for 
subsequent cardiovascular (CV) events and not adequately controlled 
with currently available lipid modifying therapy (LMT) access to 
alirocumab ahead of commercial availability and to document the overall 
safety and tolerability of alirocumab in this patient population. 
Secondary objective(s) 
• 
To document the effect of alirocumab on low-density lipoprotein 
cholesterol (LDL-C) levels as well as non-high-density lipoprotein 
cholesterol (non-HDL-C), total cholesterol (total-C), high-density 
lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels after 
12 weeks of treatment. 
• 
To document patient’s acceptability of self-injection (Self Injection 
Assessment Questionnaire, SIAQ). 
STUDY DESIGN 
This study will be conducted as a multi-country, multi-center prospective, single 
arm, open-label, phase IIIb clinical trial. 
After enrollment, patients will receive study treatment alirocumab 150 mg 
subcutaneous (SC) once every 2 weeks (Q2W) or 75 mg subcutaneous (SC) Q2W. 
During the study, the dose may be adjusted according to the investigator, based on 
treatment response, Alirocumab will be administered on top of stable maximally 
tolerated statin therapy ±other LMTs.  
The study consists of: 
• 
A screening period of up to 3 weeks, including an intermediate visit 
during which the patient or another designated person (such as spouse, 
relative, etc) will be trained to self-inject/inject. 
• 
An open-label treatment period with alirocumab of at least 12 weeks and 
until the product becomes commercially available and reimbursed. 
However, the open label treatment period will not exceed 30 months.  
• 
An end-of-study visit will take place at least 14 days after the last 
treatment injection. 
 
Patients should be on a stable diet (NCEP-ATPIII TLC diet or equivalent) 
throughout the entire study duration from screening to the end of the study 
treatment. 
Statin dose and dose regimen as well as dose and dose regimen of other LMTs 
(if applicable) should be stable throughout the whole study duration including the 
screening period. 
Nevertheless, modification of LMT is allowed under certain conditions after 
enrollment as described in Section 8. 
(electronic 
 
 
 
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STUDY POPULATION  
Main selection criteria 
Inclusion Criteria: 
• 
Signed written informed consent.  
• 
Age ≥18 years or legal age of majority at screening visit. 
• 
Either A, B, C, D or E below and not adequately controlled with a 
maximally tolerated dose of statin* with or without other LMT, all at stable 
doses for at least 4 weeks prior to the screening visit (Week -3): 
• 
A- Patients suffering from heterozygous familial hypercholesterolemia 
(heFH) with LDL-C concentrations ≥160 mg/dL (4.14 mmol/L) despite 
treatment. 
• 
B- Patients suffering from heFH with LDL-C concentrations ≥130 mg/dL 
(3.36 mmol/L) despite treatment and two or more CV risk factors among 
this list : 
- 
LDL-C >250 mg/dL (6.46 mmol/L) at the time of the familial 
hypercholesterolemia (FH) diagnosis (before treatment), 
- 
Family history of premature-onset coronary heart disease (CHD) 
(first-degree male relative with onset before age 55 years;  
first-degree female relative with onset before age 65 years), 
- 
Metabolic syndrome (cf. definition), 
- 
HDL-C <40 mg/dL (1.03 mmol/L), 
- 
Hypertension (BP >140/90 mmHg or drug treatment), 
- 
Lipoprotein a [Lp(a)] ≥50 mg/dL (1.78 µmol/L), 
- 
Tendon xanthoma. 
• 
C- Patients suffering from heFH with LDL-C concentrations ≥130 mg/dL 
(3.36 mmol/L) despite treatment and one of the following characteristics: 
- 
Established CHD or other CVD (history of acute myocardial 
infarction, ischemic stroke, peripheral arterial disease, coronary or 
peripheral arterial revascularization, stable or unstable angina, 
transient ischemic attack, carotid artery stenosis ≥50%, aortic 
abdominal aneurysm), 
- 
Drug treated type 2 diabetes mellitus or type 1 with target organ 
damage, 
- 
Family history of first or second degree relative with very premature 
onset CHD (first or second degree male relative onset before 
age 45; first or second degree female relative onset before age 55). 
• 
D- Non-FH patients suffering from established CHD or other CVD 
(history of acute myocardial infarction (MI), ischemic stroke, peripheral 
arterial disease (PAD), coronary or peripheral arterial revascularization, 
stable or unstable angina, transient ischemic attack (TIA), carotid artery 
stenosis ≥50%, aortic abdominal aneurysm) and with LDL cholesterol 
concentrations ≥130 mg/dL (3.36 mmol/L). 
• 
E- Patients suffering from progressive cardiovascular disease [coronary 
artery disease, or peripheral arterial occlusive disease or 
cerebrovascular disease as documented clinically or by imaging 
techniques, with a subsequent CV event (acute MI, ischemic stroke, 
ischemia driven revascularization, unstable angina, TIA) occurring 
despite stable doses of maximally tolerated LMT] with LDL cholesterol 
concentrations ≥100 mg/dL (2.59 mmol/L). 
(electronic 
 
 
 
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Amended Clinical Trial Protocol 01  
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Page 5 
 
Note: 
* Definition of maximally tolerated dose (any of the following are acceptable): 
• 
Rosuvastatin 20 mg or 40 mg daily. 
• 
Atorvastatin 40 mg or 80 mg daily. 
• 
Simvastatin 80 mg daily (if already on this dose for >1 year). 
• 
Patients not able to be on any of the above statin doses should be 
treated with the dose of atorvastatin, rosuvastatin or simvastatin which is 
considered appropriate for the patient as per the investigator's judgment 
or concerns.  
NB: in exceptional and well documented cases described in Exclusion 
criteria E04, another statin regimen may be used. 
• 
Some examples of acceptable reasons for a patient taking a lower statin 
dose include, but are not limited to: adverse effects on higher doses, 
advanced age, low body mass index, concomitant medications, and co-
morbid conditions such as impaired glucose tolerance /impaired fasting 
glucose. The reason(s) will need to be documented in the case report 
form. 
 
Exclusion criteria 
• 
Not on a stable dose of LMT (including statin) for at least 4 weeks prior to 
the screening visit (Week -3) and from screening to enrollment. 
• 
Use of a fibrate other than fenofibrate within 4 weeks of the screening 
visit (Week-3) or between screening and enrollment. 
• 
Daily doses above atorvastatin 80 mg, rosuvastatin 40 mg or simvastatin 
40 mg (except for patients on simvastatin 80 mg for more than one year, 
who are eligible). 
• 
Use of statin other than simvastatin, atorvastatin or rosuvastatin, prior to 
the screening visit (Week-3) or between screening and enrolment with 
the exception of the cases in which there is a documented reason for 
intolerance to the above mentioned potent statins in which case the use 
of a different statin is allowed. 
• 
Fasting serum TG >400 mg/dL (>4.52 mmol/L) at the screening visit 
(Week-3). 
• 
Uncontrolled hypertension (>180 mm Hg systolic and/or >110 mm Hg 
diastolic at screening or inclusion visit). 
• 
New York Heart Association class III or IV congestive heart failure 
persisting despite treatment. 
 
• 
History of hemorrhagic stroke. 
• 
Liver transaminases >3 times upper limit of normal at screening visit. 
• 
Laboratory evidence of current hepatitis B or C infection. 
• 
Creatine kinase >3 times upper limit of normal at screening visit. 
• 
Estimated glomerular filtration rate <30 mL/min (1.73 m2) at screening 
visit. 
• 
Pregnant or breastfeeding woman or with childbearing potential without 
appropriate contraception. 
• 
Patients eligible for enrollment into an ongoing clinical study of 
alirocumab conducted at same investigational site. 
• 
Hypersensitivity to alirocumab or any of the excipients. 
• 
For a full list of exclusion criteria, see Section 7.2. 
Total expected number of patients It is anticipated that approximately 1300 patients will be enrolled in this study. 
(electronic 
 
 
 
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Amended Clinical Trial Protocol 01  
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Page 6 
STUDY TREATMENT(s) 
 
Investigational medicinal 
product(s) 
Alirocumab. 
Prefilled pens containing alirocumab 75 mg/mL or 150mg/mL.  
Formulation 
Sterile alirocumab drug product supplied at a concentration of 75 mg/mL and 
150 mg/mL in histidine, pH 6.0, polysorbate 20, and sucrose, both as 1 mL volume 
in a pre-filled pen. 
Route(s) of administration 
Subcutaneous (SC) injections in the abdomen, thigh or outer area of upper arm. 
Dose regimen 
The dose is 75 mg or 150 mg administered subcutaneously once every 2 weeks 
(Q2W). 
The dose selection should be based on individual patient characteristics and goal 
of therapy. The dose can be adjusted based on treatment response. 
Injection for training 
Placebo for alirocumab. 
Formulation 
Sterile solution consisting of histidine, pH 6.0, polysorbate 20, and sucrose, as 
1 mL volume in a pre-filled pen. 
Route of administration 
Subcutaneous (SC) injections in the abdomen, thigh or outer area of upper arm. 
ENDPOINT(S) 
Primary endpoint: 
Safety parameters (adverse events, adverse events of special interest, laboratory 
data, product complaints and vital signs) assessed throughout the study. 
Secondary endpoint(s): 
Patients’ acceptability of self-injection (Self Injection Assessment Questionnaire). 
Among other endpoints of interest, see Section 9.2.2: 
• 
Proportion of patients reaching calculated LDL-C <100 mg/dL 
(2.59mmol/L) at Week 12. 
• 
Proportion of patients reaching calculated LDL-C <70 mg/dL 
(1.81mmol/L) at Week 12. 
• 
Proportion of patients with LDL-C <70 mg/dL (1.81 mmol/L) and/or  
≥50% reduction from baseline in LDL-C (if LDL-C ≥70 mg/dL 
[(1.81 mmol/L]) at Week 12. 
• 
Percent changes from baseline in LDL-C as well as non-HDL-C, total-C, 
HDL-C, and TG levels after 12 weeks of treatment. 
All endpoints will be defined in the SAP. 
ASSESSMENT SCHEDULE 
Patient’s assessments in the screening period: 
• 
On-site visits: Week -3 (screening visit), Week -1 (injection training visit if 
needed). 
Patient’s assessments in the treatment period: 
• 
On-site visits: Week 0 (inclusion visit), Week 4, Week 8, Week 12, 
Week 24, Week 48, then every 12 weeks until end of treatment 
(EOT/EOS). 
• 
Phone calls: Week 2 and Week 18. 
• 
Dispensation visits every 12 Weeks after Week 24. 
 
(electronic 
 
 
 
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Amended Clinical Trial Protocol 01  
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Page 7 
STATISTICAL CONSIDERATIONS 
Sample size determination: 
No formal sample size calculation is performed. 
The table below displays the 95% Confidence intervals (95%CI) associated to a 
variety of adverse event rates for a targeted sample size of 1300 patients.  
Expected 95% Confidence interval for various event rates 
Adverse event rates 
10% 
20% 
30% 
40% 
50% 
95%CI 
[8.4%; 
11.6%] 
[17.8%; 
22.2%] 
[27.5%; 
32.5%] 
[37.3%; 
42.7%] 
[47.3%; 
52.7%] 
For a rare non observed event, by using the rule of three, it can be estimated that 
the upper limit of the 95% confidence interval of the event rate is approximately 
0.23% (1 per 433). 
Analysis population: 
Safety population: all enrolled patients who actually received at least one dose or 
partial dose of alirocumab. 
Efficacy population: 
Modified Intend To Treat population (mITT): all enrolled patients who received at 
least one dose or partial dose of alirocumab, with a baseline LDL-C value available 
and with at least one on-treatment LDL-C measurement during the efficacy 
treatment period. 
Primary analysis: 
Safety analysis (adverse events, laboratory, product complaints and vital signs) will 
be performed on the safety population. Only descriptive summaries will be 
provided. 
The number of adverse events (AEs) during the study will be displayed. Adverse 
event incidence tables will present, by system organ class (SOC) high level group 
term (HLGT), high level term (HLT) and preferred term (PT), the number (n) and 
percentage (%) of patients experiencing an AE. 
Secondary analysis: 
The effects of alirocumab will be documented by the proportion of patients 
reaching calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 12, the proportion 
of patients reaching calculated LDL-C < 70 mg/dL (1.81 mmol/L) at Week 12 as 
well as by values and percent changes from baseline in LDL-C, non-HDL-C, 
 total-C, HDL-C, and TG levels after 12 weeks of treatment and at other time 
points. 
A descriptive analysis of the SIAQ will be done on the safety population.  
More details regarding statistical analyses will be provided in the SAP. 
DURATION OF STUDY (PER 
PATIENT) 
The study duration includes up to 3 weeks of screening period, a minimum of 
12 weeks and up to a maximum 30 months of open label study treatment period 
and at least 2 weeks after the last study treatment injection. 
In each country, patient recruitment will end when alirocumab becomes 
commercially available (ie, accessible to the patient as per each country regulation) 
and reimbursed. In this case, study treatment can be switched to the commercial 
product once the patient has completed the minimum of 12 weeks of study 
treatment. 
(electronic 
 
 
 
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Page 8 
STUDY COMMITTEES 
Steering Committee:  
 Yes    
 No 
Data Monitoring Committee: 
 Yes    
 No 
Adjudication Committee:  
 Yes    
 No 
 
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Amended Clinical Trial Protocol 01  
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1 
FLOW CHART 
1.1 
GRAPHICAL STUDY DESIGN 
 
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Amended Clinical Trial Protocol 01  
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Page 10 
1.2 
STUDY FLOW CHART 
 
 
Screening period 
Inclusion 
visit 
Study Treatment 
Study time points 
W-3 
 
(D-21 to -8) 
Screening 
visit 
W-1 
 
D-7 
Injection 
training 
visit * 
(optional) 
W0 
 
D1 
W2 
 
D15 
 
W4 
 
D29 
W8 
 
D57 
W12 
 
D85 
W18 
 
D127 
 
W24 
 
D169 
W36 
** 
D253 
W48 
 
D337 
W60 
** 
D421 
W72 
 
D505 
W84 
** 
D589 
W96 
 
D673 
W108 
** 
D757 
EOT/EOS 
Week 120 
*** 
Day 841 
+2 weeks 
after last 
injection 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
V17 
Visit windows 
 
 
+3 
±3 
±3 
±3 
±3 
±5 
±5 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
+7 
Inclusion and exclusion criteria  
9 
 
9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility confirmation and 
enrollment 
 
 
9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent form 
9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/Concomitant 
medication/LMT a 
9 
 
9 
9 
9 
9 
9 
9 
9 
9 
9 
9 
9 
9 
9 
9 
9 
Review of diet 
9 
 
 
 
9 
9 
9 
 
9 
 
9 
 
9 
 
9 
 
9 
Patient diary: dispensation / 
review / collection 
 
 
9 
 
9 
9 
9 
 
9 
9 
9 
9 
9 
9 
9 
9 
9 
Injection training 
9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SIAQ  PRE 
9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SIAQ  POST 
 
 
9 
 
9 
9 
9 
 
9 
 
9 
 
9 
 
9 
 
 
Physical examination b 
9 
 
9 
 
9 
9 
9 
 
9 
 
9 
 
9 
 
9 
 
9 
(electronic 
 
 
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Amended Clinical Trial Protocol 01  
01-Mar-2016 
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Page 11 
 
Screening period 
Inclusion 
visit 
Study Treatment 
Study time points 
W-3 
 
(D-21 to -8) 
Screening 
visit 
W-1 
 
D-7 
Injection 
training 
visit * 
(optional) 
W0 
 
D1 
W2 
 
D15 
 
W4 
 
D29 
W8 
 
D57 
W12 
 
D85 
W18 
 
D127 
 
W24 
 
D169 
W36 
** 
D253 
W48 
 
D337 
W60 
** 
D421 
W72 
 
D505 
W84 
** 
D589 
W96 
 
D673 
W108 
** 
D757 
EOT/EOS 
Week 120 
*** 
Day 841 
+2 weeks 
after last 
injection 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
V17 
Visit windows 
 
 
+3 
±3 
±3 
±3 
±3 
±5 
±5 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
+7 
Hematology and biochemistryc 
d 
9 
 
 
 
9 
 
9 
 
9 
 
9 
 
9 
 
9 
 
9j 
HbA1c 
9 
 
 
 
 
 
9 
 
9 
 
9 
 
9 
 
9 
 
9j 
Lipid profile e 
9 
 
 
 
9 
9 
9 
 
9 
 
9 
 
9 
 
9 
 
9j 
Urinalysis 
9 
 
9 
 
 
 
9 
 
 
 
 
 
 
 
 
 
9 
Liver panel f  
9 
 
 
 
9 
9 
9 
 
9 
 
9 
 
9 
 
9 
 
9j 
Hepatitis B and C serology 
9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9 l 
Telephone assessment  
 
 
 
9 
 
 
 
9 
 
 
 
 
 
 
 
 
 
Study treatment dispensation 
 
 
9 
 
9k 
9k 
9 
 
9 
9 
9 
9 
9 
9 
9 
9 
 
Compliance check i 
 
 
 
 
9 
9 
9 
 
9 
9 
9 
9 
9 
9 
9 
9 
9 
Study treatment administration g 
 
 
9 
 
 
Pregnancy test (women of 
childbearing potential) 
9m 
 
9n 
 
9n 
+AE/SAE recording h 
9 
* 
Injection training can also be performed during the screening or the inclusion visit. 
** 
Dispensation visits. 
*** 
Those patients with unresolved SAE/AESI at the EOT/EOS visit will be followed up by the investigator for as long as medically indicated, but without further recording in the eCRF 
a. 
Prior and concomitant medications started within 4 weeks before screening visit, lipid lowering therapies, antihypertensive medications, AEs/SAEs corrective therapies. 
(electronic 
 
 
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Amended Clinical Trial Protocol 01  
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Page 12 
 
Screening period 
Inclusion 
visit 
Study Treatment 
Study time points 
W-3 
 
(D-21 to -8) 
Screening 
visit 
W-1 
 
D-7 
Injection 
training 
visit * 
(optional) 
W0 
 
D1 
W2 
 
D15 
 
W4 
 
D29 
W8 
 
D57 
W12 
 
D85 
W18 
 
D127 
 
W24 
 
D169 
W36 
** 
D253 
W48 
 
D337 
W60 
** 
D421 
W72 
 
D505 
W84 
** 
D589 
W96 
 
D673 
W108 
** 
D757 
EOT/EOS 
Week 120 
*** 
Day 841 
+2 weeks 
after last 
injection 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
V17 
Visit windows 
 
 
+3 
±3 
±3 
±3 
±3 
±5 
±5 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
+7 
b. 
Physical examination and vital signs: height (only at screening), weight, HR, BP. 
c. 
Hematology: hemoglobin, RBC, Hb, Hematocrit, platelets, WBC count with differential blood count. Recent (1 week) lab result may be used instead. In case of unexpected or aberrant value a retest 
must be done before inclusion. 
d. 
Biochemistry: glucose, urea, calculated creatinine clearance, creatinine and eGFR using MDRD study equation, total CPK, sodium, potassium, chloride, bicarbonate, calcium, phosphorus, uric acid, 
total protein, LDH, albumin, GGT, Hepatitis C antibody (at screening, EOT/EOS and in case of transaminases elevation) to be confirmed by reflexive testing when positive, Hepatitis B antigen 
(screening only). Recent (1 week) lab result may be used instead. In case of unexpected or aberrant value a retest must be done before inclusion. 
e. 
Lipid profile: Total Cholesterol, Triglycerides, Calculated LDL-C, HDL-C, non-HDL-C. Recent (1 week) lab result may be used instead. In case of unexpected or aberrant value a retest must be done 
before inclusion. 
f. 
Liver panel: SGOT (AST), SGPT (ALT), alkaline phosphatase, total bilirubin. Recent (1 week) lab result may be used instead. 
g. 
Dose regimen: alirocumab 75 mg/mL or 150 mg/mL, SC, Q2W for the entire study treatment duration. Depending on the clinical situation, alirocumab can be started at 75 mg or 150 mg administered 
once every 2 weeks. During the study, the dose may be adjusted according to the investigator, based on treatment response. 
h. 
Safety evaluation: Adverse Events (AEs), product complaints, regardless of seriousness or relationship to alirocumab treatment, will be collected from the time the patient signs the informed consent 
form up to the EOT/EOS visit   
i. 
Review patient diary and treatment kit +data collection on study treatment administration. 
j. 
Repeat lab only in case of abnormality at EOT/EOS. 
k. 
New kit dispensation only if needed as per lab results. 
l. 
Hepatitis C only. 
m. 
Serum pregnancy test. 
n. 
Urine pregnancy test. 
 
 
 
(electronic 
 
 
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2 
TABLE OF CONTENTS 
1 
FLOW CHART.................................................................................................................................9 
1.1 
GRAPHICAL STUDY DESIGN ........................................................................................................9 
1.2 
STUDY FLOW CHART ..................................................................................................................10 
2 
TABLE OF CONTENTS ................................................................................................................13 
3 
LIST OF ABBREVIATIONS ..........................................................................................................18 
4 
INTRODUCTION AND RATIONALE.............................................................................................20 
5 
STUDY OBJECTIVES ...................................................................................................................30 
5.1 
PRIMARY.......................................................................................................................................30 
5.2 
SECONDARY ................................................................................................................................30 
6 
STUDY DESIGN ............................................................................................................................31 
6.1 
DESCRIPTION OF THE PROTOCOL...........................................................................................31 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................32 
6.2.1 
Duration of study participation for each patient .............................................................................32 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................32 
6.3 
INTERIM ANALYSIS......................................................................................................................32 
7 
SELECTION OF PATIENTS..........................................................................................................33 
7.1 
INCLUSION CRITERIA..................................................................................................................33 
7.2 
EXCLUSION CRITERIA ................................................................................................................35 
7.2.1 
Exclusion criteria related to study methodology ............................................................................35 
7.2.2 
Exclusion criteria related to the mandatory background therapies................................................37 
7.2.3 
Exclusion criteria related to the current knowledge of Sanofi compound......................................37 
8 
STUDY TREATMENTS .................................................................................................................38 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) ..........................................................................38 
8.1.1 
Route and method of administration..............................................................................................38 
8.1.2 
Timing of administration.................................................................................................................39 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) ..................................................................39 
8.3 
BLINDING PROCEDURES............................................................................................................40 
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8.4 
PACKAGING AND LABELING ......................................................................................................40 
8.5 
STORAGE CONDITIONS AND SHELF LIFE................................................................................40 
8.6 
RESPONSIBILITIES ......................................................................................................................40 
8.6.1 
Treatment accountability and compliance......................................................................................41 
8.6.2 
Return and/or destruction of treatments ........................................................................................42 
8.7 
CONCOMITANT MEDICATION.....................................................................................................42 
8.7.1 
Management of background lipid-modifying therapy .....................................................................42 
8.7.2 
Contraception.................................................................................................................................42 
8.7.3 
Prohibited concomitant medications ..............................................................................................43 
8.7.4 
Life style and dietary habits ...........................................................................................................43 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................44 
9.1 
PRIMARY ENDPOINTS.................................................................................................................44 
9.1.1 
Adverse events ..............................................................................................................................44 
9.1.2 
Safety laboratory............................................................................................................................45 
9.1.3 
Vital signs measurement................................................................................................................46 
9.2 
SECONDARY ENDPOINTS ..........................................................................................................46 
9.2.1 
Secondary efficacy endpoints........................................................................................................46 
9.2.1.1 
Efficacy assessment method .........................................................................................................46 
9.2.2 
Other secondary endpoints............................................................................................................46 
9.2.3 
Patient’s reported outcomes: patient’s acceptability of self-injection.............................................47 
9.3 
APPROPRIATENESS OF MEASUREMENTS ..............................................................................47 
10 
STUDY PROCEDURES ................................................................................................................48 
10.1 
VISIT SCHEDULE..........................................................................................................................50 
10.1.1 
Screening period............................................................................................................................50 
10.1.2 
Open-label Treatment Period.........................................................................................................52 
10.1.2.1 Inclusion visit (Visit 3 / Week 0 / Day 1 +3)....................................................................................52 
10.1.2.2 Phone calls: Visit 4 / Week 2 (Day 15 ±3), Visit 8 / Week 18 (Day 127 ±5) ..................................53 
10.1.2.3 Visit 5 / Week 4 (Day 29 ±3), Visit 6 / Week 8 (Day 57 ±3), Visit 7 / Week 12 (Day 85 ±3), 
Visit 9 / Week 24 (Day 169 ±5), Visit 11 / Week 48 (Day 337 ±7), Visit 13 / Week 72 (Day 
505 ±7), Visit 15 / Week 96 (Day 673 ±7)......................................................................................53 
10.1.2.4 Dispensation visits: Visit 10 / Week 36 (Day 253 ±7), Visit 12 /Week 60 (Day 421 ±7), Visit 
14 / Week 84 (Day 589 ±7), Visit 16 / Week 108 (Day 757 ±7).....................................................54 
10.1.2.5 End-of-treatment (EOT/EOS) visit: Visit 17 / Week 120 (Day 841 +7) ..........................................54 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................55 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................56 
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10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) ...........................56 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) ...........................57 
10.3.2.1 List of criteria for permanent treatment discontinuation.................................................................57 
10.3.2.2 Handling of patients after permanent treatment discontinuation ...................................................57 
10.3.2.3 Procedure and consequence for patient withdrawal from study....................................................58 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................58 
10.4.1 
Definitions of adverse events.........................................................................................................58 
10.4.1.1 Adverse event ................................................................................................................................58 
10.4.1.2 Serious adverse event ...................................................................................................................59 
10.4.1.3 Adverse event of special interest...................................................................................................60 
10.4.1.4 Local injection site reactions (non-allergic or allergic not requiring consultation)..........................61 
10.4.1.5 Device Deficiency...........................................................................................................................61 
10.4.2 
General guidelines for reporting adverse events (and product complaints) ..................................61 
10.4.3 
Instructions for reporting serious adverse events ..........................................................................62 
10.4.4 
Guidelines for reporting adverse events of special interest...........................................................63 
10.4.5 
Guidelines for management of specific laboratory abnormalities ..................................................63 
10.5 
OBLIGATIONS OF THE SPONSOR .............................................................................................64 
10.6 
SAFETY INSTRUCTIONS .............................................................................................................64 
10.6.1 
Local injection site reactions (non-allergic or allergic not requiring consultation)..........................64 
10.6.2 
Allergic Adverse Events .................................................................................................................65 
10.6.3 
Allergic adverse event with cutaneous involvement ......................................................................65 
10.6.4 
Acute allergic injection reactions....................................................................................................66 
10.7 
ADVERSE EVENTS MONITORING..............................................................................................66 
11 
STATISTICAL CONSIDERATIONS..............................................................................................67 
11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................67 
11.2 
DISPOSITION OF PATIENTS .......................................................................................................67 
11.3 
ANALYSIS POPULATIONS...........................................................................................................68 
11.3.1 
Efficacy population.........................................................................................................................68 
11.3.1.1 Modified intent-to-treat population .................................................................................................68 
11.3.2 
Safety population ...........................................................................................................................68 
11.3.3 
Other analysis population ..............................................................................................................68 
11.4 
STATISTICAL METHODS .............................................................................................................68 
11.4.1 
Extent of alirocumab exposure and compliance ............................................................................69 
11.4.1.1 Extent of investigational medicinal product exposure....................................................................69 
11.4.1.2 Compliance ....................................................................................................................................69 
11.4.2 
Analyses of safety data (see Section 9.1) .....................................................................................70 
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11.4.2.1 Analysis of adverse events ............................................................................................................70 
11.4.2.2 Analysis of laboratory data and vital signs.....................................................................................71 
11.4.3 
Analyses of efficacy data (see Section 9.2.1)................................................................................71 
11.4.4 
Analysis of other endpoint(s) (see Section 9.2.2)..........................................................................72 
11.4.5 
Analyses of patient’s acceptability of self-injection (see Section 9.2.3).........................................72 
11.5 
INTERIM ANALYSIS......................................................................................................................72 
12 
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................73 
12.1 
ETHICAL PRINCIPLES..................................................................................................................73 
12.2 
LAWS AND REGULATIONS .........................................................................................................73 
12.3 
ETHICAL AND REGULATORY STANDARDS ..............................................................................73 
12.4 
INFORMED CONSENT .................................................................................................................73 
12.5 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) ..............74 
13 
STUDY MONITORING...................................................................................................................75 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).......................................................................75 
13.2 
RESPONSIBILITIES OF THE SPONSOR.....................................................................................75 
13.3 
SOURCE DOCUMENT REQUIREMENTS....................................................................................76 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST......................................................................................................................................76 
13.5 
USE OF COMPUTERIZED SYSTEMS..........................................................................................76 
14 
ADDITIONAL REQUIREMENTS...................................................................................................77 
14.1 
CURRICULUM VITAE....................................................................................................................77 
14.2 
RECORD RETENTION IN STUDY SITES ....................................................................................77 
14.3 
CONFIDENTIALITY .......................................................................................................................77 
14.4 
PROPERTY RIGHTS.....................................................................................................................78 
14.5 
DATA PROTECTION.....................................................................................................................78 
14.6 
INSURANCE COMPENSATION....................................................................................................78 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES .................................79 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE............................................................................................................................................79 
14.8.1 
By the Sponsor...............................................................................................................................79 
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14.8.2 
By the Investigator .........................................................................................................................80 
14.9 
CLINICAL TRIAL RESULTS ..........................................................................................................80 
14.10 
PUBLICATIONS AND COMMUNICATIONS .................................................................................80 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ..........................................................................81 
16 
BIBLIOGRAPHIC REFERENCES.................................................................................................82 
17 
APPENDICES................................................................................................................................84 
APPENDIX A 
SUMMARY OF TLC DIET FOR HIGH CHOLESTEROL.....................................................85 
APPENDIX B 
WHO CRITERIA (DUTCH LIPID NETWORK CLINICAL CRITERIA) FOR 
DIAGNOSIS OF HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA (HEFH)..............86 
APPENDIX C SIMON BROOME REGISTER DIAGNOSTIC CRITERIA FOR HETEROZYGOUS 
FAMILIAL HYPERCHOLESTEROLEMIA......................................................................................87 
APPENDIX D THE STAGES OF HEART FAILURE – NYHA CLASSIFICATION .....................................88 
APPENDIX E 
SUMMARY OF ADVERSE EVENTS REPORTING INSTRUCTIONS AT SANOFI............89 
APPENDIX F GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI......................................................................................................91 
APPENDIX G 
SELF-INJECTION ASSESSMENT SCALE (SIAQ).............................................................96 
APPENDIX H ASSESSMENT OF LOCAL INJECTION SITE REACTIONS............................................104 
APPENDIX I 
GUIDANCE ON CONTRACEPTIVE METHODS FOR DENMARK ONLY .........................105 
APPENDIX J 
GUIDANCE ON CONTRACEPTIVE METHODS FOR SWEDEN ONLY...........................106 
APPENDIX K 
GUIDANCE ON CONTRACEPTIVE METHODS AND COLLECTION OF 
PREGNANCY INFORMATION....................................................................................................107 
APPENDIX L COUNTRY-SPECIFIC REQUIREMENT............................................................................111 
 
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3 
LIST OF ABBREVIATIONS 
 
AE  
adverse event 
AESI  
adverse events of special interest 
ALP  
alkaline phosphatase 
ALT  
alanine aminotransferase 
Apo  
apolipoprotein 
AST  
aspartate aminotransferase 
CABG  
coronary artery bypasses graft surgery 
CHD  
coronary heart disease 
CIB  
clinical investigator's brochure 
CPK  
creatine phosphokinase 
CT  
computed tomography 
CV/CVD  
cardiovascular/cardiovascular disease 
DNA  
deoxyribonucleic acid 
DRF  
discrepancy resolution form 
eCRF  
electronic case report form 
eGFR  
estimated glomerular filtration rate 
EZE 
ezetimibe 
FH  
familial hypercholesterolemia 
GCP  
good clinical practice 
γGT  
gamma-glutamyl transferase 
HbA1c  
glycated hemoglobin A1c 
HDL-C  
high density lipoprotein cholesterol 
HLGT  
high level group term 
HLT  
high level term 
ICF  
informed consent form 
ICH  
international conference on harmonization 
IEC  
Independent Ethics Committee 
IMP  
investigational medicinal product 
IRB  
institutional review board 
ITT  
intent-to-treat 
IV  
intravenous 
IVRS  
interactive voice response system 
IWRS  
interactive web response system 
LDH  
lactic dehydrogenase 
LDL-C  
low density lipoprotein cholesterol 
LDL-R  
low-density lipoprotein receptor 
LLN  
lower limit of normal range 
LMT  
lipid modifying therapy 
Lp(a)  
lipoprotein a 
MDRD  
modification of diet in renal disease 
MI  
myocardial infarction 
mITT  
modified intent-to-treat 
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mmHg  
millimeter of mercury 
NCEP-ATP III  
National Cholesterol Education Program Adult Treatment Panel III 
NYHA  
New York Heart Association 
NIMP  
non investigational medicinal product 
PCI  
percutaneous coronary intervention 
PCSA  
potentially clinically significant abnormality 
PCSK9  
proprotein convertase subtilisin/kexin type 9 
PRO 
patient reported outcomes 
PT  
preferred term 
Q2W  
Quoque 2 weeks 
SAE  
serious adverse event 
SAP  
statistical analysis plan 
SC 
subcutaneous 
SOC  
system-organ-class 
SUSAR  
suspected unexpected serious adverse reaction 
TOTAL-C  
total cholesterol 
TEAE  
treatment emergent adverse event 
TG  
triglycerides 
TLC  
therapeutic lifestyle changes 
TSH 
thyroid stimulating hormone 
ULN  
upper limit of normal range 
WOCBP  
women 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), being developed for the treatment of hypercholesterolemia. All 
relevant information concerning the compound is available in the latest version of the Clinical 
Investigator’s Brochure (CIB). 
Alirocumab is also referred to as “SAR236553/REGN727” in previous documents. However, in 
the context of the LPS14245 study protocol, it will be referred to as “alirocumab”. 
Background: 
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). 
Low-density lipoprotein cholesterol (LDL-C) is identified as the primary target of cholesterol 
lowering therapy (3) and is accepted as a valid surrogate endpoint (4, 5). Numerous studies have 
demonstrated that reducing LDL-C levels mainly with 3-hydroxy-3-methyl-glutaryl-CoA 
reductase (HMG CoA) inhibitors (commonly referred to as statins), 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% (6).  
Greater reductions in LDL-C produce greater reduction in events, and comparative data of 
intensive versus standard statin treatment suggest that the lower the LDL-C level, the greater the 
benefit in patients at high cardiovascular risk (6, 7, 8, 9). Accumulating data on the benefits of 
effective LDL-C lowering therapy led to the evolution of therapeutic guidelines over time, with 
more aggressive LDL-C goals in patients at high risk for CHD (3, 10, 11, 12). 
The long-term elevations of LDL-C leading to a progressive accumulation of coronary 
atherosclerosis require a long-term management which includes lifestyle measures as the primary 
intervention. However since lifestyle measures rarely reduce plasma LDL-C by >15%, use of 
pharmacologic treatments are needed to adequately treat dyslipidemic patients (13). Current 
LDL-C lowering medications include statins, ezetimibe (EZE), bile acid sequestrants, niacin, and 
fibrates, of which statins are the most commonly prescribed, as they have shown a great ability to 
lower LDL-C and reduce CHD events.  
Introduction to proprotein convertase subtilisin kexin type 9 (PCSK9): 
PCSK9 belongs to the subtilisin family of serine proteases and is highly expressed in the liver. 
PCSK9 is involved in regulating the levels of the low-density lipoprotein receptor (LDL-R) 
protein (14, 15). Once PCSK9 is secreted into plasma it directly binds to the LDL-R and promotes 
its lysosomal degradation after internalization. The increased degradation of LDLRs leads to a 
reduced LDL-C removal and, therefore higher LDL-C circulating levels. Experiments with mice 
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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 (16, 17). In humans, 
PCSK9 mutations have been identified: the gain-of-function mutations are rare and cause an 
autosomal dominant form of severe hypercholesterolemia and premature CHD, whereas 
loss- of-function mutations are more common and are associated with reduced plasma levels of 
LDL-C and protection from CHD (18, 19). 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 (20).  
Summary of clinical studies with alirocumab published to date: 
Phase 2 studies: 
Three Phase 2 studies (DFI11565, R727-CL-1003, DFI11566) have been conducted in patients 
receiving a statin (with or without ezetimibe) as background therapy: overall, a total of 
274 patients were exposed to at least one dose of alirocumab in these three Phase 2 studies. In 
addition, a fourth Phase 2 study (DFI12361) has been conducted in Japanese patients with 
75 patients exposed to at least one dose of alirocumab.  
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%. (LS mean difference versus placebo of -67.3% in DFI11565, -69.1% in 
DFI12361, -57.2% in R727-CL-1003; all p <0.0001) (21).  
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 (ie, the time interval between the two injections) in all these statin-treated patients. 
The same magnitude of effect was shown for the dose of 150 mg Q2W in the DFI11566 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 (Total-C), apolipoprotein B (ApoB), non-high density lipoprotein cholesterol 
(non HDL-C) and ApoB/ApoA-1 ratio. A favorable trend was also observed for HDL-C, ApoA-1, 
triglycerides (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 with no dose 
relationship. Rare cases of hypersensitivity reactions were reported. Among all serious adverse 
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events (SAE)s reported for all alirocumab studies, only one case, leucocytoclastic vasculitis 
(angiitis), was reported as being related to alirocumab (DFI11565 study). The patient developed 
one episode of diarrhea followed on the same evening by rash in arms, legs and abdomen 9 days 
after the first administration of 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 
treatment emergent adverse events (TEAEs) related to musculoskeletal or connective tissue 
disorders as well as no elevations in liver enzymes. For detailed information, please refer to the 
CIB. 
Selection of the dose:  
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.  
Two dosing regimens of alirocumab administered Q2W dosing are evaluated in the on-going 
ODYSSEY Phase 3 program: 
• 
Initiation with 75 mg, with up-titration to 150 mg in patients who do not reach pre-defined 
LDL-C goals based on their CV risk, and, 
• 
Initiation with the 150 mg Q2W dose. 
In the present study, the dose selection should be based on individual patient’s characteristics and 
goal of therapy. The dose can be adjusted based on treatment response. Lipid levels can be 
analyzed after 4 weeks, when maximum LDL-C reduction is usually achieved.  
Summary of Efficacy and Safety Findings of Completed Phase 3 Studies 
(as of 11 November 2014)  
The Phase 3 program is comprised of 14 studies mainly carried out in HeFH, patients at high 
CV risk, and statin-intolerant patients. Most had a background of lipid modifying therapy, 
including statins. Efficacy and safety summaries of completed Phase 3 studies (COMBO I, 
OPTIONS I, OPTIONS II, MONO, ALTERNATIVE) in addition to LONG TERM and HIGH FH 
which are relevant to the present study are described below. 
ODYSSEY COMBO I (EFC11568) is a randomized, double-blind, placebo-controlled, 
parallel-group study to evaluate the efficacy and safety of alirocumab in high cardiovascular risk 
patients with hypercholesterolemia not adequately controlled with their lipid modifying therapy.  
The numbers of treated patients were 207 and 107 in the alirocumab and placebo group, 
respectively. Patients with hypercholesterolemia and CHD or CHD risk equivalents on a 
maximally-tolerated dose of a potent statin, with 63% receiving atorvastatin 40 to 80 mg, 
rosuvastatin 20 to 40 mg or simvastatin 80 mg daily, had a mean (SD) overall calculated LDL-C 
at baseline of 102.2 (31.6) mg/dL (2.646 [0.820] mmol/L). They were administered with 
alirocumab 75 mg (with possibility for up titration to 150 mg at Week 12) or placebo Q2W.  
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A decrease in calculated LDL-C from baseline (intent-to-treat [ITT] analysis) was observed in the 
alirocumab group (LS mean [standard error (SE)] versus baseline: -48.2% [1.9]), compared to the 
placebo group (LS Mean [SE] versus baseline: -2.3% [2.7]), with an LS mean difference for the 
percent change from baseline of -45.9% ([95% CI: -52.5 to -39.3]; p <0.0001) at Week 24. The 
LS mean calculated LDL-C in the alirocumab group was 51.4 mg/dL (1.332 mmol/L) at Week 24 
as compared to 97.8 mg/dL (2.533 mmol/L) in the placebo group. Results of the on-treatment 
analysis at Week 24 were consistent with the ITT analysis. A calculated LDL-C reduction 
compared with baseline in the alirocumab group was observed from the first post-dose 
measurement at Week 4 and was maintained at all-time points up to Week 52. Alirocumab at the 
dose of 75 mg every 2 weeks (Q2W) used as initiation dose provided a statistically significant 
decrease in calculated LDL-C at Week 12 (LS mean difference for the percent change from 
baseline for the alirocumab versus placebo groups of -47.4% (95% CI: -53.6 to - 41.3; p <0.0001) 
(ITT analysis). At Week 24, the proportion of patients achieving a pre-defined calculated LDL-C 
target of <70 mg/dL [<1.81 mmol/L] was greater for alirocumab treatment (75.0%) compared 
with placebo (9.0%) in the ITT analysis. 
In the alirocumab group, 3 patients reported serious general allergic TEAEs (Asthma in 2 patients 
and Interstitial Lung Disease in 1 patient). Two patients on alirocumab permanently discontinued 
treatment due to a general allergic TEAE (Interstitial Lung Disease and Rash Generalized). 
One patient in the alirocumab group reporting an SAE of Retinal Detachment and another 
reported Muscular Weakness considered being an SAE. Three death cases were reported in each 
of the alirocumab and placebo groups, but none was related to the alirocumab. Thirty-nine 
patients (19.5%) in the alirocumab group had 2 consecutive calculated LDL-C values <25 mg/dL 
(<0.65 mmol/L) including 9 patients with 2 consecutive calculated LDL-C values <15 mg/dL 
(<0.39 mmol/L) in this study. No particular safety concerns were observed in these patients. 
ODYSSEY OPTIONS I (R727-CL-1110) is a randomized, double-blind, parallel-group study of 
the efficacy and safety of alirocumab added-on to atorvastatin versus ezetimibe added-on to 
atorvastatin versus atorvastatin dose increase versus switch to rosuvastatin in patients who are not 
controlled on atorvastatin. The number of patients treated with alirocumab, ezetimibe and double 
dose of statin were 104, 101 and 149, respectively. All patients in this study had 
hypercholesterolemia with a high or very high CV risk and they were on an atorvastatin treatment 
regimen (20 mg or 40 mg daily) at screening. They were administered with alirocumab 
75 mg Q2W (with possibility for up titration to 150 mg at Week 12) or ezetimibe 10 mg daily as 
add-on to atorvastatin, or increasing dose of atorvastatin, or rosuvastatin 40 mg daily. The mean 
(SD) calculated baseline LDL-C for all patients was 105.1 (34.1) mg/dL (2.723 [0.884] mmol/L). 
A statistically significant difference in the percent change from baseline in calculated LDL-C at 
Week 24 in the ITT analysis was observed for all prespecified comparisons between the addition 
of alirocumab to baseline therapy compared with other treatment choices. In the atorvastatin 
20 mg baseline regimen, reductions from baseline in LS mean LDL-C at Week 24 were 
significantly greater in the alirocumab + atorvastatin 20 mg group (-44.1%) compared with the 
atorvastatin 40 mg (-5.0%; p <0.0001) and atorvastatin 20 mg + ezetimibe 10 mg (-20.5%; 
p =0.0004) groups. In the atorvastatin 40 mg baseline regimen, LS mean reductions from baseline 
in LDL-C at Week 24 were significantly greater in the alirocumab + atorvastatin 40 mg group 
(-54.0%) compared with the rosuvastatin 40 mg (-21.4%; p <0.0001), the atorvastatin 80 mg 
(-4.8%; p <0.0001), and atorvastatin 40 mg + ezetimibe 10 mg (-22.6%; p <0.0001) groups. 
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Two patient deaths were reported in the study; both patients were in the atorvastatin 20 mg + 
ezetimibe 10 mg treatment group. Treatment-emergent SAEs occurred in 4 patients (3.8%) in the 
pooled alirocumab treatment group, 8 patients (5.4%) in the pooled statin intensification treatment 
group, and 7 patients (6.9%) in the pooled ezetimibe treatment group. A total of 19 patients 
discontinued study treatment early due to a TEAE, specifically 7 patients (6.7%) in the pooled 
alirocumab treatment group, 8 patients (5.4%) in the pooled statin intensification treatment group, 
and 4 patients (4.0%) in the pooled ezetimibe treatment group. Nineteen patients (18.3%) in the 
pooled alirocumab treatment group had 2 consecutive LDL-C values <25 mg/dL (0.65 mmol/L) 
during the treatment period compared with 1 patient (0.7%) in the pooled statin intensification 
group and none in the pooled ezetimibe add-on group. None of the TEAEs occurred in these 
patients was serious or led to treatment discontinuations. No other safety findings were reported. 
ODYSSEY OPTIONS II (R727-CL-1118) is a randomized, double-blind study of the efficacy 
and safety of alirocumab added-on to rosuvastatin versus ezetimibe added-on to rosuvastatin 
versus rosuvastatin dose increase in patients who are not controlled on rosuvastatin. The number 
of patients treated with alirocumab 75 mg Q2W, ezetimibe 10 mg daily and double dose of 
rosuvastatin were 103, 101 and 101, respectively. All patients in this study had 
hypercholesterolemia with high or very high CV risk on a baseline daily dose of either 
rosuvastatin 10 mg or rosuvastatin 20 mg. The mean (SD) calculated baseline LDL-C for all 
patients was 111.3 mg/dL (39.0) (2.882 mmol/L [1.009]). Patients received alirocumab 
75 mg Q2W (with possibility for up titration to 150 mg at Week 12) or ezetimibe10 mg daily or 
increasing dose of rosuvastatin (10, 20 or 40 mg daily) as add-on therapies to baseline 
rosuvastatin. A statistically significant difference in the percent change in calculated LDL-C from 
baseline to Week 24 in the ITT analysis was observed for the rosuvastatin 10 mg baseline 
regimen, but not for the rosuvastatin 20 mg baseline regimen. In the rosuvastatin 10 mg baseline 
regimen, reductions from baseline in LS mean LDL-C at week 24 were significantly greater in the 
alirocumab + rosuvastatin 10 mg treatment group (-50.6%) compared with the rosuvastatin 20 mg 
(-16.3%; p<0.0001) and ezetimibe 10 mg + rosuvastatin 10 mg (-14.4%; p <0.0001) treatment 
groups. However, in the rosuvastatin 20 mg baseline regimen, LS mean reductions from baseline 
in LDL-C at Week 24 were numerically, but not significantly, greater in the 
alirocumab + rosuvastatin 20 mg treatment group (-36.3%) compared with the rosuvastatin 40 mg 
(-15.9%; p =0.0453) and ezetimibe 10 mg + rosuvastatin 20 mg (-11.0%; p =0.0136) treatment 
groups based upon the established level of significance of p <0.0125. The failure to reach 
statistical significance is partly due to larger variability than previously observed in the Phase 2 
studies. One patient died during the course of the study. This patient, a 71 year old male receiving 
ezetimibe 10 mg + rosuvastatin 20 mg experienced a fatal Subdural Hematoma on study Day 56. 
A total of 18 patients (5.9%) discontinued treatment prematurely due to a TEAE: 5 patients 
(4.9%) in the alirocumab add-on group, 5 patients (5.0%) in the double-dose rosuvastatin group, 
and 8 patients (7.9%) in the ezetimibe add-on group. Thirteen patients (12.6%) reported 
2 consecutive calculated LDL-C measurements below 25 mg/dL and all occurrences were 
reported in the alirocumab add-on group. None of the TEAEs occurred in these patients was 
serious or led to treatment discontinuations. 
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ODYSSEY MONO (EFC11716) is a randomized, double-blind, active-controlled, parallel-group 
study to evaluate the efficacy and safety of alirocumab over 24 weeks in patients with primary 
hypercholesterolemia. In this study, 52 patients were treated with alirocumab and 51 with 
ezetimibe 10 mg daily. Patients with moderate CV risk not treated with a statin nor with another 
lipid modifying therapy (LMT) had a mean (SD) overall baseline LDL-C of 139.7 (25.8) mg/dL 
(3.619 [0.668] mmol/L). They received alirocumab 75 mg Q2W (with the possibility for up 
titration to150 mg Q2W) or ezetimibe 10 mg daily. At the end of the 24-week treatment period, 
the percent change from baseline in LDL-C in the ITT population was greater in the alirocumab 
group (LS mean percent change from baseline: -47.2%) compared to the ezetimibe group (LS 
mean percent change from baseline: -15.6%), with a statistically significant LS mean difference 
versus ezetimibe of  
-31.6% [95% CI: -40.2 to -23.0], p <0.0001). The large percent decrease observed with 
alirocumab was achieved from Week 4 and maintained at all further time points throughout the 
study. At Week 12, before possible up-titration of alirocumab to 150 mg Q2W, statistical 
significance was also reached in the ITT population with the 75 mg Q2W dose (LS mean percent 
change from baseline: -48.1% for the alirocumab group versus -19.6% for the ezetimibe group), 
with an LS mean difference versus ezetimibe of -28.5%, (95% CI: -35.7 to -21.2), p <0.0001. The 
proportion of patients reaching LDL-C <100 mg/dL (2.59 mmol/L) was 88.1% patients in the 
alirocumab group compared with 32.2% patients in the ezetimibe group at Week 24. The 
proportion of patients reaching LDL-C <70 mg/dL (1.81 mmol/L) was 59.4% patients in the 
alirocumab group compared with 2.4% patients in the ezetimibe group at Week 24. 
Two treatment-emergent SAEs were reported, 1 Pulmonary Embolism in a patient in the 
Alirocumab group and 1 Bone Erosion in a patient in the ezetimibe group. Neither of the SAEs 
was considered to be related to the alirocumab by the Investigator. Nine patients prematurely 
discontinued treatment due to an adverse event (AE), 5 patients (9.6%) in the alirocumab group 
and 4 patients (7.8%) in the ezetimibe group. Treatment-emergent AEs leading to permanent 
treatment discontinuation in the Alirocumab group were Flushing (with concomitant symptoms of 
fatigue, nausea, and headache in 1 patient), Pulmonary Embolism, Diarrhea, Arthralgia 
(generalized aching), and Injection Site Reaction. 
ODYSSEY ALTERNATIVE (R727-CL-1119) is a randomized, double-blind, active-controlled 
study to evaluate the efficacy and safety of alirocumab in patients with primary 
hypercholesterolemia who are intolerant to statins. The number of patients treated with 
alirocumab, ezetimibe and atorvastatin were 126, 124 and 63, respectively. In this study of 
patients with primary hypercholesterolemia who were considered statin intolerant, the majority of 
patients was considered “very high CV risk” and was diagnosed with non-familial 
hypercholesterolemia (FH). Baseline LDL-C levels were high (mean 191.3 mg/dL in all patients) 
and all patients had a history of prior LMT use. They received alirocumab 75 mg Q2W (with 
possibility for up titration to 150 mg at Week 12) or ezetimibe 10 mg daily, or atorvastatin 20 mg 
daily. The primary efficacy endpoint in the ITT analysis demonstrated a statistically significant 
reduction in percent change from baseline calculated LDL-C in alirocumab treated patients 
(LS mean -45.0%) when compared with ezetimibe treated patients (LS mean -14.6%), with an LS 
mean difference between treatment groups of -30.4% (p <0.0001). Among the 109 patients who 
received at least 1 alirocumab injection after Week 12, 54 patients (49.5%) received automatic 
dose up titration to 150 mg Q2W. The proportion of very high CV risk patents reaching calculated 
LDL-C <70 mg/dL (<1.81 mmol/L) or moderate or high CV risk patients reaching calculated 
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LDL-C <100 mg/dL (<2.59 mmol/L) and the proportion of patients reaching calculated LDL-C 
<70 mg/dL (<1.81 mmol/L) at Week 24 were greater in the alirocumab treatment group than in 
the ezetimibe treatment group. Treatment-emergent SAEs occurred in 12 patients (9.5%) in the 
alirocumab treatment group, 7 patients (11.1%) in the atorvastatin treatment group, and 10 (8.1%) 
patients in the ezetimibe treatment group. A somewhat lower percentage of patients in the 
alirocumab treatment group experienced TEAEs leading to discontinuation of study treatment 
(18.3%) when compared with the atorvastatin treatment group (25.4%) and the ezetimibe 
treatment group (25.0%). The most frequent TEAEs leading to study drug discontinuation were in 
the system-organ-class (SOC) Musculoskeletal and Connective Tissues Disorders and within this 
SOC, the most frequently reported preferred term (PT) leading to study drug discontinuation was 
Myalgia. 
Summary of Efficacy and Safety Findings of ODYSSEY HIGH FH and LONG TERM (as of 
November 2014) 
ODYSSEY HIGH FH (EFC12732) is a randomized, double-blind, placebo-controlled, 
parallel-group study to evaluate the efficacy and safety of alirocumab over 78 weeks in patients 
with heterozygous familial hypercholesterolemia and LDL-C higher or equal to 160 mg/dL with 
their lipid modifying therapy. In this study, 72 patients were treated with alirocumab 
150 mg Q2W and 35 with placebo. All patients were on a maximum tolerated dose of statin 
± other lipid modifying therapies. Baseline LDL-C values were 196.3 (57.9) mg/dL in the 
alirocumab group and 201.0 (43.4) mg/dL in the placebo group. The percent change from baseline 
in LDL-C in the ITT population at Week 24 (primary study endpoint) was greater in the 
alirocumab group (LS mean percent change from baseline: -45.7%) compared to placebo group 
(LS mean percent change from baseline: -6.6%), with a statistically significant LS mean 
difference versus placebo of -39.1 % (6.0) (p <0.0001). Fifty-seven percent of alirocumab patients 
compared to 11% of placebo patients achieved an LDL-C< 100 mg/dL (p <0.0001). The current 
safety analysis for HIGH FH included all data collected until the last patient visit at Week 52 of 
the study. TEAEs occurred in 61.1% (44) and 71.4% (25) in alirocumab and placebo groups 
respectively. Treatment emergent SAEs occurred in 11.1% (8) of alirocumab patients and 
11.4% (4) of placebo patients. TEAEs leading to discontinuation occurred in 4.2% (3) of 
alirocumab patients and 2.9% (1) of placebo patients. There were no TEAEs leading to death in 
the study.  
ODYSSEY LONG TERM (LTS11717) is a randomized, double-blind, placebo-controlled, 
parallel-group study to evaluate the long-term safety, tolerability, and efficacy of alirocumab over 
78 weeks in HeFH or high cardiovascular risk hypercholesterolemia patients not adequately 
controlled with their lipid modifying therapy. In this study, 1553 patients were treated with 
alirocumab 150 mg Q2W and 788 with placebo. All patients were on a maximum tolerated dose 
of statin ± other lipid modifying therapies. Baseline LDL-C values were 122.7 (42.6) mg/dL in the 
alirocumab group and 121.9 (41.4) mg/dL in the placebo group. Just over 17% of patients in both 
treatment groups had HeFH. The percent change from baseline in LDL-C in the ITT population at 
Week 24 (primary study endpoint) was greater in the alirocumab group (LS mean percent change 
from baseline: -61.0%) compared to placebo group (LS mean percent change from baseline: 
±0.8%), with a statistically significant LS mean difference versus placebo of -61.9% (1.3) 
(p <0.0001). Seventy-nine percent of alirocumab patients compared to 8% of placebo patients 
achieved an LDL-C< 70 mg/dL (p <0.0001).  
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The current safety analysis for LONG TERM included at least 52 weeks for all patients 
continuing treatment, including 607 patients who completed Week 78 visit. TEAEs occurred in 
78.6% (1218) and 80.6% (635) in alirocumab and placebo groups respectively. Treatment 
emergent SAEs occurred in 16.5% (255) of alirocumab patients and 17.6% (139) of placebo 
patients. TEAEs leading to discontinuation occurred in 6.2% (96) of alirocumab patients and 
5.5% (43) of placebo patients. TEAEs leading to death occurred in 0.5% (7) of alirocumab 
patients and 1.0% (8) of placebo patients.  
Conclusion on the benefit risk assessment with alirocumab: 
Based on the clinical data available to date, treatment with alirocumab has demonstrated a 
significant LDL-C lowering effect and was generally well tolerated in a population of 
hypercholesterolemic patients with non-FH or with heFH, including patients with a history of 
intolerance to statins. The efficacy on LDL-C was associated with consistent results in Total-C, 
ApoB, non-HDL-C and ApoB/ApoA-1 ratio. Reduction in triglycerides and lipoprotein (a) and 
increases in HDL-C were also observed with alirocumab treatment. There was no evidence that 
alirocumab adversely affects body weight, blood pressure, glucose, or high sensitivity C-reactive 
protein. 
No safety signal has been confirmed with regard to neurologic events and neurocognitive 
disorders, alanine aminotransferase (ALT) increase and hepatic disorders, adjudicated CV events, 
diabetes mellitus or ophthalmologic events overall; however, more cataracts were noted in 
patients treated with alirocumab who achieved 2 consecutive LDL-C values <25 mg/dL (2.1%) 
compared to those treated with alirocumab who did not meet this criterion (0.6%). Injection site 
reactions, influenza (upper respiratory symptoms), and pruritus were identified as ADRs. Rare 
and sometimes serious allergic adverse reactions (eg, hypersensitivity, eczema nummular, 
urticaria, and hypersensitivity vasculitis) have been reported from clinical studies in patients 
receiving alirocumab. Alirocumab lowered LDL-C below 25 mg/dL in some patients. Safety of 
such low LDL-C values is still being assessed, including a potential risk of cataract with LDL-C 
values <25 mg/dL (0.65 mmol/L), but no safety issues have been confirmed.  
The benefit of alirocumab on cardiovascular morbidity and mortality has not yet been determined 
and is under investigation in the on-going ODYSSEY OUTCOMES trial.  
Note: ODYSSEY program refers to the alirocumab clinical trial program. 
Despite treatment with potent statins, achieving LDL-cholesterol-level goals remains a challenge 
in individuals who have very high baseline LDL-cholesterol levels (such as familial 
hypercholesterolemia), in those with very high CVD risk who require intensive therapy goals; or 
in patients for whom statin dosage is limited owing to potentially serious drug interactions, 
comorbid conditions or intolerance to high drug doses. 
As a result, there is a need to provide these patients with poorly controlled LDL-C levels with 
more effective LDL-C lowering therapies in addition to standard of care in order to adequately 
reduce their LDL-C attributable CV risk. 
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In all clinical trials completed to date, alirocumab in combination with maximally-tolerated 
statins, with or without other LMTs, or as monotherapy showed significant, sustained LDL-C 
reductions from baseline and similar rates of adverse events versus comparators. 
Alirocumab is now is approved for use in the U.S. and Europe. In the US, alirocumab is approved 
as adjunct to diet and maximally tolerated statin therapy for the treatment of adults with 
heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who 
require additional lowering of low-density lipoprotein cholesterol.  
The European Commission approved alirocumab for the treatment of adult patients with primary 
hypercholesterolemia (HeFH and non-familial) or mixed dyslipidemia as an adjunct to diet: a) in 
combination with a statin, or statin with other lipid-lowering therapies in patients unable to reach 
their LDL-cholesterol goals with the maximally-tolerated statin or b) alone or in combination with 
other lipid-lowering therapies for patients who are statin intolerant, or for whom a statin is 
contraindicated. The effect of alirocumab on cardiovascular morbidity and mortality has not yet 
been determined. The ability of alirocumab to reduce major CV events is being investigated in the 
ongoing ODYSSEY OUTCOMES trial, with results anticipated in 2017.The use of a  
non-registered or non-yet reimbursed product within an early access program (ie, before 
marketing authorization and reimbursement are granted in a country) may be a treatment option 
for patients with an unmet medical need for which no suitable or clinically satisfactory alternative 
is currently available. 
This study is therefore aimed at providing patients with severe hypercholesterolemia at risk for 
subsequent cardiovascular (CV) events and not adequately controlled with maximally tolerated 
doses of currently available lipid modifying therapy (LMT) with access to alirocumab ahead of 
commercial availability. 
This study will also permit collection of data with the aim to document the overall safety and 
tolerability of alirocumab in this patient population, the effect of alirocumab on atherogenic 
lipoproteins and the patient’s acceptability of self-injection. 
By providing data from a close to real- life setting, this study will further extend the 
understanding of the efficacy, safety and tolerability profile of alirocumab in a severe 
hypercholesterolemic population. 
Rationale for the study population 
The study population of the present trial includes patients with familial or non-familial severe 
hypercholesterolemia, who despite maximally tolerated doses of high potent statins ±other lipid 
lowering therapies have LDL-Cholesterol levels far from the guideline recommended targets. 
Individuals with familial hypercholesterolemias (FH) have a very high lifetime risk of coronary 
heart disease (CHD) and are at very high risk of premature onset CHD. 
Any of the following places FH patients at higher CHD risk: clinically evident CHD or other 
atherosclerotic CVD, diabetes, a family history of very early CHD (in men, 45 years of age and 
women, 55 years of age), current smoking, two or more CHD risk factors, or high lipoprotein (a) 
≥50 mg/dL using an isoform insensitive assay (22). Patients featuring these characteristics will be 
enrolled in the present study. 
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Recent guidelines recommend that in FH patients without any of the characteristics listed above, 
intensification of drug therapy may be considered if LDL cholesterol remains ≥160 mg/dL (22). 
These patients are also part of the current study. 
Patients with non-familial hypercholesterolemia with CVD are at the highest priority for 
treatment. European guidelines on cardiovascular disease prevention (3) recommend for these 
patients an LDL-C goal of less than 70 mg/dL (<1.8 mmol/L) or a ≥50% LDL cholesterol 
reduction when the target level cannot be reached. 
The ODYSSEY LTS11717 trial, the largest (2,400 patients) and longest (65 weeks – mean 
treatment duration) blinded study with a PCSK9 inhibitor reported so far enrolled around 20% of 
patients with HeFH and 68% of patients with previous CHD. More than 25% of patients enrolled 
in this study had an LDL-C at baseline >130 mg/dl placing these patients at the highest risk of 
CVD: interquartile range Q1-Q3 of LDL-C (mg/dL): 96.4-140.9 and 90.7-132.8 for calculated and 
measured LDL-C, respectively. 
Based on these data, the current study aims to enroll this subgroup of patients who are at the 
highest cardiovascular risk for a subsequent event. 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
The primary objective of this study for patients with severe hypercholesterolemia at risk for 
subsequent cardiovascular (CV) events and not adequately controlled with currently available 
lipid modifying therapy (LMT) is to provide access to alirocumab ahead of commercial 
availability and to document the overall safety and tolerability of alirocumab in this patient 
population. 
5.2 
SECONDARY 
The secondary objectives are: 
• 
To document the effect of alirocumab on low-density lipoprotein cholesterol (LDL-C) 
levels as well as non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol 
(total-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG) levels, after 
12 weeks of treatment. 
• 
To document patient acceptability of self-injection (Self Injection Assessment 
Questionnaire, SIAQ) throughout the study. 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE PROTOCOL 
This trial is to be conducted as a multi-country, multi-center prospective, single arm, open-label, 
phase IIIb clinical trial. 
After enrollment, patients will receive study treatment alirocumab 150 mg SC once every 2 weeks 
(Q2W) or 75 mg SC Q2W. The dose may be adjusted according to the investigator, based on 
treatment response. 
Alirocumab will be administered on top of stable maximally tolerated statin therapy ±other LMTs 
over a period of at least 12 weeks and until the product becomes commercially available and 
reimbursed . 
The investigator will manage, based on his/her own judgment and LDL-C value, adjustment of 
alirocumab doses (either up-titration from 75 to 150 mg every 2 weeks or down-titration from 
150 to 75 mg every 2 weeks, or maintenance of the dose, will be possible). In case a modification 
of the current dose is decided, the patient will be contacted by the site staff and an unscheduled 
visit will be planned to dispense the new treatment kit and retrieve the current one. 
The study consists of: 
• 
A screening period of up to 3 weeks, including an injection training during which the 
patient or another designated person (such as spouse, relative, etc) will be trained to  
self-inject/inject). An optional dedicated visit could be scheduled as needed. 
• 
An open-label treatment period with alirocumab of at least 12 weeks and until the product 
becomes commercially available and reimbursed. However, the open label treatment 
period will not exceed 30 months. 
• 
An End-of-Treatment/End-of-Study visit will take place at least 2 weeks after last study 
treatment injection. 
Patients should be on a stable diet (NCEP-ATPIII TLC diet or equivalent, see Appendix A) 
throughout the entire study duration from screening to the end of the study treatment. 
Statin dose and dose regimen as well as dose and dose regimen of other LMTs (if applicable) 
should be stable throughout the whole study duration including the screening period. 
Nevertheless, modification of LMT is allowed under certain conditions after enrollment as 
described in Section 8. 
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6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
The study duration includes up to 3 weeks of screening period, a minimum of 12 weeks and up to 
a maximum 30 months of open label study treatment period and at least 2 weeks after the last 
alirocumab injection. 
In each country, patient recruitment will end when alirocumab becomes commercially available 
(ie, accessible to the patient as per each country regulation) and reimbursed. In this case, study 
treatment can be switched to the commercial product (or another LMT) once the patient has 
completed the minimum of 12 weeks of study treatment. 
The end of the study per patient is the last protocol planned visit or the resolution/stabilization of 
all SAEs and adverse event of special interest (AESI), or death, whichever comes last. 
6.2.2 Determination of end of clinical trial (all patients) 
The end of study is defined as being the last patient last on site visit as scheduled per protocol 
(ie, no later than beginning 2018). 
6.3 
INTERIM ANALYSIS 
No formal interim analysis is planned for this study. However some descriptive analyses might be 
performed before the end of the study in order to support the submission of a reimbursement 
dossier if requested by local health authorities. 
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7 
SELECTION OF PATIENTS 
7.1 
INCLUSION CRITERIA 
I 01. Signed written informed consent.  
I 02. Age ≥18 years or legal age of majority at screening visit. 
I 03. Either A, B, C, D or E below and not adequately controlled with a maximally tolerated 
dose of statin* with or without other lipid modifying therapy (LMT), all at stable doses for 
at least 4 weeks prior to the screening visit (Week -3). 
A. Patients suffering from heterozygous familial hypercholesterolemia** (heFH) with 
LDL-C concentrations ≥160 mg/dL (4.14 mmol/L) despite treatment 
B. Patients suffering from heFH with LDL-C concentrations ≥130 mg/dL 
(3.36 mmol/L) despite treatment and two or more CV risk factors among this list: 
- LDL-C >250 mg/dL (6.46 mmol/L) at the time of the FH diagnosis (before 
treatment), 
- Family history of premature-onset CHD (first-degree male relative with onset 
before age 55 years; first-degree female relative with onset before age 65 years), 
- Metabolic syndrome (cf. definition), 
- HDL-C <40 mg/dL (1.03 mmol/L), 
- Hypertension (BP >140/90 mmHg or drug treatment), 
- Lp(a) ≥50 mg/dL (1.78 µmol/L), 
- Tendon xanthoma. 
C. Patients suffering from heFH with LDL-C concentrations ≥130 mg/dL 
(3.36 mmol/L) despite treatment and one of the following characteristics: 
- established CHD or other CVD (history of acute myocardial infarction, ischemic 
stroke, peripheral arterial disease, coronary or peripheral arterial revascularization, 
stable or unstable angina, transient ischemic attack, carotid artery stenosis ≥50%, 
aortic abdominal aneurysm), 
- drug treated type 2 diabetes mellitus or type 1 with target organ damage,  
- family history of first or second degree relative with very premature onset 
CHD (first or second degree male relative onset before age 45; first or second 
degree female relative onset before age 55).  
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D. Non-FH patients suffering from established CHD or other CVD (history of acute 
myocardial infarction, ischemic stroke, peripheral arterial disease, coronary or 
peripheral arterial revascularization, stable or unstable angina, transient ischemic attack, 
carotid artery stenosis ≥50%, aortic abdominal aneurysm) and with LDL cholesterol 
concentrations ≥130 mg/dL (3.36 mmol/L). 
E. Patients suffering from progressive cardiovascular disease [coronary artery disease, 
or peripheral arterial occlusive disease or cerebrovascular disease as documented 
clinically or by imaging techniques, with a subsequent CV event (acute myocardial 
infarction, ischemic stroke, ischemia driven revascularization, unstable angina, 
transient ischemic attack) occurring despite stable doses of maximally tolerated  
LMT] with LDL cholesterol concentrations ≥100 mg/dL (2.59 mmol/L). 
For HeFH diagnosis, please refer to Appendix B and Appendix C. 
Metabolic syndrome is defined as follows: 3 of 5 characteristics: 
- Increased waist circumference: 
Men >40” (>37” in some populations) and women >35”, 
- Blood pressure ≥130 mm Hg or ≥80 mm Hg or drug treatment, 
- Triglycerides ≥150 mg/dL or drug treatment, 
- Low HDL-C: 
Men <40 mg/dL and women <50 mg/dL, 
- Elevated glucose ≥100 mg/dL or drug treatment. 
 
Note: 
* Definition of maximally tolerated dose (any of the following are acceptable): 
• 
Rosuvastatin 20 mg or 40 mg daily. 
• 
Atorvastatin 40 mg or 80 mg daily. 
• 
Simvastatin 80 mg daily (if already on this dose for >1 year). 
Patients not able to be on any of the above statin doses should be treated with the dose of daily 
atorvastatin, rosuvastatin or simvastatin which is considered appropriate for the patient as per the 
investigator's judgment or concerns. 
Some examples of acceptable reasons for a patient taking a lower statin dose include, but are not 
limited to: adverse effects on higher doses, advanced age, low body mass index, concomitant 
medications, and co-morbid conditions such as impaired glucose tolerance /impaired fasting 
glucose. The reason(s) will need to be documented in the case report form. 
NB: in exceptional and well documented cases described in Exclusion criteria E04, another statin 
regimen may be used. 
** Diagnosis of heFH will be documented, either by genotyping or by clinical criteria. For 
patients who are not genotyped, the clinical diagnosis will be based on either the Simon 
Broome criteria or the WHO/Dutch Lipid Network criteria and the diagnostic must be 
“definite” (see Simon Broome criteria for “definite” or a diagnostic scoring >8 for WHO 
criteria). 
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7.2 
EXCLUSION CRITERIA 
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following 3 subsections:  
7.2.1 Exclusion criteria related to study methodology 
E 01. Not on a stable dose of lipid lowering therapy (statin or other LMT), for at least 4 weeks 
prior to the screening visit (Week-3) or from screening to enrollment. 
E 02. Use of a fibrate other than fenofibrate within 4 weeks of the screening visit (Week-3) or 
between screening and enrollment. 
E 03. Daily doses above atorvastatin 80 mg, rosuvastatin 40 mg or simvastatin 40 mg (except for 
patients on simvastatin 80 mg for more than one year, who are eligible). 
E 04. Use of statin other than simvastatin, atorvastatin or rosuvastatin, prior to the screening visit 
(Week-3) or between screening and enrolment with the exception of the cases in which 
there is a documented reason for intolerance to the above mentioned potent statins in 
which case the use of a different statin is allowed. 
E 05. Systolic blood pressure (BP) >180 mmHg or diastolic BP >110 mmHg at screening 
(Week-3) and/or enrollment (Week 0) visit. 
E 06. History of New York Heart Association (NYHA) Class III or IV heart failure within the 
past 12 months (see Appendix D). 
E 07. History of a MI, unstable angina leading to hospitalization, coronary artery bypass graft 
surgery (CABG), percutaneous coronary intervention (PCI), uncontrolled cardiac 
arrhythmia, carotid surgery or stenting, stroke, transient ischemic attack, carotid 
revascularization, endovascular procedure or surgical intervention for peripheral vascular 
disease within 1 month prior to the screening visit (Week-3). 
E 08. Known history of hemorrhagic stroke. 
E 09. Patients not previously instructed on a cholesterol-lowering diet prior to the screening visit 
(Week-3). 
E 10. 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 of thyroxin 
has been stable for at least 3 months prior to screening and their sensitive-Thyroid 
Stimulating Hormone (s-TSH) levels is within ±10% of the normal ranges of the site 
laboratory. 
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E 11. Use of systemic corticosteroids, unless used as replacement therapy for pituitary/adrenal 
disease with a stable regimen for at least 6 weeks prior to screening. 
Note: Topical, intra-articular, nasal, inhaled and ophthalmic steroid therapies are not 
considered as “systemic” and are allowed. 
E 12. New cancer or active progression of cancer within the past 5 years, except for adequately 
treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer. 
E 13. Known history of a positive HIV test. 
E 14. Patient who has taken any active investigational drugs with the exception of alirocumab 
within 1 month or 5 half-lives, whichever is longer. 
NB: Patients who received an investigational drug before 1 month or 5 half-lives 
(whichever is longer) and who fulfill all the other selection criteria can be enrolled but 
only after the formal approval from the Sponsor. 
E 15. Known history of homozygous familial hypercholesterolemia. 
E 16. Use of continuous hormone replacement therapy unless the regimen has been stable in the 
past 6 weeks prior to the Screening visit (Week-3) and no plans to change the regimen 
during the study. 
E 17. Patient who withdraws consent during the screening period (patient who is not willing to 
continue or fails to return). 
E 18. Any clinically significant abnormality identified at the time of screening that in the 
judgment of the Investigator or any sub-Investigator would preclude safe completion of the 
study or constrain endpoints assessment such as major systemic diseases, patients with 
short life expectancy. 
E 19. Patients considered by the Investigator or any sub-Investigator as inappropriate for this 
study for any reason, eg: 
- Those deemed unable to meet specific protocol requirements, such as scheduled visits, 
- Those 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 (eg, 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 20. Laboratory findings during the screening period:  
- Positive test for Hepatitis B surface antigen or Hepatitis C antibody, 
- Positive serum or urine pregnancy (including Week 0) test in women of childbearing 
potential, 
- Triglycerides >400 mg/dL (>4.52 mmol/L) (1 repeat lab is allowed), 
- Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m² according to 4-
variable modification of diet in renal disease (MDRD) Study equation, 
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 x upper limit 
normal range (ULN [1 repeat lab is allowed]), 
- Creatine phosphokinase (CPK) >3 x ULN (1 repeat lab is allowed), 
- Thyroid stimulating hormone (TSH) < Lower limit of the normal range (LLN) or 
>ULN (for patients on thyroid replacement therapy see earlier exclusion criterion 
(E.10); within ±10% of the normal ranges of the site laboratory is accepted. 
E 21. Patients eligible for enrollment into an ongoing clinical study of alirocumab conducted at 
same investigational site. 
E 22. Any country-related specific regulation that would prevent the subject to entering the 
study.  See Appendix L (country-specific requirements). 
7.2.2 Exclusion criteria related to the mandatory background therapies  
E 23. All contraindications to the background statins or warning/precaution of use (when 
appropriate as displayed in the respective National Product Labeling). However, patients 
with documented medical history of adverse reactions with statins (eg, rhabdomyolysis, 
transaminases elevations, muscle symptoms…) preventing the subsequent use of any statin 
at any dose may be included in this study once the formal approval is obtained from the 
Sponsor. 
7.2.3 Exclusion criteria related to the current knowledge of Sanofi compound  
E 24. Known hypersensitivity to alirocumab or any component of the excipients. 
E 25. Pregnant or breast-feeding women.  
E 26. Women of childbearing potential not protected by highly-effective method(s) of birth 
control (as defined in the informed consent form and/or in a local protocol addendum) 
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 inclusion visits. They must use an effective contraceptive method 
throughout the entire duration of the study treatment and for at least 10 weeks after the last 
study treatment injection. The applied methods of contraception have to meet the criteria 
for a highly effective method of birth control according to the “International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use. M3 (R2): Guidance on nonclinical safety studies for the conduct of human clinical 
trials and marketing authorization for pharmaceuticals. ICH. 2009 Jun:1-25.” 
Postmenopausal women must be amenorrheic for at least 12 months. 
E 27. Male participant with a female partner of childbearing potential not protected by a highly- 
effective method(s) of birth control. See Appendix K (country-specific requirements). 
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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
Sterile alirocumab drug product will be supplied at a concentration of 75 mg/mL and 
150 mg/mL in histidine, pH 6.0, polysorbate 20, both as 1 mL volume in an auto-injector (also 
known as pre-filled pen). 
Patient (or another designated person) will have to perform during the screening period (V1 or 
dedicated V2) or at the latest on V3 (Day 1) a placebo self-injection training, using a pre-filled 
pen, before the first alirocumab administration.  
Injection for training: sterile placebo for alirocumab will be prepared in the same formulation as 
alirocumab without the addition of protein as 1 mL volume in a pre-filled pen, for the patients to 
perform an injection training. 
Each alirocumab administration will consist of 1mL subcutaneous injection over the abdomen, 
thigh, or outer area of upper arm (ie, deltoid region). 
The recommended dose is 75 mg or 150 mg administered subcutaneously once every 2 weeks 
(Q2W). 
The dose selection should be based on individual patient characteristics and goal of therapy.  
The dose can be adjusted based on treatment response. Lipid levels will be analyzed from Week 4, 
when maximum LDL-C reduction is usually achieved.  
The Investigator is free to adjust the dose (up and down-titration) throughout the study based on 
clinical judgment. 
8.1.1 Route and method of administration 
A manual for IMP administration (injection instruction manual) will be provided to patients 
containing detailed instructions on use. 
The investigational medicinal product (IMP) could be administered by self-injection or by another 
designated person (such as a spouse, relative, etc). The used pre-filled pen will be discarded in a 
sharps container which will be provided to patients. It is recommended that the subcutaneous IMP 
injections be rotated within an anatomical area (eg, right thigh then left thigh or right abdomen 
then left abdomen). Patients also have the option to inject in a different anatomical area (eg, thigh 
then abdomen the outer area of upper arm) during the study. 
In case a designated person is due to inject alirocumab to a patient during the study, it must be 
ensured that this person has been adequately trained previously. 
If another concomitant drug is being injected at the same site planned for the IMP injection, then 
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Patients 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 about 30 to 40 minutes. Thereafter, the IMP 
should be administered as soon as possible. 
Instructions should be provided to the patient (or another designated person [such as spouse, 
relative, etc] that will administer the injections) at training and as needed during the course of the 
study. Close supervision and feedback should be given at the first visit, and other visits as needed. 
Anyone that plans to administer the IMP must be trained by the study staff. 
8.1.2 Timing of administration 
During screening period, patients will have to perform a placebo self-injection training using a 
pre-filled pen, before the first alirocumab injection. 
At inclusion visit, the first alirocumab injection will be done at the site by the patient or another 
designated person (such as spouse, relative, etc.) under direct site staff supervision. Patients will 
be monitored at the investigational site for at least 30 minutes after this first injection in this study. 
Alirocumab subcutaneous injections will then be performed outside of the clinic, every two weeks 
up to the last injection. If the injection is scheduled to take place on the same date as the site visit, 
then the IMP should be administered after the blood sampling has been completed. 
Alirocumab should be administered subcutaneously every two weeks ideally at approximately the 
same time of the day. The time of the day is based upon patient’s preference; however it is 
acceptable to have a window period (see study procedures Section 10).  
If by mistake or due to other circumstances an injection is delayed: 
• 
By more than 7 days or completely missed, then the patient should return to the original 
schedule of study treatment administration without administering delayed injections.  
• 
By less than or equal to 7 days from the missed date, then the patient should administer the 
delayed injection and then resume the original schedule of study treatment administration. 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) 
The following classes of drugs are identified as non-IMP because the medication is either a 
background therapy or a potential rescue medication: 
• 
Statins. 
• 
Cholesterol absorption inhibitors (ezetimibe). 
• 
Bile acid-binding sequestrants (such as cholestyramine, colestipol, colesevelam). 
• 
Nicotinic acid. 
• 
Fenofibrate. 
• 
Omega-3 fatty acids (≥1000 mg daily). 
Please see Section 8.7 for further information. 
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8.3 
BLINDING PROCEDURES 
Not applicable. 
This is an open-label study and every patient will receive alirocumab. Treatment kit numbers will 
be allocated via interactive voice/web response system (IVRS/IWRS).  
8.4 
PACKAGING AND LABELING 
Each alirocumab treatment kit will be prepared to contain 6 pre-filled pens.  
In addition to the alirocumab treatment kits, a training kit containing 1 placebo pre-filled pen will 
be prepared for the purpose of instructing patients or caregiver on injection administration. 
The content of the labeling is in accordance with the local regulatory specifications and 
requirements. 
8.5 
STORAGE CONDITIONS AND SHELF LIFE 
Investigators or other authorized persons (eg, 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 (eg, refrigerated storage) and 
information on in-use stability and instructions for handling the Sanofi compound should be 
managed according to the rules provided by the Sponsor. 
The IMP will be stored in a refrigerator between +2°C and +8°C (36°F to 46° F) by the site. The 
temperature of the site refrigerator should be checked daily and recorded on a log sheet. 
The IMP that will be stored at the investigational site should be kept in an appropriate locked 
room, under the responsibility of the Investigator or designee or other authorized person in 
accordance with the storage conditions indicated on the label. 
After the supply of IMP kits to patients at the study site visits, appropriate provisions will be in 
place for transportation of the IMP kits from the study site to the patient’s refrigerator. 
8.6 
RESPONSIBILITIES 
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the Sponsor and in accordance with applicable regulatory requirements. 
All IMP will be dispensed in accordance with the Investigator's prescription and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
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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. Deficiencies related to the pre-filled pen should be recorded through a complaint 
procedure. 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party, allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
8.6.1 Treatment accountability and compliance 
• 
IMP accountability: 
- Used and unused treatment kits are returned by the patient at each visit, 
- The Investigator or designee counts the number of remaining unused pre-filled pens in 
the returned packs, fills in the Treatment Log Form, 
- The Investigator or designee records the dosing information on the appropriate page(s) 
of the CRF, 
- The monitor in charge of the study then checks the information by comparing the used 
or unused treatment kits with treatment log forms and source data.  
IMP administration data will be recorded by the patients onto a patient’s diary. 
Measures taken to ensure and document IMP compliance and accountability are described below: 
• 
The Investigator or designee will obtain via IVRS/IWRS the treatment kit number(s) and 
he/she will dispense the treatment kit(s) to the patient. 
The accountability is to be performed at IMP kit re-supply visits only (see Section 10.1.1). The 
used and unused kit(s) should be brought back by the patient to such visits for accountability 
purposes. 
• 
The Investigator or designee will complete the corresponding treatment log form. 
• 
The monitor will check the data consistency between e-CRF pages, treatment log forms 
using patient’s diary, IVRS transaction confirmations and returned unused pre-filled pen 
of a corresponding kit. 
The patient will be instructed on the importance to stay under study treatment. 
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8.6.2 Return and/or destruction of treatments 
A detailed treatment log of the destroyed 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. 
Sharp containers containing all used pens will be brought back on site by the patient for 
destruction purpose. 
If the site is not able to destroy or destruction is not allowed in the country, all treatments kits will 
be retrieved by the Sponsor. A detailed treatment log of the returned IMP will be established with 
the Investigator or designee and countersigned by the Investigator and the Monitoring Team. 
8.7 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment received by the patient concomitantly to the study.  
Concomitant medications should be kept to a minimum during the study. However, if these are 
considered necessary for the patient’s welfare and are unlikely to interfere with the IMP, they may 
be given at the discretion of the Investigator, with a stable dose (when possible). Besides the 
specific information related to concomitant medications provided in this Section, any other 
concomitant medication(s) will be allowed and will have to be recorded in the e-CRF and source 
data. 
8.7.1 Management of background lipid-modifying therapy 
For background LMT, including statins, sites must follow the national product labeling for the 
safety monitoring and management of patients. 
Throughout the whole treatment period, the patients should stay, as far as possible, on the stable 
maximally tolerated registered daily dose of statins, with or without other LMT that was received 
in the 4 weeks prior to screening visit.  
Dose adjustment of LMT, including statins, might take place as per the investigator’s judgment, 
for example in case of tolerability issue. Any adjustment will be documented in the e-CRF. 
For adjustments based on LDL-C values, simultaneous adjustment in alirocumab dose and any 
LMT should be avoided, unless required for a safety/tolerability issue. 
8.7.2 Contraception  
Women of childbearing potential must take an effective contraceptive method throughout the 
study treatment and during the 10-week period after the last study treatment injection. In some 
participating countries, specific contraceptive methods must be used by women of childbearing 
potential participating in a clinical trial (see Protocol Appendix I and Appendix J). 
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8.7.3 Prohibited concomitant medications 
Forbidden concomitant medications from the initial screening visit until the end of treatment visit 
include the following: 
• 
Statins other than simvastatin, atorvastatin, rosuvastatin unless there is a documented 
intolerance to the above mentioned potent statins in which case other statins are allowed. 
• 
Fibrates other than fenofibrate. 
• 
Other PCSK9-inhibitor. 
• 
Systemic corticosteroids, unless used as replacement therapy for pituitary/adrenal disease 
with a stable regimen for at least 6 weeks prior to randomization, are prohibited during the 
study duration. 
8.7.4 Life style and dietary habits 
Life styles and dietary habits should be maintained if possible throughout the entire study 
duration, as medically feasible, with minimum changes. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
PRIMARY ENDPOINTS 
In this study, primary endpoints only relate to safety assessments.  
Safety will be assessed throughout the study by the following parameters: 
• 
Recording of adverse events (including serious adverse events and adverse events of 
special interest). 
• 
Standard laboratory tests: hematology (hemoglobin, WBC, platelet count) and 
biochemistry (urea, creatinine, glucose, glycated hemoglobin A1c [HbA1c], total CK). 
• 
Liver function tests: SGOT (AST), SGPT (ALT), alkaline phosphatase (ALP), total 
bilirubin. 
• 
Physical examination and vital signs: height (only at screening), weight, heart rate, systolic 
and diastolic blood pressure 
• 
Device related complaints will be recorded and described as well. 
Reporting procedures for AEs, SAEs and AESI are detailed in Section 10.4, Section 10.5, 
Section 10.6, Section 10.7.  
The assessment of tolerability refers to local injection site reactions (see Appendix H). 
9.1.1 Adverse events 
The observation of safety data will be as follows: 
Pre-treatment period: 
The Pre-treatment observation period is defined from the signed informed consent up to the first 
dose of IMP. 
TEAE period:  
The TEAE period will include a study period of 2 weeks after last study treatment injection.  This 
means that TEAE period will cover a period from first dose to + 14 days after last dose. Safety 
reporting under commercial alirocumab intake will be documented via spontaneous reporting. 
Death observation period: 
The death observations are per the observation period defined above. In addition, “post- study” 
death includes all deaths reported after the end of the study (see definition of end of study period 
per patient in Section 6.2.1). 
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Adverse events, including AESIs and SAEs, will be collected from the time the patient signs the 
informed consent to the completion of the safety observation period. 
All AEs will be coded to a “lowest level term (LLT)”, “preferred term (PT)”, “high level term 
(HLT)”, “high level group term (HLGT)” and associated primary “system organ class (SOC)” 
using the version of Medical Dictionary for Regulatory Activities (MedDRA) currently in effect 
at Sanofi at the time of the considered database lock. 
Adverse events of special interest may be modified during a study by protocol amendment, which 
will enable the Company to collect additional information to better assess any potential and 
identified risks during the development. 
For this study, the following AEs are AESI:  
• 
Increase in alanine transaminase (ALT): ALT ≥3 x ULN (if baseline ALT <ULN) or 
ALT ≥2 times the baseline value (if baseline ALT ≥ULN). 
• 
Allergic events and/or local injection site reaction that are allergic in nature and that 
require consultation with another physician for further evaluation. 
• 
Pregnancy. 
• 
Symptomatic overdose with IMP. 
• 
Neurologic events that require additional examinations/procedures and/or referral to a 
specialist. 
• 
Neurocognitive events. 
Additional information can be found in Section 10.4.1.3 and Appendix E. 
9.1.2 Safety laboratory 
The clinical laboratory data consist of urinalysis and blood analysis: 
• 
Hematology (RBC count, hemoglobin, hematocrit, platelets, WBC count with differential 
blood count).  
• 
Standard chemistry (fasting plasma glucose, sodium, potassium, chloride, bicarbonate, 
CPK, calcium, phosphorous, urea nitrogen, creatinine and calculated creatinine clearance 
using Cockroft-Gault formula or eGFR using MDRD Study equation, uric acid, total 
protein, lactic dehydrogenase (LDH), albumin, γ Glutamyl Transferase [γGT] Hepatitis B 
antigen, Hepatitis C antibody). 
• 
HbA1c. 
• 
Liver panel (ALT, AST, ALP, and total bilirubin). 
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. 
Standard international units will be used in all listings and tables. 
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9.1.3 Vital signs measurement 
Vital signs include: heart rate, systolic and diastolic BP in sitting position. 
9.2 
SECONDARY ENDPOINTS 
9.2.1 Secondary efficacy endpoints 
The main efficacy secondary endpoint will be: 
• 
The percent change in calculated LDL-C from baseline to Week 12 (main timepoint). 
The key secondary efficacy endpoints will include: 
• 
The proportion of patients reaching calculated LDL-C <100 mg/dL (2.59mmol/L) at 
Week 12. 
• 
The proportion of patients reaching calculated LDL-C <70 mg/dL (1.81mmol/L) at 
Week 12. 
• 
Proportion of patients with LDL-C <70 mg/dL (1.81 mmol/L) and/or ≥50% reduction from 
baseline in LDL-C (if LDL- C ≥70 mg/dL [1.81 mmol/L]) at Week 12. 
• 
The percent change from baseline to Week 12 in non-HDL-C, total-C, HDL-C, and TG 
levels.  
Since the study duration for each participating country will depend on when alirocumab becomes 
commercially available and reimbursed, with a minimum duration of patient’s participation of 
12 weeks and up to a maximum of 30 months, the secondary efficacy endpoints listed above will 
also be assessed at the following time points depending on countries: Weeks 4, 8, 12, 24, 48, 72, 
96, 108, and EOT/EOS. 
9.2.1.1 Efficacy assessment method 
9.2.1.1.1 Lipid parameters 
Total-C, HDL-C, TG, non-HDL-C will be directly measured by a local Laboratory as per the 
schedule in Section 10.1.  
LDL-C will be calculated using the Friedewald formula at all site visits. 
Efficacy endpoints will not be considered as AEs, such as those involving abnormalities in lipid 
levels, unless meeting the criteria in Section 10.4.2. 
9.2.2 Other secondary endpoints  
The other secondary efficacy endpoints will include: 
• 
The proportion of patients who were up-titrated to 150 mg of alirocumab based on 
investigator’s judgment. 
• 
The proportion of patients who were down-titrated to 75 mg of alirocumab based on 
investigator’s judgment. 
• 
The reasons (ie, LDL-C threshold, AE) that triggered a down-titration or an up-titration of 
alirocumab. 
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9.2.3 Patient’s reported outcomes: patient’s acceptability of self-injection  
Patient’s acceptability of self-injection will be documented by using the Self Injection Assessment 
Questionnaire (version 2 SIAQ, Appendix G), to be completed only by those patients who give 
themselves an injection.  
This paper questionnaire will be collected separately from the e-CRF. 
The SIAQ is a patient reported outcome (PRO) measure that contains two modules; one to be 
completed before the first self-injection (PRE module) and another to be completed after 
self-injection (POST module). The response for each item is provided on a five point Likert scale 
where a score of one corresponds to the patient’s worst experience and a score of five corresponds 
to the best experience.   
Some instructions to complete the questionnaire: 
1/ the PRE Module must be completed before the training self-injection with placebo. 
The PRE module consists of seven items that can be grouped into three domains: feelings about 
injections (items 1-3); self-confidence (items 4-6); and satisfaction with self-injection (item 7). 
2/ the POST Module must be completed preferably within 30 minutes (maximum 1hour) after the 
self-injection of a SC medication. 
The POST module consists of 18 items that can be grouped into six domains: feelings about 
injections (items 1-3); self-image (item 4); self-confidence (items 5-7); pain and skin reactions 
(items 8-9); ease of use (items 10-11); and satisfaction with self-injection (items 12-18). Domain 
scores are calculated as the mean of the item scores included in the domain. 
The POST module will be completed at week 4, week 8, week 12, week 24, week 48, and then 
every 12 weeks until last alirocumab injection.  
9.3 
APPROPRIATENESS OF MEASUREMENTS  
See Section 4. 
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10 
STUDY PROCEDURES 
For all visits after Day 1/Week 0 (inclusion visit), a timeframe of a certain number of days will be 
allowed. The window period for Week 0 up to Week 12 included is ±3 days, then for Week 18 
and Week 24 it is ±5 days and then for the subsequent visits it is ±7 days.  
For all visits after Day 1/inclusion visit, if one visit date is changed, then the next visit should take 
place according to the original schedule as outlined in Section 1.2. 
Blood samplings: 
The blood samplings including the determination of lipid parameters (ie, total-C, LDL-C, HDL-C, 
TG, non-HDL-C, FPG and HbA1C) should be performed in the morning, in fasting condition 
(ie, overnight, at least 10 to 12 hours fast and refrain from smoking), and before IMP injection for 
all site visits throughout the study. Alcohol consumption within 48 hours and intense physical 
exercise within 24 hours preceding the blood sampling are discouraged. 
Note: if the patient is not in fasting conditions, the blood sample will not be collected and a new 
appointment will be given the day after (or as close as possible to this date) to the patient with 
instruction to be fasted (see above conditions) and not having taken IMP (injection to be delayed 
accordingly). 
In case the lipid results are made available during the visit, the lipid results performed at local 
laboratory will be reviewed at the on-site visit by the investigator, and, in case a dose adjustment 
is required, the dose will be modified immediately or the patient will be requested to come to the 
site within a few days for an unscheduled visit, so that the dose can be adjusted as needed.  
The unscheduled dispensation visit will be similar to the “dispensation only” visits, eg, V10/W36. 
Laboratory tests: 
The laboratory data are collected in accordance with the study schedule in Section 1.2 and 
forwarded to the local Laboratory: 
• 
Hematology: (all site visits except V2, V3/inclusion, V6/W8, dispensation visits and 
EOT/EOS: see Section 9.2 for details. 
• 
Chemistry: (all site visits except V2, V3/inclusion, V6/W8, dispensation visits, 
EOT/EOT): see Section 9.2 for details. 
• 
Lipid profile: (screening, Week 4, Week 8, Week 12, Week 24, Week 48, Week 72, 
Week 96, and EOT/EOS): see Section 9.2.1.1.1. 
• 
Liver panel: in case of total bilirubin values above the normal range, differentiation into 
conjugated and non-conjugated bilirubin will occur automatically (screening, Week 4, 
Week 8, Week 12, Week 24, Week 48, Week 72, Week 96, EOT/EOS): see Section 9.2 for 
details. 
• 
Hepatitis B surface antigen (screening). 
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• 
Hepatitis C antibody, at screening and EOT/EOS; in case of ALT increase during the 
study, hepatitis C antibody should be determined and if positive a reflexive testing should 
be performed). 
• 
Serum pregnancy test (screening only). 
• 
Urine pregnancy test (inclusion and EOT/EOS). 
Urine samplings: 
Urinalysis - dipstick will be performed at site or at the local Laboratory at screening, inclusion, 
W12, EOT/EOS visits and as needed during the study at investigator’s discretion. 
It will assess for pH, specific gravity, and for the presence of blood, protein, glucose, ketones, 
nitrates, leukocyte esterase, uro-bilinogen and bilirubin. If the dipstick is abnormal then standard 
microscopy will be conducted. 
Notes: Any clinically relevant abnormal laboratory value should be immediately rechecked for 
confirmation before making any decision for the concerned patient. It should be documented as an 
AE/SAE if one or more criteria in Section 10.4.2 are met. Please also refer to Section 10.4.1.3. 
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix E, Appendix F and should be followed by investigators. In case of ALT increase 
≥3 x ULN (or ≥2 X baseline ALT if ALT elevated at baseline), the local Laboratory will perform 
the required additional testing. 
Other assessments: 
All other blood parameters will also be measured by a local 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 at screening, V7, V9, V11, V13, V15 and EOT/EOS visits 
and serum glucose at screening, V5, V7, V9, V11, V13, V15 and EOT/EOS visits) will be 
measured by a local Laboratory, as per the schedule in Section 1.2. 
Note: in case of high HbA1c values at screening, the Investigator is responsible for the 
optimization of the patient’s treatment to achieve HbA1c targets as defined by local guidelines or 
the Standards of Medical Care in Diabetes-2012 by the American Diabetes Association. 
Physical examination: 
A general physical examination should be performed at the time points indicated in the study 
schedule flowchart Section 1.2. If a new clinically significant abnormality or worsening from 
baseline is detected after inclusion, then an AE should be reported and the patient should be 
considered for further clinical investigations and/or specialist consultation as per the Investigator’s 
medical judgment. 
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Blood pressure (BP)/heart rate (HR): 
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 comfortably 
in sitting position for at least 5 minutes).Values are to be recorded in the electronic case report form 
(eCRF); both systolic BP and diastolic BP should be recorded. At the first screening visit, BP 
should be measured in both arms.  The arm with the highest diastolic pressure will be determined at 
this visit, and BP should be measured on this arm throughout the study. This highest value will be 
recorded in the eCRF. 
Heart rate will be measured at the time of the measurement of BP. 
Notes: in case of high BP values at screening the Investigator is responsible for the optimization of 
the patient’s treatment to achieve BP targets as defined by local guidelines or the Eighth Report of 
the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood 
Pressure (JNC 8).   
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. 
Height needs to be measured, as self-reported heights are not acceptable. 
Self-injection assessment questionnaire (SIAQ): 
The SIAQ is a patient reported outcome (PRO) measure that contains two modules; one to be 
completed before the first self-injection at training (PRE module) and another to be completed 
after self-injection (POST module). The response for each item is provided on a five point Likert 
scale where a score of one corresponded to the patient’s worst experience and a score of five 
corresponded to the best experience.   
See Section 9.2.3. 
10.1 
VISIT SCHEDULE 
10.1.1 Screening period 
Only patients who meet the inclusion criteria as noted in Section 7.1 should be screened. The 
screening period will take place up to 3 weeks or 21 days (and as soon as possible after receipt of 
laboratory eligibility criteria) prior to inclusion/Day 1 visit. The first screening visit (Week-3) can 
take place from 21 to 8 days before the inclusion 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. 
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Screening Visit (Visit 1 / Week -3 / Day -21 up to -8): 
During screening visit the below will be performed: 
• 
Complete informed consent - the patient will receive complete information about the study 
both verbally and in writing. Written informed consent for the study must be obtained 
prior to any study related investigations or procedures. 
• 
Assess inclusion/exclusion criteria. 
• 
Obtain patient demography – age, gender, race, and ethnicity. 
• 
Obtain medical history (including menopausal status), surgical history, alcohol habits, and 
smoking habits. 
• 
Obtain family medical history (including risk factors relating to premature CHD (before 
55 years of age in a male, 65 years in a female first degree relative), allergy and Type 2 
diabetes). 
• 
Document prior medication history within the previous 12 weeks, especially for lipid 
modifying therapy (including statin) and nutraceutical products that may affect lipids 
(eg, omega-3 fatty acids, plant stanols such as found in Benecol, flax seed oil, psyllium). 
• 
Record concomitant medication. 
• 
Perform physical examination. 
• 
Obtain body weight and height measurements. 
• 
Take vital signs including HR and BP as per directions in Section 10 above. 
• 
Collect AEs from informed consent form (ICF) signature onward: 
- All AEs and SAEs will be collected from the time of informed consent signature and 
throughout the study until the post study treatment follow up visit. 
• 
Urinalysis (dipstick and if abnormal then microscopy). 
• 
Obtain fasting blood sample for: 
- Lipids: measure or calculation of total-C, LDL-C, HDL-C, TG, non-HDL-C, 
- Hematology: red blood cell count including hematocrit, hemoglobin, red blood cell, 
WBC count with differential count and platelets, 
- Chemistry: sodium, potassium, chloride, bicarbonate, fasting glucose, calcium, 
phosphorous, urea, creatinine, uric acid, total protein, LDH, albumin, and γGT, 
- HbA1c, 
- Liver panel (ALT, AST, ALP, and total bilirubin), 
- CPK, 
- Hepatitis B surface antigen and hepatitis C antibody tests, 
- Serum pregnancy test (women of childbearing potential only), 
Note: All patients will be qualified for inclusion based on the laboratory results, including 
LDL-C value obtained at this visit, as well as other lab values where repeat is not allowed 
by protocol. 
• 
Give instruction on diet. 
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Injection training during screening period (V2/D -7): 
Injection training visit can take place at all time between V1/Screening and V3 Inclusion and also 
can be done during one of these two visits. 
Injection training should be provided as outlined in Section 8.1. The placebo for alirocumab 
should be administered by the patient or another designated person (such as spouse, relative, etc) 
at the study site under supervision of site staff with appropriate feedback.  
If it is planned to have another designated person administering the injections to the patient during 
the study, then this person should also be present at the next visit (injection training visit at 
Week -1). If feasible, it is acceptable that the injection training with placebo be performed at the 
inclusion visit (before the first IMP injection).  
• 
Before injection training patient would be requested to complete SIAQ PRE self-injection 
module. 
• 
Collect AEs. 
• 
Record batch number allocated in eCRF.  
• 
An appointment will be given for the next visit.  
10.1.2 Open-label Treatment Period  
10.1.2.1 Inclusion visit (Visit 3 / Week 0 / Day 1 +3) 
During inclusion visit the below will be performed: 
• 
Assess Inclusion/Exclusion Criteria: confirm eligibility and include the patient. 
• 
Collect AEs. 
• 
Record concomitant medication. 
• 
Review patient’s diet. Patient should be on a NCEP-ATPIII TLC diet or equivalent. 
• 
Physical examination. 
• 
Urine pregnancy test (females of childbearing potential only).  
• 
Urinalysis. 
• 
Injection training reminder could be performed at inclusion visit as needed. 
• 
If the patient is confirmed eligible, the Investigator will start the next study procedures: 
- IVRS/IWRS contact for allocation of one 7-digit treatment kit number according to the 
list for the alirocumab injections. Investigators should never allocate a treatment kit 
number to a patient without contacting IVRS/IWRS, 
- IMP kit dispensation as per treatment kit number provided by IVRS along with 
schedule reminder. The patient injection instruction manual and treatment 
administration package should be provided, 
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- The first open-label IMP injection will take place at the study site, but only after the 
assessment of all evaluations planned at that visit. Close supervision, feedback and 
further training to be provided for IMP administration. The patient should be observed 
for at least 30 minutes after the injection. 
• 
Ask the patient to complete the SIAQ (post-module). 
Reminders: 
• 
An appointment will be given for the next study site visit. 
• 
Remind patient to be in fasting conditions (ie, overnight, at least 10 to 12 hours fast and 
refrain from smoking) for next study site visit. Also, alcohol consumption within 48 hours 
and intense physical exercise within 24 hours preceding the next study site visit are 
discouraged. 
• 
Patient will be provided with a diary and instructed on its completion. Patient will be 
asked to bring the diary to the next study site visit. 
• 
Patient will be given a sharp container to discard all used pens. 
10.1.2.2 Phone calls: Visit 4 / Week 2 (Day 15 ±3), Visit 8 / Week 18 (Day 127 ±5) 
During phone calls the below will be checked: 
• 
Vital status.  
• 
Prior and concomitant medications. 
• 
Safety and product-related complaint information. 
In case of any safety concerns the investigator may request the patient to come back to the site for 
complementary assessments. 
10.1.2.3 Visit 5 / Week 4 (Day 29 ±3), Visit 6 / Week 8 (Day 57 ±3), Visit 7 / 
Week 12 (Day 85 ±3), Visit 9 / Week 24 (Day 169 ±5), Visit 11 / Week 48 
(Day 337 ±7), Visit 13 / Week 72 (Day 505 ±7), Visit 15 / Week 96 (Day 673 ±7) 
During these visits the below will be performed: 
• 
Collect AEs. 
• 
Check product complaints. 
• 
Check compliance on IMP (review patient diary and treatment kit) and data collection on 
IMP administration. 
• 
Record concomitant medication. 
• 
Perform physical examination. 
• 
Take vital signs including HR and BP. 
• 
Urinalysis (only at V7). 
• 
Laboratory tests: Hematology, Biochemistry, Liver panel, Lipid profile (hematology and 
biochemistry not needed for V6), HbA1c (except at V5 and V6). 
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• 
Remind Nutritional Counseling (including reviewing patient’s diet). 
• 
Provide any injection training reminder as needed. 
• 
IVRS contact for treatment kit dispensing (at V5 and V6, new treatment kit dispensing 
would be done as per titration needs). 
Reminders: 
• 
An appointment will be given for the next study site visit, to be done before next IMP 
administration. 
• 
Remind patient to be in fasting conditions (ie, overnight, at least 10 to 12 hours fast and 
refrain from smoking) for next study site visit. Also, alcohol consumption within 48 hours 
and intense physical exercise within 24 hours preceding the next study site visit are 
discouraged. 
• 
Ask the patient to complete the SIAQ POST (ie, after alirocumab injection). 
• 
Patient to bring the diary to the next study site visit. 
• 
If upon review of the laboratory blood test results, the investigator judges that a dose 
titration of the patient dose is necessary, then he/she will contact the patient and plan an 
unscheduled visit. The assessments of the unscheduled visit will be at minimum the same 
of the “dispensation only” visit (eg, V10/Week 36). 
10.1.2.4 Dispensation visits: Visit 10 / Week 36 (Day 253 ±7), Visit 12 /Week 60 
(Day 421 ±7), Visit 14 / Week 84 (Day 589 ±7), Visit 16 / Week 108 (Day 757 ±7) 
During dispensation visits the below will be performed: 
• 
Treatment compliance will be checked.  
• 
Patient’ diaries will be reviewed. 
• 
Safety and concomitant medication will be reviewed. 
• 
Check product complaints. 
• 
Provide any injection training reminder as needed. 
• 
Treatment kit dispensing. 
10.1.2.5 End-of-treatment (EOT/EOS) visit: Visit 17 / Week 120 (Day 841 +7) 
This EOT/EOS visit should occur at least 14 days (+7 days) after last injection (ie, within a  
14-21 days’ time window). 
This visit may occur before Week 120 if the commercial alirocumab (Praluent) becomes available 
before this date in a given country. 
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During the EOT/EOS visit the below will be performed: 
• 
Collect AEs. 
• 
Check product complaints. 
• 
Check compliance on IMP (review patient diary and treatment kit) and data collection on 
IMP administration. 
• 
Record concomitant medication. 
• 
Perform physical examination. 
• 
Take vital signs including HR and BP. 
• 
Laboratory tests: Hematology, Biochemistry, Liver panel (including Hepatitis C antibody, 
with reflexive testing if positive), Lipid profile, HbA1c. In case of abnormal results, a 
retest should be performed as soon as possible. 
• 
Urinalysis (dipstick and if abnormal then microscopy). 
• 
Urine pregnancy test (women of childbearing potential only). 
• 
Document the end of treatment with collection of the following: 
- Last dose as per diary,  
- Reason for permanent treatment discontinuation, 
- Whether the patient switches to commercial alirocumab or to another therapy. 
• 
Remind Nutritional Counseling (including reviewing patient’s diet). 
• 
IVRS/IWRS contact to register the patient’s EOT/EOS. 
Reminders:  
• 
An appointment for lab sampling will be scheduled in case of any persistent laboratory 
abnormality at EOT/EOS visit. 
10.2 
DEFINITION OF SOURCE DATA 
• 
Agreement, date, and signature of informed consent mentioning the study identification. 
• 
Patient identification, last participation in a clinical trial, medical history, associated 
diseases, and data related to the studied pathology. 
• 
Contraception methods for women of childbearing potential (WOCBP). 
• 
Previous and concomitant medications (including the lipid modifying therapy, especially 
statins used, with doses, to document statin intolerance). 
• 
Study identification. 
• 
Treatment number, dates of administration. 
• 
Dates of visits and assessments including the examination report. 
• 
Vital signs (heart rate, blood pressure), height, body weight. 
• 
Faxed lab reports (dated and signed by the Principal Investigator or Sub-Investigator 
documenting timeliness of review). 
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• 
IVRS/IWRS confirmation fax. 
• 
Adverse events and follow-up: 
- In case of SAE, the site should file in the source document at least copies of the 
hospitalization reports and any relevant examination reports documenting the 
follow-up of the SAE. 
• 
Date of premature study discontinuation (if any) and reason. 
Source documentation may be found in the following: 
• 
Patient’s identity. 
• 
Medical history. 
• 
Hospital records. 
• 
Nursing notes. 
• 
Physician’s notes. 
• 
Laboratory and procedure reports. 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION  
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop can be made temporarily; permanent IMP discontinuation should be 
a 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.  
Pregnancy will lead to definitive treatment discontinuation in all cases. 
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 
Section 7.2). 
All temporary treatment interruption duration should be recorded by the Investigator in the 
appropriate eCRF screens when considered as confirmed. 
Treatment interruption is defined as one or more scheduled injections that are not administered to 
the patient as decided by the Investigator.  
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10.3.2 Permanent treatment discontinuation with investigational medicinal product(s) 
Permanent treatment discontinuation (also referred to as treatment discontinuation) is any 
treatment discontinuation associated with the definitive decision from the Investigator or the 
patient not to re-expose the patient to the IMP at any time. 
Patient withdrawal from the study treatment or from the study should be avoided as much as 
possible. 
10.3.2.1 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. 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 for the following reasons: 
• 
Pregnancy, intention for pregnancy, or no longer with effective contraceptive method of 
birth control (females of childbearing potential only). 
• 
Acute injection reaction of clinical concern. 
• 
At patient request, ie, withdrawal of the consent for treatment; 
• 
Serious adverse event (or non-serious but severe in intensity) of hypersensitivity reaction 
considered related to IMP. 
• 
If, in the Investigator's opinion, continuation with the administration of the IMP would be 
detrimental to the patient's well-being. 
• 
Intercurrent condition that requires discontinuation of the IMP (eg, laboratory 
abnormalities, please refer to decision tree Appendix F). 
• 
At the specific request of the Sponsor. 
• 
Any abnormal laboratory value will be immediately rechecked for confirmation before 
making a decision of permanent discontinuation of the IMP for the concerned patient.  
10.3.2.2 Handling of patients after permanent treatment discontinuation 
Patients who prematurely discontinue study treatment (regardless of the reason) should, at the time 
of treatment discontinuation: 
• 
Have, as soon as possible, an unscheduled visit with assessments normally planned at end 
of treatment visit (this should take place within 5 days of treatment discontinuation, if 
possible).  
•  At a minimum, should then be followed up to recovery or stabilization of any AE as 
specified in this protocol.  
• 
Undergo a final end of study visit (EOT/EOS) at least 2 weeks after the last study treatment 
injection. 
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 confirmed. 
IVRS/IWRS should be notified when a patient prematurely discontinues study treatment. 
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10.3.2.3 Procedure and consequence for patient withdrawal from study 
The patients may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason. Withdrawal of consent for treatment should be distinguished 
from withdrawal of consent for follow-up visits and from withdrawal of consent for non-patient 
contact follow-up, eg, medical records check. Patients requesting withdrawal should be informed 
that withdrawal of consent for follow-up may jeopardize the public health value of the study. 
If possible, the patients should be assessed using the procedures defined above. 
Patients who withdraw should be explicitly asked about the contribution of possible AEs to their 
decision to withdraw consent, and any AE information elicited should be documented. Preferably 
the patient should withdraw consent in writing and, if the patient or the patient’s representative 
refuses or is physically unavailable, the site should document and sign the reason for the patient’s 
failure to withdraw consent in writing.  
All study withdrawals 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. In the medical record, 
at least the date of the withdrawal and the reason should be documented. 
For patients who fail to return to the site for the EOT/EOS visit, unless the patient withdraws the 
consent for follow-up, the Investigator should make the best effort to re-contact the patient 
(eg, contact patient’s family or private physician, review available registries or health care 
databases), and to determine his/her health status, including at least his/her vital status. Attempts 
to contact such patients must be documented in the patient’s records (eg, times and dates of 
attempted telephone contacts, receipt for sending a registered letter). 
The statistical analysis plan 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 included in the study again. Their 
inclusion and treatment numbers 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. 
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10.4.1.2 Serious adverse event 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• 
Results in death, or, 
• 
Is life-threatening, or, 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, or, 
• 
Results in persistent or significant disability/incapacity, or, 
• 
Is a congenital anomaly/birth defect. 
• 
Is a medically important event. 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
treatment) to prevent one of the other outcomes listed in the definition above. 
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: 
• 
Intensive treatment in an emergency room or at home for: 
- Allergic bronchospasm, 
- Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc.),  
- Convulsions (seizures, epilepsy, epileptic fit, absence, etc.). 
• 
Development of drug dependence or drug abuse. 
• 
ALT >3 x ULN + total bilirubin >2 x ULN or asymptomatic ALT increase >10 x ULN. 
• 
Suicide attempt or any event suggestive of suicidality. 
• 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling). 
• 
Bullous cutaneous eruptions. 
• 
Cancers diagnosed during the study or aggravated during the study (only if judged 
unusual/significant by the Investigators in oncology studies). 
• 
Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study 
(only if judged unusual/significant by the Investigators in studies assessing specifically the 
effect of a study drug on these diseases). 
• 
Suspected transmission of an infection agent: if any suspected transmission of an 
infectious agent via a medicinal product (eg product contamination). 
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10.4.1.3 Adverse event of special interest 
An adverse event of special interest (AESI) is an AE (serious or non-serious) that needs to be 
monitored, documented, and managed in a pre-specified manner described in the protocol.  
For this study, the AESIs are the following (refer also to Section 10.4.4 for the reporting time 
frame, and the corresponding complementary forms in the e-CRF to be filled): 
• 
Increase in alanine aminotransferase (ALT): 
- 
ALT ≥3 x ULN (if baseline ALT <ULN) or ALT ≥ 2 times the baseline value 
(if baseline ALT ≥ULN) (Please refer to related flowchart in Appendix F). 
• 
Allergic events that require consultation with another physician for further evaluation 
of hypersensitivity/allergy as per the Investigator’s medical judgment. 
• 
Local injection site reactions that are allergic in nature: 
- 
Local injection site reactions deemed to be allergic by the Investigator (or have an 
allergic component) and that require consultation with another physician for further 
evaluation of hypersensitivity/allergy as per the Investigator’s medical judgment 
should be reported as AESIs. 
Note: Other local injection site reactions are non-AESIs. Please see Section 10.4.1.4 
for details. 
Note: The safety instructions on allergic events and local injection site reactions are 
detailed in Section 10.6. 
• 
Pregnancy: 
- 
Pregnancy occurring in a female patient or the female partner of a male patient (if data 
collection is permitted by the female partner and by local regulatory authorities) during 
the study or within 70 days (10 weeks) following the last dose of IMP.  
- 
Pregnancy will be recorded as AESI in all cases. Pregnancy will be qualified as an 
SAE only if it fulfils one or more SAE criteria.  
- 
In the event of pregnancy of a female patient included in the study, the IMP should be 
permanently discontinued.  
- 
The follow-up of the pregnancy will be mandatory until the outcome is determined.  
• 
Symptomatic overdose with IMP: 
- 
An overdose (accidental or intentional) is an event suspected by the Investigator or 
spontaneously notified by the patient (not based on systematic injection counts) and 
defined as at least twice of the intended dose within the intended therapeutic interval 
(ie, 2 or more injections of the study treatment are administered in <7 calendar days). 
The symptomatic overdose should be reported using the term “symptomatic overdose 
(accidental or intentional)”, indicating the circumstance in parentheses 
(eg, “symptomatic overdose [accidental]” or “symptomatic overdose [intentional]”). 
The patient should be monitored and appropriate symptomatic treatment instituted, 
- 
The circumstances of the overdose should be clearly specified in the verbatim, and the 
symptoms, if any, entered on separate AE/SAE forms, 
- 
Of note, asymptomatic overdose should be reported as a standard AE.  
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• 
Neurologic events: 
- 
Neurologic events that require additional examinations/procedures and/or referral to a 
specialist should be reported as an AESI. If the event does not require additional 
examinations/procedures and/or referral to a specialist, it should be reported as a 
standard adverse event. 
• 
Neurocognitive events: 
- 
All neurocognitive events will be considered as AESI. 
10.4.1.4 Local injection site reactions (non-allergic or allergic not requiring consultation) 
Local injection site reactions that are considered non-allergic (eg, local injection site reactions 
related to mechanics of injection) or allergic but not requiring consultation with another physician 
are not considered as AESIs. 
The definition of local injection site reactions, the reporting time frame, and the corresponding 
complementary forms in the e-CRF to be filled are summarized in Appendix E. 
10.4.1.5 Device Deficiency 
• 
A device Deficiency is any inadequacy related to the identity, quality, durability, 
reliability, safety or performance of the medical device including malfunctions, use errors, 
and inadequate labeling. 
• 
Product Complaints (PC): 
- Product Complaints is defined as any written, electronic, or oral communication that 
alleges deficiencies related to the identity, quality, durability, reliability, safety, 
efficacy or performance of a product after it is released for distribution. Patients will 
be instructed to contact their site for any questions or difficulties. 
• 
All product complaints (PC) must be reported on a product complaint form when there is a 
reason to suspect a problem with the device. 
• 
In case of a PC associated with the occurrence of an AE, the AE must be documented on 
an AE page in the CRF.  
• 
In the case of a PC associated with the occurrence of a SAE, the SAE must be reported as 
in Section 10.4.3 in accordance with the serious adverse event reporting procedures.  
10.4.2 General guidelines for reporting adverse events (and product complaints) 
• 
All AEs, regardless of seriousness or relationship to investigational medical 
product (IMP)/ non investigational medical product (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. 
• 
All products complaints associated or not to an AE are to be recorded immediately on 
the corresponding products (study medical device) complaints  pages and reported to 
local Complaint Service immediately (within 24 hours). 
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• 
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, or until death, in order to ensure the safety of the patients. This may imply that 
observations will continue beyond the last planned visit per protocol, and that additional 
investigations may be requested by the monitoring team up to as noticed by the Sponsor. 
• 
Patients who experience an ongoing SAE or an AESI, at the prespecified study end-date, 
should be followed until resolution, stabilization, or death and related data will be 
collected. The duration of post study follow-up and reporting of AEs will be specified 
(eg, until recovery). 
• 
When treatment is prematurely discontinued, the patient will have an EOT (=EOS) visit at 
least 2 weeks after the last study treatment injection unless there is an AE to be followed 
until final outcome and related data will be collected.  
• 
Laboratory or vital signs are to be recorded as AEs only if:  
- Symptomatic and/or, 
- Requiring either corrective treatment or consultation, and/or, 
- Leading to IMP discontinuation or modification of dosing, and/or, 
- Fulfilling a seriousness criterion, and/or, 
- Defined as an AESI. 
Instructions for AE reporting are summarized in Appendix E. 
• 
Adverse event (injection site reactions) recorded in patient’s questionnaire: 
The Investigator must compare the injection site reaction information recorded by the 
patient in the SIAQ to the information recorded in patient diaries. Based on his/her clinical 
assessment the investigator would complete an adverse event, when required. 
10.4.3 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator or designee must immediately: 
• 
ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the e-CRF; the system will automatically send a notification to the monitoring team after 
approval of the Investigator within the e-CRF or after a standard delay. 
• 
SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the monitoring 
team whose name, fax number, and email address appear on the clinical trial protocol. 
Care should be taken to ensure that the patient's identity is protected and the patient's 
identifiers in the clinical trial are properly mentioned on any copy of a source document 
provided to the Sponsor. For laboratory results, include the laboratory normal ranges. 
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• 
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 knowledge of the SAE. In addition, every effort should be made to 
further document any SAE that is fatal or life threatening within a week (7 days) of the 
initial notification. 
• 
A back-up plan (using a paper CRF process) is available and should be used 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 monitoring team. 
10.4.4 Guidelines for reporting adverse events of special interest  
For these AEs, the Sponsor must be informed immediately (ie, within 24 hours), as per SAEs 
notification described in Section 10.4.3, even if not fulfilling a seriousness criterion, using the 
corresponding screens in the e-CRF. Please refer to Section 10.4.1.3 for a listing of AESI and 
Appendix E for a summary of reporting adverse events. 
For each defined AESI, the Investigator or any designees must make every attempt to collect 
additional specific information such as: 
• 
Preexisting related condition or lifestyle of interest for the AE (eg, habits, CV risk factor). 
• 
Expected list of associated signs and symptoms. 
• 
Corrective actions (eg, treatment discontinuation, concomitant treatment). 
• 
Diagnostic actions (eg, test[s] or procedure[s] results). 
• 
Additional descriptive factors. 
• 
Sequelae. 
10.4.5 Guidelines for management of specific laboratory abnormalities 
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix F.  
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices.  
• 
Neutropenia. 
• 
Thrombocytopenia. 
• 
Increase in ALT. 
• 
Acute renal insufficiency. 
• 
Increase in CPK and suspicion of rhabdomyolysis. 
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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 Reactions, SUSAR), to the regulatory authorities, 
independent ethics committees (IECs)/institutional review boards (IRBs) as appropriate 
and to the Investigators.    
• 
All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
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 Investigator’s Brochure or in this protocol 
will be considered unexpected. 
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report. 
10.6 
SAFETY INSTRUCTIONS 
10.6.1 Local injection site reactions (non-allergic or allergic not requiring consultation) 
The classification of local injection site reactions, the reporting time frame, and the corresponding 
complementary forms in the e-CRF to be filled are summarized in Appendix H. 
In case the Investigator or the patient recognizes any signs of local intolerability, the patient 
should be treated and followed-up as per the Investigator’s medical judgment. 
Specific e-CRF screens (General Allergic Reaction and/or Local Injection Site Reaction 
Complementary Form) are to be filled (Appendix E). The local symptoms should be reported in 
the “local injection site reaction” section of the complementary form. If the injection site reaction 
progress/expand/worsen/etc, both “local injection site reaction” and “general allergic reaction” of 
the complementary form should be completed. 
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. 
Under certain circumstances, no AE of local injection site reactions should be reported, as this is 
not typically considered a clinically important finding: 
The patient has erythema, redness, and/or swelling, that is <2.5 cm in diameter, AND 
• 
The swelling does not interfere with activity, AND 
• 
No other signs or symptoms are involved. 
Note: if the patient has a reaction of swelling with a diameter <2.5 cm that interferes with activity, 
it should be considered as a clinically relevant finding and should be reported as an AE with a 
corresponding intensity of moderate or severe, in accordance with Appendix E. 
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10.6.2 Allergic Adverse Events 
Specific eCRF 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 (eg, generalized itch, nasal itch, swelling at 
injection site, flushing, hives, swelling at lips, eyes, face, tongue, hands, feet, lump in throat, 
difficulty to swallow, hoarseness, change in pitch of voice, incapacity to speak, wheezing, chest 
tightness, stridor, 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 (eg, 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 10.6.3 and General Allergic Reaction Complementary 
form should be completed. 
The IMP should be immediately interrupted (temporarily discontinued) if there is a suspicion of 
an allergic event related to IMP. See Section 10.3.1 for further information on treatment 
interruption and Section 10.3.2 for criteria for permanent treatment discontinuation. 
10.6.3 Allergic adverse event with cutaneous involvement 
Adverse events with cutaneous involvement which are obviously of allergic origin or injection site 
reactions which progress/expand/worsen/etc. should be evaluated by a dermatologist as soon as 
possible, and preferably within one week of the site first becoming aware of the event. 
The Investigator should evaluate the patient for possible etiologies (new medications, etc.) and 
extracutaneous symptoms and signs. An unscheduled Local Laboratory assessment for 
hematology, chemistry, liver panel should be obtained. If it is possible, the site will take pictures of 
the skin lesions in order to provide the patient with them for the dermatologist’s visit. If the photos 
are obtained, then copies should be kept as source documents which may later be collected by the 
sponsor. The Investigator will provide a summary of the patient's case, reason for consultation, 
and information being requested to the consulting dermatologist. 
A full consultation report should be sent by the dermatologist to the Investigator. The full report 
should contain, at a minimum, the following information; a detailed description of the rash 
(such as the morphology [lesion type], shape of individual lesions, arrangement of multiple lesions 
[eg, scattered, grouped, linear], distribution, color, consistency, presence of pruritus or pain, and 
other clinical signs) and in case a skin biopsy (including histopathology and immunofluorescence) 
was done (if it was deemed necessary as per the dermatologist’s or Investigator’s medical 
judgment), the results of this investigation with, if applicable, a specific diagnosis of the AE.  
The Investigator will fax the full report and the corrected AE form if necessary, to the Monitoring 
Team Representative within 24 hours. 
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10.6.4 Acute allergic injection reactions 
Acute allergic injection reaction (which are considered under the category of general allergic 
reactions) is defined as any AE that occurs during or shortly after injection of the IMP 
(characterized by but not limited to hypotension, bronchoconstriction, urticaria, edema, 
angioedema, nausea, vomiting). Emergency equipment and medication for the treatment of these 
potential adverse effects (eg, antihistamines, bronchodilators, IV saline, corticosteroids, 
acetaminophen, and epinephrine) must be available for immediate use for the injections at the 
training, and inclusion visits. 
Patients will be observed at the investigational site for at least 30 minutes following the injection 
that takes place at the inclusion visit. Patients should be treated symptomatically if any AEs are 
observed. Patients are to remain at the site until any acute injection reaction is assessed as stable, 
per the Investigator’s discretion. General Allergic Reaction and/or Local Injection Site Reaction 
Complementary Form will have to be completed. 
10.7 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final clinical study report. 
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11 
STATISTICAL CONSIDERATIONS 
The material of this Section is the basis for the Statistical Analysis Plan for the study. This plan 
may be revised during the study to accommodate clinical trial protocol amendments and to make 
changes to adapt to unexpected issues in study execution and data that affect planned analysis. 
Thus a final plan should be issued before database lock. 
11.1 
DETERMINATION OF SAMPLE SIZE 
No formal sample size calculation has been done. The Safety analyses of this study will be 
descriptive. The table below provides the precision (95% CI) associated to a variety of AE event 
rates for a targeted sample size of 1300 patients: 
Table 1 - Expected 95% CI for various event rates 
Adverse event rates 
10% 
20% 
30% 
40% 
50% 
95%CI 
[8.4%; 11.6%] 
[17.8%; 22.2%] 
[27.5%; 32.5%] 
[37.3%; 42.7%] 
[47.3%; 52.7%] 
 
For a rare non observed event, by using the rule of three, it can be estimated that the upper limit of 
the 95% confidence interval of the event rate is approximately 0.23% (1 per 433). 
11.2 
DISPOSITION OF PATIENTS 
Screened patients are defined as any patient who met the inclusion criteria and signed the 
informed consent.  
Enrolled patients consist of all screened patients, with a treatment kit number allocated and 
recorded in the IVRS/IWRS database, regardless of whether treatment kit was used or not. 
Reasons for treatment discontinuation as well as reasons for withdrawal from the study will be 
summarized. 
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11.3 
ANALYSIS POPULATIONS 
11.3.1 Efficacy population 
11.3.1.1 Modified intent-to-treat population 
Modified intent-to-treat population (mITT): all enrolled patients who took at least one dose or part 
of a dose of alirocumab and had an evaluable efficacy endpoint during the efficacy treatment 
period. The main efficacy endpoint will be evaluable provided that the two following conditions 
are met: 
• 
Availability of a baseline calculated LDL-C value (last value available prior to the first 
injection of alirocumab). 
• 
Availability of at least one calculated LDL-C value during the efficacy treatment period 
and within one of the analysis windows up to Week 12. 
The efficacy treatment period is defined as the time period from the first injection of alirocumab 
up to the day of last injection +21 days. 
11.3.2 Safety population 
The safety population will consist of the patients who have signed the informed consent form and 
who have received at least one dose or partial dose of alirocumab. 
11.3.3 Other analysis population 
The analysis of the “POST-self-injection” module of the SIAQ will be performed in the patients 
of the safety population who gave themselves at least one alirocumab injection. 
11.4 
STATISTICAL METHODS 
All statistical analyses described in this section will be provided at the time of the final analysis. 
The number and percentage of patients will be provided for qualitative variables. The following 
information will be provided for continuous variables: number of patients (N), mean, standard 
deviation, median, as well as minimum and maximum. The first quartile (Q1) and the third 
quartile (Q3) will also be provided for some baseline lipid and laboratory parameters.  
Analyses will also be performed on some sub-groups of interest such as patients with HeFH, 
Type 1 and Type 2 diabetes mellitus, established CHD or other CVD (including patients suffering 
from progressive cardiovascular disease). 
For the final analysis, the results will be displayed globally and in some cases per country or 
region if the sample size is deemed sufficiently large. 
Final analysis will be performed after the global Data Base Lock. 
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11.4.1 Extent of alirocumab exposure and compliance 
The extent of alirocumab treatment exposure and compliance will be assessed and summarized by 
actual treatment received within the safety population. 
11.4.1.1 Extent of investigational medicinal product exposure 
The total exposure will be assessed by: 
• 
Duration of alirocumab exposure in weeks defined as: (last alirocumab injection date  
+ 14 - first alirocumab injection date) / 7, regardless of unplanned intermittent 
discontinuations. 
• 
The total number of injections by patient. 
11.4.1.2 Compliance 
Compliance will be assessed using the following parameters: 
• 
The mean injection frequency will be defined for each patient as the average number of 
days between 2 consecutive injections, that is: (last dose date – first dose date)/(number of 
injections -1). 
This parameter will be summarized descriptively (N, Mean, SD, Median, Min and Max). 
• 
The overall compliance 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): 
- 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, 
- 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 a days above-planned 
dosing. 
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11.4.2 Analyses of safety data (see Section 9.1) 
All safety analyses will be performed on the Safety population.  For each of safety parameter, the 
baseline value will be defined as the last available value before the first injection. 
The safety analysis will focus on the Treatment Emergent Adverse Events (TEAE) period defined 
as the time from the first dose of alirocumab to the last dose of IMP +14 to 21 days. 
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. 
Potentially clinically significant abnormality (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. 
AE definition: 
• 
Pre-treatment AEs are AEs that developed or worsened or became serious during the 
PRE-TREATMENT period. 
• 
Treatment-emergent AEs (TEAEs) are AEs that developed or worsened or became serious 
during the TEAE period. 
• 
Post-treatment AEs are AEs that developed or worsened or became serious during the 
POST-TREATMENT period. 
11.4.2.1 Analysis of adverse events 
Adverse event incidence tables will be presented by system organ class (SOC), high-level group 
term (HLGT), high level term (HLT) and preferred term (PT) sorted in alphabetical order, 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 will be the safety population. 
Adverse event incidence table will be provided for all types of TEAEs: all TEAEs, all treatment 
emergent AESI, all treatment emergent SAEs and all TEAEs leading to permanent treatment 
discontinuation. 
If any clinically significant signal is detected and need further characterization or for adverse 
event of clinical interest, exploration of time to onset could be performed for these selected TEAEs 
as described below to account for the differential exposure time in all patients. 
Selected TEAEs will be also analyzed using time-to-event approach (Kaplan-Meier 
methodology). Time from the first dose of IMP injection to the first occurrence of the event will 
be calculated (only the first event will be counted). Patients without any event will be censored at 
the end of the TEAE period. Incidence rates at different time points of exposure will be 
presented and Kaplan-Meier curves will be provided. 
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Death: 
The following deaths summaries will be generated: 
• 
Number (%) of patients who died by study period (TEAE, on-study, post-study) 
summarized on the safety population. 
• 
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. 
11.4.2.2 Analysis of laboratory data and vital signs 
The summary statistics (including mean, median, Q1, Q3, standard error, minimum and maximum) 
of all laboratory variables, all vital signs parameters (raw data and changes from baseline) will be 
calculated for each visit, last and worst value assessed during the treatment period. For selected 
parameters, mean changes from baseline with the corresponding standard error will be plotted over 
time (at same time points). 
• 
The incidence of PCSAs at any time during the TEAE period (on-treatment PCSAs) will be 
summarized whatever the baseline level and/or according to the following baseline 
categories: 
- Normal/missing, 
- Abnormal according to PCSA criterion or criteria. 
For laboratory parameters for which PCSA criterion is not defined, similar table(s) using the 
normal range could be provided. 
The absolute change in HbA1c (%) will be assessed from baseline to Week 12, 24, 72, 96 and 
EOT/EOS. 
11.4.3 Analyses of efficacy data (see Section 9.2.1) 
Efficacy variables will be explored through descriptive statistics.  
Percent changes from baseline will be summarized at Weeks 4, 8, 12 and 24 and at Week 48, 72, 
96, EOT/EOS in the mITT population using number of available data, mean, SD, median, 
minimum, and maximum. For percent changes, 95% confidence intervals of the mean will also be 
provided.  
All measurements, scheduled or unscheduled will be assigned to analysis windows defined in the 
statistical analysis plan (SAP).  
The proportions of patients reaching the different targets defined for LDL-C will be provided with 
their corresponding 95% confidence intervals. 
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11.4.4 Analysis of other endpoint(s) (see Section 9.2.2)  
The number (n) and percentage (%) of patients with an up-titration to 150 mg of alirocumab will 
be described as well as the detailed reasons that triggered the up-titration. 
The number (n) and percentage (%) of patients with a down-titration to 75 mg of alirocumab will 
be described as well as the detailed reasons that triggered the down-titration. 
Further details will be provided in SAP. 
11.4.5 Analyses of patient’s acceptability of self-injection (see Section 9.2.3) 
Analysis of the SIAQ will be conducted on the safety population. 
A descriptive summary of total and domain scores will be provided for each visit and change from 
baseline at Weeks 4, 8, 12, 24, 48, 72 and 96. 
Further details will be provided in the SAP. 
11.5 
INTERIM ANALYSIS 
No formal interim analysis is planned for this study. However some descriptive analyses might be 
performed before the end of the study in order to support the submission of a reimbursement 
dossier if requested by local health authorities. 
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12 
ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 
ETHICAL PRINCIPLES 
This Clinical Trial will be conducted in accordance with the principles laid down by the 18th 
World Medical Assembly (Helsinki, 1964) and all applicable amendments laid down by the 
World Medical Assemblies and the International Conference on Harmonization (ICH) guidelines 
for Good Clinical Practice (GCP). 
In compliance with Sanofi public disclosure commitments, this clinical trial will be recorded in the 
public registry website clinicaltrials.gov before the enrollment of the first patient. The registry will 
contain basic information about the trial sufficient to inform interested patients (and their 
healthcare practitioners) how to enroll in the trial. 
12.2 
LAWS AND REGULATIONS 
This Clinical Trial will be conducted in compliance with all international guidelines, and national 
laws and regulations of the country(ies) in which the Clinical Trial is performed, as well as any 
applicable guidelines. Please see Section 13.1. 
12.3 
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 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.  
12.4 
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 informed consent form 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 informed consent form will be provided to the patient.  
The informed consent form must be reviewed and approved by the Sponsor prior to submission to 
the appropriate Ethics Committee (IRB/IEC) for approval/favorable opinion. 
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12.5 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) 
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the appropriate IRB/IEC, and is required to forward to the respective other party  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 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-investigator 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 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 to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE documentation, IMP allocation, material and 
study medical devices allocation and accountability, complaints documentation 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 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 informed 
consent form 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 (eg, patient's medical file, 
appointment books, original laboratory records). These personnel, bound by professional secrecy, 
must maintain the confidentiality of all personal identity or personal medical information 
(according to confidentiality and personal data protection rules). 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (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.  
Should a correction be made, the corrected information will be entered in the e-CRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the Sponsor as soon as they are entered in the e-CRF. 
The computerized handling of the data by the Sponsor may generate additional requests (DRF) to 
which the Investigator is obliged to respond by confirming or modifying the data questioned. The 
requests with their responses will be managed through the e-CRF.  
13.5 
USE OF COMPUTERIZED SYSTEMS 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor and Investigator study files. 
Computerized systems used during the different steps of the study are: 
• 
For data management activities, Inform 5.0. 
• 
For statistical activities, SAS. 
• 
For pharmacovigilance activities, AWARE, Business Object XI. 
• 
For monitoring activities, Clubnet. 
• 
For medical writing activities, DOMASYS. 
External data loading is planned for this clinical trial. 
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14 
ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Subinvestigator will be signed, dated and provided to the Sponsor prior to 
the beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES 
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee.  
14.3 
CONFIDENTIALITY 
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the CRFs, the Investigator's Brochure and the 
results obtained during the course of the clinical trial, is confidential, prior to the publication of 
results. The Investigator and any person under his/her authority agree to undertake to keep 
confidential and not to disclose the information to any third party without the prior written 
approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
Ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The Subinvestigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Subinvestigators of the confidential nature of the clinical trial. 
The Investigator and the Sub investigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
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14.4 
PROPERTY RIGHTS 
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff /Subinvestigator not to 
mention any information or the Product in any application for a patent or for any other intellectual 
property rights. 
All the results, data, documents and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Sub investigators shall provide all assistance 
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.5 
DATA PROTECTION 
• 
The patient's personal data, which are included in the Sponsor database shall be treated in 
compliance with all applicable laws and regulations. 
• 
When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 
• 
The Sponsor also collects specific data regarding Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations. 
Subject race or ethnicity ("Caucasian/white, Black, Asian/Oriental, others") will be collected in 
this study because these data are required by several regulatory authorities 
(eg, on African- American population for FDA, on Japanese population for the PMDA in Japan, 
or on Chinese population for the CFDA in China). 
The data collected in this study will only be used for the purpose(s) of the study and to document 
the evaluation of the benefit/ risk ratio, efficacy and safety of the product(s). They may be further 
processed if they have been anonymized. 
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, Good Clinical Practice and 
applicable regulatory requirements, the Investigator should permit auditing by or on the behalf of 
the Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
14.8.1 By the Sponsor  
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
• 
The information on the product leads to doubt as to the benefit/risk ratio. 
• 
Patient enrollment is unsatisfactory. 
• 
The Investigator has received from the Sponsor all IMP, means and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon. 
• 
Non-compliance of the Investigator or Subinvestigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP. 
• 
The total number of patients is included earlier than expected. 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
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14.8.2 By the Investigator 
The Investigator may terminate his/her participation upon thirty (30) days' prior written notice if 
the study site or the Investigator for any reason becomes unable to perform or complete the 
clinical trial.  
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.9 
CLINICAL TRIAL RESULTS 
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS 
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway or 
planned within twelve (12) months of the completion of this study at all sites, the Investigator 
shall have the right to publish or present independently the results of this study in agreement with 
other Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of 
any such presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication.  In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
90 days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights.  
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes of the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) 
to clinical trial patients, or when the change(s) involves only logistical or administrative aspects of 
the trial. Any change agreed upon will be recorded in writing, the written amendment will be 
signed by the Investigator and by the Sponsor and the signed amendment will be filed with this 
clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In some instances, an amendment may require a change to the 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 
BIBLIOGRAPHIC REFERENCES 
1. Sharrett AR, Ballantyne CM, Coady SA, Heiss G, Sorlie PD, Catellier D, et al. Coronary heart 
disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), 
apolipoproteins A-I and B, and HDL density subfractions. The Atherosclerosis Risk in 
Communities (ARIC) Study. Circulation. 2001;104:1108-13. 
2. American Heart Association. Heart disease and stroke statistics–2008 update. 2008.  
www.americanheart.org/downloadable/heart/1200082005246HS_Stats%202008.final.pdf. 
3. European Association for Cardiovascular Prevention & Rehabilitation, Reiner Z, Catapano 
AL, De Backer G, Graham I, Taskinen MR, et al. ESC/EAS Guidelines for the management of  
dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society 
of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 
2011;32:1769-818. 
4. CPMP Note for Guidance on Clinical Investigation of Medicinal Products in the Treatment of 
Lipid Disorders (CPMP/EWP/3020/03) – European Agency for the Evaluation of Medicinal 
Products (EMEA). 2004. 
5. CPMP Draft Guidelines on Lipid Lowering agents (EMA/CPMP/3020/2003). Release for 
consultation, Nov 2010. 
6. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, Emberson J, 
Holland LE, Reith C, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: 
a meta-analysis of data from 170000 participants in 26 randomised trials. Lancet. 
2010;376:1670-81. 
7. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, et al. Pravastatin or 
Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 
Investigators. Intensive versus moderate lipid lowering with statins after acute coronary 
syndromes. N Engl J Med. 2004;350:1495-504. 
8. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, et al. Intensive lipid 
lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 
2005;352:1425–35. 
9. Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Holme I, et al. On behalf 
of the Incremental Decrease in End Points through Aggressive Lipid Lowering Study Group. 
High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial 
infarction. The IDEAL study: a randomized controlled trial. JAMA. 2005;294:2437-45. 
Erratum in: JAMA. 2005;294(24):3092. 
10. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. 
Executive summary of the Third Report of the National Cholesterol Education Program 
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(NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in 
Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-97. 
11. De Backer G, Ambrosioni E, Borch-Johnsen K, Brotons C, Cifkova R, Dallongeville J. Third 
Joint Task Force of European and other Societies on Cardiovascular Disease Prevention in 
Clinical Practice. Eur J Cardiovasc Prev Rehabil. 2003;10:S1-S10. 
12. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, et al. 
Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult 
Treatment Panel III Guidelines. Circulation. 2004;110:227-39. 
13. Pollex RL, Joy TR, Hegele RA. Emerging antidyslipidemic drugs. Expert Opin Emerg Drugs. 
2008;13:363-81. 
14. Horton JD, Cohen JC, Hobbs HH. Molecular biology of PCSK9: its role in LDL metabolism. 
Trends Biochem Sci. 2007;32:71-7. 
15. Benjannet S, Rhainds D, Essalmani R, Mayne J, Wickham L, Jin W, et al. NARC-1/PCSK9 
and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) 
receptor and LDL cholesterol. J Biol Chem. 2004;279:48865-75. 
16. Park SW, Moon YA, Horton JD. Post-transcriptional regulation of low density lipoprotein 
receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J Biol Chem. 
2004;279:50630-8. 
17. Rashid S, Curtis DE, Garuti R, Anderson NN, Bashmakov Y, Ho YK, et al. Decreased plasma 
cholesterol and hypersensitivity to statins in mice lacking PCSK9. Proc Natl Acad Sci USA. 
2005;102:5374-9. 
18. Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M, et al. Mutations in 
PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34:154-6. 
19. Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH. Sequence variations in PCSK9, low LDL 
and protection against coronary heart disease. N Engl J Med. 2006;354:1264-72. 
20. Steinberg D, Witztum JL. Inhibition of PCSK9: a powerful weapon for achieving ideal LDL 
cholesterol levels. Proc Natl Acad Sci U S A. 2009;106:9546-7. 
21. 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. 
22. Robinson JG, Goldberg AC. Treatment of adults with familial hypercholesterolemia and 
evidence for treatment: recommendations from the National Lipid Association Expert Panel 
on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5(3suppl),S18-29. 
 
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APPENDICES 
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Appendix A 
Summary of TLC Diet for High Cholesterol 
 
Total Fat 
25% to 35% total 
calories* Saturated fat* 
<7% total calories 
Polyunsaturated fat 
up to 10% total calories 
Monounsaturated fat 
up to 20% total calories 
Carbohydrates† 
50% to 60% total calories* 
Protein 
~15% total calories 
Cholesterol 
<200 mg/day (5.172 mmol/day) 
Plant Sterols 
2 g 
Soluble Fiber such as psyllium 
10 g to 25 g 
* ATP III allows an increase of total fat to 35 percent of total calories and a reduction in carbohydrate to 50 percent for persons with the 
metabolic syndrome. Any increase in fat intake should be in the form of either polyunsaturated or monounsaturated fat. Trans fatty acids are 
another LDL-raising fat that should be kept at a low intake. 
† Carbohydrate should derive predominantly from foods rich in complex carbohydrates including grains - especially whole grains - fruits, and 
vegetables. 
 
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Appendix B 
WHO Criteria (Dutch Lipid Network clinical criteria) for diagnosis of 
Heterozygous Familial Hypercholesterolemia (heFH) 
 
Diagnostic Scoring for Heterozygous Familial Hypercholesterolemia 
Family history 
a 
First degree relative with known premature (men <55 yrs, women <60 yrs) coronary and vascular disease. OR 
1 
b 
First degree relative with known LDL-cholesterol >95th percentile for age and sex. 
 
and/or 
a 
First degree relative with tendon xanthomata and/or arcus cornealis. OR 
2 
b 
Children below 18 yrs. with LDL-cholesterol >95th percentile for age and sex. 
 
 
 
 
Clinical history 
a 
Patient has premature (men <55 yrs, women <60 yrs) coronary artery disease 
2 
b 
Patient has premature (men <55 yrs, women <60 yrs) cerebral or peripheral vascular disease. 
1 
 
 
 
Physical examination 
a 
Tendon xanthomata 
6 
b 
Arcus cornealis below the age of 45 yrs. 
4 
 
 
 
Laboratory analysis 
 
 
mmol/L 
mg/dL 
 
a 
LDL-cholesterol 
>8.5 
>325 
8 
b 
LDL-cholesterol 
6.5-8.4 
251-325 
5 
c 
LDL-cholesterol 
5.0-6.4 
190-250 
3 
d 
LDL-cholesterol 
4.0-4.9 
155-190 
1 
 
 
 
Deoxyribonucleic acid (DNA)-analysis 
a 
Functional mutation low-density lipoprotein receptor gene present 
8 
 
 
 
Diagnosis of heFH is: 
Definite When 
>8 points 
Probable When 
6-8 points 
Possible When 
3-5 points 
 
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Appendix C 
Simon Broome Register Diagnostic Criteria for Heterozygous 
Familial Hypercholesterolemia 
Definite familial hypercholesterolemia is defined as: 
• 
Total-C >6.7 mmol/L (260 mg/dL) or LDL cholesterol above 4.0 mmol/L (155 mg/dL) in 
a child <16 years or Total-C >7.5 mmol/L (290 mg/dL) or LDL cholesterol above 
4.9 mmol/L (190 mg/dL) in an adult. (Levels either pre-treatment or highest on treatment). 
PLUS 
• 
Tendon xanthomas in patient, or in 1st degree relative (parent, sibling, child), or in 
2nd degree relative (grandparent, uncle, aunt). 
OR 
• 
DNA-based evidence of an LDL receptor mutation or familial defective apo B-100. 
 
Possible familial hypercholesterolemia is defined as: 
• 
Total-C >6.7 mmol/L (260 mg/dL) or LDL cholesterol above 4.0 mmol/L (155 mg/dL) in 
a child <16 years or Total-C >7.5 mmol/L (290 mg/dL) or LDL cholesterol above 
4.9 mmol/L (190 mg/dL) in an adult. (Levels either pre-treatment or highest on treatment). 
And at least one of the following: 
• 
Family history of myocardial infarction below 50 years of age in 2nd degree relative or 
below 60 years of age in 1st degree relative. 
• 
Family history of raised cholesterols >7.5 mmol/L (290 mg/dL) in adult 1st or 2nd degree 
relative or >6.7 mmol/L (260 mg/dL) in child or sibling under 16 years of age. 
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Appendix D 
The Stages of Heart Failure – NYHA classification 
Physicians often assess the stages of heart failure according to the New York Heart Association 
(NYHA) functional classification system. This system relates to symptoms to everyday activity 
and the patient’s quality of life. 
 
Class  
Patient Symptoms  
Class I (Normal)  
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, 
or dyspnea (shortness of breath).  
Class II (Mild)  
Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, 
palpitation, or dyspnea.  
Class III (Moderate)  Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, 
palpitation, or dyspnea.  
Class IV (Severe)  
Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency at rest. If 
any physical activity is undertaken, discomfort is increased.  
 
 
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Appendix E 
Summary of Adverse Events reporting instructions at Sanofi 
 
CASE REPORT FORM 
COMPLETION 
EVENT 
CATEGORY 
REPORTING 
TIMEFRAME 
SPECIFIC EVENTS IN THIS 
CATEGORY 
AE 
form
Safety 
complementary 
Form a 
Other 
specific 
forms 
Adverse event  
(non-SAE,  
non-AESI) 
Routine 
Any AE that is not SAE or AESI 
Yes 
No 
No 
Serious Adverse 
Event  
(non-AESI or AESI) 
Expedited 
(within 24 hours) 
Any AE meeting seriousness criterion 
per Section 10.4.1.2 
Yes 
Yes 
No, 
unless 
applicable 
Pregnancy of female patient/subject 
(including male subject’s partner as 
described in Section 10.4.1.3) 
Yes 
Yes 
Yes 
Symptomatic overdose with IMP 
Yes 
Yes 
No 
Increase in ALT as follows: 
- ALT ≥3 ULN (if baseline ALT <ULN) or  
- ALT ≥2 times the baseline value 
(if baseline ALT ≥ULN)  
Please refer to related flowchart 
(per Appendix C) 
Yes 
Yes 
Yes 
Allergic drug reactions and/or local 
injection site reactions deemed to be 
allergic and requiring consultation with 
another physician as specified in 
Section 10.4.1.3. 
Yes 
Yes 
Yes b 
Neurologic events (requiring additional 
examinations/procedures and/or 
consultation with a specialist as 
specified in Section 10.4.1.3) 
Yes 
Yes 
Yes 
Adverse Event of 
Special Interest 
(AESI)  
Expedited 
(within 24 hours) 
Neurocognitive events 
(Section 10.4.1.3) 
Yes 
Yes 
Yes 
Local injection site 
reaction  
Routine 
Non-allergic or allergic not requiring 
consultation with another physician, 
as described in Section 10.4.1.4. 
Yes 
No 
Yes b 
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CASE REPORT FORM 
COMPLETION 
EVENT 
CATEGORY 
REPORTING 
TIMEFRAME 
SPECIFIC EVENTS IN THIS 
CATEGORY 
AE 
form
Safety 
complementary 
Form a 
Other 
specific 
forms 
Laboratory or vital 
sign abnormality 
(non-SAE,  
non-AESI) that is:  
- Symptomatic 
- Requiring 
corrective 
treatment or 
consultation 
- Leading to IMP 
discontinuation or 
dose regimen 
modification  
Routine 
- Neutropenia 
- Thrombocytopenia 
- Acute renal insufficiency  
- Increase in CPK and suspicion of 
rhabdomyolysis 
Per Appendix C. 
Yes 
No 
No 
a. Completion of a Safety Complementary Form is required for any AE meeting a seriousness or AESI criterion, even if this is not otherwise 
required according to the table for a particular type of AE 
b. General allergic reaction or local site reaction sections of the Complementary Form should be completed as applicable according to the type 
of reaction (general or local). However, for local injection site reactions that progress/expand/worsen/etc, both sections (local and general) of 
the Complementary Form should be completed.  
 
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Appendix F 
General Guidance for the follow-up of laboratory abnormalities by 
Sanofi 
Neutrophils < 1500/mm3 or according to ethnic 
group
NEUTROPENIA
Repeat immediately a full blood count if value 
close to 1500/mm3
Neutrophils < 1500/mm3 confirmed 
with signs of infection  
Neutrophils < 1500/mm3 confirmed 
with no signs of infection  
1.
DISCONTINUE
Investigational Medicinal 
Product, hospitalization 
should be considered
2.
PERFORM biological 
investigations for infection
1.
DISCONTINUE
Investigational 
Medicinal Product
2.
INVESTIGATE for 
infection
In both situations
3.
INFORM the local monitor
4.
INVESTIGATE previous treatments particularly long-term, even a long time ago, 
exposure to toxic agents, e.g., benzene, X-rays, etc.
5.
PERFORM and collect the following investigations (results): 
•
RBC and platelet counts
•
Serology: EBV, (HIV), mumps, measles, rubella
6.
DECISION for bone marrow aspiration: to be taken in specialized unit
7.
COLLECT/STORE one sample following handling procedures described in PK 
sections (for studies with PK sampling) and freeze one serum sample (5 mL) on 
Day 1 (cessation of investigational medicinal product) and Day 5 (for further 
investigations)
8.
MONITOR the leukocyte count 3 times per week for at least one  week, then twice a 
month until it returns to normal
Note: 
•The procedures described in the above flowchart are to be discussed with the patient only in case 
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs.
•For individuals of African descent, the relevant value of concern is <1000/mm3
Neutropenia is to be recorded as AE only if at least one of the criteria listed in Section 10.4.3 is met
 
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Platelets < 100 000/mm3 (rule out EDTA – induced 
pseudo-thrombocytopenia)
THROMBOCYTOPENIA
Repeat immediately the count (rule out EDTA 
anticoagulant in the sample)
Platelets  < 100 000/mm3 confirmed 
with bleeding  
Platelets  < 100 000/mm3 confirmed 
with no bleeding
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
HOSPITALIZATION
should be considered
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
INVESTIGATE for 
bleeding
In both situations
3.
INFORM the local Monitor
4.
QUESTION about last intake of quinine (drinks), alcoholism, heparin administration
5.
PERFORM or collect the following investigations: 
•
Complete blood count, schizocytes, creatinine
•
Bleeding time and coagulation test (fibrinogen, INR or PT, aPTT), Fibrin 
Degradation Product
•
Viral serology: EBV, HIV, mumps, measles, rubella
6.
COLLECT/STORE one sample following handling procedures described in PK 
sections (for studies with PK sampling) and freeze one serum sample (5 mL) on 
Day 1 (cessation of investigational medicinal product) and Day 5 (for further 
investigations)
7.
DECISION for bone marrow aspiration: to be taken in specialized unit
•
On Day 1 in the case of associated anemia and/or leukopenia
•
On Day 8 if platelets remain < 50 000/mm3
8.
MONITOR the platelet count every day for at least one week and then regularly 
until it returns to normal
Note: 
The procedures above flowchart are to be discussed with the patient only in case described in the 
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs.
Thrombocytopenia is to be recorded as AE only if at least one of the criteria listed in Section 10.4.3 
is met
 
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NOTE: ALT ≥ 3 ULN (if baseline ALT < ULN) or ALT ≥ 2 TIMES THE BASELINE VALUE (if baseline ALT ≥ ULN) SHOULD BE 
NOTIFIED WITHIN 24 HOURS TO THE MONITORING TEAM (SEE Section 10.4.1.3, Section 10.4.4, and Section 10.4.5). IN 
ADDITION, IF ALT < 3 ULN MEETS A SERIOUSNESS CRITERION, THE EVENT SHOULD BE NOTIFIED WITHIN 24 HOURS 
TO THE MONITORING TEAM 
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Rapid increase in serum creatinine over 150 µmol/L 
or rapid decrease in creatinine clearance below
50 mL/mn
ACUTE RENAL FAILURE
Can be rapidly reversed:
• By volume repletion
• Or relief of urinary tract 
obstruction (according to etiology)
Cannot be rapidly reversed: 
• Occurrence/aggravation of life 
threatening symptoms of ARF: anemia, 
hyperkalemia, hyperuricemia, metabolic 
acidosis, cardiac insufficiency, 
pulmonary edema, arrhythmia, DIC, etc.
• And/or predominant elimination of 
Investigational Medicinal Product by 
renal route
1.
Investigational Medicinal 
Product may be continued
2.
MONITOR serum creatinine 
until return to baseline level
1.
INFORM the local monitor
2.
DISCONTINUE
Investigational Medicinal Product 
administration
3.
HOSPITALIZATION should be 
considered and seek for nephrologic  
advice
4.
PERFORM the following 
examinations: 
•
BP, HR, hydration status, ECG
•
Blood count
•
Liver function tests + CPK
•
Biochemistry, including urea
•
Urinalysis
5.
COLLECT/STORE one sample 
following handling procedures 
described in PK sections (for studies 
with PK sampling) and freeze one 
serum sample (5 mL) on Day 1 
(cessation of investigational 
medicinal product)
6.
MONITOR renal function until 
return to baseline level (every day at 
the beginning, then every week)
Acute renal failure is to be recorded as AE only if at least one of the criteria listed in 
Section 10.4.3 is met
 
 
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If Increase in CPK (expressed in ULN)
> 3 ULN
Repeat immediately the count.
If confirmed, inform the local monitor and
INVESTIGATE for the origin:
- PERFORM:
•
ECG
•
CPK-MB -MM 
•
Troponin
•
Creatinine
•
Iono (k+, Ca2+)
•
Transaminases + Total and conjugated bilirubin
•
Myoglobin (serum and urines)
- COLLECT/STORE one sample following handling procedures described in PK sections (for 
studies with PK sampling) and freeze one serum sample (5 mL) on Day 1 (cessation of 
investigational medicinal product). 
- INTERVIEW the patient about a recent intensive muscular effort, trauma, convulsions, electrical 
injury, injury or stress to the skeletal muscle, multiple intramuscular injections, recent surgery, 
concomitant medications, consumption of alcohol, morphine, cocaine.
- SEARCH for alternative causes to cardiac or muscular toxicity, ie: stroke, pulmonary infarction, 
dermatomyositis or polymyositis, convulsions, hypothyroidism, delirium tremens, muscular 
dystrophies.
If either the cardiac origin or the 
rhabdomyolysis is confirmed or if CPK 
> 10 ULN:
1. DISCONTINUE Investigational 
Medicinal Product administration
2. MONITOR CPK every 3 days for the 
first week then once weekly until return 
to normal or for at least 3 months
3. HOSPITALIZATION should be 
considered
If the cardiac origin or the rhabdomyolysis is 
ruled out and if CPK ≤10 ULN:
MONITOR CPK every 3 days for the first week 
then once weekly until return to normal or for 
at least 3 months
Muscular symptoms (myalgia, pain, weakness, 
dark urines)
Systematic CPK assessment as per 
protocol
Perform CPK
SUSPICION OF RHABDOMYOLYSIS
Suspicion of rhabdomyolysis is to be recorded as AE only if at least one of the criteria listed in Section 10.4.3 
is met
 
 
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Appendix G 
Self-injection Assessment Scale (SIAQ) 
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Appendix H 
Assessment of Local Injection Site Reactions 
 
Local, Non-
Allergic Reaction 
to Injectable 
Product 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Very Severe 
(Grade 4) 
Pain 
Does not interfere 
with activity 
Interferes with activity or 
repeated use of non-
narcotic pain reliever 
Prevents daily activity or 
repeated use of narcotic 
pain reliever 
Emergency Room 
(ER) visit or 
hospitalization 
Tenderness 
Mild pain to touch 
Pain with movement 
Significant pain at rest 
ER visit or 
hospitalization 
Erythema / Redness * 
2.5 – 5 cm 
5.1 – 10 cm 
>10 cm 
Necrosis or 
exfoliative dermatitis 
Swelling ** 
2.5 – 5 cm and does 
not interfere with 
activity 
5.1 – 10 cm or interferes 
with activity 
>10 cm or prevents daily 
activity 
Necrosis 
Itching 
Does not interfere 
with activity 
Interferes with activity or 
repeated use of topical or 
systemic treatment 
Prevents daily activity or 
leads to other significant 
dermatologic conditions 
(such as infection, 
scarring, etc.) 
Emergency Room 
(ER) visit or 
hospitalization 
Other (Please 
specify)*** 
No modification of 
daily activities and/or 
does not require 
symptomatic 
treatment. 
Hinders normal daily 
activities and/or requires 
symptomatic treatment. 
Prevents daily activities 
and requires 
symptomatic treatment. 
Emergency Room 
(ER) visit or 
hospitalization 
* 
In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as a 
continuous variable. 
** 
Swelling should be evaluated and graded using the functional scale as well as the actual measurement. 
*** Please specify the other signs or symptoms (for example, hematoma, discoloration, reactivation, etc.). 
ADAPTED from the toxicity grading scale table from the FDA Draft Guidance for Industry: Toxicity Grading Scale for Healthy Adult 
and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials April 2005. 
 
 
 
 
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Appendix I 
Guidance on contraceptive methods for Denmark only 
The acceptable methods of contraception for female subjects included in this study in Denmark 
will include the following: 
• 
Intra-uterine devices (IUD). 
• 
Hormonal contraceptives (contraceptive pills, implants, transdermal patches, hormonal 
vaginal devices or injections with prolonged release). 
• 
Subjects using a double-barrier contraceptive method (condom used with a diaphragm for 
example).  However, this is limited to exceptional cases or conditions where the patient 
cannot use other contraceptive methods (ie, hormonal contraceptives or IUD). 
• 
Subjects having a sterilized permanent partner may be allowed to participate. 
The allowed methods of contraception can also be described in the patient’s information (subject 
information leaflet. 
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Appendix J 
Guidance on contraceptive methods for Sweden only 
The acceptable methods of contraception for female subjects included in this study in Sweden will 
include the following: 
Women of childbearing potential must use a highly-effective contraceptive method throughout the 
study treatment, and for 10 weeks after the last IMP injection for those patients who discontinue 
prematurely. 
Below a list of contraceptive methods considered as highly-effective method for birth control: 
• 
Oral (except low-dose gestagen (lynestrenol and norestisteron)), injectable, or implanted 
hormonal contraceptives. 
• 
Intrauterine device. 
• 
Intrauterine system (for example, progestin-releasing coil). 
• 
Vasectomized male (with appropriate post-vasectomy documentation of the absence of 
sperm in the ejaculate) for 10 weeks after the last IMP injection for those patients who 
discontinue prematurely. 
 
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Appendix K 
Guidance on contraceptive methods and collection of pregnancy 
information 
DEFINITIONS 
Nonreproductive potential 
1. Premenopausal female with 1 of the following: 
- Documented hysterectomy, 
- Documented bilateral salpingectomy, 
- Documented bilateral oophorectomy. 
2. Postmenopausal 
- A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.  
- Females on hormone replacement therapy (HRT) and whose menopausal status is in 
doubt will be required to use 1 of the highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrolment. 
Reproductive potential (WOCBP) 
A woman is considered of reproductive potential (WOCBP), ie, fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
CONTRACEPTIVE GUIDANCE 
Male subjects 
• 
Male subjects with heterosexual partners of reproductive potential (WOCBP) are eligible 
to participate if they agree to use the following during the protocol defined timeline: 
- Refrain from donating sperm,  
and 
- At least 1 of the following conditions applies: 
- 
Are and agree to remain abstinent from penile-vaginal intercourse on a long term 
and persistent basis, when this is their preferred and usual lifestyle, 
or 
- 
Agree to use a male condom plus an additional contraceptive method with a failure 
rate of <1% per year (see table for female subjects). 
• 
Men with a pregnant or breastfeeding partner must agree to remain abstinent from  
penile-vaginal intercourse or use a male condom for the time defined in the protocol. 
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Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly a 
• 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with inhibition of ovulation b 
- 
oral 
- 
intravaginal 
- 
transdermal 
• 
Progestogen-only hormone contraception associated with inhibition of ovulation b 
- 
oral 
- 
injectable 
Highly Effective Methods That Are User Independent 
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulation b  
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual partner 
of the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional highly 
effective method(s) of contraception should be used. Spermatogenesis cycle is approximately 90 days.) 
• 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs 
to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the subject.) 
NOTES: 
a) 
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations regarding the use of 
contraceptive methods for subjects participating in clinical studies. 
b) 
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of the contraceptive method. In this case 
TWO highly effective methods of contraception should be used during the treatment period and for at least [XX, corresponding to time needed to 
eliminate study treatment plus 30 days for study treatments with genotoxic potential] after the last dose of study treatment. 
 
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Female subjects: 
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly a 
• 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with inhibition of ovulation b 
- 
oral 
- 
intravaginal 
- 
transdermal 
• 
Progestogen-only hormone contraception associated with inhibition of ovulation b 
- 
oral 
- 
injectable 
Highly Effective Methods That Are User Independent 
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulation b  
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual 
partner of the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional 
highly effective method(s) of contraception should be used. Spermatogenesis cycle is approximately 90 days.) 
• 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study drug. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the subject.) 
NOTES: 
a) 
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations regarding the use 
of contraceptive methods for subjects participating in clinical studies. 
b) 
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of the contraceptive method. In this case 
TWO highly effective methods of contraception should be used during the treatment period and for at least [XX, corresponding to time needed to 
eliminate study treatment plus 30 days for study treatments with genotoxic potential] after the last dose of study treatment. 
COLLECTION OF PREGNANCY INFORMATION 
Male subjects with partners of reproductive potential who become pregnant  
• 
The Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study. This applies 
only to subjects who receive study treatment. 
• 
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy  
• 
Partner will also be followed to determine the outcome of the pregnancy. Information on 
the status of the mother and child will be forwarded to the Sponsor.  
• 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date. Any termination of the pregnancy will be reported regardless of fetal status (presence 
or absence of anomalies) or indication for procedure  
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Female subjects who become pregnant  
• 
The Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study  
• 
Information will be recorded on the appropriate form and submitted to the Sponsor within 
24 hours of learning of a participant's pregnancy.  
• 
Participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on participant and neonate, which will be forwarded to 
the Sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks beyond 
the estimated delivery date.  
• 
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy will be reported as an AE or SAE.  
• 
A spontaneous abortion is always considered to be an SAE and will be reported as such. 
• 
Any SAE occurring as a result of a post-study pregnancy which is considered reasonably 
related to the study treatment by the Investigator, will be reported to the Sponsor as 
described in Section 10.4. While the Investigator is not obligated to actively seek this 
information in former study subjects, he or she may learn of an SAE through spontaneous 
reporting.  
 
 
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Appendix L 
Country-specific requirement 
Will be added as necessary by the concerned country. 
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