A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Alirocumab in Insulin Treated Patients With Type 1 or Type 2 Diabetes and With Hypercholesterolemia at High Cardiovascular Risk Not Adequately Controlled on Maximally Tolerated LDL-C Lowering Therapy
Phase: PHASE3
Conditions: Hypercholesterolaemia
Sponsor: Sanofi

Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-002579 VERSION N°11.0 (19-MAR-2015) 
Page 1 
CLINICAL TRIAL PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to 
Evaluate the Efficacy and Safety of Alirocumab in Insulin Treated Patients with 
Type 1 or Type 2 Diabetes and With Hypercholesterolemia at High Cardiovascular 
Risk Not Adequately Controlled on Maximally Tolerated LDL-C Lowering Therapy 
COMPOUND: alirocumab (SAR236553) 
STUDY NUMBER: LPS14355 
STUDY NAME: ODYSSEY DM - Insulin 
Version 
Number: 
1  
EudraCT and/or IND 
Number(s):  
2015-000799-92 and 
105574 
Date: 
08-Jul-2015
Total number of pages: 
109 
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NCT02585778

Clinical Trial Protocol  
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Version number: 1 
Property of the Sanofi Group- strictly confidential 
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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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Clinical Trial Protocol  
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CLINICAL TRIAL SUMMARY 
 
COMPOUND: SAR236553 
(alirocumab)  
STUDY No: LPS14355  
TITLE 
A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to 
Evaluate the Efficacy and Safety of Alirocumab in Insulin Treated Patients 
with Type 1 or Type 2 Diabetes and With Hypercholesterolemia at High 
Cardiovascular Risk Not Adequately Controlled on Maximally Tolerated 
LDL-C Lowering Therapy (ODYSSEY DM – Insulin) 
INVESTIGATOR/TRIAL LOCATION 
Multinational - Multicenter 
PHASE OF DEVELOPMENT 
3b 
STUDY OBJECTIVE(S) 
 
Primary Objectives 
x 
To demonstrate the superiority of alirocumab in comparison with 
placebo in the reduction of calculated low-density lipoprotein 
cholesterol (LDL-C) after 24 weeks of treatment in patients with 
diabetes treated with insulin and with hypercholesterolemia at high 
cardiovascular risk not adequately controlled on maximally tolerated 
LDL-C lowering therapy 
x 
To evaluate the safety and tolerability of alirocumab in patients with 
diabetes treated with insulin 
Secondary Objective 
x 
To demonstrate that alirocumab is superior in comparison to 
placebo in its effects on other lipid parameters at Weeks 12 and 24 
(ie, measured LDL-C, non-high-density lipoprotein cholesterol 
[non-HDL-C], apolipoprotein B [Apo B], total cholesterol [TC], 
lipoprotein a [Lp(a)]), high-density lipoprotein cholesterol (HDL-C), 
triglyceride (TG) levels, triglyceride rich lipoproteins (TGRL), 
apolipoprotein A-1 (Apo A-1), apolipoprotein C-III (Apo C-III), and 
LDL particle number and size) 
STUDY DESIGN 
This is a Phase 3b randomized, double-blind, placebo-controlled study to 
assess the efficacy and safety of alirocumab administered by subcutaneous 
(SC) injection in insulin treated patients with Type 1 or Type 2 diabetes and 
with hypercholesterolemia at high cardiovascular risk not adequately 
controlled on maximally tolerated LDL-C lowering therapy. 
Patients, unless they are statin intolerant, will be taking a stable, maximum 
dose/regimen of statin therapy that is tolerated by the patient, based on the 
Investigator’s judgment, with or without other lipid modifying therapies (LMT). 
Randomization will be unbalanced (2:1, alirocumab:placebo) 
The study will be a multinational, multicenter study. 
Patients will be stratified by diabetes type (ie, Type 1 diabetes versus Type 2 
diabetes). Recruitment of patients with Type 2 diabetes will complete when 
approximately 400 patients have been randomized. Recruitment of patients 
with Type 1 diabetes will continue until approximately 100 patients have been 
randomized or the end of the targeted recruitment period (summer 2016), 
whichever comes first. 
 
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Alirocumab will be administered subcutaneously with a starting dose of 75 mg 
every 2 weeks (Q2W) for 12 weeks with a blinded uptitration to alirocumab 
150 mg Q2W at Week 12 if the LDL-C at the Week 8 visit is 70 mg/dL 
(1.81 mmol/L). Patients who have an LDL-C <70 mg/dL (1.81 mmol/L) at the 
Week 8 visit will continue with alirocumab 75 mg every two weeks until the 
end of the double-blind treatment period. 
The study consists of: 
x 
A screening period of up to 3 weeks; 
x 
A double-blind treatment period of 24 weeks; 
x 
A safety observation period (off-treatment) of 8 weeks after the end 
of the double-blind treatment period. 
Note, the Investigator will need to document in the case report form (CRF) 
any adverse events (AEs) that have occurred within 70 days of the last dose 
of IMP that (s)he is aware of. A phone visit will take place at Week 32 in order 
to ensure documentation of any AEs occurring during this period.       
Patients should be on a stable diet for glucose and lipid management 
throughout the entire study duration from screening to the Week 24 visit. 
There shall be no significant changes in nutritional composition of the diet or 
in the quantity/pattern of food consumed. Patients must be receiving 
treatment for diabetes in accordance with local/regional standards of care. 
Statin dose and dose regimen as well as dose and dose regimen of other lipid 
modifying treatment(s) (if applicable) should be stable for 4 weeks prior to the 
screening period and throughout the entire study duration, including from the 
screening visit to randomization.  
The data on lipid parameters from blood samples will be masked after 
randomization. No attempts should be made by the Investigator or patient to 
have the patient’s lipid values independently evaluated after randomization 
until after the Week 24 visit, except for the safety of the patient as per the 
Investigator’s judgment. At the end of the double-blind treatment period 
(Week 24 visit), the Investigator will continue to manage the patient’s lipids in 
accordance with standard practice. Any lipid values after randomization (eg, if 
done for patient safety) should be redacted in the source documents and not 
shared with the Sponsor. 
Duration of study treatment will be 24 weeks with the last injection 
administered at Week 22.  
Patients will visit the study site at Weeks -3, 0, 8, 12, 20, and 24 with lab work 
at each visit; in addition phone visits are scheduled at Weeks 4 and 32. Week 
8 is a critical visit because it will be the only scheduled visit where an LDL-C 
value for uptitration will be available.  
STUDY POPULATION  
Main selection criteria 
Inclusion criteria  
I 01. 
Patients with Type 1 or Type 2 diabetes treated with insulin with 
LDL-C 70 mg/dL (1.81 mmol/L), not adequately controlled by a 
stable, maximum dose/regimen of statin that is tolerated by the 
patient for at least 4 weeks prior to the screening visit (Week -3) with 
or without other LMT.  
Note:  The maximum dose/regimen of statin that is tolerated by the 
patient is the highest registered dose/regimen tolerated by the 
patient based on the Investigator’s judgment or concerns. Some 
examples of acceptable reasons for a patient taking a lower statin 
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dose include, but are not limited to adverse effects on higher doses, 
advanced age, low body mass index (BMI), regional practices, local 
prescribing information, or concomitant medications. Patients may 
be on an alternate day dose of statin as long as the dose is 
consistently taken (eg, dose every Monday, Wednesday, Friday, 
etc.). Concomitant treatment with more than 1 statin is not 
permitted. Patients who have documented statin intolerance, as 
judged by the Investigator, and who are no longer on statin therapy 
as a result will also be eligible for the study. The reason(s) for not 
being on a maximum dose/regimen of statin (including statin 
intolerance) will need to be documented in the case report form. 
I 02. 
Patients 18 years of age or legal age of majority at screening visit, 
whichever is greater. 
I 03. 
Patients diagnosed with Type 1 or Type 2 diabetes at least one year 
prior to the screening visit (Week -3). 
Note: Patients diagnosed with Type 1 diabetes need to meet all of 
the following criteria: 
x 
diagnosis prior to the age of 30 years 
x 
treated with a multiple daily injection regimen/basal-prandial insulin 
regimen or insulin pump regimen within 6 months after diagnosis 
x 
C-peptide <0.2 pmol/mL at the screening visit 
I 04. 
HbA1c <10% at the screening visit (Week -3). 
Note: Patients with an elevated HbA1c (up to 10%) are eligible 
provided that there is no plan to target a lower HbA1c during the 
study, based on the judgment of the Investigator). 
I 05. 
Patients with documented history of cardiovascular disease (CVD) 
(including CHD and/or CHD risk equivalents) and/or at least one 
additional cardiovascular risk factor.  
Notes:  
History of CHD includes at least one of the following: 
x 
acute myocardial infarction (MI),  
x 
silent MI,  
x 
unstable angina,  
x 
coronary revascularization procedure (eg, percutaneuous coronary 
intervention [PCI] or coronary artery bypass graft surgery [CABG]), 
x 
clinically significant CHD diagnosed by invasive or noninvasive 
testing (such as coronary angiography, stress test using treadmill, 
stress echocardiography, or nuclear imaging).  
AND/OR 
CHD risk equivalents include at least one of the following: 
x 
Documented peripheral arterial disease (one of the following criteria 
[a, b, or c] must be satisfied): 
a) 
Current intermittent claudication (muscle discomfort in the 
lower limb that is both reproducible and produced by exercise 
and relieved by rest within 10 minutes) of presumed 
atherosclerotic origin TOGETHER WITH ankle-brachial index 
 0.90 in either leg at rest, OR 
b) 
History of intermittent claudication (muscle discomfort in the 
lower limb that is both reproducible and produced by exercise 
and relieved by rest within 10 minutes) TOGETHER WITH 
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endovascular procedure or surgical intervention in one or both 
legs because of atherosclerotic disease OR 
c) 
History of critical limb ischemia TOGETHER WITH 
thrombolysis, endovascular procedure or surgical intervention 
in one or both legs because of atherosclerotic disease. 
x 
Documented previous ischemic stroke with a focal ischemic 
neurological deficit that persisted more than 24 hours, considered 
as being of atherothrombotic origin. Computed tomography or 
magnetic radio imaging must have been performed to rule out 
hemorrhage and non-ischemic neurological disease. 
AND/OR 
Cardiovascular risk factors include at least one of the following: 
x 
hypertension (established on antihypertensive medicine) 
x 
current cigarette smoker 
x 
age 45 years for men and 55 years for women 
x 
 history of micro/macroalbuminuria 
x 
 history of diabetic retinopathy (preproliferative or proliferative) 
x 
family history of premature CHD (in father or brother before 55 
years of age; in mother or sister before 65 years of age) 
x 
low HDL-C (male <40 mg/dL [1.0 mmol/L] and female <50 mg/dL 
[1.3 mmol/L]) 
x 
documented chronic kidney disease (CKD) as defined by 
15 eGFR <60 mL/min/1.73 m2 for 3 months or more, including the 
screening visit). 
I 06. 
Signed written informed consent 
 
Key Exclusion criteria 
x 
Not on a stable dose of LMT (including statin or other LMT) for at 
least 4 weeks prior to the screening visit (Week -3) or from 
screening to randomization, unless statin intolerant, in which case 
there will be no statin for 4 weeks prior to the screening visit/during 
the screening period 
x 
Plans to initiate new LMT during the course of the study or to modify 
the dose of the current LMT 
x 
Serum TG >400 mg/dL (4.52 mmol/L) at the screening visit 
(Week -3). 
x 
eGFR<15 ml/min/1.73 m2 according to 4-variable MDRD equation 
at the screening visit (Week -3) 
x 
Currently receiving or plans to receive renal replacement therapy 
during the study (eg, hemodialysis, renal transplant, etc) 
x 
Unstable weight defined as a variation of >5 kg within 2 months 
prior to the screening visit, as judged by the Investigator. 
x 
BMI >45 kg/m2 or plans to undergo bariatric surgery, weight loss 
program, or to initiate weight loss drugs during the course of the 
study. 
x 
Patients not treated with insulin for at least 6 months prior to the 
screening visit or not on a stable insulin regimen (ie, a change in 
type of insulin, general timing/frequency of injections, mode or 
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pattern of administration such as basal only [Type 2 diabetes]], 
basal-prandial, etc) for at least 3 months prior to the screening visit, 
or likelihood of requiring a change in insulin type/frequency or mode 
of injection during the study period. 
x 
Not on a stable insulin dose for at least 3 months prior to screening 
(ie, more than a 30% variation in total daily insulin dose as judged 
by the Investigator), or 
likelihood of requiring intensification of insulin/antihyperglycemic 
regimen during the course of the study, as judged by the 
Investigator (eg, addition of new agent, plans for titration of insulin 
dose, etc). 
x 
Other antihyperglycemic medications taken by the patient have not 
been stable for at least 3 months before the screening visit.  
x 
History of recent decompensation of diabetes within 2 months prior 
to the screening visit (ie, diabetic ketoacidosis, hyperosmolar 
hyperglycemic state [HHS]). 
Total expected number of patients 
A total of approximately 500 patients are expected (approximately 
400 patients with Type 2 diabetes and up to 100 patients with Type 1 
diabetes). The recruitment of patients with Type 2 diabetes will complete 
when approximately 400 patients have been randomized. Recruitment of 
patients with Type 1 diabetes will continue until approximately 100 patients 
have been randomized or the end of the targeted recruitment period (summer 
2016), whichever comes first. 
STUDY TREATMENT(s) 
 
Investigational medicinal 
product(s) 
Formulation 
Alirocumab or placebo for alirocumab.  
Prefilled pen; Sterile alirocumab drug product supplied at a concentration of 
75 mg/mL or 150 mg/mL in histidine, pH 6.0, polysorbate 20, and sucrose. 
Placebo contains histidine, pH 6.0, polysorbate 20, and sucrose. 
Route(s) of administration 
Subcutaneous (SC); one injection of 1 mL subcutaneously in the abdomen, 
thigh, or outer area of upper arm (ie, deltoid region) 
Dose regimen 
Alirocumab 75 mg every two weeks (Q2W) with possible uptitration at 
Week 12 to 150 Q2W or placebo for alirocumab Q2W. The last planned 
injection of IMP is to be administered at Week 22. 
Note: A placebo injection for training purposes will be administered to the 
patient at screening, with the option of a second training injection prior to 
randomization.  If the person who is designated to administer IMP to the 
patient changes during the course of the study, the new designated person 
will be trained with a placebo. 
Noninvestigational medicinal 
product(s) (if applicable) 
 
Formulation 
No non-investigational products will be provided by the Sponsor. The 
following non-investigational products may be taken by the patient, as 
applicable, and in accordance with the eligibility criteria: antihyperglycemic 
medications (eg, insulin, metformin, etc), statins (HMG CoA reductase 
inhibitors), other LMTs (eg, cholesterol absorption inhibitors, bile acid-binding 
sequestrants, nicotinic acid, fibrates, omega-3 fatty acids). 
Route(s) of administration 
As applicable and in accordance with local labeling. 
Dose regimen 
As applicable and in accordance with local labeling. 
(electronic 
 
 
 
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ENDPOINT(S) 
 
Primary efficacy endpoint: 
x 
Percent change in calculated LDL-C from baseline to Week 24 in 
the intent-to-treat (ITT) population 
Primary safety endpoints: 
x 
Safety parameters (treatment emergent adverse events [TEAEs], 
adverse events of special interest [AESIs], product complaints, 
laboratory data, vital signs [including change in body weight and 
BMI]) 
Note: collection of AESI may be reassessed based on product labeling should 
alirocumab receive regulatory approval during the study period. 
Key secondary efficacy endpoints 
x 
Percent change in calculated LDL-C from baseline to Week 24, 
using all LDL-C values during the efficacy treatment period 
(on-treatment estimand) 
x 
Percent change in measured LDL-C from baseline to Week 24 (ITT 
estimand) 
x 
Percent change in calculated LDL-C from baseline to Week 12 (ITT 
estimand) 
x 
Percent change in measured LDL-C from baseline to Week 12 (ITT 
estimand) 
x 
Percent change in non-HDL-C from baseline to Week 24 (ITT 
estimand) 
x 
Percent change in Apo B from baseline to Week 24 (ITT estimand) 
x 
Percent change in total cholesterol from baseline to Week 24 (ITT 
estimand) 
x 
The proportion of patients reaching calculated LDL-C <70 mg/dL at 
Week 24 (on-treatment estimand) 
x 
The proportion of patients reaching calculated LDL-C <50 mg/dL at 
Week 24 (on-treatment estimand) 
x 
The proportion of patients reaching non-HDL-C <100 mg/dL at 
Week 24 (on-treatment estimand) 
x 
The proportion of patients reaching non-HDL-C <80 mg/dL at Week 
24 (on-treatment estimand) 
x 
The percent change in Lp(a) from baseline to Week 24 (ITT 
estimand) 
x 
The percent change in HDL-C from baseline to Week 24 (ITT 
estimand) 
x 
The percent change in TG from baseline to Week 24 (ITT estimand) 
x 
The percent change in LDL-C particle number from baseline to 
Week 24 (ITT estimand) 
x 
The percent change in LDL-C particle size from baseline to Week 
24 (ITT estimand)  
Diabetes-related endpoints  
x 
Absolute change in HbA1c from baseline to Weeks 12 and 24 (ITT 
and on-treatment estimands) 
x 
Absolute change in FPG from baseline to Weeks 12 and 24 (ITT 
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and on-treatment estimands) 
x 
Absolute change in total daily insulin dose from baseline to Weeks 
12 and 24 (ITT and on-treatment estimands) 
x 
Absolute change in number of glucose-lowering treatments from 
baseline to Weeks 12 and 24 (ITT and on-treatment estimands) 
Other efficacy endpoints 
The following endpoints will be evaluated as other efficacy endpoints and will 
be further detailed in the statistical analysis plan (SAP).  
x 
Percent change in calculated LDL-C from baseline to Week 12 
(on-treatment estimand) 
x 
Percent change in measured LDL-C from baseline to Weeks 12 and 
24 (on-treatment estimand) 
x 
Percent change in non-HDL, Apo B, total cholesterol, Lp(a), HDL-C, 
and TG from baseline to Weeks 12 (ITT and on-treatment 
estimands) and Week 24 (on-treatment estimand) 
x 
Proportion of patients reaching calculated LDL-C <50 and also 
<70 mg/dL at Weeks 12 (ITT and on-treatment estimands) and 24 
(ITT estimand) 
x 
Proportion of patients with 50% or greater reduction from baseline 
in calculated LDL-C at Weeks 12 and 24 (ITT estimand) 
x 
Proportion of patients reaching non-HDL-C <80 mg/dL and also 
<100 mg/dL at Weeks 12 (ITT and on treatment estimands) and 24 
(ITT estimand) 
x 
Proportion of patients reaching Apo B <80 mg/dL at Weeks 12 and 
24 (ITT and on-treatment estimands) 
x 
Percent change in LDL-C particle number and size from baseline to 
Week 12 (ITT and on-treatment estimands) and Week 24 
(on-treatment estimand) 
x 
Percent change in TGRL, Apo A-1, and Apo C-III from baseline to 
Weeks 12 and 24 (ITT and on treatment estimands) 
x 
Absolute change in ratio Apo B/Apo A-1 and TC/HDL-C from 
baseline to Weeks 12 and 24 (ITT and on-treatment estimands) 
x 
Proportion of patients reaching calculated LDL-C <70 and 
<50 mg/dL at Weeks 12 and 24 according to baseline A1c of <8% 
or 8% (ITT and on-treatment estimands) 
x 
Proportion of patients reaching calculated LDL-C <70 mg/dL and 
<50 mg/dL at Weeks 12 and 24 according to baseline A1c of 
<median A1c or median A1c (ITT and on-treatment estimands) 
 
x 
 
 
 
Other Endpoints 
x 
Anti-alirocumab antibodies assessed throughout the study. 
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ASSESSMENT SCHEDULE 
V1: (Week -3 [Day -21 to -8]): screening, investigational medicinal product 
(IMP) training, and safety.  
V2: (Week 0 [Day 1 +3 days]): baseline, randomization, first administration 
with double-blind IMP, and safety.  
V3: (Week 4 [Day 29 ±7 days]): telephone contact 
V4: (Week 8 [Day 57 ±3 days]); V5: (Week 12, [Day 85 ±3 days]); V6: 
(Week 20 [Day 141 ±7 days]) (efficacy and safety assessments) 
V5: (Week 12) Second allocation of double-blind IMP  
V7: (Week 24 [Day 169 ±3 days]): End of treatment (EOT) visit (efficacy and 
safety assessments) 
V8: (Week 32 [Day 225 ±7 days]): telephone contact (safety assessment) 
If one visit is changed, the next visit should take place according to the 
original schedule. Note: Patients who prematurely discontinue treatment 
should be followed as scheduled. 
STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
 
 
 
 
 
 
 
 
 
 
Analysis Population: 
Randomized population includes any patients who have been allocated to a 
randomized treatment regardless of whether the treatment kit was used or 
not. 
The primary efficacy analysis population will be the ITT population, defined as 
all randomized patients who had an evaluable primary efficacy endpoint.  
The primary efficacy endpoint will be considered evaluable when both of the 
following conditions are met: 
x 
The baseline calculated LDL-C value is available 
x 
A least one calculated LDL-C value is available within one of the 
analysis windows up to Week 24. 
The mITT population (otherwise referred to as the on-treatment population) is 
defined as all randomized patients who took at least one dose or part of dose 
of the double-blind IMP injection and had an evaluable primary efficacy 
endpoint during the efficacy treatment period. 
The primary efficacy endpoint will be considered evaluable during the efficacy 
treatment period when both of the following conditions are met: 
x 
The baseline calculated LDL-C value is available 
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x 
At least one calculated LDL-C value is available during the efficacy 
treatment period and within one of the analysis windows up to Week 
24. 
The efficacy treatment period will be defined as: 
x 
The time period from the first double-blind IMP injection up to 21 
days after the last double-blind IMP injection. 
Patients in the ITT and mITT populations will be analyzed according to the 
treatment group allocated by randomization.  
The safety population consists of the randomized population who actually 
received at least one dose or partial dose of IMP. The safety population will 
be analyzed according to the treatment actually received. 
Separate analyses will be performed for Type 1 diabetes patients on one 
hand and Type 2 diabetes patients on the other hand. However, some 
endpoints may also be analyzed on the pooled data (Type 1 and Type 2 
diabetes patients together). These analyses will be defined later in the 
statistical analysis plan. 
Primary Analysis: 
The percent change in calculated LDL-C from baseline to Week 24 will be 
analyzed in the ITT population using a mixed-effect model with repeated 
measures (MMRM) approach. All post-baseline data available within Week 8 
to Week 24 analysis windows will be used and missing data are accounted for 
by the MMRM model. 
The model will include the fixed categorical effects of treatment group 
(placebo versus alirocumab), time point (Week 8, Week 12, Week 20, 
Week 24), treatment-by-time point interaction, as well as the continuous fixed 
covariates of baseline LDL-C value and baseline value-by-time point 
interaction. Alirocumab will be compared to placebo using appropriate 
contrasts, and the 95% confidence interval (CI) of the difference will be 
provided. 
Analysis of key secondary endpoints and other efficacy 
endpoints: 
A hierarchical procedure (concerning key secondary endpoints only) will be 
used to control the type I error and handle multiple endpoints. If the primary 
endpoint analysis is significant at the 5% alpha level, secondary endpoints will 
be tested sequentially, using the order defined in section “Key Secondary 
endpoints”.  
Continuous secondary endpoints anticipated to have a normal distribution, will 
be analyzed using the same MMRM model as for the primary endpoint with 
the continuous fixed covariates of corresponding baseline value and baseline 
value-by-time point interaction. Continuous secondary endpoints anticipated 
to have a non-normal distribution will be analyzed using multiple imputation 
approach for handling of missing values followed by robust regression. Binary 
secondary endpoints will be analyzed using multiple imputation approach for 
handling of missing values followed by logistic regression. 
Analysis of diabetes-related endpoints and other 
endpoints: 
Descriptive analyses will be performed concerning diabetes-related endpoints 
and other endpoints such as anti-alirocumab antibodies. 
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Safety analysis: 
Safety analysis (TEAEs, AESIs, product complaints, laboratory parameters, 
vital signs) will be descriptive, based on the safety population. The safety 
analysis will focus on the TEAE period defined as the time from the first 
double-blind dose to the last double-blind dose of IMP +70 days (10 weeks). 
Timing of the analyses: 
All the efficacy data will be available for final analysis at a cut-off date 
corresponding to the Week 24 visit of the last patient.  All the safety data will 
be available at the end of the study (Week 32). If needed for the purpose of 
scientific communication, both the efficacy and safety analyses will be 
performed at the Week 24 cut-off date and an update of the safety analysis at 
the end of the study.  If analyses are not needed at Week 24, then there will 
be only a one time analysis at the end of the study. 
DURATION OF STUDY PERIOD (per 
patient)  
The duration of the study is approximately 9 months to include a 3-week 
screening period and 24-week treatment period and an 8 week safety 
observation period. 
Patients with an SAE or an AESI should be followed until resolution, 
stabilization, or death. 
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1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
 
W 0
Screening 
Visit 
R*
Alirocumab 
Alirocumab
75 mg Q2W
150 mg Q2W
Alirocumab Placebo Q2W
N = 333
N=167
W 24
Screening period 
up to 3 weeks
*R : Randomization : As a principle, it should occur after signature of the informed consent form and just before the
first dosing of the IMP.  The Randomization Day is always Day 1. 
*First IMP administration.
*Phone call visits are indicated in italics
 
 
Up -titration if  W8 LDL - C 
is 70 mg/dLor greater 
Treatment Period (24 weeks) 
W - 3 
W 12
W 4
W 8
W 20
Primary endpoint 
EOT visit
Randomization
-
Diet and statin at maximum dose tolerated by the patient (or no statin if statin intolerant) with or without 
other LMT (as applicable)
-
 
W 32
Safety observation
period 
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1.2 
STUDY FLOW CHART 
 
 
Screening 
Double-blind Treatment Period  
Safety 
observation 
period 
VISIT  
1 (Week -3) 
2 (Week 0) 
3 (Week 4)a  
 
4 (Week 8) 
 
5 (Week 12) 6 (Week 20) 
7 (Week 24)/ EOT 
8 (Week 32)/10 
weeks after last 
injection of IMP a 
DAY (visit window days) 
-21 (-21 to -8) 
1 (+ 3) 
29 (± 7) 
57 (±3) 
85 (±3) 
141 (±7) 
169 (±3) 
225 (±7) 
Informed consent  
X 
 
 
 
 
 
 
 
Review of inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
Patient demography 
X 
 
 
 
 
 
 
 
Medical/surgical history, alcohol habits, 
smoking habits 
X 
 
 
 
 
 
 
 
Prior medication history 
X 
 
 
 
 
 
 
 
Physical examinationb 
X 
X 
 
 
X 
 
X 
 
Vital signsb: 
 
 
 
 
 
 
 
 
Heart rate (HR), blood pressure (BP) 
X 
X 
 
X 
X 
X 
X 
 
Measured body weight 
X 
X 
 
X 
X 
X 
X 
 
Measured height 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Confirm patient diet 
 
X 
X 
X 
X 
X 
X 
 
Insulin log 
 
 
 
 
 
 
 
 
Dispensation/collection  
X 
X 
 
X 
X 
X 
X 
 
Review 
 
X 
X 
X 
X 
X 
X 
 
IVRS/IWRS contact 
X 
X 
 
 
X 
 
X 
 
Injection training with placeboc 
X 
 
 
 
 
 
 
 
Double-blind IMP 
dispensationd 
 
X 
 
 
X 
 
 
 
Concomitant medication checke 
X 
X 
X 
X 
X 
X 
X 
X 
Patient diary dispensation 
 
X 
 
X 
X 
X 
 
 
Patient diary review (compliance check of 
IMP and data collection on IMP 
administration) 
 
 
X 
X 
X 
X 
X 
 
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Screening 
Double-blind Treatment Period  
Safety 
observation 
period 
VISIT  
1 (Week -3) 
2 (Week 0) 
3 (Week 4)a  
 
4 (Week 8) 
 
5 (Week 12) 6 (Week 20) 
7 (Week 24)/ EOT 
8 (Week 32)/10 
weeks after last 
injection of IMP a 
Safety: 
 
 
 
 
 
 
 
 
AE /SAE recording / Product Technical 
Complaintsf (if any) 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting Laboratory Testing – Efficacy: 
 
 
 
 
 
 
 
 
Lipid Panel (TC, Calculated LDL-Cg, 
HDL-C, TG, non-HDL-C) 
X 
X 
 
X 
X 
X 
X 
 
Measured LDL-C (via beta quantification) 
 
X 
 
 
X 
 
X 
 
Apo B, Apo A-1, Apo C-III, LDL particle 
size and number, Lp(a)  
 
X 
 
 
X 
 
X 
 
Fasting Laboratory Testing-Safety: 
 
 
 
 
 
 
 
 
Hematology and chemistry (including 
plasma glucose)h 
X 
Xi 
 
X 
X 
 
X 
 
Creatine phosphokinase 
X 
Xi 
 
X 
X 
 
X 
 
Liver panelj 
X 
Xi 
 
X 
X 
 
X 
 
Pregnancy test (for women of 
childbearing potential)k 
X 
X 
 
 
 
 
X 
 
Standard urinalysis and spot urine 
albumin:creatininel 
X 
 
 
 
 
 
X 
 
HbA1c 
X 
X 
 
 
X 
 
X 
 
C-peptide 
X 
 
 
 
 
 
 
 
Hepatitis B Surface Antigenh 
X 
 
 
 
 
 
 
 
Hepatitis C Antibodyh 
X 
 
 
 
 
 
X 
 
Thyroid Stimulating Hormoneh 
X 
 
 
 
 
 
 
 
Anti-alirocumab antibodies 
 
X 
 
 
X 
 
X 
 
Serum PCSK9 levels 
 
X 
 
 
 
 
 
 
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Screening 
Double-blind Treatment Period  
Safety 
observation 
period 
VISIT  
1 (Week -3) 
2 (Week 0) 
3 (Week 4)a  
 
4 (Week 8) 
 
5 (Week 12) 6 (Week 20) 
7 (Week 24)/ EOT 
8 (Week 32)/10 
weeks after last 
injection of IMP a 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
a Weeks 4 and 32 are telephone visits only 
b Physical examination and Vital signs:  Height, Weight, HR, and BP. Abnormal vital signs are to be recorded as AEs only if they are medically relevant: symptomatic, requiring corrective 
treatment, leading to discontinuation of IMP and/or fulfilling a seriousness criterion. 
c Injection-training prior to randomization is performed with placebo. Investigators will have the option of providing a second placebo for alirocumab for patients who require additional 
self-injection training.  The first double-blind injection is administered at the site by the patient or a trained designated person with double-blind study treatment kit allocated by IVRS. Further 
training with double-blind treatment can be done at an additional unscheduled visit(s), as per patient or Investigator’s judgment. If a designated person changes during the course of the study, 
then the person will be trained using placebo. 
d For kit dispensation:  Along with kit dispensation, the treatment administration package should be given as well as the Patient diary and injection instruction manual, as needed. 
e Patients will be asked to additionally keep a log of the daily insulin dose for 7 days prior to each visit (including daily basal dose and daily prandial dose, as applicable). 
f Safety evaluation: Adverse Events (AEs), and product complaints regardless of seriousness or relationship to alirocumab treatment, will be collected from the time the patient signs the 
informed consent form (ICF) until the end of the study (Week 32). 
g LDL-C will be calculated using the Friedewald formula. If TG values exceed 400 mg/dL (4.52 mmol/L), then the central lab will reflexively measure (via the beta quantification method) the 
LDL-C rather than calculating it. 
h Hematology includes: complete blood cell count (CBC) including hematocrit, hemoglobin, red blood cell (RBC) count, red blood cell distribution width (RDW), white blood cell (WBC) count with 
differential count, and platelets.  Chemistry includes: plasma glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, urea nitrogen, creatinine, uric acid, lactate 
dehydrogenase (LDH), total protein, albumin, and GGT, Hepatitis C antibody (at screening, Week 24 and in case of transaminases elevation), Hepatitis B antigen (screening only).  Note that 
any Hepatitis C antibody that returns abnormal during the study will need to be followed by confirmatory testing.  TSH values should be performed at screening for patients who are on thyroid 
hormone replacement only.  
i 
Samples to be collected only if required per judgment of the Investigator. The only exception is plasma glucose which must be collected at Week 0. 
j 
Liver panel: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin 
k Pregnancy status should be checked by serum pregnancy test at screening in women of childbearing potential only.  Pregnancy status shall be assessed at Week 0 and Week 24 by urine 
pregnancy test.   
l 
Urinalysis and spot urine albumin: creatinine ratio: To be performed at screening and Week 24.  Additional urine testing to be repeated if needed based on Investigator judgment. 
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2 
TABLE OF CONTENTS 
CLINICAL TRIAL PROTOCOL.......................................................................................................................1 
1 
FLOW CHARTS.............................................................................................................................13 
1.1 
GRAPHICAL STUDY DESIGN ......................................................................................................13 
1.2 
STUDY FLOW CHART ..................................................................................................................14 
2 
TABLE OF CONTENTS ................................................................................................................17 
3 
LIST OF ABBREVIATIONS ..........................................................................................................22 
4 
INTRODUCTION AND RATIONALE.............................................................................................24 
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 ....................................................................................31 
6.2.1 
Duration of study participation for each patient .............................................................................31 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................32 
6.3 
INTERIM ANALYSIS......................................................................................................................32 
6.4 
STUDY COMMITTEES..................................................................................................................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 active comparator and/or mandatory background therapies.......38 
7.2.3 
Exclusion criteria related to the current knowledge of alirocumab ................................................38 
8 
STUDY TREATMENTS .................................................................................................................39 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) ..........................................................................39 
8.1.1 
Route and method of administration..............................................................................................40 
8.1.2 
Timing of administration.................................................................................................................40 
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8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCTS.....................................................................41 
8.3 
BLINDING PROCEDURES............................................................................................................41 
8.3.1 
Methods of blinding........................................................................................................................42 
8.3.1.1 
Adverse event ................................................................................................................................42 
8.3.1.2 
Lipid parameters ............................................................................................................................42 
8.3.1.3 
Anti-alirocumab antibodies.............................................................................................................42 
8.3.2 
Randomization code breaking during the study.............................................................................42 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................43 
8.5 
PACKAGING AND LABELING ......................................................................................................44 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................44 
8.7 
RESPONSIBILITIES ......................................................................................................................45 
8.7.1 
Treatment accountability and compliance......................................................................................45 
8.7.2 
Return and/or destruction of treatments ........................................................................................46 
8.8 
CONCOMITANT MEDICATION.....................................................................................................46 
8.8.1 
Management of background lipid-modifying therapy.....................................................................46 
8.8.2 
Contraception.................................................................................................................................47 
8.8.3 
Prohibited concomitant medications ..............................................................................................47 
8.8.4 
Lifestyle and dietary habits ............................................................................................................47 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................48 
9.1 
PRIMARY ENDPOINTS.................................................................................................................48 
9.1.1 
Primary efficacy endpoint...............................................................................................................48 
9.1.2 
Primary safety endpoints ...............................................................................................................49 
9.1.2.1 
Adverse events ..............................................................................................................................49 
9.1.2.2 
Laboratory safety variables............................................................................................................50 
9.1.2.3 
Vital signs.......................................................................................................................................50 
9.2 
SECONDARY ENDPOINTS ..........................................................................................................50 
9.2.1 
Key secondary efficacy endpoints .................................................................................................50 
9.2.2 
Diabetes-related endpoints ............................................................................................................51 
9.2.3 
Other efficacy endpoints ................................................................................................................51 
9.2.4 
............................................................................................52 
9.3 
FUTURE USE OF SAMPLES ........................................................................................................52 
9.4 
APPROPRIATENESS OF MEASUREMENTS ..............................................................................52 
10 
STUDY PROCEDURES ................................................................................................................53 
10.1 
VISIT SCHEDULE..........................................................................................................................55 
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10.1.1 
Screening period............................................................................................................................55 
10.1.2 
Double-blind treatment period (study site visits)............................................................................57 
10.1.2.1 Randomization visit (Week 0/Day 1)..............................................................................................57 
10.1.2.2 Week 4 (phone call) .......................................................................................................................59 
10.1.2.3 Week 8, Week 12, and Week 20 ...................................................................................................59 
10.1.2.4 Week 24 / end of treatment visit ....................................................................................................60 
10.1.2.5 Week 32 / 10 weeks after last IMP injection (phone call) ..............................................................61 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................61 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................62 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) ...........................63 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) ...........................63 
10.3.3 
List of criteria for permanent treatment discontinuation.................................................................63 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................64 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................64 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................65 
10.4.1 
Definitions of adverse events.........................................................................................................65 
10.4.1.1 Adverse event ................................................................................................................................65 
10.4.1.2 Serious adverse event ...................................................................................................................65 
10.4.1.3 Adverse event of special interest...................................................................................................66 
10.4.1.4 Local injection site reactions..........................................................................................................67 
10.4.1.5 Device deficiency ...........................................................................................................................67 
10.4.2 
General guidelines for reporting adverse events ...........................................................................68 
10.4.3 
Instructions for reporting serious adverse events ..........................................................................68 
10.4.4 
Guidelines for reporting adverse events of special interest...........................................................69 
10.4.5 
Guidelines for management of specific laboratory abnormalities ..................................................70 
10.5 
OBLIGATIONS OF THE SPONSOR .............................................................................................71 
10.6 
SAFETY INSTRUCTIONS .............................................................................................................71 
10.6.1 
Local tolerability (local injection site reactions)..............................................................................71 
10.6.2 
Allergic adverse events..................................................................................................................71 
10.6.2.1 Allergic adverse event with cutaneous involvement ......................................................................72 
10.6.2.2 Acute allergic injection reactions....................................................................................................73 
10.7 
ADVERSE EVENTS MONITORING..............................................................................................73 
11 
STATISTICAL CONSIDERATIONS..............................................................................................74 
11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................74 
11.2 
DISPOSITION OF PATIENTS .......................................................................................................74 
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11.3 
ANALYSIS POPULATIONS...........................................................................................................74 
11.3.1 
Efficacy populations .......................................................................................................................74 
11.3.1.1 Intent–to-treat population ...............................................................................................................75 
11.3.1.2 Modified intent-to-treat population .................................................................................................75 
11.3.2 
Safety population ...........................................................................................................................75 
11.3.3 
Other analysis population ..............................................................................................................76 
11.4 
STATISTICAL METHODS .............................................................................................................76 
11.4.1 
Extent of study treatment exposure and compliance.....................................................................76 
11.4.1.1 Extent of investigational medicinal product exposure....................................................................76 
11.4.1.2 Compliance ....................................................................................................................................77 
11.4.2 
Analyses of efficacy endpoints.......................................................................................................77 
11.4.2.1 Analysis of primary efficacy endpoint(s) ........................................................................................77 
11.4.2.2 Analyses of secondary efficacy endpoints.....................................................................................78 
11.4.2.3 Multiplicity considerations ..............................................................................................................79 
11.4.3 
Analyses of safety data..................................................................................................................79 
11.4.3.1 Adverse events ..............................................................................................................................80 
11.4.3.2 Laboratory data and vital signs......................................................................................................81 
11.4.4 
Analyses of diabetes-related endpoints.........................................................................................82 
11.4.5 
82 
11.5 
INTERIM ANALYSIS......................................................................................................................82 
12 
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................84 
12.1 
ETHICAL AND REGULATORY STANDARDS ..............................................................................84 
12.2 
INFORMED CONSENT .................................................................................................................84 
12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) ..............84 
13 
STUDY MONITORING...................................................................................................................86 
13.1 
RESPONSIBILITIES OF THE INVESTIGATORS .........................................................................86 
13.2 
RESPONSIBILITIES OF THE SPONSOR.....................................................................................86 
13.3 
SOURCE DOCUMENT REQUIREMENTS....................................................................................86 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST......................................................................................................................................87 
13.5 
USE OF COMPUTERIZED SYSTEMS..........................................................................................87 
14 
ADDITIONAL REQUIREMENTS...................................................................................................88 
14.1 
CURRICULUM VITAE....................................................................................................................88 
14.2 
RECORD RETENTION IN STUDY SITES ....................................................................................88 
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14.3 
CONFIDENTIALITY .......................................................................................................................88 
14.4 
PROPERTY RIGHTS.....................................................................................................................89 
14.5 
DATA PROTECTION.....................................................................................................................89 
14.6 
INSURANCE COMPENSATION....................................................................................................90 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES .................................90 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE............................................................................................................................................90 
14.8.1 
By the Sponsor...............................................................................................................................90 
14.8.2 
By the Investigator .........................................................................................................................91 
14.9 
CLINICAL TRIAL RESULTS ..........................................................................................................91 
14.10 
PUBLICATIONS AND COMMUNICATIONS .................................................................................91 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ..........................................................................92 
16 
BIBLIOGRAPHIC REFERENCES.................................................................................................93 
17 
APPENDICES................................................................................................................................97 
APPENDIX A 
THE STAGES OF HEART FAILURE – NYHA CLASSIFICATION......................................98 
APPENDIX B 
SUMMARY OF ADVERSE EVENTS REPORTING INSTRUCTIONS AT SANOFI............99 
APPENDIX C GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI....................................................................................................101 
APPENDIX D 
..................................................................................................................................106 
APPENDIX E 
ASSESSMENT OF LOCAL INJECTION SITE REACTIONS............................................109 
 
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3 
LIST OF ABBREVIATIONS 
 
ADR: 
adverse drug reaction 
AE: 
adverse event(s) 
AESI: 
adverse event(s) of special interest 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
Apo A-1: 
apolipoprotein A-1 
Apo B: 
apolipoprotein B 
Apo C-III: 
apolipoprotein C-III 
AST: 
aspartate aminotransferase 
BMI: 
body mass index 
BP: 
blood pressure 
CABG: 
coronary artery bypass graft surgery 
CHD: 
coronary heart disease 
CI: 
confidence interval 
CPK: 
creatine phosphokinase 
CRF: 
case report form 
CV: 
cardiovascular 
CVD: 
cardiovascular disease 
DRF: 
discrepancy resolution form 
eGFR: 
estimated glomerular filtration rate 
EOT: 
end of treatment 
GCP: 
good clinical practice 
HbA1c: 
glycosylated hemoglobin 
HDL-C: 
high density lipoprotein cholesterol 
heFH: 
heterozygous familial hypercholesterolemia 
HHS: 
hyperosmolar hyperglycemic state 
HLGT: 
high level group term 
HLT: 
high level term 
ICF: 
informed consent form 
IMP: 
investigational medicinal product 
 
 
ITT: 
intent-to-treat 
IVRS: 
interactive voice response system 
IWRS: 
interactive web response system 
LDH: 
lactate dehydrogenase 
LDL-C: 
low density lipoprotein cholesterol 
LDL-R: 
low-density lipoprotein receptor 
LLT: 
lowest level term 
LMT: 
lipid modifying therapy 
LOCF: 
last observation carried forward 
Lp(a): 
lipoprotein a 
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LS: 
least square 
MDRD: 
modification in diet of renal disease 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MI: 
myocardial infarction 
mITT: 
modified intent-to-treat 
MMRM: 
model with repeated measures 
non-FH: 
non familial hypercholesterolemia 
non-HDL-C: 
non-high density lipoprotein cholesterol 
NYHA: 
New York Heart Association 
PCI: 
perutaneuous coronary intervention 
PCSA: 
potentially clinically significant abnormality 
PCSK9: 
proprotein convertase subtilisin kexin type 9 
PRO: 
patient reported outcome 
PT: 
preferred term 
Q2W: 
every 2 weeks 
Q4W: 
every 4 weeks 
RBC: 
red blood cell 
RDW: 
red blood cell distribution width 
SAE: 
serious adverse event(s) 
SAP: 
statistical analysis plan 
SC: 
subcutaneous 
SE: 
standard error 
SMQ: 
standardized MedDRA query 
SOC: 
system organ class 
s-TSH: 
sensitive thyroid stimulating hormone 
SUSAR: 
Suspected Unexpected Serious Adverse Reaction 
TC: 
total cholesterol 
TEAE: 
treatment-emergent adverse event(s) 
TG: 
triglycerides 
TGRL: 
triglyceride rich lipoproteins 
TIA: 
transient ischemic attack 
WBC: 
white blood cell(s) 
 
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4 
INTRODUCTION AND RATIONALE 
Background on Patient Populations 
This study will include adult patients with Type 1 or Type 2 diabetes on insulin therapy with 
hypercholesterolemia at high cardiovascular (CV) risk that is not adequately controlled on a 
maximally tolerated dose of statin with or without other lipid modifying therapy (LMT).   
Type 2 diabetes 
More than 380 million people worldwide have diabetes (1), most of whom will die from 
cardiovascular disease (CVD) (2, 3, 4). Compared to people without diabetes, those with diabetes 
are at higher risk of developing CVD, develop associated clinical complications and at an earlier 
age, and have shortened life expectancy by about 6 to 7 years (5, 6, 7). In addition to the high 
human cost of disease, CVD contributes greatly to the overall healthcare expenditure in these 
patients (4). 
The development of CVD in people with diabetes is a progressive process and insulin requiring 
patients with Type 2 diabetes are at even higher risk than those at an earlier stage of disease (5). 
Dyslipidemia is a major risk factor for macrovascular complications in individuals with diabetes. 
In Type 2 diabetes, the dyslipidemia includes a range of lipid abnormalities including elevated 
low density lipoprotein cholesterol (LDL-C), elevated triglycerides (TG), and reduced high 
density lipoprotein cholesterol (HDL-C) (8).While an elevation of LDL-C may be variable, 
patients often present with an elevation of small, dense LDL particles which are particularly 
atherogenic. These disturbances, particularly that of LDL-C elevation, contribute to the greater 
CV risk observed in those with diabetes compared with those without (8). Low density lipoprotein 
cholesterol is identified as the primary target of cholesterol lowering therapy (9) and is accepted 
as a valid surrogate endpoint (10, 11, 12). 
Multiple clinical trials with statins and subgroup analyses in patients with diabetes (done 
primarily in patients with Type 2 diabetes) have demonstrated that significant reductions in CV 
events can be achieved through lowering of LDL-C (13, 14, 15, 16, 17, 18). The benefits of 
further intensification of LDL-C lowering, which included patients with diabetes, were recently 
demonstrated by adding ezetimibe to a statin (19).Greater reductions in LDL-C produce greater 
reduction in CV 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 CV risk (20, 21, 22, 23). 
Data from a meta-analyses including over 18000 patients with diabetes suggests that, for each 
1 mmol/L (39 mg/dL) decrease in LDL-C patients with diabetes experienced a 9% reduction in 
all-cause mortality and a 13% reduction in vascular mortality over a mean follow up period of 
4.3 years (18). 
The specific LDL-C target differs depending on the guidelines consulted and the severity of risk 
experienced by the patient, but they generally recommend a target of <1.8 mmol/L (70 mg/dL) in 
patients with Type 1 and Type 2 diabetes at high CV risk or at least a 50% LDL-C reduction 
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(4, 5, 6, 9, 24). Despite the widespread use of statin therapies, many patients with diabetes and 
dyslipidemia remain sub-optimally treated (25, 26, 27), or may be intolerant to statin therapy, due 
to troubling side effects, and may go on to experience additional CV events. For example, in the 
latest EUROASPIRE survey, although 79% of those with diabetes were on a statin, 47% had an 
LDL-C above target (26). Similarly, in the cohort of statin-treated diabetes patients in the DYSIS 
survey, 41.3% had an LDL-C above target (27). 
Type 1 diabetes 
Type 1 diabetes is one of the most common chronic autoimmune disorders with age-adjusted 
incidence from 0.1 per 100 000 people per year in China to 40.9 in Finland. In the US, around 
15 000 children and a similar number of adults are diagnosed every year. Aside from the 
enormous psychological and health burden on the individual patients, the disease costs the 
health-care system an estimated US $14.9 billion annually (28). Type 1 diabetes is associated with 
a substantially increased risk of premature death as compared to general population. Among 
persons with diabetes who are younger than 30 years of age, excess mortality is largely explained 
by acute complications of diabetes, including diabetic ketoacidosis and hypoglycemia, while CVD 
is the main cause of death later in life (29). A recent study showed that for Type 1 diabetes 
patients with on-target glycemic control, the risk of death from CV causes was more than twice 
the risk in the general population (30). Type 1 diabetes may also be accompanied by dyslipidemia 
that may predispose an individual to precocious CVD, particularly when renal dysfunction is 
present. Although the majority of participants in statin trials had Type 2 diabetes, there was no 
evidence that the effects of statin therapy on LDL-C lowering or major vascular events in people 
with Type 1 diabetes differed from that in those with Type 2 diabetes; indeed, the reduction in 
major vascular events in people with Type 1 diabetes was statistically significant (18). 
Background to proprotein convertase subtilisin kexin type 9 
The investigational medicinal product (IMP) in this study is alirocumab, a monoclonal antibody to 
proprotein convertase subtilisin kexin type 9 (PCSK9). PCSK9 is involved in regulating the levels 
of the low-density lipoprotein receptor (LDL-R) protein. Once PCSK9 is secreted into plasma it 
directly binds to the LDL-R and promotes its degradation. The increased degradation of LDLRs 
leads to a reduced LDL particle removal and, therefore higher LDL-C circulating levels. Blocking 
PCSK9 binding to the LDL-R can potentially benefit patients with hypercholesterolemia by 
decreasing their plasma LDL-C levels (31, 32, 33, 34, 35). 
Summary of select clinical studies with alirocumab 
As of 31 December 2014, 12 Phase 3 studies were completed or had a first step analysis 
completed, with 10 evaluating alirocumab administered every 2 weeks (Q2W regimen) and 2 
evaluating alirocumab administered every 4 weeks (Q4W regimen). These studies evaluated 
heterozygous familial hypercholesterolemia (heFH) patients, patients with a range of CV risk but 
predominately high and very high risk, and patients not taking statins including statin intolerant 
patients. 
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Phase 3 studies that evaluated Q2W regimen – efficacy results 
Ten studies that were completed or had a first step analysis evaluating 75 mg Q2W (with possible 
up-titration to 150 mg Q2W at Week 12) and 150 mg Q2W as initiation dose/dose regimen were 
performed.  Averaged across the various studies, Alirocumab use resulted in a mean -45.6 to -
48.9% reduction in LDL-C from baseline to Week 24 in studies that investigated the up-titration 
regimen and -60.4% in studies that solely investigated 150 mg Q2W dosing, whereas control rates 
were 0.5 to 4.2% (placebo) and -19.3 to -22.3 (ezetimibe). Superiority in LDL-C reduction was 
demonstrated in all placebo-controlled studies with alirocumab administered as add-on to a 
maximally tolerated dose of statin. Superiority in LDL-C reduction was also demonstrated in all 
ezetimibe-controlled studies, with alirocumab being administered as add-on to statin, or to LMTs 
other than statin, or in monotherapy. Overall, absolute reductions in LDL-C in the range 
of -40 to -90 mg/dL (-1.03 to -2.33 mmol/L) were observed in the alirocumab treatment arms. 
LDL-C reduction observed at Week 24 was maintained over time in all the studies including those 
up to 78 weeks. In all studies, the LDL-C reduction was observed at the first LDL-C measurement 
following the first alirocumab dose at Week 4. 
Significant and clinically meaningful reductions were also observed in pro-atherogenic 
biomarkers, including non-HDL-C, Apo B, and TC. Alirocumab was also superior to placebo, and 
to ezetimibe in most studies, for the reduction in lipoprotein a (Lp[a]). Modest but consistent 
reductions in fasting TGs and increases in HDL-C were also observed with alirocumab treatment. 
Phase 3 studies that evaluated Q4W regimen – efficacy results 
Two studies EFC13786 and R727-CL-1308 (first-step analysis), have evaluated the 150 mg Q4W 
and 300 mg Q4W, respectively, as initiation dose regimen with a possible up-titration to 150 mg 
Q2W. For both studies, LDL-C reduction was observed at Week 4 was maintained over time up to 
Week 24. As with Q2W dosing, changes in Non-HDL-C, Apo B, and TC showed good correlation 
with LDL-C. 
The R727-CL-1308 (CHOICE I) study included patients with and without concomitant statin.  In 
both of these populations, there were statistically significant effects in favor of alirocumab 
300 mg Q4W with possible up-titration to 150 mg Q2W for both co-primary efficacy endpoints 
(percent change in LDL-C from baseline to Week 24 and to averaged Weeks 21 – 24). For LDL-C 
reduction, the least square (LS) mean treatment difference for alirocumab versus placebo at 
Week 24 was -52.4% and -58.7% for the no concomitant statin population and concomitant statin 
population, respectively.  The results obtained at Week 12 were consistent with those at Week 24 
for both populations, whereby the Week 12 effect assessed the sole contribution of the 300 mg 
Q4W dose regimen. Approximately 15% of patients treated with Q4W dosing who received at 
least 1 injection after Week 12 were up-titrated to Q2W dosing. 
The EFC13786 (CHOICE II) study included a vast majority of statin intolerant patients with many 
on background ezetimibe therapy. At Week 24, a statistically significant LS mean treatment 
difference for alirocumab (150 mg Q4W with possible up-titration to 150 mg Q2W) versus 
placebo of -56.4% was achieved for LDL-C reduction. The results obtained at Week 12 showed a 
statistically significant LS mean treatment difference of -44.9%, whereby the Week 12 effect 
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assessed the sole contribution of the 150 mg Q4W dose regimen. Approximately 50% of patients 
treated with Q4W dosing who received at least 1 injection after Week 12 were up-titrated to Q2W 
dosing. 
Clinical safety 
In the completed studies, or studies with first-step analysis, 391 patients from phase 1, and 
4300 patients from phase 2 and phase 3 have been exposed to 1 or more doses of alirocumab. 
 
 
. 
Phase 2 and phase 3 safety results 
Safety data was analyzed from pooled phase 2 and phase 3 studies with a Q2W dosing, which 
included a total of 5234 patients, of which 3340 patients were treated with alirocumab at a dose of 
75 or 150 mg Q2W.  
In the placebo-controlled and ezetimibe-controlled pooled studies, no dose relationship was noted 
for any adverse events (AEs) and there was no evidence of a pattern in the type of AEs observed. 
The percentages of patients who experienced at least 1 treatment-emergent adverse event (TEAE), 
at least 1 treatment-emergent serious adverse event (SAE) and any TEAEs leading to permanent 
treatment discontinuation were similar between the alirocumab and control groups.  
There was no safety signal observed with neurologic events and neurocognitive disorders, ALT 
increase and hepatic disorders, adjudicated CV events, diabetes mellitus, and ophthalmologic 
disorders in the alirocumab-treated group overall, but more cataracts (2.1%) were noted in 
patients treated with alirocumab who achieved 2 consecutive LDL-C values <25 mg/dL compared 
to those treated with alirocumab who did not meet this criterion (0.6%). 
The most common adverse reactions in patients treated with alirocumab were local injection site 
reactions (6.2% patients in the alirocumab group versus 4.2% in control groups in the global 
pool). Injection site reactions, influenza and pruritus were identified as adverse drug reactions 
(ADRs). Rare and sometimes serious allergic adverse reactions (eg, hypersensitivity, eczema 
nummular, urticaria, and hypersensitivity vasculitis) have been reported from clinical studies in 
patients receiving alirocumab. 
The analysis of the safety data with Q2W dosing did not suggest a safety signal as of 
31 December 2014.  
Overall, the safety profile of the alirocumab Q4W dosing regimen was similar to alirocumab 
Q2W regimen, except for the frequency and onset of injection site reactions. The reactions tended 
to occur sooner after the first drug injection, and last longer, in the alirocumab group.   
Further details on alirocumab are provided in the Investigator’s Brochure. 
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Rationale for this study 
The objective of the present study is to assess the efficacy and safety of alirocumab in insulin 
treated patients with Type 1 or Type 2 diabetes who currently have an LDL-C 70 mg/dL 
(1.81 mmol/L) and who, at baseline, have required, in addition to lifestyle modification, statin 
treatment with or without other LMT in order to achieve their LDL-C treatment goal, or who are 
statin intolerant. There is interest in the impact of lipid lowering therapy on measures of glycemic 
control as evidence has accumulated and suggests that the use of statin therapy is associated with 
an increased risk of diabetes. This is particularly true for people with risk factors for diabetes. 
Despite an increased relative risk of diabetes with statin therapy, the absolute risk is quite small. 
On average, it has been estimated that treatment of 255 people over a period of 4 years will result 
in 1 additional case of diabetes. 
When balancing the benefit of therapy, treating the same number of people would prevent 
5.4 vascular events (36). While this risk impacts patients with previously undiagnosed diabetes, it 
suggests that lipid lowering treatment could modulate glycemia. In fact, evidence suggests that it 
may be transmembrane cholesterol transport that imparts the added risk as a reduced prevalence 
of diabetes has been found in patients with familial hypercholesterolemia as compared to patients 
without the disease (37). As a result, understanding the impact of alirocumab on glycemic control 
in patients with diabetes is of interest. 
In the Phase 3 program, involving a total of 5293 study participants, limited information is 
available in patients with diabetes who are treated with insulin and in those patients with Type 1 
diabetes. Focusing the target population on patients with Type 1 or Type 2 diabetes treated with 
insulin will provide additional information on this potential treatment group, both from an 
efficacy and safety point of view (concomitant use of insulin and a monoclonal antibody). In 
addition, this study will provide useful information on the use of alirocumab in patients already 
familiar with self-injection. 
It should be noted that all patients, except those with statin intolerance, will be on the maximum 
dose/regimen of statin that is tolerated by the patient, based on the Investigator’s judgment, with 
or without other LMT. Those patients who are on statins and/or other LMTs at randomization 
should continue the treatments unchanged throughout the study. 
Alirocumab will be evaluated at a dose of 75 mg Q2W with an increase of dose to 150 mg Q2W if 
LDL-C values at Week 8 are not <70 mg/dL.  
It is possible that some patients in the alirocumab arm may attain LDL-C levels well below 
70 mg/dL. Persons with genetic mutations such as heterozygous form of hypobetalipoproteinemia 
linked to Apo B mutations or loss of function PCSK9 mutations have very low LDL-C levels 
throughout life and have low vascular risk, and no apparent adverse effects (35, 38, 39, 40). 
The sample size of 500 patients with treatment duration 
of 24 weeks is intended to provide a broad safety experience in this patient population and to 
assess the impact of uptitration of alirocumab on efficacy and safety parameters. The control 
group is composed of patients receiving an injectable placebo of alirocumab and is appropriate for 
the objectives of this study since it will provide the most robust assessment of efficacy and safety 
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of alirocumab. The use of placebo is ethically acceptable as all patients should be receiving 
standard of care treatment including maximum dose/regimen of statins that is tolerated by the 
patient, based on the Investigator’s judgment, with or without other lipid modifying agents. 
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-familial hypercholesterolemia (non-FH) or with 
heterozygous familial hypercholesterolemia (heFH), including patients with a history of 
intolerance to statin. The efficacy on LDL-C was associated with consistent results in total 
cholesterol (TC), apolipoprotein B (Apo B), non-high density lipoprotein cholesterol 
(non-HDL-C) and Apo B/Apo A-1 ratio. Reductions in Lp(a) and TG and increases in HDL-C 
were also observed with alirocumab treatment.  There was no safety signal observed with 
neurologic events and neurocognitive disorders, ALT increase and hepatic disorders, adjudicated 
CV events, diabetes mellitus, and ophthalmologic disorders. 
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. 
 
The benefit of alirocumab on CV morbidity and mortality has not yet been determined and is 
under investigation in the on-going ODYSSEY OUTCOMES trial. 
This study is being undertaken to evaluate the risk benefit profile of alirocumab in patients with 
diabetes treated with insulin, given the high CV risk of this population. Since no study in the 
ODYSSEY program (ie, the alirocumab clinical trial program) has specifically focused on 
patients with diabetes and that it included a limited number of patients on insulin these data 
should provide important information concerning the efficacy and safety of alirocumab when used 
concomitantly with insulin in this high risk group. 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
The primary objectives are: 
x 
To demonstrate the superiority of alirocumab in comparison with placebo in the reduction 
of calculated low-density lipoprotein cholesterol (LDL-C) after 24 weeks of treatment in 
patients with diabetes treated with insulin and with hypercholesterolemia at high 
cardiovascular risk not adequately controlled on maximally tolerated LDL-C lowering 
therapy 
x 
To evaluate the safety and tolerability of alirocumab in patients with diabetes treated with 
insulin 
5.2 
SECONDARY 
The secondary objective is: 
x 
To demonstrate that alirocumab is superior in comparison to placebo in its effects on other 
lipid parameters at Weeks 12 and 24 (ie, measured LDL-C, non-high-density lipoprotein 
cholesterol [non-HDL-C], apolipoprotein B [Apo B], total cholesterol [TC], lipoprotein a 
[Lp(a)], high-density lipoprotein cholesterol [HDL-C], triglyceride [TG] levels, 
triglyceride rich lipoproteins [TGRL], apolipoprotein A-1 [Apo A-1], apolipoprotein C-III 
[Apo C-III], LDL particle number and size) 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE PROTOCOL 
This is a Phase 3b randomized, double-blind, placebo-controlled study to assess the efficacy and 
safety of alirocumab administered by subcutaneous (SC) injection in insulin treated patients with 
Type 1 or Type 2 diabetes and with hypercholesterolemia at high CV risk not adequately 
controlled on maximally tolerated LDL-C lowering therapy. The study will be multinational and 
multicenter. The study consists of a screening period of up to 3 weeks, a double-blind treatment 
period of 24 weeks, and a safety observation period of 8 weeks. 
Patients, unless they are statin intolerant, will be taking a stable, maximally tolerated dose of 
statin therapy with or without other lipid modifying therapies (LMT). Statin dose and dose 
regimen as well as dose and dose regimen of other lipid modifying treatment(s) (if applicable) 
should be stable throughout the entire study duration including for 4 weeks prior to the screening 
period, during the screening period, and from screening to randomization. Patients should be on a 
stable diet for glucose and lipid management throughout the entire study duration from screening 
to the Week 24 visit. Patients should be receiving treatment for diabetes in accordance with 
local/regional standards of care. 
Patients will be stratified by diabetes type (ie, Type 1 diabetes versus Type 2 diabetes). 
Recruitment of patients with Type 2 diabetes will complete when approximately 400 patients have 
been randomized. Recruitment of patients with Type 1 diabetes will continue until approximately 
100 patients have been randomized or the end of the targeted recruitment period (summer 2016), 
whichever comes first. 
Alirocumab will be administered subcutaneously with a starting dose of 75 mg Q2W for 12 weeks 
with a blinded uptitration to alirocumab 150 mg Q2W at Week 12 if the LDL-C at the Week 8 
visit is 70 mg/dL (1.81 mmol/L). Patients who have an LDL-C <70 mg/dL (1.81 mmol/L) at the 
Week 8 visit will continue with alirocumab 75 mg Q2W until the end of the treatment period. 
The data on lipid parameters from blood samples will be masked after randomization. No attempts 
should be made by the Investigator or patient to have the patient’s lipid values independently 
evaluated after randomization until after the Week 24 visit, except for the safety of the patient, as 
per the Investigator’s judgment. 
Patients will visit the study site at Weeks -3, 0, 8, 12, 20, and 24 with lab work at each visit; in 
addition a phone visit is scheduled at Weeks 4 and 32. 
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
The duration of the study is approximately 9 months to include: 
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x 
a 3-week screening period from signed informed consent form (ICF) to randomization 
x 
a 24-week double-blind treatment period 
x 
a safety observation period (off-treatment) of 8 weeks after the end of the double-blind 
treatment period 
Note, the Investigator will need to document in the CRF any AEs that have occurred within 
70 days of the last dose of IMP that (s)he is aware of. A phone visit will take place at Week 32 in 
order to ensure documentation of any AEs occurring during this period. Patients with an SAE or 
an adverse event of special interest (AESI) should be followed until resolution, stabilization, or 
death. 
6.2.2 Determination of end of clinical trial (all patients) 
The end of study is defined as being the last patient last visit/contact.  
6.3 
INTERIM ANALYSIS 
If needed for the purpose of scientific communication, an analysis of efficacy and safety may be 
conducted after the last patient has completed the Week 24 visit. At that time, all the efficacy data 
will be available for final analysis. Since safety data are being collected until the end of the study 
(Week 32), if the analysis with Week 24 data is performed, an update of the safety analysis will be 
performed at the end of the study.  If analyses are not needed at Week 24, then there will be only a 
one time analysis at the end of the study.  
6.4 
STUDY COMMITTEES 
Steering committee 
The Steering Committee is composed of university-based scientists (experts in lipids field, and/or 
Endocrinology/Diabetology) with clinical and study conduct expertise, working in collaboration 
with Sponsor based scientists. The committee will provide guidance on designing and conducting 
a scientifically sound study and ensure accurate reporting of the study. The Steering Committee 
will address and resolve scientific issues if encountered during the study. They will also help with 
the study recruitment, as needed. The Steering Committee members and Sponsor based scientists 
will participate in face-to-face meetings at regular intervals throughout the study and in regularly 
scheduled teleconferences. Detailed activities and responsibilities of the Steering Committee will 
be described in the Steering Committee Charter. 
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7 
SELECTION OF PATIENTS 
7.1 
INCLUSION CRITERIA 
I 01. Patients with Type 1 or Type 2 diabetes treated with insulin with LDL 70 mg/dL 
(1.81 mmol/L), not adequately controlled by a stable, maximum dose/regimen of statin that 
is tolerated by the patient (see note below) for at least 4 weeks prior to the screening visit 
(Week -3) with or without other LMT.  
Note:  The maximum dose/regimen of statin that is tolerated by the patient is the highest 
registered dose/regimen tolerated by the patient based on the Investigator’s judgment or 
concerns. Some examples of acceptable reasons for a patient taking a lower statin dose 
include, but are not limited to adverse effects on higher doses, advanced age, low body 
mass index (BMI), regional practices, local prescribing information, or concomitant 
medications. Patients may be on an alternate day dose of statin as long as the dose is 
consistently taken (eg, dose every Monday, Wednesday, Friday, etc). Concomitant 
treatment with more than 1 statin is not permitted. Patients who have documented statin 
intolerance, as judged by the Investigator, and who are no longer on statin therapy as a 
result will also be eligible for the study. The reason(s) for not being on a maximum 
dose/regimen of statin (including statin intolerance) will need to be documented in the case 
report form. 
I 02. Patients 18 years of age or legal age of majority at screening visit, whichever is greater. 
I 03. Patients diagnosed with Type 1 or Type 2 diabetes at least one year prior to the screening 
visit (Week -3). 
Note:  Patients diagnosed with Type 1 diabetes need to meet all of the following criteria: 
x 
diagnosis prior to the age of 30 years  
x 
treated with a multiple daily injection regimen/basal-prandial insulin regimen or insulin 
pump regimen within 6 months after diagnosis 
x 
C-peptide <0.2 pmol/mL at the screening visit 
I 04. Glycosylated hemoglobin (HbA1c) <10% (Week -3) 
Note: Patients with an elevated HbA1c (up to 10%) are eligible provided that there is no 
plan to target a lower HbA1c during the study, based on the judgment of the Investigator. 
I 05. Patients with documented history of CVD (including CHD and/or CHD risk equivalents) 
and/or at least one additional CV risk factor. 
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Notes: 
History of CHD includes at least one of the following: 
x 
acute myocardial infarction (MI),  
x 
silent MI,  
x 
unstable angina,  
x 
coronary revascularization procedure (eg, percutaneuous coronary intervention [PCI] or 
coronary artery bypass graft surgery [CABG]), 
x 
clinically significant CHD diagnosed by invasive or noninvasive testing (such as coronary 
angiography, stress test using treadmill, stress echocardiography, or nuclear imaging) 
AND/OR 
CHD risk equivalents include at least one of the following: 
x 
Documented peripheral arterial disease (one of the following criteria [a, b, or c] must be 
satisfied): 
a) Current intermittent claudication (muscle discomfort in the lower limb that is both 
reproducible and produced by exercise and relieved by rest within 10 minutes) of 
presumed atherosclerotic origin TOGETHER WITH ankle-brachial index  0.90 in 
either leg at rest, OR 
b) History of intermittent claudication (muscle discomfort in the lower limb that is both 
reproducible and produced by exercise and relieved by rest within 10 minutes) 
TOGETHER WITH endovascular procedure or surgical intervention in one or both 
legs because of atherosclerotic disease OR 
c) History of critical limb ischemia TOGETHER WITH thrombolysis, endovascular 
procedure or surgical intervention in one or both legs because of atherosclerotic 
disease. 
x 
Documented previous ischemic stroke with a focal ischemic neurological deficit that 
persisted more than 24 hours, considered as being of atherothrombotic origin. Computed 
tomography or magnetic radio imaging must have been performed to rule out hemorrhage 
and non-ischemic neurological disease. 
AND/OR 
Cardiovascular risk factors include at least one of the following: 
x 
hypertension (established on antihypertensive medicine) 
x 
current cigarette smoker 
x 
age 45 years for men and 55 years for women 
x 
history of micro/macroalbuminuria 
x 
history of diabetic retinopathy (preproliferative or proliferative) 
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x 
family history of premature CHD (in father or brother before 55 years of age; in mother or 
sister before 65 years of age) 
x 
low HDL-C (male <40 mg/dL [1.0 mmol/L] and female <50 mg/dL [1.3 mmol/L]) 
x 
documented chronic kidney disease (CKD) as defined by 15 eGFR <60 mL/min/1.73 m2 
for 3 months or more, including the screening visit) 
I 06. Signed written informed consent 
7.2 
EXCLUSION CRITERIA 
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following 3 subsections:  
7.2.1 Exclusion criteria related to study methodology 
E 01. Plans to initiate new LMT during the course of the study or to modify the dose of the 
current LMT. 
E 02. Not on a stable dose of LMT (including statin or other LMT) for at least 4 weeks prior to 
the screening visit (Week -3) or from screening to randomization, unless statin intolerant, 
in which case there will be no statin for 4 weeks prior to the screening visit/during the 
screening period. 
E 03. Use of nutraceutical products or over-the-counter therapies that may affect lipids which 
have not been at a stable dose for at least 4 weeks prior to the screening visit (Week -3) or 
between screening and randomization visits. 
E 04. Use of red yeast rice products within 4 weeks of the screening visit (Week -3) or between 
screening and randomization visits. 
E 05. Use of systemic corticosteroids, unless used as replacement therapy for pituitary/adrenal 
disease with a stable regimen for at least 6 weeks prior to randomization. 
Note: Topical, intra-articular, nasal, inhaled and ophthalmic steroid therapies are not considered 
as “systemic” and are allowed. 
E 06. 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 07. Recent (within 3 months prior to the screening visit (Week -3) or between screening and 
randomization visits) MI, unstable angina leading to hospitalization, uncontrolled cardiac 
arrhythmia, CABG, PCI, carotid surgery or stenting, stroke, transient ischemic attack 
(TIA), endovascular procedure or surgical intervention for peripheral vascular disease. 
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E 08. Planned to undergo scheduled PCI, CABG, carotid or peripheral revascularization during 
the study. 
E 09. History of New York Heart Association (NYHA) Class III or IV heart failure within the 
past 12 months (Appendix A). 
E 10. Systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg at screening 
or randomization visit. 
E 11. Patient who has received plasmapharesis treatment either within 2 months prior to the 
screening visit (Week -3), between screening and randomization, or who has plans to 
receive it. 
E 12. Known history of hemorrhagic stroke. 
E 13. Known history of loss of function of PCSK9 (ie, genetic mutation or sequence variation) or 
known history of homozygous familial hypercholesterolemia. 
E 14. 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 15. Known history of positive HIV test. 
E 16. Patient who has taken any active investigational drugs within 1 month or 5 half-lives, 
whichever is longer.  
E 17. Patients not previously instructed on a cholesterol lowering diet prior to the screening visit 
(Week -3). 
E 18. Patient who withdraws consent during the screening (starting from signed ICF). 
E 19. Unstable weight defined as a variation of >5 kg within 2 months prior to the screening 
visit, as judged by the Investigator. 
E 20. BMI >45 kg/m2 or plans to undergo bariatric surgery, weight loss program, or to initiate 
weight loss drugs during the course of the study. 
E 21. Recent initiation of weight loss drugs (ie, within 3 months prior to the screening visit or 
between screening and randomization) or recent bariatric surgery (within the last 
6 months) and in an active weight loss phase, as judged by the Investigator. 
E 22. Patients not treated with insulin for at least 6 months prior to the screening visit or not on a 
stable insulin regimen (ie, a change in type of insulin, general timing/frequency of 
injections, mode or pattern of administration such as basal only [Type 2 diabetes], 
basal-prandial, etc) for at least 3 months prior to the screening visit, or likelihood of 
requiring a change in insulin type/frequency or mode of injection during the study period. 
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E 23. Not on a stable insulin dose for at least 3 months prior to screening (ie, more than a 
30% variation in total daily insulin dose as judged by the Investigator), or likelihood of 
requiring intensification of insulin/antihyperglycemic regimen during the course of the 
study, as judged by the Investigator (eg, addition of new agent, plans for titration of insulin 
dose, etc). 
E 24. Other antihyperglycemic medications taken by the patient have not been stable for at least 
3 months before the screening visit. 
E 25. History of recent decompensation of diabetes within 2 months prior to the screening visit 
(ie, diabetic ketoacidosis or hyperosmolar hyperglycemic state [HHS]). 
E 26. Currently receiving or plans to receive renal replacement therapy during the study (eg, 
hemodialysis, renal transplant, etc). 
E 27. 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 the patient’s sensitive thyroid stimulating 
hormone (s-TSH) levels are within ±10% of the normal range of the laboratory at the screening 
visit. 
E 28. Laboratory findings during the screening period (not including randomization labs, except 
for pregnancy test): 
A) Serum TG >400 mg/dL (4.52 mmol/L) (1 repeat lab is allowed) 
B) Positive serum or urine pregnancy test in women of childbearing potential 
C) Positive test for Hepatitis B surface antigen or Hepatitis C antibody 
D) eGFR <15 mL/min/1.73 m2 according to 4-variable modification in diet of renal disease 
(MDRD) equation 
E) ALT or AST >3 x ULN (1 repeat lab is allowed) 
F) Creatine Phosphokinase (CPK) >3 x ULN (1 repeat lab is allowed) 
E 29. Conditions/situations such as: 
x Patients with short life expectancy 
x Requirement for concomitant treatment that could bias primary evaluation 
x Impossibility to meet specific protocol requirements (eg, need for hospitalization, ability 
to make study visits, etc) 
x Patient is the Investigator or any Sub-Investigator, research assistant, pharmacist, study 
coordinator, other staff or relative thereof directly involved in the conduct of the protocol 
x Uncooperative or any condition that could make the patient potentially non-compliant to 
the study procedures 
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x Any technical/administrative reason that makes it impossible to randomize the patient in 
the study 
x Any clinically significant abnormality identified at the time of screening that in the 
judgment of the Investigator or Sub-Investigator would preclude safe completion of the 
study or constrain endpoint assessments such as major systemic diseases, patients with 
short life expectancy 
7.2.2 Exclusion criteria related to the active comparator and/or mandatory background 
therapies  
E 30. All contraindications to the background therapy(ies) or warning/precaution of use (when 
appropriate) as displayed in the respective National Product Labeling. 
7.2.3 Exclusion criteria related to the current knowledge of alirocumab  
E 31. Hypersensitivity to alirocumab or to any of the ingredients of alirocumab 
E 32. Pregnant or breastfeeding woman 
E 33. Woman of childbearing potential not protected by highly-effective method(s) of birth 
control (as defined in the ICF and/or in a local protocol addendum in case of specific local 
requirement) 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 injection of IMP. 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. 
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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 an aqueous buffer, pH 6.0, containing sucrose, histidine, and polysorbate 20, both as 1 mL 
volume, in an auto-injector (also known as prefilled pen). 
Sterile placebo for alirocumab will be prepared in the same formulation as alirocumab without the 
addition of protein as 1 mL volume in a prefilled pen, for the patients to perform injection 
training, as well as for those in the placebo treatment arm. 
During the screening period, the patient (or another designated person) will have to perform a 
placebo self-injection training, using a prefilled pen, before the first administration of IMP.   
For those patients randomized to alirocumab, the initial dose is 75 mg administered 
subcutaneously once Q2W. The dose will be increased in a blinded fashion to 150 mg Q2W at 
Week 12 for patients randomized to alirocumab if the Week 8 LDL-C value is 70 mg/dL 
(1.81 mmol/L).   
Those patients randomized to placebo will be administered their injection subcutaneously Q2W 
throughout the duration of the 24-week treatment period. 
NOTE: in order to ensure the continuity of the study treatment without interruption (only in the 
event the manufacturer faces any performance or supply issues of the prefilled pen), contingency 
alternatives are: 
x in case of disruption of the 150 mg prefilled pen only, if the use of 75 mg prefilled pens is 
maintained, patients will need to administer 2 injections as follows: 
- 
2 injections of 75 mg as 1 mL each in a prefilled pen for patients receiving the 150 mg 
dose 
- 
1 injection of 75 mg as 1 mL in a prefilled pen plus 1 injection of placebo as 1 mL in a 
prefilled pen for patients receiving the 75 mg dose 
- 
2 placebo injections as 1 mL each in a prefilled pen for patients receiving placebo 
OR 
x in case of disruption of either 75 mg or 150 mg or both prefilled pens, patients will be 
switched to the use of prefilled syringes of placebo, 75 mg and 150 mg, with one injection 
of 1 mL for each of these doses 
Should this occur, the alternative IMP will be maintained until the end of the study. 
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8.1.1 Route and method of administration 
A prefilled pen training guide (auto-injector training guide) will be provided to the sites and 
instructions for use (auto-injector for use) will be provided to the patient. Each administration of 
IMP will consist of 1mL subcutaneous injection in the abdomen, thigh, or outer area of upper arm 
(ie, deltoid region). If another concomitant drug is being injected at the same site planned for the 
IMP injection, then the patient should be advised to use an alternate location for administration of 
the IMP. 
The IMP could be administered by self-injection or by another designated person (such as a 
spouse, relative, etc). 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 prior to administering 
the injection. Anyone that plans to administer the IMP must be trained by the study staff. 
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.  
The used prefilled 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 or the outer area of upper arm, etc) 
during the study. 
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. 
8.1.2 Timing of administration 
During the screening period, patients or the designated person will have to perform a placebo 
self-injection training using a prefilled pen, before the first IMP injection. 
At the randomization visit, the first IMP 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. If 
the designated person changes during the course of the study, the new designated person will need 
to be trained with placebo. 
IMP subcutaneous injections will then be performed outside of the clinic, Q2W 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. In exceptional cases, if a 
patient prefers to have the injection performed at the study site and provisions are able to be made 
to accommodate the administration of injections at the site, it may also be allowed. 
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IMP should be administered subcutaneously Q2W, ideally at approximately the same time of the 
day; however, it is acceptable to have a window period of ±3 days. The time of the day is based 
upon the patient’s preference. 
If by mistake or due to other circumstances an injection is delayed by: 
x more than 7 days from the missed date or completely missed, then the patient should 
return to the original schedule of IMP administration without administering delayed 
injections. 
x 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 IMP administration. 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCTS 
The following classes of drugs are identified as non-IMP because the medication is either a 
background therapy or a potential rescue medication: 
x 
Statins, 
x 
Cholesterol absorption inhibitors (ezetimibe), 
x 
Bile acid-binding sequestrants (such as cholestyramine, colestipol, colesevelam), 
x 
Nicotinic acid, 
x 
Fibrates (such as Fenofibrate), 
x 
Omega-3 fatty acids (1000 mg daily), 
x 
Insulins.  
Please see Section 8.8 for further information. All fibrates are allowed at entry if the patient has 
tolerated the medication and remained on a stable dose. Background LMT and insulin will not be 
provided by the Sponsor. Patients will obtain these medications in compliance with local 
regulations. 
8.3 
BLINDING PROCEDURES 
Alirocumab and placebo for alirocumab will be provided in identically matched prefilled pens and 
packaged identically, which includes labeling to protect the blind. Each treatment kit will be 
labeled with a number which will be generated by a computer program from Sanofi. The 
treatment kit numbers will be obtained by the Investigator at the time of patient randomization 
and subsequent patient visits scheduled via IVRS/IWRS that will be available 24 hours-a-day, 
7 days-a-week. 
In accordance with the double-blind design, study patients, Investigators and study site personnel 
will remain blinded to study treatment and will not have access to the randomization (treatment 
codes) except under circumstances described in the following subsections. 
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8.3.1 Methods of blinding 
8.3.1.1 Adverse event 
The treatment code will be unblinded by the Pharmacovigilance Department for reporting to the 
Health Authority of any Suspected Unexpected Serious Adverse Reaction (SUSAR), ie, any 
Serious Adverse Event that is both unexpected (per the specific section of the CIB) and 
reasonably associated with the use of the IMP according to either the judgment of the Investigator 
and /or the Sponsor. 
Refer to Section 10.5 for suspected unexpected ADR unblinding by the Sponsor and Section 8.3.2 
(Randomization code breaking during the study) for unblinding an AE under exceptional 
circumstances when knowledge of the Investigational Medicinal Product is essential for treating 
the patient. 
8.3.1.2 Lipid parameters 
Lipid parameter values from blood samples obtained after the randomization visit, run by the 
central lab, will not be communicated to the sites so that they cannot deduce the treatment group 
of their patients based on LDL-C level attained.  The sponsor’s operational team will not have 
access to lipid parameters associated with patient identification until after the final database lock 
has occurred. For safety purposes, TG alerts for TG values 500 mg/dL any time after 
randomization will be sent to the Investigator (Section 8.8.1 and Section 9). 
At the end of the double-blind treatment period (Week 24 visit) the Investigator will continue to 
manage the patient’s lipids in accordance with standard practice. Any lipid values after 
randomization should be redacted in the source documents and not shared with the Sponsor. 
8.3.1.3 Anti-alirocumab antibodies 
Patient anti-alirocumab antibody results will not be communicated to the sites while the study is 
ongoing. 
The sponsor’s operational team will not have access to anti-alirocumab antibody results associated 
with a patient identification number until after the final database lock has occurred. 
The lab technicians involved in the determination of patient anti-alirocumab antibody titers are 
excluded from the operations team and a process will be set up to prevent any potential 
unblinding. 
8.3.2 Randomization code breaking during the study 
In case of an AE, the code should only be broken in circumstances when knowledge of the IMP is 
required for treating the patient. If possible, contact should be initiated with the Monitoring 
Team/Study Physician before breaking the code. All calls will be documented by the Monitoring 
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Team as appropriate to include date and time of the call, name of the person contacted within the 
Monitoring Team, patient ID, documentation of the request, and decision for unblinding or not. 
Code breaking can be performed at any time by using the proper module of the interactive voice 
response system (IVRS)/interactive web response system (IWRS), depending on which system is 
used for the site, and/or by calling any other phone number provided by the Sponsor for that 
purpose. However, it is preferable to contact the Study Physician to discuss the case before 
unblinding the case. If the blind is broken, the Investigator should document the date, time of day, 
and reason for code breaking, and report this information on the appropriate page of the e-CRF.  
Note that when documenting the reason for unblinding, the Investigator must not provide any 
detail regarding the nature of the IMP. The Investigator should not divulge IMP detail to the 
Sponsor’s representative or to any staff members until database closure. Furthermore, when 
completing forms (eg, AE, SAE), the study treatment should not be disclosed on the forms.   
The code-breaking material will be also kept at the entity responsible for the “24 hour alert 
system”; but this system should be used in very exceptional cases only (ie, unavailability of 
IVR/IWR system or inability to contact Investigator and/or site staff). However, the preferred 
option is to unblind using IVRS. The Investigators will be informed by the clinical monitoring 
team about the availability of the local code-breaking material. A patient card, including the 
relevant “24 hour alert system” telephone number will be provided to every patient who will 
participate in the study. Unblinding may also be performed by the Sponsor for some SAEs in 
order to conform to regulatory reporting requirements (ie, for some SAEs that are both related and 
unexpected). 
If the code is broken, the patient must permanently discontinue IMP administration.  
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP 
The randomized list of treatment kit numbers will be generated centrally by Sanofi. The IMP 
(alirocumab 75 or 150 mg kits, or placebo kit) will be packaged in accordance with this list. 
The Trial Supply Operations Manager will provide the randomized list of treatment kit numbers 
and the Study Biostatistician will provide the randomization scheme to the centralized treatment 
allocation system provider. Then, this centralized treatment allocation system provider will 
generate the patient randomization list according to which it will allocate the treatments to the 
patients. 
Patients will be randomized to receive either placebo or alirocumab during the double-blind 
treatment period. The randomization ratio alirocumab:placebo will be 2:1. For each randomized 
patient, there will be several corresponding treatment kit numbers (resupply visits), which will be 
allocated through the centralized treatment allocation system. The randomization is stratified by 
diabetes type (ie, Type 1 versus Type 2). 
The treatment kit numbers will be allocated using the centralized treatment allocation system on 
randomization visit (Day 1, Week 0), and then at Week 12 as re-supply visits, and at unscheduled 
visits if needed. 
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For patients in the alirocumab treatment arm, the treatment kit allocated at Week 12 will be based 
on their Week 8 LDL-C level following the up-titration rules (see Section 6.1). Regular transfer of 
data will be planned between the central laboratory and the centralized treatment allocation 
system provider in order to proceed in a blinded manner for study sites and sponsor. 
Before randomizing a patient, the Investigator or designee will have to contact the centralized 
treatment allocation system. 
A randomized patient is defined as a patient who is registered and assigned with a treatment kit 
number from the centralized treatment allocation system, as documented from its log file. A 
patient cannot be randomized more than once in the study. If a treatment is used without 
contacting the centralized treatment allocation system, then the patient will be considered as not 
randomized and withdrawn from the study. 
Two types of centralized treatment allocation systems will be used, the IVRS and the IWRS 
depending on the choice of the site. 
8.5 
PACKAGING AND LABELING 
For the double-blind treatment period, each double-blind treatment kit, either alirocumab or 
placebo for alirocumab, will be prepared to contain 6 prefilled pens in a child resistant package.  
In order to protect the blind, all double-blind treatment kit boxes for injection will have the same 
look and feel and therefore will be labeled with a double-blind label. 
In addition to the double-blind treatment kits for injection, a training kit containing 1 placebo for 
alirocumab prefilled pen will be prepared for the purpose of instructing patients on injection 
administration which is to be performed prior to randomization at screening visit (Week-3, 
Visit 1). If deemed necessary, a second injection training with placebo for alirocumab can be 
performed using an additional training kit prior to randomization. Injection training with placebo 
will be performed and documented in the CRF, including if the designated person who 
administers IMP to the patient changes during the course of the study. 
Packaging is in accordance with the administration schedule. The content of the labeling is in 
accordance with the local regulatory specifications and requirements. 
8.6 
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 IMP should be managed 
according to the rules provided by the Sponsor. 
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The IMP will be stored in a refrigerator between +2°C and +8°C (36°F to 46° F) at 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. 
8.7 
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. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) should be promptly notified to the 
Sponsor. Some deficiencies may be recorded through a complaint procedure. 
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. 
8.7.1 Treatment accountability and compliance 
Measures taken to ensure and document IMP compliance and accountability are described below: 
x 
The Investigator or designee will obtain via IVRS/IWRS the treatment kit number(s) and 
he/she will dispense the treatment kit(s) to the patient. 
x 
The Investigator or designee will enter the treatment kit packaging number(s) and the kit 
numbers in the e-CRF. 
x 
IMP administration data will be recorded by the patients onto a Patient diary 
x 
Used pens (sharps container) and the treatment kit dispensed at the previous dispensation 
visit are brought back by the patient at IMP kit re-supply visits only 
x 
The Investigator or designee counts the number of remaining unused prefilled pens in the 
returned packs and fills in the Treatment Log Form at IMP kit re-supply visits; 
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x 
The monitor will check the data consistency between e-CRF pages and treatment log 
forms using the patient diary and returned, unused prefilled pen of a corresponding kit. 
The patient will be instructed on the importance to take the study treatment as planned for the 
remainder of the treatment duration. 
8.7.2 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 before the Sponsor provides written authorization. 
Sharp containers containing all used pens will be brought back to the site by the patient for the 
purpose of destruction. 
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. 
8.8 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment received by the patient concomitantly during the 
study, until Week 32. This medication is not provided by the Sponsor. 
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. 
Nutraceutical products or over-the-counter therapies that may affect lipids are allowed (see 
Section 8.8.3 for exceptions) only if they have been used at a stable dose for at least 4 weeks prior 
to screening visit, during the screening period and during the 24 weeks of the double-blind 
treatment period. Examples of such nutraceutical products or over-the-counter therapies include 
omega-3 fatty acids at doses <1000 mg, plant stanols such as found in Benecol, flax seed oil, and 
psyllium. 
8.8.1 Management of background lipid-modifying therapy 
For background LMT, including statins, sites must follow the national product label for the safety 
monitoring and management of patients. 
Patients will be on stable, maximum dose/regimen of statin therapy that is tolerated by the patient 
with or without other LMT during the study as indicated in Section 7.  
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Lipid profile values will be blinded from samples obtained after randomization. Nevertheless, for 
safety reasons, sites will be made aware of TG alerts, in order to make decisions on the patient’s 
background LMT (Section 9). 
From the screening visit (Week -3) until the Week 24 visit, the background LMT should not be 
changed. No dose adjustment, discontinuation or initiation of other statins or other LMT should 
take place during this time, barring exceptional circumstances whereby overriding concerns 
(including but not limited to a TG alert posted by the central lab) warrant such changes, as per the 
Investigator’s judgment. For a TG alert that has been confirmed by repeat testing, the Investigator 
should perform investigations, manage the patient, and modify the background LMT as per 
his/her medical judgment. 
While all fibrates are allowed at entry if the patient has tolerated the medication and remained on 
a stable dose, should the patient require the introduction of a fibrate during the course of the study 
(ie, as rescue treatment in response to a TG alert) only fenofibrate will be allowed to be added. 
8.8.2 Contraception 
Women of childbearing potential must use an effective contraceptive method throughout the 
entire duration of the study treatment and for at least 10 weeks after the last injection of IMP. 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.”  
8.8.3 Prohibited concomitant medications 
The following therapies are not allowed during the study (including the screening period until the 
EOT visit): 
x 
Red yeast rice products 
x 
Other PCSK9 inhibitors 
Note: while red yeast rice is considered a dietary supplement/nutraceutical, it contains HMG 
CoA reductase inhibitor activity (mechanism of action of statins), along with other active 
ingredients. Because such products lack standardization, varying amounts of the active 
substance could lead to alterations in lipids during the study and potentially confound 
endpoint assessment. 
8.8.4 Lifestyle and dietary habits 
Lifestyle and dietary habits should be maintained if possible throughout the entire study duration, 
as medically feasible, with minimum changes. There shall be no significant changes in nutritional 
composition of the diet or in the quantity/pattern of food consumed. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
Lipid parameters 
Blood sampling to determine lipid parameters (ie, TC, LDL-C, HDL-C, TG, non-HDL-C, Apo B, 
Apo A-1, ratio Apo B/Apo A-1, Apo C III, LDL particle size and number, and Lp [a]) should be 
performed 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. 
TC, HDL-C, TG, Apo B, Apo A-1, Apo C-III and Lp(a) will be directly measured by the Central 
Laboratory as per the schedule in Section 1.2. LDL-C will be directly measured via beta 
quantification method by the Central Laboratory as per the schedule in Section 1.2. LDL-C will 
be calculated using the Friedewald formula at all visits (except Weeks 4 and 32). If TG values 
exceed 400 mg/dL (4.52 mmol/L) then the central lab will reflexively measure (via the beta 
quantification method) the LDL-C rather than calculating it. Non-HDL-C will be calculated by 
subtracting HDL-C from the TC. Ratio Apo B/Apo A-1 will be calculated. Triglyceride rich 
lipopoprotein will be calculated by total cholesterol minus HDL cholesterol minus LDL 
cholesterol. Detailed procedures of sample preparation, storage and shipment will be described in 
the specific laboratory manual which will be provided to sites. 
 
All patients will qualify for randomization based on the LDL-C value obtained at Week -3 visit. If 
the patient is not fasting at this or any other visit requiring fasting, then he/she will be asked to 
come the day after or as close as possible to this date for the blood sampling.  
Communication of lipid results by central lab 
The lipid results from blood samples obtained after the randomization visit will not be 
communicated to the Investigators. However, sites will be notified in the event of a TG level 
500 mg/dL (5.65 mmol/L) obtained any time after randomization (ie, TG alert). Repeat testing 
should be done as soon as possible after a TG alert. For a confirmed TG alert, please refer to 
relevant information in Section 8.8.1. 
Efficacy endpoints will not be considered as AEs, such as those involving abnormalities in lipid 
levels, unless meeting the criteria in Section 10.4. 
9.1 
PRIMARY ENDPOINTS 
9.1.1 Primary efficacy endpoint 
The primary efficacy endpoint is the percent change in LDL-C from baseline to Week 24 in the 
intent-to-treat (ITT) population, using all LDL-C values regardless of adherence to treatment (ITT 
estimand). The percent change is defined as: 
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100x (calculated LDL-C value at Week 24 - calculated LDL-C value at baseline)/calculated 
LDL-C value at baseline. 
The baseline calculated LDL-C value will be the last LDL-C level obtained before the first 
double-blind IMP injection. The calculated LDL-C at Week 24 will be the LDL-C level obtained 
within the Week 24 analysis window.  
All calculated LDL-C values (scheduled or unscheduled, fasting or not fasting) between Weeks 8 
to 24 may be used to provide a value for the primary efficacy endpoint, if appropriate, according 
to above definition.  
The analysis window used to allocate a time point to a measurement will be defined in the SAP.  
9.1.2 Primary safety endpoints 
Safety parameters (AEs, laboratory parameters, vital signs) will be assessed throughout the study. 
The observation of safety data will be as follows: 
x 
Pre-treatment period is defined from the signed informed consent up to the first dose of 
double-blind IMP injection. 
x 
Treatment Emergent Adverse Event (TEAE) period is defined as the time from the first 
dose of double-blind IMP injection to the last dose of IMP injection + 70 days (10 weeks) 
as residual effect of treatment is expected until 10 weeks after the stop of double-blind 
IMP. 
x 
Post-treatment period is defined as the time starting the day after the end of the TEAE 
period up to resolution/stabilization of all SAE and AESI, whichever comes last. 
9.1.2.1 Adverse events 
All AEs diagnosed by the Investigator will be reported and described.  
All AEs will be coded to a “Lowest Level Term (LLT)”, “Preferred Term (PT)”, “High Level 
term (HLT)”, “High Level Group Term (HLGT)” and associated primary “System Organ Class 
(SOC)” using the version of MedDRA (Medical Dictionary for Regulatory Activities) currently in 
effect at Sanofi at the time of the considered database lock. 
Adverse events/AESIs, SAEs, and product complaints will be collected from the time the patient 
signs the ICF to the last scheduled study visit, as applicable.  
Definitions for AEs, SAEs, and AESI, as well as obligation for reporting are further defined in 
Section 10.4. 
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Adverse events of special interest 
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: 
x Increase in alanine aminotransferase (ALT) 
x Allergic events  
x Local injection site reactions that are allergic in nature 
x Pregnancy  
x Symptomatic overdose with IMP 
x Neurologic events  
x Neurocognitive events 
Additional information can be found in Section 10.4.1.3 and Appendix B. 
9.1.2.2 Laboratory safety variables 
The clinical laboratory data consist of blood analyses (including hematology, clinical chemistry, 
etc) and urine analyses. Clinical laboratory values will be analyzed after conversion into standard 
international units.  
9.1.2.3  Vital signs 
Vital signs include: height at baseline, weight, BMI, heart rate, systolic and diastolic blood 
pressure.  
9.2 
SECONDARY ENDPOINTS 
9.2.1 Key secondary efficacy endpoints 
x 
Percent change in calculated LDL-C from baseline to Week 24, using all LDL-C values 
during the efficacy treatment period (on-treatment estimand) 
x 
Percent change in measured LDL-C from baseline to Week 24 (ITT estimand) 
x 
Percent change in calculated LDL-C from baseline to Week 12 (ITT estimand) 
x 
Percent change in measured LDL-C from baseline to Weeks 12 (ITT estimand) 
x 
Percent change in non-HDL-C from baseline to Week 24 (ITT estimand) 
x 
Percent change in Apo B from baseline to Week 24 (ITT estimand) 
x 
Percent change in total cholesterol from baseline to Week 24 (ITT estimand) 
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x 
The proportion of patients reaching LDL-C <70 mg/dL at Week 24 (on-treatment 
estimand) 
x 
The proportion of patients reaching LDL-C <50 mg/dL at Week 24 (on-treatment 
estimand) 
x 
The proportion of patients reaching non-HDL-C <100 mg/dL at Week 24 (on-treatment 
estimand) 
x 
The proportion of patients reaching non-HDL-C <80 mg/dL at Week 24 (on-treatment 
estimand) 
x 
The percent change in Lp(a) from baseline to Week 24 (ITT estimand) 
x 
The percent change in HDL-C from baseline to Week 24 (ITT estimand) 
x 
The percent change in TG from baseline to Week 24 (ITT estimand)  
x 
The percent change in LDL-C particle number from baseline to Week 24 (ITT estimand) 
x 
The percent change in LDL-C particle size from baseline to Week 24  (ITT estimand) 
9.2.2 Diabetes-related endpoints 
x 
Absolute change in HbA1c from baseline to Weeks 12 and 24 (ITT and on-treatment 
estimands) 
x 
Absolute change in FPG from baseline to Weeks 12 and 24 (ITT and on-treatment 
estimands) 
x 
Absolute change in total daily insulin dose from baseline to Weeks 12 and 24 (ITT and 
on-treatment estimands) 
x 
Absolute change in number of glucose-lowering treatments from baseline to Weeks 12 and 
24 (ITT and on treatment estimands) 
9.2.3 Other efficacy endpoints 
x 
Percent change in calculated LDL-C from baseline to Week 12 (on-treatment estimand) 
x 
Percent change in measured LDL-C from baseline to Weeks 12 and 24 (on-treatment 
estimand) 
x 
Percent change non-HDL, Apo B, total cholesterol, Lp(a), HDL-C, and TG from baseline 
to Weeks 12 (ITT and on-treatment estimands) and Week 24 (on-treatment estimand) 
x 
Proportion of patients reaching calculated LDL-C <50 and also <70 mg/dL at Weeks 12 
(ITT and on-treatment estimands) and 24 (ITT estimand) 
x 
Proportion of patients with 50% or greater reduction from baseline in calculated LDL-C at 
Weeks 12 and 24 (ITT estimand) 
x 
Proportion of patients reaching non-HDL-C <80 mg/dL and also <100 mg/dL at Weeks 12 
(ITT and on-treatment estimands) and Week 24 (ITT estimand) 
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x 
Proportion of patients reaching Apo B <80 mg/dL at Weeks 12 and 24 (ITT and 
on-treatment estimands) 
x 
Percent change in LDL-C particle number and size from baseline to Week 12 (ITT and 
on-treatment estimands) and Week 24 (on-treatment estimand) 
x 
Percent change in TGRL, Apo A-1, and Apo C-III from baseline to Weeks 12 and 24 (ITT 
and on treatment estimands)  
x 
Absolute change in ratio Apo B/Apo A-1 and TC/HDL-C from baseline to Weeks 12 and 
24 (ITT and on-treatment estimands) 
x 
Proportion of patients reaching calculated LDL-C <70 and <50 mg/dL at Weeks 12 and 24 
according to baseline A1c of <8% or 8% (ITT and on-treatment estimands) 
x 
Proportion of patients reaching calculated LDL-C <70 mg/dL and <50 mg/dL at Weeks 12 
and 24 according to baseline A1c of <median A1c or median A1c (ITT and on-treatment 
estimands) 
9.2.4 
  
 
 
 
 
  
9.3 
FUTURE USE OF SAMPLES 
Not applicable. 
9.4 
APPROPRIATENESS OF MEASUREMENTS  
The primary endpoint of the change in LDL-C from baseline is a valid surrogate measure to 
determine CV risk, as explained in Section 4.  
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10 
STUDY PROCEDURES 
The window period for Week 0 is +3 days.  The window period for Weeks 8, 12 and 24 is 
±3 days. The window period for Weeks 4, 20, and 32 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 the Study Flow Chart (Section 1.2). 
Blood sampling 
All blood sampling, including the blood sampling for determination of lipid parameters (eg, TC, 
LDL-C, HDL-C, TG, non-HDL-C, Apo A, Apo B, Apo C-III, Lp(a), LDL particle size and 
number) and also for plasma glucose 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 to the patient for the day after (or as close as possible to this date), with 
instructions to fast (see above conditions). 
Laboratory tests 
The laboratory data are collected in accordance with the study schedule and the details provided 
in the Study Flow Chart (Section 1.2). 
x Hematology: all visits except Weeks 4 and 20; may be performed at Week 0 as applicable 
and based on the clinical discretion of the Investigator 
x Chemistry: all visits except Visits 3 and 6; may be performed at Week 0 as applicable and 
based on the clinical discretion of the Investigator, except for plasma glucose which 
should be performed at Week 0 for all patients 
x HbA1c: screening and Weeks 0, 12, and 24 
x Lipid panel: screening and Weeks 0, 8, 12, 20, and 24 
x Measured LDL-C via beta quantification: Weeks 0, 12, and 24 
x Other lipid assessments (Apo B, Apo A-1, Apo C-III, LDL particle size and number, 
Lp[a]): Weeks 0, 12, and 24 
x Liver panel: all visits except Visits 3 and 6; may be performed at Week 0 as applicable and 
based on the clinical discretion of the Investigator. In case of total bilirubin values above 
the normal range, differentiation into conjugated and non-conjugated bilirubin will occur 
automatically 
x Creatine Phosphokinase (CPK): all visits except Visits 3 and 6; may be performed at 
Week 0 as applicable and based on the clinical discretion of the Investigator. 
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x Hepatitis B surface antigen: screening only. 
x Hepatitis C antibody: at screening and Week 24; in case of ALT increase during the study, 
hepatitis C antibody should be determined. If Hepatitis C antibody is positive during the 
study, reflexive testing should be performed. 
x Pregnancy testing (in women of child bearing potential only):  serum pregnancy test at 
screening only. Urine pregnancy test at Weeks 0 and 24. 
x Thyroid stimulating hormone: screening only for patients who are taking thyroid hormone 
replacement 
x C-peptide: screening only 
x PCSK9 levels will be performed only at Week 0. 
x Anti-alirocumab antibodies (Week 0, Week 12, and Week 24).  
Urine samplings 
Urinalysis will be performed at screening and Week 24 visits. Dipstick will be performed and 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. Microscopy will evaluate for the presence of red blood cells 
(RBC), RBC clumps, white blood cells (WBC), WBC clumps, epithelial cells (transitional, renal 
tubular, and squamous), casts (hyaline, epithelial, WBC, RBC, granular, fatty, cellular, broad, 
waxy), crystals (triple phosphate, calcium oxalate, calcium phosphate, calcium carbonate, uric 
acid, amorphous, ammonium biurate, bilirubin, leucine, tyrosine, cystine), bacteria, 
yeast- budding, yeast-hyphae, trichomonas, oval fat body, fat, mucous, and sperm. 
Spot urine testing will be performed for albumin and creatinine to calculate the albumin: 
creatinine ratio at the screening and Week 24 visits. 
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/AESI/SAE if one or more criteria in Section 10.4 are met.  
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix C and should be followed by Investigators. 
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/heart rate  
Blood pressure (BP) should be measured in sitting position under standardized conditions, 
approximately at the same time of the day, on the same arm, with the same apparatus (after the 
patient has rested comfortably in sitting position for at least 5 minutes). Values are to be recorded 
in the e-CRF; both systolic BP and diastolic BP should be recorded. At the first screening visit, 
BP should be measured in both arms. The arm with the highest diastolic pressure will be 
determined at this visit, and BP should be measured on this arm throughout the study. This highest 
value will be recorded in the e-CRF. 
Heart rate will be measured at the time of the measurement of BP. 
Notes: in case of high BP values, the Investigator is responsible for the optimization of the 
patient’s treatment to achieve BP targets as defined by local guidelines/regional standards of care. 
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. 
  
 
Insulin log 
Patient should be instructed to complete the insulin log in order to record his/her daily insulin 
dose (for basal insulin and for prandial insulin, as applicable) for at least 7 days prior to each visit, 
and to bring this information to the next study visit. The patient may record the daily insulin dose 
for more than 7 days prior to the study visits, however only the information collected for the last 
7 days prior to each visit will be entered into the CRF. 
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 prior to randomization/Day 1 visit. 
Please note that every effort should be made to ensure that the screening window is as short as 
possible. If it is planned to have another designated person administer the injections to the patient 
during the study, then this person should be present for injection training. 
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Screening visit (Week -3/ Day -21 up to Day -8) 
x 
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 investigations. 
x 
Assess inclusion/exclusion criteria 
x 
Obtain patient demography – age, gender, race, and ethnicity 
x 
Obtain medical history (including menopausal status), diabetes history, surgical history, 
alcohol habits, and smoking habits 
x 
Obtain family medical history (including risk factors relating to premature CHD [before 
55 years of age in a male and 65 years of age in a female, first degree relative], and family 
history of allergy)  
x 
Take prior medication history within the previous 12 weeks, especially for LMT and 
nutraceutical products that may affect lipids (eg, omega-3 fatty acids at doses <1000 mg, 
plant stanols such as found in Benecol, flax seed oil, psyllium) 
x 
Record concomitant medication 
x 
Perform physical examination  
x 
Get body weight and height measurements. 
x 
Take vital signs including heart rate and blood pressure 
x 
Contact IVRS/IWRS for notification of screening.  Patient number will be allocated by the 
IVRS/IWRS.  This patient number is composed of a 9-digit number containing the 3-digit 
country code, the 3-digit center code and the 3-digit patient chronological number (the 
3-digit patient chronological number is 001 for the first patient screened at a center, 002 
for the second patient screened at the same center...). 
x 
Collect AEs from this point onward 
x 
Collect Urinalysis/spot urine albumin: creatinine  
x 
Obtain fasting blood samples for: 
- 
Lipids: TC, calculated LDL-C, HDL-C, TG, non-HDL-C 
- 
Hematology: blood cell count including hematocrit, hemoglobin, RBC count, red 
blood cell distribution width (RDW), WBC count with differential count and platelets 
- 
Chemistry: plasma glucose, sodium, potassium, chloride, bicarbonate, calcium, 
phosphorous, urea nitrogen, creatinine, uric acid, total protein, albumin, LDH, and 
ȖGT 
- 
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). 
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- 
TSH (for patients on thyroid hormone replacement therapy) 
- 
C-peptide 
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 (at least 10 to 12 hours fasting). Alcohol consumption within 48 hours and 
intense physical exercise within 24 hours preceding the blood sampling are discouraged. 
x 
Perform injection training 
Injection training should be provided as outlined in Section 8.1. The training injection 
(placebo) 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. 
x 
If patient will undergo the second optional injection training, then the following steps are 
needed.  However, if patient does not need a second optional training injection with 
placebo then do not perform these steps. 
- 
Recontact IVRS/IWRS for allocation of a second new packaging number for a second 
training kit. 
- 
Record the second packaging number allocated in e-CRF. 
- 
Dispense the second training injection kit to the patient for self-administration. 
Note: All patients will be qualified for randomization based on the LDL-C value obtained at this 
visit. 
x Give an appointment for the next visit. 
x If it is planned to have another designated person administer the injections to the patient 
during the study, and the designated person did not perform injection training at the 
screening visit, then the designated person should also be present at the next visit 
(Week 0). 
x Dispense the Insulin log and instruct the patient on how to complete it. 
10.1.2 Double-blind treatment period (study site visits) 
10.1.2.1 Randomization visit (Week 0/Day 1) 
x 
Assess Inclusion/Exclusion Criteria 
x 
Collect AEs 
x 
Record concomitant medication 
x 
Get body weight measurement 
x Confirm no changes to patient diet 
x Perform physical examination 
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x Take vital signs including heart rate and blood pressure 
x If the patient is confirmed eligible, the Investigator will start the next study procedures: 
- 
IVRS/IWRS contact for randomization and allocation of a 7-digit treatment kit number 
according to the randomization list. Investigators should never allocate a treatment kit 
number to a patient without contacting IVRS/IWRS. 
x 
Urine pregnancy test (women of childbearing potential only). 
x 
Obtain fasting blood sample for: 
- 
Lipids: TC, LDL-C (calculated via Friedewald and measured via beta quantification), 
HDL-C, TG, non-HDL-C, Apo B, Apo A-1, Apo C-III, ratio Apo B/Apo A-1, LDL 
particle size and number and Lp(a) 
- 
HbA1c 
- 
Anti-alirocumab antibodies 
- 
Serum PCSK9 levels 
- 
Plasma glucose 
x 
Obtain blood samples for the following only if clinically relevant abnormal values at the 
screening visit, based on the judgment of the Investigator: 
- 
Hematology: blood cell count including hematocrit, hemoglobin, RBC count, RDW, 
WBC count with differential count and platelets 
- 
Chemistry: sodium, potassium, chloride, bicarbonate, calcium, phosphorous, urea 
nitrogen, creatinine, uric acid, total protein, albumin, LDH and ȖGT 
- 
Liver panel (ALT, AST, ALP, and total bilirubin) 
- 
CPK 
x 
Review the Insulin log dispensed at Screening 
x 
Dispense a new Insulin log 
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 (at least 10 to 12 hours fasting). Alcohol consumption within 48 hours and 
intense physical exercise within 24 hours preceding the blood sampling are discouraged. 
x 
Provide double-blind IMP kit  
- 
The first IMP administration will take place at the study site, but only after the 
collection of the fasting blood samples. 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. 
x 
Provide the Patient diary and instruct the patient to complete it 
x 
Reminders to be communicated to the patient 
- 
An appointment will be given for the next phone call and study site visit. 
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- 
Remind patient to be in fasting conditions (ie, overnight, at least 10-12 hours fast and 
refrain from smoking) for next study site visit. Also, alcohol consumption within48 
hours and intense physical exercise within 24 hours preceding the next study site visit 
are discouraged. 
10.1.2.2 Week 4 (phone call)  
x 
Record concomitant medication 
x 
Collect information on IMP administration (Patient diary) 
x 
Collect information on AEs/product complaints (if any) 
x 
Review the Insulin log 
x 
Confirm no changes to patient diet 
x 
Reminders to be communicated to the patient: 
- 
IMP administration should be Q2W 
- 
Next study site visit appointment 
- 
Fasting conditions (ie, overnight, at least 10-12 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. 
- 
Bring the Patient diary and Insulin log completed since randomization to the next 
study site visit 
10.1.2.3 Week 8, Week 12, and Week 20 
x 
Collect AEs/product complaints 
x 
Record concomitant medication 
x 
Get body weight measurement 
x 
Confirm no changes to patient diet 
x 
Take vital signs including heart rate and blood pressure 
x 
Perform physical examination (Week 12 only) 
x 
IVRS/IWRS contact (Week 12 only) 
x 
Data collection on IMP administration and IMP compliance check by review of Patient 
diary  
x 
Provide (Week 12 only): 
- 
Double-blind IMP kit  
- 
Instruction for use 
x 
Provide patient diary  
x 
 
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x 
Review and collect Insulin log 
x 
Dispense a new Insulin log 
x 
Obtain fasting blood sample for:  
- 
TC, LDL-C, HDL-C, TG, non-HDL-C,  
- 
measured LDL-C (beta quantification): week 12 only 
- 
Apo B, Apo A-1, ratio Apo B/Apo A-1, Apo C-III, LDL particle size and number and 
Lp(a): week 12 only 
x 
Obtain blood samples for 
- 
Hematology: blood cell count including hematocrit, hemoglobin, RBC count, RDW, 
WBC count with differential count and platelets (Weeks 8 and 12 only) 
- 
Chemistry: plasma glucose, sodium, potassium, chloride, bicarbonate, calcium, 
phosphorous, urea nitrogen, creatinine, uric acid, total protein, albumin, LDH, and 
ȖGT (Weeks 8 and 12 only) 
- 
HbA1c (Week 12 only) 
- 
Liver panel (ALT, AST, ALP, and total bilirubin) (Weeks 8 and 12 only) 
- 
CPK (Weeks 8 and 12 only) 
- 
Anti-alirocumab antibodies (Week 12 only) 
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 (at least 10 to 12 hours fasting). Alcohol consumption within 48 hours and 
intense physical exercise within 24 hours preceding the blood sampling are discouraged. 
x Reminders to be communicated to the patient 
- 
An appointment will be given for the next study site visit. 
- 
Remind patient to be in fasting conditions (ie, overnight, at least 10-12 hours fast and 
refrain from smoking) for next study site visit. Alcohol consumption within 48 hours 
and intense physical exercise within 24 hours preceding the next study site visit are 
discouraged. 
- 
Bring used pens (sharps container) and the treatment kit dispensed at the previous 
dispensation visits (Weeks 12 and 24) 
10.1.2.4 Week 24 / end of treatment visit 
x Collect AEs/product complaints 
x Record concomitant medication 
x Get body weight measurement 
x Confirm no changes to patient diet 
x Take vital signs including heart rate and blood pressure 
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x Perform physical examination  
x IVRS/IWRS contact  
x Data collection on IMP administration and IMP compliance check by review of Patient 
diary and treatment kit  
x 
  
x Review and collect Insulin log 
x Urinalysis and spot albumin: creatinine 
x Urine pregnancy test (women of childbearing potential only). 
x Obtain fasting blood sample for lipids: 
- 
TC, LDL-C, HDL-C, TG, non-HDL-C, Apo B, Apo A-1, ratio Apo B/Apo A-1, Apo 
C-III, LDL particle size and number and Lp(a) 
- 
measured LDL-C (beta quantification) 
x Obtain blood samples for 
- 
Hematology: blood cell count including hematocrit, hemoglobin, RBC count, RDW, 
WBC count with differential count and platelets 
- 
Chemistry: plasma glucose, sodium, potassium, chloride, bicarbonate, calcium, 
phosphorous, urea nitrogen, creatinine, uric acid, total protein, albumin, LDH, and 
ȖGT 
- 
Hepatitis C Antibody Test 
- 
HbA1c 
- 
Liver panel (ALT, AST, ALP, and total bilirubin) 
- 
CPK 
- 
Anti-alirocumab antibodies 
x Reminder to report any AEs up to 70 days after the last dose of IMP  
10.1.2.5 Week 32 / 10 weeks after last IMP injection (phone call) 
x 
Record concomitant medication, noting also whether the patient has started a 
commercially available PCSK9 inhibitor 
x 
Collect information on AEs (if any) 
10.2 
DEFINITION OF SOURCE DATA 
x 
Agreement, date, and signature of informed consent mentioning the study identification. 
x 
Patient identification, last participation in a clinical trial, medical history, associated 
diseases, and data related to the studied pathology. 
x 
Contraception methods for women of child bearing potential. 
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x 
Previous and concomitant medications (including insulin use [eg, type of insulin, 
frequency, and dose], and the use of LMT, especially statins used, with doses, or to 
document statin intolerance). 
x 
Study identification. 
x 
Treatment number, dates of administration. 
x 
Dates of visits and assessments including the examination report. 
x 
Vital signs (heart rate, blood pressure), height, body weight. 
x 
Faxed lab reports (dated and signed by the Principal Investigator or Sub-Investigator 
documenting timeliness of review). 
x 
IVRS/IWRS confirmation fax. 
x 
  
x 
Patient diary 
x 
Insulin log 
x 
Adverse events and follow-up: 
In case of SAE/AESI, 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/AESI. The site should make every effort to obtain details of all consultations, hospital 
records, etc to document the event. All attempts to obtain information should be noted in the 
source documents. 
x 
Date of premature study discontinuation (if any) and reason.  
x 
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.  
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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). 
For all temporary treatment discontinuations, duration should be recorded by the Investigator in 
the appropriate pages of the CRF.  
Temporary treatment discontinuation is defined as one or more scheduled injections that are not 
administered to the patient as decided by the Investigator. 
10.3.2 Permanent treatment discontinuation with investigational medicinal product(s) 
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator or the patient not to re-expose the patient to the IMP at 
any time. Patient withdrawal from the study treatment or study should be avoided as much as 
possible. 
10.3.3 List of criteria for permanent treatment discontinuation 
The patients may withdraw from treatment 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 CRF or 
e-CRF. Patients should discontinue IMP for the following reasons: 
x Pregnancy, intention for pregnancy, or no longer with effective contraceptive method of 
birth control (females only). 
x Acute injection reaction of clinical concern. 
x SAE (or non-serious but severe in intensity) of hypersensitivity reaction considered related 
to IMP. 
x At patient request. 
x If, in the Investigator's opinion, continuation with the administration of the IMP would be 
detrimental to the patient's well-being. 
x Intercurrent condition that requires discontinuation of the IMP (eg, laboratory 
abnormalities, please refer to decision tree in Appendix C). 
x At the specific request of the Sponsor. 
x Any code breaking requested by the Investigator. 
x Patient receives double-blind treatment prior to randomization 
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Any abnormal laboratory value will be immediately rechecked for confirmation (within 24 hours 
if possible), before making a decision of permanent discontinuation of the IMP for the concerned 
patient.   
10.3.4 Handling of patients after permanent treatment discontinuation 
Patients who prematurely discontinue study treatment (regardless of the reason) should still 
continue the study and undergo all visits and procedures as described in Section 1.2 with the 
exception of study treatment administration and its associated procedures. At the time of treatment 
discontinuation, the patient should have, as soon as possible, an unscheduled visit with 
assessments normally planned at EOT visit (this should take place within 5 days of treatment 
discontinuation, if possible) and then resume the original study schedule until end of study. 
If after treatment discontinuation, the patient refuses to resume the original study schedule until 
the end of the study, then if possible, the patient should undergo an unscheduled visit with 
assessments normally planned at the EOT visit (it should take place within 5 days of treatment 
discontinuation, if possible). The patient, at a minimum, should then be followed-up for at least 
10 weeks from the last administration of IMP or until recovery or stabilization of any AE as 
specified in this protocol, whichever comes last. A final end of study phone visit will take place 
10 weeks after the premature discontinuation. 
All definitive discontinuation of study treatment should be recorded by the Investigator in the 
appropriate pages of the CRF when considered as confirmed. IVRS/IWRS should be notified 
when a patient prematurely discontinues study treatment. 
10.3.5 Procedure and consequence for patient withdrawal from study  
The patients may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason. 
If possible, the patients are assessed using the procedure normally planned for the EOT visit. 
For patients who fail to return to the site, the Investigator should make the best effort to recontact 
the patient (eg, contacting patient’s family or private physician, reviewing 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 contact, receipt for sending a registered letter). 
The statistical analysis plan will specify how the primary endpoints of patients who are lost to 
follow-up will be considered. 
Patients who have withdrawn from the study cannot be rerandomized (treated) in the study. Their 
inclusion and treatment numbers must not be reused.  
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10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.4.1 Definitions of adverse events  
10.4.1.1 Adverse event 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. 
10.4.1.2 Serious adverse event 
An SAE is any untoward medical occurrence that at any dose: 
x 
Results in death, or 
x 
Is life-threatening, or 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
x 
Requires inpatient hospitalization or prolongation of existing hospitalization, or 
x 
Results in persistent or significant disability/incapacity, or 
x 
Is a congenital anomaly/birth defect 
x 
Is a medically important event 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention (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 
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- 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling) 
- 
Bullous cutaneous eruptions 
- 
Cancers diagnosed during the study or aggravated during the study  
- 
Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study  
- 
Suspected transmission of an infectious agent, if any suspected transmission of an 
infectious agent via a medicinal product (eg, product contamination) 
10.4.1.3 Adverse event of special interest 
An 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 (Appendix B). 
For this study, the AESI are:  
x Increase in ALT: 
ALT 3 x ULN (if baseline ALT <ULN) Or ALT 2 times the baseline value (if baseline 
ALT ULN) (Appendix C). 
x Allergic events. 
- 
Allergic drug reactions and/or local injection site reactions deemed to be allergic by 
the Investigator (or have an allergic component), that require consultation with another 
physician for further evaluation of hypersensitivity/allergy as per the Investigator’s 
medical judgment should be reported as an AESI. 
x Pregnancy: 
- 
Pregnancy occurring in a female patient or the partner of a male patient (if permitted 
by the female partner and by local regulatory authorities) during the study or within 
70 days following the last dose of study drug.  
- 
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, study product 
should be discontinued.   
- 
The follow-up of the pregnancy will be mandatory until the outcome has been 
determined.   
x 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 are administered in <7 calendar days), to be reported using the 
Term “symptomatic OVERDOSE (accidental or intentional), indicating the 
circumstance in parentheses (eg, “symptomatic overdose [accidental]” or 
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“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 
symptoms, if any, entered on separate AE/SAE forms.  
- 
Of note, asymptomatic overdose should be reported as a standard AE.  
x 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 AE. 
x Neurocognitive events 
- 
All neurocognitive events will be considered as AESI 
10.4.1.4 Local injection site reactions 
Local injection site reactions that are considered by the Investigator as non-allergic events and 
that are related to the alirocumab injection, as opposed to another injectable agent, should be 
further characterized by evaluating the related symptoms that comprise an injection site reaction 
such as but not limited to redness, pain, etc. If the patient experiences a local injection site 
reaction with no signs or symptoms except for erythema/redness, and/or swelling, and the 
diameter of the erythema/ redness, or swelling measure <2.5 cm, no AE for local injection site 
reaction needs to be reported as this is not typically considered a clinically important finding. 
However, if the patient has a reaction of swelling with a diameter <2.5 cm that interferes with 
activity, then it should be considered as a clinically relevant finding and should be reported as an 
AE with a corresponding grade of moderate or severe, in accordance with 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: 
x A product complaint 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. 
x All product complaints must be reported on a product complaint form when there is a 
reason to suspect a problem with the device. 
x In case of a product complaint associated with the occurrence of an AE, the AE must be 
documented on an AE page in the CRF. 
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x In the case of a product complaint associated with the occurrence of a SAE, the SAE must 
be reported as in Section 10.4.3 in accordance with the SAE reporting procedures 
x Please note that all product complaints require reporting within 24 hours (please refer to 
Appendix B). 
10.4.2 General guidelines for reporting adverse events 
x All AEs, regardless of seriousness or relationship to IMP/NIMP, spanning from the 
signature of the ICF 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. 
x All product complaints associated or not to an AE are to be recorded immediately on the 
corresponding products (study medical device) complaints pages and reported to the local 
Complaint Service immediately (within 24 hours). 
x Whenever possible, a 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).  
x 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 for certain events, such as SAEs/AESI, 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.  
x When treatment is prematurely discontinued, the patient’s observations will continue until 
the end of the study as defined by the protocol for that patient, if possible. 
x Laboratory or vital sign abnormalities are to be recorded as AEs only if:  
- 
Symptomatic and/or  
- 
Requiring either corrective treatment or consultation, and/or  
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI (Appendix C) 
10.4.3 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator must immediately: 
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x 
ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the e-CRF; the system will automatically send a notification to the monitoring team after 
approval of the Investigator within the e-CRF or after a standard delay.  
x 
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. If 
for any reason, results of lipid values are indicated on any source documents (done for the 
safety of a patient in exceptional circumstances only), all such information should be 
redacted. 
x 
All further data updates should be recorded in the e-CRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of 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. 
x 
A back-up plan (using a paper CRF process) is available and should be used when the 
e-CRF system does not work 
In case of e-CRF back-up: 
x 
SEND (within 24 hours, preferably by fax or e-mail) the signed and dated corresponding 
page(s) from the CRF to the representative of the monitoring team whose name, fax 
number and e-mail address appear in the clinical trial protocol 
x 
ATTACH a photocopy of all examinations carried out and the dates on which these 
examinations were performed. 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  
x 
All further documentation should be sent 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. 
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 each defined AESI the Investigator must make every attempt to collect additional specific 
information such as: 
x Preexisting related condition or lifestyle of interest for the AE (eg, habits, CV risk factor). 
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x Expected list of associated signs and symptoms. 
x Corrective actions (eg, treatment discontinuation, concomitant treatment). 
x Diagnostic actions (eg, test(s) or procedure(s) results). 
x Additional descriptive factors. 
x Sequelae. 
For these AEs, the Sponsor must be informed immediately (ie, within 24 hours), as per SAEs 
notification described in Section 10.4.4, even if not fulfilling a seriousness criterion, using the 
corresponding screens in the e-CRF. Please refer to Section 10.4.1.3 for a listing of AESI and 
Appendix B for a summary of reporting AEs. 
10.4.5 Guidelines for management of specific laboratory abnormalities 
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in Appendix C. Reporting instructions are provided in 
Appendix B. 
x 
Neutropenia 
x 
Thrombocytopenia 
x 
Increase in ALT 
x 
Acute renal insufficiency 
x 
Increase in CPK (other than cardiac-related) and suspicion of rhabdomyolysis 
Investigators are strongly encouraged to follow these algorithms in Appendix B and Appendix C, 
especially in situations where the abnormality persists or when there is no clear explanation for 
the observed abnormality. However there may be situations where these algorithms are not 
entirely applicable; therefore, the Investigator may use his/her best judgment. Also, in some 
situations, the Sponsor may wish to discuss with the Investigator. Examples where these 
algorithms may not be applicable include, but are not limited to, the following situations: 
x Patients with known stable, low or borderline neutrophil count at baseline 
x Patients with known stable, low or borderline platelet count at baseline 
x Patients with impaired renal function at baseline 
The Investigator should attempt to have a diagnosis for the observed finding and should use 
his/her best judgment as whether to or not enroll such patients, and if the patient is enrolled, how 
to best monitor these baseline abnormalities throughout the study.  
Additional examples where these algorithms may not be applicable include, but are not limited to, 
the following situations: 
x Patients with ALT increase for which the abnormality resolves following statin dose 
reduction or statin discontinuation 
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x Patients with elevated creatinine kinase for which the abnormality resolves following 
statin dose reduction or statin discontinuation 
x Patients with elevated creatinine kinase caused by a myocardial infarction 
In addition, discontinuation caused by a laboratory abnormality can be either permanent or 
temporary, depending on the particular case. There is no requirement for permanent treatment 
discontinuation in every case of the general guidance for the follow-up of selected laboratory 
abnormalities mentioned in Appendix C. 
10.5 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner: 
x 
All SAEs that are both unexpected and at least reasonably related to the IMP (SUSAR), to 
the regulatory authorities, IECs/IRBs as appropriate and to the Investigators. 
x 
All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations. 
The AESIs listed in Section 10.4.1.3 will be reported to those regulatory authorities who require 
such reporting.  
In this study, some AEs are considered related to the underlying condition and thus will not be 
considered unexpected as indicated in the Investigator’s Brochure. 
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 tolerability (local injection site reactions) 
In case the Investigator or the patient recognizes any signs of local intolerability, then this should 
be treated and followed-up as per the Investigator’s medical judgment. Specific e-CRF screens are 
to be filled in. Information on classifying the reaction are given in Section 10.4.1.4 and on 
reporting these reactions is given in Appendix B. 
10.6.2 Allergic adverse events 
Specific e-CRF screens are to be filled in to assess allergic reactions or allergic-like reactions that 
may occur during the clinical studies conducted with alirocumab. 
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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 Appendix E 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. 
10.6.2.1 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 assessment for hematology, chemistry, liver 
panel should be obtained. An additional blood sample will have to be drawn for PK and 
anti-alirocumab antibody analyses (adequate instructions will be provided to the site by the 
Monitor). 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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10.6.2.2 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 
11.1 
DETERMINATION OF SAMPLE SIZE 
 
 
 
 
  
 
 
 
 
 
 
11.2 
DISPOSITION OF PATIENTS 
Screened patients are defined as any patient who met the inclusion criteria and signed the 
informed consent.  
Randomized patients consist of all screened patients, with a double-blind treatment kit number 
allocated and recorded in the IVRS/IWRS database, regardless of whether the treatment kit was 
used or not. Patients treated without being randomized or treated with a double-blind treatment kit 
before the randomization will not be considered as randomized and will not be included in any 
analysis population. The safety experience of patients treated and not randomized will be reported 
separately and these patients will not be in the safety population. 
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population. The safety experience associated with any later 
randomization will be assessed separately. 
11.3 
ANALYSIS POPULATIONS 
11.3.1 Efficacy populations 
The primary efficacy analysis population will be the ITT population as defined below. 
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11.3.1.1 Intent–to-treat population 
The ITT population is defined as all randomized patients who have an evaluable primary efficacy 
endpoint.  
Patients in the ITT population will be analyzed according to the treatment group allocated by 
randomization. 
The primary efficacy endpoint is evaluable when the two following conditions are met: 
x The baseline calculated LDL-C value is available 
x A least one calculated LDL-C value is available within one of the analysis windows up to 
Week 24. 
11.3.1.2 Modified intent-to-treat population 
The modified ITT (mITT) population (otherwise referred to as the on-treatment population) is 
defined as all randomized patients who took at least one dose or part of a dose of the double-blind 
IMP and have an evaluable primary efficacy endpoint during the efficacy treatment period. 
Patients in the mITT population will be analyzed according to the treatment group allocated by 
randomization. 
The primary efficacy endpoint is considered as evaluable when the two following conditions are 
met: 
x The baseline calculated LDL-C value is available 
x At least one calculated LDL-C value is available during the efficacy treatment period and 
within one of the analysis windows up to Week 24. 
The efficacy treatment period is defined as the time period from the first double-blind IMP 
injection up to 21 days after the last double-blind IMP injection. 
11.3.2 Safety population 
The safety population considered for safety analyses will be the randomized population who did 
actually receive at least one dose or part of a dose of the double-blind IMP. Patients will be 
analyzed according to the treatment actually received (placebo or alirocumab). 
The safety analysis will focus on the Treatment Emergent Adverse Events (TEAE) period defined 
as the time from the first double-blind dose to the last double-blind dose of IMP + 70 days 
(10 weeks). 
In addition:  
x 
Nonrandomized but treated patients will not be part of the safety population, but their 
safety data will be presented separately.  
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x 
Randomized patients for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized. 
x 
For patients receiving more than 1 study treatment during the trial, the treatment group 
allocation for as-treated analysis will be the one to which the patient was treated with the 
longest duration  
11.3.3 Other analysis population  
The anti-alirocumab antibody analysis will be performed on all treated patients (safety population) 
with a blood sample at Week 0 (baseline) and at least one evaluable blood sample for antibodies 
post-double-blind IMP injection. 
 
 
 
11.4 
STATISTICAL METHODS 
Separate analyses will be performed for Type 1 diabetes patients on one hand and Type 2 diabetes 
patients on the other hand. However, some endpoints may also be analyzed on the pooled data 
(Type 1 and Type 2 diabetes patients together). These analyses will be defined later in the 
statistical analysis plan. 
11.4.1 Extent of study treatment exposure and compliance 
The extent of study treatment exposure and compliance will be assessed and summarized by 
actual treatment received within the safety population. 
In order to ensure the continuity of the investigational treatment for the patients without 
interruption (only in case a disruption occurs in the availability of device components or during 
production of the prefilled pen), back-up plans may be implemented as described in Section 8.1. 
In that case, exposure to initial device and back-up device will be summarized and impact on 
study results will be assessed. More details will be provided in the SAP, if applicable. 
11.4.1.1 Extent of investigational medicinal product exposure 
The total exposure will be assessed by: 
x 
Duration of IMP exposure in weeks is defined as:  (last dose of double-blind IMP injection 
date – first dose of double-blind IMP injection date + 14 days)/7, regardless of unplanned 
intermittent discontinuations.  
x 
The total number of injections by patient. 
The number (n) and percentage (%) of patients with an up-titration in the alirocumab group will 
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11.4.1.2 Compliance  
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for patients with 
missing or incomplete data.  
Compliance will be assessed using the following parameters: 
x 
The injection frequency will be defined for each patient as the average number of days 
between 2 injections, that is: (last dose date – first dose date)/(number of injections -1). 
This parameter will be summarized descriptively (N, Mean, SD, Median, Min and Max). 
11.4.2 Analyses of efficacy endpoints 
11.4.2.1 Analysis of primary efficacy endpoint(s) 
The percent change in calculated LDL-C from baseline to Week 24 as defined in Section 9.1.1 
will be analyzed in the ITT population using a mixed effect model with repeated measures 
(MMRM) approach. All post-baseline data available within Week 8 to Week 24 analysis windows 
will be used and missing data are accounted for by the MMRM model.  
The model will include the fixed categorical effects of treatment group (placebo versus 
alirocumab), time point (Week 8, Week 12, Week 20 and Week 24), treatment-by-time point 
interaction, as well as the continuous fixed covariates of baseline LDL-C value and baseline 
value-by-time point interaction. Model assumptions for normality will be explored prior to the 
analysis testing. 
This model will be run using SAS Mixed procedure with an unstructured correlation matrix to 
model the within-patient errors. Parameters will be estimated using restricted maximum likelihood 
method with the Newton-Raphson algorithm. Denominator degrees of freedom will be estimated 
using Satterthwaite’s approximation. This model will provide baseline adjusted LS means 
estimates at Week 24 for both treatment groups with their corresponding standard errors (SEs) and 
95% confidence intervals (CIs). To compare the alirocumab group to the placebo group, an 
appropriate contrast statement will be used to test the differences of these estimates, at the 2-sided 
0.05 level. Separate analyses will be performed for Type 1 diabetes patients on one hand (alpha 
risk = 0.05) and Type 2 diabetes patients on the other hand (alpha risk = 0.05). 
Let μ0 and μ1 be the population means of the percent change from baseline in calculated LDL-C 
at Week 24 under placebo and alirocumab, respectively. The null hypothesis that will be tested is: 
 
H0 : μ0 = μ1 
versus 
H1 : μ0  μ1 
Robustness of this statistical method will be assessed via sensitivity analyses detailed in the SAP, 
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mixture modeling). In addition, sensitivity analysis will be conducted using measured LDL-C to 
evaluate the robustness of the results regardless of the way to assess LDL-C. Correlation of 
calculated LDL-C with measured LDL-C will be explored graphically as deemed necessary. 
11.4.2.2 Analyses of secondary efficacy endpoints 
Method for controlling the overall type-I error rate when testing the key secondary efficacy 
endpoints is described in Section 11.4.2.3.  
For key secondary efficacy endpoints (defined in Section 9.2.1) and other efficacy endpoints 
(described in Section 9.2.3), descriptive summaries and analyses will be performed in the ITT 
population or mITT population depending on the estimand used.  
For descriptive summaries, percent change from baseline in calculated LDL C, C, HDL-C, TG, 
and non-HDL-C will be provided at each time point for each treatment group. All measurements, 
scheduled or unscheduled will be assigned to analysis windows defined in the SAP in order to 
provide an assessment for these time points. Laboratory assessments other than the ones provided 
by the central laboratory will be excluded. The time profile of each parameter will be plotted by 
treatment group with the corresponding SEs.  
Similar tables (with either percent change from baseline or absolute change from baseline for the 
ratio) and plots will be provided for other efficacy endpoints: Apo B, Apo A-1, ratio 
Apo B/Apo A-1, Apo C-III, Lp(a), TGRL, LDL-C particle size, and LDL-C particle number. For 
TG and Lp(a), summary statistics will include Q1 and Q3, and medians (instead of means) by 
time point will be plotted.  
Multiple types of measurements are planned to be analyzed during differing time points in the 
trial, specifically continuous measurements expected to have a normal distribution (eg, percent 
change in calculated LDL-C), continuous measurements expected to have a non-normal 
distribution (eg, TG), and binary measurements (eg, proportion of patients reaching LDL-C 
<70 mg/dL). 
Continuous endpoints anticipated to have a normal distribution 
Continuous secondary variables defined in Section 9.2 anticipated to have a normal distribution 
(eg, lipids other than TG and Lp[a]) will be analyzed using the same MMRM model as for the 
primary endpoint. Specifically, the model will contain fixed categorical effects of treatment 
group, planned time points to Week 24 and treatment-by-time point interaction, as well as, the 
continuous fixed covariates of corresponding baseline value and baseline value-by-time point 
interaction. 
Continuous endpoints anticipated to have a non-normal distribution 
Continuous secondary efficacy endpoints defined in Section 9.2, anticipated to have a nonnormal 
distribution (ie, TG and Lp[a]), will be analyzed using a robust regression model (ie, 
ROBUSTREG SAS procedure with M-estimation option) with treatment group as main effect and 
corresponding baseline value(s) as covariate. Missing values will be addressed using a multiple 
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imputation approach, which will be described in the SAP. The variables in the multiple imputation 
model will at least include the same variables as used in the robust regression model. The 
treatment group combined means will be provided with respective SE estimates. The combined 
mean difference between the treatment groups will be provided with the SE, 95% CI and p-value. 
Binary endpoints 
Binary secondary efficacy endpoints defined in Section 9.2 will be analyzed using logistic 
regression with treatment group as main effect and corresponding baseline value(s) as covariate. 
Missing values will be addressed using a multiple imputation approach which will be described in 
the SAP. The variables in the multiple imputation model will at least include the same variables as 
used in the logistic regression model. Treatment effects will be compared and the combined odds 
ratio estimate between the treatment groups, with their corresponding 95% CIs and p-value will 
be provided.  
In the data dependent case that the logistic regression method is not applicable (eg, the response 
rate is zero in 1 treatment arm and thus the maximum likelihood estimate may not exist), the Last 
Observation Carried Forward (LOCF) approach would be used for handling of missing values and 
an exact conditional logistic regression would be performed to compare treatment effects. The 
LOCF imputation method will consist of using the last value obtained up to the Week 24 analysis 
window (or Week 12 as applicable) to impute the missing week 24 value (or Week 12 
respectively). 
11.4.2.3 Multiplicity considerations 
In order to handle multiple key secondary efficacy endpoints, the overall type-I error will be 
controlled by the use of a sequential inferential approach. Statistical significance of the primary 
parameter at the 0.05 alpha level is required before drawing inferential conclusions about first key 
secondary parameter (refer to order of list in Section 9.2.1).  
Inferential conclusions about successive key secondary parameters require statistical significance 
of the prior one. This fixed hierarchical approach will ensure a strong control of the overall type-I 
error rate at the 0.05 level.  
No further adjustments will be made for other efficacy endpoints for which p-values will be 
provided for descriptive purpose only. 
11.4.3 Analyses of safety data 
The summary of safety results will be presented by treatment group. No formal inferential testing 
will be performed. Summaries will be descriptive in nature. 
All safety analyses will be performed on the Safety population using the following common rules: 
x The baseline value is defined generally as the last available value before the first injection 
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The following definitions will be applied to laboratory parameters and vital signs. 
x The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests and vital signs. 
x PCSA criteria will determine which patients had at least 1 PCSA during the on-treatment 
period, taking into account all evaluations performed during the on-treatment period, 
including unscheduled or repeated evaluations.  The number of all such patients will be the 
numerator for the on-treatment PCSA percentage. 
x Treatment period: the treatment period used for quantitative analysis is defined as the time 
from first dose of double-blind IMP injection to the last dose of double-blind IMP 
injection + 21 days 
The following definitions will be applied to AEs 
x Pre-treatment AEs are AEs that developed or worsened or became serious during the 
pre-treatment period 
x TEAEs are AEs that developed or worsened or became serious during the TEAE period 
x Post-treatment AEs are AEs that developed or worsened or became serious during the 
post-treatment period 
Liver function tests 
The liver function tests, namely ALT, AST, alkaline phosphatase and total bilirubin, are used to 
assess possible drug induced liver toxicity. The proportion of patients with PCSA values at any 
postbaseline visit by baseline status will be displayed by treatment group for each parameter.  
A graph of distribution of peak values of ALT versus peak values of total bilirubin will also be 
presented. Note that the ALT and total bilirubin values are presented on a logarithmic scale. The 
graph will be divided into 4 quadrants with a vertical line corresponding to 3 x ULN for ALT and 
a horizontal line corresponding to 2 x ULN for total bilirubin. 
The incidence of liver-related AEs will be summarized by treatment group. The selection of 
preferred terms will be based on standardized MedDRA query (SMQ) Hepatic disorder. Time to 
liver-related treatment discontinuation and time to liver death may also be provided based on 
hepatic disorder SMQ. 
11.4.3.1 Adverse events 
Adverse event incidence tables will present by system organ class (SOC) (sorted by 
internationally agreed order), high-level group term (HLGT), high level term (HLT) and preferred 
term (PT) sorted in alphabetical order for each treatment group, the number (n) and percentage 
(%) of patients experiencing an AE. Multiple occurrences of the same event in the same patient 
will be counted only once in the tables within a treatment phase. The denominator for 
computation of percentages is the safety population within each treatment group. 
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Adverse event incidence table will be provided by treatment group for all types of TEAEs: all 
TEAEs, all treatment-emergent AESI (defined with a PT or a prespecified grouping), all 
treatment-emergent SAEs and all TEAEs leading to permanent treatment discontinuation. 
If any clinically significant signal is detected and needs further characterization or for AE of 
clinical interest, exploration of time to onset will be performed for these selected TEAEs as 
described below to account for the differential exposure time in all patients.  
Selected TEAEs will be also analyzed using time-to-event approach (Kaplan-Meier 
methodology). Time from the first dose of double-blind IMP injection to the first occurrence of 
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 6 months of exposure will be 
presented and Kaplan-Meier curves will be provided. 
Death: The following deaths summaries will be generated: 
x 
Number (%) of patients who died by study period (TEAE, on-study, post-study) 
summarized on the safety population by treatment received 
x 
Death in non-randomized patients or randomized and not treated patients   
x TEAE leading to death (death as an outcome on the AE CRF page as reported by the 
Investigator) by primary SOC, HLGT, HLT and PT showing number (%) of patients 
sorted by internationally agreed order of SOC and alphabetic order of HLGT, HLT, and 
PT. 
11.4.3.2 Laboratory data and vital signs 
The summary statistics (including mean, median, Q1, Q3, SE, 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 and presented 
by treatment group. 
For selected parameters, mean changes from baseline with the corresponding SE will be plotted 
over time (at same time points) in each treatment group. 
The incidence of PCSAs at any time during the TEAE period (on-treatment PCSAs) will be 
summarized by treatment group whatever the baseline level and/or according to the following 
baseline categories: 
x 
Normal/missing 
x 
Abnormal according to PCSA criterion or criteria 
For laboratory parameters for which PCSA criterion is not defined, similar table(s) using the 
normal range could be provided. 
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Hepatitis C Test 
The number and percentage of patients with an observed seroconversion for Hepatitis C Test will 
be provided by treatment group. Further details will be provided in SAP. 
11.4.4 Analyses of diabetes-related endpoints 
The analyses of diabetes-related endpoints will be performed on the ITT and mITT population and 
will be descriptive only. Summary statistics, including the mean, median, Q1, Q3, SE, minimum, 
and maximum of the 4 endpoints (HbA1c, FPG, total daily insulin dose, and number of glucose 
lowering treatment) will be calculated for each visit and presented by treatment group, as well as 
the change from baseline. 
11.4.5
 
 
 
 
 
Handling missing data 
The algorithm used to calculate the scores accounts for missing items. 
 
 
 
 
 
11.5 
INTERIM ANALYSIS 
If needed for the purpose of scientific communication, both the efficacy and safety analyses will 
be performed at the Week 24 cut-off date and an update of the safety analysis at the end of the 
study, a two-step analysis as described below. All the efficacy data will be available for final 
analysis at a cut-off date corresponding to the Week 24 visit of the last patient. Since safety data 
are collected until the end of the study (Week 32), if the analysis with Week 24 data is performed, 
an update of the safety analysis will be performed at the end of the study. If analyses are not 
needed at Week 24, then there will be only a one time analysis at the end of the study. 
The first-step analysis will be conducted as soon as all patients have been randomized and have at 
least all their data up to Week 24 collected and validated, and will consist of a final analysis of the 
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primary and secondary efficacy endpoints up to Week 24. The safety analysis will be performed 
on all safety data collected and validated at the time of this first-step analysis.  
The second-step analysis will consist of the updated analysis of safety endpoints until Week 32. 
Even in the case of a two-step analysis, there is no multiplicity issue because all efficacy analyses 
will be completed at the time of the advanced analysis.  
Selected individuals who are not involved in the conduct of the study after the first step analysis 
will perform the second step analysis; individual patient identification will not be released to 
anyone who is directly involved in the conduct of the study. The second step analysis process, the 
measures used to protect the blind and the integrity of the study, as well as a communication plan 
and confidentially agreement will be described in a separate document if two analyses are to be 
conducted. 
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12 
ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 
ETHICAL AND REGULATORY STANDARDS 
This clinical trial will be conducted by the Sponsor, the Investigator, delegated Investigator staff 
and Subinvestigator, in accordance with the principles laid down by the 18th World Medical 
Assembly (Helsinki, 1964) and all applicable amendments laid down by the World Medical 
Assemblies, and the ICH guidelines for good clinical practice (GCP), all applicable laws, rules 
and regulations. 
This clinical trial will be recorded in a free, publicly accessible, internet-based registry, no later 
than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with Sanofi public disclosure commitments.  
12.2 
INFORMED CONSENT 
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the patient of all 
pertinent aspects of the clinical trial including the written information giving approval/favorable 
opinion by the Ethics Committee (IRB/IEC). All participants should be informed to the fullest 
extent possible about the study, in language and terms they are able to understand. 
Prior to a patient’s participation in the clinical trial, the written ICF should be signed, name filled 
in and personally dated by the patient or by the patient’s legally acceptable representative, and by 
the person who conducted the informed consent discussion. A copy of the signed and dated 
written ICF will be provided to the patient.  
The ICF used by the Investigator for obtaining the patient's informed consent must be reviewed 
and approved by the Sponsor prior to submission to the appropriate Ethics Committee (IRB/IEC) 
for approval/favorable opinion. 
12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) 
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the appropriate IRB/IEC, and is required to forward to the respective other party  a 
copy of the written and dated approval/favorable opinion signed by the Chairman with IRB/IEC 
composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, ICF, 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. 
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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 INVESTIGATORS 
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 
Subinvestigators and/or Study Coordinators to assist in the conduct of the clinical trial in 
accordance with the clinical trial protocol. All Subinvestigators and Study Coordinators shall be 
appointed and listed in a timely manner. The Subinvestigators and Study Coordinators 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, patient 
compliance with the IMP regimen, IMP accountability, concomitant therapy use and quality of 
data. 
13.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH GCP, the monitoring team must check the CRF entries against the source 
documents, except for the pre-identified source data directly recorded in the CRF. The ICF will 
include a statement by which the patient allows the Sponsor’s duly authorized personnel, the 
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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, etc). These personnel, bound by professional secrecy, must 
maintain the confidentiality of all personal identity or personal medical information (according to 
confidentiality and personal data protection rules). 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST 
It is the responsibility of the Investigator to maintain adequate and accurate CRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All written 
information should be completed in a neat, legible manner to ensure accurate interpretation of 
data.  
Should a correction be made, the corrected information will be entered in the e-CRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the Sponsor as soon as they are entered in the e-CRF. 
The computerized handling of the data by the Sponsor may generate additional requests (DRF) to 
which the Investigator is obliged to respond by confirming or modifying the data questioned. The 
requests with their responses will be managed through the e-CRF. 
13.5 
USE OF COMPUTERIZED SYSTEMS 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor and Investigator study files. 
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 
 
 
 
 
 
 
 
 
 
 
 
 
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14.4 
PROPERTY RIGHTS 
 
 
 
 
 
 
 
 
 
 
 
 
14.5 
DATA PROTECTION 
x 
The patient's personal data, which are included in the Sponsor database shall be treated in 
compliance with all applicable laws and regulations; 
x 
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. 
x 
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 (ie, Caucasian/white, Black, Asian/Oriental, others) will be collected in 
this study because these data are required by several regulatory authorities (eg, on afro 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 purposes of the study and to document 
the evaluation of the benefit/ risk ratio, efficacy and safety of the product. They may be further 
processed if they have been anonymized. 
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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.  
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 are 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:  
x 
The information on the product leads to doubt as to the benefit/risk ratio; 
x 
Patient enrollment is unsatisfactory; 
x 
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; 
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x 
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; 
x 
The total number of patients are included earlier than expected; 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes of the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) 
to clinical trial patients, or when the change(s) involves only logistical or administrative aspects of 
the trial. Any change agreed upon will be recorded in writing, the written amendment will be 
signed by the Investigator and by the Sponsor and the signed amendment will be filed with this 
clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In some instances, an amendment may require a change to the ICF. The Investigator must receive 
an IRB/IEC approval/favorable opinion concerning the revised ICF prior to implementation of the 
change and patient signature should be re-collected if necessary. 
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16 
BIBLIOGRAPHIC REFERENCES 
1. IDF Diabetes Atlas. International Diabetes Federation. 6th ed. 2013. Available from: 
http://www.idf.org/diabetesatlas. 
2. Lee WL, Cheung AM, Cape D, Zinman B. Impact of diabetes on coronary artery disease in 
women and men: a meta-analysis of prospective studies. Diabetes Care. 2000 Jul;23(7):962-8. 
3. Booth GL, Kapral MK, Fung K, Tu JV. Relation between age and cardiovascular disease in 
men and women with diabetes compared with non-diabetic people: a population-based 
retrospective cohort study. Lancet. 2006 Jul 1;368(9529):29-36. 
4. American Diabetes Association. Cardiovascular disease and risk management. In: Standards 
of Medical Care in Diabetes-2015. Diabetes Care. 2015 Jan;38 Suppl 1:S49-57. 
5. Ryden L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin Net, al. ESC Guidelines on 
diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: 
the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society 
of Cardiology (ESC) and developed in collaboration with the European Association for the 
Study of Diabetes (EASD). Eur Heart J. 2013 Oct;34(39):3035-87. 
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